e1
e1 The Safety and Quality
of Health Care
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 mea-
surement 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 in-
tend 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 of-
ten during care delivery; e.g., when someone intends to write an order
but forgets because they have to complete another action first. “Mis-
takes,” 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 mis-
takes 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 in-
stance 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 pro-
longed shifts. A recent study of house officers in the intensive care unit
demonstrated that they were about one-third more likely to make er-
rors 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 Col-
lege 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-relat-
ed errors, i.e., extended-duty shifts. High levels of stress and workload
can also increase error rates. Thus, in extremely high-pressure situa-
tions, such as cardiac arrests, errors are more likely to occur. Strategies
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Some holes due
Hazards
CHAPTER e1
to active failures
Other holes due to
latent conditions
(resident "pathogens")
The Safety and Quality of Health Care
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 manage-
ment. 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 er-
rors. 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 spe-
cific diagnosis. Tools that emphasize specific abnormalities or combi-
nations 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 ex-
changing 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 out-
patient setting. The Harvard Medical Practice Study was one of the
largest studies to address this issue, and was performed with hospital-
ized 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 diagnos-
tic mishaps, 14% were therapeutic mishaps, 13% were procedure-
related, and 5% were falls.
ADEs have been studied more than any other category. Studies fo-
cusing specifically on ADEs have found that they appear to be much
 e2 more frequent than was suggested by the Medical Practice Study, al-
though most other studies use more inclusive criteria. Detection ap-
proaches in the research setting include chart review and use of a
computerized ADE monitor, which is a tool that explores the database
PART 1
and identifies signals that suggest an ADE may have occurred. Studies
that use multiple approaches find more ADEs than any individual ap-
proach, 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
Introduction to Clinical Medicine
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 pub-
lished as yet.
Computerized physician order entry (CPOE) linked with clinical
decision support has been found to reduce the serious medication er-
ror rate—serious medication errors are those that harm someone or
have the potential to do so. In one study, CPOE, even with limited de-
cision support, decreased the serious medication error rate by 55%.
CPOE can prevent medication errors by suggesting a default dose, en-
suring that all orders are complete (e.g., include a dose, route, and fre-
quency), 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-cod-
ing linked with an electronic medication administration record. Bar-
coding 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 re-
ceived. 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 ad-
minister 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 Accredita-
tion of Healthcare Organizations (JCAHO) requirement.
The National Picture around Safety Several organizations, including
the National Quality Forum (NQF) and the JCAHO, have made rec-
ommendations about how to improve safety. In particular, the NQF
has released recommendations to the country’s hospitals about what
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
practices will most improve the safety of care, which all hospitals are
expected to implement (Table e1-1). Many of these practices arise fre-
quently in routine care. One example is “readback,” which is the prac-
tice 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 ab-
breviations 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 search-
ing 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 noso-
comial infections, hospitals have little idea about the true frequency of
safety issues.
Nonetheless, all providers have the responsibility to report prob-
lems 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 set-
ting, much more is known about the epidemiology of safety in the in-
patient setting, and a number of effective strategies for improving
safety have been identified and are being used increasingly. Some ef-
fective strategies are also available in the outpatient setting. Transi-
tions appear to be especially risky. The solutions to improving care will
often involve leveraging information technology, but they will also in-
volve 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 as-
pirin 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, in-
cluding 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 provid-
ers rather than finding a few poor performers and punishing them.
This view suggests that systems changes are especially likely to be help-
ful in improving quality, since large numbers of providers may be af-
fected simultaneously.
The theory of continuous quality improvement suggests that organi-
zations should be evaluating the care they deliver on an on-going basis
and continually making small changes to improve their individual pro-
cesses. This approach can be very powerful if embraced over time.
 TABLE e1-1 SAFE PRACTICES FOR BETTER HEALTH CARE a processes, making this tool especially impor- e3
tant for improvement.
1. Create a health care culture of safety.
2. For designated high-risk, elective surgical procedures or other specified care, patients should be

CHAPTER e1
clearly informed of the likely reduced risk of an adverse outcome at treatment facilities that have Factors Relating to Quality Many factors can
demonstrated superior outcomes and should be referred to such facilities in accordance with the decrease the level of quality, including stress to
patient’s stated preference. providers, high or low levels of production
3. Specify an explicit protocol to be used to ensure an adequate level of nursing based on the institu- pressure, and poor systems, to name but a few
tion’s usual patient mix and the experience and training of its nursing staff.
examples. Stress can adversely affect quality
4. All patients in general intensive care units (both adult and pediatric) should be managed by physi-
cians having specific training and certification in critical care medicine (“critical care certified”). because it can lead providers to omit impor-
5. Pharmacists should actively participate in the medication-use process, including, at a minimum, tant steps, as can a high level of production
being available for consultation with prescribers on medication ordering, interpretation and re- pressure. Low levels of production pressure

The Safety and Quality of Health Care

view of medication orders, preparation of medications, dispensing of medications, and adminis- can also sometimes result in worse quality, as
tration and monitoring of medications. providers may be bored or have little experi-
6. Verbal orders should be recorded whenever possible and immediately read back to the pre-
ence with a specific problem. Poor systems can
scriber—i.e., a health care provider receiving a verbal order should read or repeat back the infor-
mation that the prescriber conveys in order to verify the accuracy of what was heard. have a tremendous impact on quality, and
7. Use only standardized abbreviations and dose designations. even extremely dedicated providers typically
8. Patient care summaries or other similar records should not be prepared from memory. cannot achieve high levels of performance if
9. Ensure that care information, especially changes in orders and new diagnostic information, is they are operating within a poor system.
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.
Data about the Current State of Quality A re-
10. Ask each patient or legal surrogate to recount what he or she has been told during the informed
consent discussion. cent RAND study has provided the most com-
11. Ensure that written documentation of the patient’s preference for life-sustaining treatments is plete picture of quality of care delivered in the
prominently displayed in his or her chart. United States to date. The results were sober-
12. Implement a computerized prescriber order entry system. ing. The authors found that across a wide
13. Implement a standardized protocol to prevent the mislabeling of radiographs. range of quality parameters, patients in the
14. Implement standardized protocols to prevent the occurrence of wrong-site procedures or wrong-
United States received only 55% of recom-
patient procedures.
15. Evaluate each patient undergoing elective surgery for risk of an acute ischemic cardiac event dur- mended care overall; there was little variation
ing surgery, and provide prophylactic treatment of high-risk patients with beta blockers. by subtype, with scores of 54% for preventive
16. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing pressure care, 54% for acute care, and 56% for care of
ulcers. This evaluation should be repeated at regular intervals during care. Clinically appropriate chronic conditions, leading the authors to
preventive methods should be implemented consequent to the evaluation. conclude that the chances of getting high-
17. Evaluate each patient upon admission, and regularly thereafter, for the risk of developing deep
quality care in the United States broadly were
vein thrombosis (DVT)/venous thromboembolism (VTE). Utilize clinically appropriate methods to
prevent DVT/VTE. little better than those of winning a coin flip.
18. Utilize dedicated anti-thrombotic (anti-coagulation) services that facilitate coordinated care
management. Strategies for Improving Quality and
19. Upon admission, and regularly thereafter, evaluate each patient for the risk of aspiration. Performance A number of specific strategies
20. Adhere to effective methods of preventing central venous catheter–associated bloodstream can be used to improve quality at the individu-
infections.
al level, including rationing, education, feed-
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 back, incentives, and penalties. Rationing has
measures based on that evaluation. been effective in some specific areas, such as
22. Utilize validated protocols to evaluate patients who are at risk for contrast media-induced renal convincing physicians to prescribe within a
failure, and utilize a clinically appropriate method for reducing risk of renal injury based on the formulary, but it generally has been resisted.
patient’s kidney function evaluation. Education is effective in the short run and is
23. Evaluate each patient upon admission, and regularly thereafter, for risk of malnutrition. Employ
necessary for changing opinions, but its effect
clinically appropriate strategies to prevent malnutrition.
24. Whenever a pneumatic tourniquet is used, evaluate the patient for the risk of an ischemic and/or decays fairly rapidly with time. Feedback on
thrombotic complication, and utilize appropriate prophylactic measures. performance can be given either at the group
25. Decontaminate hands with either a hygienic hand rub or by washing with a disinfectant soap prior or individual level. Feedback is most effective
to and after direct contact with the patient or objects immediately around the patient. if it is individualized and if it is given in close
26. Vaccinate health care workers against influenza to protect both them and patients from influenza. temporal proximity to the original events. In-
27. Keep workspaces where medications are prepared clean, orderly, well lit, and free of clutter, dis-
centives can be effective, and many believe that
traction, and noise.
28. Standardize the methods for labeling, packaging, and storing medications. this will be a key to improving quality, espe-
29. Identify all “high alert” drugs (e.g., intravenous adrenergic agonists and antagonists, chemotherapy cially if pay-for-performance with sufficient
agents, anticoagulants and anti-thrombotics, concentrated parenteral electrolytes, general anes- incentives is broadly implemented (see below).
thetics, neuromuscular blockers, insulin and oral hypoglycemics, narcotics and opiates). Penalties produce provider resentment and are
30. Dispense medications in unit-dose or, when appropriate, unit-of-use form, whenever possible. 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 quali-
health care; the NQF believes these should be universally utilized in applicable care settings to reduce the risk of pa- ty involves changing the systems of care. An ex-
tient 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 hos-
cess, e.g., the time for a patient with pneumonia to receive antibi- pitals have now implemented a bundle for ventilator-associated pneumo-
otics 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.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e4 Adopt or abandon Identify potential National State of Quality Measurement In the inpatient setting, qual-
strategies based Pl improvement ity measurement is now being performed by a very large proportion of
on results ct an strategies hospitals for several conditions, including myocardial infarction, con-
A
gestive heart failure, pneumonia, and surgical infection prevention; 20
PART 1

measures are included in all. This is the result of the Hospital Quality
Initiative, which represents a collaboration among many entities, in-
cluding 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
Ch Hospital Compare. These data are voluntarily reported and are avail-
Introduction to Clinical Medicine

ec able for a very high proportion of the nation’s hospitals; they were first
k released in April 2006. Early analyses demonstrate that there is sub-

Do
Measure
effectiveness Try out stantial regional variation in quality and that there are important dif-
of strategies strategies ferences among hospitals. Analyses by the Joint Commission for very
FIGURE e1-2 Plan-do-check-act (or PDCA) cycle. The PDCA cycle similar indicators demonstrate that performance on measures by hos-
approach can be used to improve a specific process rapidly. First, plan- pitals did improve over time, and that, as might be hoped, lower per-
ning is performed, and several potential improvement strategies are formers improved more than higher performers. Analogous national
identified. Next, these strategies are trialed in small “tests of change.” data for ambulatory care are not yet available, but a group called the
“Checking” is measuring whether or not they appeared to make a dif- Ambulatory care Quality Alliance (AQA) has been formed and is de-
ference, and “act” refers to acting on the results. veloping an analogous set of measures.

Public Reporting Overall, public reporting of quality data is becom-

Perhaps the most pressing need is to improve the quality of care for ing increasingly common. There are now commercial websites that
chronic diseases. The Chronic Care Model has been developed by have quality-related data for most regions of the country that can be
Wagner and colleagues (Fig. e1-3); it suggests that a combination of accessed for a fee. Similarly, national data for hospitals are available.
strategies will be necessary, including self-management support, The evidence to date is that patients have not used such data very
changes in delivery system design, decision support, and information much, but that such data have had an important effect on provider
systems, and that these must be delivered by a practice team composed and organization behavior. Instead, patients have relied on provider
of several providers, not just a physician. reputation to make choices. Part of the reason for this choice basis is
Recent evidence about the relative efficacy of strategies in reducing that until very recently little information was available, and it was not
hemoglobin A1c (HbA1c) in outpatient diabetes care (Fig. e1-4) sup- necessarily represented in ways that were easy for patients to access.
ports this general premise. It is especially notable that the outcome was Many believe that as more information about quality becomes avail-
HbA1c, as it has generally been much more difficult to improve outcome able, it will become increasingly central to patient choices about where
measures than process measures (such as whether a HbA1c was per- to access care.
formed). 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 Pay-for-Performance Currently, providers in the United States get
manager. When cost-effectiveness is considered in addition, it appears paid exactly the same amount for a specific service regardless of what
likely that an amalgam of strategies will be needed. However, the more quality care is delivered. The theory of pay-for-performance suggests
expensive strategies, such as use of case managers, will likely be imple- that if providers are paid more for higher-quality care, they will invest
mented widely only if pay-for-performance takes hold. in strategies that enable them to deliver that care. The current key is-
sues in the pay-for-performance debate relate to (1) how effective it is,
(2) what levels of incentives are needed, and (3) what perverse conse-
quences are produced. The evidence about effectiveness is fairly limit-
ed to date, although a number of studies are ongoing. With respect to
Community Health System levels, most performance incentives around quality have accounted for
Resources and policies Organization of health care
merely 1–2% of total payment in this country to date, but in the Unit-
Self- Delivery Decision Clinical ed Kingdom, 40% of general practitioners’ salaries have recently been
management system support information placed at risk based on performance across a wide array of parameters.
Support design systems
This has been associated with large improvements in reported quality
performance, although it is still unclear as to what extent this repre-
sents 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
Informed, Prepared, to transfer the sickest patients to other providers and systems. Another
activated Productive proactive concern is that providers will pay too much attention to quality mea-
patient interactions practice team sures with incentives, and ignore the rest of the quality picture. The
validity of these concerns remains to be determined.

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 es-
sential. (From Wagner et al: Eff Clin Pract 1:2, 1998.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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-for-
performance should make it much easier for organizations to justify
investments in improving these parameters, including health informa-
 Favors Favors much more robust; it would be particularly useful e5
Quality Improvement Strategy No. of Trials intervention control if organizations had measures that they could use
Team changes 26 in routine operations to assess safety at reasonable

CHAPTER e1
Case management 26 cost. While the quality measures available are more
Patient reminders 14 robust than those for safety, they still cover a rela-
Patient education 38
tively small proportion of the entire domain of
quality, and more need to be developed. The pub-
Electronic patient registry 8
lic and payers are now demanding better informa-
Clinician education 20
tion about safety and quality, as well as better
Facilitated relay of clinical information 15
performance in these areas. The clear implication
Self-management 20
is that these domains will need to be addressed di-

The Safety and Quality of Health Care

Audit and feedback 9 rectly by providers.
Clinician reminders 18
Continuous quality improvement 3
All interventions 66 FURTHER READINGS
–1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 BATES DW et al: Effect of computerized physician
0.4
order entry and a team intervention on preven-
Difference in postintervention HbA1c, %
tion of serious medication errors. JAMA
FIGURE e1-4 The efficacy of various strategies for improving diabetes care in out- 280:1311, 1998
patients. Shojania et al. performed a meta-analysis of evaluating the efficacy of strategies BRENNAN TA et al: Incidence of adverse events and
for reducing hemoglobin A1c (HbA1c) in diabetic outpatients; they found that team negligence in hospitalized patients: Results
changes and case management had the largest impact on HbA1c, although there was a from the Harvard Medical Practice Study I. N
trend toward improvement for many strategies. Interventions in which nurse or pharma- Engl J Med 324:370, 1991
cist case managers can make medication adjustments without awaiting physician autho- MCGLYNN EA et al: The quality of health care de-
rization resulted in the largest reductions. (From Shojania et al: JAMA 296:427, 2006.) livered to adults in the United States. N Engl J
Med 348:2635, 2003
SHOJANIA KG et al: Effects of quality improvement
tion technology; however, many will also require changing the struc- strategies for type 2 diabetes on glycemic control: A meta-regres-
ture 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 evi-
measures of safety are still relatively immature and could be made dence into action. Health Aff (Millwood) 20:64, 2001

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


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 fo-
cused 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 in-
creased from about $27 billion to $2.1 trillion. This growth in spend-
ing was about 2–3% higher per year than growth in the overall
economy, causing health care spending to rise from 6% of gross do-
mestic product to >16%. This increase in spending has produced
enormous challenges for everyone who pays for health care. For gov-
ernment, these challenges include rising federal, state, and local gov-
ernment health care budgets, which have required increases in taxes.
For firms and their workers, the biggest challenge is the high cost of in-
suring workers, which causes employers to drop (or reduce) health in-
surance 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 insur-
ance 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 out-
of-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 con-
sume no health care, the fraction of health care costs paid out of pock-
et 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 univer-
sal coverage and have health outcomes that are as good as or better
than those in the United States, has understandably created wide-
spread 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 deliv-
ery 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 per-
sons 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 result-
ing 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 in-
surance in the United States, one possible cause of rising health care
costs since 1960 for which there is strong evidence is the increasing in-
Copyright © 2008 by McGraw-Hill Company. All rights reserved.
surance coverage of health care and resulting increases in demand for e7
health care. Some scholars date the growth in health insurance cover-
age to the beginning of World War II when an Internal Revenue Ser-
CHAPTER e2
vice 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 insur-
ance, 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
Economic Considerations in the Practice of Medicine
these programs. Nevertheless, based on data from the effects of health
insurance coverage on the demand for health care, experts have esti-
mated 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 tech-
nologies 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% annual-
ly 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, percutane-
ous coronary intervention, and coronary bypass surgery—either fell
or increased minimally. The change in the overall cost occurred be-
cause the more expensive treatment options (e.g., revascularization)
were increasingly used over the less expensive ones (e.g., medical man-
agement). 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 expan-
sion 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 con-
tributes 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 insur-
ance 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 insur-
ance will cover are a strategy to address this tendency for excessive
consumption but are often sources of controversy and patient dissat-
isfaction. 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 unac-
ceptable financial risk, health care insurance is better constructed by
 e8 designing a package of benefits that provides variable subsidies for ac-
cess to different medical technologies that can improve health while
leaving an acceptable level of financial risk and an affordable annual
premium. These tradeoffs are increasingly being put in the hands of
PART 1
consumers as they choose among health plans. 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, in so doing, undermine the ability of insurance to spread costs
and risk among patient groups. An example of adverse selection would
be if a low-cost plan were chosen only by healthy individuals, leaving
sicker persons alone in the high-cost plan, which might then become
Introduction to Clinical Medicine
unaffordable. These types of concerns greatly complicate the creation
of successful insurance markets.
Medicare and Medicaid Medicare provides health insurance for almost
all Americans age 65 and older. Established in 1965, Medicare covers
both hospital care (part A) and physician fees (part B). In 2006 Medicare
also began offering a prescription drug benefit (part D). Insurance cov-
erage within Medicare has some idiosyncrasies that, in part, reflect its
origins in being modeled based on private health insurance in the 1960s.
These include lifetime caps on benefits and copayment rates that are
sometimes lower for low-use patients than for higher-use patients. Med-
icare beneficiaries who can afford them can purchase supplemental
Medicare (Medigap) policies that can sometimes fill these gaps in cover-
age. Medicare also interfaces with the Medicaid program to address the
needs of lower income older persons, as discussed below.
The Part D program in Medicare addresses a long-standing need to
provide older persons with better access to pharmaceuticals. This pro-
gram has a complicated benefit structure, with varying copayment rates
depending on an individual’s prescription drug expenditures within the
year. There are also significant variations in the coverage provided by
different plans, but online tools are available at www.medicare.gov to
help patients and their families to make informed decisions. Medicare
Advantage is a program developed by Medicare to provide managed
care options for Medicare beneficiaries. Patients in these programs gen-
erally 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 has a special program that provides health insurance cov-
erage for persons with end-stage renal disease.
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. Medicaid currently provides cov-
erage to about 14% of the U.S. population. Like Medicare, Medicaid is
managed by the Centers for Medicare and Medicaid services (CMS).
However, unlike Medicare, Medicaid is a federal-state partnership
with funding that is shared, and there is a great deal of variation across
states as to who is eligible and what benefits are provided. In general,
Medicaid tends to have lower copayments than other types of health
insurance, which is important because of the limited income of the re-
cipients of Medicaid. Older persons whose incomes and assets are low
enough to qualify may be eligible for both Medicare and Medicaid
(“dual-eligible”). One aspect of Medicaid coverage that is especially
important for older persons and their families is that it pays for nurs-
ing home coverage for those whose income and assets are sufficiently
low. For patients and their families for whom high health care costs
and insurance coverage are major concerns, referral to a social worker,
patient advocate, 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.
SUPPLY OF HEALTH CARE
Physicians, nurses and other health professionals, hospitals, manufac-
turers of pharmaceuticals and devices, and researchers all provide key
inputs into the health care system.
Health Professionals The economics of medical practice are shaped
by the high level of investment in tuition and time (foregone earnings)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
that physicians must make during their training. Typically, longer
training periods are associated with higher earnings. Nevertheless,
some specialties with the longest training periods still offer exception-
ally high returns on investment. In a competitive market with free en-
try, one might expect the returns on investment to equalize across
specialties as high earnings encourage more entrants into a field and
lowers average earnings. 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. In addition,
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.
In the past, physicians usually owned their own practices, but this is
increasingly less common in the United States as physicians more of-
ten work as part of large groups or for health plans. These models
sometimes pay doctors fixed salaries, although incentives to see more
patients are common. Incentives for physicians to provide services can
lead to concerns about “demand inducement,” in which physicians
provide more care than is desirable because of the financial returns
they receive from providing that care, but the evidence for this being
common is not compelling. Legal constraints exist to prevent physi-
cians from gaining economically from referring patients for the servic-
es of other providers.
Nurses and other health professionals also have complex labor mar-
ket issues. Often the boundaries of practice between different forms of
training (e.g., ophthalmologists and optometrists or nurse practitio-
ners and physician assistants) are not clear, and so there can be intense
competition between, as well as within, specialty areas.
Hospitals These are complex organizations that require expensive
capital investments, a large and complex staff, and close ties with phy-
sicians. Most hospitals are not-for-profit (NFP), meaning that any sur-
plus left at the end of each year must be reinvested in the hospital or
the health of the community it serves. This contrasts with a for-profit
(FP) hospital, which can return profits to shareholders and is not re-
quired to provide benefits to its community in the same way as NFP
hospitals are required to. NFP hospitals are exempt from many taxes,
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. Hospital management in NFP hospitals is supervised
by a board of directors that typically includes community, staff, and
physician participation. In contrast, FP hospitals are managed by a
corporate structure. However, managers in both NFP and FP hospitals
use similar tools to analyze and improve the cost and quality of care
they provide. Increasingly, management tools such as process map-
ping, human factors analysis, and continuous quality improvement
approaches (e.g., plan-do-study-act cycles) are becoming essential
tools of a modern physician leader.
The Pharmaceutical and Device Industries The pharmaceutical indus-
try and its close cousin, the medical device industry, 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, such as medications to treat hypertension, immunizations, and
devices such as joint replacements and artificial lenses that allow the
removal of cataracts. Concerns about the rising cost of pharmaceuti-
cals, safety, direct-to-consumer advertising, and inappropriate mar-
keting strategies have made the pharmaceutical industry and its
regulators [e.g., the U.S. Food and Drug Administration (FDA)] the
subject of a great deal of recent scrutiny. Another major concern is the
rising costs of developing new drugs, which has recently been estimat-
ed to be in the vicinity of $1 billion per new chemical entity brought to
market. The rising cost of prescription drugs and concern that prices
charged in the United States are above those charged in other coun-
tries have led to calls for efforts to control drug pricing in the United
States. Attempts to bring down the costs of prescription drugs both in
the United States and internationally must balance their short-term ef-
fects on the cost of health care with longer-term effects on the incen-
tives to produce innovative new drugs and effects on access to patients
within and across countries with varying incomes and ability to pay.
Innovation Medical innovation is also produced by academia and gov-
ernment, often in close collaboration. The National Institutes of Health
(NIH) is the source of the vast majority of federal funding for health re-
search, 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. NIH, CDC, and
AHRQ support basic, translational, and clinical research as well as a
wide range of programs to support the training and ongoing career de-
velopment of researchers. There are also loan repayment programs to
encourage entry into research careers. The federal government also sup-
ports academic medicine through extra payments to academic medical
centers through Medicare. Teaching hospitals have traditionally made
profits on their clinical care that have allowed them to subsidize their ed-
ucational and research activities, but the increasingly competitive health
care market place is making this progressively more difficult. Therefore,
it is more important that research activities be supported by govern-
ment, private foundations, philanthropy, or industry.
Practice Variation Another major concern about health care spend-
ing is the large degree of variation in spending across small geographic
areas around the United States. 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, suggesting that much of
the excess utilization in high-cost areas is of little value. 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, they will
come”). However, other experts have argued that variations in use
across small areas may reflect differences in physician beliefs about ap-
propriate practice patterns that are shaped by the influence of peers in
their local area.
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. Some early programs focused
on direct regulation of health care, such as the requirement that a “cer-
tificate of need” be issued by a local health authority before construc-
tion of a new medical facility can proceed. Other strategies have
included direct regulation of payments through publicly established
fee schedules for Medicare or Medicaid that often influence private
payment rates. Sometimes fee schedules have been created with multi-
ple policy goals. One example is the resource-based relative value scale
(RBRVS), which was developed with the intent to realign incentives to
encourage physicians to enter needed medical specialties (such as pri-
mary care) and be rewarded based on the effort and complexity of the
work they do.
Prospective Payment This is probably the most important cost-con-
trol strategy that has been adopted in the United States. Under a pro-
spective payment system, a health care provider is provided a fixed
amount of money to provide care for a patient over a specified episode
of care. This contrasts with a retrospective reimbursement system, in
which a provider is paid based on the amount of care they provide.
The most important example of such a system has been the Medicare
Prospective Payment system. This was established in 1983 and re-
placed the prior system, in which Medicare reimbursed hospitals
based on the specific services they provided with a system that provid-
ed a fixed payment for a hospital stay for any given diagnosis, classified
according to one of several hundred diagnosis-related groups, or
DRGs. This provided strong incentives to decrease hospital length of
stay and costs and had large effects on hospital cost growth for several
years. It was also coupled with the creation of Professional Review Or-
ganizations (PROs) that, among other things, sought to ensure that
hospitals were acting appropriately in admitting patients according to
Copyright © 2008 by McGraw-Hill Company. All rights reserved.
the criteria for each DRG, and providing quality care within that diag- e9
nosis. This linkage of quality improvement and payment policy was an
important move in the history of Medicare, from serving merely as a
CHAPTER e2
payer to acting as an increasingly active manager of care.
Pay for Performance Today’s interest in pay for performance, in
which providers receive higher reimbursement rates for care that
meets specified quality indicators is an extension of this. Prospective
payment is a key idea underlying the use of managed care organiza-
tions to control costs by providing a fixed payment for providing care
for a patient over a given period of time. Because managed care orga-
Economic Considerations in the Practice of Medicine
nizations are responsible for all of the care of the patient over this time
period, they may have more incentives and ability to provide integrat-
ed care. Health maintenance organizations (HMOs) and other man-
aged care organizations may emphasize prevention as a key aspect of
their strategy for managing care and controlling costs. However, 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, even in HMOs. This is one motivation for the use of re-
port cards for health plans, which often report on the rate at which
various preventive care goals are met. As with prospective payment of
hospitals, 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. Likewise, 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.
Competition This has been another important strategy used to at-
tempt to control costs. Competitive bidding for contracts in which
only the low-price bidders are able to provide services, often called se-
lective contracting, is now common in medical care and provides a
powerful strategy to encourage providers to lower their prices and, ac-
cordingly, costs. Competition does not always lower costs, however.
For example, when hospital reimbursement was retrospective, compe-
tition between hospitals tended to increase costs as hospitals provided
more and more services to attract patients and were well reimbursed
for them. In the era of prospective payment, competition has the op-
posite effect of lowering costs because hospitals can no longer charge
insurers for added costs and because, with a fixed reimbursement,
hospitals can be more profitable only if they lower their costs. The
combination of competition and prospective payment may be particu-
larly powerful in reducing costs but can also create incentives to de-
crease the amount of care provided to the sickest patients within a
given category, the costs of whose care may often exceed reimburse-
ment. For this reason, it is especially important that quality-of-care
measures not neglect the special needs of the sickest patients.
Consumer-Driven Care Another cost-containment strategy that has
recently received increasing attention is the idea of consumer-driven
care, in which patients select an insurance plan tailored to their per-
sonal needs, but often with more limited coverage of certain services.
Given the evidence on the effect of health insurance on the demand
for medical care, consumer-driven health care will likely have only a
modest effect on overall health care demand over the short run. Nev-
ertheless, 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. It is also possi-
ble—though still unproven—that the development of novel new in-
surance mechanisms, such as health savings accounts paired with
high-deductible health insurance coverage for catastrophic care, could
induce far more price sensitivity and cost control than was possible
with traditional insurance arrangements.
Cost-Effectiveness Analyses In making medical decisions, especially
in making decisions when costs are a concern, cost-effectiveness analy-
 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. In cost-effectiveness analysis, the health bene-
fits and costs of a medical intervention are compared to one or more
PART 1
other options by calculating a ratio of costs (C) to effectiveness (E),
where the C/E ratio = change in health benefits/change in costs. Often
benefits will be measured using a metric of quality-adjusted life years,
or QALYs, 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 general, cost-ef-
fectiveness theory suggests that interventions that cost less than some
Introduction to Clinical Medicine
threshold value per QALY (often $50,000/QALY or $100,000/QALY)
would be considered cost-effective, though the appropriate threshold
remains highly controversial.
In countries (such as the United Kingdom) where cost-effective-
ness analysis is used to inform coverage policy, it is most commonly
used as part of a broader process of technology assessment that may
incorporate other forms of evidence, including expert judgment and
political concerns emanating from patient and providers, and from
producers of new technologies. It is generally agreed that cost-effec-
tiveness analysis take a societal perspective, accounting for all costs
and benefits of a medical intervention regardless of to whom they ac-
crue. There is also a strong case to be made for considering multiple
perspectives in a cost-effectiveness analysis. For example, a cost-
effectiveness analysis done from the perspective of an HMO might
find that intensive therapy for diabetes, for which most benefits are
far in the future, is not cost-effective from a business perspective,
even if it is cost-effective from a societal perspective. In such a case,
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. 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.
Evidence-Based Medicine and Physician Practice Patterns To the ex-
tent that variation in practice patterns is an important contributor to
higher health care costs, it becomes important to control practice vari-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
ations by improving alignment of practice patterns using evidence on
the costs and benefits of care. The scientific literature provides impor-
tant data for such evidence-based practice. Nevertheless, it is well es-
tablished that there are large gaps between the time evidence becomes
available and the time it is incorporated into practice. As a result, 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. Health information
systems provide a variety of tools, and their increasing use has already
begun to show promise in addressing practice variations to improve
meaningfully both the cost and effectiveness of care.
Costs and the Clinician Economic concerns arise in clinical care on a
daily basis. They range from patient–oriented concerns (such as out-
of-pocket costs or insurance purchase decisions) to system-oriented
concerns (such as hospital or health plan management) to physician-
oriented concerns (practice management and personal earnings). To
be fully effective, physicians need to develop and maintain an under-
standing of these economic considerations in the practice of medicine
and to reflect them in their professional behavior.
FURTHER READINGS
BODENHEIMER T: High and rising health care costs. Part 3: The role of
health care providers. Ann Intern Med 142(12):996, 2005
CUTLER DM, MCCLELLAN M: Is technological change in medicine
worth it? Health Affairs 20(5):11, 2001
FISHER ES et al: The implications of regional variations in medicare
spending. Part 1: The content, quality, and accessibility of care.
Ann Intern Med 138(4):273, 2003
MELTZER D et al: Does competition under Medicare Prospective Pay-
ment selectively reduce expenditures on high-cost patients? RAND
J Econ 33(3):447, 2002
MURPHY KM, TOPEL RH: Measuring the Gains from Medical Research:
An Economic Approach. Chicago, University of Chicago Press, 2003
NEWHOUSE JP: Consumer-directed health plans and the RAND health
insurance experiment. Health Affairs 23(6):107, 2004
Primer on cost-effectiveness analysis. Effect Clin Pract September/Oc-
tober, 253–255, 2000
 80 e11

e3 Racial and Ethnic Disparities 2002

2003
in Health Care

CHAPTER e3
60
Joseph R. Betancourt, David Blumenthal

Percent
Over the course of its history, the United States has experienced dra- 40
matic improvements in overall health and life expectancy due largely
to initiatives in public health, health promotion, disease prevention,
and chronic care management. Our ability to prevent, detect, and treat

Racial and Ethnic Disparities in Health Care

diseases in their early stages has allowed us to target and reduce mor- 20
bidity and mortality. Despite interventions that have improved the
overall health of the majority of Americans, racial and ethnic minori-
ties (Blacks, Hispanics/Latinos, Native Americans/Alaska Natives, 0
Asian/Pacific Islanders) have benefited less from these advances and al e k ian N ic
To
t hit Bl
ac /A an
suffer poorer health outcomes than whites from many major diseases W As NA sp
anic an
ic Hi
(e.g., cardiovascular disease, cancer, diabetes) in the United States. Re- isp isp
-H n-H
search has highlighted that minorities may receive lower quality of n
No
No
care than whites in the health care setting, even when confounders
such as stage of presentation and comorbidities are controlled for and FIGURE e3-2 Recommended hospital care received by Medicare
they have the same level of health insurance. These differences in qual- patients with pneumonia, by race/ethnicity, 2002–2003. Refer-
ity are called racial and ethnic disparities in health care. This chapter ence population is Medicare beneficiaries with pneumonia who are
will provide an overview of racial and ethnic disparities in health and hospitalized. Composite is calculated by averaging the percentage of
health care, identify root causes, and provide key recommendations to the population that received each of the five incorporated compo-
address them at both the health system and clinical level. nents of care. NA/AN, Native American or Alaska Native. (Adapted from
Agency for Health Care Research and Quality: The 2005 National Health
NATURE AND EXTENT OF RACIAL AND ETHNIC DISPARITIES Care Disparities Report.)
IN HEALTH AND HEALTH CARE
Minority Americans have poorer health outcomes (compared with all resulting in avoidable hospitalizations, emergency hospital care,
whites) from preventable and treatable conditions such as cardiovas- and adverse health outcomes.
cular disease, diabetes, asthma, cancer, and HIV/AIDS, among others In addition to the existence of racial and ethnic disparities in health,
(Fig. e3-1). Multiple factors contribute to these racial and ethnic dis- there are racial/ethnic disparities in the quality of care for those with
parities in health. First and foremost, there is little doubt that social access to the health care system. For instance, disparities have been
determinants—such as lower levels of education, overall lower socio- found in the treatment of pneumonia (Fig. e3-2) and congestive heart
economic status, inadequate and unsafe housing, racism, and living in failure (African Americans receiving less optimal care than whites
close proximity to environmental hazards—disproportionately impact when hospitalized for these conditions) and referral to renal trans-
minority populations and thus contribute to poorer health outcomes. plantation (African Americans with end-stage renal disease being re-
For example, three of the five largest landfills in the country are found ferred less often to the transplant list than whites) (Fig. e3-3).
in African-American and Latino communities; these environmental Disparities have also been found in the utilization of cardiac diagnos-
hazards have contributed to some of the highest rates of pediatric as- tic and therapeutic procedures (African Americans being referred less
thma among these populations. Second, lack of access to care also than whites for cardiac catheterization and bypass grafting), prescrip-
takes a significant toll, as uninsured individuals are less likely to have a tion of analgesia for pain control (African Americans and Latinos re-
regular source of care, are more likely to report delaying seeking care, ceiving less pain medication than whites for long bone fractures and
and are more likely to report that they have not received needed care— cancer), and surgical treatment of lung cancer (African Americans re-

White Black women

White women
Black 100 Black men
American Indian or Alaska Native White men
80.3 82.2
Percentage of patients

Asian or Pacific Islander 80

68.9 67.9
200 Hispanic 59.6
60 57.9

40.3 40.6
150 40

100 20

0
50 Referred Placed on waiting list
for evaluation or received transplant
0 FIGURE e3-3 Referral for evaluation at a transplantation center or
Diseases Cerebrovascular Malignant Diabetes mellitus placement on a waiting list or receipt of a renal transplantation within 18
of heart diseases neoplasms
months after the start of dialysis among patients who wanted a transplant,
FIGURE e3-1 Age-adjusted death rates for selected causes by according to race and sex. Reference population is 239 black women, 280
race and Hispanic origin, 2000. (From Institute of Medicine: Unequal white women, 271 black men, and 271 white men. Racial differences were
Treatment: Confronting Racial and Ethnic Disparities in Health Care. statistically significant among the women and the men (p<.0001 for each
Washington, DC, National Academy Press, 2002.) comparison). (From JZ Ayanian et al: N Engl J Med 341:1661,1999.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e12 ceiving less curative surgery than whites for non-small cell lung can- Total hip replacement
cer), among others. Again, many of these disparities occurred even 3.5
when variations in factors such as insurance status, income, age, co-
3.0 White women
morbid conditions, and symptom expression are taken into account.

Rate (per 1000 enrollees)

PART 1

Little progress has been made in addressing racial/ethnic disparities 2.5 White men
in cardiovascular procedures and other advanced surgical procedures,
while some progress has been made in eliminating disparities in pri- 2.0
Black women
mary care process measures. Data from the National Registry of Myo- 1.5
cardial Infarction found no evidence that the racial differences in rates
Black men
of reperfusion therapy, coronary angiography, and in-hospital death 1.0
after myocardial infarction have narrowed between 1994 and 2002
0.5
Introduction to Clinical Medicine

(Fig. e3-4). Black women fared worst of all groups, while white men
were significantly more likely to receive more aggressive interventions. 0.0
Using Medicare data from 1992–2001 on annual rates of receipt of 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
nine surgical procedures (such as coronary artery bypass surgery and Year
total hip replacement) previously shown to have disparities, the differ- FIGURE e3-5 Racial trends in the use of total hip replacement,
ence between the rates among whites and blacks increased significantly 1992–2001. Reference population is men and women enrolled in
for five of the nine procedures, remained unchanged for three proce- Medicare from 1992 through 2001. (From AK Jha et al: N Engl J Med
dures, and narrowed significantly for only one procedure (Fig. e3-5). 353:683, 2005.)
Overall, there were no meaningful or consistent reductions in the gaps
in care between black and white Medicare enrollees. Using data from
measured between blacks and whites, 58% are narrowing, while 42%
enrollees in Medicare managed care plans, there is evidence for a nar-
are widening. For disparities measures between Hispanics/Latinos and
rowing in racial disparities between 1997 and 2003 in several “report
whites, 41% are narrowing while 59% are widening. For both popula-
card” preventive care measures such as mammography and glucose
tions, significant disparities persist, yet for Hispanics/Latinos, the situ-
and cholesterol testing. However, racial disparities in more complex
ation seems to be getting worse, not better. Ultimately, in none of the
items such as glucose control in diabetics and cholesterol levels in pa-
measured areas have disparities been eliminated.
tients after a heart attack had actually worsened.
The second National Healthcare Disparities Report (NHDR), re-
ROOT CAUSES FOR RACIAL/ETHNIC DISPARITIES IN HEALTH CARE
leased by the Agency for Healthcare Research and Quality in January
The Institute of Medicine (IOM) report Unequal Treatment, released
2006, found that in comparison to the previous year, disparities for
in March 2002, remains the preeminent study of the issue of racial and
blacks are improving in some areas, but disparities for Hispanic/Lati-
ethnic disparities in health care in the United States. The IOM was
no populations appear to be widening. For example, for disparities
charged to assess the extent of racial/ethnic differences in health care
that are not otherwise attributable to known factors such as access to
Reperfusion therapy care. To provide recommendations regarding interventions to elimi-
50 nate health care disparities, the IOM studied health system, provider,
White men
White women and patient factors. The report found the following:
Percentage of patients

40 Black men
Black women • Racial and ethnic disparities in health care exist and, because they
are associated with worse health outcomes, are unacceptable.
30
• Racial and ethnic disparities in health care occur in the context of
(1) broader historic and contemporary social and economic in-
20
equality and (2) evidence of persistent racial and ethnic discrimina-
tion in many sectors of American life.
10 • Many sources—including health systems, health care providers,
patients, and utilization managers—may contribute to racial and
0 ethnic disparities in health care.
1994–1996 1996–1998 1998–2000 2000–2002
• Bias, stereotyping, prejudice, and clinical uncertainty on the part of
health care providers may contribute to racial and ethnic dispari-
Beta-blockers ties in health care.
50 • A small number of studies suggest that certain patients may be
more likely to refuse treatments, yet these refusal rates are generally
40 small and do not fully explain health care disparities.
Percentage of patients

Unequal Treatment went on to identify a set of root causes that includ-

30
ed the following, among others:
20 White men • Health system factors: These include issues related to the complexi-
White women ty of the health care system, the difficulty that minority patients
Black men may have in navigating this complex health system, and the lack of
10 Black women
availability of interpreter services to assist patients with limited En-
0
glish proficiency.
1994–1996 1996–1998 1998–2000 2000–2002 • Provider-level factors: These include issues related to the health
care provider, including stereotyping, the impact of race/ethnicity
FIGURE e3-4 Sex and racial differences in the management of
on clinical decision-making, and clinical uncertainty due to poor
acute myocardial infarction, 1994–2002. Reference population is
communication.
598,911 patients hospitalized with myocardial infarction between
• Patient-level factors: These include patient’s refusal of services,
1994 and 2002 who were ideal candidates for particular treatments;
poor adherence to treatment, and delay in seeking care.
data from the National Registry of Myocardial Infarction. (From V Vac-
carino et al: N Engl J Med 353:671, 2005.) A more detailed analysis of these root causes is presented here.

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

Health System Factors • HEALTH SYSTEM COMPLEXITY Even among
those who are insured and educated, and who have a high degree of
health literacy, navigating the health care system can be complicated
and confusing. Some individuals, however, may be at higher risk for
receiving substandard care because of their difficulty navigating the
complexities of the U.S. health care system. These individuals may in-
clude those from cultures unfamiliar with the Western model of health
care delivery, those with limited English proficiency, those with low
health literacy, and those who are mistrustful of the health care system.
People from these backgrounds may have difficulty knowing how and
where to go for a referral to a specialist; how to prepare for a proce-
dure, such as a colonoscopy; or how to follow up on an abnormal test,
such as a mammogram, for example. Since people of color in the Unit-
ed States tend to be overrepresented among the groups listed above,
the inherent complexity of navigating our health care system has been
seen as a root cause for racial/ethnic disparities in health care.
Provider-Level Factors • PROVIDER-PATIENT COMMUNICATION S i g -
nificant evidence highlights the impact of sociocultural factors, race,
ethnicity, and limited English proficiency on health and clinical care.
Health care professionals frequently care for diverse patient popula-
tions who present varied perspectives, values, beliefs, and behaviors
regarding health and well-being. These include variations in recogni-
tion of symptoms, thresholds for seeking care, comprehension of
management strategies, expectations of care (including preferences for
or against diagnostic and therapeutic procedures), and adherence to
preventive measures and medications. In addition, sociocultural dif-
ferences between patient and provider influence communication and
clinical decision-making and are especially pertinent given evidence
that clearly links provider-patient communication to improved pa-
tient satisfaction, adherence, and, subsequently, better health out-
comes (Fig. e3-6) . Thus, when sociocultural differences between
patient and provider aren’t appreciated, explored, understood, or
communicated effectively in the medical encounter, patient dissatis-
faction, poor adherence, poorer health outcomes, and racial/ethnic
disparities in care may result.
A survey of 6722 Americans age 18 and older is particularly relevant
given the important link between provider-patient communication
and health outcomes. Whites, African Americans, Hispanics/Latinos,
and Asian Americans who had a medical visit in the last 2 years were
asked whether they had trouble understanding their doctor; whether
they felt the doctor did not listen; and whether they had medical ques-
tions they were afraid to ask. The survey found that 19% of all patients
experienced one or more of these problems, yet whites experienced
them 16% of the time, compared with 23% of the time for African
Americans, 33% for Hispanics/Latinos, and 27% for Asian Americans
(Fig. e3-7).
In addition, provider-patient communication without an interpret-
er, in the setting of even a minimal language barrier, is recognized as a
major challenge to effective health care delivery. Spanish-speaking pa-
tients discharged from the emergency room are less likely than their
English-speaking counterparts to understand their diagnosis, pre-
How do we link communication to outcomes?
Communication
Patient satisfaction
Adherence
Health outcomes
FIGURE e3-6 The link between effective communication, patient
satisfaction, adherence, and health outcomes. (From Institute of
Medicine: Unequal Treatment: Confronting Racial and Ethnic Disparities in
Health Care. Washington, DC, National Academy Press, 2002.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Percent of adults with one or more communication problems* e13
40
CHAPTER e3
33%
27%
23%
20 19%
16%
Racial and Ethnic Disparities in Health Care
0
Total White African Hispanic Asian
American American
Base: Adults with health care visit in past two years
*Problems include understanding doctor, feeling doctor listened,
had questions but did not ask.
FIGURE e3-7 Communication difficulties with physicians, by
race/ethnicity. 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, whether they
felt the doctor did not listen, and whether they had medical questions
they were afraid to ask. (From Commonwealth Fund Health Care Quality
Survey, 2001.)
scribed medications, special instructions, and plans for follow-up care;
less likely to be satisfied with their care or willing to return if they have
a problem; more likely to report problems with their care; and less sat-
isfied with the patient-provider relationship. In addition, physicians
who have access to trained interpreters report a significantly higher
quality of patient-physician communication than physicians who used
other methods. Hispanic patients with language-discordant physicians
are more likely to omit medication, miss office appointments, and visit
the emergency department for care. 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.
CLINICAL DECISION-MAKING Theory and research on clinical decision-
making suggest that physicians’ understanding and interpretations of
information obtained from patients, as well as assumptions about pa-
tients themselves, may contribute to racial and ethnic disparities in
health care. Two factors are central to this process: clinical uncertainty
and stereotyping. A doctor’s decision-making process is nested in clin-
ical uncertainty—in sum, doctors must depend on inferences about
severity based on what they understand about illness, and the infor-
mation they obtain from the patient. If the doctor is caring for a pa-
tient for whom they have difficulty understanding the symptoms and
are less sure of the “signal”—the set of clues and indications that phy-
sicians rely on to make clinical decisions—their decisions may not be
the same for two patients who present with the exact same condition.
Given that the expression of symptoms may differ among and between
cultural and racial groups, doctors—the overwhelming majority of
whom are white—may understand symptoms best from patients of
their own racial group. The consequence is that white patients may be
treated differently from minority patients. Differences in clinical deci-
sions from this mechanism can arise when the doctor has the same re-
gard for each patient (i.e., no prejudice).
Stereotyping can be defined as the process by which people use so-
cial categories (e.g., race, gender) in acquiring, processing, and recall-
ing information about others. The literature on social cognitive theory
highlights the ways in which natural tendencies to stereotype may in-
fluence clinical decision-making. Faced with enormous information
loads and the need to make many decisions, people subconsciously
simplify the decision-making process and lessen cognitive effort by us-
 e14 ing “categories” or “stereotypes” that group information and decisions
into groups or types that can be more quickly processed and executed.
Sometimes, those stereotypes are applied to individuals who are
lumped together into groups to which certain beliefs and expectations
PART 1
are attached. Interestingly, people may not be aware of their attitudes
or they may consciously endorse stereotyping. Nevertheless, when
people assign someone to a particular class or group, they tend to
make a “snap judgment” in which they subconsciously and automati-
cally assign the group’s characteristics to that individual. Although
functional, stereotyping can be systematically biased as people are au-
tomatically classified into social categories relating to dimensions such
Introduction to Clinical Medicine
as race, gender, and age. These biases may exist in overt forms, as repre-
sented by outward racism or bigotry. However, because of their origins
in virtually universal social categorization processes, they may also ex-
ist, often subconsciously, among people who strongly endorse egalitar-
ian principles and truly believe they are not prejudiced. Moreover, this
social categorization enhances perceptions of similarities within
groups and differences between groups (particularly with respect to
one’s own group), which emphasizes social difference and group dis-
tinctiveness. In the process of categorizing people into two different
groups, people typically classify themselves into one of the social cate-
gories and out of the other. Upon categorization of individuals into
in-groups and out-groups, people experience more positive feelings
toward the in-group, as well as favor them in terms of evaluation and
resource allocation. Although stereotyping may be a normal cognitive
process, the cues that lead to particular stereotypes are also strongly
influenced by the messages presented consciously and subconsciously
in society. For instance, if the media constantly present images of mi-
norities as being less educated, violent, and nonadherent to health care
recommendations, these impressions may generate stereotypes that
unnaturally and unjustly impact clinical decision-making. Thus, as
signs of racism, classism, gender bias, and ageism are experienced—
consciously or unconsciously in our society—stereotypes may be cre-
ated that impact the way doctors manage patients from these groups.
In addition, based on training or practice location, doctors may devel-
op certain perceptions about race/ethnicity, culture, and class that may
evolve into stereotypes. For example, many medical students and resi-
dents are often trained—and minorities cared for—in academic health
centers or public hospitals located in socioeconomically disadvantaged
areas. As a result, doctors may begin to equate certain races and eth-
nicities with specific health beliefs and behaviors (e.g., “these patients”
engage in risky behaviors, or “those patients” tend to be noncompli-
ant) that are more associated with the social environment (e.g., pover-
ty) than a patient’s racial/ethnic background or cultural traditions.
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 result
over time may be that doctors begin to believe that “these patients”
don’t like invasive procedures, and thus they may not offer them as op-
tions very ardently, if at all.
In addition, doctors are commonly taught that their own personal
characteristics (race, ethnicity, socioeconomic status), as well as per-
sonal characteristics of the patient and the clinical setting, should be
excluded from consideration in the formulation of clinical decisions.
Many nonmedical factors, however, ranging from the patient’s physical
appearance to the organizational setting in which medical care is deliv-
ered, may have as much influence on clinical decisions as the actual
signs and symptoms of disease. These nonmedical factors include char-
acteristics of the patient (including patient age, gender, socioeconomic
status, race/ethnicity, language proficiency, and insurance status), char-
acteristics of the doctor (including the specialty, level of training, clini-
cal experience, age, gender, and race/ethnicity), and features of the
practice setting (including location, organization of practice, form of
compensation, performance expectations, and incentives). This may
furthermore contribute to unconscious stereotyping.
It is important to differentiate stereotyping from prejudice and dis-
crimination, both conscious processes. Prejudice is a conscious,
knowledgeable prejudgment of individuals that may lead to disparate
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
treatment, and discrimination is conscious and intentional disparate
treatment. All individuals stereotype subconsciously, despite the best
intentions to treat every patient equitably. The challenge is that if left
unchecked, stereotyping (especially based on stereotypes derived ab-
normally from conscious and subconscious societal cues, 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. What is particularly salient is that
stereotypes tend to be activated most in environments where the indi-
vidual is stressed, multitasking, and under the time pressure—the
hallmarks of the clinical encounter.
Patient-Level Factors • MISTRUST Lack of trust has become a ma-
jor concern for many health care institutions today. For example, an
Institute of Medicine Report, To Err Is Human: Building a Safer Health
System, documented alarming rates of medical errors and made pa-
tients feel vulnerable and less trustful of the U.S. health care system.
The increased media and academic attention to problems of quality of
care (and even disparities themselves) have clearly diminished trust in
doctors and nurses.
Trust is a crucial element in the therapeutic alliance between patient
and health care provider. It facilitates open communication and is di-
rectly correlated with adherence to physician recommendations and
patient satisfaction. Patients who mistrust their health care providers
are less satisfied with the care they receive, and mistrust of the health
care system greatly affects patients’ use of services. This lack of confi-
dence in physicians also results in inconsistent care, doctor-shopping,
self-medicating, and an increased demand for referrals and diagnostic
tests by patients.
Based on historic factors of discrimination, segregation, and medi-
cal experimentation, African Americans may be especially mistrustful
of providers. The exploitation of African Americans by the U.S. Public
Health Service during the Tuskegee study left a legacy of mistrust that
persists even today among this population. A national survey by the
Kaiser Family Foundation found that there is significant mistrust of
the health care system among minority populations. Of the 3884 indi-
viduals surveyed, 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. Per-
haps even more alarming, 65% of African Americans and 58% of His-
panics (compared with 22% of whites) were afraid of being treated
unfairly in the future based on their race/ethnicity (Fig. e3-8).
This mistrust may contribute to wariness in accepting or following
recommendations, undergoing invasive procedures, or participating
in clinical research. This in turn may lead doctors to misunderstand
Whites
race/ethnicity
15
Tx based on
Past unfair
Blacks
35 Latinos
36
22
race/ethnicity
Future unfair
Tx based on
65
58
0 20 40 60 80
Percent
FIGURE e3-8 Patient perspectives regarding how fairly they have
been treated in the health care system, by race/ethnicity. Refer-
ence population is 3884 individuals surveyed about how fairly they
have been treated in the health care system in the past, and how fairly
they feel they will be treated in the future based on their race/ethnic-
ity. (From Race, Ethnicity & Medical Care: A Survey of Public Perceptions
and Experiences. Kaiser Family Foundation, 2005.)
why African-American populations seem less adherent to or less inter-
ested in aggressive treatments.
KEY RECOMMENDATIONS TO ADDRESS RACIAL/ETHNIC
DISPARITIES IN HEALTH CARE
The publication Unequal Treatment provides a series of recommenda-
tions to address racial and ethnic disparities in health care, focusing on a
broad set of stakeholders. These include health systems interventions, pro-
vider interventions, and patient interventions, as well as general recom-
mendations. These recommendations are described in more detail below.
Health System Interventions 1. 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, and
there is less known about the disparities for minority groups (Hispan-
ics, Asian Americans, Pacific Islanders, Native Americans, and Alaska
Natives) other than African Americans. For instance, only in the mid-
1980s did the Medicare database begin to collect data on patient
groups outside the standard categories of “white,” “black,” and “other.”
Federal, private, and state-supported data collection efforts are scat-
tered and unsystematic, and many health care systems and hospitals,
with a few notable exceptions, do not collect data on the race, ethnici-
ty, or primary language of patients or enrollees. 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, or use indirect methods to obtain aggregate data on race. 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.
2. Encourage the use of evidence-based guidelines and quality improvement
Unequal Treatment highlights the subjectivity of clinical decision-mak-
ing 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, even in the presence of well-delineated practice
guidelines. Therefore, the adoption and implementation of evidence-
based guidelines broadly is a major recommendation to eliminate dis-
parities. For instance, there now exist evidence-based guidelines for the
management of diabetes, HIV/AIDS, cardiovascular diseases, cancer
screening and management, and asthma—all areas where significant
disparities exist. As part of ongoing quality improvement efforts, par-
ticular attention should be paid to the implementation of evidence-
based guidelines for all patients, regardless of their race and ethnicity.
3. Support the use of language interpretation services in the clinical setting
As described previously, health care systems that lack interpreter ser-
vices can lead to patient dissatisfaction, poor comprehension and
compliance, and ineffective/lower-quality care for patients with limit-
ed English proficiency. Unequal Treatment’s recommendation to sup-
port the use of interpretation services has clear implications for
delivery of quality health care by improving doctors’ ability to com-
municate effectively with patients with limited English proficiency.
4. Increase the proportion of underrepresented minorities in the health
care workforce
Recent data from the American Medical Association indicate that of
the 70.5% of U.S. physicians whose race and ethnicity is known, His-
panics make up 3.5%, African Americans 2.6%, and American Indian
and Alaska Natives less than 0.5% percent. Data regarding the racial/
ethnic composition of medical school faculty are no different, with
minorities composing only 4.2% nationally. 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. Despite
composing 30% of the population, minority students accounted for
approximately 10% of medical school graduates in 2001. It will be dif-
ficult 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.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Provider Interventions Integrate Cross-Cultural Education into the e15
Training of All Health Care Professionals The goal of cross-cultural ed-
ucation is to improve providers’ ability to understand, communicate
CHAPTER e3
with, and care for patients from diverse backgrounds; such education
focuses on enhancing awareness of sociocultural influences on health
beliefs and behaviors, and on providing skills to understand and man-
age these factors in the medical encounter. Cross-cultural education
includes curricula on health care disparities, how to use an interpreter,
and how to effectively communicate and negotiate across cultures.
These curricula can be incorporated into health professions training in
medical schools and nursing schools, and as part of continuing educa-
Racial and Ethnic Disparities in Health Care
tion. Despite the importance of this area of education, as well as the at-
tention it has attracted from medical education accreditation bodies, a
national survey of resident physicians by Weissman and colleagues
found that more than one in five felt unprepared to deal with cross-
cultural issues, including caring for patients who have religious beliefs
that may affect treatment, patients who use complementary medicine,
patients with health beliefs at odds with Western medicine, patients
with mistrust of the health care system, and new immigrants. Efforts
to incorporate cross-cultural education into undergraduate and grad-
uate medical education will contribute to improving doctor-patient
communication and to better quality of care.
Incorporate Teaching on the Impact of Race, Ethnicity, and Culture on Clinical
Decision-Making Unequal Treatment found that stereotyping by
health care providers might lead to disparate treatment based on a pa-
tient’s race or ethnicity. The LCME—the body that accredits medical
schools—now has a directive that medical education should teach how
a patient’s race, ethnicity, and culture might subconsciously impact on
communication and clinical decision-making.
Patient Interventions Educate Patients on How to Navigate the Health
Care System and How to Be More Active in the Medical Encounter Difficul-
ty navigating the health care system and obtaining access to care can be
a hindrance to all populations, particularly to minorities. Similarly,
lack of empowerment or involvement in the medical encounter by mi-
norities can be a barrier to care as well. Interventions should be used
to increase patients’ knowledge of how to best access care and partici-
pate in treatment decisions.
General Recommendations Increase Awareness of Racial/Ethnic Dispari-
ties in Health Care Recent 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. For example,
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. In 2003, short-
ly after the release of Unequal Treatment, a national survey was con-
ducted in which individuals were asked “Do all Americans receive the
same quality of health care?” Most thought so, and the majority of
physicians felt patients were treated equally regardless of their race or
ethnicity. These beliefs were held despite a large body of published re-
search to the contrary. A poll in 2005 showed that the majority of
Americans were actually unaware that racial and ethnic minorities re-
ceive poorer care than whites, with the lack of awareness being greatest
among whites. Despite this lack of awareness, most believed that all
Americans deserve quality care, regardless of their background. In-
creasing awareness of racial and ethnic disparities among health care
professionals and the public is an important first step in addressing
disparities in health care. The ultimate goal is to generate discourse
and mobilize action to address disparities in multiple areas, including
at the level of health policy, health systems, and the community.
Conduct Further Research to Identify Sources of Disparities and Promising
Interventions While the literature that formed the basis of the find-
ings and recommendations of Unequal Treatment provided significant
evidence for racial and ethnic disparities, additional research is needed
 e16 in several areas. First, most of the literature on disparities focuses on
black-versus-white differences; much less is known about the experi-
ences of other minority groups. Improving the ability to collect racial
and ethnic patient data should facilitate this process, but in instances
PART 1
where those systems are not yet in place, racial and ethnic patient data
may be collected prospectively in the setting of clinical or health ser-
vices research to better understand disparities for other populations.
Second, much of the literature on disparities to date has focused on
defining areas where they exist, but much less has been done to identi-
fy the multiple factors that contribute to disparities, and very little has
been done to test interventions to address them. There is clearly a need
Introduction to Clinical Medicine
for a research agenda that identifies promising practices and solutions
to disparities.
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. These
approaches are discussed here.
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. Only then can they be at-
tuned to monitoring their behavior and clinical practice so as to en-
sure that all patients receive the highest quality of care, regardless of
their race, ethnicity, or culture.
Practice Culturally Competent Care Many have thought of “cultural
competence” as simply the skills necessary for addressing language
barriers in the clinical encounter, or learning as much as you can
about patients from specific cultures. While the former is important
and remains a key component of cultural competence, the latter is an
area in evolution. Previous efforts in cultural competence have aimed
to teach clinicians about the attitudes, values, beliefs, and behaviors of
certain cultural groups—the key practice “do’s and don’ts” for caring
for “the Hispanic patient,” for example. In certain situations, learning
about a particular local community or cultural group can be helpful
(following the principles of community-oriented primary care), but,
when broadly and uncritically applied, this approach can also lead to
stereotyping and oversimplification of culture without respect for its
complexity.
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 pa-
tient-centered care. Patient-centeredness encompasses the qualities of
compassion, empathy, and responsiveness to the needs, values, and ex-
pressed preferences of the individual patient. Cultural competence
aims to take this a step further, by expanding the repertoire of knowl-
edge and skills classically defined as patient-centered to include those
that are especially useful in cross-cultural interactions (but remain vi-
tal to all clinical encounters). This includes eliciting the patient’s un-
derstanding of his or her condition, identifying and negotiating
different styles of communication, assessing decision-making prefer-
ences and the role of family, determining the patient’s perception of
biomedicine and complementary and alternative medicine, recogniz-
ing sexual and gender issues, and being aware of mistrust, prejudice,
and racism, among others. For example, while it is important to un-
derstand all patients’ health beliefs, it may be particularly crucial to
understand the health beliefs of those who come from a different cul-
ture or have a different health care experience. With the individual pa-
tient as teacher, one can adjust their practice style accordingly to meet
their specific needs.
Avoid Stereotyping Several strategies can allow us to counteract,
both systemically and individually, our normal tendency to stereo-
type. For example, 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, a sense of camaraderie de-
velops and prevents the future development of stereotypes based on
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
race/ethnicity, gender, culture, or class. Thus, we should aim to gain
experiences working with, and learning from, a diverse set of col-
leagues. In addition, simply being aware of the operation of social
cognitive factors allows one to actively “check” or “monitor” behav-
ior. For instance, physicians can constantly ensure that they are offer-
ing the same things, in the same ways, to all patients. Understanding
how we are susceptible to stereotyping—and how this may lead to
disparities—is essential if we are to provide equitable, high-quality
care 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,
from decreased patient satisfaction to the delay of care. Although the
historic legacy of discrimination can never be erased, several steps can
be taken to build trust with patients and address disparities. First, pro-
viders must be aware that mistrust exists and may be more prevalent
among minority populations given this nation’s history. Second, pro-
viders must reassure patients that they come first, and that we will do
everything in our power to ensure that they always get the best care
possible, and that we will serve as their advocates. Third, interpersonal
skills and communication techniques that demonstrate honesty, open-
ness, compassion, and respect on the part of the health care provider
are essential tools in dismantling mistrust. Finally, patients indicate
that trust is built when there is shared, participatory decision-making
and the provider makes a concerted effort to understand the patient’s
background. By reframing the doctor-patient relationship as one of
solidarity, the patient’s sense of vulnerability can be transformed into
one of trust. For the process of eliminating disparities to be successful,
we must utilize trust-building interventions and strengthen the doc-
tor-patient relationship.
New Areas for Exploration • DISPARITIES AND QUALITY IMPROVE-
MENT A major advance is that key health care stakeholders have be-
gun to understand that disparities are an inequality in quality. Health
plans and hospitals, for example, have begun to consider the impor-
tance of stratifying their quality data by race/ethnicity so as to identify
disparities and develop interventions to address them. The emergence
of targeting disparities through quality improvement has gained sig-
nificant traction nationally, especially given the fact that the IOM re-
port 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, ethnic-
ity, and gender. There is no doubt that the quality approach to address
disparities has great promise.
GEOGRAPHIC VARIATIONS IN CARE Where a patient lives can itself have a
large impact on the level and quality of health care. Since black or His-
panic populations tend to live in different areas from non-Hispanic
white populations, location likely matters in the measurement and in-
terpretation of health (and health care) disparities. There is prelimi-
nary evidence to suggest wide variation in racial disparities across
geographic lines: some areas have substantial disparities, while others
have equal treatment. The problem of differences in quality of care
across regions remains an important area of study and should remain
a target of policy makers, as reducing quality disparities would play a
major role in improving the health care received by all Americans and
by minority Americans in particular.
CONCLUSION
The issue of racial and ethnic disparities in health care has gained na-
tional prominence, both with the release of the IOM report Unequal
Treatment and with the many recent articles that have confirmed their
persistence. Furthermore, another influential IOM report, Crossing the
Quality Chasm, 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. There are many obvi-
ous opportunities for interventions to eliminate racial and ethnic dis-
parities in health care. Greater attention to addressing the root causes
of disparities will improve the care provided to all patients, not just
those who are racial and ethnic minorities.
FURTHER READINGS
AGENCY FOR HEALTH CARE RESEARCH AND QUALITY: The 2005 Na-
tional Health Care Disparities Report. Rockville, MD, Agency for
Health Care Research and Quality, 2006
ANDRULIS DP: Access to care is the centerpiece in the elimination of
socioeconomic disparities in health. Ann Intern Med 129:412, 1998
AYANIAN JZ et al: Quality of care by race and gender for congestive
heart failure and pneumonia. Med Care 37:1260, 1999
——— et al: The effect of patients’ preferences on racial differences in
access to renal transplantation. N Engl J Med 341:1661, 1999
———, EPSTEIN AM: Differences in the use of procedures between
women and men hospitalized for coronary heart disease. N Engl J
Med 325:226, 1991
BACH PB et al: Racial differences in the treatment of early-stage lung
cancer. N Engl J Med 341:1198, 1999
BAICKER K et al: Who you are and where you live: How race and geog-
raphy affect the treatment of medicare beneficiaries. Health Aff
(Millwood) Suppl Web Exclusive: VAR 33-44, 2004
BERGER JT: Culture and ethnicity in clinical care. Arch Intern Med
158:2085, 1998
BETANCOURT JR: Cultural competence—marginal or mainstream
movement? N Engl J Med 351:953, 2004
——— et al: Hypertension in multicultural and minority popula-
tions: Linking communication to compliance. Curr Hypertens Rep
1:482, 1999
CARRASQUILLO O et al: Impact of language barriers on patient satisfac-
tion in an emergency department. J Gen Intern Med 14:82, 1999
CARRILLO JE et al: Cross-cultural primary care: A patient-based ap-
proach. Ann Intern Med 130:829, 1999
FLORES G et al: The health of Latino children: Urgent priorities, unan-
swered questions, and a research agenda. JAMA 288:82, 2002
GAMBLE V: Under the shadow of Tuskegee: African-Americans and
health care. Am J Pub Health 87:1773, 1997
INSTITUTE OF MEDICINE: Health Literacy: A Prescription to End Con-
fusion. Washington, DC, National Academy Press, 2004
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
———: In the Nation’s Compelling Interest: Ensuring Diversity in e17
the Health Care Workforce. Washington, DC, National Academy
Press, 2004
CHAPTER e3
———: Unequal Treatment: Confronting Racial and Ethnic Disparities
in Health Care. Washington, DC, National Academy Press, 2002
———: Crossing the Quality Chasm: A New Health System for the
21st Century. Washington, DC, National Academy Press, 2001
———: To Err Is Human: Building a Safer Health System. Washing-
ton, DC, National Academy Press, 2000
JHA AK et al: Racial trends in the use of major procedures among the
elderly. N Engl J Med 353:683, 2005
Racial and Ethnic Disparities in Health Care
MCKINLAY JB et al: Non-medical influences on medical decision-
making. Soc Sci Med 42:769, 1996
PEREZ-STABLE EJ et al: The effects of ethnicity and language on medi-
cal outcomes of patients with hypertension or diabetes. Med Care
35:1212, 1997
PINCUS T et al: Social conditions and self-management are more pow-
erful determinants of health than access to care. Ann Intern Med
129: 406, 1998
RATHORE SS et al: The effects of patient sex and race on medical stu-
dents’ ratings of quality of life. Am J Med 108:561, 2000
SCHULMAN KA et al: The effect of race and sex on physicians’ recom-
mendations for cardiac catheterization. N Engl J Med 340:618, 1999
SKINNER J et al: Mortality after acute myocardial infarction in hospi-
tals that disproportionately treat black patients. Circulation
12:2634, 2005
STEWART M et al: Evidence on patient-doctor communication. Cancer
Prev Control 3:25, 1999
TODD KH et al: Ethnicity as a risk factor for inadequate emergency de-
partment analgesia. JAMA 269:1537, 1993
TRIVEDI AN et al: Trends in the quality of care and racial disparities in
Medicare managed care. N Engl J Med 353:692, 2005
VACCARINO V et al: Sex and race differences in the management of
acute myocardial infarction, 1994-2002. N Engl J Med 353:671,
2005
VAN RYN M, BURKE J: The effect of patient race and socio-economic sta-
tus on physician’s perceptions of patients. Soc Sci Med 50:813, 2000
WEISSMAN JS et al: Resident physicians’ preparedness to provide
cross-cultural care. JAMA 294:1058, 2005

e4 Ethical Issues in Clinical Medicine
Bernard Lo
Physicians frequently confront ethical issues in clinical practice that
are perplexing, time-consuming, and emotionally draining. Experi-
ence, common sense, and simply being a good person do not guarantee
that physicians can identify or resolve ethical dilemmas. Knowledge
about common ethical dilemmas is also essential.
FUNDAMENTAL ETHICAL GUIDELINES
Physicians should follow two fundamental but frequently conflicting
ethical guidelines: respecting patient autonomy and acting in the pa-
tient’s best interests.
RESPECTING PATIENT AUTONOMY
Treating patients with respect requires doctors to accept the medical
decisions of persons who are informed and acting freely. Individuals
place different values on health, medical care, and risk. In most clinical
settings different goals and approaches are possible, outcomes are un-
certain, and an intervention may cause both benefits and harms. Thus
competent, informed patients may refuse recommended interventions
and choose among reasonable alternatives.
Informed Consent For patients to make informed decisions, physi-
cians need to discuss with them the nature of the proposed care, the
alternatives, the risks and benefits of each, and the likely consequences,
and to obtain the patient’s agreement to care. Informed consent in-
volves more than obtaining signatures on consent forms. Physicians
need to educate patients, answer questions, make recommendations,
and help them deliberate. Patients can be overwhelmed with medical
jargon, needlessly complicated explanations, or too much information
at once.
Nondisclosure of Information Physicians may consider withholding a
serious diagnosis, misrepresenting it, or limiting discussions of prog-
nosis or risks because they fear that a patient will develop severe anxi-
ety or depression or refuse needed care. Generally, physicians should
provide relevant information, while adjusting the pace of disclosure,
offering empathy and hope, and helping patients cope with bad news.
In many cultures, patients traditionally are not told of a diagnosis of
cancer or of other serious illness. In these cultures, disclosure of a
grave diagnosis is believed to cause patients to suffer, while withhold-
ing information promotes serenity, security, and hope. Patients should
not be forced to receive information against their will, even in the
name of promoting informed decisions. However, many individuals in
these groups want to know their diagnosis and prognosis, even if they
are terminally ill. Health care providers therefore should ask patients
how they want decisions to be made, saying that they usually provide
information and make decisions together with patients, while offering
patients the option not to receive information or to turn over deci-
sion-making to someone else.
Emergency Care Informed consent is not required when patients can-
not give consent and when delay of treatment would place their lives
or health in peril. People are presumed to want such emergency care,
unless they have previously indicated otherwise.
Futile Interventions Autonomy does not entitle patients to insist on
whatever care they want. Physicians are not obligated to provide futile
interventions that have no physiologic rationale or have already failed.
For example, cardiopulmonary resuscitation would be futile in a pa-
tient with progressive hypotension despite maximal therapy. But phy-
sicians 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, no worthwhile goals can be
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
achieved, the patient’s quality of life is unacceptable, or the costs are e19
too high. Such looser usages of the term are problematic because they
may be inconsistent and mask important value judgments.
CHAPTER e4
Maintaining Confidentiality Confidentiality respects patients’ auton-
omy and privacy, encourages them to seek treatment and discuss their
problems candidly, and prevents discrimination. However, maintain-
ing confidentiality is not an absolute rule. Confidentiality may be
overridden in certain situations to prevent serious harm to third par-
ties or to the patient. The law may require physicians to override confi-
dentiality in order to protect third parties. For example, public health
Ethical Issues in Clinical Medicine
laws require reporting of tuberculosis and syphilis. In other situations,
medical providers have a legal duty to report victims of elder abuse,
child abuse, and domestic violence. These exceptions to confidentiality
are justified because the risk is serious and probable, there are no less-
restrictive measures to avert risk, the adverse effects of overriding con-
fidentiality are minimized, and these adverse effects are deemed
acceptable by society.
The recent HIPAA (Health Insurance Portability and Accountabili-
ty Act) health privacy regulations have heightened awareness of the
importance of confidentiality. These regulations are not meant to in-
hibit transmission of information needed for patient treatment: dis-
closure of patient information to other health care providers for the
purposes of treatment without having the patient sign an authoriza-
tion form is permissible.
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. Lying refers to statements that the
speaker knows are false and that are intended to mislead the listener.
Deception, which is broader, may be defined as statements and ac-
tions that are intended to mislead the listener, whether or not they are
literally true. For example, the health care provider may tell a patient
that she has a “small growth” so that she does not think she has can-
cer. Or the provider may complete and sign a form for a patient to get
a bus pass, even though he does not meet the criteria for physical dis-
ability. Although such deception may be motivated by a desire to help
the patient, it is ethically problematic. The person who is deceived
cannot make informed decisions if they receive misleading informa-
tion. Furthermore, deception undermines physicians’ credibility and
trustworthiness.
ACTING IN THE BEST INTERESTS OF PATIENTS
The guideline of beneficence requires physicians to act for the patient’s
benefit. Laypeople do not possess medical expertise and may be vul-
nerable because of their illness. They justifiably rely on physicians to
provide sound advice and to promote their well-being. Physicians en-
courage such trust. Hence, physicians have a fiduciary duty to act in
the best interests of their patients. The interests of the patient should
prevail over physicians’ self-interest or the interests of third parties,
such as hospitals or insurers. These fiduciary obligations of physicians
contrast sharply with business relationships, which are characterized
by “let the buyer beware,” not by trust and reliance. The guideline of
“do no harm” forbids physicians from providing ineffective interven-
tions or acting without due care. This precept, while often cited, pro-
vides only limited guidance, because many beneficial interventions
also have serious risks.
CONFLICTS BETWEEN BENEFICENCE AND AUTONOMY
Patients’ refusals of care may thwart their own goals or cause them se-
rious harm. For example, a young man with asthma may refuse me-
chanical ventilation for reversible respiratory failure. Simply to accept
such refusals, in the name of respecting autonomy, seems morally con-
stricted. Physicians can elicit patients’ expectations and concerns, cor-
rect misunderstandings, and try to persuade them to accept beneficial
therapies. If disagreements persist after discussions, the patient’s in-
formed choices and view of his or her best interests should prevail.
While refusing recommended care does not render a patient incompe-
 e20 tent, it may lead the physician to probe further to ensure that the pa-
tient is able to make informed decisions.
JUSTICE
PART 1
The term justice is used in a general sense to mean fairness: people
should receive what they deserve. In addition, it is important to act
consistently in cases that are similar in ethically relevant ways. Other-
wise, decisions would be arbitrary, biased, and unfair. Justice forbids
discrimination in health care based on race, religion, or gender and
supports a moral right to health care, with access based on medical
need rather than ability to pay.
Introduction to Clinical Medicine
PATIENTS WHO LACK DECISION-MAKING CAPACITY
Patients may not be able to make informed decisions because of un-
consciousness, dementia, delirium, or other conditions. Physicians
should ask two questions regarding such patients: Who is the appro-
priate surrogate? What would the patient want done?
ASSESSING CAPACITY TO MAKE MEDICAL DECISIONS
All adults are considered legally competent unless declared incompe-
tent by a court. In practice, physicians usually determine that patients
lack the capacity to make health care decisions and arrange for surro-
gates to make them, without involving the courts. By definition, com-
petent patients can express a choice and appreciate the medical
situation; the nature of the proposed care; the alternatives; and the
risks, benefits, and consequences of each. Their choices should be con-
sistent with their values and should not result from delusions or hallu-
cinations. Psychiatrists may help in difficult cases because they are
skilled at interviewing mentally impaired patients and can identify
treatable depression or psychosis. When impairments are fluctuating
or reversible, decisions should be postponed if possible until the pa-
tient recovers decision-making capacity.
CHOICE OF SURROGATE
If a patient lacks decision-making capacity, physicians routinely ask
family members to serve as surrogates. Most patients want their family
members to be surrogates, and family members generally know the
patient’s preferences and have the patient’s best interests at heart. Pa-
tients may designate a particular individual to serve as proxy; such
choices should be respected. Some states have established a prioritized
list of which relative may serve as surrogate if the patient has not desig-
nated a proxy.
STANDARDS FOR SURROGATE DECISION-MAKING
Advance Directives These are statements by competent patients to di-
rect care if they lose decision-making capacity. They may indicate (1) what
interventions they would refuse or accept, or (2) who should serve as sur-
rogate. Following the patient’s advance directives, the surrogate respects
the patient’s autonomy.
Oral conversations are the most frequent form of advance direc-
tives. While such conversations are customarily followed in clinical
practice, casual or vague comments may not be trustworthy. Living
wills direct physicians to forego or provide life-sustaining interven-
tions if the patient develops a terminal condition or persistent vegeta-
tive state. Generally patients may refuse only interventions that
“merely prolong the process of dying.”
A health care proxy is someone appointed by the patient to make
health care decisions if he or she loses decision-making capacity. It is
more flexible and comprehensive than the living will, applying when-
ever the patient is unable to make decisions.
Physicians can encourage patients to provide advance directives, to
indicate both what they would want and who should be the surrogate,
and to discuss their preferences with surrogates. In discussions with
patients, physicians can ensure that advance directives are informed,
up-to-date, and address likely clinical scenarios. Such discussions are
best carried out in the ambulatory setting. The federal Patient Self-
Determination Act requires hospitals and health maintenance organi-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
zations to inform patients of their right to make health care decisions
and to provide advance directives.
Substituted Judgment In the absence of clear advance directives, sur-
rogates and physicians should try to decide as the patient would under
the circumstances, using all information that they know about the pa-
tient. While such substituted judgments try to respect the patient’s val-
ues, they may be speculative or inaccurate. A surrogate may be
mistaken about the patient’s preferences, particularly when they have
not been discussed explicitly.
Best Interests When the patient’s preferences are unclear or unknown,
decisions should be based on the patient’s best interests. Patients gener-
ally take into account the quality of life as well as the duration of life
when making decisions for themselves. It is understandable that surro-
gates would also consider quality of life of patients who lack decision-
making capacity. Judgments about quality of life are appropriate if they
reflect the patient’s own values. Bias or discrimination may occur, how-
ever, if others project their values onto the patient or weigh the per-
ceived social worth of the patient. Most patients with chronic illness rate
their quality of life higher than their family members and physicians do.
Legal Issues Physicians need to know pertinent state laws regarding
patients who lack decision-making capacity. A few state courts allow
doctors to forego life-sustaining interventions only if patients have
provided written advance directives or very specific oral ones.
Disagreements Disagreements may occur among potential surro-
gates or between the physician and surrogate. Physicians can remind
everyone to base decisions on what the patient would want, not what
they would want for themselves. Consultation with the hospital ethics
committee or with another physician often helps resolve disputes.
Such consultation is also helpful when patients have no surrogate and
no advance directives. The courts should be used only as a last resort
when disagreements cannot be resolved in the clinical setting.
DECISIONS ABOUT LIFE-SUSTAINING INTERVENTIONS
Although medical technology can save lives, it can also prolong the
process of dying. Competent, informed patients may refuse life-sus-
taining interventions. When patients lack decision-making capacity,
such interventions may also be withheld on the basis of advance direc-
tives or decisions by appropriate surrogates. Courts have ruled that
foregoing life-sustaining interventions is neither suicide nor murder.
MISLEADING DISTINCTIONS
People commonly draw distinctions that are intuitively plausible but
prove untenable on closer analysis.
Extraordinary and Ordinary Care Some physicians are willing to fore-
go “extraordinary” or “heroic” interventions, such as surgery, mechan-
ical ventilation, or renal dialysis but insist on providing “ordinary”
ones, such as antibiotics, IV fluids, or feeding tubes. However, this dis-
tinction is not logical because all medical interventions have both risks
and benefits. Any intervention may be withheld, if the burdens for the
individual patient outweigh the benefits.
Withdrawing and Withholding Interventions Many health care pro-
viders find it more difficult to discontinue interventions than to with-
hold them in the first place. Although such emotions need to be
acknowledged, there is no logical distinction between the two acts.
Justifications for withholding interventions, such as refusal by patients
or surrogates, are also justifications for withdrawing them. In addi-
tion, after an intervention has been started, new data may indicate that
it is no longer appropriate. The intervention may prove unsuccessful,
or it may be learned that the patient did not want the intervention. If
interventions could never be discontinued, patients and surrogates
might not even attempt treatments that might prove beneficial.
DO NOT RESUSCITATE (DNR) ORDERS
When a patient suffers a cardiopulmonary arrest, cardiopulmonary re-
suscitation (CPR) is initiated unless a DNR order has been made. Al-
though CPR can restore people to vigorous health, it can also disrupt a
peaceful death. After CPR is attempted on a general hospital service,
only 14% of patients survive to discharge, and even fewer in certain
subgroups. DNR orders are appropriate if the patient or surrogate re-
quests them or if CPR would be futile. To prevent misunderstandings,
physicians should write DNR orders and the reasons for them in the
medical record. “Slow” or “show” codes that merely appear to provide
CPR are deceptive and therefore unacceptable. Although a DNR order
signifies only that CPR will be withheld, the reasons that justify DNR
orders may lead to a reconsideration of other plans for care.
ASSISTED SUICIDE AND ACTIVE EUTHANASIA
Proponents of these controversial acts believe that competent, termi-
nally ill patients should have control over the end of life and that phy-
sicians should relieve refractory suffering. Opponents assert that such
actions violate the sanctity of life, that suffering can generally be re-
lieved, that abuses are inevitable, and that such actions are outside the
physician’s proper role. These actions are illegal throughout the United
States, except that physician-assisted suicide is legal in Oregon under
restricted circumstances. Whatever their personal views, physicians
should respond to patients’ inquiries about these actions with com-
passion and concern. Physicians should elicit and address any under-
lying problems, such as physical symptoms, loss of control, or
depression. Often, additional efforts to relieve distress are successful,
and after this is done patients generally withdraw their requests for
these acts.
CARE OF DYING PATIENTS
Patients often suffer unrelieved pain and other symptoms during their
final days of life. Physicians may hesitate to order high doses of narcot-
ics and sedatives, fearing they will hasten death. Relieving pain in ter-
minal illness and alleviating dyspnea when patients forego mechanical
ventilation enhances patient comfort and dignity. If lower doses of
narcotics and sedatives have failed to relieve suffering, 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, not hasten death. Such palliative sedation is distin-
guished ethically and legally from active euthanasia, which is adminis-
tering a lethal dose with the intention of ending the patient’s life.
Physicians can also relieve suffering by spending time with dying pa-
tients, listening to them, and attending to their psychological distress.
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 hospi-
tals. The ethical ideal is to keep the patient’s interests paramount. Even
the appearance of a conflict of interest may undermine trust in the
profession.
FINANCIAL INCENTIVES
In managed care systems, physicians may serve as gatekeepers or
bear financial risk for expenditures. Although such incentives are in-
tended to reduce inefficiency and waste, there is concern that physi-
cians may withhold beneficial care in order to control costs. In
contrast, physicians have incentives to provide more care than indi-
cated when they receive fee-for-service reimbursement or when they
refer patients to laboratory or imaging facilities in which they have
invested. Regardless of financial incentives, physicians should recom-
mend available care that is in the patient’s best interests, no more
and no less.
GIFTS FROM PHARMACEUTICAL COMPANIES
Physicians may be offered gifts ranging from pens and notepads to lav-
ish entertainment. Critics contend that any gift from drug companies
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
can impair objectivity, increase the cost of health care, and give the ap- e21
pearance of conflict of interest. A helpful rule of thumb is to consider
whether patients would approve of the gift if they knew physicians had
CHAPTER e4
accepted it.
OCCUPATIONAL RISKS
Some health care workers, fearing fatal occupational infections,
refuse to care for persons with HIV infection or multidrug-resistant
tuberculosis. Such fears about personal safety need to be acknowl-
edged, and health care institutions should reduce occupational risk
by providing proper training, protective equipment, and supervi-
Ethical Issues in Clinical Medicine
sion. To fulfill their mission of helping patients, physicians should
provide appropriate care within their clinical expertise, despite some
personal risk.
MEDICAL ERRORS
Errors are inevitable in clinical medicine. They may cause serious
harm to patients or result in substantial changes in management. Phy-
sicians and students may fear that disclosing such errors could damage
their careers. Without disclosure, however, patients cannot understand
their clinical situation or make informed choices about subsequent
care. Furthermore, patients are often outraged when physicians do not
acknowledge errors. Similarly, unless attending physicians are in-
formed of trainees’ errors, they cannot provide optimal care and help
trainees learn from mistakes.
LEARNING CLINICAL SKILLS
Learning clinical medicine, particularly learning to perform invasive
procedures, may present inconvenience or risk to patients. To ensure
patient cooperation, students may be introduced as physicians or pa-
tients may not be told that trainees will be performing procedures.
Such misrepresentation undermines trust, may lead to more elaborate
deception, and makes it difficult for patients to make informed choices
about their care. Patients should be told who is providing care, what
benefits and burdens can be attributed to trainees, and how trainees
are supervised. Most patients, when informed, allow trainees to play
an active role in their care.
IMPAIRED PHYSICIANS
Physicians may hesitate to intervene when colleagues impaired by al-
cohol abuse, drug abuse, or psychiatric or medical illness place pa-
tients at risk. However, society relies on physicians to regulate
themselves. If colleagues of an impaired physician do not take steps to
protect patients, no one else may be in a position to do so.
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, avoiding misrepresentation of their role, and reporting im-
paired colleagues. Discussing such dilemmas with more senior physi-
cians can help trainees check their interpretation of the situation and
obtain advice and assistance.
ALLOCATING RESOURCES JUSTLY
Patient access to needed care is a moral aspiration rather than estab-
lished public policy in the United States. Physicians caring for under-
served populations must act ethically in a health care system that has
serious ethical shortcomings in access to and quality of care. Some pa-
tients with a clear need for medical care cannot pay for medications,
tests, or hospitalizations, or the insurer may deny coverage. If this oc-
curs, physicians should advocate for patients, trying to help them ob-
tain essential care. Doctors might consider, or patients might request,
using lying or deception to help them gain such benefits. While physi-
cians understandably want to help patients, such misrepresentation
undermines physicians’ credibility and trustworthiness. Avoiding de-
ception is a basic ethical guideline that sets limits on advocating for
patients. Allocation of health care resources is unavoidable because re-
 e22 sources are limited. Ideally, allocation decisions should be made as
public policy, with physician input. Allocation of resources at the bed-
side is problematic because it may be inconsistent, unfair, and ineffec-
tive. At the bedside, physicians generally should act as patient
PART 1
advocates within constraints set by society, reasonable insurance cov-
erage, and evidence-based practice. For example, a patient’s insurer
may have a higher co-payment for non-formulary drugs. It is reason-
able for physicians to advocate for non-formulary drugs only if there
are compelling reasons for an exception, as when the formulary drugs
are ineffective or not tolerated.
Introduction to Clinical Medicine
ASSISTANCE WITH ETHICAL ISSUES
Discussing perplexing ethical issues with other members of the health
care team, colleagues, or the hospital ethics committee often clarifies is-
sues and suggests ways to improve communication and to deal with
strong emotions. When struggling with difficult ethical issues, physi-
cians may need to reevaluate their basic convictions, tolerate uncertain-
ty, and maintain their integrity while respecting the opinions of others.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
FURTHER READINGS
BEAUCHAMP TL, CHILDRESS JF: Principles of Biomedical Ethics, 5th ed.
New York, Oxford University Press, 2001
BERG JW et al: Informed Consent: Legal Theory and Clinical Practice, 2d
ed. New York, Oxford University Press, 2001
CHIONG W: Justifying patient risks associated with medical education.
JAMA 298:1046, 2007
KITE S, WILKINSON S: Beyond futility: To what extent is the concept of
futility useful in clinical decision-making about CPR? Lancet Oncol
3:638, 2002
LO B: Resolving Ethical Dilemmas: A Guide for Clinicians, 3d ed. Balti-
more, Lippincott Williams & Wilkins, 2005
LO B et al: Discussing palliative care with patients. Ann Intern Med
130:744, 1999
MEISEL A: The Right to Die, 2d ed. New York, John Wiley & Sons,
1995
SNYDER L, LEFFLER C: Ethics and Humans Rights Committee of the
American College of Physicians. Ethics Manual: Fifth Edition. Ann
Intern Med 142:560, 2005
 e23

e5 Atlas of Rashes Associated

with Fever
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 pre-

CHAPTER e5
sents high-quality images of a variety of rashes that have an infectious
etiology and are commonly associated with fever.

Atlas of Rashes Associated with Fever

FIGURE e5-3 In measles, discrete erythematous lesions become con-
fluent on the face and neck over 2–3 days as the rash spreads down-
ward 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 Kop-
lik’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.

 e24
PART 2

FIGURE e5-5 Exanthem subitum occurs most commonly in young

children. A diffuse maculopapular exanthem follows resolution of fe-
ver. (Photo courtesy of Stephen E. Gellis, MD; with permission.)
Cardinal Manifestations and Presentation of Diseases
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 FIGURE e5-9 Rose spots are evident as erythematous macules on the
from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, trunk of this patient with typhoid fever.
5th ed. New York, McGraw-Hill, 2005.)

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 con-
fluent, distributed symmetrically on the trunk and extremities. Ampicil-
lin 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.
 e25

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.)

Atlas of Rashes Associated with Fever

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.)

FIGURE e5-12 Discoid lupus erythematosus. Violaceous, hyperpig-

mented, atrophic plaques, often with evidence of follicular plugging
(which may result in scarring), are characteristic of this cutaneous form FIGURE e5-15 Erysipelas is a streptococcal infection of the superficial
of lupus. (Courtesy of Marilynne McKay, MD; with permission.) dermis and consists of well-demarcated, erythematous, edematous,
warm plaques.

FIGURE e5-13 The rash of Still’s disease typically exhibits evanescent, er-
ythematous 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.
 e26
PART 2

FIGURE e5-18 Secondary syphilis demonstrating the papulosqua-

mous truncal eruption.
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 pa-
tient. Bottom: Close-up of lesions from the same patient. (Photos cour-
tesy of Lindsey Baden, MD; with permission.)

FIGURE e5-19 Secondary syphilis commonly affects the palms and

soles with scaling, firm, red-brown papules.

FIGURE e5-17 Primary syphilis with a firm, nontender chancre.

FIGURE e5-20 Condylomata lata are moist, somewhat verrucous in-

tertriginous plaques seen in secondary syphilis.

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

 e27

CHAPTER e5
FIGURE e5-21 Mucous patches on the tongue of a patient with sec-

Atlas of Rashes Associated with Fever

ondary syphilis. (Courtesy of Ron Roddy; with permission.)

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.

 e28
PART 2

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
FIGURE e5-25 Erythema multiforme is characterized by multiple ery- Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Dermatology, 5th ed.
thematous plaques with a target or iris morphology and usually represents New York, McGraw-Hill, 2005.)
a hypersensitivity reaction to drugs or infections (especially herpes simplex
virus). (Courtesy of the Yale Resident’s Slide Collection; with permission.)
Cardinal Manifestations and Presentation of Diseases

FIGURE e5-28 Diffuse erythema and scaling are present in this patient
with psoriasis and the exfoliative erythroderma syndrome. (Re-
FIGURE e5-26 Scarlet fever exanthem. Finely punctuated erythema printed from K Wolff, RA Johnson: Color Atlas & Synopsis of Clinical Derma-
has become confluent (scarlatiniform); accentuation of linear ery- tology, 5th ed. New York, McGraw-Hill, 2005.)
thema 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.)

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

 e29

CHAPTER e5
FIGURE e5-31 Numerous
varicella lesions at vari-
ous stages of evolution:
vesicles on an erythema-
tous base, umbilical vesi-
cles, and crusts. (Courtesy
of R. Hartman; with per-
mission.)

Atlas of Rashes Associated with Fever

FIGURE e5-29 This infant with staphylococcal scalded skin syn-
drome 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 le-

sions 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 zos-
ter is seen in this HIV-infected
patient as hemorrhagic vesi-
cles and pustules on an ery-
thematous 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 e5-35 Ecthyma gangrenosum in a neutropenic patient with

Pseudomonas aeruginosa bacteremia.

FIGURE e5-36 Urticaria showing characteristic discrete and confluent,

edematous, erythematous papules and plaques.

FIGURE e5-34 Top: Eschar at the site of the mite bite in a patient with
rickettsialpox. Middle: Papulovesicular lesions on the trunk of the
same patient. Bottom: Close-up of lesions from the same patient. (Re-
printed from A Krusell et al: Emerg Infect Dis 8:727, 2002. Photos obtained
by Kenneth M. Kaye, MD.)

FIGURE e5-37 Disseminated cryptococcal infection. A liver trans-

plant recipient developed six cutaneous lesions similar to the one
shown. Biopsy and serum antigen testing demonstrated Cryptococcus.
Important features of the lesion include a benign-appearing fleshy
papule with central umbilication resembling molluscum contagio-
sum. (Photo courtesy of Lindsey Baden, MD; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e31

CHAPTER e5
FIGURE e5-38 Disseminated candidiasis. Tender, erythematous,
nodular lesions developed in a neutropenic patient with leukemia
who was undergoing induction chemotherapy. (Photo courtesy of Lind-
sey Baden, MD; 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. (Courtesy of Robert Swerlick, MD; with permission.)

FIGURE e5-39 Disseminated Aspergillus infection. Multiple necrotic

lesions developed in this neutropenic patient undergoing hematopoi-
etic stem cell transplantation. The lesion in the photograph is on the
inner thigh and is several centimeters in diameter. Biopsy demon-
strated infarction caused by Aspergillus fumigatus. (Courtesy of Lindsey
Baden, MD; with permission.)
FIGURE e5-41 Sweet’s syndrome: an erythematous indurated plaque
with a pseudovesicular border. (Courtesy of Robert Swerlick, MD; with
permission.)

FIGURE e5-42 Fulminant meningococcemia with extensive angular

purpuric patches. (Courtesy of Stephen E. Gellis, MD; with permission.)

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

 e32

FIGURE e5-46 The thumb of a patient with a necrotic ulcer of tulare-

mia. (From the Centers for Disease Control and Prevention.)
PART 2

FIGURE e5-43 Erythematous papular lesions are seen on the leg of this
patient with chronic meningococcemia. (Courtesy of Kenneth M.
Kaye, MD, and Elaine T. Kaye, MD; with permission.)
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. Tula-
remia was diagnosed. (Courtesy of Lindsey Baden, MD; with permission.)

FIGURE e5-44 Disseminated gonococcemia in the skin is seen as

hemorrhagic papules and pustules with purpuric centers in a centrifu-
gal distribution. (Courtesy of Daniel M. Musher, MD; with permission.)

FIGURE e5-45 Palpable purpuric papules on the lower legs are seen in
this patient with cutaneous small-vessel vasculitis. (Courtesy of
Robert Swerlick, MD; with permission.)

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

 tive memory is supported by evidence that episodic and semantic e33

e6 Memory Loss
Thomas D. Bird, Bruce L. Miller
memory have distinctive anatomic substrates.

Episodic Memory In the MTL, the hippocampal formation receives

processed sensory information from association areas in the frontal,
Memory allows us to store, retain, and retrieve information. These parietal, and occipital lobes via the parahippocampal cortex. Given
three processes influence and are modified by the type of information these multiple cortical neuroanatomical connections, the hippocampus
that is to be remembered, the duration of time over which it must be is well placed to create associations between simultaneously occurring
retained, and the way in which the brain will use the information in stimuli in our sensory world. Key structures involved with episodic
the future. The neural circuits underlying these processes are dynamic, memory include the hippocampus, entorhinal cortex, mammillary
reflecting the flexibility of memory itself. To delineate the neural cir- bodies, and thalamus. Alterations of episodic memory can be devastat-
cuitry underlying it, it is helpful to break down memory into simpler ing. Overly intense or painful episodic memories can result in posttrau-

CHAPTER e6
components. This categorization, however, need not lead to the as- matic stress disorder, a devastating illness in which patients repeatedly
sumption that memory is not a unitary phenomenon. reexperience unpleasant episodes from their lives. By contrast, loss of
episodic memories, as in Alzheimer’s disease (AD), will prevent the in-
dividual from learning new things about the world and will eventually
LONG-TERM MEMORY strip away the old memories that constitute a life biography.
In an effort to explain why focal brain damage affects some aspects of Given its anatomic placement and architecture, the hippocampus has
memory but not others, a fundamental distinction has been made be- the unique ability to bind together “what happened,” “when it hap-
tween declarative memory, which refers to the conscious memory for pened,” and “where it happened.” The architecture of the hippocampus

Memory Loss
facts and events, and nondeclarative memory, which refers to memory includes a circular pathway of neurons from the entorhinal cortex to the
for skills, habits, or other manifestations of learning that can be ex- dentate gyrus and CA3 and CA1 neurons of the hippocampus to the
pressed without awareness of what was learned (Fig. e6-1). Patients subiculum and back to the entorhinal cortex. This pathway is heavily
with bilateral medial temporal lobe (MTL) damage show declarative damaged in AD. Individual elements of episodic memories are perma-
memory deficits in the face of intact nondeclarative memory. For ex- nently stored within the same neocortical regions that are involved in
ample, such a patient may learn to play the piano, over time, without initial processing and analyzing of sensory information (neocortex).
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. of a given memory, and all regions participate together in the creation of
a complete memory representation. The hippocampal formation, then,
DECLARATIVE MEMORY is saddled with the task of binding together these different regional con-
Within the declarative memory system, episodic and semantic memory tributions into a coherent memory trace. The connections within the
can be distinguished. Episodic memory allows the recollection of hippocampal formation and between the MTL and neocortical regions
unique personal experiences. With episodic memory, the person reex- are formed more rapidly than are the connections between disparate
periences the sights, sounds, smells, and other details of a specific cortical regions. Therefore, when a particular cue in the environment or
event. Many episodic memories are kept for minutes and hours but the mental state of the person activates cells in the cortical regions, the
soon discarded. Others remain for the course of a lifetime. This tem- MTL network that is associated with that cue is reactivated and the entire
poral difference in storage probably reflects different physiologic pro- neocortical representation is strengthened. As multiple reactivations oc-
cesses at work (see below). Semantic memory, in contrast, refers to cur, the connections between the relevant neocortical regions are slowly
knowledge about the world; 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.
details of the time when the words or facts were remembered. One’s While the MTL learns quickly and has a limited capacity for storage,
vocabulary and knowledge of the associations between verbal concepts the neocortex learns slowly and has a very large storage capacity. In
make up the bulk of semantic memory. This fractionation of declara- both regions, learning occurs via Hebbian synapses, whereby “cells that
fire together, wire together.” With repeated acti-
vations, memories become “consolidated” in the
neocortex and, therefore, independent of the
MTL. This process, by which the burden of long-
term (permanent) memory storage is gradually
assumed by the neocortex, ensures that the MTL
system is constantly available for the acquisition
of new information. Recent evidence, however,
points to the hippocampus as serving a critical
function in the retrieval of detailed episodic
memories, regardless of the age of the memory.
Injury anywhere along this septohippocam-
pal pathway can lead to severe loss of episodic
memory. Patients with injury to this system will
exhibit anterograde amnesia, an inability to
commit new information to memory. Memories
that were established before the injury (remote
memories) tend to be relatively preserved, al-
though a retrograde amnesia, going back any-
where from minutes to years, is usually evident.
Larger lesions cause a more extensive retrograde
memory deficit. Also, as brain injury improves
over time, the retrograde memory impairment
FIGURE e6-1 Fractionation of long-term memory. (Adapted from LR Squire, SM Zola: Proc tends to diminish, and the temporal gradient for
Natl Acad Sci U S A, 24: 13515, 1996.) memory loss shrinks.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e34 The most common cause for entorhinal dysfunction is AD, which
begins in the entorhinal cortex and then spreads to the hippocampus.
A common mechanism for hippocampal dysfunction is traumatic in-
jury because the hippocampi sit adjacent to, and are easily pushed
against, bone in the middle cranial fossa. The hippocampus, particu-
larly the CA1 and subicular region, is very sensitive to metabolic in-
sults, including hypoxia, hypoglycemia, and prolonged seizures.
Vascular infarction can occur with occlusion of the hippocampal
branches off the posterior cerebral arteries. Infections, in particular
herpes simplex encephalitis, can selectively attack the medial temporal
regions, leading to severe and permanent deficits in episodic memory.
Additionally, severe loss of episodic memory can also be due to dys-
function in the mammillothalamic memory system. The amnesia of
Korsakoff ’s syndrome is due to injury from hemorrhage into the
PART 2
mammillary bodies and dorsomedial nuclei of the thalamus. Further-
more, recent studies of patients with stroke in the left dorsomedial nu-
cleus of the thalamus suggest that injury here alone will precipitate a
severe amnesia. Finally, tumors can injure the septum, fornix, or me-
dial temporal lobes, leading to amnesia.
Emotion plays a key role in enhancing the ability to remember per-
Cardinal Manifestations and Presentation of Diseases
sonal episodes and other information encoded in a particular affective
state. Emotionally charged events are more easily remembered than
emotionally neutral episodes, and highly vivid “flashbulb” memories
are often laid down during traumatic or emotional events; sometimes
during positive but often during negative events. In humans, the
amygdala modulates memory processes during emotional experiences.
One simple way to test episodic memory is to ask the patient to re-
call recent events such as what he did on the last big holiday, what is go-
ing on in the news, or what she had for breakfast. With regard to
personal episodic memories, it is always necessary to have a historian
who can verify that the recent memories are correct (not confabulated).
Semantic Memory Unlike episodic memory, the recall of semantic
memory does not lead to the retrieval of details of when, or where, the
information was acquired. For example, 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. Semantic memo-
ry is composed of a complex hierarchy of knowledge about the world.
Knowing that a fork is generally used for eating depends on under-
standing that in certain social situations, eating with only our hands is
inappropriate, and that some foods are more easily eaten with a fork
than another available utensil, such as a spoon. While a fork may be
useful in many different situations, our semantic hierarchy reminds us
that its main function is to facilitate eating. These ideas are held to-
gether in the semantic memory system, which spans across the associ-
ation areas of the neocortex. Therefore, if we are in a situation that
requires using a fork as a tool in a novel manner, we can still call upon
our semantic memory system to aid us in solving the problem.
Evidence that semantic memories are independent of the septohip-
pocampal and mamillothalamic memory systems comes from humans
with injury to these systems who maintain access to semantic knowl-
edge despite profound deficits in episodic memory. In contrast, pa-
tients with primarily anterior and lateral temporal lobe damage show
intact episodic memory but impaired semantic memory. 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 episod-
ic memory.
In semantic dementia, a syndrome associated with neurodegenera-
tive disease that begins in the anterior temporal lobes, both the simple
labeling process (naming) and knowledge about the identity of people
and objects are lost. Patients with semantic dementia classify objects
into increasingly superordinate categories, having lost access to specific
exemplars. Hence, a hawk becomes a “hunting bird,” then a “bird,” then
an “animal,” and then a “thing” as the disease worsens. Eventually all
objects are classified with a series of simple stereotyped phrases. Bilat-
eral anterior temporal dysfunction is the anatomic substrate of seman-
tic dementia, a subtype of the frontotemporal lobar degenerations.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Aside from semantic dementia, the other disorders that lead to this syn-
drome include limbic encephalitis, associated with viral or paraneo-
plastic processes, and herpes simplex encephalitis.
Bedside assessment of semantic memory is difficult, 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.
NONDECLARATIVE MEMORY
Nondeclarative memory is an umbrella term for a heterogeneous collec-
tion of nonconscious memory abilities that involve multiple distinct
neural regions, including the amygdala, basal ganglia, cerebellum, and
sensory cortex (Fig. e6-1). Procedural memory is one type of nondeclar-
ative memory. The difference between declarative memory and proce-
dural memory is the difference between “knowing that” and “knowing
how.” Procedural learning describes the formation of skills and habits.
Because it requires extensive practice, it is a slow and inflexible learning
system that eventually takes on an automatic or reflexive quality. It is,
however, long-lasting and reliable: even after years of absence from a bi-
cycle, a bike rider does not lose the skill entirely.
Procedural memory involves motor, perceptual, and cognitive pro-
cesses. For example, flipping pancakes is a motor skill, a parent’s atten-
tiveness to his or her baby’s cry in a distant room involves perceptual
learning, and increasing alacrity in solving Sudoku puzzles with prac-
tice requires cognitive skills. While declarative memory can, in some
cases, enhance or hasten the acquisition of skills and habits, conscious
awareness of learning is not necessary; once the information is ac-
quired, it often becomes difficult to verbalize how it was learned. Cog-
nitive psychologists have shown that in some cases, declarative
memory processes can hinder nondeclarative learning, suggesting that
there are times when the two memory “systems” may compete for cog-
nitive resources.
The forms of perceptual and motor learning that can occur without
conscious recollections are mediated in part by contractions and ex-
pansions of representations in the sensory and motor cortex. One
study, for example, has shown that the cortical representation of the
fingers of the left hand of musical string players is larger than that in
nonmusicians, 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. Discrete cortical regions exist in the anterior temporal
lobes in which object knowledge (such as words related to color, ani-
mals, tools, or action) is organized as a distributed system. Here the at-
tributes of an object are stored close to the regions of the cortex that
mediate perception of those attributes.
Recent research now points to the basal ganglia as fundamental in
motor skill learning, while the cerebellum is involved in the associa-
tion of a visual cue with a motor action. Parkinson’s disease (PD)
causes damage to the basal ganglia and is associated with impair-
ments in habit learning but spares declarative memory. The basal
ganglia project to and receive projections from the frontal cortex, and
this corticostriatal loop has been implicated in the learning of skills
and habits. Furthermore, 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. That is, basal ganglia activity is
negatively correlated with MTL activity when both systems are en-
gaged by a particular task.
Bedside testing of nondeclarative memory is outside the realm of the
generalist, but deficits may be reported by patients or their families.
MOLECULAR AND NEUROCHEMICAL BASIS OF LONG-TERM MEMORY
Long-term potentiation (LTP), which refers to a long-lasting enhance-
ment of synaptic transmission resulting from repetitive stimulation of
excitatory synapses, is presumed to be involved in episodic memory ac-
quisition and storage. 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. Animal experiments have
shown that the formation of new episodic memories leads to physio-
logic changes in the synapse, while longer-term memory requires new
protein synthesis and leads to physical changes at neuronal synapses.
The cholinergic system also plays an important role in memory,
and anticholinergic agents such as atropine and scopolamine interfere
with memory. Choline acetyltransferase (the enzyme catalyzing the
formation of acetylcholine) is known to be deficient in the cortex of
patients with AD. The brains of AD patients show severe neuronal loss
in the nucleus basalis of Meynert, the major source of cholinergic in-
put to the cerebral cortex. These findings form the basis for the use of
cholinesterase inhibitors in the treatment of AD, with benefits thought
to arise from increased levels of available acetylcholine. Behavior and
mood are modulated by noradrenergic, serotonergic, and dopaminer-
gic pathways, and norepinephrine has been shown to be reduced in the
brainstem locus coeruleus in AD. Also, neurotrophins are postulated
to play a role in memory in part by preserving cholinergic neurons.
GABA agonists including the benzodiazepines are associated with re-
versible but sometimes severe episodes of amnesia. Working memory
(see below) is strongly modulated by dopamine.
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, another major division
of memory has used time as the distinguishing characteristic. While
some information is retained for only a few seconds—enough time to
hear, remember and dial a phone number—other memories are seem-
ingly remembered throughout a life span. This brief type of memory
differs from long-term memory, not only in terms of duration of reten-
tion but also with regard to its function and neuroanatomy.
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.e., rotated or integrated with existing informa-
tion in semantic memory). The capacity of working memory is limited
by attention. Normal individuals can hold about seven (plus or minus
two) “bits” of information in working memory; these bits can be manip-
ulated and either discarded or associated and transferred into long-term
memory. Working memory is highly vulnerable to distraction and some-
times is even called working attention to emphasize the conscious and
effortful processes that it entails. In the most widely accepted conceptu-
alization of working memory, there are four main components: (1) a
central executive that keeps track of and gathers information; (2) a visual
system called the visuospatial scratchpad, which holds visual representa-
tions of objects; (3) a phonologic “system” that holds verbal information;
and (4) an episodic buffer that is capable of binding together informa-
tion from different modalities into a coherent trace.
Lesions that disrupt the structure or function of the dorsolateral
frontal or posterior parietal regions decimate working memory. These
deficits in working memory have a profound effect on the organism by
disrupting the learning process downstream to working memory, or
by affecting activities that directly depend on an intact working mem-
ory. In the classic amnesic syndrome, patients have intact working
memory but cannot transfer information from working memory into
long-term store.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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. These neurons appear to provide an im-
portant functional basis for working memory. Similarly, functional
imaging studies from humans show that the dorsolateral frontal lobes,
particularly Brodmann area 46, are critical for working memory.
TESTING MEMORY AT THE BEDSIDE
Testing of memory should be performed in anyone in whom memory
deficits are a concern, whether these concerns are raised by the patient,
family, or health care workers. If the deficits are subtle, the testing may
CHAPTER e6
require a comprehensive consultation with a neuropsychologist, neu-
ropsychiatrist, or behavioral neurologist. However, memory testing can
be an extremely valuable component of the neurologic examination and
performed effectively at the bedside. There are a wide variety of brief
standardized screens of cognition, but the most commonly used test is
the Mini Mental Status Examination (Table 365-5), a 30-point test that
is strongly dependent on working (spell “world” backwards) and epi-
sodic memory (orientation and three-word recall). Testing semantic and
Memory Loss
procedural memory is usually outside the realm of the generalist, but if
deficits in these systems are suspected, further tests are warranted.
Of all the memory processes, working memory is perhaps the easiest
to assess at the bedside. The most common bedside test of working
memory involves asking patients to repeat a series of digits orally, with
the clinician gradually increasing the number of to-be-retained digits.
There are two ways of administering the test. Asking the patient to re-
peat the digits in the same order as they were delivered is called digit
span forward. In contrast, the clinician may also ask the patient to repeat
the digits in reverse order, called digit span backward. Digit span forward
is a test of attention, while digit span backward is a simple probe of
working memory. The capacity for digit span forward is typically six
numbers, while normal adults can generally repeat five digits backward.
FURTHER READINGS
BADDELEY A: Working memory: Looking back and looking forward.
Nat Rev Neurosci 4:829, 2003
EICHENBAUM H et al: The medial temporal lobe and recognition
memory. Ann Rev Neurosci 30:123, 2007
GILBOA A et al: Retrieval of autobiographical memory in Alzheimer’s
disease: Relation to volumes of medial temporal lobe and other
structures. Hippocampus 15:535, 2005
NADEL L, MOSCOVITCH M: Memory consolidation, retrograde amne-
sia and the hippocampal complex. Curr Opin Neurobiol 7:217,
1997
PACKARD MG, KNOWLTON BJ: Learning and memory functions of the
basal ganglia. Annu Rev Neursci 25:563, 2002
PERRY RJ, HODGES JR: Spectrum of memory dysfunction in degenera-
tive disease. Curr Opin Neurol 9:281, 1996
POLDRACK RA et al: Interactive memory systems in the human brain.
Nature 414:546, 2001
SQUIRE LR, ZOLA-MORGAN S: The medial temporal lobe memory sys-
tem. Science 253:1380, 1991
——— et al: The medial temporal lobe. Annu Rev Neurosci 27:279,
2004
 e37

e7 Atlas of Oral Manifestations

of Disease
Samuel C. Durso, Janet A. Yellowitz, Jane C. Atkinson

The health status of the oral cavity is linked to cardiovascular disease,

diabetes, and other systemic illnesses. Thus, there is significant clinical
value in examining the oral cavity for signs of disease. This chapter
presents numerous outstanding clinical photographs illustrating many
of the conditions discussed in Chap. 32, Oral Manifestations of Dis-

CHAPTER e7
ease. Conditions affecting the teeth, periodontal tissues, and oral mu-
cosa are all represented.

Atlas of Oral Manifestations of Disease

FIGURE e7-3 Erosive lichen planus.

FIGURE e7-1 Gingival overgrowth secondary to calcium channel blocker

use.

FIGURE e7-4 Stevens-Johnson syndrome—reaction to nevirapine.

FIGURE e7-2 Oral lichen planus.

FIGURE e7-5 Inflamed palate.

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

 e38
PART 2

FIGURE e7-6 Severe periodontitis.

Cardinal Manifestations and Presentation of Diseases

FIGURE e7-7 Angular cheilitis.

FIGURE e7-8 Sublingual leukoplakia.

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

 e39

CHAPTER e7
Atlas of Oral Manifestations of Disease
FIGURE e7-9 A. Epulis (gingival hypertrophy) under denture. B. Epulis fissuratum.

FIGURE e7-10 Traumatic lesion inside of cheek. FIGURE e7-12 Oral carcinoma.

FIGURE e7-11 Sublingual keratosis. FIGURE e7-13 Healthy mouth.

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

 e40
PART 2

FIGURE e7-17 Heavy calculus and gingival inflammation.

FIGURE e7-14 Geographic tongue.

Cardinal Manifestations and Presentation of Diseases

FIGURE e7-18 Severe gingival inflammation and heavy calculus.

FIGURE e7-15 Moderate gingivitis.

FIGURE e7-19 Heavy plaque and gingival inflammation.

FIGURE e7-16 Gingival recession.

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

 e41

CHAPTER e7
FIGURE e7-23 Salivary stone.
FIGURE e7-20 Ulcer on lateral border of tongue—potential carcinoma.

Atlas of Oral Manifestations of Disease

FIGURE e7-24 A. Calculus. B. Teeth cleaned.

FIGURE e7-21 Osteonecrosis.

FIGURE e7-25 Traumatic ulcer.

FIGURE e7-22 Severe periodontal disease, missing tooth, very mobile

teeth.

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

 e42
PART 2

FIGURE e7-26 Fissured tongue.

Cardinal Manifestations and Presentation of Diseases

FIGURE e7-27 White coated tongue—likely candidiasis.

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


e8 Approach to the Patient
with a Heart Murmur
Patrick T. O’Gara, Eugene Braunwald
The differential diagnosis of a heart murmur begins with a careful as-
sessment of its major attributes and response to bedside maneuvers.
The history, clinical context, and associated findings provide addition-
al clues by which the significance of a heart murmur is established.
Following completion of these initial steps, noninvasive testing can be
pursued to clarify any remaining ambiguity and to provide additional
anatomic and physiologic information that will impact patient man-
agement. Accurate bedside identification of a heart murmur can also
inform decisions regarding referral to a cardiovascular specialist, the
indications for antibiotic or rheumatic fever prophylaxis, and the need
to restrict various forms of physical activity.
Heart murmurs are caused by audible vibrations that are due to in-
creased turbulence from accelerated blood flow through normal or ab-
normal orifices; flow through a narrowed or irregular orifice into a
dilated vessel or chamber; or backward flow through an incompetent
valve, ventricular septal defect, or patent ductus arteriosus. They are
traditionally defined in terms of their timing within the cardiac cycle
(Fig. e8-1). Systolic murmurs begin with or after the first heart sound
(S1) and terminate at or before the component (A2 or P2) of the sec-
ond heart sound (S2) that corresponds to their side of origin (left or
right, respectively). Diastolic murmurs begin with or after the associat-
ed component of S2 and end at or before the subsequent S1. Continu-
ous murmurs are not confined to either phase of the cardiac cycle, but
rather begin in early systole and proceed through S2 into all or part of
diastole. The accurate timing of heart murmurs is the first step in their
identification. The distinction between S1 and S2, and therefore systole
and diastole, is usually a straightforward process, but can be difficult
in the setting of a tachyarrhythmia, in which case the heart sounds can
be distinguished by simultaneous palpation of the carotid arterial
pulse. The upstroke should closely follow S1.
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, the left ventricle and the aorta, the right ventricle
and the pulmonary artery, or the great vessels. The magnitude and vari-
ability of this pressure difference dictate the velocity of flow; the degree
of turbulence; and the resulting frequency, configuration, and intensity
of the murmur. The diastolic murmur of chronic aortic regurgitation
(AR) is a blowing, high-frequency event, whereas the murmur of mitral
stenosis (MS), indicative of the left atrial–left ventricular diastolic pres-
sure gradient, is a low-frequency event, heard as a rumbling sound with
the bell of the stethoscope. The frequency components of a heart mur-
mur may vary at different sites of auscultation. The coarse systolic mur-
mur of aortic stenosis (AS) may sound higher-pitched and more
acoustically pure at the apex, a phenomenon eponymously referred to as
the Gallavardin effect. Some murmurs may have a distinct or unusual
quality, such as the “honking” sound appreciated in some patients with
mitral regurgitation (MR) due to mitral valve prolapse (MVP).
The configuration of a heart murmur may be crescendo, decrescen-
do, crescendo-decrescendo, or plateau. The decrescendo configuration
of the murmur of chronic AR (Fig. e8-1E) can be understood in terms
of the progressive decline in the diastolic pressure gradient between
the aorta and the left ventricle. The crescendo-decrescendo configura-
tion of the murmur of AS reflects the changes in the systolic pressure
gradient between the left ventricle and the aorta as ejection occurs,
whereas the plateau configuration of the murmur of chronic rheumat-
ic MR (Fig. e8-1B) is consistent with the large and nearly constant
pressure difference between the left ventricle and the left atrium.
Intensity The intensity of a heart murmur is graded on a scale of 1–6
(or I–VI). A grade 1 murmur is very soft and is heard with great effort.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
S1 S2 e43
A
B
C
A2
CHAPTER e8
P2
D
E
OS
Approach to the Patient with a Heart Murmur
F
S3
G
H
FIGURE e8-1 Diagram depicting principal heart murmurs. A. Pre-
systolic murmur of mitral or tricuspid stenosis. B. Holosystolic (pansys-
tolic) murmur of mitral or tricuspid regurgitation or of ventricular
septal defect. C. Aortic ejection murmur beginning with an ejection
click and fading before the second heart sound. D. Systolic murmur in
pulmonic stenosis spilling through the aortic second sound, pulmonic
valve closure being delayed. E. Aortic or pulmonary diastolic murmur.
F. Long diastolic murmur of mitral stenosis following the opening
snap. G. Short mid-diastolic inflow murmur following a third heart
sound. H. Continuous murmur of patent ductus arteriosus. (Adapted
from P Wood, Diseases of the Heart and Circulation, London, Eyre & Spot-
tiswood, Ltd.,1968.)
A grade 2 murmur is easily heard, but not particularly loud. A grade 3
murmur is loud, but is not accompanied by a palpable thrill over the
site of maximal intensity. A grade 4 murmur is very loud and accom-
panied by a thrill. A grade 5 murmur is loud enough to be heard with
only the edge of the stethoscope touching the chest, whereas a grade 6
murmur is loud enough to be heard with the stethoscope slightly off the
chest. 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. Small ventricular septal defects (VSDs), for ex-
ample, are accompanied by loud, usually grade 4 or greater, systolic
murmurs as blood is ejected at high velocity from the left to the right
ventricle. Low velocity events, such as left-to-right shunting across an
atrial septal defect (ASD), are usually silent. The intensity of a heart
murmur may also be diminished by any process that increases the dis-
tance between the intracardiac source and the stethoscope on the chest
wall, such as obesity, obstructive lung disease, and a large pericardial
effusion. The intensity of a murmur may also be misleadingly soft
when cardiac output is significantly reduced.
Location and Radiation Recognition of the location and radiation of
the murmur helps facilitate its accurate identification (Fig. e8-2). Ad-
ventitious sounds, such as a systolic click or diastolic snap, or abnor-
malities of S1 or S2, may provide additional clues. Careful attention to
the characteristics of the murmur and other heart sounds during the
 e44 TABLE e8-1 PRINCIPAL CAUSES OF HEART MURMURS
Systolic Murmurs

Early systolic
Aortic Pulm Mitral
Acute MR
VSD
Muscular
VSD Nonrestrictive with pulmonary hypertension
MR Tricuspid
TR with normal pulmonary artery pressure
Vibratory
Mid-systolic
HCM Aortic
Obstructive
Supravalvular—supravalvular aortic stenosis, coarctation of the aorta
PART 2

FIGURE e8-2 Maximal intensity and radiation of six isolated sys- Valvular—AS and aortic sclerosis
tolic murmurs. HOCM, hypertrophic obstructive cardiomyopathy; Subvalvular—discrete, tunnel or HOCM
MR, mitral regurgitation; Pulm, pulmonary stenosis; Aortic, aortic ste- Increased flow, hyperkinetic states, AR, complete heart block
nosis; VSD, ventricular septal defect. (From JB Barlow, Perspectives on the Dilatation of ascending aorta, atheroma, aortitis
Mitral Valve. Philadelphia, FA Davis, 1987, p 140.) Pulmonary
Obstructive
Supravalvular—pulmonary artery stenosis
respiratory cycle and the performance of simple bedside maneuvers Valvular–pulmonic valve stenosis
Cardinal Manifestations and Presentation of Diseases

when indicated complete the auscultatory examination. These fea- Subvalvular–infundibular stenosis (dynamic)
tures, and recommendations for further testing, are discussed below in Increased flow, hyperkinetic states, left-to-right shunt (e.g., ASD)
the context of specific systolic, diastolic, and continuous heart mur- Dilatation of pulmonary artery
murs (Table e8-1). Late systolic
Mitral
MVP, acute myocardial ischemia
SYSTOLIC HEART MURMURS Tricuspid
Early Systolic Murmurs Early systolic murmurs begin with S1 and ex- TVP
tend for a variable period of time, ending well before S2. Their causes Holosystolic
are relatively few in number. Acute severe MR into a normal-sized, rel- Atrioventricular valve regurgitation (MR, TR)
atively noncompliant left atrium results in an early, decrescendo sys- Left-to-right shunt at ventricular level (VSD)
tolic murmur best heard at or just medial to the apical impulse. These Early Diastolic Murmurs
characteristics reflect the progressive attenuation of the pressure gradi-
ent between the left ventricle and the left atrium during systole due to Aortic regurgitation
Valvular: congenital (bicuspid valve), rheumatic deformity, endocarditis,
the rapid rise in left atrial pressure caused by the sudden volume load prolapse, trauma, post-valvulotomy
into an unprepared chamber, and contrast sharply with the ausculta- Dilatation of valve ring: aorta dissection, annulo-aortic ectasia, cystic
tory features of chronic MR. Clinical settings in which acute, severe medial degeneration, hypertension, ankylosing spondylitis
MR occur include: (1) papillary muscle rupture complicating acute Widening of commissures: syphilis
myocardial infarction (MI) (Chap. 239), (2) rupture of chordae Pulmonic regurgitation
tendineae in the setting of myxomatous mitral valve disease (MVP, Valvular: post-valvulotomy, endocarditis, rheumatic fever, carcinoid
Dilatation of valve ring: pulmonary hypertension; Marfan syndrome
Chap. 230), (3) infective endocarditis (Chap. 118), and (4) blunt chest Congenital: isolated or associated with tetralogy of Fallot, VSD, pulmonic
wall trauma. stenosis
Acute, severe MR from papillary muscle rupture usually accompa-
Mid-Diastolic Murmurs
nies an inferior, posterior, or lateral MI and occurs 2–7 days after pre-
sentation. It is often signaled by chest pain, hypotension, and Mitral
pulmonary edema, but a murmur may be absent in up to 50% of cas- Mitral stenosis
es. The posteromedial papillary muscle is involved six to ten times Carey-Coombs murmur (mid-diastolic apical murmur in acute rheumatic
more frequently than the anterolateral papillary muscle. The murmur fever)
Increased flow across nonstenotic mitral valve (e.g., MR, VSD, PDA, high-
is to be distinguished from that associated with post-MI ventricular
output states, and complete heart block)
septal rupture, which is accompanied by a systolic thrill at the left ster- Tricuspid
nal border in nearly all patients and is holosystolic in duration. A new Tricuspid stenosis
heart murmur following MI is an indication for transthoracic echo- Increased flow across nonstenotic tricuspid valve (e.g., TR, ASD, and
cardiography (TTE) (Chap. 222), which allows bedside delineation of anomalous pulmonary venous return)
its etiology and pathophysiologic significance. The distinction be- Left and right atrial tumors (myxoma)
Severe AR (Austin Flint murmur)
tween acute MR and ventricular septal rupture can also be achieved
with right heart catheterization, sequential determination of oxygen Continuous Murmurs
saturations, and analysis of the pressure waveforms (tall v wave in the
Patent ductus arteriosus Proximal coronary artery stenosis
pulmonary artery wedge pressure in MR). Post-MI mechanical com- Coronary AV fistula Mammary souffle of pregnancy
plications of this nature mandate aggressive medical stabilization and Ruptured sinus of Valsalva aneurysm Pulmonary artery branch stenosis
prompt referral for surgical repair. Aortic septal defect Bronchial collateral circulation
Spontaneous chordal rupture can complicate the course of myx- Cervical venous hum Small (restrictive) ASD with MS
omatous mitral valve disease (MVP) and result in new-onset or “acute Anomalous left coronary artery Intercostal AV fistula
on chronic” severe MR. MVP may occur as an isolated phenomenon Note: AR, aortic regurgitation; AS, aortic stenosis; ASD, atrial septal defect; AV, arterio-
or the lesion may be part of a more generalized connective tissue dis- venous; HOCM, hypertrophic obstructive cardiomyopathy; MR, mitral regurgitation;
order as seen, for example, in patients with Marfan syndrome. Acute MS, mitral stenosis; MVP, mitral valve prolapse; PDA, patent ductus arteriosus; TR, tri-
severe MR as a consequence of infective endocarditis results from de- cuspid regurgitation; TVP, tricuspid valve prolapse; VSD, ventricular septal defect.
struction of leaflet tissue, chordal rupture, or both. Blunt chest wall Source: E Braunwald, JK Perloff, in D Zipes et al (eds): Braunwald’s Heart Disease, 7th
ed. Philadelphia, Elsevier, 2005; PJ Norton, RA O’Rourke, in E Braunwald, L Goldman
trauma is usually self-evident, but may be disarmingly trivial. It can
(eds): Primary Cardiology, 2d ed. Philadelphia, Elsevier, 2003.
result in papillary muscle contusion and rupture, chordal detachment,
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
or leaflet avulsion. TTE is indicated in all cases of suspected acute se-
vere MR to define its mechanism and severity, delineate left ventricu-
lar size and systolic function, and provide an assessment of suitability
for primary valve repair.
A congenital, small muscular VSD (Chap. 229) may be associated
with an early systolic murmur. The defect closes progressively during
septal contraction and thus the murmur is confined to early systole. It
is localized to the left sternal border (Fig. e8-2) and is usually of grade
4 or 5 intensity. Signs of pulmonary hypertension or left ventricular
volume overload are absent. Anatomically large and uncorrected VSDs,
which usually involve the membranous portion of the septum, may
lead to pulmonary hypertension. The murmur associated with the
left-to-right shunt, which may earlier have been holosystolic, becomes
limited to the first portion of systole as the elevated pulmonary vascu-
lar resistance leads to an abrupt rise in right ventricular pressure and
an attenuation of the interventricular pressure gradient during the re-
mainder of the cardiac cycle. In such instances, signs of pulmonary hy-
pertension (right ventricular lift, loud and single or closely split S2)
may predominate. The murmur is best heard along the left sternal
border but is softer. Suspicion of a VSD is an indication for TTE.
Tricuspid regurgitation (TR) with normal pulmonary artery pres-
sures, as may occur with infective endocarditis, may produce an early
systolic murmur. The murmur is soft (grade 1 or 2), best heard at the
lower left sternal border, and may increase in intensity with inspira-
tion (Carvallo’s sign). Regurgitant “c-v” waves may be visible in the
jugular venous pulse. TR in this setting is not associated with signs of
right heart failure.
Mid-Systolic Murmurs Mid-systolic murmurs begin at a short interval
following S1, end before S2 (Fig. e8-1C), and are usually crescendo-de-
crescendo in configuration. Aortic stenosis is the most common cause
of a mid-systolic murmur in an adult. The murmur of AS is usually
loudest to the right of the sternum in the second intercostal space
(aortic area, Fig. e8-2) and radiates into the carotids. Transmission of
the mid-systolic murmur to the apex, where it becomes higher
pitched, is common (Gallavardin effect, see above).
Differentiation of this apical systolic murmur from MR can be diffi-
cult. The murmur of AS will increase in intensity, or become louder, in
the beat following a premature beat, whereas the murmur of MR will
remain of constant intensity from beat to beat. The intensity of the AS
murmur also varies directly with the cardiac output. With a normal
cardiac output, a systolic thrill and grade 4 or higher murmur suggest
severe AS. The murmur is softer in the setting of heart failure and low
cardiac output. Other auscultatory findings of severe AS include a soft
or absent A2, paradoxical splitting of S2, an apical S4, and a late-peak-
ing systolic murmur. In children, adolescents, and young adults with
congenital valvular AS, an early ejection sound (click) is usually audi-
ble, more often along the left sternal border than at the base. Its pres-
ence signifies a flexible, noncalcified bicuspid valve (or one of its
variants) and localizes the left ventricular outflow obstruction to the
valvular (rather than sub- or supravalvular) level.
Assessment of the volume and rate of rise of the carotid pulse can
provide additional information. A small and delayed upstroke (parvus
et tardus) is consistent with severe AS. The carotid pulse examination
is less discriminatory, however, in older patients with stiffened arter-
ies. The electrocardiogram (ECG) shows signs of left ventricular hy-
pertrophy (LVH) as the severity of the stenosis increases. TTE is
indicated to assess the anatomic features of the aortic valve, the severi-
ty of the stenosis, left ventricular size, wall thickness and function, and
the size and contour of the aortic root and proximal ascending aorta.
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. 231, Fig. e8-2). The murmur is produced by both dynam-
ic left ventricular outflow tract obstruction and MR, and thus its con-
figuration is a hybrid between ejection and regurgitant phenomena.
The intensity of the murmur may vary from beat to beat, and follow-
ing provocative maneuvers, but usually does not exceed grade 3. The
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Supine e45
S1
S2
C
Standing
CHAPTER e8
S1
S2
C
Squatting
Approach to the Patient with a Heart Murmur
S1
S2
C
FIGURE e8-3 A mid-systolic nonejection sound (C) occurs in mi-
tral valve prolapse and is followed by a late systolic murmur that
crescendos to the second heart sound (S2). Standing decreases
venous return; the heart becomes smaller; C moves closer to the first
heart sound (S1) and the mitral regurgitant murmur has an earlier on-
set. With prompt squatting, venous return increases; the heart be-
comes larger; C moves toward S2, and the duration of the murmur
shortens. (From JA Shaver, JJ Leonard, DF Leon, Examination of the Heart,
Part IV, Auscultation of the Heart. Dallas, American Heart Association,
1990, p 13. Copyright, American Heart Association.)
murmur will classically increase in intensity with maneuvers that re-
sult in increasing degrees of outflow tract obstruction, such as a reduc-
tion in preload or afterload (Valsalva, standing, vasodilators) or to an
augmentation of contractility (inotropic stimulation). Maneuvers that
increase preload (squatting, passive leg raising, volume administra-
tion) or afterload (squatting, vasopressors) or that reduce contractility
(β-adrenoreceptor blockers) decrease the intensity of the murmur. In
rare patients, there may be reversed splitting of S2. A sustained left
ventricular apical impulse and an S4 may be appreciated. In contrast to
AS, the carotid upstroke is rapid and of normal volume. Rarely, it is
bisferiens or bifid in contour (see Fig. 220-2D) due to mid-systolic
closure of the aortic valve. LVH is present on the ECG and the diagno-
sis is confirmed by TTE. 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. e8-3), these two le-
sions 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.
The mid-systolic, crescendo-decrescendo murmur of congenital
pulmonic stenosis (PS, Chap. 229), is best appreciated in the second
and third left intercostal spaces (pulmonic area) (Figs. e8-2 and e8-4).
The duration of the murmur lengthens and the intensity of P2 dimin-
ishes with increasing degrees of valvular stenosis (Fig. e8-1D). An ear-
ly ejection sound, the intensity of which decreases with inspiration, is
heard in younger patients. A parasternal lift and ECG evidence of right
ventricular hypertrophy indicate severe pressure overload. If obtained,
the chest x-ray may show poststenotic dilatation of the main pulmo-
nary artery. TTE is recommended for complete characterization.
Significant left-to-right intracardiac shunting due to an ASD (Chap.
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
 e46 Pulmonic stenosis Tetralogy of Fallot
S1 S2 S1 S2
A2
P.Ej
S1 S2 S1 S2
A2 P2 A2
PART 2
P.Ej
S1 S2 S1 S2
S4
A2 P2 A.Ej A2
Cardinal Manifestations and Presentation of Diseases
P.Ej = Pulmonary ejection (valvular) A.Ej = Aortic ejection (root)
FIGURE e8-4 Left. In valvular pulmonic stenosis with intact ventricular
septum, right ventricular systolic ejection becomes progressively
longer, with increasing obstruction to flow. As a result, the murmur
becomes longer and louder, enveloping the aortic component of the
second heart sound (A2). The pulmonic component (P2) occurs later,
and splitting becomes wider but more difficult to hear because A2 is
lost in the murmur and P2 becomes progressively fainter and lower
pitched. As the pulmonic gradient increases, isometric contraction
shortens until the pulmonary valvular ejection sound fuses with the
first heart sound (S1). In severe pulmonic stenosis with concentric hy-
pertrophy and decreasing right ventricular compliance, a fourth heart
sound appears. Right. In tetralogy of Fallot with increasing obstruc-
tion at pulmonic infundibular area, an increasing amount of right ven-
tricular blood is shunted across the silent ventricular septal defect and
flow across the obstructed outflow tract decreases. Therefore, with in-
creasing obstruction the murmur becomes shorter, earlier, and fainter.
P2 is absent in severe tetralogy of Fallot. A large aortic root receives al-
most all cardiac output from both ventricular chambers, and the aorta
dilates and is accompanied by a root ejection sound that does not
vary with respiration. (From JA Shaver, JJ Leonard, DF Leon, Examination
of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart As-
sociation, 1990, p 45. Copyright, American Heart Association.)
splitting of S2. Ostium secundum ASDs are most common. 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. With sinus venosus ASDs, the left-to-right shunt is
usually not large enough to result in a systolic murmur, though the
ECG may show abnormalities of sinus node function. 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.
A pulmonary ejection sound is present. TTE is indicated to evaluate a
grade 2 or 3 mid-systolic murmur when there are other signs of cardi-
ac disease.
An isolated grade 1 or 2 midsystolic murmur, heard in the absence
of symptoms or signs of heart disease, is most often a benign finding
for which no further evaluation, including TTE, is necessary. The most
common example of a murmur of this type in an older adult patient is
the crescendo-decrescendo murmur of aortic valve sclerosis, heard at
the second right interspace (Fig. e8-2). Aortic sclerosis is defined as fo-
cal thickening and calcification of the aortic valve to a degree that does
not interfere with leaflet opening. The carotid upstrokes are normal
and electrocardiographic LVH is not present. A grade 1 or 2 mid-sys-
tolic murmur can often be heard at the left sternal border with preg-
nancy, hyperthyroidism, or anemia, physiologic states that are
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
associated with accelerated blood flow. Still’s murmur refers to a be-
nign grade 2, vibratory mid-systolic murmur at the lower left sternal
border in normal children and adolescents (Fig. e8-2).
Late Systolic Murmurs A late systolic murmur that is best heard at the
left ventricular apex is often due to MVP (Chap. 230). Often, this mur-
mur is introduced by one or more nonejection clicks. The radiation of
P2
the murmur can help identify the specific mitral leaflet involved in the
process of prolapse or flail. The term flail refers to the movement made
by an unsupported portion of the leaflet after loss of its chordal attach-
ment(s). With posterior leaflet prolapse or flail, the resultant jet of MR
is directed anteriorly and medially, as a result of which the murmur ra-
diates to the base of the heart and masquerades as AS. Anterior leaflet
prolapse or flail results in a posteriorly directed MR jet that radiates to
the axilla or left infrascapular region. Leaflet flail is associated with a
murmur of grade 3 or 4 intensity that can be heard throughout the
precordium in thin-chested patients. The presence of an S3 or a short,
rumbling mid-diastolic murmur, signifies severe MR.
Bedside maneuvers that decrease left ventricular preload, such as
standing, will cause the click and murmur of MVP to move closer to
the first heart sound, as leaflet prolapse occurs earlier in systole. Stand-
ing also causes the murmur to become louder and longer. With squat-
ting, left ventricular preload and afterload are increased abruptly, and
the click and murmur move away from the first heart sound, as leaflet
prolapse is delayed. The murmur becomes softer and shorter in dura-
tion (Fig. e8-3). As noted above, these responses to standing and
squatting are similar to those observed in patients with HOCM.
A late, apical systolic murmur indicative of MR may be heard tran-
siently in the setting of acute myocardial ischemia. It is due to apical
tethering and malcoaptation of the leaflets in response to structural
and functional changes of the ventricle and mitral annulus. The inten-
sity of the murmur varies as a function of left ventricular afterload and
will increase in the setting of hypertension. TTE is recommended for
assessment of late systolic murmurs.
Holosystolic Murmurs (Figs. e8-1B and e8-5) Holosystolic murmurs
begin with S1 and continue through systole to S2. They are usually in-
dicative of chronic mitral or tricuspid valve regurgitation or a VSD,
and warrant TTE for further characterization. The holosystolic mur-
mur of chronic MR is best heard at the left ventricular apex and radi-
ates to the axilla (Fig. e8-2). It is usually high pitched and plateau in
configuration because of the wide difference between left ventricular
and left atrial pressure throughout systole. In contrast to acute MR,
left atrial compliance is normal or even increased in chronic MR. As a
result, there is only a small increase in left atrial pressure for any in-
crease in regurgitant volume.
There are several conditions associated with chronic MR and an
apical holosystolic murmur, including rheumatic scarring of the leaf-
lets, mitral annular calcification, and severe left ventricular chamber
enlargement. 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. 231). The
severity of the MR is worsened by any contribution from apical dis-
placement of the papillary muscles and leaflet tethering. Because the
mitral annulus is contiguous with the left atrial endocardium, gradual
enlargement of the left atrium from chronic MR will result in further
stretching of the annulus and more MR and thus, “MR begets MR.”
Chronic severe MR results in enlargement and leftward displacement
of the left ventricular apex beat and, in some patients, a diastolic filling
complex as described previously.
The holosystolic murmur of chronic TR is generally softer than that
of MR, is loudest at the left lower sternal border, and usually increases
in intensity with inspiration (Carvallo’s sign). Associated signs include
“c-v” waves in the jugular venous pulse, an enlarged and pulsatile liver,
ascites, and peripheral edema. The abnormal jugular venous wave
forms are the predominant finding and are very often seen in the ab-
sence of an audible murmur, despite Doppler echocardiographic veri-
fication of TR. Causes of primary TR include myxomatous disease
 e47
Onset with S1 terminates at or beyond S2

Maximum intensity over Maximum intensity over left sternal Maximum intensity over
apex border lower left third and
Radiation to axilla or Radiation to epigastrium and right fourth interspace
base sternal border Widespread radiation,
A 2 not heard over apex Increased intensity during inspiration palpable thrill
Decreased intensity Prominent cv wave with sharp y Decreased intensity
with amyl nitrate descent in jugular venous pulse with amyl nitrate
No change in intensity
during inspiration

CHAPTER e8
Mitral regurgitation Tricuspid regurgitation Wide splitting of S2

Hyperdynamic left Sustained left Prominent left parasternal Sustained systolic left Favors ventricular
ventricular impulse ventricular impulse diastolic impulse parasternal impulse septal defect;
Wide splitting of S2 Single S2 or narrow Normal brief left paraster- Narrow splitting of S2 often difficult to
splitting of S2 nal systolic impulse with marked increase differentiate from
Normal P2 in intensity of P2 mitral regurgitant
Rarely paradoxical S2 murmur

Approach to the Patient with a Heart Murmur

Primary mitral Secondary mitral Primary Secondary to
regurgitation (e.g., regurgitation (dilated pulmonary
rheumatic, ruptured cardiomyopathy; papillary hypertension
chordae) muscle dysfunction, or
late stage of primary
mitral regurgitation)

FIGURE e8-5 Differential diagnosis of a holosystolic murmur. S1, sound. [From C Chatterjee, in K Chatterjee et al (eds): Cardiology: An illus-
first heart sound; S2, second heart sound; A2, aortic component of the trated Text/Reference, Philadelphia, Lippincott, 1991, with permission.]
second heart sound; P2, pulmonic component of the second heart

(prolapse), endocarditis, rheumatic disease, carcinoid, Ebstein’s anom-
aly, and chordal detachment following the performance of right ven-
tricular endomyocardial biopsy. TR is more commonly a passive
process that results secondarily from chronic elevations of pulmonary
artery and right ventricular pressures, leading to right ventricular en-
largement, annular dilatation, papillary muscle displacement, and fail-
ure of leaflet coaptation.
The holosystolic murmur of a VSD is loudest at the mid- to lower
left sternal border (Fig. e8-2) and radiates widely. A thrill is present at
the site of maximal intensity in the majority of patients. There is no
change in the intensity of the murmur with inspiration. The intensity
of the murmur varies as a function of the anatomic size of the defect.
Small, restrictive VSDs, as exemplified by the maladie de Roger, create a
very loud murmur due to the significant and sustained systolic pres-
sure gradient between the left and right ventricles. With large defects,
the ventricular pressures tend to equalize, shunt flow is balanced, and
a murmur is not appreciated. The distinction between post-MI ven-
tricular septal rupture and MR has been reviewed previously.
DIASTOLIC HEART MURMURS
Early Diastolic Murmurs (Fig. e8-1E) Chronic AR results in a high-
pitched, blowing, decrescendo, early to mid-diastolic murmur that be-
gins following the aortic component of S2 (A2) and is best heard at the
second right interspace (Fig. e8-6). The murmur may be soft and diffi-
cult to hear, unless auscultation is performed with the patient leaning
forward at end-expiration. This maneuver brings the aortic root closer
to the anterior chest wall. Radiation of the murmur may provide a clue
as to the cause of the AR. With primary valve disease, such as that due
to congenital bicuspid disease, prolapse, or endocarditis, the diastolic
murmur tends to radiate along the left sternal border. When AR is
caused by aortic root disease, the diastolic murmur may radiate along
the right sternal border. Diseases of the aortic root cause dilatation or
distortion of the aortic annulus and failure of leaflet coaptation. Caus-
es include Marfan syndrome with aneurysm formation, annulo-aortic
ectasia, ankylosing spondylitis, and aortic dissection.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Chronic, severe AR may also produce a lower pitched mid- to late,
grade 1 or 2 diastolic murmur at the apex (Austin Flint murmur),
which is thought to reflect turbulence at the mitral inflow area from
the admixture of regurgitant (aortic) and forward (mitral) blood flow
(Fig. e8-1G). This lower pitched apical diastolic murmur can be dis-
tinguished from that due to MS by the absence of an opening snap and
the response of the murmur to a vasodilator challenge. Lowering after-
load with an agent such as amyl nitrite will decrease the duration and
magnitude of the aortic–left ventricular diastolic pressure gradient,
and thus the Austin Flint murmur of severe AR will become shorter
and softer. The intensity of the diastolic murmur of mitral stenosis
(Fig. e8-7) may either remain constant or increase with afterload re-
duction because of the reflex increase in cardiac output and mitral
valve flow.
Although AS and AR may coexist, a grade 2 or 3 crescendo-decre-
scendo mid-systolic murmur is frequently heard at the base of the
heart in patients with isolated severe AR, and is due to an increased
volume and rate of systolic flow. Accurate bedside identification of co-
existent AS can be difficult, unless the carotid pulse examination is ab-
normal or the mid-systolic murmur is of grade 4 or greater intensity.
In the absence of heart failure, chronic severe AR is accompanied by
several peripheral signs of significant diastolic run-off, including a
wide pulse pressure, a water-hammer carotid upstroke (Corrigan’s
pulse), and Quincke’s pulsations of the nail beds. The diastolic mur-
mur of acute severe AR (Fig. e8-6) is notably shorter in duration and
lower pitched than the murmur of chronic AR. It can be very difficult
to appreciate in the presence of a rapid heart rate. These attributes re-
flect the abrupt rate of rise of diastolic pressure within the unprepared
and noncompliant left ventricle, and the correspondingly rapid de-
cline in the aortic–left ventricular diastolic pressure gradient. Left ven-
tricular diastolic pressure may increase sufficiently to result in
premature closure of the mitral valve and a soft first heart sound. Pe-
ripheral signs of significant diastolic run-off are absent.
Pulmonic regurgitation (PR) results in a decrescendo, early to mid-
diastolic murmur (Graham Steell murmur) that begins after the pul-
 e48 Aortic Regurgitation of the murmur increases during maneuvers that increase
cardiac output and mitral valve flow, such as exercise.
Chronic Acute
The duration of the murmur reflects the length of time
SEM SEM over which left atrial pressure exceeds left ventricular
pressure. An increase in the intensity of the murmur just
Base before S1, a phenomenon known as pre-systolic accentua-
tion (Figs. e8-1A, e8-7), occurs in patients in sinus
rhythm and is due to a late increase in transmitral flow
S1 S2 S1 S1 S2 S1 with atrial contraction. Pre-systolic accentuation does
not occur in patients with atrial fibrillation.
S3 S3
The mid-diastolic murmur associated with tricuspid
Apex stenosis is best heard at the lower left sternal border and
AF AF increases in intensity with inspiration. A prolonged y de-
scent may be visible in the jugular venous wave form.
PART 2

FIGURE e8-6 Contrast between the auscultatory findings in chronic and acute This murmur is very difficult to hear and often obscured
aortic regurgitation. In chronic aortic regurgitation, a prominent systolic ejection by left-sided acoustical events.
murmur resulting from the large forward stroke volume is heard at the base and the There are several other causes of mid-diastolic mur-
apex and ends well before the second heart sound (S2). The aortic diastolic regur- murs. Large left atrial myxomas may prolapse across the
gitant murmur begins with S2 and continues in a decrescendo fashion, terminating mitral valve and cause variable degrees of obstruction to
before the first heart sound (S1). At the apex, the mid-diastolic component of Austin left ventricular inflow (Chap. 233). The murmur associ-
Flint murmur (AF) is introduced by a prominent third heart sound (S3). A pre-systolic ated with an atrial myxoma may change in duration and
Cardinal Manifestations and Presentation of Diseases

component of the AF is also heard. In acute aortic regurgitation there is a significant intensity with changes in body position. 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 accentua-
chronic aortic regurgitation because of the decreased forward stroke volume. S1 is tion. Augmented mitral diastolic flow can occur with
markedly decreased in intensity because of premature closure of the mitral valve, 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 early di- the ventricular or great vessel level and produce a soft,
astolic murmur at the base ends well before S1 because of equilibration of the left rapid filling sound (S ) followed by a short, low-pitched
3
ventricle and aortic end-diastolic pressure. Significant tachycardia is usually present. mid-diastolic apical murmur. The Austin Flint murmur
(From JA Shaver: Heart Dis Stroke 2:100, 1994.) of severe, chronic AR has already been described.
A short mid-diastolic murmur is rarely heard during
monic component of S2 (P2), is best heard at the second left inter- an episode of acute rheumatic fever (Carey-Coombs murmur) and is
space, and radiates along the left sternal border. The intensity of the due to enhanced flow through an edematous mitral valve. An opening
murmur may increase with inspiration. 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- resolution of the acute attack. Complete heart block with dyssynchro-
nary artery pressure. Signs of pulmonary hypertension, including a nous atrial and ventricular activation may be associated with intermit-
right ventricular lift and a loud, single or narrowly split S2, are present. tent mid- to-late diastolic murmurs if atrial contraction occurs when
These features also help distinguish PR from AR as the cause of a de- the mitral valve is partially closed. Mid-diastolic murmurs indicative
crescendo diastolic murmur heard along the left sternal border. PR in of increased tricuspid valve flow can occur with severe, isolated TR
the absence of pulmonary hypertension can occur with endocarditis and with large ASDs and significant left-to-right shunting. Other signs
or a congenitally deformed valve. It is usually present following
repair of tetralogy of Fallot in childhood. When pulmonary hy-
pertension is not present, the diastolic murmur is softer and Diastolic Filling Murmur (Rumble)
lower pitched than the classic Graham Steell murmur, and the Mitral Stenosis
examiner can be misled as to the severity of the PR. S1 S2 S1 S2
TTE is indicated for the further evaluation of the patient O.S. O.S.
with an early to mid-diastolic murmur. Longitudinal assess- Mild
ment of the severity of the valve lesion and ventricular size and
systolic function help guide the decision for surgical manage- A2 P2 A2 P2
ment. TTE can also provide anatomic information regarding
the root and proximal ascending aorta, though computed to- ECG
mographic or magnetic resonance angiography may be indicat- S1 S2 S1 S2
ed for more precise characterization (Chap. 222). O.S. O.S.

Mid-Diastolic Murmurs (Figs. e8-1G and e8-1H) Mid-diastolic
murmurs result from obstruction and/or augmented flow at the
level of the mitral or tricuspid valve. Rheumatic fever is the
most common cause of MS (Fig. e8-7). In younger patients with
pliable valves, S1 is loud and the murmur begins after an open-
ing snap, which is a high-pitched sound that occurs shortly after
S2. The distance between the pulmonic component of the sec-
ond heart sound (P2) and the opening snap is inversely related
to the magnitude of the left atrial to left ventricular pressure
gradient. The murmur of MS is low pitched and thus is best
heard with the bell of the stethoscope. It is loudest at the left
ventricular apex and often only appreciated when the patient is
turned in the left lateral decubitus position. It is usually of grade
1 or 2 intensity, but may be absent when the cardiac output is
severely reduced despite significant obstruction. The intensity
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Severe
A2 P2 A2 P2
FIGURE e8-7 Diastolic filling murmur (rumble) in mitral stenosis. In mild
mitral stenosis, the diastolic gradient across the valve is limited to the two
phases of rapid ventricular filling in early diastole and pre-systole. The rumble
may occur during either or both periods. As the stenotic process becomes se-
vere, a large pressure gradient exists across the valve during the entire dia-
stolic filling period, and the rumble persists throughout diastole. As the left
atrial pressure becomes greater, the interval between A2 and the opening
snap shortens. In severe mitral stenosis, secondary pulmonary hypertension
develops and results in a loud P2 and the splitting interval usually narrows.
ECG, electrocardiogram. (From JA Shaver, JJ Leonard, DF Leon, Examination of
the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association,
1990, p 55. Copyright, American Heart Association.)
 Continuous Murmur vs. To-Fro Murmur TABLE e8-2 DYNAMIC AUSCULTATION: BEDSIDE MANEUVERS THAT e49
S1 S2 S1 S2
CAN BE USED TO CHANGE THE INTENSITY OF CARDIAC
MURMURS (SEE TEXT)
Continuous murmur 1. Respiration
2. Isometric exercise (handgrip)
3. Transient arterial occlusion
S1 S2 S1 S2 4. Pharmacologic manipulation of preload and/or afterload
5. Valsalva maneuver
6. Rapid standing/squatting
To-fro murmur 7. Post-premature beat

FIGURE e8-8 Comparison of the continuous murmur and the to-fro

murmur. During abnormal communication between high-pressure and
low-pressure systems, a large pressure gradient exists throughout the car-
diac cycle, producing a continuous murmur. A classic example is patent
ductus arteriosus. At times, this type of murmur can be confused with a to-
fro murmur, which is a combination of systolic ejection murmur and a mur-
mur of semilunar valve incompetence. A classic example of a to-fro murmur
is aortic stenosis and regurgitation. A continuous murmur crescendos to
around the second heart sound (S2), whereas a to-fro murmur has two com-
CHAPTER e8
Respiration Auscultation should be performed during quiet
respiration or with a modest increase in inspiratory effort, as
more forceful movement of the chest tends to obscure the heart
sounds. Left-sided murmurs may be best heard at end-expira-
tion, when lung volumes are minimized and the heart and great
vessels are brought closer to the chest wall. This phenomenon is
characteristic of the murmur of AR. Murmurs of right-sided ori-
gin, such as tricuspid or pulmonic regurgitation, increase in in-

Approach to the Patient with a Heart Murmur

ponents. The mid-systolic ejection component decrescendos and disap- tensity during inspiration. The intensity of left-sided murmurs
pears as it approaches S2. (From JA Shaver, JJ Leonard, DF Leon, Examination either remains constant or decreases with inspiration.
of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Associa- Bedside assessment should also account for the behavior of S2
tion, 1990, p 55. Copyright, American Heart Association.) with respiration and the dynamic relationship between the aortic
and pulmonic components (Fig. e8-9). Reversed splitting can be
a feature of severe AS, HOCM, left bundle branch block, right
of an ASD are present (Chap. 229), including fixed-splitting of S2 and ventricular apical pacing, or acute myocardial ischemia. Fixed splitting
a mid-systolic murmur at the mid- to upper left sternal border. TTE is of S2 in the presence of a grade 2 or 3 mid-systolic murmur at the mid-
indicated for evaluation of the patient with a mid- to late diastolic or upper left sternal border indicates an ASD. Physiologic but wide
murmur. Findings specific to the diseases discussed above will help splitting during the respiratory cycle implies either premature aortic
guide management.
Normal Physiological Splitting
CONTINUOUS MURMURS A2
P2
(Figs. e8-1H and e8-8) Continuous murmurs begin in systole, peak
near the second heart sound, and continue into all or part of diastole.
Their presence throughout the cardiac cycle implies a pressure gradient S1 S2 S1 S2
between two chambers or vessels during both systole and diastole. The
continuous murmur associated with a patent ductus arteriosus is best Audible Expiratory Splitting
heard at the upper left sternal border. Large, uncorrected shunts may Expiration Inspiration
lead to pulmonary hypertension, attenuation or obliteration of the dia-
stolic component of the murmur, reversal of shunt flow, and differential A2 P A2 P
2 2
Wide physiological
cyanosis of the lower extremities. A ruptured sinus of Valsalva aneurysm splitting
creates a continuous murmur of abrupt onset at the upper right sternal
border. Rupture typically occurs into a right heart chamber, and the S1 S2 S1 S2
murmur is indicative of a continuous pressure difference between the
A2 P2 A2
aorta and either the right ventricle or right atrium. A continuous mur- P2
mur may also be audible along the left sternal border with a coronary ar- Reversed splitting
teriovenous fistula and at the site of an arteriovenous fistula used for
hemodialysis access. Enhanced flow through enlarged intercostal collat- S1 S2 S1 S2
eral arteries in patients with aortic coarctation may produce a continu-
ous murmur along the course of one or more ribs. A cervical bruit with A2 P2
Narrow physiological
both systolic and diastolic components (a to-fro murmur, Fig. e8-8)
splitting (↑P2)
usually indicates a high-grade carotid artery stenosis.
Not all continuous murmurs are pathologic. A continuous venous S1 S2 S1 S2
hum can be heard in healthy children and young adults, especially FIGURE e8-9 Top. Normal physiologic splitting. During expiration, the
during pregnancy. It is best appreciated in the right supraclavicular aortic (A2) and pulmonic (P2) components of the second heart sound
fossa and can be obliterated by pressure over the right internal jugular are separated by <30 ms and are appreciated as a single sound. Dur-
vein or by having the patient turn his/her head toward the examiner. ing inspiration, the splitting interval widens, and A2 and P2 are clearly
The continuous mammary souffle of pregnancy is created by en- separated into two distinct sounds. Bottom. Audible expiratory split-
hanced arterial flow through engorged breasts and usually appears ting. Wide physiologic splitting is caused by a delay in P2. Reversed
during the late third trimester or early puerperium. The murmur is splitting is caused by a delay in A2, resulting in paradoxical movement;
louder in systole. Firm pressure with the diaphragm of the stethoscope i.e., with inspiration P2 moves towards A2, and the splitting interval
can eliminate the diastolic portion of the murmur. narrows. Narrow physiologic splitting occurs in pulmonary hyperten-
sion, and both A2 and P2 are heard during expiration at a narrow split-
DYNAMIC AUSCULTATION ting interval because of the increased intensity and high-frequency
(Tables e8-2 and 220-1) Careful attention to the behavior of heart composition of P2. (From JA Shaver, JJ Leonard, DF Leon, Examination of
murmurs during simple maneuvers that alter cardiac hemodynamics the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Associ-
can provide important clues as to their cause and significance. ation, 1990, p 17. Copyright, American Heart Association.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e50 valve closure, as can occur with severe MR, or delayed pulmonic valve
closure due to PS or right bundle branch block.
Alterations of Systemic Vascular Resistance Murmurs can change char-
acteristics following maneuvers that alter systemic vascular resistance and
left ventricular afterload. The systolic murmurs of MR and VSD become
louder during sustained handgrip, simultaneous inflation of blood pres-
sure cuffs on both upper extremities to pressures 20–40 mmHg above sys-
tolic pressure for 20 s, or infusion of a vasopressor agent. The murmurs
associated with AS or HOCM will either become softer or remain un-
changed with these maneuvers. The diastolic murmur of AR becomes
louder in response to interventions that raise systemic vascular resistance.
Opposite changes in systolic and diastolic murmurs may occur with
the use of pharmacologic agents that lower systemic vascular resis-
PART 2
tained earlier and may contain valuable information. A patient with
suspected infective endocarditis, for example, may have a murmur in
the setting of fever, chills, anorexia, fatigue, dyspnea, splenomegaly,
petechiae, and positive blood cultures. A new systolic murmur in a pa-
tient with a marked fall in blood pressure after a recent MI suggests
myocardial rupture. On the other hand, an isolated grade 1 or 2 mid-
systolic murmur at the left sternal border in a healthy, active, and
asymptomatic young adult is most likely a benign finding for which no
further evaluation is indicated. The context in which the murmur is
appreciated often dictates the need for further testing.
ECHOCARDIOGRAPHY
(See Fig. e8-10, Chaps. 220 and 222) Echocardiography with color
flow and spectral Doppler is a valuable tool for the assessment of car-

tance. 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. The former two murmurs increase in intensity, whereas
the latter two become softer after exposure to amyl nitrite. As noted
previously, the Austin Flint murmur of severe AR becomes softer, but
the mid-diastolic rumble of MS becomes louder, in response to the
Cardinal Manifestations and Presentation of Diseases
diac murmurs. Information regarding valve structure and function,
chamber size, wall thickness, ventricular function, estimated pulmo-
nary artery pressures, intracardiac shunt flow, pulmonary and hepatic
vein flow, and aortic flow can be readily ascertained. It is important to
note that Doppler signals of trace or mild valvular regurgitation of no
clinical consequence can be detected with structurally normal tricus-

abrupt lowering of systemic vascular resistance with amyl nitrite.
Changes in Venous Return The Valsalva maneuver results in an in-
crease in intrathoracic pressure, followed by a decrease in venous return,
ventricular filling, and cardiac output. The majority of murmurs de-
crease in intensity during the strain phase of the maneuver. Two notable
exceptions are the murmurs associated with MVP and obstructive
HOCM, both of which become louder during the Valsalva maneuver.
The murmur of MVP may also become longer as leaflet prolapse occurs
earlier in systole at smaller ventricular volumes. These murmurs behave
in a similar and parallel fashion with standing. Both the click and the
murmur of MVP move closer in timing to S1 on rapid standing (Fig. e8-
3). The increase in the intensity of the murmur of HOCM is predicated
on the augmentation of the dynamic left ventricular outflow tract gradi-
ent that occurs with reduced ventricular filling. Squatting results in
abrupt increases in both venous return and left ventricular afterload,
changes that predictably cause a decrease in the intensity and duration
of the murmurs associated with MVP and HOCM. The click and mur-
mur of MVP move away from S1 with squatting.
Post-Premature Ventricular Contraction A change in the intensity of a
systolic murmur in the first beat after a premature beat, or in the beat af-
ter a long cycle length in patients with atrial fibrilla-
tion, can help distinguish AS from MR, particularly
in an older patient in whom the murmur of AS is well
transmitted to the apex. Systolic murmurs due to left
ventricular outflow obstruction, including that due
to AS, increase in intensity in the beat following a
premature beat because of the combined effects of
enhanced left ventricular filling and post-extrasystol-
ic potentiation of contractile function. Forward flow
accelerates, causing an increase in the gradient and a Midsystolic, grade
louder murmur. The intensity of the murmur of MR 2 or less
does not change in the post-premature beat as there is
relatively little further increase in mitral valve flow or
change in the left ventricular to left atrial gradient.
pid, pulmonic, and mitral valves. Such signals are not likely to gener-
ate enough turbulence to create a murmur.
Echocardiography is indicated for the evaluation of patients with
early, late, or holosystolic murmurs, and for patients with grade 3 or
louder mid-systolic murmurs. Patients with grade 1 or 2 mid-systolic
murmurs, but other symptoms or signs of cardiovascular disease, in-
cluding those from ECG or chest x-ray, should also undergo echocar-
diography. 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. Echocardi-
ography should also be considered when there is a clinical need to ver-
ify normal cardiac structure and function in a patient whose
symptoms and signs are likely noncardiac in origin. The performance
of serial echocardiography to follow the course of asymptomatic indi-
viduals with valvular heart disease is a central feature of their longitu-
dinal assessment and provides valuable information that may impact
on decisions regarding the timing of surgery. Routine echocardiogra-
phy is not recommended for asymptomatic patients with a grade 1 or 2
mid-systolic murmur without other signs of heart disease. For this cat-
egory of patients, referral to a cardiovascular specialist should be con-
sidered if doubt exists regarding the significance of the murmur after
the initial examination.
Cardiac murmur
Systolic murmur Diastolic murmur Continuous murmur
• Early systolic
• Midsystolic, grade
3 or more TTE
• Late systolic
• Holosystolic

THE CLINICAL CONTEXT

Additional clues as to the etiology and importance Asymptomatic and Symptomatic or TEE, cardiac MR, • Venous hum
no associated other signs of catheterization if • Mammary souffle
of a heart murmur can be gleaned from the history
findings cardiac disease* appropriate
and other physical examination findings. Symptoms
suggestive of cardiovascular, neurologic, or pulmo-
No further workup
nary disease should help focus the differential diag-
nosis, as should findings relevant to the jugular
venous pressure and wave forms, the arterial pulses, FIGURE e8-10 Strategy for evaluating heart murmurs. *If an electrocardiogram or
other heart sounds, the lungs, abdomen, skin, and chest x-ray has been obtained and is abnormal, echocardiography is indicated. TTE, trans-
extremities. In many instances, laboratory studies, thoracic echocardiography; TEE, transesophageal echocardiography; MR, magnetic reso-
an ECG, and/or a chest x-ray may have been ob- nance. (Adapted from Bonow et al.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 The selective use of echocardiography outlined above has not been
subjected to rigorous cost-effective analysis. At least one study has sug-
gested that initial referral of pediatric patients with heart murmurs to
a specialist results in modest cost savings. For some clinicians, hand-
held or miniaturized cardiac ultrasound devices have replaced the
stethoscope. Although several reports attest to the improved sensitivity
of such devices for the detection of valvular heart disease, accuracy is
highly operator dependent and incremental cost considerations have
not been adequately addressed. The use of electronic or digital stetho-
scopes with spectral display capabilities has also been proposed as a
method to improve the characterization of heart murmurs and the
teaching of cardiac auscultation.
OTHER CARDIAC TESTING
(Chap. 222, Fig. e8-10) In relatively few patients, clinical assessment and
TTE do not adequately characterize the origin and significance of a heart
murmur. Transesophageal echocardiography (TEE) can be considered
for further evaluation, especially when the TTE windows are limited by
body size, chest configuration, or intrathoracic pathology. TEE offers en-
hanced sensitivity for the detection of a wide range of structural cardiac
disorders. Electrocardiographically gated cardiac magnetic resonance
(CMR) imaging, although limited in its ability to display valvular mor-
phology, can provide quantitative information regarding valvular func-
tion, stenosis severity, regurgitant fraction, shunt flow, chamber and
great vessel size, ventricular function, and myocardial perfusion. 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 be-
tween the clinical and echocardiographic findings. Coronary angiogra-
phy is performed routinely in most adult patients prior to valve surgery,
especially when there is a suspicion of coronary artery disease predicated
on symptoms, risk factors, and/or age.
INTEGRATED APPROACH
The accurate identification of a heart murmur begins with a systemat-
ic approach to cardiac auscultation. Characterization of its major at-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
tributes, as reviewed above, allows the examiner to construct a e51
preliminary differential diagnosis, which is then refined by integration
of information available from the history, associated cardiac findings,
the general physical examination, and the clinical context. The need
for and urgency of further testing follow sequentially. Correlation of
the findings on auscultation with the noninvasive data provides an ed-
ucational feedback loop and an opportunity for improving physical
examination skills. Cost constraints mandate that noninvasive imag-
ing be justified on the basis of its incremental contribution to diagno-
sis, treatment, and outcome. Additional study is required to assess the
cost-effective application of newer imaging technology.
CHAPTER e8
FURTHER READINGS
BARRETT MJ et al: Mastering cardiac murmurs: The power of repeti-
tion. Chest 126(2):470, 2004
BONOW RO et al: ACC/AHA 2006 Guidelines for the management of
patients with valvular heart disease: A report of the American Col-
lege of Cardiology/American Heart Association Task Force on
Practice Guidelines (Committee on Management of Patients with
Approach to the Patient with a Heart Murmur
Valvular Heart Disease). American College of Cardiology Web Site.
Available at http://www.acc.org/clinical/guidelines/valvular/index.pdf
CHOUNDHRY NK, ETCHELLS EE: Does this patient have aortic regurgi-
tation? JAMA 281:2231, 1999
ETCHELLS E et al: Does this patient have an abnormal systolic heart
murmur? JAMA 277(7):564, 1997
FANG J, O’GARA P: The history and physical examination, in Braun-
wald’s Heart Disease. A Textbook of Cardiovascular Medicine, 8th ed,
P Libby et al (eds). Philadelphia, Saunders Elsevier, 2008
MURGO JP: Systolic ejection murmurs in the era of modern cardiol-
ogy. What do we really know? J Am Coll Cardiol 32(6):1596, 1998
TAVEL ME: Cardiac auscultation: A glorious past—and it does have a
future! Circulation 113:1255, 2006
VUKANOVIC-CRILEY JM et al: Competency in cardiac examination
skills in medical students, trainees, physicians and faculty: A multi-
center study. Arch Intern Med 166(6):610, 2006
 e53

e9 Atlas of Urinary Sediments

and Renal Biopsies
Agnes B. Fogo, Eric G. Neilson

Key diagnostic features of selected diseases in renal biopsy and urinal-

ysis are illustrated, with light, immunofluorescence, and electron mi-
croscopic images. Common urinalysis findings are also documented.

CHAPTER e9
Atlas of Urinary Sediments and Renal Biopsies
FIGURE e9-1 Minimal change disease. In minimal change disease, light microscopy is unre-
markable (left), while electron microscopy reveals podocyte injury evidenced by complete foot
process effacement. (ABF/Vanderbilt Collection.)

FIGURE e9-2 Focal segmental glomerulosclerosis. There is a well- FIGURE e9-3 Collapsing glomerulopathy. There is segmental col-
defined segmental increase in matrix and obliteration of capillary lapse of the glomerular capillary loops and overlying podocyte hyper-
loops, the sine qua non of segmental sclerosis. (EGN/UPenn Collection.) plasia. This lesion may be idiopathic or associated with HIV infection
and has a particularly poor prognosis. (ABF/Vanderbilt Collection.)

FIGURE e9-4 Postinfectious (poststreptococcal) glomerulone- subepithelial pattern and stain dominantly for C3 and to a lesser ex-
phritis. The glomerular tuft shows proliferative changes with numer- tent for IgG (middle). Subepithelial hump-shaped deposits are seen
ous PMNs, with a crescentic reaction in severe cases (left). These by electron microscopy (right). (ABF/Vanderbilt Collection.)
deposits localize in the mesangium and along the capillary wall in a

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

 e54

FIGURE e9-5 Membranous glomerulopathy. Membranous glomeru- IgG, revealing diffuse granular capillary loop staining (middle). By elec-
lopathy is due to subepithelial deposits, with resulting basement mem- tron microscopy, the subepithelial location of the deposits and early sur-
PART 2

brane reaction, resulting in the appearance of spike-like projections on rounding basement membrane reaction is evident, with overlying foot
silver stain (left). The deposits are directly visualized by fluorescent anti- process effacement (right). (ABF/Vanderbilt Collection.)
Cardinal Manifestations and Presentation of Diseases

FIGURE e9-6 IgA nephropathy. There is variable mesangial expansion due to mesangial de-
posits, with some cases also showing endocapillary proliferation or segmental sclerosis (left). By
immunofluorescence, deposits are evident (right). (ABF/Vanderbilt Collection.)

FIGURE e9-7 Membranoproliferative glomerulonephritis. There is
mesangial expansion and endocapillary proliferation resulting in the
“tram-track” sign of cellular interposition along the glomerular base-
ment membrane. (EGN/UPenn Collection.)
FIGURE e9-8 Dense deposit disease (membranoproliferative glo-
merulonephritis type II). By light microscopy, there is a membrano-
proliferative pattern. By electron microscopy, there is a dense
transformation of the glomerular basement membrane with round,
globular deposits within the mesangium. By immunofluorescence,
only C3 staining is usually present. (ABF/Vanderbilt Collection.)

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

 e55

CHAPTER e9
FIGURE e9-9 Membranoproliferative glomerulonephritis. This spec-
imen shows pink subepithelial deposits with spike reaction and the “tram-
track” sign of reduplication of glomerular basement membrane, resulting
from subendothelial deposits, as may be seen in mixed membranous and
proliferative lupus nephritis (ISN/RPS class V and IV) or membranoprolifer-
ative glomerulonephritis type III. (EGN/UPenn Collection.)

Atlas of Urinary Sediments and Renal Biopsies

FIGURE e9-10 Lupus nephritis. Proliferative lupus nephritis, ISN/RPS
class III or IV, manifests as endocapillary proliferation, which may result
in segmental necrosis due to deposits, particularly in the subendothe-
lial area (left). By immunofluorescence, chunky irregular mesangial
and capillary loop deposits are evident, with some of the peripheral
loop deposits having a smooth, molded outer contour due to their
subendothelial location. These deposits typically stain for all three im-
munoglobulins, IgG, IgA, IgM, and both C3 and C1q (middle). By elec-
tron microscopy, subendothelial, mesangial, and rare subepithelial
dense immune complex deposits are evident, along with extensive
foot process effacement (right). (ABF/Vanderbilt Collection.)

FIGURE e9-11 Wegener’s granulomatosis. This pauci-immune necrotiz-

ing crescentic glomerulonephritis shows numerous breaks in the glomeru-
lar basement membrane with associated segmental fibrinoid necrosis, and
a crescent formed by proliferation of the parietal epithelium. Note that the
uninvolved segment of the glomerulus (at ~5 o’clock) shows no evidence
of proliferation or immune complexes. (ABF/Vanderbilt Collection.)

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

 e56

FIGURE e9-12 Anti-GBM antibody-mediated glomerulonephritis. There is segmental ne-

crosis with a break of the glomerular basement membrane and a cellular crescent (left), and im-
PART 2

munofluorescence for IgG shows linear staining of the glomerular basement membrane with a
small crescent at ~1 o’clock. (ABF/Vanderbilt Collection.)
Cardinal Manifestations and Presentation of Diseases

FIGURE e9-13 Amyloidosis. Amyloidosis shows amorphous, acellular expansion

of the mesangium, with material often also infiltrating glomerular basement mem-
branes, vessels, and in the interstitium, with apple-green birefringence by polar-
ized Congo red stain (left). The deposits are composed of randomly organized
9- to 11-nm fibrils by electron microscopy (right). (ABF/Vanderbilt Collection.)

FIGURE e9-14 Light chain deposition disease. There is mesangial electron microscopy (right), the deposits show an amorphous granu-
expansion, often nodular by light microscopy (left), with immunofluo- lar appearance and line the inside of the glomerular basement mem-
rescence showing monoclonal staining, more commonly with kappa brane and are also found along the tubular basement membranes.
than lambda light chain, of tubules (middle) and glomerular tufts. By (ABF/Vanderbilt Collection.)

FIGURE e9-15 Light chain cast nephropathy (myeloma kidney).

Monoclonal light chains precipitate in tubules and result in a syncytial
giant cell reaction (left) surrounding the cast, and a surrounding
chronic interstitial nephritis with tubulointerstitial fibrosis. (ABF/
Vanderbilt Collection.)

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

 e57

FIGURE e9-16 Fabry’s disease. Due to deficiency of α-galactosidase, there is abnormal accumulation

CHAPTER e9
of glycolipids, resulting in foamy podocytes by light microscopy (left). These deposits can be directly
visualized by electron microscopy (right), where the glycosphingolipid appears as whorled so-called
myeloid bodies, particularly in the podocytes. (ABF/Vanderbilt Collection.)

Atlas of Urinary Sediments and Renal Biopsies

FIGURE e9-17 Alport’s syndrome and thin glomerular basement membrane lesion. In
Alport’s syndrome, there is irregular thinning alternating with thickened so-called basket-weaving
abnormal organization of the glomerular basement membrane (left). In benign familial hematuria,
or in early cases of Alport’s syndrome or female carriers, only extensive thinning of the GBM is seen
by electron microscopy (right). (ABF/Vanderbilt Collection.)

FIGURE e9-18 Diabetic nephropathy. There is nodular mesangial ex-

pansion, so-called Kimmelstiel-Wilson nodules, with increased mesan-
gial matrix and cellularity, microaneurysm formation in the glomerulus
on the left, and prominent glomerular basement membranes without
evidence of immune deposits and arteriolar hyalinosis of both afferent
and efferent arterioles. (ABF/Vanderbilt Collection.)

FIGURE e9-19 Arterionephrosclerosis. Hypertension-associated injury often mani-

fests extensive global sclerosis of glomeruli, with accompanying and proportional tu-
bulointerstitial fibrosis and pericapsular fibrosis, and there may be segmental sclerosis
(left). The vessels show disproportionately severe changes of intimal fibrosis, medial
hypertrophy, and arteriolar hyaline deposits (right). (ABF/Vanderbilt Collection.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e58

FIGURE e9-20 Cholesterol emboli. Cholesterol emboli cause cleft-like FIGURE e9-21 Hemolytic uremic syndrome. There are characteristic
spaces where the lipid has been extracted during processing, with intraglomerular fibrin thrombi, with a chunky pink appearance. The re-
PART 2

smooth outer contours, and surrounding fibrotic and mononuclear maining portion of the capillary tuft shows corrugation of the glomer-
cell reaction in these arterioles. (ABF/Vanderbilt Collection.) ular basement membrane due to ischemia. (ABF/Vanderbilt Collection.)
Cardinal Manifestations and Presentation of Diseases

FIGURE e9-22 Progressive systemic sclerosis. Acutely, there is fibrinoid necrosis of interlobular and
larger vessels, with intervening normal vessels and ischemic change in the glomeruli (left). Chronically,
this injury leads to intimal proliferation, the so-called onion-skinning appearance (right). (ABF/Vander-
bilt Collection.)

FIGURE e9-23 Acute pyelonephritis. There are characteristic intratu- FIGURE e9-24 Acute tubular necrosis. There is extensive flattening of
bular plugs and casts of PMNs with inflammation extending into the the tubular epithelium and loss of the brush border, with mild intersti-
surrounding interstitium, and accompanying tubular injury. (ABF/ tial edema. (ABF/Vanderbilt Collection.)
Vanderbilt Collection.)

FIGURE e9-25 Acute interstitial nephritis. There is extensive interstitial lymphoplasmocytic infiltrate
with mild edema and associated tubular injury (left), which is frequently associated with interstitial eo-
sinophils (right) when caused by a drug hypersensitivity reaction. (ABF/Vanderbilt Collection.)

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

 e59

FIGURE e9-26 Oxalosis. Calcium oxalate crystals have caused extensive tubular injury,

CHAPTER e9
with flattening and regeneration of tubular epithelium (left). Crystals are well visualized as
sheaves when viewed under polarized light (right). (ABF/Vanderbilt Collection.)

Atlas of Urinary Sediments and Renal Biopsies

FIGURE e9-27 Sarcoidosis. There is chronic interstitial nephritis with FIGURE e9-28 Hyaline cast. (ABF/Vanderbilt Collection.)
numerous, confluent, non-necrotizing granulomas. The glomeruli are
unremarkable, but there is moderate tubular interstitial fibrosis. (ABF/
Vanderbilt Collection.)

FIGURE e9-29 Coarse granular cast. (ABF/Vanderbilt Collection.) FIGURE e9-30 Fine granular cast. (ABF/Vanderbilt Collection.)

FIGURE e9-31 Red blood cell cast. (ABF/Vanderbilt Collection.) FIGURE e9-32 WBC cast. (ABF/Vanderbilt Collection.)

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

 e60

FIGURE e9-33 Triple phosphate crystals. (ABF/Vanderbilt Collection.) FIGURE e9-34 “Maltese cross” formation in an oval fat body. (ABF/
Vanderbilt Collection.)
PART 2
Cardinal Manifestations and Presentation of Diseases

FIGURE e9-35 Uric acid crystals. (ABF/Vanderbilt Collection.)

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

 e61

e10 Atlas of Skin Manifestations

of Internal Disease
Thomas J. Lawley, Stephen F. Templeton

In the practice of medicine, virtually every clinician encounters patients

with skin disease. Physicians of all specialties face the daily task of de-
termining the nature and clinical implication of dermatologic disease.
In patients with skin eruptions and rashes, the physician must confront
the question of whether the cutaneous process is confined to the skin,

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

representing a pure dermatologic event, or whether it is a manifestation
of internal disease relating to the patient’s overall medical condition.
Evaluation and accurate diagnosis of skin lesions are also critical given
the marked rise in both melanoma and nonmelanoma skin cancer. FIGURE e10-2 Acne rosacea with prominent facial erythema, telangi-
Dermatologic conditions can be classified and categorized in many dif- ectasias, scattered papules, and small pustules. (Courtesy of Robert
ferent ways, and in this Atlas, a selected group of inflammatory skin Swerlick, MD; with permission.)
eruptions and neoplastic conditions are grouped in the following man-
ner: (A) common skin diseases and lesions, (B) nonmelanoma skin
cancer, (C) melanoma and pigmented lesions, (D) infectious disease
and the skin, (E) immunologically mediated skin disease, and (F) skin
manifestations of internal disease.

COMMON SKIN DISEASES AND LESIONS

(Figs. e10-1 to e10-19) In this section, several common inflammatory
skin diseases and benign neoplastic and reactive lesions are presented.
While most of these dermatoses usually present as a predominantly
dermatologic process, underlying systemic associations may be made
in some settings. Atopic dermatitis is often present in patients with an
atopic diathesis, including asthma and sinusitis. Psoriasis ranges from
limited patches on the elbows and knees to severe erythrodermic in-
volvement and associated psoriatic arthritis. Some patients with alo-
pecia areata may have an underlying thyroid abnormality requiring
FIGURE e10-3 Psoriasis is characterized by small and large erythema-
screening. Finally, even acne vulgaris, one of the most common in-
tous plaques with adherent silvery scale.
flammatory dermatoses, can be associated with a systemic process
such as polycystic ovarian syndrome.

FIGURE e10-1 Acne vulgaris with inflammatory papules, pustules, FIGURE e10-4 Atopic dermatitis with hyperpigmentation, lichenifica-
and comedones. (Courtesy of Kalman Watsky, MD; with permission.) tion, and scaling in the antecubital fossae. (Courtesy of Robert Swerlick,
MD; with permission.)

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

 e62
PART 2

FIGURE e10-5 Dyshidrotic eczema, characterized by deep-seated

vesicles and scaling on palms and lateral fingers, is often associated
Cardinal Manifestations and Presentation of Diseases

with an atopic diathesis.

FIGURE e10-8 A. Allergic contact dermatitis, acute phase, with

sharply demarcated, weeping, eczematous plaques in a perioral distri-
bution. B. Allergic contact dermatitis to nickel, chronic phase dem-
onstrating an erythematous, lichenified, weeping plaque on skin
chronically exposed to a metal snap. (B, Courtesy of Robert Swerlick, MD;
with permission.)

FIGURE e10-6 Seborrheic dermatitis showing central facial ery-

thema with overlying greasy, yellowish scale. (Courtesy of Jean Bo-
lognia, MD; with permission.)

FIGURE e10-9 Lichen planus showing multiple flat-topped, viola-

ceous papules and plaques. Nail dystrophy as seen in this patient’s
thumbnail may also be a feature. (Courtesy of Robert Swerlick, MD; with
permission.)

FIGURE e10-7 Stasis dermatitis showing erythematous, scaly, and

oozing patches over the lower leg. Several stasis ulcers are also seen in
this patient.

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 e63

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

FIGURE e10-10 Seborrheic keratoses are seen as “stuck on,” waxy, FIGURE e10-12 Alopecia areata characterized by a sharply demar-
verrucous papules and plaques with a variety of colors ranging from cated circular patch of scalp completely devoid of hairs. Follicular ori-
light tan to black. fices are preserved, indicating a nonscarring alopecia. (Courtesy of
Robert Swerlick, MD; with permission.)

FIGURE e10-11 Vitiligo in a typical acral distribution demonstrating

striking cutaneous depigmentation, as a result of loss of melanocytes. FIGURE e10-13 Pityriasis rosea. Multiple round to oval erythematous
patches with fine central scale are distributed along the skin tension
lines on the trunk.

FIGURE e10-14 A. Urticaria showing characteristic discrete and confluent, edematous,

erythematous papules and plaques. B. Dermatographism. Erythema and whealing
that developed after firm stroking of the skin. (B, Courtesy of Robert Swerlick, MD; with
permission.)

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

 e64
PART 2

FIGURE e10-17 Cherry hemangiomas are very common and arise in

middle-aged to older adults. They are characterized by multiple ery-
FIGURE e10-15 Epidermoid cysts. Several inflamed and noninflamed thematous to dark purple papules, usually located on the trunk.
firm, cystic nodules are seen in this patient. Often a patulous follicular
punctum is observed on the overlying epidermal surface.
Cardinal Manifestations and Presentation of Diseases

FIGURE e10-18 Frostbite with vesiculation, surrounded by edema and

FIGURE e10-16 Keloids resulting from ear piercing, with firm exo-
erythema. (Courtesy of Daniel F. Danzl, MD; with permission.)
phytic flesh-colored to erythematous nodules of scar tissue.

FIGURE e10-19 Frostbite with vesiculation, surrounded by edema and ery-

thema. (Courtesy of Daniel F. Danzl, MD; with permission.)

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

NONMELANOMA SKIN CANCER e65
(Figs. e10-20 to e10-27) In more fair-skinned ethnic populations,
nonmelanoma skin cancer is increasing at an alarming rate. Basal cell
carcinoma is the most common cancer in humans and is strongly
linked to ultraviolet radiation. Squamous cell carcinoma, including
keratoacanthoma-type squamous cell carcinoma, is the second most
common skin cancer in most ethnic populations and is also most
commonly linked to ultraviolet radiation. Less common cutaneous
malignancies include cutaneous T cell lymphoma (mycosis fungoides)
and carcinoma and lymphoma metastatic to skin.

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

FIGURE e10-22 Basal cell carcinoma showing central ulceration and
a pearly, rolled, telangiectatic tumor border.

FIGURE e10-20 Kaposi’s sarcoma in a patient with AIDS demonstrat-

ing patch, plaque, and tumor stages.

FIGURE e10-21 Non-Hodgkin’s lymphoma involving the skin with typ- FIGURE e10-23 Mycosis fungoides is a cutaneous T cell lymphoma,
ical violaceous, “plum-colored” nodules. (Courtesy of Jean Bolognia, MD; and plaque stage lesions are seen in this patient.
with permission.)

FIGURE e10-24 Metastatic carcinoma to the skin is characterized by

inflammatory, often ulcerated dermal nodules.

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 e66
PART 2
FIGURE e10-25 Keratoacanthoma is a low-grade squamous cell carci-
noma that presents as an exophytic nodule with central keratinous
debris.
Cardinal Manifestations and Presentation of Diseases
FIGURE e10-26 Squamous cell carcinoma seen here as a hyperkera-
totic crusted and somewhat eroded plaque on the lower lip. Sun-ex-
posed skin such as the head, neck, hands, and arms are other typical
sites of involvement.
FIGURE e10-27 Actinic keratoses consist of hyperkeratotic erythem-
atous papules and patches on sun-exposed skin. They arise in mid-
dle-aged to older adults and have some potential for malignant
transformation. (Courtesy of Robert Swerlick, MD; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
MELANOMA AND BENIGN PIGMENTED LESIONS
(Figs. e10-28 to e10-33) As the prognosis of melanoma is primarily re-
lated to microscopic depth of invasion, and early detection with surgi-
cal treatment can be curative in a high percentage of patients, it is
essential that all clinicians acquire some facility in evaluating pigment-
ed lesions. Three of the clinicopathologic subtypes of melanoma, su-
perficial spreading, lentigo maligna, and acral lentiginous melanoma,
typically display features noted in the “ABCD rule.” Asymmetry—one
half of the lesion varies from the other half. Border irregularity—the
circumferential border exhibits an irregular, sometimes jagged appear-
ance. Color—there is uneven coloration and tone to the pigmented le-
sion with varying shades of brown, black, red, and white within
different areas of the lesion. Diameter—is typically >6 mm. The more
uncommon subtype, nodular melanoma, may not manifest all these
features but present as a more symmetric, evenly pigmented or amel-
anotic lesion. Dysplastic (atypical) melanocytic nevi may occur as sol-
itary or multiple lesions as well as in the setting of familial melanoma.
They display some degree of asymmetry, border irregularity, and color
variation. Ordinary nevi may be acquired or congenital and are quite
common.
FIGURE e10-28 Nevus. Nevi are benign proliferations of nevomelano-
cytes characterized by regularly shaped hyperpigmented macules or
papules of a uniform color.
FIGURE e10-29 Dysplastic nevi are irregularly pigmented and shaped
nevomelanocytic lesions which may be associated with familial mela-
noma.
 e67

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

FIGURE e10-33 Acral lentiginous
melanoma is more common in
blacks, Asians, and Hispanics and oc-
curs as an enlarging hyperpig-
FIGURE e10-30 Superficial spreading melanoma is the most com- mented macule or plaque on the
mon type of malignant melanoma and demonstrates color variega- palms or soles. Lateral pigment diffu-
tion (black, blue, brown, pink, and white) and irregular borders. sion is present.

INFECTIOUS DISEASE AND THE SKIN

(Figs. e10-34 to e10-59) One of the roles of the skin is to function as a
barrier from the outside world. In this capacity, exposure to infectious
agents occurs, and bacterial, viral, fungal, and parasitic infections may
result. In addition the skin may be secondarily involved and provide
diagnostic clues to systemic infections such as meningococcemia,
Rocky Mountain spotted fever, Lyme disease, and septic emboli. Most
sexually transmitted bacterial and viral diseases exhibit cutaneous in-
volvement, and examples include primary and secondary syphilis,
chancroid, genital herpes simplex, and condyloma accuminatum.

FIGURE e10-31 Lentigo maligna melanoma occurs on sun-exposed

skin as a large, hyperpigmented macule or plaque with irregular bor-
ders and variable pigmentation. (Courtesy of Alvin Solomon, MD; with
permission.) FIGURE e10-34 Erysipelas is a strep-
tococcal infection of the superficial
dermis and consists of well-demar-
cated, erythematous, edematous,
warm plaques.

FIGURE e10-32 Nodular melanoma most commonly manifests itself

as a rapidly growing, often ulcerated or crusted black nodule. (Courtesy
of S. Wright Caughman, MD; with permission.)

FIGURE e10-35 Spread of herpes zoster with chemotherapy. The

patient reported external ear pain. A vesicular rash on the concha and
antihelix suggested Ramsay Hunt syndrome.

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

 e68
PART 2

FIGURE e10-39 Tender vesicles and erosions in the mouth of a pa-

tient with hand-foot-and-mouth disease. (Courtesy of Stephen D. Gellis,
MD; with permission.)
Cardinal Manifestations and Presentation of Diseases

FIGURE e10-36 Varicella showing numerous lesions in various stages

of evolution: vesicles on an erythematous base, umbilicated vesicles,
and crusts. (Courtesy of Robert Hartman, MD; with permission.)

FIGURE e10-40 Lacy reticular rash of erythema infectiosum (fifth

disease).

FIGURE e10-37 Herpes zoster is seen in this HIV-infected patient as hem-

orrhagic vesicles and pustules on an erythematous base grouped in a der-
matomal distribution. (Courtesy of Robert Swerlick, MD; with permission.)

FIGURE e10-41 Molluscum contagiosum is a cutaneous poxvirus in-

fection characterized by multiple umbilicated flesh-colored or hypo-
pigmented papules. (Courtesy of Yale Resident’s Slide Collection; with
permission.)

FIGURE e10-38 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.)
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 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. (From K Wolff, RA Johnson, D Suurmond: Fitzpatrick’s Color
Atlas & Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill,
2005. www.accessmedicine.com.)
FIGURE e10-45 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 e10-43 Fulminant meningococcemia with extensive angu-

lar purpuric patches. (Courtesy of Stephen D. Gellis, MD; with permission.)
FIGURE e10-46 Primary syphilis with a firm, nontender chancre.
(Courtesy of Gregory Cox, MD; with permission.)

FIGURE e10-44 Rocky Mountain spotted fever demonstrating pin-

point petechial lesions on the palm and volar aspect of the wrist.
(Courtesy of Robert Swerlick, MD; with permission.)

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 e70
PART 2

FIGURE e10-50 Tinea corporis is a superficial fungal infection, seen

here as an erythematous annular scaly plaque with central clearing.
FIGURE e10-47 Secondary syphilis commonly affects the palms and
Cardinal Manifestations and Presentation of Diseases

soles with scaling, firm, red-brown papules. (Courtesy of Alvin Solomon,

MD; with permission.)

FIGURE e10-51 Scabies showing typical scaling erythematous papules

and few linear burrows.

FIGURE e10-48 Condylomata lata are moist, somewhat verrucous in-

tertriginous plaques seen in secondary syphilis. (Courtesy of Yale Resi-
dent’s Slide Collection; with permission.)

FIGURE e10-52 Skin lesions caused by Chironex fleckeri sting. (Cour-

tesy of V. Pranava Murthy, MD; with permission.)

FIGURE e10-49 Secondary syphilis demonstrating the papulosqua-

mous truncal eruption.

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


FIGURE e10-53 Chancroid with character-
istic penile ulcers and associated left in-
guinal adenitis (bubo).
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
FIGURE e10-54 Condylomata acuminata
are lesions induced by human papillomavi-
rus and in this patient are seen as multiple
verrucous papules coalescing into plaques.
(Courtesy of S. Wright Caughman, MD; with
permission.)
e71
CHAPTER e10 Atlas of Skin Manifestations of Internal Disease
FIGURE e10-55 A patient with features of
polar lepromatous leprosy; multiple
nodular skin lesions, particularly of the fore-
head, and loss of eyebrows. (Courtesy of
Robert Gelber, MD; with permission.)
FIGURE e10-56 Skin lesions of
neutropenic patients. A. Pap-
ules related to Escherichia coli
bacteremia in a neutropenic pa-
tient with acute lymphocytic leu-
kemia. B. The same lesion the
following day. C. Ecthyma gan-
grenosum in a neutropenic pa-
tient with Pseudomonas aeruginosa
bacteremia. D. Papule in a neutro-
penic patient with Candida tropica-
lis fungemia.
 e72
PART 2

FIGURE e10-57 Septic emboli with hemorrhage and infarction due to FIGURE e10-58 Vegetations (arrows) due to viridans streptococcal en-
acute Staphylococcus aureus endocarditis. (Courtesy of L. Baden, MD; docarditis involving the mitral valve. (Courtesy of AW Kerchner, MD; with
with permission.) permission.)
Cardinal Manifestations and Presentation of Diseases

IMMUNOLOGICALLY MEDIATED SKIN DISEASE

FIGURE e10-59 Disseminated gonococcemia in the skin is seen as
hemorrhagic papules and pustules with purpuric centers in an acral
distribution. (Courtesy of Daniel M. Musher, MD; with permission.)
(Figs. 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, pemphigoid, and dermatitis
herpetiformis. In diseases such as systemic lupus erythematosus, der-
matomyositis, and vasculitis, skin manifestations are often only one el-
ement of a widespread process.

FIGURE e10-60 A. Systemic

lupus erythematosus show-
ing prominent, scaly, malar er-
ythema. Involvement of other
sun-exposed sites is also com-
mon. B. Acute lupus erythe-
matosus on the upper chest
demonstrating brightly ery-
thematous and slightly edem-
atous coalescence of papules
and plaques. (B, Courtesy of
Robert Swerlick, MD; with per-
mission.)

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

 e73

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

FIGURE e10-64 Dermatomyositis often involves the hands as ery-
thematous flat-topped papules over the knuckles (Gottron’s sign) and
FIGURE e10-61 Discoid lupus erythematosus. Violaceous, hyperpig-
periungual telangiectasias.
mented, 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 e10-65 Scleroderma showing acral sclerosis and focal digital

ulcers.

FIGURE e10-62 Dermatomyositis. Periorbital violaceous erythema

characterizes the classic heliotrope rash. (Courtesy of James Krell, MD;
with permission.)

FIGURE e10-66 Erythema multiforme is characterized by multiple er-

ythematous plaques with a target or iris morphology and usually rep-
resents a hypersensitivity reaction to drugs or infections (especially
herpes simplex virus). (Courtesy of Yale Resident’s Slide Collection; with
permission.)

FIGURE e10-63 Scleroderma characterized by typical expressionless,

mask-like facies.

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PART 2

FIGURE e10-67 Dermatitis herpetiformis manifested by pruritic,

grouped vesicles in a typical location. The vesicles are often excoriated
and may occur on knees, buttocks, and posterior scalp.

FIGURE e10-69 Erythema nodosum is a panniculitis characterized by

Cardinal Manifestations and Presentation of Diseases

tender deep-seated nodules and plaques usually located on the lower

extremities. (Courtesy of Robert Swerlick, MD; with permission.)

FIGURE e10-70 Vasculitis. Palpable purpuric papules on the lower

legs are seen in this patient with cutaneous small vessel vasculitis.
(Courtesy of Robert Swerlick, MD; with permission.)

FIGURE e10-68 A. Pemphigus vulgaris demonstrating flaccid bullae

that are easily ruptured, resulting in multiple erosions and crusted
plaques. B. Pemphigus vulgaris almost invariably involves the oral
mucosa and may present with erosions involving the gingiva, buccal
mucosa, palate, posterior pharynx, or the tongue. (B, Courtesy of Robert FIGURE e10-71 Bullous pemphigoid with tense vesicles and bullae
Swerlick, MD; with permission.) on an erythematous, urticarial base. (Courtesy of Yale Resident’s Slide
Collection; with permission.)

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

SKIN MANIFESTATIONS OF INTERNAL DISEASE e75
(Figs. e10-72 to e10-79) While many systemic diseases also have cutane-
ous manifestations, there are some well recognized dermatologic mark-
ers of internal disease, and some are demonstrated in this section. Many
of these dermatologic markers may precede, accompany, or follow diag-
nosis of systemic disease. Acanthosis nigricans is a prototypical derma-
tologic process often occurring in association with underlying systemic
abnormalities, most commonly obesity and insulin resistance. It may
also be associated with other endocrine disorders and several rare genet-
ic syndromes. Malignant acanthosis nigricans may occur in association
with several malignancies, especially adenocarcinoma of the gastrointes-
tinal tract, lung, and breast. Other markers of internal disease in this sec-

CHAPTER e10 Atlas of Skin Manifestations of Internal Disease

tion include pretibial myxedema, which is associated with thyroid
disease, and Sweet’s syndrome, which may be associated with hemato-
logic malignancies, solid tumors, or inflammatory bowel disease. The FIGURE e10-75 Bilateral rheumatoid nodules of the upper extremi-
skin is also involved in many systemic inflammatory diseases such as ties. (Courtesy of Robert Swerlick, MD; with permission.)
sarcoidosis, rheumatoid arthritis, and lupus erythematosus.

FIGURE e10-76 Neurofibromatosis demonstrating numerous flesh-

FIGURE e10-72 Acanthosis nigricans demonstrating typical hyper- colored cutaneous neurofibromas.
pigmented axillary plaques with a velvet-like, verrucous surface.

FIGURE e10-77 Coumarin necrosis showing cutaneous and subcuta-

neous necrosis of a breast. Other fatty areas such as buttocks and
thighs are also common sites of involvement. (Courtesy of Kim Yancey,
FIGURE e10-73 Pretibial myxedema manifesting as waxy, infiltrated MD; with permission.)
plaques in a patient with Graves’ disease.

FIGURE e10-74 Plaque of Sweet’s syndrome demonstrating an ery-

thematous indurated plaque with a pseudo-vesicular border. (Courtesy
of Robert Swerlick, MD, with permission.)
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 e76
PART 2
Cardinal Manifestations and Presentation of Diseases

FIGURE e10-78 A. Sarcoid. Infiltrated papules and plaques of vari-

able color are seen in a typical paranasal and periorbital location.
B. Sarcoid. Infiltrated, hyperpigmented, and slightly erythematous
coalescent papules and plaques on the upper arm. (B, Courtesy of
Robert Swerlick, MD; with permission.)

FIGURE e10-79 Pyoderma gangrenosum on the posterior-lateral as-

pect of the lower leg demonstrating multiple purulent draining ulcers
on an infiltrated erythematous plaque. (Courtesy of Robert Swerlick, MD;
with permission.)

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

 5. Polychromatophilia—the red cell cytoplasm has a bluish hue, re- e77

e11 Atlas of Hematology

and Analysis of
Peripheral Blood Smears
flecting the persistence of ribosomes still actively making hemoglo-
bin in a young red cell

Vital stains are necessary to see precipitated hemoglobin called Heinz

bodies.
Dan L. Longo Red cells can take on a variety of different shapes. All abnormally
shaped red cells are poikilocytes. Small red cells without the central pal-
lor are spherocytes; they can be seen in hereditary spherocytosis,
Some of the relevant findings in peripheral blood, enlarged lymph
hemolytic anemias of other causes, and clostridial sepsis. Dacrocytes
nodes, and bone marrow are illustrated here. Systematic histologic ex-
are teardrop-shaped cells that can be seen in hemolytic anemias, severe
amination of the bone marrow and lymph node are beyond the scope
iron deficiency, thalassemias, myelofibrosis, and myelodysplastic syn-
of a general medicine textbook. However, every internist should know

CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears

dromes. Schistocytes are helmet-shaped cells that reflect microangio-
how to examine a peripheral blood smear.
pathic hemolytic anemia or fragmentation on an artificial heart valve.
The examination of the peripheral blood smear is one of the most
Echinocytes are spiculated red cells with the spikes evenly spaced; they
informative exercises a physician can perform. While advances in au-
can represent an artifact of abnormal drying of the blood smear or re-
tomated technology have made the examination of the peripheral
flect changes in stored blood. They can also be seen in renal failure and
blood smear by the physician seem less important, the technology is
malnutrition and are often reversible. Acanthocytes are spiculated red
not a completely satisfactory replacement for blood smear interpreta-
cells with the spikes irregularly distributed. This process tends to be ir-
tion by a trained medical professional who also knows the patient’s
reversible and reflects underlying renal disease, abetalipoproteinemia,
clinical history, family history, social history, and physical findings. It
or splenectomy. Elliptocytes are elliptical-shaped red cells that can re-
is useful to ask the laboratory to generate a Wright’s-stained peripheral
flect an inherited defect in the red cell membrane, but they are also
blood smear and to examine it.
seen in iron deficiency, myelodysplastic syndrome, megaloblastic ane-
The best place to examine blood cell morphology is the feathered
mia, and thalassemias. Stomatocytes are red cells in which the area of
edge of the blood smear where red cells lie in a single layer, side by
central pallor takes on the morphology of a slit instead of the usual
side, just barely touching each other but not overlapping. My own ap-
round shape. Stomatocytes can indicate an inherited red cell mem-
proach is to look at the smallest cellular elements first, the platelets,
brane defect and can also be seen in alcoholism. Target cells have an
and work my way up in size to red cells and then white cells.
area of central pallor that contains a dense center, or bull’s eye. These
Using an oil immersion lens that magnifies the cells 100-fold, one
cells are seen classically in thalassemia, but they are also present in iron
first counts the platelets in five to six fields, averages the number per
deficiency, cholestatic liver disease, and some hemoglobinopathies.
field, and multiplies by 20,000 to get a rough estimate of the platelet
They can also be generated artifactually by improper slide making.
count. The platelets are usually 1–2 μm in diameter and have a blue
One last feature of the red cells to assess before moving to the white
granulated appearance. There is usually 1 platelet for every 20 or so
blood cells is the distribution of the red cells on the smear. In most in-
red cells. Of course, the automated counter is much more accurate,
dividuals, the cells lie side by side in a single layer. Some patients have
but gross disparities between the automated and manual counts
red cell clumping (called agglutination) in which the red cells pile upon
should be assessed. Large platelets may be a sign of rapid platelet turn-
one another; it is seen in certain paraproteinemias and autoimmune
over, as young platelets are often larger than old platelets; alternatively,
hemolytic anemias. Another abnormal distribution involves red cells
certain rare inherited syndromes can produce large platelets. Platelet
lying in single cell rows on top of one another like stacks of coins. This
clumping visible on the smear can be associated with falsely low auto-
is called rouleaux formation and reflects abnormal serum protein levels.
mated platelet counts. Similarly, neutrophil fragmentation can be a
Finally, one examines the white blood cells. Three types of granulo-
source of falsely elevated automated platelet counts.
cytes are usually present; neutrophils, eosinophils, and basophils, in
Next one examines the red blood cells. One can gauge their size by
decreasing frequency. Neutrophils are generally the most abundant
comparing the red cell to the nucleus of a small lymphocyte. Both are
white cell. They are round, 10–14 μm wide, and contain a lobulated
normally about 8 μm wide. Red cells that are smaller than the small lym-
nucleus with two to five lobes connected by a thin chromatin thread.
phocyte nucleus may be microcytic; those larger than the small lympho-
Bands are immature neutrophils that have not yet completed nuclear
cyte nucleus may be macrocytic. The automated mean corpuscular
condensation and have a U-shaped nucleus. Bands reflect a left shift in
volume (MCV) can assist in making a classification. However, some pa-
neutrophil maturation in an effort to make more cells more rapidly.
tients may have both iron and vitamin B12 deficiency, which will produce
Neutrophils can provide clues to a variety of conditions. Vacuolated
an MCV in the normal range but wide variation in red cell size. When
neutrophils may be a sign of bacterial sepsis. The presence of 1- to 2-
the red cells vary greatly in size, anisocytosis is said to be present. When
μm blue cytoplasmic inclusions, called Dohle bodies, can reflect infec-
the red cells vary greatly in shape, poikilocytosis is said to be present.
tions, burns, or other inflammatory states. If the neutrophil granules
After red cell size is assessed, one examines the hemoglobin content
are larger than normal and stain a darker blue, “toxic granulations” are
of the cells. They are either normal in color (normochromic) or they
said to be present, and they also suggest a systemic inflammation. The
are pale in color (hypochromic). They are never “hyperchromic.” If
presence of neutrophils with more than five nuclear lobes suggests
more than the normal amount of hemoglobin is made, the cells get
megaloblastic anemia. Large misshapen granules may reflect the in-
larger—they do not become darker. In addition to hemoglobin con-
herited Chédiak-Higashi syndrome.
tent, the red cells are examined for inclusions. Red cell inclusions are
Eosinophils are slightly larger than neutrophils, have bilobed nuclei,
the following:
and contain large red granules. Diseases of eosinophils are associated
1. Basophilic stippling—diffuse fine or coarse blue dots in the red cell with too many of them rather than any morphologic or qualitative
representing usually RNA residue—especially common in lead poi- change. They normally total less than one-thirtieth the number of
soning neutrophils. Basophils are even more rare than eosinophils in the
2. Howell-Jolly bodies—dense blue circular inclusions that represent blood. They have large dark-blue granules and may be increased as
nuclear remnants—their presence implies defective splenic function part of chronic myeloid leukemia,
3. Nuclei—red cells may be released or pushed out of the marrow pre- Lymphocytes can be present in several morphologic forms. Most
maturely before nuclear extrusion—often implies a myelophthisic common in healthy individuals are the small lymphocytes with a small
process dark nucleus and scarce cytoplasm. In the presence of viral infections,
4. Parasites—red cell parasites include malaria and babesia (Chap. more of the lymphocytes are larger, about the size of neutrophils, with
e18) abundant cytoplasm and a less condensed nuclear chromatin. These

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

 e78 are called reactive lymphocytes. About 1% of the lymphocytes are larger
and contain blue granules in a light blue cytoplasm; these are called
large granular lymphocytes. In chronic lymphoid leukemia, the small
lymphocytes are increased in number, and many of them are ruptured
in making the blood smear, leaving a smudge of nuclear material with-
out a surrounding cytoplasm or cell membrane; these are called
smudge cells and are rare in the absence of chronic lymphoid leukemia.
Monocytes are the largest white blood cells, ranging from 15–22
μm in diameter. The nucleus can take on a variety of shapes but usual-
ly appears to be folded; the cytoplasm is gray.
Abnormal cells may appear in the blood. Most often the abnormal
cells originate from neoplasms of bone marrow–derived cells includ-
ing lymphoid cells, myeloid cells, and occasionally red cells. More
rarely, other types of tumors can get access to the blood stream, and
PART 2

rare epithelial malignant cells may be identified. The chances of seeing

such abnormal cells is increased by examining blood smears made
from buffy coats, the layer of cells that is visible on top of sedimenting FIGURE e11-3 Hypochromic microcytic anemia of iron deficiency.
red cells when blood is left in the test tube for an hour. Smears made Small lymphocyte in field helps assess the red blood cell size.
from finger sticks may include rare endothelial cells.
Cardinal Manifestations and Presentation of Diseases

ACKNOWLEDGMENT
Figures in this e-chapter were borrowed from Williams Hematology, 7th
edition, M Lichtman et al (eds). New York, McGraw-Hill, 2005; Hema-
tology in General Practice, 4th edition, RS Hillman, KA Ault, New York,
McGraw-Hill, 2005.

FIGURE e11-4 Iron deficiency anemia next to normal red blood

cells. Microcytes (right panel ) are smaller than normal red blood cells
(cell diameter < 7 μm) and may or may not be poorly hemoglobinized
(hypochromic).

FIGURE e11-1 Normal peripheral blood smear. 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.

FIGURE e11-5 Polychromatophilia. Note large red cells with light

purple coloring.

FIGURE e11-2 Reticulocyte count preparation. This new methylene

blue–stained blood smear shows large numbers of heavily stained retic-
ulocytes (the cells containing the dark blue–staining RNA precipitates).

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 e79

CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears

FIGURE e11-6 Macrocytosis. These cells are both larger than normal FIGURE e11-9 Rouleaux formation. Small lymphocyte in center of
(mean corpuscular volume > 100) and are somewhat oval in shape. field. These red cells align themselves in stacks and are related to in-
Some morphologists call these cells “macroovalocytes.” creased serum protein levels.

FIGURE e11-7 Hypersegmented neutrophils. Hypersegmented neu- FIGURE e11-10 Red cell agglutination. Small lymphocyte and seg-
trophils (multilobed polymorphonuclear leukocytes) are larger than mented neutrophil upper left center. Note irregular collections of ag-
normal neutrophils with five or more segmented nuclear lobes. They gregated red cells.
are commonly seen with folic acid or vitamin B12 deficiency.

FIGURE e11-11 Fragmented red cells. Heart valve hemolysis.

FIGURE e11-8 Spherocytosis. Note small hyperchromatic cells with-
out the usual clear area in the center.

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 e80
PART 2

FIGURE e11-12 Sickle cells. Homozygous sickle cell disease. A nucle-
ated red cell and neutrophil are also in the field.
Cardinal Manifestations and Presentation of Diseases
FIGURE e11-15 Stomatocytosis. Red cells characterized by a wide
transverse slit or stoma. This is often seen as an artifact in a dehydrated
blood smear. These cells can be seen in hemolytic anemias and in
conditions in which the red cell is overhydrated or dehydrated.

FIGURE e11-13 Target cells. Target cells are recognized by the bull’s-
eye appearance of the cell. Small numbers of target cells are seen with
liver disease and thalassemia. Larger numbers are typical of hemoglo-
bin C disease.
FIGURE e11-16 Acanthocytosis. Spiculated red cells are of two types:
acanthocytes are contracted dense cells with irregular membrane pro-
jections that vary in length and width; echinocytes have small, uniform,
and evenly spaced membrane projections. Acanthocytes are present
in severe liver disease, in patients with abetalipoproteinemia, and in
rare patients with McLeod blood group. Echinocytes are found in pa-
tients with severe uremia, in glycolytic red cell enzyme defects, and in
microangiopathic hemolytic anemia.

FIGURE e11-14 Elliptocytosis. Small lymphocyte in center of field. El-

liptical shape of red cells related to weakened membrane structure,
usually due to mutations in spectrin.

FIGURE e11-17 Howell-Jolly bodies. Howell-Jolly bodies are tiny nu-

clear remnants that are normally removed by the spleen. They appear
in the blood after splenectomy (defect in removal) and with matura-
tion/dysplastic disorders (excess production).

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 e81

CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears

FIGURE e11-18 Teardrop cells and nucleated red blood cells char- FIGURE e11-21 Stippled red cell in lead poisoning. Mild hypochro-
acteristic of myelofibrosis. A teardrop-shaped red blood cell (left mia. Coarsely stippled red cell.
panel ) and a nucleated red blood cell (right panel ) as typically seen
with myelofibrosis and extramedullary hematopoiesis.

FIGURE e11-22 Heinz bodies. Blood mixed with hypotonic solution of

crystal violet. The stained material is precipitates of denatured hemo-
FIGURE e11-19 Myelofibrosis of the bone marrow. Total replace- globin within cells.
ment of marrow precursors and fat cells by a dense infiltrate of reticu-
lin fibers and collagen (H&E stain).

FIGURE e11-23 Giant platelets. Giant platelets, together with a

marked increase in the platelet count, are seen in myeloproliferative
disorders, especially primary thrombocythemia.

FIGURE e11-20 Reticulin stain of marrow myelofibrosis. Silver stain

of a myelofibrotic marrow showing an increase in reticulin fibers
(black-staining threads).

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 e82

FIGURE e11-24 Normal granulocytes. The normal granulocyte has a

segmented nucleus with heavy, clumped chromatin; fine neutrophilic
PART 2

granules are dispersed throughout the cytoplasm.

FIGURE e11-27 Normal basophil. The film was prepared from the buffy
coat of the blood from a normal donor. L, lymphocyte; B, basophil.
Cardinal Manifestations and Presentation of Diseases

FIGURE e11-28 Pelger-Hüet anomaly. In this benign disorder, the

majority of granulocytes are bilobed. The nucleus frequently has a
spectacle-like, or “pince-nez” configuration.
FIGURE e11-25 Normal monocytes. The film was prepared from the
buffy coat of the blood from a normal donor. L, lymphocyte; M mono-
cyte; N, neutrophil.

FIGURE e11-29 Döhle body. Neutrophil band with Döhle body. The
neutrophil with a sausage-shaped nucleus in the center of the field is a
band form. Döhle bodies are discrete, blue-staining nongranular areas
found in the periphery of the cytoplasm of the neutrophil in infections
and other toxic states. They represent aggregates of rough endoplas-
mic reticulum.

FIGURE e11-26 Normal eosinophils. The film was prepared from the
buffy coat of the blood from a normal donor. N, neutrophil; E, eosinophil.

FIGURE e11-30 Chédiak-Higashi disease. Note giant granules in

neutrophil.

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


FIGURE e11-31 Normal bone marrow. Low-power view of normal
adult marrow (H&E stain), showing a mix of fat cells (clear areas) and
hematopoietic cells. The percentage of the space that is hematopoi-
etic cells is referred to as marrow cellularity. In adults, normal marrow
cellularity is 35–40%. If demands for increased marrow production oc-
cur, cellularity may increase to meet the demand. As we age, the mar-
row cellularity decreases and the marrow fat increases. Patients >70
years may have a 20–30% marrow cellularity.
FIGURE e11-32 Aplastic anemia bone marrow. Normal hematopoi-
etic precursor cells are virtually absent, leaving behind fat cells, reticu-
loendothelial cells, and the underlying sinusoidal structure.
FIGURE e11-33 Metastatic cancer in the bone marrow. Marrow bi-
opsy specimen infiltrated with metastatic breast cancer and reactive
fibrosis (H&E stain).
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e83
CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears
FIGURE e11-34 Lymphoma in the bone marrow. Nodular (follicular)
lymphoma infiltrate in a marrow biopsy specimen. Note the character-
istic paratrabecular location of the lymphoma cells.
FIGURE e11-35 Erythroid hyperplasia of the marrow. Marrow aspi-
rate specimen with a myeloid/erythroid ratio (M/E ratio) of 1:1–2, typi-
cal for a patient with a hemolytic anemia or recovering from blood
loss.
FIGURE e11-36 Myeloid hyperplasia of the marrow. Marrow aspi-
rate specimen showing a myeloid/erythroid ratio of ≥3:1, suggesting
either a loss of red blood cell precursors or an expansion of myeloid
elements.
 e84
PART 2

FIGURE e11-37 Megaloblastic erythropoiesis. High-power view of FIGURE e11-40 Acute myeloid leukemia. Leukemic myeloblast with
megaloblastic red blood cell precursors from a patient with a macro- an Auer rod. Note two to four large, prominent nucleoli in each cell.
cytic anemia. Maturation is delayed with late normoblasts showing a
more immature appearing nucleus with a lattice-like pattern with nor-
Cardinal Manifestations and Presentation of Diseases

mal cytoplasmic maturation.

FIGURE e11-41 Acute promyelocytic leukemia. Note prominent cy-

toplasmic granules in the leukemia cells.

FIGURE e11-38 Prussian blue staining of marrow iron stores. Iron

stores can be graded on a scale of 0 to 4+. A: a marrow with excess
iron stores (>4+); B: normal stores (2–3+); C: minimal stores (1+); and
D: absent iron stores (0).

FIGURE e11-42 Acute erythroleukemia. Note giant dysmorphic

erythroblasts, two are binucleate and one is multinucleate.

FIGURE e11-39 Ringed sideroblast. An orthochromatic normoblast

with a collar of blue granules (mitochondria encrusted with iron) sur-
rounding the nucleus.

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 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, acute lymphoblastic leukemia.

FIGURE e11-47 Sézary’s syndrome. Lymphocytes with frequently
convoluted nuclei (Sézary cells) in a patient with advanced mycosis
fungoides.

FIGURE e11-48 Adult T cell leukemia. Peripheral blood smear show-

ing leukemia cells with typical “flower-shaped” nucleus.

FIGURE e11-45 Chronic myeloid leukemia in the peripheral blood.

FIGURE e11-49 Follicular lymphoma in a lymph node. The normal

nodal architecture is effaced by nodular expansions of tumor cells.
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.
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 e86

FIGURE e11-50 Diffuse large B cell lymphoma in a lymph node.
The neoplastic cells are heterogeneous but predominantly large cells
with vesicular chromatin and prominent nucleoli.
PART 2
FIGURE e11-53 Hodgkin’s disease. A Reed-Sternberg cell is present
near the center of the field; a large cell with a bilobed nucleus and
prominent nucleoli giving an “owl’s eyes” appearance. The majority of
the cells are normal lymphocytes, neutrophils, and eosinophils that

form a pleiomorphic cellular infiltrate.

Cardinal Manifestations and Presentation of Diseases

FIGURE e11-51 Burkitt’s lymphoma in a lymph node. Burkitt’s lym-

phoma with starry-sky appearance. The lighter areas are macrophages
attempting to clear dead cells.
FIGURE e11-54 Lacunar cell; Reed-Sternberg cell variant in nodu-
lar sclerosing Hodgkin’s disease. High-power view of single mono-
nuclear lacunar cell with retracted cytoplasm in a patient with nodular
sclerosing Hodgkin’s disease.

FIGURE e11-52 Erythrophagocytosis accompanying aggressive

lymphoma. The central macrophage is ingesting red cells, neutro-
phils, and platelets. (Courtesy of Dr. Kiyomi Tsukimori, Kyushu University,
Fukuoka, Japan.)

FIGURE e11-55 Normal plasma cell.

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CHAPTER e11 Atlas of Hematology and Analysis of Peripheral Blood Smears

FIGURE e11-56 Multiple myeloma.
FIGURE e11-57 Color serum in hemoglobinemia. The distinctive red
coloration of plasma (hemoglobinemia) in a spun blood sample in a
patient with intravascular hemolysis.

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


e12 Thymoma
Dan L. Longo
The thymus is derived from the third and fourth pharyngeal pouches
and is located in the anterior mediastinum. The thymus is composed
of epithelial and stromal cells derived from the pharyngeal pouch and
lymphoid precursors derived from mesodermal cells. It is the site to
which bone marrow precursors that are committed to differentiate
into T cells migrate to complete their differentiation. Like many or-
gans, it is organized into functional regions—in this case, the cortex
and the medulla. The cortex of the thymus contains ~85% of the lym-
phoid cells and the medulla ~15%. It appears that the primitive bone
marrow progenitors enter the thymus at the corticomedullary junc-
tion and migrate first through the cortex toward the periphery of the
gland and then toward the medulla as they mature. Medullary thy-
mocytes have a phenotype that cannot readily be distinguished from
mature peripheral blood and lymph node T cells.
Several things can go wrong with the thymus, but thymic abnormal-
ities are very rare. If the thymus does not develop properly, serious defi-
ciencies in T cell development ensue and severe immunodeficiency is
seen (e.g., DiGeorge syndrome, Chap. 310). If a lymphoid cell within
the thymus becomes neoplastic, the disease that develops is a lympho-
ma. The majority of lymphoid tumors that develop in the thymus are
derived from the precursor T cells, and the tumor is a precursor T cell
lymphoblastic lymphoma (Chap. 105). Rare B cells exist in the thymus,
and when these become neoplastic, the tumor is a mediastinal (thymic)
B cell lymphoma (Chap. 105). Germ cell tumors and carcinoid tumors
may occasionally arise in the thymus. If the epithelial cells of the thy-
mus become neoplastic, the tumor that develops is a thymoma.
CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS
Thymoma is the most common cause of an anterior mediastinal mass
in adults, accounting for ~40% of all mediastinal masses. The other
major causes of anterior mediastinal mass are lymphomas, germ cell
tumors, and substernal thyroid tumors. Carcinoid tumors, lipomas,
and thymic cysts may also produce radiographic masses. Thymomas
are most common in the fifth and sixth decades, are uncommon in
children, and are distributed evenly between men and women.
About 40–50% of patients are asymptomatic; masses are detected
incidentally on routine chest radiographs. When symptomatic, pa-
tients may have cough, chest pain, dyspnea, fever, wheezing, fatigue,
weight loss, night sweats, or anorexia. Occasionally, thymomas may
obstruct the superior vena cava. About 40% of patients with thymoma
have another systemic autoimmune illness related to the thymoma.
About 30% of patients with thymoma have myasthenia gravis, 5–8%
have pure red cell aplasia, and ~5% have hypogammaglobulinemia.
Among patients with myasthenia gravis, ~10–15% have a thymoma.
Thymoma more rarely may be associated with polymyositis, systemic
lupus erythematosus, thyroiditis, Sjögren’s syndrome, ulcerative coli-
tis, pernicious anemia, Addison’s disease, scleroderma, and panhypo-
pituitarism. In one series, 70% of patients with thymoma were found
to have another systemic illness (Souadjian et al, 1974).
DIAGNOSIS AND STAGING
Once a mediastinal mass is detected, a surgical procedure is required
for definitive diagnosis. An initial mediastinoscopy or limited thora-
cotomy can be undertaken to get sufficient tissue to make an accurate
diagnosis. Fine-needle aspiration is poor at distinguishing between
lymphomas and thymomas but is more reliable in diagnosing germ
cell tumors and metastatic carcinoma. Thymomas and lymphomas re-
quire sufficient tissue to examine the tumor architecture to assure an
accurate diagnosis and obtain prognostic information.
Once a diagnosis of thymoma is defined, subsequent staging gener-
ally occurs at surgery. However, chest CT scans can assess local inva-
siveness in some instances. MRI has a defined role in the staging of
posterior mediastinal tumors, but it is not yet clear that it adds impor-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TABLE e12-1 MASAOKA STAGING SYSTEM FOR THYMOMAS e89
Stage
I
Diagnostic Criteria
Macroscopically and microscopically completely encapsulated;
no invasion through capsule
II
IIA Microscopic invasion outside of the capsule
IIB Macroscopic invasion into surrounding fat or grossly adherent
to pleura or pericardium
III
IIIA Macroscopic invasion into neighboring organs, pericardium, or
pleura but not the great vessels
IIIB Macroscopic invasion into neighboring organs that includes
CHAPTER e12 Thymoma
great vessels
IV
IVA Pleural or pericardial dissemination
IVB Lymphatic or hematogenous metastases
Stage 5-Year 10-Year
Distribution, % Survival, % Survival, %
I 65 95–100 86–100
II 25 70–100 5–100
III 5 50–70 47–60
IV 5 11–50 0–11
Source: From A Masaoka et al: Cancer 48:2485, 1981.
tant information to the CT scan in anterior mediastinal tumors. So-
matostatin receptor imaging with indium-labeled somatostatin
analogues may be of value (Lin et al, 1999). If invasion is not distin-
guished by noninvasive testing, an effort to resect the entire tumor
should be undertaken. If invasion is present, neoadjuvant chemother-
apy may be warranted before surgery (see “Treatment,” below).
Some 90% of thymomas are in the anterior mediastinum, but some
may be in other mediastinal sites or even the neck, based on aberrant
migration of the developing thymic enlage.
The staging system for thymoma was developed by Masaoka and
colleagues (Table e12-1). It is an anatomic system in which the stage
is increased based on the degree of invasiveness. The 5-year survival
of patients in the various stages is as follows: stage I, 96%; stage II,
86%; stage III, 69%; stage IV, 50%. The French Study Group on Thy-
mic Tumors (GETT; Cowen et al, 1998) has proposed modifications
to the Masaoka scheme based upon the degree of surgical removal be-
cause the extent of surgery has been noted to be a prognostic indica-
tor. In their system, stage I tumors are divided into A and B based on
whether the surgeon suspects adhesions to adjacent structures; stage
III tumors are divided into A and B based upon whether disease was
subtotally resected or only biopsied. The concurrence between the
two systems is high.
PATHOLOGY AND ETIOLOGY
Thymomas are epithelial tumors and all of them have malignant po-
tential. It is not worthwhile to try to divide them into benign and ma-
lignant forms; the key prognostic feature is whether they are
noninvasive or invasive. About 65% of thymomas are encapsulated
and noninvasive and about 35% are invasive. They may have a variable
percentage of lymphocytes within the tumor, but genetic studies sug-
gest that the lymphocytes are benign polyclonal cells. 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). Cytologic
features are not reliable predictors of biological behavior. About 90%
of A, AB, and B1 tumors are localized. A very small number of patients
have aggressive histology features characteristic of carcinomas. Thy-
mic carcinomas are invasive and carry a poor prognosis.
The genetic lesions in thymomas are not well characterized. Some
data suggest that Epstein-Barr virus may be associated with thymomas
(Dimery et al, 1988). Some tumors overexpress the p21 ras gene prod-
uct. However, molecular pathogenesis remains undefined. A thymoma
susceptibility locus has been defined on rat chromosome 7, but the re-
 e90 TABLE e12-2 WHO HISTOLOGIC CLASSIFICATION OF THYMUS TUMORS a Some thymic carcinomas express c-kit, and one patient whose c-kit lo-
cus was mutated responded dramatically to imatanib. Many thymomas ex-
Type Histologic Description press epidermal growth factor receptors, but the antibodies to the
A Medullary thymoma receptor and kinase inhibitors that block its action have not been system-
AB Mixed thymoma atically evaluated. Octreotide plus prednisone produces responses in
B1 Predominantly cortical thymoma about one-third of patients.
B2 Cortical thymoma
B3 Well-differentiated thymic carcinoma
C Thymic carcinoma INFLUENCE OF THYMECTOMY ON THE COURSE OF ACCOMPANYING DISEASES
Patients with myasthenia gravis have a high incidence of thymic ab-
Prognosis (10-year
normalities (~80%) but overt thymoma is present in only ~10–15%
Type Distribution, % disease-free survival), %
of patients with myasthenia gravis. It is thought that the thymus plays
A 8 100 a role in breaking self-tolerance and generating T cells that recognize
AB 17 100 the acetylcholine receptor as a foreign antigen. Although patients
PART 6

B1 27 83 with thymoma and myasthenia gravis are less likely to have a remis-
B2 8 83
sion in the myasthenia as a consequence of thymectomy than are pa-
B3 12 36
C 28 28 tients with thymic abnormalities other than thymoma, the course of
myasthenia gravis is not significantly different in patients with or
aWHO, World Health Organization.
without thymoma (Bril et al, 1998). Thymectomy produces at least
some symptomatic improvement in ~65% of patients with myasthe-
nia gravis.
Oncology and Hematology

lationship between this gene locus, termed Tsr1, and human thymoma
has not yet been examined.
THYMOMA
Treatment is determined by the stage of disease. For patients with encap-
sulated tumors and stage I disease, complete resection is sufficient to cure
96% of patients. For patients with stage II disease, complete resection is
usually followed by 30–60 Gy of postoperative radiation therapy to the site
of the primary tumor. For patients with stage III and IV disease, the use of
neoadjuvant chemotherapy followed by radical surgery, radiation therapy,
and additional consolidation chemotherapy has been associated with ex-
cellent survival in a small group of patients so treated (Shin et al, 1998). In-
duction chemotherapy consisted of cyclophosphamide 500 mg/m2 on
day 1; continuous-infusion doxorubicin, 20 mg/m2 per day on days 1–3
(total 60 mg/m2); cisplatin, 30 mg/m2 per day on days 1–3 (total 90 mg/
m2); and prednisone, 100 mg/d on days 1–5. Three cycles were given in 3-
to 4-week intervals. Of 12 patients treated with this regimen, 3 had com-
plete responses, 8 had partial responses, and 1 had a minor response.
These patients then underwent surgical resection; tumor was completely
resected in nine and incompletely resected in two patients (one patient re-
fused surgery and received radiation therapy only). After surgery, all pa-
tients received radiation therapy (50–60 Gy) and three additional courses
of chemotherapy at 80% of the doses used for neoadjuvant therapy. At a
median follow-up of 43 months, 10 of the 12 patients were free of disease,
and the 2 patients who had local recurrence remain alive with disease. Sur-
vival at 7 years is 100%.
This multimodality approach appears to be superior to the use of sur-
gery followed by radiation therapy alone, which produces a 5-year survival
of ≤50% in patients with advanced-stage disease.
About 30–50% of patients with pure red cell aplasia have a thymo-
ma. Thymectomy results in the resolution of pure red cell aplasia in
~30% of patients. About 10% of patients with hypogammaglobuline-
mia have a thymoma, but hypogammaglobulinemia rarely responds to
thymectomy.
FURTHER READINGS
BRIL V et al: The long-term clinical outcome of myasthenia gravis in pa-
tients with thymoma. Neurology 51:1198, 1998 [PMID: 9781560]
COWEN D et al: Natural history and treatment of malignant thymoma.
Oncology 12:1001, 1998 [PMID: 9684271]
DIMERY IW et al: Association of Epstein-Barr virus with lymphoepi-
thelioma of the thymus. Cancer 61:2475, 1998 [PMID: 2835144]
GIACCONE G: Treatment of malignant thymoma. Curr Opin Oncol
17:140, 2005 [PMID: 15725919]
LIN K et al: Somatostatin receptor scintigraphy and somatostatin ther-
apy in the evaluation and treatment of malignant thymoma. Clin
Nucl Med 24:24, 1999 [PMID: 9890489]
PETRIE HT: Cell migration and the control of post-natal T-cell lym-
phopoiesis in the thymus. Nat Rev Immunol 3:859, 2003 [PMID:
14668802]
SHIN DM et al: A multidisciplinary approach to therapy for unresecta-
ble malignant thymoma. Ann Intern Med 129:100, 1998 [PMID:
9669967]
SOUADJIAN JV et al: The spectrum of diseases associated with thy-
moma. Arch Intern Med 134:374, 1974 [PMID: 4602050]
WRIGHT CD: Management of thymomas. Crit Rev Oncol Hematol 64,
2007 [PMID: 17570676]

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

 (such as blind loops leading to malabsorption) or interfere with nor- e91

e13 Late Consequences of Cancer

and Its Treatment
Michael C. Perry, Dan L. 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,
and many will experience long-term complications, including medical
problems, psychosocial disturbances, sexual dysfunction, and inability
to find employment or insurance.
mal organ function (splenectomy leading to impaired immune re-
sponse). Radiation therapy can damage organ function directly
(salivary gland toxicity leading to dry mouth and dental caries), act as
a carcinogen (second solid tumors in radiation ports), or promote ac-
celerated aging-associated changes (atherosclerosis). Cancer chemo-
therapy can produce damage to the bone marrow and immune system
and induce a spectrum of organ dysfunctions. Therapy may produce
subclinical damage that may only become recognized in the presence
of a second inciting factor (such as the increased incidence of melano-
ma in patients with dysplastic nevus syndrome treated for Hodgkin’s
disease with radiation therapy). Finally, cancer and its treatment are

CHAPTER e13 Late Consequences of Cancer and Its Treatment

Problems may be related to the cancer itself (e.g., patients with pri- associated with psychosocial problems that can impair the survivor’s
mary cancers of the head and neck are at increased risk for subsequent ability to adapt to life after cancer.
lung cancer) or to the normal aging process (surviving one cancer does Late effects by treatment modality are shown in Table e13-1. Drug
not necessarily alter the risk of other common tumors that increase in toxicities and radiation therapy toxicities are discussed in Chap. 81.
frequency with age). However, many of the problems affecting cured pa-
tients are related to the treatments. Individuals carefully followed for pe-
riods up to 30 years have taught us the spectrum of problems that can be CONSEQUENCES BY ORGAN SYSTEM
encountered. Because of heterogeneity in treatment details and incom- CARDIOVASCULAR DYSFUNCTION
pleteness of follow-up, some treatment-related problems went undetec- Most anthracyclines damage the heart muscle. A dose-dependent
ted for many years. However, studies of long-term survivors of dropout of myocardial cells is seen on endomyocardial biopsy, and
childhood cancers, acute leukemia, Hodgkin’s disease, lymphomas, tes- eventually ventricular failure ensues. About 5% of patients who receive
ticular cancer, 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. (CHF). Coexisting cardiac disease, hypertension, advanced age, 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. This reticence is due onset of CHF. Anthracycline-induced CHF is not readily reversible;
to the uncertainty associated with changing a
treatment that is known to work before having a
replacement that works as well. TABLE e13-1 LATE EFFECTS OF CANCER THERAPY
Survivorship issues have been addressed by
Surgical Procedure Effect
the Institute of Medicine and the National Re-
search Council, who have published a mono- Amputation Functional loss
graph on this subject—From Cancer Patient to Lymph node dissection Risk of lymphedema
Cancer Survivor: Lost in Transition. Their “Sur- Ostomy Psychosocial impact
Splenectomy Risk of sepsis
vivorship Care Plan,” if uniformly carried out,
Adhesions Risk of obstruction
would inform clinicians who assume the care Bowel anastomoses Malabsorption syndromes
of cancer survivors of their previous treat-
ments; signs and symptoms of late effects; and, Radiation Therapy Effect
where established, guidelines for intervention. Organ
An “End-of-Treatment Consultation Note” Bone Premature termination of growth, osteonecrosis
would include the date, physician’s name, date Soft tissues Atrophy, fibrosis
of tissue diagnosis, diagnosis, stage, pathologic Brain Neuropsychiatric deficits, cognitive dysfunction
findings, initial treatment plan, and treatment Thyroid Hypothyroidism, Graves’ disease, cancer
received. In addition, unusual or unexpected Salivary glands Dry mouth, caries, dysgeusia
Eyes Cataracts
toxicities would be noted and the expected Heart Pericarditis, myocarditis, coronary artery disease
short- and long-term effects of treatment de- Lung Pulmonary fibrosis
tailed. Suggestions for monitoring for late tox- Kidney Decreased function, hypertension
icity should be given as well, including Liver Decreased function
recommendations for surveillance for recur- Intestine Malabsorption, stricture
rence and second malignancies, the physi- Gonads Infertility, premature menopause
Any Secondary neoplasia
cian(s) responsible for monitoring, and any
identified psychosocial issues or concerns. Chemotherapy Effect
The first task in a newly diagnosed patient is
Organ Drug
always to eradicate the diagnosed malignancy. Bone Glucocorticoids Osteoporosis, avascular necrosis
Late problems occurring in cured patients re- Brain Methotrexate, ara-C, Neuropsychiatric deficits, cognitive decline?
flect the success of such treatment. These prob- others
lems never develop in those who do not Peripheral nerves Vincristine, platinum, Neuropathy, hearing loss
survive the cancer. Morbidity and mortality taxanes
from iatrogenic disease should be avoided, if Eyes Glucocorticoids Cataracts
Heart Anthracyclines, Cardiomyopathy
possible; however, the risk of late complica- trastuzumab
tions should not lead to the failure to apply po- Lung Bleomycin Pulmonary fibrosis
tentially curative treatment. The challenge is to Methotrexate Pulmonary hypersensitivity
preserve or augment the cure rate while de- Kidney Platinum, others Decreased function, hypomagnesemia
creasing the risk of serious treatment-related Liver Various Altered function
illness. Gonads Alkylating agents, Infertility, premature menopause
others
The mechanisms of damage vary. Surgical Bone marrow Various Aplasia, myelodysplasia, secondary leukemia
procedures can create abnormal physiology

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

 e92 mortality is as high as 50%, thus, prevention is the best approach.
Mitoxantrone is a related drug that has less cardiac toxicity. Adminis-
tration of doxorubicin by continuous intravenous infusion or encap-
sulated in liposomes appears to decrease the risk of heart damage.
Dexrazoxane, an intracellular iron chelator, may protect the heart
against anthracycline toxicity by preventing iron-dependent free-radi-
cal generation. Concern about antagonism of antitumor effects has re-
stricted its use.
Mediastinal radiation therapy that includes the heart can induce
acute pericarditis, chronic constrictive pericarditis, myocardial fibro-
sis, valvular abnormalities, or accelerated premature coronary athero-
sclerosis. The incidence of acute pericarditis is 5–13%; patients may
be asymptomatic or have dyspnea on exertion, fever, and chest pain.
The onset is insidious, with a peak about 9 months after treatment.
PART 6
Pericardial effusion may be present. Chronic constrictive pericarditis
can develop 5–10 years after treatment and usually presents with
dyspnea on exertion. Myocardial fibrosis may present as unexplained
CHF with diagnostic evaluation showing restrictive cardiomyopathy.
Patients may have aortic insufficiency from valvular thickening or mi-
tral regurgitation from papillary muscle dysfunction. Patients who re-
Oncology and Hematology
ceive mantle field radiation therapy have a threefold increased risk of
fatal myocardial infarction. Similarly, radiation of the carotids is asso-
ciated with premature atherosclerosis of the carotids and can produce
central nervous system (CNS) embolic disease. At very high doses,
such as those used before hematopoietic stem cell transplantation, cy-
clophosphamide can produce a hemorrhagic myocarditis. Trastu-
zumab (herceptin) has been associated with heart failure, particularly
in patients also receiving anthracyclines. Compromised ejection frac-
tion is noted in about 10% of patients; it is usually reversible with the
cessation of therapy.
PULMONARY DYSFUNCTION
Pulmonary fibrosis from bleomycin is dose-related, with potential ex-
acerbation by age, preexisting lung disease, thoracic radiation, high
concentrations of inhaled oxygen, and the concomitant use of other
chemotherapeutic agents. Several other chemotherapy agents and ra-
diation therapy can cause pulmonary fibrosis, and several can cause
pulmonary venoocclusive disease, especially following high-dose ther-
apy such as that involved in hematopoietic stem cell transplantation.
LIVER DYSFUNCTION
Clinically significant long-term damage to the liver from standard-
dose chemotherapy is relatively infrequent and mostly confined to
patients who have received chronic methotrexate for maintenance
therapy of acute lymphoblastic leukemia. Radiation doses to the liver
>1500 cGy can produce liver dysfunction. Although rarely seen with
standard-dose chemotherapy, hepatic venoocclusive disease is more
common with high-dose therapy, such as that given to prepare pa-
tients for autologous or allogeneic stem cell transplantation. Endothe-
lial damage is probably the inciting event.
RENAL/BLADDER DYSFUNCTION
Reduced renal function may be produced by cisplatin; it is usually
asymptomatic but may render the patient more susceptible to other
renal insults. Cyclophosphamide cystitis may eventually lead to the de-
velopment of bladder cancer. Ifosfamide produces cystitis and a proxi-
mal tubular defect, a Fanconi-like syndrome that is usually, but not
always, reversible.
ENDOCRINE DYSFUNCTION
Long-term survivors of childhood cancer who received cranial irradia-
tion are shorter, more likely to be obese, and have reductions in
strength, exercise tolerance, and bone mineral density. The obesity
may be related to alterations in leptin biology. Growth hormone defi-
ciency is the most common hormone deficiency.
Thyroid disease is common in patients who have received radia-
tion therapy to the neck, such as patients with Hodgkin’s disease, with
an incidence of up to 62% at 26 years post-therapy. Hypothyroidism
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
is the most common abnormality, followed by Graves’ disease, thy-
roiditis, and cancer. Such patients should have frequent measurement
of thyroid-stimulating hormone (TSH) levels to detect hypothyroid-
ism early and suppress the TSH drive, which may contribute to thy-
roid cancer.
NERVOUS SYSTEM DYSFUNCTION
Although many patients experience peripheral neuropathy during che-
motherapy, only a few have chronic problems, perhaps because they
have other coexisting diseases such as diabetes mellitus. High doses of
cisplatin can produce severe sensorimotor neuropathy. Vincristine may
produce permanent numbness and tingling in the fingers and toes.
Neurocognitive sequelae from intrathecal chemotherapy, with or
without radiation therapy, are recognized complications of the suc-
cessful therapy of childhood acute lymphoblastic leukemia. Cognitive
decline has been attributed to CNS radiation in the treatment of a va-
riety of tumor types. In addition, cognitive decline (“chemo brain”)
can follow the use of adjuvant chemotherapy in women being treated
for breast cancer. Because the agents are given at modest doses and are
not thought to cross the blood-brain barrier, the mechanism of the
cognitive decline is not defined. The phenomenon has not yet been
documented in adequately designed studies that take into account the
normal age-associated decline in cognition.
Many patients suffer intrusive thoughts about cancer recurrence for
many years after successful treatment. Adjustment to normal expecta-
tions can be difficult. Cancer survivors may often have more problems
holding a job, staying in a stable relationship, and coping with the usu-
al stresses of daily life. Suicidal symptoms are reported by a significant
minority of adult survivors of childhood cancer and represent treat-
able conditions requiring follow-up care.
A dose-related hearing loss can occur with the use of cisplatin, usu-
ally with doses >400 mg/m2. This is irreversible, and patients should
be screened with audiometric examinations periodically during such
therapy.
EYES
Cataracts may be caused by chronic glucocorticoid use, radiation ther-
apy to the head, and, rarely, by tamoxifen.
SEXUAL AND REPRODUCTIVE DYSFUNCTION
Reversible azoospermia can be caused by many chemotherapy agents.
The gonads may also be permanently damaged by radiation therapy or
by chemotherapeutic agents, particularly the alkylating agents. The ex-
tent of the damage depends upon the patient’s age and the total dose
administered. As a woman nears menopause, smaller amounts of che-
motherapy will produce ovarian failure. In men, chemotherapy may
produce infertility, but hormone production is not usually affected.
Women, however, commonly lose both fertility and hormone produc-
tion. The premature induction of menopause in a young woman can
have serious medical and psychological consequences. Hormone re-
placement therapy is controversial. Paroxetine and related drugs may
be useful in controlling hot flashes.
MUSCULOSKELETAL DYSFUNCTION
Late consequences of radiation therapy on the musculoskeletal system
occur mostly in children and are related to the radiation dose, volume
of tissue irradiated, and the age of the child at the time of therapy.
Damage to the microvasculature of the epiphyseal growth zone may
result in leg length discrepancy, scoliosis, and short stature.
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. The mechanism is unknown.
ORAL COMPLICATIONS
Radiation therapy can damage the salivary glands, producing dry
mouth. Without saliva, dental caries develop, and many patients have
poor dentition. In rare patients, taste can be adversely affected and ap-
petite can be suppressed.
SECOND MALIGNANCIES
Second malignancies are a major cause of death for those cured of can-
cer. Second malignancies can be grouped into three categories: those
associated with the primary cancer, those caused by radiation therapy,
and those caused by chemotherapy.
Primary cancers increase the risk of secondary cancers in a number
of settings. Patients with head and neck cancers are at increased risk of
developing a lung or esophageal cancer, and vice versa, probably be-
cause of shared risk factors, especially tobacco abuse. Patients with
breast cancer are at increased risk of a second breast cancer in the con-
tralateral breast. Patients with Hodgkin’s disease are at increased risk
of non-Hodgkin’s lymphoma. Patients with genetic syndromes, such
as multiple endocrine neoplasia type 1 or Lynch syndrome, are at in-
creased risk of second cancers of specific types. In none of these exam-
ples does it appear that treatment of the primary cancer is the cause of
the secondary cancer, but a role for treatment is difficult to exclude.
These predispositions should result in heightened surveillance in per-
sons at risk. The risk of second cancer is often sufficiently high that
cured cancer patients would make excellent candidates to assess
chemoprevention strategies.
Patients treated with radiation therapy have an increasing and appar-
ently lifelong risk of developing second solid tumors, usually in or adja-
cent to the radiation field. The risk is modest in the first decade after
treatment but reaches 1–2% per year in the second decade, such that
populations followed for 25 years or more have a ≥25% chance of devel-
oping a second treatment-related tumor. Some organs differ in their
susceptibility to radiation carcinogenesis with age; women receiving
chest radiation therapy after age 30 have a small increased risk of breast
cancer, but those <30 have a 19-fold increased risk. A 25-year-old wom-
an 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 chances of curing the second malignancies hinge on early diagnosis.
Patients who were treated with radiation therapy should be carefully ex-
amined on an annual basis and evaluated for any abnormalities in or-
gans and tissues that were in the radiation field. Symptoms in a patient
cured of cancer should not be dismissed as they may be an early sign of
second cancers. Studies are needed to assess preventive measures in pa-
tients at high risk of second cancers.
Chemotherapy produces two clinical syndromes that can be fatal:
myelodysplasia and acute myeloid leukemia. Two types of acute leuke-
mia have been described. The first occurs in patients treated with alkyl-
ating agents, especially over a protracted period. The malignant cells
frequently carry genetic deletions in chromosomes 5 or 7. The lifetime
risk is about 2%; the risk is increased by the addition of radiation thera-
py and is about three times higher in people treated over age 40. It peaks
in incidence 4–6 years after treatment; the risk returns to baseline if no
disease has developed within 10 years of treatment. The second type of
acute leukemia occurs after exposure to topoisomerase II inhibitors such
as doxorubicin or etoposide. It is morphologically indistinguishable
from the first but contains a characteristic chromosome translocation
involving 10q23. The incidence is <1%, and it usually occurs 1.5–3 years
after treatment. Both forms of acute leukemia are highly refractory to
treatment, and no preventive strategy has been developed.
Hormonal manipulations can also cause second tumors. Tamoxifen
induces endometrial cancer in about 1–2% of women taking it for 5
years or longer. Usually these tumors are found at an early stage; mor-
tality from endometrial cancer is very low compared to the benefit
from tamoxifen use as adjuvant therapy in women with breast cancer.
CONSEQUENCES BY CANCER TYPE
PEDIATRIC CANCERS
Quality of life is often excellent, although the majority have at least
one late effect. About one-third of long-term survivors have moderate
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
to severe problems. Cognitive function may be impaired. Late effects e93
are worse for those with poor socioeconomic status. Functional im-
pairments in the cardiovascular system due to radiation therapy and
anthracyclines, and in the lungs due to radiation therapy, are rare. Sco-
liosis and/or delayed growth due to radiation of the skeleton are more
common. Many survivors have psychosocial and sexual problems. Sec-
ond malignant neoplasms are a significant cause of death.
HODGKIN’S DISEASE
The patient cured of Hodgkin’s disease remains subject to long-term
medical problems such as thyroid dysfunction, premature coronary ar-
tery disease, gonadal dysfunction, postsplenectomy sepsis, and second
CHAPTER e13 Late Consequences of Cancer and Its Treatment
malignancies. The second malignancies encountered include myelodys-
plasia and acute myeloid leukemia, non-Hodgkin’s lymphomas, breast
cancer, lung cancer, and melanoma. The major risk factor for hemato-
logic malignancies is treatment with alkylating agents plus radiation
therapy, while solid tumors are more likely to be seen with the use of ra-
diation therapy. Patients cured of Hodgkin’s disease seem to experience
greater fatigue, have more psychosocial and sexual problems, and report
a poorer quality of life than patients cured of acute leukemia.
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. Chronic exposure to cyclo-
phosphamide increases the risk of bladder cancer. Patients cured of
lymphoma report a very good quality of life.
ACUTE LEUKEMIA
The late effects of antileukemic therapy include second malignancies
(hematologic and solid tumors), neuropsychiatric difficulties, subnor-
mal growth, thyroid abnormalities, and infertility.
HEAD AND NECK CANCER
Patients frequently have poor dentition, dry mouth, trismus, difficulty
in eating, and poor nutrition. Those with nasopharyngeal cancer re-
port the poorest long-term quality of life, possibly related to the vol-
ume of disease that is radiated.
STEM CELL TRANSPLANTATION
Cured patients are at risk of second cancers, especially if radiation
therapy was part of the treatment. They are also subject to gonadal
damage and infertility. Graft-versus-host disease is the leading factor
contributing to the morbidity and mortality from allogeneic bone
marrow transplantation, with an immune-mediated attack against the
skin, liver, and gut epithelium. About half of patients report psycho-
sexual problems.
BREAST CANCER
Patients treated with adjuvant chemotherapy and/or hormonal thera-
py for breast cancer are at risk for endometrial cancer from the use of
tamoxifen. The alternatives to tamoxifen, the aromatase inhibitors, do
not protect against osteoporosis and may increase the risk of this com-
plication. Those patients who have received chemotherapy may be at
risk from doxorubicin- or radiation-induced cardiomyopathy and
acute leukemia. Trastuzumab (Herceptin) may contribute to heart
failure. The development of premature ovarian failure from chemo-
therapy may cause hormone-deficient symptoms (hot flashes, de-
creased vaginal secretions, dyspareunia) and places women at risk for
osteoporosis and cardiovascular death. Patients commonly report in-
trusive thoughts of cancer and psychological distress.
TESTICULAR CANCER
Depending on the modalities used for therapy, patients cured of testic-
ular cancer can anticipate Raynaud’s phenomenon, renal and/or pul-
monary damage from chemotherapy, and retrograde ejaculation from
retroperitoneal lymph node dissection. Sexual dysfunction is reported
by 15% of patients cured of testicular cancer.
 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 colo-
rectal cancer. Quality of life is reported as high in long-term survivors.
PROSTATE CANCER
Radical surgical treatment is often accompanied by impotence, and
about 10–15% develop some urine incontinence. Use of radiation
therapy increases the risk of second cancers and may produce chronic
prostitis or cystitis.
OUTLOOK
The challenge for the future is to integrate new chemotherapy and bio-
PART 6
logic agents and newer techniques of delivering radiation therapy in a
fashion that increases cure rates and lowers the late effects of treat-
ment. Additional populations at risk for late effects include those with
cancers where therapy is becoming more effective, such as ovarian
cancer, and cancers where chemotherapy and radiation therapy are
used together in an organ-sparing approach, such as bladder, anal, and
Oncology and Hematology
laryngeal cancers. Patients who have been cured of a cancer represent
an important resource for cancer prevention studies. The Childhood
Cancer Survivor Study reported that survivors have a high rate of ill-
ness due to chronic health conditions. This incidence increases with
time and does not appear to plateau, indicating that monitoring of
survivors is a critical component of their overall health care.
FURTHER READINGS
AHLES T et al: Neuropsychiatric impact of standard-dose chemother-
apy in long-term survivors of breast cancer and lymphoma. J Clin
Oncol 20:485, 2002
BOOKMAN MA et al: Late complications of curative treatment in
Hodgkin’s disease. JAMA 260:680, 1988
BROWN LM et al: Risk of second non-hematologic malignancies
among 376,825 breast cancer survivors. Breast Cancer Res Treat Feb
3, 2007 PMID:17277968
HEWITT M et al (eds): From Cancer Patient to Cancer Survivor: Lost in
Transition. (Committee on Cancer Survivorship: Improving Care
and Quality of Life.) Washington, DC, National Academies Press,
2006
MACKIE E et al: Adult psychosocial outcomes in long-term survivors
of acute lymphoblastic leukemia and Wilms’ tumor: A controlled
study. Lancet 355:1310, 2000
TRAVIS LB et al: Cumulative absolute breast cancer risk for young
women treated for Hodgkin lymphoma. J Natl Cancer Inst
97:1428, 2005
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BEATY O et al: Subsequent malignancies in children and adolescents
after treatment for Hodgkin’s disease. J Clin Oncol 13:603, 1995
BINES J et al: Ovarian function in premenopausal women treated with
adjuvant chemotherapy for breast cancer. J Clin Oncol 14:1718,
1996
BJERGAARD JP et al: Acute nonlymphocytic leukemia, preleukemia,
and solid tumors following intensive chemotherapy of small cell
carcinoma of the lung. Blood 66:1393, 1985
BYRD R: Late effects of treatment of cancer in children. Pediatr Clin
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CHATTERJEE R, GOLDSTONE AH: Gonadal damage and effects on fer-
tility in adult patients with haematological malignancy undergoing
stem cell transplantation. Bone Marrow Transplant 17:5, 1996
CURTIS RE et al: Solid cancers after bone marrow transplantation. N
Engl J Med 336:897, 1997
DELAAT CA, LAMPKIN BC: Long-term survivors of childhood cancer:
Evaluation and identification of sequelae of treatment. CA Cancer J
Clin 42:263, 1992
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DILLER L: Rhabdomyosarcoma and other soft tissue sarcomas of
childhood. Curr Opin Oncol 4:689, 1992
DOLL DC: Vascular toxicity, in The Chemotherapy Sourcebook, 3d ed,
MC Perry (ed). Philadelphia, Lippincott Williams & Wilkins, 2001,
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EWER MS, BENJAMIN RS: Cardiotoxicity of chemotherapeutic drugs,
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FISHER B et al: Endometrial cancer in tamoxifen-treated breast cancer
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cer. Acta Oncol 31:243, 1992
GREEN DM et al: Late effects of treatment for Wilms’ tumor. Hematol
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HANCOCK SL et al: Thyroid diseases after treatment of Hodgkin’s dis-
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——— et al: Cardiac disease following treatment of Hodgkin’s disease
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——— et al: Factors affecting late mortality from heart disease after
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HENRY-AMAR M et al: Causes of death after therapy for early stage
Hodgkin’s disease entered on EORTC protocols. Int J Radiat Oncol
Biol Phys 19:1155, 1990
HYDZIK CA: Late effects of chemotherapy: Implications for patient
management and rehabilitation. Adv Oncol Nurs 25:423, 1990
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small cell lung cancer. Am J Med 81:962, 1986
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in children. Cancer Treat and Res 41:195, 1989
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cancer. Antibiot Chemother 41:199, 1988
LI F, MEADOWS AS: Cancer survivors: Future clinical and research is-
sues. ASCO Education Book, Spring 1998, pp 115–117
LIPSHULTZ S et al: Late cardiac effects of doxorubicin therapy for acute
lymphoblastic leukemia in childhood. N Engl J Med 324:808, 1991
—— et al: Female sex and higher drug dose as risk factors for late car-
diotoxic effects of doxorubicin therapy for childhood cancer. N
Engl J Med 332:1738, 1995
MARINA N: Long-term survivors of childhood cancer: The medical
consequences of cure. Pediatr Clin North Am 44:1021, 1997
MEADORS, M et al: Pulmonary toxicity of chemotherapy. Semin Oncol
33:98, 2006
MEISTER LA, MEADOWS AT: Late effects of childhood cancer therapy.
Curr Probl Pediatr 23:102, 1993
MOHN A et al: Thyroid function in children treated for acute lympho-
blastic leukemia. J Endocrinol Invest 20:215, 1997
MORRIS JONES PH: The late effects of cancer therapy in childhood (ed-
itorial). Br J Cancer 64:1, 1991
NEGLIA JP, NESBITT ME: Care and treatment of long-term survivors of
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NICHOLSON HS, BYRNE J: Fertility and pregnancy after treatment for
cancer during childhood or adolescence. Cancer 71:3392, 1993
NICHOLSON HS, MULVIHILL JJ: Late effects of therapy in survivors of
childhood and adolescent osteosarcoma. Cancer Treat Res 62:45, 1992
OCHS J, MULHERN RK: Late effects of antileukemic treatment. Pediatr
Clin North Am 35:815, 1988
———: Long-term sequelae of therapy for childhood acute lympho-
blastic leukaemia. Baillieres Clin Haematol 7:365, 1994
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lando, FL, Grune and Stratton, 1984, pp 1–19
RATAIN MJ et al: Acute nonlymphocytic leukemia following etoposide
and cisplatin combination chemotherapy for advanced non-small
cell carcinoma of the lung. Blood 70:1412, 1987
RECKLITIS CI et al: Suicidal ideation and attempts in adult survivors of
childhood cancer. J Clin Oncol 24:3852, 2006
REID H et al: Late effects of cancer treatment in children. Pediatr Dent
17:273, 1995
REID HL, JAFFE N: Radiation-induced changes in long-term survivors
of childhood cancer after treatment with radiation therapy. Semin
Roentgenol 29:6, 1994
ROWLAND KM, MURTHY A: Hodgkin’s disease: Long term effects of
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SCHELLONG G: The balance between cure and late effects in childhood
Hodgkin’s lymphoma: The experience of the German-Austrian
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SHAPIRO CL, HENDERSON IC: Adjuvant therapy of breast cancer. He-
matol Oncol Clin North Am 8:213, 1994
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
———, RECHT A: Late effects of adjuvant therapy for breast cancer. J e95
Natl Cancer Inst Monogr 16:101, 1994
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CHAPTER e13 Late Consequences of Cancer and Its Treatment
———: Risk of acute myelogenous leukaemia and myelodysplasia
following cancer treatment. Baillieres Clin Haematol 7:57, 1996
VOGELZANG NJ et al: Raynaud’s phenomenon: A common toxicity
after combination chemotherapy for testicular cancer. Ann Intern
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and adults: A review of 110 cases. Am J Med 62:200, 1977

e14 Laboratory Diagnosis
of Infectious Diseases
Alexander J. McAdam, Andrew B. Onderdonk
The laboratory diagnosis of infection requires the demonstration—ei-
ther direct or indirect—of viral, bacterial, fungal, or parasitic agents in
tissues, fluids, or excreta of the host. Clinical microbiology laborato-
ries are responsible for processing these specimens and also for deter-
mining the antibiotic susceptibility of bacterial and fungal pathogens.
Traditionally, detection of pathogenic agents has relied largely on ei-
ther the microscopic visualization of pathogens in clinical material or
the growth of microorganisms in the laboratory. Identification is gen-
erally based on phenotypic characteristics, such as fermentation pro-
files for bacteria, cytopathic effects in tissue culture for viral agents,
and microscopic morphology for fungi and parasites. These tech-
niques are reliable but are often time-consuming. Increasingly, the use
of nucleic acid probes is becoming a standard method for detection,
quantitation, and/or identification in the clinical microbiology labora-
tory, gradually replacing phenotypic characterization and microscopic
visualization methods.
DETECTION METHODS
Reappraisal of the methods employed in the clinical microbiology lab-
oratory has led to the development of strategies for detection of patho-
genic agents through nonvisual biologic signal detection systems.
Much of this methodology is based on the use of either electronic de-
tection systems involving relatively inexpensive but sophisticated com-
puters or nucleic acid probes directed at specific DNA or RNA targets.
This chapter discusses both the methods that are currently available
and those that are being developed.
BIOLOGIC SIGNALS
A biologic signal is a material that can be reproducibly differentiated
from other substances present in the same physical environment. Key
issues in the use of a biologic (or electronic) signal are distinguishing it
from background noise and translating it into meaningful informa-
tion. Examples of biologic signals applicable to clinical microbiology
include structural components of bacteria, fungi, and viruses; specific
antigens; metabolic end products; unique DNA or RNA base sequenc-
es; enzymes; toxins or other proteins; and surface polysaccharides.
DETECTION SYSTEMS
A detector is used to sense a signal and to discriminate between the
signal and background noise. Detection systems range from the
trained eyes of a technologist assessing morphologic variations to sen-
sitive electronic instruments, such as gas-liquid chromatographs cou-
pled to computer systems for signal analysis. The sensitivity with
which signals can be detected varies widely. It is essential to use a de-
tection system that discerns small amounts of signal even when bio-
logic background noise is present—i.e., that is both sensitive and
specific. Common detection systems include immunofluorescence;
chemiluminescence for DNA/RNA probes; flame ionization detection
of short- or long-chain fatty acids; and detection of substrate utiliza-
tion or end-product formation as color changes, of enzyme activity as
a change in light absorbance, of turbidity changes as a measure of
growth, of cytopathic effects in cell lines, and of particle agglutination
as a measure of antigen presence.
AMPLIFICATION
Amplification enhances the sensitivity with which weak signals can be
detected. 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. The ad-
vantage of growth as an amplification method is that it requires only
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
an appropriate growth medium; the disadvantage is the amount of e97
time required for amplification. More rapid specific amplification of
biologic signals can be achieved with techniques such as polymerase
chain reaction (PCR) or ligase chain reaction (LCR, for DNA/RNA),
enzyme immunoassays (EIAs, for antigens and antibodies), electronic
amplification (for gas-liquid chromatography assays), antibody cap-
ture methods (for concentration and/or separation), and selective fil-
tration or centrifugation. Although a variety of methods are available
for the amplification and detection of biologic signals in research,
thorough testing is required before these methods are validated as di-
agnostic assays.
DIRECT DETECTION
MICROSCOPY
The field of microbiology has been defined largely by the development
and use of the microscope. The examination of specimens by micro-
scopic methods rapidly provides useful diagnostic information. Stain-
ing techniques permit organisms to be seen more clearly.
The simplest method for microscopic evaluation is the wet mount,
which is used, for example, to examine cerebrospinal fluid (CSF) for
CHAPTER e14 Laboratory Diagnosis of Infectious Diseases
the presence of Cryptococcus neoformans, with India ink as a back-
ground against which to visualize large-capsuled yeast cells. Wet
mounts with dark-field illumination are also used to detect spiro-
chetes from genital lesions and to reveal Borrelia or Leptospira in
blood. 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 flu-
orescing structures. Staining of wet mounts—e.g., with lactophenol
cotton blue stain for fungal elements—is often used for morphologic
identification. These techniques enhance signal detection and de-
crease the background, making it easier to identify specific fungal
structures.
STAINING
Gram’s Stain Without staining, bacteria are difficult to see at the
magnifications (400× to 1000×) used for their detection. Although
simple one-step stains can be used, differential stains are more com-
mon. Gram’s stain differentiates between organisms with thick pepti-
doglycan cell walls (gram-positive) and those with thin peptidoglycan
cell walls and outer membranes that can be dissolved with alcohol or
acetone (gram-negative). Cellular morphology and Gram’s stain char-
acteristics can often be used to categorize stained organisms into
groups such as streptococci, staphylococci, and clostridia (Fig. e14-1).
Gram’s stain is particularly useful for examining sputum for poly-
morphonuclear leukocytes (PMNs) and bacteria. Sputum specimens
from immunocompetent patients with ≥25 PMNs and <10 epithelial
cells per low-power field often provide clinically useful information.
However, the presence in “sputum” samples of >10 epithelial cells per
low-power field and of multiple bacterial types suggests contamina-
tion with oral microflora. Despite the difficulty of discriminating be-
tween normal microflora and pathogens, Gram’s stain may prove
useful for specimens from areas with a large resident microflora if a
useful biologic marker (signal) is available. 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 vagi-
nosis. Similarly, examination of stained stool specimens for leukocytes
is useful as a screening procedure before testing for Clostridium diffi-
cile toxin or other enteric pathogens.
The examination of CSF and joint, pleural, or peritoneal fluid with
Gram’s stain is useful for determining whether bacteria and/or PMNs
are present. The sensitivity is such that >104 bacteria per milliliter
should be detected. Centrifugation is often performed before staining
to concentrate specimens thought to contain low numbers of organ-
isms. The pellet is examined after staining. This simple method is par-
ticularly useful for examination of CSF for bacteria and white blood
cells or of sputum for acid-fast bacilli (AFB).
 e98 Gram-Negative Organisms or in viral cell cultures. The bio-
logic signal in each case is the an-
GRx only Oxidase + Oxidase – Fastidious Anaerobic Curved tigen to be detected. Monoclonal
Rod Pseudomonas Enterobacteriaceae Haemophilus Bacteroides Vibrio or polyclonal antibodies cou-
Aeromonas Others Legionella Prevotella Campylobacter pled to a reporter (such as latex
Pasteurella Bordetella Fusobacterium particles or an enzyme) are used
Others Brucella Others for detection of antibody-anti-
Francisella
Others
gen binding reactions.
Techniques such as direct ag-
Coccus Neisseria Veillonella glutination of bacterial cells with
Branhamella Acidaminococcus
specific antibody are simple but
Megasphaera
relatively insensitive, while latex
agglutination and EIAs are more
Gram-Positive Organisms
sensitive. Some cell-associated
Branching Spores Acid-Fast Catalase + Catalase – antigens, such as capsular poly-
saccharides and lipopolysac-
Rod Nocardia Clostridium Mycobacterium Corynebacterium Lactobacillus
Actinomyces Bacillus Listeria Others charides, can be detected by
Bifidobacterium Others agglutination of a suspension of
bacterial cells when antibody is
Coccus Staphylococcus Streptococcus added; this method is useful for
Micrococcus
Others
typing of the somatic antigens of
Shigella and Salmonella. In sys-
FIGURE e14-1 Interpretation of Gram’s stain. tems such as EIAs, which employ
PART 7

antibodies coupled to an en-

zyme, an antigen-antibody reac-
Acid-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., Myco- product. Because the coupling of an enzyme to the antibody can amplify
bacterium spp.). Modifications of this procedure allow the differen- a weak biologic signal, the sensitivity of such assays is often high. In each
tiation of Actinomyces from Nocardia or other weakly (or partially) instance, the basis for antigen detection is antigen-antibody binding,
acid-fast organisms. The acid-fast stain is applied to sputum, other with the detection system changed to accommodate the biologic signal.
Infectious Diseases

fluids, and tissue samples when AFB (e.g., Mycobacterium spp.) are Most such assays provide information as to whether antigen is present
suspected. The identification of the pink/red AFB against the blue but do not quantify the antigen. EIAs are also useful for detecting bacte-
background of the counterstain requires a trained eye, since few AFB rial toxins—e.g., C. difficile toxins A and B in stool.
may be detected in an entire smear, even when the specimen has been Rapid and simple tests for antigens of group A Streptococcus, influ-
concentrated by centrifugation. An alternative method is the au- enza virus, and respiratory syncytial virus can be used in the clinic set-
ramine-rhodamine combination fluorescent dye technique. ting, without a specialized diagnostic laboratory. Such tests are usually
reasonably specific but may have only modest sensitivity.
Fluorochrome Stains Fluorochrome stains, such as acridine orange,
are used to identify white blood cells, yeasts, and bacteria in body flu-
ids. Other specialized stains, such as Dappe’s stain, may be used for the DETECTION OF PATHOGENIC AGENTS BY CULTURE
detection of mycoplasmas in cell cultures. Capsular, flagellar, and SPECIMEN COLLECTION AND TRANSPORT
spore stains are used for identification or demonstration of character- To culture bacterial, mycotic, or viral pathogens, an appropriate sam-
istic structures. ple must be placed into the proper medium for growth (amplifica-
tion). 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 laborato-
technique uses antibody coupled to a fluorescing compound, such as ry-processing algorithm suitable for the specific sample/agent. In
fluorescein, and directed at a specific antigenic target to visualize or- some instances, it is better for specimens to be plated at the time of
ganisms or subcellular structures. When samples are examined under collection rather than first being transported to the laboratory (e.g.,
appropriate conditions, 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. specimens for pneumococci). In general, the more rapidly a specimen
In the indirect immunofluorescent antibody technique, an unlabeled is plated onto appropriate media, the better the chance for isolating
(target) antibody binds a specific antigen. The specimen is then bacterial pathogens. 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. Ta-
target antibody. 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. Because there are many pathogen-specific paradigms for
antibody, the visual signal can be intensified (i.e., amplified). This these procedures, 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.
used to generate the signal for detection of the antigen. Both direct
and indirect methods detect viral antigens (e.g., cytomegalovirus, her- ISOLATION OF BACTERIAL PATHOGENS
pes simplex virus, 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. Such media
(e.g., Legionella pneumophila) directly in clinical specimens. are composed of agar, which is not metabolized by bacteria; nutrients
to support the growth of the species of interest; and sometimes sub-
MACROSCOPIC ANTIGEN DETECTION stances to inhibit the growth of other bacteria. Broth is employed for
Latex agglutination assays and EIAs are rapid and inexpensive methods growth (amplification) of organisms from specimens with few bacte-
for identifying organisms, extracellular toxins, and viral agents by means ria, such as peritoneal dialysis fluid, CSF, or samples in which anaer-
of protein and polysaccharide antigens. Such assays may be performed obes or other fastidious organisms may be present. The general use of
directly on clinical samples or after growth of organisms on agar plates liquid medium for all specimens is not worthwhile.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE e99
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 sus-
pected. This information determines the selection of culture media and the length of culture time.

Type of Culture
(Synonyms) Specimen Minimum Volume Container Other Considerations
Blood
Blood, routine Whole blood 10 mL in each of 2 bottles See below.a See below.b
(blood culture for for adults and children;
aerobes, anaer- 5 mL, if possible, in aer-
obes, and yeasts) obic bottles for infants;
less for neonates
Blood for fungi/My- Whole blood 10 mL in each of 2 bot- Same as for routine blood Specify “hold for extended incuba-
cobacterium spp. tles, as for routine blood culture tion,” since fungal agents may re-
cultures, or in Isolator quire ≥4 weeks to grow.
tube requested from
laboratory
Blood, Isolator (lysis Whole blood 10 mL Isolator tubes Use mainly for isolation of fungi, Myco-
centrifugation) bacterium, or other fastidious aerobes
and for elimination of antibiotics from
cultured blood in which organisms are
concentrated by centrifugation.

CHAPTER e14 Laboratory Diagnosis of Infectious Diseases

Respiratory Tract
Nose Swab from nares
Throat Swab of posterior phar-
ynx, ulcerations, or
areas of suspected
purulence
Sputum Fresh sputum (not
saliva)
Bronchial aspirates Transtracheal aspirate,
bronchoscopy speci-
men, or bronchial
aspirate
Stool
Stool for routine cul- Rectal swab or (prefera-
ture; stool for Sal- bly) fresh, randomly
monella, Shigella, collected stool
and Campylobacter
Stool for Yersinia, E. Fresh, randomly
coli O157 collected stool
Stool for Aeromonas Fresh, randomly
and Plesiomonas collected stool
Urogenital Tract
Urine Clean-voided urine spec-
imen or urine col-
lected by catheter
Urogenital secre- Vaginal or urethral
tions secretions, cervical
swabs, uterine fluid,
prostatic fluid, etc.
Body Fluids, Aspirates, and Tissues
Cerebrospinal fluid Spinal fluid
(lumbar puncture)
Body fluids Aseptically aspirated
body fluids
1 swab Sterile culturette or similar trans-
port system containing hold-
ing medium
1 swab Sterile culturette or similar swab
specimen collection system
containing holding medium
2 mL Commercially available sputum
collection system or similar
sterile container with screw
cap
1 mL of aspirate or brush Sterile aspirate or bronchoscopy
in transport medium tube, bronchoscopy brush in a
separate sterile container
1 g of stool or 2 rectal Plastic-coated cardboard cup or
swabs plastic cup with tight-fitting
lid. Other leak-proof containers
are also acceptable.
1g Plastic-coated cardboard cup or
plastic cup with tight-fitting lid
1g Plastic-coated cardboard cup or
plastic cup with tight-fitting lid
0.5 mL Sterile, leak-proof container with
screw cap or special urine
transfer tube
1 swab or 0.5 mL of fluid Vaginal and rectal swabs trans-
ported in Amies transport
medium or similar holding
medium for group B Strepto-
coccus; direct inoculation pre-
ferred for Neisseria gonorrhoeae
1 mL for routine cultures; Sterile tube with tight-fitting cap
≥5 mL for Mycobacterium
1 mL for routine cultures Sterile tube with tight-fitting
cap. Specimen may be left in
syringe used for collection if
the syringe is capped before
transport.
Swabs made of calcium alginate may
be used.
See below.c
Cause for rejection: Care must be taken
to ensure that the specimen is spu-
tum and not saliva. Examination of
Gram’s stain, with number of epithe-
lial cells and PMNs noted, can be an
important part of the evaluation
process. Induced sputum specimens
should not be rejected.
Special precautions may be required,
depending on diagnostic consider-
ations (e.g., Pneumocystis).
If Vibrio spp. are suspected, the labora-
tory must be notified, and appropri-
ate collection/transport methods
should be used.
Limitations: Procedure requires
enrichment techniques.
Limitations: Stool should not be cul-
tured for these organisms unless also
cultured for other enteric pathogens.
See below.d
Vaginal swab samples for “routine cul-
ture” should be discouraged when-
ever possible unless a particular
pathogen is suspected. For detec-
tion of multiple organisms (e.g.,
group B Streptococcus, Trichomonas,
Chlamydia, or Candida spp.), 1 swab
per test should be obtained.
Do not refrigerate; transfer to labora-
tory as soon as possible.
For some body fluids (e.g., peritoneal
lavage samples), increased volumes
are helpful for isolation of small
numbers of bacteria.
(continued)

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

 e100 TABLE e14-1 INSTRUCTIONS FOR COLLECTION AND TRANSPORT OF SPECIMENS FOR CULTURE (CONTINUED)
Type of Culture
(Synonyms) Specimen
Biopsy and aspirated Tissue removed at sur-
materials gery, bone, anticoagu-
lated bone marrow,
biopsy samples, or oth-
er specimens from nor-
mally sterile areas
Wounds Purulent material or ab-
scess contents ob-
tained from wound or
abscess without con-
tamination by normal
microflora
Special Recommendations
Fungi Specimen types listed
above may be used.
When urine or sputum
is cultured for fungi, a
first morning specimen
is usually preferred.
Mycobacterium Sputum, tissue, urine,
(acid-fast bacilli) body fluids
PART 7
Minimum Volume
1 mL of fluid or a 1-g
piece of tissue
2 swabs or 0.5 mL of as-
pirated pus
1 mL or as specified
above for individual
listing of specimens.
Large volumes may be
useful for urinary fungi.
10 mL of fluid or small
piece of tissue. Swabs
Container
Sterile “culturette”-type swab or
similar transport system con-
taining holding medium. Ster-
ile bottle or jar should be used
for tissue specimens.
Culturette swab or similar trans-
port system or sterile tube with
tight-fitting screw cap. For simul-
taneous anaerobic cultures, send
specimen in anaerobic transport
device or closed syringe.
Sterile, leak-proof container with
tight-fitting cap
Sterile container with tight-fit-
ting cap
Other Considerations
Accurate identification of specimen and
source is critical. Enough tissue should
be collected for both microbiologic
and histopathologic evaluations.
Collection: Abscess contents or other
fluids should be collected in a sy-
ringe (rather than with a swab)
when possible to provide an ade-
quate sample volume and an anaer-
obic environment.
Collection: Specimen should be trans-
ported to microbiology laboratory
within 1 h of collection. Contamina-
tion with normal flora from skin, rec-
tum, vaginal tract, or other body
surfaces should be avoided.
Detection of Mycobacterium spp. is im-
proved by use of concentration tech-

should not be used. niques. Smears and cultures of pleural,

peritoneal, and pericardial fluids often
have low yields. Multiple cultures from
the same patient are encouraged. Cul-
turing in liquid media shortens the
time to detection.
Legionella Pleural fluid, lung biopsy, 1 mL of fluid; any size tis- — —
bronchoalveolar lav- sue sample, although a
Infectious Diseases

age fluid, bronchial/ 0.5-g sample should be

transbronchial biopsy. obtained when possible.
Rapid transport to lab-
oratory is critical.
Anaerobic Aspirated specimens 1 mL of aspirated fluid, 1 An appropriate anaerobic trans- Specimens cultured for obligate
organisms from abscesses or body g of tissue, or 2 swabs port device is required.e anaerobes should be cultured for
fluids facultative bacteria as well. Fluid or
tissue is preferred to swabs.
Virusesf Respiratory secretions, 1 mL of fluid, 1 swab, or 1 Fluid or stool samples in sterile Most samples for culture are trans-
wash aspirates from g of stool in each ap- containers or swab samples in ported in holding medium contain-
respiratory tract, nasal propriate transport viral culturette devices (kept on ing antibiotics to prevent bacterial
swabs, blood samples medium ice but not frozen) are generally overgrowth and viral inactivation.
(including buffy coats), suitable. Plasma samples and Many specimens should be kept
vaginal and rectal buffy coats in sterile collection cool but not frozen, provided they
swabs, swab speci- tubes should be kept at 4−8°C. are transported promptly to the lab-
mens from suspicious If specimens are to be shipped oratory. Procedures and transport
skin lesions, stool sam- or kept for a long time, freezing media vary with the agent to be cul-
ples (in some cases) at −80°C is usually adequate. tured and the duration of transport.
aFor samples from adults, two bottles (smaller for pediatric samples) should be used: one screening for and identification of beta-hemolytic Streptococcus spp. and other poten-
with dextrose phosphate, tryptic soy, or another appropriate broth and the other with tially pathogenic organisms. Although considered components of the normal micro-
thioglycollate or another broth containing reducing agents appropriate for isolation of flora, organisms such as Staphylococcus aureus, Haemophilus influenzae, and
obligate anaerobes. For children, from whom only limited volumes of blood can be ob- Streptococcus pneumoniae will be identified by most laboratories, if requested. When
tained, only an aerobic culture should be done unless there is specific concern about Neisseria gonorrhoeae or Corynebacterium diphtheriae is suspected, a special culture re-
anaerobic sepsis (e.g., with abdominal infections). For special situations (e.g., suspected quest is recommended.
fungal infection, culture-negative endocarditis, or mycobacteremia), different blood col- d(1) Clean-voided specimens, midvoid specimens, and Foley or indwelling catheter

lection systems may be used (Isolator systems; see table).
bCollection: An appropriate disinfecting technique should be used on both the bottle
septum and the patient. Do not allow air bubbles to get into anaerobic broth bottles.
Special considerations: There is no more important clinical microbiology test than the de-
tection of blood-borne pathogens. The rapid identification of bacterial and fungal
agents is a major determinant of patients’ survival. Bacteria may be present in blood ei-
ther continuously (as in endocarditis, overwhelming sepsis, and the early stages of sal-
monellosis and brucellosis) or intermittently (as in most other bacterial infections, in
which bacteria are shed into the blood on a sporadic basis). Most blood culture systems
specimens that yield ≥50,000 organisms/mL and from which no more than three species
are isolated should have organisms identified. Neither indwelling catheter tips nor urine
from the bag of a catheterized patient should be cultured. (2) Straight-catheterized,
bladder-tap, and similar urine specimens should undergo a complete workup (identifi-
cation and susceptibility testing) for all potentially pathogenic organisms, regardless of
colony count. (3) Certain clinical problems (e.g., acute dysuria in women) may warrant
identification and susceptibility testing of isolates present at concentrations of <50,000
organisms/mL.
eAspirated specimens in capped syringes or other transport devices designed to limit ox-

employ two separate bottles containing broth medium: one that is vented in the labora-
tory for the growth of facultative and aerobic organisms and a second that is maintained
under anaerobic conditions. In cases of suspected continuous bacteremia/fungemia,
two or three samples should be drawn before the start of therapy, with additional sets
obtained if fastidious organisms are thought to be involved. For intermittent bacteremia,
two or three samples should be obtained at least 1 h apart during the first 24 h.
cNormal microflora includes alpha-hemolytic streptococci, saprophytic Neisseria spp.,
ygen exposure are suitable for the cultivation of obligate anaerobes. A variety of com-
mercially available transport devices may be used. Contamination of specimens with
normal microflora from the skin, rectum, vaginal vault, or another body site should be
avoided. Collection containers for aerobic culture (such as dry swabs) and inappropriate
specimens (such as refrigerated samples; expectorated sputum; stool; gastric aspirates;
and vaginal, throat, nose, and rectal swabs) should be rejected as unsuitable.
fLaboratories generally use diverse methods to detect viral agents, and the specific re-

diphtheroids, and Staphylococcus spp. Aerobic culture of the throat (“routine”) includes quirements for each specimen should be checked before a sample is sent.

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

 e101
Suspected Infectious Agent Obtain Appropriate Specimen

Bacteriology specimen Mycology specimen: Use Virology specimen: use

for rapid diagnosis or fluorochrome stain for cell culture or serologic
routine culture methods fungal elements in tissue, methods; samples include
for common and hair, and skin scrapings; buffy coat, serum, blood,
fastidious pathogens culture and identify yeast bronchial wash, stool,
isolates from blood and CSF urine
Rapid diagnosis: Latex DNA/RNA amplification
agglutination for Cryptococcus; for Chlamydia, GC, TB;
Sample preparation: Examine cell cultures
direct DNA/RNA probes; direct stain for infectious
Culture to Sabouraud’s for CPE; use serology
Gram’s stain for sputum agents such as
and other media; stain to detect antibody in
or vaginal swab Legionella, Pneumocystis
with lactophenol cotton acute and convalescent
blue or other stain; sera; use rapid DFA
Stool: Gram’s stain for Blood: Specify site and examine wet mount where possible
Urine, wound, tissue, or
fecal leukocytes; sputum: Specify site and time of collection; use
selective agar for common collection method; Isolator cultures for
Assess microscopic Use immunofluorescence
pathogens; specialized prepare sample for fungus, Mycobacterium
morphology; test for for viral agents in
media for other pathogens culture; use enrichment
substrate assimilation; cultures; use other
and selective agar
examine sporulation identification methods,
medium; use other tests such as direct DNA/RNA

CHAPTER e14 Laboratory Diagnosis of Infectious Diseases

Evaluate MacConkey’s,
HE, BAP, Tergitol agars for
pathogens; serogroup
Salmonella, Shigella;
examine specialized
media for other pathogens
Evaluate MacConkey’s,
BAP, and chocolate agar
for pathogens; use liquid
medium for fastidious
pathogens; use Gram’s
stain or other rapid tests
as appropriate (serology) probes
Examine both aerobic and
anaerobic liquid medium;
subculture to chocolate Perform fungal Viral load testing:
agar or 7H10 for TB; use susceptibility tests for Use for CMV, HIV,
other enrichment media yeasts and molds HepC; use DNA/RNA
for HACEK when necessary to amplification for
detect resistance genotyping

C. difficile: Isolation; Anaerobes: Group Isolation from

Cell culture identification of with Gram’s stain, subculture; identification
assay or EIA pathogens; perform spore test, and of pathogens; perform
for toxins A susceptibility tests; GLC; use susceptibility tests;
and B report MRSA, fermentation profile report MRSA, VREF,
VREF, ESBL for identification ESBL

FIGURE e14-2 Common specimen-processing algorithms used in Haemophilus aphrophilus/parainfluenzae/paraphrophilus, Actinobacil-

clinical microbiology laboratories. Abbreviations: BAP, blood agar
plate; CMV, cytomegalovirus; CPE, cytopathic effects; CSF, cerebrospi-
nal fluid; DFA, direct fluorescent antibody; EIA, enzyme immunoassay;
ESBL, extended-spectrum β-lactamase; GBS, group B Streptococcus;
GC, Neisseria gonorrhoeae; GLC, gas-liquid chromatography; HACEK,
lus actinomycetemcomitans, Cardiobacterium hominis, Eikenella cor-
rodens, and Kingella kingae; HE, Hektoen enteric medium; HepC,
hepatitis C virus; HIV, human immunodeficiency virus; MRSA, methicil-
lin-resistant Staphylococcus aureus; TB, Mycobacterium tuberculosis;
VREF, vancomycin-resistant Enterococcus faecium.

Two basic strategies are used to isolate pathogenic bacteria. 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, which contain
no bacteria under normal conditions. Broths that allow the growth of
small numbers of organisms may be subcultured to solid media when
growth is detected. The second strategy is to use selective media to iso-
late (amplify) specific bacterial species from stool, genital tract secre-
tions, or sputum—sites that contain many bacteria under normal
conditions. Antimicrobial agents or other inhibitory substances are in-
corporated into the agar medium to inhibit growth of all but the bac-
teria of interest. After incubation, organisms that grow on such media
are further characterized to determine whether they are pathogens. Se-
lection for organisms that may be pathogens from the normal micro-
flora shortens the time required for diagnosis (Fig. e14-2).
ISOLATION OF VIRAL AGENTS
(See also Chap. 170) Pathogenic viral agents often are sought by cul-
ture 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. The biologic signal—virus—is amplified to a detect-
able level. Although a number of techniques are available, an essential
element is a monolayer of cultured mammalian cells sensitive to infec-
tion with the suspected virus. These cells serve as the amplification
system by allowing the proliferation of viral particles. Virus may be de-
tected by direct observation of the cultured cells for cytopathic effects
or by immunofluorescent detection of viral antigens following incuba-
tion. Conventional viral culture is useful for detection of rapidly prop-
agated agents, such as herpes simplex virus. Viruses that grow more
slowly (e.g., cytomegalovirus and varicella-zoster virus) can be detect-
ed quickly by shell-vial culture, 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.
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 or-
ganisms’ integrity and ability to replicate may be damaged by humoral
defense mechanisms or antimicrobial agents. Over the years, 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. The most common systems involve either
(1) the measurement of gas pressure in the headspace to indicate bac-
terial gas production or consumption or (2) the use of reflectance op-
tics, 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. These systems measure CO2 concentration as indicative
of microbial growth. Such methods are no more sensitive than the hu-
man eye in detecting a positive culture; however, because the bottles in
an automated system are monitored more frequently, a positive cul-
ture is often detected more rapidly than by manual techniques, and
important information, including the result of Gram’s stain and pre-

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

 e102 liminary susceptibility assays, can be obtained sooner. One advantage
of automated blood culture systems is that the bottles are scanned
continuously in a noninvasive monitoring procedure, and thus the
likelihood of laboratory contamination is decreased.
Several factors affect the yield of blood culture from bacteremic pa-
tients. Increasing the volume of blood tested increases the chance of a
positive culture. An increase from 10 to 20 mL of blood increases the
proportion of positive cultures by ~30%; however, this effect is less
pronounced in patients with bacterial endocarditis. Obtaining multi-
ple cultures (up to three per 24-h period) also increases the chance of
detecting a bacterial pathogen. Prolonged culture and blind subculture
for detection of most fastidious bacteria (e.g., Haemophilus, Actinoba-
cillus, Cardiobacterium, Eikenella, and Kingella spp.) are not needed
with automated blood culture systems.
Automated systems have also been applied to the detection of micro-
bial growth from specimens other than blood, such as peritoneal and
other normally sterile fluids. Mycobacterium spp. can be detected in cer-
tain automated systems if appropriate liquid media are used for culture.
Although automated blood culture systems are more sensitive than lysis-
centrifugation methods (Isolator) for yeasts and most bacteria, lysis-cen-
trifugation culture is recommended for filamentous fungi, Histoplasma
capsulatum, and some fastidious bacteria (Legionella and Bartonella).
PART 7
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, includ-
ing Brucella, Legionella, Rickettsia, and Helicobacter pylori. The biologic
signal is usually either IgM or IgG antibody directed at surface-ex-
pressed antigen. The detection systems include those used for bacterial
Infectious Diseases
antigens (agglutination reactions, immunofluorescence, and EIA) and
unique systems such as hemolysis inhibition and complement fixation.
Serologic methods generally fall into two categories: those that deter-
mine protective antibody levels and those that measure changing anti-
body titers during infection. Determination of an antibody response as a
measure of current immunity is important in the case of viral agents for
which there are vaccines, such as rubella virus or varicella-zoster virus;
assays for this purpose normally use one or two dilutions of serum for a
qualitative determination of protective antibody levels. Quantitative se-
rologic assays to detect increases in antibody titers most often employ
paired serum samples obtained at the onset of illness and 10–14 days lat-
er (i.e., acute- and convalescent-phase samples). Since the incubation
period before symptoms are noted may be long enough for an antibody
response to occur, the demonstration of acute-phase antibody alone is
often insufficient to establish the diagnosis of active infection as op-
posed to past exposure. In such circumstances, IgM may be useful as a
measure of an early, acute-phase antibody response. A fourfold increase
in total antibody titer or in EIA activity between the acute- and conva-
lescent-phase samples is also regarded as evidence for active infection.
For certain viral agents, such as Epstein-Barr virus, the antibodies
produced may be directed at different antigens during different phases
of the infection. For this reason, most laboratories test for antibody di-
rected at both viral capsid antigens and antigens associated with re-
cently infected host cells to determine the stage of infection.
IDENTIFICATION METHODS
Once bacteria are isolated, characteristics that are readily detectable af-
ter growth on agar media (colony size, color, hemolytic reactions,
odor, microscopic appearance) may suggest a species, but definitive
identification requires additional tests. Identification methods include
classic biochemical phenotyping, which is still the most common ap-
proach, and more sophisticated methods such as gas chromatography
and nucleic acid tests.
CLASSIC PHENOTYPING
Classic phenotypic identification of bacteria entails tests for protein or
carbohydrate antigens, the production of specific enzymes, the ability
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
to metabolize specific substrates and carbon sources (such as carbohy-
drates), or the production of certain metabolites. Rapid versions of
some of these tests are available, and many common organisms can be
identified on the first day of growth. Other organisms, particularly
gram-negative bacteria, require more extensive testing, either manual
or automated.
Automated systems allow rapid phenotypic identification of bacte-
rial pathogens. Most such systems are based on biotyping techniques,
in which isolates are grown on multiple substrates and the reaction
pattern is compared with known patterns for various bacterial spe-
cies. This procedure is relatively fast, and commercially available sys-
tems include miniaturized fermentation, coding to simplify recording
of results, and probability calculations for the most likely pathogens.
If the biotyping approach is automated and the reading process is
coupled to computer-based data analysis, rapidly growing organisms
(such as Enterobacteriaceae) can be identified within hours of detec-
tion on agar plates.
Several systems use preformed enzymes for even speedier identifi-
cation (within 2–3 h). Such systems do not rely on bacterial growth
per se to determine whether a substrate has been used. They employ a
heavy inoculum in which specific bacterial enzymes are present in
amounts sufficient to convert substrate to product rapidly. In addi-
tion, some systems use fluorogenic substrate/end-product detection
methods to increase sensitivity (through signal amplification).
GAS-LIQUID CHROMATOGRAPHY
Gas-liquid chromatography is often used to detect metabolic end
products of bacterial fermentations. One common application is iden-
tification of short-chain fatty acids produced by obligate anaerobes
during glucose fermentation. Because the types and relative concen-
trations of volatile acids differ among the various genera and species
that make up this group of organisms, such information serves as a
metabolic “fingerprint” for a particular isolate.
Gas-liquid chromatography can be coupled to a sophisticated sig-
nal-analysis software system for identification and quantitation of
long-chain fatty acids (LCFAs) in the outer membranes and cell walls
of bacteria and fungi. For any given species, the types and relative con-
centrations of LCFAs are distinctive enough to allow differentiation
even from closely related species. An organism may be identified de-
finitively within a few hours after detection of growth on appropriate
media. LCFA analysis is one of the most advanced procedures current-
ly available for phenotypic characterization.
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, viral, parasitic, and fungal infections. Nu-
cleic acid tests are used for four purposes. First, they are used to detect,
and sometimes to quantify, specific pathogens in clinical specimens.
Second, such tests are used for identification of organisms (usually bac-
teria) that are difficult to identify by conventional methods. Third, nu-
cleic 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”). Last, nucleic acid tests are used to predict the sensitivity of or-
ganisms (typically viruses) to chemotherapeutic agents. Current tech-
nology encompasses a wide array of methods for amplification and
signal detection, some of which have been approved by the U.S. Food
and Drug Administration (FDA) for clinical diagnosis.
Use of nucleic acid tests generally involves lysis of intact cells or vi-
ruses and denaturation of the DNA or RNA to render it single-strand-
ed. 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, depending on the system employed. In situ hy-
bridization of a probe to a target is also possible and allows the use of
probes with agents present in tissue specimens. Once the probe(s) or
primer(s) have been hybridized to the target (biologic signal), a variety
of strategies may be employed to detect, amplify, and/or quantify the
target-probe complex (Fig. e14-3).

Lysis
Extraction
Debris
Heat
DNA/RNA
Direct Target
Detection Amplification
ssDNA/RNA ssDNA/RNA
Hybridize
Probe and
Probe
reporter
Heat
Hybridize
Complementary
strand
extension
20–30 cycles
Detection
Detection
FIGURE e14-3 Strategies for amplification and/or detection of a
target-probe complex. DNA or RNA extracted from microorganisms
is heated to create single-stranded (ss) DNA/RNA containing appropri-
ate target sequences. These target sequences may be hybridized di-
rectly (direct detection) with probes attached to reporter molecules;
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 Nucle-
ic acid probes are used for direct detection of pathogens in clinical
specimens without amplification of the target strand of DNA or
RNA. Such tests detect a relatively short sequence of bases specific
for a particular pathogen on single-stranded DNA or RNA by hy-
bridization of a complementary sequence of bases (probe) coupled
to a “reporter” system that serves as the signal for detection. Nucleic
acid probes are available commercially for direct detection of various
bacterial and parasitic pathogens, including Chlamydia trachomatis,
N. gonorrhoeae, and group A Streptococcus. A combined assay to de-
tect and differentiate agents of vaginitis/vaginosis (Gardnerella vagi-
nalis, Trichomonas vaginalis, and Candida spp.) has also been
approved. An assortment of probes are available for confirming the
identity of cultured pathogens, including some dimorphic molds,
Mycobacterium spp., and other bacteria (e.g., Campylobacter spp.,
Streptococcus spp., and Staphylococcus aureus). Probes for the direct
detection of bacterial pathogens are often aimed at highly conserved
16S ribosomal RNA sequences, of which there are many more copies
than there are of any single genomic DNA sequence in a bacterial
cell. The sensitivity and specificity of probe assays for direct detec-
tion are comparable to those of more traditional assays, including
EIA and culture.
In an alternative probe assay, called hybrid capture, an RNA probe
anneals to a DNA target, and the resulting DNA/RNA hybrid is cap-
tured on a solid support by antibody specific for DNA/RNA hybrids
(concentration/amplification) and detected by chemiluminescent-
labeled antibody specific for DNA/RNA hybrids. Hybrid capture as-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Intact cell e103
(as DNA/RNA)
DNA/RNA
ss
Signal Hybrid
Amplification Capture
ssDNA/RNA ssRNA
DNA probe
Probe (bDNA)
Hybridize
Hybridize
DNA/RNA hybrid
Solid support
Antibody capture
CHAPTER e14 Laboratory Diagnosis of Infectious Diseases
Reporter
Antibody and
reporter
Detection Detection
probe; or the original target-probe signal may be amplified via hybrid-
ization with an additional probe containing multiple copies of a sec-
ondary reporter target sequence (branched-chain DNA, or bDNA).
DNA/RNA hybrids can also be “captured” on a solid support (hybrid
capture), with antibody directed at the DNA/RNA hybrids used to con-
centrate them and a second antibody coupled to a reporter molecule
attached to the captured hybrid.
says are available for C. trachomatis, N. gonorrhoeae, cytomegalovirus,
and human papillomavirus.
Many laboratories have developed their own probes for pathogens;
however, unless a method-validation protocol for diagnostic testing
has been performed, federal law in the United States restricts the use of
such probes to research.
Nucleic Acid Amplification Test Strategies In theory, a single target
nucleic acid sequence can be amplified to detectable levels. There are
several strategies for nucleic acid amplification tests (NAATs), includ-
ing PCR, LCR, strand displacement amplification, and self-sustaining
sequence replication. In each case, exponential amplification of a
pathogen-specific DNA or RNA sequence depends on primers that an-
neal to the target sequence. The amplified nucleic acid can be detected
after the reaction is complete or (in real-time detection) as amplifica-
tion proceeds. PCR, the first and still most common NAAT, requires
repeated heating of the DNA to separate the two complementary
strands of the double helix, hybridization of a primer sequence to the
appropriate target sequence, target amplification using the PCR for
complementary strand extension, and signal detection via a labeled
probe. Methods for the monitoring of PCR after each amplification
cycle—via either incorporation of fluorescent dyes into the DNA dur-
ing primer extension or use of fluorescent probes capable of fluores-
cence resonance energy transfer—have now decreased the period
required to detect a specific target. The sensitivity of NAATs is far
greater than that of traditional assay methods such as culture. Howev-
er, the care with which the assays are performed is important, because
 e104 cross-contamination of clinical material with DNA or RNA from other
sources (even at low levels) can cause false-positive results. An alterna-
tive NAAT employs transcription-mediated amplification, in which an
RNA target sequence is converted to DNA, which is then exponentially
transcribed into RNA target. The advantage of this method is that only
a single heating/annealing step is required for amplification. At
present, amplification assays for Mycobacterium tuberculosis, N. gonor-
rhoeae, C. trachomatis, Mycoplasma hominis, group B Streptococcus,
and methicillin-resistant S. aureus are on the market. Again, many lab-
oratories have used commercially available taq polymerase, probe se-
quences, and analyte-specific reagents (ASRs) to develop “in-house”
assays for diagnostic use. Issues related to quality control, interpreta-
tion of results, sample processing, and regulatory requirements have
slowed the commercial development of many diagnostic assay kits.
Identification of otherwise difficult-to-identify bacteria involves an
initial amplification of a highly conserved region of 16S rDNA by
PCR. Automated sequencing of several hundred bases is then per-
formed, and the sequence information is compared with large data-
bases containing sequence information for thousands of different
organisms. While 16S sequencing is not as rapid as other methods and
is still relatively expensive for routine use in the clinical microbiology
laboratory, it is becoming the definitive method for identification of
unusual or difficult-to-cultivate organisms.
PART 7
Quantitative Nucleic Acid Test Strategies With the advent of newer
therapeutic regimens for HIV-associated disease, cytomegalovirus infec-
tion, and hepatitis B and C virus infections, the response to therapy has
been monitored by determining both genotype and “viral load” at vari-
ous times after treatment initiation. Quantitative NAATs are available
for HIV (PCR), cytomegalovirus (PCR), hepatitis B (PCR), and hepati-
Infectious Diseases
tis C (PCR and transcription-mediated amplification, or TMA). Many
laboratories have validated and perform quantitative assays for these
and other pathogens (e.g., Epstein-Barr virus), using ASRs for NAATs.
Branched-chain DNA (bDNA) testing is an alternative to NAATs for
quantitative nucleic acid testing. In such testing, bDNA attaches to a
site different from the target-binding sequence of the original probe.
Chemiluminescent-labeled oligonucleotides can then bind to multiple
repeating sequences on the bDNA. The amplified bDNA signal is de-
tected by chemiluminescence. bDNA assays for viral load of HIV, hep-
atitis B virus, and hepatitis C virus have been approved by the FDA.
The advantage of bDNA over PCR is that only a single heating/anneal-
ing step is required to hybridize the target-binding probe to the target
sequence for amplification.
Application of Nucleic Acid Tests In addition to the applications al-
ready discussed, nucleic acid tests are used to detect and identify
difficult-to-grow or noncultivable bacterial pathogens, such as My-
cobacterium, Legionella, Ehrlichia, Rickettsia, Babesia, Borrelia, and
Tropheryma whippelii. In addition, methods for rapid detection of
agents of public health concern, such as Bacillus anthracis, smallpox
virus, and Yersinia pestis, have been developed.
Nucleic acid tests are also used to determine how close the relation-
ship is among different isolates of the same species of pathogen. The
demonstration that bacteria of a single clone have infected multiple
patients in the context of a possible means of transmission (e.g., a
health care provider) offers confirmatory evidence for an outbreak.
Pulse-field gel electrophoresis remains the usual gold standard for bac-
terial strain analysis. This method involves the use of restriction en-
zymes that recognize rare sequences of nucleotides to digest the
bacterial DNA, resulting in large DNA fragments. These fragments are
separated by gel electrophoresis with variable polarity of the electro-
phoretic current and then are visualized. Similar band patterns (i.e.,
differences in ≤3 bands) suggest that different bacterial isolates are
closely related, or clonal. Simpler methods of strain typing include se-
quencing of single or multiple genes and PCR-based amplification of
repetitive DNA sequences in the bacterial chromosome.
Future applications of nucleic acid testing will likely include the re-
placement of culture for identification of many pathogens with solid-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
state DNA/RNA chip technology, in which thousands of unique nucle-
ic acid sequences can be detected on a single silicon chip.
SUSCEPTIBILITY TESTING OF BACTERIA
A principal responsibility of the clinical microbiology laboratory is to
determine which antimicrobial agents inhibit a specific bacterial iso-
late. Such testing is used to screen for infection control problems, such
as methicillin-resistant S. aureus or vancomycin-resistant Enterococcus
faecium. Two approaches are useful. The first is a qualitative assess-
ment of susceptibility, with responses categorized as susceptible, resis-
tant, or intermediate. 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 diffu-
sion method), with measurement of the zones of growth inhibition
following incubation, or the use of broth cultures containing a set con-
centration of antibiotic (breakpoint method). These methods have
been carefully calibrated against quantitative methods and clinical ex-
perience with each antibiotic, and zones of inhibition and breakpoints
have been calculated on a species-by-species basis.
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. The lowest concentration of antibiotic that inhibits visu-
al microbial growth in this test system is known as the minimum inhib-
itory concentration (MIC). If tubes in which no growth is seen are
subcultured, the minimum concentration of antibiotic required to kill
99.9% of the starting inoculum can also be determined (minimum
bactericidal concentration, or MBC). The MIC value can be given a cat-
egorical interpretation of susceptible, resistant, or intermediate and so
is more widely used than the MBC. Quantitative susceptibility testing
by the microbroth dilution technique, a miniaturized version of the
broth dilution technique using microwell plates, lends itself to auto-
mation and is commonly used in larger clinical laboratories.
A novel version of the disk/agar diffusion method employs a quan-
titative diffusion gradient, or epsilometer (E-test), and uses an absor-
bent strip with a known gradient of antibiotic concentrations along its
length. When the strip is placed on the surface of an agar plate seeded
with a bacterial strain to be tested, antibiotic diffuses into the medium,
and bacterial growth is inhibited. The MIC is estimated as the lowest
concentration that inhibits visible growth.
For some organisms, such as obligate anaerobes, routine suscepti-
bility testing generally is not performed because of the difficulty of
growing the organisms and the predictable sensitivity of most isolates
to specific antibiotics.
SUSCEPTIBILITY TESTING OF FUNGAL AGENTS
With the advent of many new agents for treating yeasts and systemic fun-
gal agents, the need for testing of individual isolates for susceptibility to
specific antifungal agents has increased. In the past, few laboratories par-
ticipated in such testing because of a lack of standard methods like those
available for testing bacterial agents. However, several systems have now
been approved for antifungal susceptibility testing. These methods,
which determine the minimal fungicidal concentration (MFC), are simi-
lar to the broth microdilution methods used to determine the MIC for
bacteria. The E-test method is approved for testing the susceptibility of
yeasts to fluconazole, itraconazole, and flucytosine, and disk diffusion
can be used to test the susceptibility of Candida spp. to fluconazole and
voriconazole. Methods for determining the MFC against fungal agents
such as Aspergillus spp. are technically difficult, and most clinical labora-
tories refer requests for such testing to reference laboratories.
ANTIVIRAL TESTING
See Chap. 170.
FURTHER READINGS
AIRES DE SOUSA M, DE LENCASTRE H: Bridges from hospitals to the
laboratory: Genetic portraits of methicillin-resistant Staphylococcus
aureus clones. FEMS Immunol Med Microbiol 40:101, 2004
BARON EJ et al: Prolonged incubation and extensive subculturing do
not increase recovery of clinically significant microorganisms from
standard automated blood cultures. Clin Infect Dis 41:1677, 2005
CALIENDO AM et al: Distinguishing cytomegalovirus (CMV) infection
and disease with CMV nucleic acid assays. J Clin Microbiol
40:1581, 2002
COCKERHILL FR et al: Optimal testing parameters for blood cultures.
Clin Infect Dis 38:1724, 2004
DOMIATI-SAAD R, SCHEUERMANN RH: Nucleic acid testing for viral
burden and viral genotyping. Clin Chim Acta 363:197, 2005
MAGIORAKOS AP, HADLEY S: Impact of real-time fungal susceptibility
on clinical practices. Curr Opin Infect Dis 17:511, 2004
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
PANCHOLI P et al: Rapid detection of cytomegalovirus infection in e105
transplant patients. Expert Rev Mol Diagn 4:231, 2004
PFALLER MA et al: Clinical evaluation of a frozen commercially pre-
pared microdilution panel for antifungal susceptibility testing of
seven antifungal agents, including the new triazoles posacona-
zole, ravuconazole and voriconazole. J Clin Microbiol 40:1694,
2002
SERVOSS JC, FRIEDMAN LS: Serologic and molecular diagnosis of hepa-
titis B virus. Clin Liver Dis 8:267, 2004
YEGHIAZARIAN T et al: Quantitation of human immunodeficiency
virus type 1 RNA levels in plasma by using small-volume-format
branched-DNA assays. J Clin Microbiol 36:2096, 1998
CHAPTER e14 Laboratory Diagnosis of Infectious Diseases

e15 Infectious Complications
of Burns and Bites
Lawrence C. Madoff, Florencia Pereyra
The skin is an essential component of the nonspecific immune system,
protecting the host from potential pathogens in the environment.
Breaches in this protective barrier thus represent a form of immuno-
compromise that predisposes the patient to infection. Thermal burns
may cause massive destruction of the integument as well as derange-
ments in humoral and cellular immunity, permitting the development
of infection caused by environmental opportunists and components of
the host’s skin flora. Bites and scratches from animals and humans al-
low the inoculation of microorganisms past the skin’s protective barri-
er into deeper, susceptible host tissues.
BURNS
EPIDEMIOLOGY
Over the past decade, the estimated incidence of burn injuries in the
United States has steadily declined; still, however, >1 million burn in-
juries are brought to medical attention each year. While many burn in-
juries are minor and require little or no intervention, 50,000 persons
are hospitalized for these injuries, and 20,000 have major burns in-
volving at least 25% of the total body surface area. The majority of
burn patients are men. Infants account for ~10% of all reported cases.
Scalds, structural fires, and flammable liquids and gases are the major
causes of burns, but electrical, chemical, and smoking-related sources
are also important. Burns predispose to infection by damaging the
protective barrier function of the skin, thus facilitating the entry of
pathogenic microorganisms, and by inducing systemic immunosup-
pression. It is therefore not surprising that multiorgan failure and in-
fectious complications are the major causes of morbidity and death in
serious burn injury and that as many as 10,000 patients in the United
States die of burn-related infections each year.
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. Initially, the wound is colonized with gram-positive bacteria
from the surrounding tissue, but the number of bacteria grows rapidly
beneath the burn eschar, reaching ~8.4 × 103 cfu/g on day 4 after the
burn. The avascularity of the eschar, along with the impairment of lo-
cal immune responses, favors further bacterial colonization and prolif-
eration. By day 7, the wound is colonized with other microbes,
including gram-positive bacteria, gram-negative bacteria, and yeasts
derived from the gastrointestinal and upper respiratory flora. Invasive
infection—localized and/or systemic—occurs when these bacteria
penetrate viable tissue. In addition, a role for biofilms has been recog-
nized in experimental animal models of burn-wound infection. (Bio-
films are surface-associated communities of bacteria, often embedded
in a matrix, that allow the microbes to persist and to resist the effects
of host immunity and antimicrobial agents.)
Streptococci and staphylococci were the predominant causes of
burn-wound infection in the preantibiotic era and remain important
pathogens at present. With the advent of antimicrobial agents,
Pseudomonas aeruginosa became a major problem in burn-wound
management. Less common anaerobic bacteria are typically found in
infections of electrical burns or when open wound dressings are used.
As antibiotics more effective against Pseudomonas have become avail-
able, fungi (particularly Candida albicans, Aspergillus spp., and the
agents of mucormycosis) have emerged as increasingly important
pathogens in burn-wound patients. Herpes simplex virus (HSV) infec-
tion has also been found in burn wounds, especially those on the face.
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-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
step process: The burn injury itself, with ensuing hypovolemia and tis- e107
sue hypoxia, is followed by invasive infection arising from large
amounts of devitalized tissue. The frequency of infection parallels the
extent and severity of the burn injury. Severe burn injuries cause a
state of immunosuppression that affects innate and adaptive immune
responses. The substantial impact of immunocompromise on infec-
tion is due to effects on both the cellular and the humoral arms of the
immune system. For example, decreases in the number and activity of
circulating helper T cells, increases in suppressor T cells, decreases in
production and release of monocytes and macrophages, and diminu-
tion in levels of immunoglobulin follow major burns. Neutrophil and
complement functions have also been shown to be impaired after
burns. The increased levels of multiple cytokines detected in burn pa-
tients are compatible with the widely held belief that the inflammatory
response becomes dysregulated in these individuals; bacterial cell
products play a potent role in inducing proinflammatory mediators
that contribute to this uncontrolled systemic inflammatory response.
Increased permeability of the gut wall to bacteria and their compo-
nents (e.g., endotoxin) also contributes to immune dysregulation and
sepsis. Thus, the burn patient is predisposed to infection at remote
sites (see below) as well as at the sites of burn injury. Another contrib-
CHAPTER e15 Infectious Complications of Burns and Bites
utor to secondary immunosuppression after burn injuries is the endo-
crine system; increasing levels of vasopressin, aldosterone, cortisol,
glucagon, growth hormone, catecholamines, and other hormones that
directly affect lymphocyte proliferation, secretion of proinflammatory
cytokines, natural killer cell activity, and suppressive T cells are seen.
CLINICAL MANIFESTATIONS
Since clinical indications of wound infection are difficult to interpret,
wounds must be monitored carefully for changes that may reflect in-
fection. A margin of erythema frequently surrounds the sites of burns
and by itself is not usually indicative of infection. Signs of infection in-
clude the conversion of a partial-thickness to a full-thickness burn,
color changes (e.g., the appearance of a dark brown or black discolora-
tion of the wound), the new appearance of erythema or violaceous
edema in normal tissue at the wound margins, the sudden separation
of the eschar from subcutaneous tissues, and the degeneration of the
wound with the appearance of a new eschar.
Early surgical excision of devitalized tissue is now widely used, and
burn-wound infections can be classified in relation to the excision site
as (1) burn-wound impetigo (infection characterized by loss of epithe-
lium from a previously reepithelialized surface, as seen in a partial-
thickness burn that is allowed to close by secondary intention, a grafted
burn, or a healed skin donor site); (2) burn-related surgical wound in-
fection (purulent infection of excised burn and donor sites that have
not yet epithelialized, accompanied by positive cultures); (3) burn-
wound cellulitis (extension of infection to surrounding healthy tissue;
Fig. e15-1); and (4) invasive infection in unexcised burn wounds (in-
fection that is secondary to a partial- or full-thickness burn wound
and is manifested by separation of the eschar or by violaceous, dark
brown, or black discoloration of the eschar; Fig. e15-2). The appear-
ance of a green discoloration of the wound or subcutaneous fat (Fig.
e15-3) or the development of ecthyma gangrenosum at a remote site
points to a diagnosis of invasive P. aeruginosa infection.
Changes in body temperature, hypotension, tachycardia, altered
mentation, neutropenia or neutrophilia, thrombocytopenia, and renal
failure may result from invasive burn wounds and sepsis. However, be-
cause profound alterations in homeostasis occur as a consequence of
burns per se and because inflammation without infection is a normal
component of these injuries, the assessment of these changes is compli-
cated. Alterations in body temperature, for example, are attributable to
thermoregulatory dysfunction; tachycardia and hyperventilation ac-
company the metabolic changes induced by extensive burn injury and
are not necessarily indicative of bacterial sepsis.
Given the difficulty of evaluating burn wounds solely on the basis of
clinical observation and laboratory data, wound biopsies are necessary
for definitive diagnosis of infection. The timing of these biopsies can be
guided by clinical changes, but in some centers burn wounds are rou-
 e108
FIGURE e15-1 Cellulitis complicating a burn wound of the arm
and demonstrating extension of the infection to adjacent healthy tis-
sue. (Courtesy of Dr. Robert L. Sheridan, Massachusetts General Hospital,
Boston; with permission.)
PART 7
Infectious Diseases
FIGURE e15-2 A severe upper-extremity burn infected with
Pseudomonas aeruginosa. The wound requires additional debride-
ment. Note the dark brown to black discoloration of the eschar. (Cour-
tesy of Dr. Robert L. Sheridan, Massachusetts General Hospital, Boston;
with permission.)
FIGURE e15-3 A burn wound infected with Pseudomonas aerugi-
nosa, with liquefaction of tissue. Note the green discoloration at
the wound margins, which is suggestive of Pseudomonas infection.
(Courtesy of Dr. Robert L. Sheridan, Massachusetts General Hospital, Bos-
ton; with permission.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
tinely biopsied at regular intervals. The biopsy specimen is examined
for histologic evidence of bacterial invasion, and quantitative microbio-
logic cultures are performed. The presence of >105 viable bacteria per
gram of tissue is highly suggestive of invasive infection and of a dramat-
ically increased risk of sepsis. Histopathologic evidence of invasion of
viable tissue by microorganisms is a more definitive indicator of infec-
tion. A blood culture positive for the same organism seen in large
quantities in biopsied tissue is a reliable indicator of burn sepsis. Sur-
face cultures may provide some indication of the microorganisms
present in the hospital environment but are not indicative of the etiolo-
gy of infection. This noninvasive technique might be of use in deter-
mining the flora present in excised burn areas or in areas where the skin
is too thin for biopsy (e.g., over the ears, eyes, or digits).
In addition to infection of the burn wound itself, 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. Pneumonia, now the most common infectious complication
among hospitalized burn patients, is most often nosocomially ac-
quired via the respiratory route; among the risk factors associated with
secondary pneumonia are inhalation injury, intubation, full-thickness
chest wall burns, immobility, and uncontrolled wound sepsis with he-
matogenous spread. Septic pulmonary emboli may also occur. Suppu-
rative thrombophlebitis may complicate the vascular catheterization
necessary for fluid and nutritional support in burns. Endocarditis, uri-
nary tract infection, bacterial chondritis (particularly in patients with
burned ears), and intraabdominal infection also complicate serious
burn injury.
BURN-WOUND INFECTIONS
The ultimate goal of burn-wound management is closure and healing of
the wound. Early surgical excision of burned tissue, with extensive debride-
ment of necrotic tissue and grafting of skin or skin substitutes, greatly de-
creases mortality rates associated with severe burns. In addition, the four
widely used topical antimicrobial agents—silver sulfadiazine cream, ma-
fenide acetate cream, silver nitrate cream, and nanocrystalline silver dress-
ings—dramatically decrease the bacterial burden of burn wounds and
reduce the incidence of burn-wound infection; these agents are routinely
applied to partial- and full-thickness burns. The bactericidal properties of
silver are related to its effect on respiratory enzymes on bacterial cell walls;
its interaction with structural proteins causes keratinocyte and fibroblast
toxicity that can delay wound healing if silver-based compounds are used
indiscriminately. All four agents are broadly active against many bacteria
and some fungi and are useful before bacterial colonization is established.
Silver sulfadiazine is often used initially, but its value can be limited by bac-
terial resistance, poor wound penetration, or toxicity (leukopenia). Ma-
fenide acetate has broader activity against gram-negative bacteria. The
cream penetrates eschars and thus can prevent or treat infection beneath
them; its use without dressings allows regular examination of the wound
area. The foremost disadvantages of mafenide acetate are that it can inhib-
it carbonic anhydrase, resulting in metabolic acidosis, and that it elicits hy-
persensitivity reactions in up to 7% of patients. This agent is most often
used when gram-negative bacteria invade the burn wound and when
treatment with silver sulfadiazine fails. The activity of mafenide acetate
against gram-positive bacteria is limited. Nanocrystalline silver dressings
provide broader antimicrobial coverage than any other available topical
preparation, exhibiting activity against methicillin-resistant Staphylococcus
aureus (MRSA) and vancomycin-resistant enterococci (VRE), moderate abil-
ity to penetrate eschars, and limited toxicity. In addition, this approach pro-
vides controlled and prolonged release of nanocrystalline silver into the
wound, limiting the number of dressing changes and therefore reducing
the risk of nosocomial infections as well as the cost of treatment. Mupiro-
cin, a topical antimicrobial agent used to eradicate nasal colonization with
MRSA, is increasingly being used in burn units where MRSA is prevalent.
The efficacy of mupirocin in reducing burn-wound bacterial counts and
preventing systemic infections is comparable to that of silver sulfadiazine.
In recent years, rates of fungal infection have increased in burn patients.
When superficial fungal infection occurs, nystatin may be mixed with silver
sulfadiazine or mafenide acetate as topical therapy. A small study found
that nystatin powder (6 million units/g) was effective for treatment of su-
perficial and deep burn-wound infections caused by Aspergillus or Fusari-
um spp. In addition to these products, moisture-retention ointments with
antimicrobial properties can promote rapid autolysis, debridement, and
moist healing of partial-thickness wounds.
When invasive wound infection is diagnosed, topical therapy should be
changed to mafenide acetate. Subeschar clysis (the direct instillation of an
antibiotic, often piperacillin, into wound tissues under the eschar) is a use-
ful adjunct to surgical and systemic antimicrobial therapy. Systemic treat-
ment with antibiotics active against the pathogens present in the wound
should be instituted. In the absence of culture data, treatment should be
broad in spectrum, covering organisms commonly encountered in that
particular burn unit. Such coverage is usually achieved with an antibiotic
active against gram-positive pathogens (e.g., oxacillin, 2 g IV every 4 h) and
with a drug active against P. aeruginosa and other gram-negative rods (e.g.,
mezlocillin, 3 g IV every 4 h; and gentamicin, 5 mg/kg IV per day). In peni-
cillin-allergic patients, vancomycin (1 g IV every 12 h) may be substituted
for oxacillin (and is efficacious against MRSA), and ciprofloxacin (400 mg IV
every 12 h) may be substituted for mezlocillin. Patients with burn wounds
frequently have alterations in metabolism and renal clearance mecha-
nisms that mandate the monitoring of serum antibiotic levels; the levels
achieved with standard doses are often subtherapeutic.
Treatment of infections caused by emerging resistant pathogens re-
mains a challenge in the care of burn patients. MRSA, resistant enterococci,
multidrug-resistant gram-negative rods, and Enterobacteriaceae producing
extended-spectrum β-lactamases have been associated with burn-wound
infections and identified in burn-unit outbreaks. Strict infection-control
practices (including microbiologic surveillance in burn units) and appropri-
ate antimicrobial therapy remain important measures in reducing rates of
infection due to resistant organisms.
In general, prophylactic systemic antibiotics have no role in the manage-
ment of burn wounds and can in fact lead to colonization with resistant mi-
croorganisms. In some studies, 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. An exception
involves cases requiring burn-wound manipulation. Since procedures such
as debridement, excision, or grafting frequently result in bacteremia, prophy-
lactic systemic antibiotics are administered at the time of wound manipula-
tion; the specific agents used should be chosen on the basis of data
obtained by wound culture or data on the hospital’s resident flora.
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. In a randomized, double-
blind, placebo-controlled trial in patients with burns involving >20% of the
total body surface area, 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. The effects of SDD on the normal anaerobic
bowel flora must be taken into consideration before this approach is used.
All burn-injury patients should undergo tetanus booster immunization if
they have completed primary immunization but have not received a boost-
er dose in the past 5 years. Patients without prior immunization should re-
ceive tetanus immune globulin and undergo primary immunization.
BITES AND SCRATCHES
Each year in the United States, millions of animal-bite wounds are sus-
tained. The vast majority are inflicted by pet dogs and cats, which
number >100 million; the annual incidence of dog and cat bites has
been reported as 300 bites per 100,000 population. Other bite wounds
are a consequence of encounters with animals in the wild or in occu-
pational settings. While many of these wounds require minimal or no
therapy, a significant number result in infection, which may be life-
threatening. The microbiology of bite-wound infections in general re-
flects the oropharyngeal flora of the biting animal, although organisms
from the soil, the skin of the animal and victim, and the animal’s feces
may also be involved.
DOG BITES
In the United States, dogs bite >4.7 million people each year and are
responsible for 80% of all animal-bite wounds, an estimated 15–20%
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
of which become infected. Each year, 800,000 Americans seek medical e109
attention for dog bites; of those injured, 386,000 require treatment in
an emergency department, with >1000 emergency department visits
each day and about a dozen deaths per year. Most dog bites are pro-
voked and are inflicted by the victim’s pet or by a dog known to the
victim. These bites frequently occur during efforts to break up a dog-
fight. Children are more likely than adults to sustain canine bites, with
the highest incidence of 6 bites per 1000 population among boys 5–9
years old. Victims are more often male than female, and bites most of-
ten involve an upper extremity. Among children <4 years old, two-
thirds of all these injuries involve the head or neck. Infection typically
manifests 8–24 h after the bite as pain at the site of injury with celluli-
tis accompanied by purulent, sometimes foul-smelling discharge. Sep-
tic arthritis and osteomyelitis may develop if a canine tooth penetrates
synovium or bone. Systemic manifestations (e.g., fever, lymphadenop-
athy, and lymphangitis) may also occur. The microbiology of dog-bite
wound infections is usually mixed and includes β-hemolytic strepto-
cocci, Pasteurella spp., Staphylococcus spp., Eikenella corrodens, and
Capnocytophaga canimorsus (formerly designated DF-2). Many wounds
also include anaerobic bacteria such as Actinomyces, Fusobacterium,
Prevotella, and Porphyromonas spp.
CHAPTER e15 Infectious Complications of Burns and Bites
While most infections resulting from dog-bite injuries are localized
to the area of injury, many of the microorganisms involved are capable
of causing systemic infection, including bacteremia, meningitis, brain
abscess, endocarditis, and chorioamnionitis. These infections are par-
ticularly likely in hosts with edema or compromised lymphatic drain-
age in the involved extremity (e.g., 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.,
glucocorticoid use, systemic lupus erythematosus, acute leukemia, or
hepatic cirrhosis). In addition, dog bites and scratches may result in
systemic illnesses such as rabies (Chap. 188) and tetanus (Chap. 133).
Infection with C. canimorsus following dog-bite wounds may result
in fulminant sepsis, disseminated intravascular coagulation, and renal
failure, particularly in hosts who have impaired hepatic function, who
have undergone splenectomy, or who are immunosuppressed. This or-
ganism is a thin gram-negative rod that is difficult to culture on most
solid media but grows in a variety of liquid media. The bacteria are oc-
casionally seen within polymorphonuclear leukocytes on Wright-
stained smears of peripheral blood from septic patients. Tularemia
(Chap. 151) has also been reported to follow dog bites.
CAT BITES
Although less common than dog bites, cat bites and scratches result in
infection in more than half of all cases. Because the narrow, sharp fe-
line incisors penetrate deeply into tissue, cat bites are more likely than
dog bites to cause septic arthritis and osteomyelitis; the development
of these conditions is particularly likely when punctures are located
over or near a joint, especially in the hand. Women sustain cat bites
more frequently than do men. These bites most often involve the
hands and arms. Both bites and scratches from cats are prone to in-
fection from organisms in the cat’s oropharynx. Pasteurella multocida,
a normal component of the feline oral flora, is a small gram-negative
coccobacillus implicated in the majority of cat-bite wound infections.
Like that of dog-bite wound infections, however, the microflora of
cat-bite wound infections is usually mixed. Other microorganisms
causing infection after cat bites are similar to those causing dog-bite
wound infections.
The same risk factors for systemic infection following dog-bite
wounds apply to cat-bite wounds. Pasteurella infections tend to ad-
vance rapidly, often within hours, causing severe inflammation ac-
companied by purulent drainage; Pasteurella may also be spread by
respiratory droplets from animals, resulting in pneumonia or bactere-
mia. Like dog-bite wounds, cat-bite wounds may result in the trans-
mission of rabies or in the development of tetanus. Infection with
Bartonella henselae causes cat-scratch disease (Chap. 153) and is an
important late consequence of cat bites and scratches. Tularemia
(Chap. 151) has also been reported to follow cat bites.
 e110 OTHER ANIMAL BITES
Infections have been attributed to bites from many animal species. Of-
ten these bites are sustained as a consequence of occupational exposure
(farmers, laboratory workers, veterinarians) or recreational exposure
(hunters and trappers, wilderness campers, owners of exotic pets). Gen-
erally, the microflora of bite wounds reflects the oral flora of the biting
animal. Most members of the cat family, including feral cats, harbor P.
multocida. Bite wounds from aquatic animals such as alligators or pira-
nhas may contain Aeromonas hydrophila. Venomous snakebites (Chap.
391) result in severe inflammatory responses and tissue necrosis—con-
ditions that render these injuries prone to infection. The snake’s oral flo-
ra includes many species of aerobes and anaerobes, such as P.
aeruginosa, Proteus spp., Staphylococcus epidermidis, Bacteroides fragilis,
and Clostridium spp. Bites from nonhuman primates are highly suscep-
tible to infection with pathogens similar to those isolated from human
bites (see below). Bites from Old World monkeys (Macaca) may also re-
sult in the transmission of B virus (Herpesvirus simiae, cercopithecine
herpesvirus), a cause of serious infection of the human central nervous
system. Bites of seals, walruses, and polar bears may cause a chronic sup-
purative infection known as seal finger, which is probably due to one or
more species of Mycoplasma colonizing these animals.
Small rodents, including rats, mice, and gerbils, as well as animals
that prey on rodents may transmit Streptobacillus moniliformis (a mi-
PART 7
croaerophilic, pleomorphic gram-negative rod) or Spirillum minor (a
spirochete), which cause a clinical illness known as rat-bite fever. The
vast majority of cases in the United States are streptobacillary, whereas
Spirillum infection occurs mainly in Asia.
In the United States, the risk of rodent bites is usually greatest
among laboratory workers or inhabitants of rodent-infested dwellings
(particularly children). Rat-bite fever is distinguished from acute bite-
Infectious Diseases
wound infection by its typical manifestation after the initial wound
has healed. Streptobacillary disease follows an incubation period of 3–
10 days. Fever, chills, myalgias, headache, and severe migratory ar-
thralgias are usually followed by a maculopapular rash, which charac-
teristically involves the palms and soles and may become confluent or
purpuric. Complications include endocarditis, myocarditis, meningi-
tis, pneumonia, and abscesses in many organs. Haverhill fever is an S.
moniliformis infection acquired from contaminated milk or drinking
water and has similar manifestations. Streptobacillary rat-bite fever
was frequently fatal in the preantibiotic era. The differential diagnosis
includes Rocky Mountain spotted fever, Lyme disease, leptospirosis,
and secondary syphilis. The diagnosis is made by direct observation of
the causative organisms in tissue or blood, by culture of the organisms
on enriched media, or by serologic testing with specific agglutinins.
Spirillum infection (referred to in Japan as sodoku) causes pain and
purple swelling at the site of the initial bite, with associated lymphan-
gitis and regional lymphadenopathy, after an incubation period of 1–4
weeks. The systemic illness includes fever, chills, and headache. The
original lesion may eventually progress to an eschar. The infection is
diagnosed by direct visualization of the spirochetes in blood or tissue
or by animal inoculation.
Finally, NO-1 (CDC nonoxidizer group 1) is a recently identified
bacterium associated with dog- and cat-bite wounds. Infections in
which NO-1 has been isolated have tended to manifest locally (i.e., as
abscess and cellulitis). These infections have occurred in healthy per-
sons with no underlying illness and in some instances have progressed
from localized to systemic illnesses. The phenotypic characteristics of
NO-1 are similar to those of asaccharolytic Acinetobacter species; i.e.,
NO-1 is oxidase-, indole-, and urease-negative. To date, all strains
identified have been shown to be susceptible to aminoglycosides, β-
lactam antibiotics, tetracyclines, quinolones, and sulfonamides.
HUMAN BITES
Human bites may be self-inflicted; may be sustained by medical person-
nel caring for patients; or may take place during fights, domestic abuse,
or sexual activity. Human-bite wounds become infected more frequent-
ly (~10–15% of the time) than do bites inflicted by other animals. These
infections reflect the diverse oral microflora of humans, which includes
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
multiple species of aerobic and anaerobic bacteria. Common aerobic
isolates include viridans streptococci, Staphylococcus aureus, E. corrodens
(which is particularly common in clenched-fist injury; see below), and
Haemophilus influenzae. Anaerobic species, including Fusobacterium
nucleatum and Prevotella, Porphyromonas, and Peptostreptococcus spp.,
are isolated from 50% of human-bite wound infections; many of these
isolates produce β-lactamases. The oral flora of hospitalized and debili-
tated patients often includes Enterobacteriaceae in addition to the usual
organisms. Hepatitis B, hepatitis C, HSV infection, syphilis, tuberculo-
sis, actinomycosis, and tetanus have been reported to be transmitted by
human bites; it is biologically possible to transmit HIV through human
bites, although this event is quite unlikely.
Human bites are categorized as “occlusional” injuries, which are in-
flicted by actual biting, and “clenched-fist” injuries, which are sus-
tained when the fist of one individual strikes the teeth of another,
causing traumatic laceration of the hand. For several reasons,
clenched-fist injuries, which are more common than occlusional inju-
ries, result in particularly serious infections. The deep spaces of the
hand, including the bones, joints, and tendons, are frequently inocu-
lated with organisms in the course of such injuries. The clenched posi-
tion of the fist during injury, followed by extension of the hand, may
further promote the introduction of bacteria as contaminated tendons
retract beneath the skin’s surface. Moreover, medical attention is often
sought only after frank infection develops.
APPROACH TO THE PATIENT:
Animal or Human Bites
A careful history should be elicited, including the type of biting an-
imal, the type of attack (provoked or unprovoked), and the
amount of time elapsed since injury. 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. 188). Suspicious hu-
man-bite wounds should provoke careful questioning regarding
domestic or child abuse. Details on antibiotic allergies, immuno-
suppression, splenectomy, liver disease, mastectomy, and immuni-
zation history should be obtained. The wound should be inspected
carefully for evidence of infection, including redness, exudate, and
foul odor. The type of wound (puncture, laceration, or scratch);
the depth of penetration; and the possible involvement of joints,
tendons, nerves, and bones should be assessed. It is often useful to
include a diagram or photograph of the wound in the medical
record. In addition, a general physical examination should be con-
ducted and should include an assessment of vital signs as well as an
evaluation for evidence of lymphangitis, lymphadenopathy, der-
matologic lesions, and functional limitations. Injuries to the hand
warrant consultation with a hand surgeon for the assessment of
tendon, nerve, and muscular damage. Radiographs should be ob-
tained when the bone may have been penetrated or a tooth frag-
ment may be present. Culture and Gram’s staining of all infected
wounds are essential; anaerobic cultures should be undertaken if
abscesses, devitalized tissue, or foul-smelling exudate is present. A
small-tipped swab may be used to culture deep punctures or small
lacerations. It is also reasonable to culture samples from uninfected
wounds due to bites inflicted by animals other than dogs and cats,
since the microorganisms causing disease are less predictable in
these cases. The white blood cell count should be determined and
blood cultured if systemic infection is suspected.
BITE-WOUND INFECTIONS
WOUND MANAGEMENT Wound closure is controversial in bite inju-
ries. Many authorities prefer not to attempt primary closure of wounds that
are or may become infected, preferring to irrigate these wounds copiously,
debride devitalized tissue, remove foreign bodies, and approximate the
wound edges. Delayed primary closure may be undertaken after the risk of
infection is over. Small uninfected wounds may be allowed to close by sec-
TABLE e15-1 MANAGEMENT OF WOUND INFECTIONS FOLLOWING ANIMAL AND HUMAN BITES e111
Prophylaxis
Advised for Early
Biting Commonly Isolated Preferred Alternative in Uninfected Other
Species Pathogens Antibiotic(s)a Penicillin-Allergic Patient Wounds Considerations
Dog Staphylococcus aureus, Pas- Amoxicillin/clavula- Clindamycin (150–300 mg PO Sometimesb Consider rabies
teurella multocida, anaer- nate (250–500 mg qid) plus either TMP-SMX (1 prophylaxis.
obes, Capnocytophaga PO tid) or ampicillin/ DS tablet PO bid) or cipro-
canimorsus sulbactam (1.5–3.0 g floxacin (500 mg PO bid)
IV q6h)
Cat P. multocida, S. aureus, Amoxicillin/clavula- Clindamycin plus TMP-SMX as Usually Consider rabies pro-
anaerobes nate or ampicillin/ above or a fluoroquinolone phylaxis. Carefully
sulbactam, as above evaluate for joint/
bone penetration.
Human, Viridans streptococci, S. au- Amoxicillin/clavula- Erythromycin (500 mg PO qid) Always
occlusional reus, Haemophilus influen- nate or ampicillin/ or a fluoroquinolone
zae, anaerobes sulbactam, as above
Human, As for occlusional plus Ampicillin/sulbactam Cefoxitinc Always Examine for tendon,
clenched- Eikenella corrodens as above or imi- nerve, or joint
fist penem (500 mg involvement.
q6h)
Monkey As for human bite As for human bite As for human bite Always For macaque mon-

CHAPTER e15 Infectious Complications of Burns and Bites

keys, consider B
virus prophylaxis
with acyclovir.
Snake Pseudomonas aeruginosa, Pro- Ampicillin/sulbactam Clindamycin plus TMP-SMX as Sometimes, espe- Antivenin for venom-
teus spp., Bacteroides fragi- as above above or a fluoroquinolone cially with ven- ous snake bite
lis, Clostridium spp. omous snakes
Rodent Streptobacillus moniliformis, Penicillin VK (500 mg Doxycycline (100 mg PO bid) Sometimes
Leptospira spp., P. multocida PO qid)
aAntibiotic choices should be based on culture data when available. These are sugges- and crush injuries; when bone or joint may be involved; and when comorbidity is
tions for empirical therapy and need to be tailored to individual circumstances and local present (see text).
conditions. IV regimens should be used for hospitalized patients. A single IV dose of anti- cMay be hazardous in patients with immediate-type hypersensitivity reaction to penicillin.

biotics may be given to patients who will be discharged after initial management. Note: TMP-SMX, trimethoprim-sulfamethoxazole; DS, double-strength.
bProphylactic antibiotics are suggested for severe or extensive wounds, facial wounds,

ondary intention. Puncture wounds due to cat bites should be left unsu-
tured because of the high rate at which they become infected. Facial
wounds are usually sutured after thorough cleaning and irrigation because
of the importance of a good cosmetic result in this area and because ana-
tomic factors such as an excellent blood supply and the absence of depen-
dent edema lessen the risk of infection.
ANTIBIOTIC THERAPY Established Infection Antibiotics should
be administered in all established bite-wound infections and should be
chosen in light of the most likely potential pathogens, as indicated by the
biting species and by Gram’s stain and culture results (Table e15-1). For
dog and cat bites, antibiotics should be effective against S. aureus, Pas-
teurella spp., C. canimorsus, streptococci, and oral anaerobes. For human
bites, agents with activity against S. aureus, H. influenzae, and β-lactamase-
positive oral anaerobes should be used. The combination of an extended-
spectrum penicillin with a β-lactamase inhibitor (amoxicillin/clavulanic
acid, ticarcillin/clavulanic acid, ampicillin/sulbactam) appears to offer the
most reliable coverage for these pathogens. Second-generation cepha-
losporins (cefuroxime, cefoxitin) also offer substantial coverage. The choice
of antibiotics for penicillin-allergic patients (particularly those in whom im-
mediate-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. The combination of an antibiotic active
against gram-positive cocci and anaerobes (such as clindamycin) with tri-
methoprim-sulfamethoxazole or a fluoroquinolone, which is active against
many of the other potential pathogens, would appear reasonable. In vitro
data suggest that azithromycin alone provides coverage against most
commonly isolated bite-wound pathogens.
Antibiotics are generally given for 10–14 days, but the response to ther-
apy must be carefully monitored. Failure to respond should prompt a con-
sideration of diagnostic alternatives and surgical evaluation for possible
drainage or debridement. Complications such as osteomyelitis or septic ar-
thritis mandate a longer duration of therapy.
Management of C. canimorsus sepsis requires a 2-week course of IV peni-
cillin G (2 million units IV every 4 h) and supportive measures. Alternative
agents for the treatment of C. canimorsus infection include cephalosporins
and fluoroquinolones. Serious infection with P. multocida (e.g., pneumonia,
sepsis, or meningitis) should also be treated with IV penicillin G. Alternative
agents include second- or third-generation cephalosporins or ciprofloxacin.
Bites by venomous snakes (Chap. 391) may not require antibiotic treat-
ment. Because it is often difficult to distinguish signs of infection from tis-
sue damage caused by the envenomation, many authorities continue to
recommend treatment directed against the snake’s oral flora—i.e., the ad-
ministration of broadly active agents such as ceftriaxone (1–2 g IV every
12–24 h) or ampicillin/sulbactam (1.5–3.0 g IV every 6 h).
Seal finger appears to respond to doxycycline (100 mg twice daily for an
interval guided by the response to therapy).
Presumptive or Prophylactic Therapy The use of antibiotics in pa-
tients presenting early after bite injury (within 8 h) is controversial. Al-
though symptomatic infection frequently will not yet have manifested at
this point, many early wounds will harbor pathogens, and many will be-
come infected. Studies of antibiotic prophylaxis for wound infections are
limited and have often included only small numbers of cases in which vari-
ous types of wounds have been managed according to various protocols.
A meta-analysis of eight randomized trials of prophylactic antibiotics in pa-
tients with dog-bite wounds demonstrated a reduction in the rate of infec-
tion by 50% with prophylaxis. However, in the absence of sound clinical
trials, many clinicians base the decision to treat bite wounds with empirical
antibiotics on the species of the biting animal; the location, severity, and
extent of the bite wound; and the existence of comorbid conditions in the
host. All human- and monkey-bite wounds should be treated presump-
tively because of the high rate of infection. Most cat-bite wounds, particu-
larly those involving the hand, should be treated. Other factors favoring
treatment for bite wounds include severe injury, as in crush wounds; po-
tential bone or joint involvement; involvement of the hands or genital re-
gion; host immunocompromise, including that due to liver disease or
splenectomy; and prior mastectomy on the side of an involved upper ex-
tremity. When prophylactic antibiotics are administered, they are usually
given for 3–5 days.

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

 e112 Rabies and Tetanus Prophylaxis Rabies prophylaxis, 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 im-
munization with rabies vaccine, should be given in consultation with local
and regional public health authorities for many wild-animal (and some do-
mestic-animal) bites and scratches as well as for certain nonbite exposures
(Chap. 188). Rabies is endemic in a variety of animals, including dogs and
cats in many areas of the world. Many local health authorities require the
reporting of all animal bites. A tetanus booster immunization should be
given if the patient has undergone primary immunization but has not re-
ceived a booster dose in the past 5 years. Patients who have not previously
completed primary immunization should be immunized and should also
receive tetanus immune globulin. Elevation of the site of injury is an impor-
tant adjunct to antimicrobial therapy. Immobilization of the infected area,
especially the hand, is also beneficial.
FURTHER READINGS
BAKER AS et al: Isolation of Mycoplasma species from a patient with
seal finger. Clin Infect Dis 27:1168, 1998
CENTERS FOR DISEASE CONTROL AND PREVENTION: Nonfatal dog bite–
related injuries treated in hospital emergency departments—
United States, 2001. MMWR 52:605, 2003
PART 7
CUMMINGS P: Antibiotics to prevent infection in patients with dog
bite wounds: A meta-analysis of randomized trials. Ann Emerg
Med 23:535, 1994
DE LA CAL M et al: Survival benefit in critically ill burned patients re-
ceiving selective decontamination of the digestive tract: A random-
ized, placebo-controlled, double-blind trial. Ann Surg 241:424,
2005
Infectious Diseases
FALLOUJI MA: Traumatic love bites. Br J Surg 77:100, 1990
FLEISHER GR: The management of bite wounds. N Engl J Med
340:138, 1999
GOLDSTEIN EJ: Bite wounds and infection. Clin Infect Dis 14:633,
1992
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
HOLMES GP et al: Guidelines for the prevention and treatment of B-
virus infections in exposed persons. The B Virus Working Group.
Clin Infect Dis 20:421, 1995
KAYE ET: Topical antibacterial agents. Infect Dis Clin North Am
14:321, 2000
KULLBERG BJ et al: Purpura fulminans and symmetrical peripheral gan-
grene caused by Capnocytophaga canimorsus (formerly DF-2) septice-
mia—a complication of dog bite. Medicine (Baltimore) 70:287, 1991
MCMANUS WF et al: Subeschar antibiotic infusion in the treatment of
burn wound infection. J Trauma 20:1021, 1980
PRUITT BJ et al: The changing epidemiology of infection in burn pa-
tients. World J Surg 16:57, 1992
SHERIDAN RL et al: Cutaneous herpetic infections complicating burns.
Burns 26:621, 2000
STEER JA et al: Quantitative microbiology in the management of burn pa-
tients. I. Correlation between quantitative and qualitative burn wound
biopsy culture and surface alginate swab culture. Burns 22:173, 1996
——— et al: Quantitative microbiology in the management of burn
patients. II. Relationship between bacterial counts obtained by
burn wound biopsy culture and surface alginate swab culture, with
clinical outcome following burn surgery and change of dressings.
Burns 22:177, 1996
TALAN DA et al: Bacteriological analysis of infected dog and cat bites.
N Engl J Med 340:85, 1999
TAN JS: Human zoonotic infections transmitted by dogs and cats.
Arch Intern Med 157:1933, 1977
WEBER DJ et al: Infections resulting from animal bites. Infect Dis Clin
North Am 5:663, 1991
WEISS HB et al: Incidence of dog bite injuries treated in emergency
departments. JAMA 279:51, 1998
YOUN YK et al: The role of mediators in the response to thermal in-
jury. World J Surg 16:30, 1992
YURT RW: Burns, in Principles and Practice of Infectious Diseases, 5th
ed, G Mandell et al (eds). New York, Churchill Livingstone, 2000,
pp 3198–3206
 ed to serve as a guide to the correct diagnostic procedures for the ma- e113

e16 Laboratory Diagnosis

of Parasitic Infections
Sharon L. Reed, Charles E. Davis
The cornerstone for the diagnosis of parasitic infections is a thorough
history of the patient’s illness. Epidemiologic aspects of the illness are
especially important because the risks of acquiring many parasites are
closely related to occupation, recreation, or travel to areas of high en-
demicity. Without a basic knowledge of the epidemiology and life cy-
cles of the major parasites, it is difficult to approach the diagnosis of
parasitic infections systematically. Accordingly, the medical classifica-
tion of important human parasites in this chapter emphasizes their
geographic distribution, their transmission, and the anatomic location
and stages of their life cycle in humans. The text and tables are intend-
jor parasitic infections and to direct the reader to other chapters that
contain more comprehensive information about each infection. Ta-
bles e16-1, e16-2, and e16-3 summarize the geographic distributions,
the anatomic locations, and the methods employed for the diagnosis
of flatworm, roundworm, and protozoal infections, respectively.
In addition to selecting the correct diagnostic procedures, physi-
cians must counsel their patients to ensure that specimens are collect-
ed properly and arrive at the laboratory promptly. For example, the
diagnosis of bancroftian filariasis is unlikely to be confirmed by the
laboratory unless blood is drawn near midnight, when the nocturnal
microfilariae are active. Laboratory personnel and surgical patholo-
gists should be notified in advance when a parasitic infection is sus-
pected. Continuing interaction with the laboratory staff and the
surgical pathologists increases the likelihood that parasites in body flu-
ids or biopsy specimens will be examined carefully by the most capa-
ble individuals.

TABLE e16-1 FLATWORM INFECTIONS

Life-Cycle Hosts Diagnosis

CHAPTER e16 Laboratory Diagnosis of Parasitic Infections

Geographic Intermediate Parasite Body Fluid Serologic
Parasite Distribution (Transmission) Definitive Stage or Tissue Tests Other
Tapeworms (Cestodes)

Intestinal tapeworms
Taenia saginata (beef Worldwide Beef Humans Ova, Feces — Motile segments
tapeworm) segments
Hymenolepis nana Worldwide Grain beetles Humans, Ova Feces — —
(dwarf tapeworm) micea
Diphyllobothrium latum Worldwide Copepods–fishc Humans, other Ova, Feces — Megaloblastic anemia
(fish tapeworm) mammals segments in 1%
T. soliumb (pork Worldwide Swine Humans Ova, Feces WB Especially Mexico,
tapeworm) segments Central and South
America, Africa
Somatic tapeworms
Echinococcus granu- Sheep-raising Sheep, camels, Dogs Hydatid Lung, liver WB, EIA Chest radiography, CT,
losus (hydatid and hunting humans, others MRI
disease) areas
E. multilocularis Subarctic areas Rodents, humans Foxes, dogs, Hydatid Liver — May resemble cholan-
(hydatid disease) cats giocellular carcinoma
T. soliumb (pork Worldwide Swine, humans Humans Cysticercus Muscles, WB CT, MRI, radiography
tapeworm) CNS
Flukes (Trematodes)

Intestinal flukes
Fasciolopsis buski China, India Snails–water Humans Ova Feces — —
chestnuts
Heterophyes heterophyes Far East, India Snails–fish Humans Ova Feces — —
Metagonimus Far East, Balkans, Snails–fish Humans Ova Feces — —
yokogawai North Africa
Liver flukes
Clonorchis sinensis China, South- Snails–fish Humans Ova Feces, bile — Recurrent bacterial
east Asia cholangitis
Fasciola hepatica Sheep-raising Snails–watercress Humans, Ova Feces,d bile EIA Cirrhosis, portal
areas sheep hypertension
Lung flukes
Paragonimus spp. Orient, Africa, Snails–crabs/ Humans, other Adults, ova Lung, spu- WB, EIA Chest radiography, CT,
South America crayfish mammals tum, feces MRI
Blood flukes
Schistosoma mansoni Africa, Central and Snails Humans Ova, adults Feces EIA, WB Rectal snips, liver
South America, biopsy
West Indies
S. haematobium Africa Snails Humans Ova, adults Urine WB Liver, urine, or
bladder biopsy
S. japonicum Far East Snails Humans Ova, adults Feces WB Liver biopsy
aLarvae also can mature in intestinal villi of humans and mice. dOva seldom reach the fecal stream during acute disease.
bT.solium can cause either intestinal infections or cysticercosis. Its ova are identical to Note: WB, western blot; CNS, central nervous system; EIA, enzyme immunoassay. Sero-
those of T. saginata; scolices and segments of the two species differ. logic tests listed in Tables e16-1, e16-2, and e16-3 are available commercially or from the
cWhen there are two intermediate hosts, the first is separated from the second by a dash. Centers for Disease Control and Prevention, Atlanta, GA.
Definitive hosts are infected by the second intermediate host.

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

 e114 TABLE e16-2 ROUNDWORM INFECTIONS
Life-Cycle Hosts Diagnosis
Geographic Intermediate Parasite Body Fluid Serologic
Parasite Distribution (Transmission) Definitive Stage or Tissue Tests Other
Intestinal Roundworms

Enterobius vermicularis Temperate and Fecal-oral Humans Ova Perianal skin — “Cellophane tape”
(pinworm) tropical zones test
Trichuris trichiura Temperate and Soil, fecal-oral Humans Ova Feces — Rectal prolapse
(whipworm) tropical zones
Ascaris lumbricoides Temperate and Soil, fecal-oral Humans Ova Feces — Sx of pulmonary
(roundworm of tropical zones migration
humans)
Ancylostoma duode- Eurasia, Africa, Soil→skin Humans Ova/larvae Feces — Sx of pulmonary mi-
nale (Old World Pacific gration, anemia
hookworm)
Necator americanus U.S., Africa, Soil→skin Humans Ova/larvae Feces — Sx of pulmonary mi-
(New World worldwide gration, anemia
hookworm)
Strongyloides stercoralis Moist tropics and Soil→skin Humans Larvae Feces, sputum, EIA Dissemination in
(strongyloidiasis) subtropics duodenal immunodeficiency
fluid
Capillaria philippinensis Southeast Asia, Raw fish Birds Ova, larvae, Feces — Malabsorption/au-
Taiwan, Egypt adults toinfection, biopsy
PART 7

Tissue Roundworms

Trichinella spiralis Worldwide Swine/humans Swine/ Larvae Muscle EIA Muscle biopsy
(trichinellosis) humans
Wuchereria bancrofti Coastal areas in Mosquitoes Humans Microfilariae Blood, lymph EIA, Nocturnal periodicitya
(filariasis) tropics and nodes RAPID
subtropics
Brugia malayi (filariasis) Asia, Indian Mosquitoes Humans Microfilariae Blood EIA, Nocturnal
Infectious Diseases

subcontinent RAPID
Loa loa (African eye West and Central Mango flies Humans Microfilariae Blood — May be visible in
worm) Africa (Chrysops) eye, diurnal
Onchocerca volvulus Africa, Mexico, Blackflies Humans Adults/larvae Skin/eye — Examine nodules or
(river blindness) Central and skin snips
South America
Dracunculus medinen- Africa Cyclops Humans Adults/larvae Skin — May be visible in
sis (guinea worm) lesion
Angiostrongylus Southeast Asia, Pa- Snails/slugs, Rats Larvae CSF (rarely — Eosinophilic
cantonensis cific, Caribbean shrimp/fish found) meningitis
Larva Migrans Syndromes

Ancylostoma braziliense Tropical and tem- Soil→skin Dogs/cats, Larvae Skin — Dog and cat hook-
(creeping eruption) perate zones humans worm
Toxocara canis and cati Tropical and tem- Soil, fecal-oral Dogs/cats, Larvae Viscera, CNS, EIAb Also caused by
(visceral larva perate zones humans eye roundworms of
migrans) other species
aBlood should be drawn at midnight, except for infection acquired in the South Pacific. RAPID, rapid immunographic assay [available at the National Institutes of Health (301-
bThe presence of hemagglutinins is a useful clue. 496-5398)].
Note: Sx, signs/symptoms; EIA, enzyme immunoassay; CNS, central nervous system;

INTESTINAL PARASITES
Most helminths and protozoa exit the body in the fecal stream. The
patient should be instructed to collect feces in a clean waxed or card-
board container and to record the time of collection on the container.
Contamination with water (which could contain free-living protozoa)
or with urine (which can damage trophozoites) should be avoided. Fe-
cal samples should be collected before ingestion of barium or other
contrast agents for radiologic procedures and before treatment with
antidiarrheal agents and antacids, because these substances change the
consistency of the feces and interfere with microscopic detection of
parasites. Because of the cyclic shedding of most parasites in the feces,
a minimum of three samples collected on alternate days should be ex-
amined. Examination of a single sample can be up to 50% less sensi-
tive. When delays in transport to the laboratory are unavoidable, fecal
samples should be kept in polyvinyl alcohol or another fixative to pre-
serve protozoal trophozoites. 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.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Refrigeration will also preserve trophozoites for a few hours and pro-
tozoal cysts and helminthic ova for several days.
Analysis of fecal samples entails both macroscopic and microscopic
examination. Watery or loose stools are more likely to contain protozoal
trophozoites, but protozoal cysts and all stages of helminths may be
found in formed feces. If adult worms or tapeworm segments are ob-
served, they should be transported promptly to the laboratory or washed
and preserved in fixative for later examination. The only tapeworm with
motile segments is Taenia saginata, the beef tapeworm, which patients
sometimes bring to the physician. Motility is an important distinguishing
characteristic, because the ova of T. saginata are morphologically indis-
tinguishable from those of Taenia solium, the cause of cysticercosis.
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. Before accepting a report of neg-
ativity for ova and parasites as final, the physician should insist that
the laboratory undertake each of these procedures. Some intestinal
parasites are more readily detected in material other than feces. For ex-
TABLE e16-3 PROTOZOAL INFECTIONS e115
Life-Cycle Hosts Diagnosis
Geographic Intermediate Parasite Body Fluid Serologic
Parasite Distribution (Transmission) Definitive Stage or Tissue Tests Other
Intestinal Protozoans

Entamoeba histolytica Worldwide, Fecal-oral Humans Troph, cyst Feces, liver EIA, antigen Ultrasound, liver CT, PCR
(amebiasis) especially detection
tropics
Giardia lamblia Worldwide Fecal-oral Humans Troph, cyst Feces Antigen String test, DFA, PCR
(giardiasis) detection
Isospora belli Worldwide Fecal-oral Humans Oocyst Feces — Acid-fasta
Cryptosporidium Worldwide Fecal-oral Humans, Oocyst Feces Antigen Acid-fast,a DFA, biopsy,
other detection PCR
animals
Cyclospora cayetanensis Worldwide? Fecal-oral Humans, Oocyst Feces — Acid-fast,a modified saf-
other ranin, autofluores-
animals? cence, biopsy, PCR
Microsporidium (Entero- Worldwide? ? Animals, Spore Feces — Modified trichrome,
cytozoon bieneusi, humans acid-fast,a biopsy, PCR
Encephalitozoon spp.)
(microsporidiosis)

CHAPTER e16 Laboratory Diagnosis of Parasitic Infections

Free-Living Amebas
Naegleria Worldwide Warm water Humans Troph, cyst CNS, nares DFA Biopsy, nasal swab,
culture
Acanthamoeba Worldwide Soil, water Humans Troph, cyst CNS, skin, DFA Biopsy, scrapings, culture
cornea
Blood and Tissue Protozoans

Plasmodium spp. (malaria) Subtropics Mosquitoes Humans Asexual Blood Limited use PCR
and tropics
Babesia microti U.S., especially Ticks Rodents, Asexual Blood IIF Animal spp. in asplenia,
(babesiosis) New humans PCR
England
Trypanosoma rhode- Sub-Saharan Tsetse flies Humans, Tryp Blood, CSF IIFb Also chancre, lymph
siense (African sleep- East Africa herbivores nodes
ing sickness)
T. gambiense (African Sub-Saharan Tsetse flies Humans, Tryp Blood, CSF Card aggluti- Also chancre, lymph
sleeping sickness) West Africa swine nation, IIFb, c nodes
T. cruzi (Chagas’ disease) Mexico→ Reduviid bugs Humans, dogs, Amastigote, Multiple IIF, EIA Reactivation in
South (triatomes) wild animals tryp organs/ immunosuppression
America blood
Leishmania tropica, etc. Widespread in Sandflies Humans, dogs, Amastigote Skin IFA, EIAd Biopsy, scrapings, culture
tropics and (Phlebotomus) rodents
subtropics
L. braziliensis Mexico→ Sandflies Humans, dogs, Amastigote Skin, IFAb, EIA Biopsy, scrapings, culture
(mucocutaneous) South (Lutzomyia) rodents mucous
America membranes
L. donovani (kala-azar) Widespread in Sandflies Humans, dogs, Amastigote RE system IFAb, EIA Biopsy, culture, PCR
tropics and (Phlebotomus) wild animals
subtropics
Toxoplasma gondii Worldwide Humans, other Cats Cyst, troph CNS, eye, EIA, IIF PCR
(toxoplasmosis) mammals muscles,
other
aAcid-fastness is best demonstrated by auramine fluorescence or modified acid-fast stain. Note: troph, trophozoite; tryp, trypomastigote form; IIF, indirect immunofluorescence;
bContact the CDC at 770-488-7760. RE, reticuloendothelial; PCR, polymerase chain reaction; EIA, enzyme immunoassay; CNS,
cCard agglutination is provided to endemic countries by the World Health Organization. central nervous system; IFA, indirect fluorescent antibody; CSF, cerebrospinal fluid; DFA,
dLimited specificity; most sensitive for L. donovani. direct fluorescent antibody.

ample, examination of duodenal contents is sometimes necessary to
detect Giardia lamblia, Cryptosporidium, and Strongyloides larvae. Use
of the “cellophane-tape” technique to detect pinworm ova on the peri-
anal skin sometimes also reveals ova of T. saginata deposited perianally
when the motile segments disintegrate (Table e16-4).
Two routine solutions are used to make wet mounts for the identifi-
cation of the various life stages of helminths and protozoa: physiologic
saline for trophozoites, cysts, ova, and larvae and dilute iodine solu-
tion for protozoal cysts and ova. Iodine solution must never be used to
examine specimens for trophozoites because it kills the parasites and
thus eliminates their characteristic motility.
The two most common concentration procedures for detecting
small numbers of cysts and ova are formalin-ether sedimentation and
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
zinc sulfate flotation. The formalin-ether technique is preferable, be-
cause all parasites sediment but not all float. Slides permanently stained
for trophozoites should be prepared before concentration. Additional
slides stained for cysts and ova may be made from the concentrate.
In many instances, especially in the differentiation of Entamoeba
histolytica from other amebas, identification of parasites from wet
mounts or concentrates must be considered tentative. Permanently
stained smears allow study of the cellular detail necessary for definitive
identification. The iron-hematoxylin stain is excellent for critical
work, but trichrome staining, which can be completed in 1 h, is a satis-
factory alternative that also reveals parasites in specimens preserved in
polyvinyl alcohol fixative. Modified acid-fast staining and fluorescent
auramine microscopy are useful adjuncts for detection and identifica-
 e116 TABLE e16-4 ALTERNATIVE PROCEDURES FOR LABORATORY DIAGNOSIS OF PARASITES FOUND IN FECES a tients with Chagas’ disease present in the
Parasites and Fecal Stages Alternative Diagnostic Procedures chronic phase, when Trypanosoma cruzi
is no longer microscopically detectable
Tapeworms (Cestodes) in blood smears. Wet mounts are some-
times more sensitive than stained smears
Taenia saginata ova and segments Perianal “cellophane tape” test for ova
T. solium ova and segments Serology; brain biopsy for neurocysticercosis
for the detection of microfilariae and Af-
rican trypanosomes because these active
Flukes (Trematodes) parasites cause noticeable movement of
Clonorchis (Opisthorchis) sinensis ova Examination of bile for ova and adults in cholangitis the erythrocytes in the microscopic field.
Fasciola hepatica ova Examination of bile for ova and adults in cholangitis Nuclepore filtration of blood facilitates
Paragonimus spp. ova Serology; sputum; biopsy of lung or brain for larvae the detection of microfilariae. The intra-
Schistosoma ova Serology for all; rectal snips (especially for S. mansoni), urine (S. cellular amastigote forms of Leishmania
haematobium), liver biopsy and liver ultrasound spp. and T. cruzi can sometimes be visu-
Roundworms alized in stained smears of peripheral
blood, but aspirates of the bone marrow,
Enterobius vermicularis ova and adults Perianal “cellophane tape” test for ova and adults liver, 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
Hookworm ova and occasional larvae Examination of sputum for larvae in lung disease Leishmania in kala-azar and of T. cruzi in
Strongyloides larvae Duodenal aspirate or jejunal biopsy; serology; sputum or lung chronic Chagas’ disease. The diagnosis
biopsy for filariform larvae in disseminated disease of malaria and the critical distinction
Protozoans among the various Plasmodium species
are made by microscopic examination of
Entamoeba histolytica trophozoites and cysts Serology; liver biopsy for trophozoites stained thick and thin blood films
PART 7

Giardia lamblia trophozoites and cysts Duodenal aspirate or jejunal biopsyb (Chap. 203).
Isospora belli oocysts Duodenal aspirate or jejunal biopsyb Although most tissue parasites stain
Cryptosporidium oocysts Duodenal aspirate or jejunal biopsy b
Microsporidium spores Duodenal aspirate or jejunal biopsy b with the traditional hematoxylin and
eosin, surgical biopsy specimens should
aStains and concentration techniques are discussed in the text.
also be stained with appropriate special
bCommercial string test is satisfactory; Isospora and Cryptosporidium are acid-fast.
stains. The surgical pathologist who is
accustomed to applying silver stains for
Infectious Diseases

tion of several intestinal protozoa, including Cryptosporidium and Cy- Pneumocystis to induced sputum and transbronchial biopsies may
clospora (Table e16-3). 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. histolytica. The clinician should also be able to advise the surgeon
Invasion of tissue by protozoa and helminths renders the choice of diag- and pathologist about optimal techniques for the identification of par-
nostic techniques more difficult. For example, physicians must under- asites in specimens obtained by certain specialized minor procedures
stand that aspiration of an amebic liver abscess rarely reveals E. histolytica (Table e16-6). For example, the excision of skin snips for the diagnosis
because the trophozoites are located primarily in the abscess wall. They of onchocerciasis, the collection of rectal snips for the diagnosis of
must remember that the urine sediment offers the best opportunity to schistosomiasis, and punch biopsy of skin lesions for the identification
detect Schistosoma haematobium in the
young Ethiopian immigrant or the Amer-
ican traveler who returns from Africa TABLE e16-5 IDENTIFICATION OF PARASITES IN BLOOD AND OTHER BODY FLUIDS
with hematuria. Tables e16-1, e16-2, and Body Fluid, Parasite Enrichment/Stain Culture Technique
e16-3, which offer a quick guide to the
geographic distribution and anatomic lo- Blood
cations of the major tissue parasites, Plasmodium spp. Thick and thin smears/Giemsa or Wright’s Not useful for diagnosis
should help the physician to select the ap- Leishmania spp. Buffy coat/Giemsa Media available from CDC
propriate body fluid or biopsy site for mi- African trypanosomesa Buffy coat, anion column/wet mount and Mouse or rat inoculationb
croscopic examination. Tables e16-5 and Giemsa
e16-6 provide additional information Trypanosoma cruzic As for African species As above and xenodiagnosis
about the identification of parasites in Toxoplasma gondii Buffy coat/Giemsa Fibroblast cell lines
Microfilariaed Nuclepore filtration/wet mount and Giemsa None
samples from specific anatomic locations.
The laboratory procedures for detection Urine
of parasites in other body fluids are simi-
Schistosoma haematobium Centrifugation/wet mount None
lar to those used in the examination of fe- Microfilariae (in chyluria) As for blood None
ces. The physician should insist on wet
mounts, concentration techniques, and Spinal Fluid
permanent stains for all body fluids. The African trypanosomes Centrifugation, anion column/wet mount As for blood
trichrome or iron-hematoxylin stain is and Giemsa
satisfactory for all tissue helminths in Naegleria fowleri Centrifugation/wet mount and Giemsa Nonnutrient agar overlaid with
body fluids other than blood, but mi- or trichrome Escherichia coli
crofilarial worms and blood protozoa are aTrypanosoma rhodesiense and T. gambiense.
more easily visualized when stained with bInject mice intraperitoneally with 0.2 mL of whole heparinized blood (0.5 mL for rats). After 5 days, tail blood should be

Giemsa or Wright’s stain. checked daily for trypanosomes as described above. Call the CDC (770-488-7775) for information on diagnosis and treatment.
cDetectable in blood by conventional techniques only during acute disease. Xenodiagnosis is successful in ∼50% of patients
The most common parasites detected
in Giemsa-stained blood smears are the with chronic Chagas’ disease.
dDay (1000–1400 h) and night (2200–0200 h) blood should be drawn to maximize the chance of detecting Wuchereria (noc-
plasmodia, microfilariae, and African
turnal except for Pacific strains), Brugia (nocturnal), and Loa loa (diurnal).
trypanosomes (Table e16-5). Most pa-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 TABLE e16-6 MINOR PROCEDURES FOR DIAGNOSIS OF PARASITIC INFECTIONS
Parasite(s) and Stage
Onchocerca volvulus and Mansonel-
la streptocerca microfilariae
Loa loa adults and O. volvulus
adults and microfilariae
Trichinella spiralis larvae (and per-
haps Taenia solium cysticerci)
Schistosoma ova of all species,
but especially S. mansoni
Trypanosoma gambiense and T.
rhodesiense trypomastigotes
Acanthamoeba spp. trophozoites
or cysts
Cutaneous and mucocutaneous
Leishmania spp.
aCounts of >100/mg are associated with significant risk of complications.
Procedure
Skin snips: Lift skin with a needle and excise ∼1 mg to a depth of 0.5 mm
from several sites. Weigh each sample, place it in 0.5 mL of saline for 4 h,
and examine wet mounts and Giemsa stains of the saline either directly
or after filtration. Count microfilariae.a
Biopsies of subcutaneous nodules: Stain routine histopathologic sections
and impression smears with Giemsa.
Muscle biopsies: Excise ~1.0 g of deltoid or gastrocnemius muscle and
squash between two glass slides for direct microscopic examination.
Rectal snips: From four areas of mucosa, take 2-mg snips, tease onto a
glass slide, and flatten with a second slide before examining directly
at 10×. Preparations may be fixed in alcohol or stained.
Aspirate of chancre or lymph node:b Aspirate center with 18-gauge nee-
dle, place a drop on a slide, and examine for motile forms. An other-
wise insufficient volume of material may be stained with Giemsa.
Corneal scrapings: Obtain sample from ophthalmologist for immediate Gi-
emsa staining and culture on nutrient agar overlaid with Escherichia coli.
Swabs, aspirates, or punch biopsies of skin lesions: Obtain specimen from
margin of lesion for Giemsa staining of impression smears, and sec-
tion and culture on special media from CDC.
Like the hypochromic, microcytic e117
anemia of heavy hookworm infections,
other nonspecific laboratory abnormali-
ties may suggest parasitic infection in pa-
tients with appropriate geographic and/
or environmental exposures. Biochemi-
cal evidence of cirrhosis or an abnormal
urine sediment in an African immigrant
certainly raises the possibility of schisto-
somiasis, and anemia and thrombocyto-
penia in a febrile traveler or immigrant
are among the hallmarks of malaria. 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.
ANTIBODY AND ANTIGEN DETECTION
Useful antibody assays for many of the
important tissue parasites are available;

CHAPTER e16 Laboratory Diagnosis of Parasitic Infections

bLymph node aspiration is contraindicated in some infections and should be used judiciously. most of those listed in Table e16-8 can
be obtained from the Centers for Dis-
ease Control and Prevention (CDC) in
and culture of cutaneous and mucocutaneous species of Leishmania Atlanta. The results of serologic tests not listed in the tables should be
are simple procedures, but the diagnosis can be missed if the speci- interpreted with caution.
mens are improperly obtained or processed.
TABLE e16-8 SEROLOGIC AND MOLECULAR TESTS FOR
NONSPECIFIC TESTS PARASITIC INFECTIONS a
Eosinophilia (>500/μL) is a common accompaniment of infections with
most of the tissue helminths; absolute numbers of eosinophils may be Parasite, Infection Antibody Antigen or DNA/RNA
high in trichinellosis and the migratory phases of filariasis (Table e16-7). Tapeworms
Intestinal helminths provoke eosinophilia only during pulmonary mi-
gration of the larval stages. Eosinophilia is not a manifestation of proto- Echinococcosis WB, EIA
zoal infections, with the possible exceptions of those due to Isospora and Cysticercosis WB
Dientamoeba fragilis. Flukes

Paragonimiasis WB, EIAb

Schistosomiasis EIA, WB
TABLE e16-7 PARASITES FREQUENTLY ASSOCIATED WITH EOSINOPHILIA a Fascioliasis EIAb
Parasite Comment Roundworms
Tapeworms (Cestodes) Strongyloidiasis EIA
Trichinellosis EIA
Echinococcus granulosus When hydatid cyst leaks
Toxocariasis EIA
Taenia solium During muscle encystation and in CSF
Filariasis EIAc RAPIDc
with neurocysticercosis
Protozoans
Flukes (Trematodes)
Amebiasis EIA EIA,b RAPID,b PCR
Paragonimus spp. Uniformly high in acute stage Giardiasis EIA,b RAPID,b DFA, PCR
Fasciola hepatica May be high in acute stage Cryptosporidiosis EIA,b DFA, RAPID,b PCR
Clonorchis (Opisthorchis) sinensis Variable Malaria (all species) IIFd PCR
Schistosoma mansoni 50% of infected travelers Babesiosis IIF PCR
S. haematobium 25% of infected travelers Chagas’ disease IIF, EIA PCR
S. japonicum Up to 6000/μL in acute infection Leishmaniasis IIF, EIA PCRb
Roundworms Toxoplasmosis IIF, EIA (IgM)e PCRb
Microsporidiosis PCR
Ascaris lumbricoides During larval migration Cyclosporiasis PCR
Hookworm species During larval migration Acanthamoebiasis DFA, PCR
Strongyloides stercoralis Profound during migration and early years Naegleriasis DFA, PCR
of infection Balmuthiasis DFA
Trichinella spiralis Up to 7000/μL
aUnless otherwise noted, all tests are available at the CDC.
Filarial speciesb Varies but can reach 5000–8000/μL
bResearch or commercial laboratories only.
Toxocara spp. >3000/μL
cAvailable at the NIH (301-496-5398) and commercially.
Ancylostoma braziliense With extensive cutaneous eruption
dOf limited use for management of acute disease.
Gnathostoma spinigerum In visceral larva migrans and eosinophilic
eDetermination of infection within the last 3 months may require additional tests by a
meningitis
Angiostrongylus cantonensis In eosinophilic meningitis research laboratory.
A. costaricensis During larval migration in mesenteric vessels Note: EIA, enzyme immunoassay; WB, western blot; IIF, indirect immunofluorescence;
DFA, direct fluorescent antibody; PCR, polymerase chain reaction; RAPID, rapid immu-
a Virtually every helminth has been associated with eosinophilia. This table includes both nographic assay. Most antigen and antibody parasite detection kits are available com-
common and uncommon parasites that frequently elicit eosinophilia during infection. mercially. Most PCRs listed are now available at the CDC and in commercial or
bWuchereria bancrofti, Brugia spp., Loa loa, and Onchocerca volvulus. research laboratories. Contact Dr. Alexandre da Silva at the CDC (770-488-4072).

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

 e118 The value of antibody assays is limited by several factors. For exam-
ple, the preparation of thick and thin blood smears remains the proce-
dure of choice for the diagnosis of malaria in individual patients
because diagnostic titers to plasmodia develop slowly and do not dif-
ferentiate species—a critical step in patient management. Filarial anti-
gens cross-react with those from other nematodes; as in assays for
antibody to most parasites, the presence of antibody in the filarial as-
say fails to distinguish between past and current infection. Despite
these specific limitations, 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. In contrast, a large proportion of the world’s population has
been exposed to Toxoplasma gondii, and the presence of IgG antibody
to T. gondii does not constitute proof of active disease.
Fewer antibody assays are available for the diagnosis of infection
with intestinal parasites. E. histolytica is the major exception. Sensitive,
specific serologic tests are invaluable in the diagnosis of amebiasis.
Commercial kits for the detection of antigen by enzyme-linked immu-
nosorbent assay or of whole organisms by fluorescent antibody assay
are now available for several protozoan parasites (Table e16-8).
MOLECULAR TECHNIQUES
DNA hybridization with probes that are repeated many times in the
PART 7
genome of a specific parasite and amplification of a specific DNA frag-
ment by the polymerase chain reaction (PCR) have now been estab-
lished as useful techniques for the diagnosis of several protozoan
infections (Table e16-8). Although PCR is very sensitive, it is an ad-
junct to conventional techniques for parasite detection and should be
requested only when microscopic and immunodiagnostic procedures
fail to establish the probable diagnosis. For example, only multiple
Infectious Diseases
negative blood smears or the failure to identify the infecting species
justifies PCR for the diagnosis or proper management of malaria. In
addition to PCR of anticoagulated blood, the CDC (contact Dr. Alex-
andre da Silva, 770-488-4072, for details) and several commercial lab-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
oratories now perform PCRs for detection of certain specific parasites
in stool samples, biopsy specimens, and bronchoalveolar lavage fluid
(Table e16-8). Although PCRs are now used primarily for the detec-
tion of protozoans, active research efforts are likely to establish their
feasibility for the detection of several helminths.
FURTHER READINGS
FLECK SL, MOODY AH: Diagnostic Techniques in Medical Parasitology.
London, Wright, 1988
FREEDMAN DO et al: Spectrum of disease and relation to place of ex-
posure among ill returned travelers. N Engl J Med 354:119, 2006
GARCIA LS: Laboratory identification of the microsporidia. J Clin Mi-
crobiol 40:1892, 2002
——— et al: Algorithms for detection and identification of parasites,
in Manual of Clinical Microbiology, 9th ed, vol 2, PR Murray et al
(eds). Washington, DC, ASM Press, 2007, pp 2020–2039
HERWALDT BL: Cyclospora cayetanensis: A review, focusing on the
outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 31:1040,
2000
SEYBOLT LM et al: Diagnostic evaluation of newly arrived asympto-
matic refugees with eosinophilia. Clin Infect Dis 42:363, 2006
TANYUKSEL M et al: Laboratory diagnosis of amebiasis. Clin Microbiol
Rev 16:713, 2003
WALKER M et al: Parasitic central nervous system infections in immu-
nocompromised hosts: Malaria, microsporidiosis, leishmaniasis,
and African trypanosomiasis. Clin Infect Dis 42:115, 2006
WILSON M et al: Toxoplasma, in Manual of Clinical Microbiology, 9th
ed, vol 2, PR Murray et al (eds). Washington, DC, ASM Press,
2007, pp 2070–2081
——— et al: Molecular immunological approaches to the diagnosis of
parasitic infection, in Manual of Molecular and Clinical Laboratory
Immunology, 7th ed, B Detrick et al (eds). Washington, DC, ASM
Press, 2006, pp 557–568

e17 Pharmacology of Agents Used
to Treat Parasitic Infections
Thomas A. Moore
This chapter deals exclusively with the pharmacologic properties of
the agents used to treat infections due to parasites. Specific treatment
recommendations for the parasitic diseases of humans are listed in the
chapters on those diseases. Information on these agents’ major toxici-
ties, spectrum of activity, and safety for use during pregnancy and lac-
tation is presented in Chap. 201. Many of the agents discussed herein
are approved by the U.S. Food and Drug Administration (FDA) but
are considered investigational for the treatment of certain infections
(see Table 201-1). 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;
www.cdc.gov/ncidod/dpd/professional/drug_service.htm). Drugs marked
with a dagger (†) are available only through their manufacturers;
contact information for these manufacturers may be available from
the CDC.
Albendazole Like all benzimidazoles, albendazole acts by selectively
binding to free β-tubulin in nematodes, inhibiting the polymerization
of tubulin and the microtubule-dependent uptake of glucose. Irrevers-
ible damage occurs in gastrointestinal (GI) cells of the nematodes, re-
sulting in starvation, death, and expulsion by the host. While highly
injurious to nematodes, this fundamental disruption of cellular me-
tabolism also offers treatment for a wide range of parasitic diseases.
Albendazole is poorly absorbed from the GI tract. Administration
with a fatty meal increases its absorption by two- to sixfold. Poor ab-
sorption may be advantageous for the treatment of intestinal hel-
minths, but successful treatment of tissue helminth infections (e.g.,
hydatid disease and neurocysticercosis) requires that a sufficient
amount of active drug reach the site of infection. The metabolite al-
bendazole sulfoxide is responsible for the drug’s therapeutic effect out-
side the gut lumen. Albendazole sulfoxide crosses the blood-brain
barrier, reaching a level significantly higher than that achieved in plas-
ma. The high concentrations of albendazole sulfoxide attained in cere-
brospinal fluid (CSF) probably explain the efficacy of albendazole in
the treatment of neurocysticercosis.
Albendazole is extensively metabolized in the liver, but there are few
data regarding the drug’s use in patients with hepatic disease. Single-
dose albendazole therapy in humans is largely without side effects
(overall frequency, ≤1%). More prolonged courses (e.g., as adminis-
tered for cystic and alveolar echinococcal disease) have been associated
with liver function abnormalities and bone marrow toxicity. Thus,
when prolonged use is anticipated, the drug should be administered in
treatment cycles of 28 days interrupted by 14 days off therapy. Pro-
longed therapy with full-dose albendazole (800 mg/d) should be ap-
proached cautiously in patients also receiving drugs with known
effects on the cytochrome P450 system.
Amodiaquine Amodiaquine has been widely used in the treatment of
malaria for >40 years. Like chloroquine (the other major 4-amino-
quinoline), amodiaquine is now of limited use because of the spread of
resistance. Amodiaquine interferes with hemozoin formation through
complexation with heme. Although rapidly absorbed, amodiaquine
behaves as a prodrug after oral administration, with the principal plas-
ma metabolite monodesethylamodiaquine as the predominant anti-
malarial agent. Amodiaquine and its metabolites are all excreted in
urine, but there are no recommendations concerning dosage adjust-
ment in patients with impaired renal function. Severe adverse events
can occur, albeit rarely (1 case in 2000 treatment courses), with amo-
diaquine administration. Agranulocytosis and hepatotoxicity can de-
velop with repeated use; therefore, this drug should not be used for
prophylaxis.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Amphotericin B See Table 201-1 and Chap. 191. e119
Antimonials* Despite associated adverse reactions and the need for
prolonged parenteral treatment, the pentavalent antimonial com-
pounds (designated Sbv) have remained the first-line therapy for all
forms of leishmaniasis throughout the world, primarily because they
are affordable, are effective, and have survived the test of time. Al-
though they have been used for almost 100 years, their mechanism of
action against Leishmania spp. has only recently come to light. Pen-
tavalent antimonials are active only after bioreduction to the trivalent
Sb(III) form. This form inhibits trypanothione reductase, a critical en-
zyme involved in the oxidative stress management of Leishmania spp.
The fact that Leishmania spp. use trypanothione rather than glutathione
(which is used by mammalian cells) may explain the parasite-specific
activity of antimonials. The drugs are taken up by the reticuloendo-
thelial system, and their activity against Leishmania spp. may be en-
hanced by this localization. Sodium stibogluconate is the only
pentavalent antimonial available in the United States; meglumine anti-
monate is principally used in francophone countries.
Resistance is a major problem in some areas. Although low-level
unresponsiveness to Sbv was identified in India in the 1970s, incre-
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
mental 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. There has since been a
steady erosion in the capacity of Sbv to induce long-term cure in pa-
tients with kala-azar who live in eastern India. Foremost among the
many factors that have probably contributed to this failure is the pro-
vision of suboptimal treatment for years, which led to the develop-
ment of drug resistance among parasites. Co-infection with HIV
impairs the treatment response.
Sodium stibogluconate is available in aqueous solution and is ad-
ministered parenterally. Antimony appears to have two elimination
phases. When administered IV, the mean half-life of the first phase is
<2 h; the mean half-life of the terminal elimination phase is nearly 36
h. This slower phase may be due to conversion of pentavalent antimo-
ny to a trivalent form that is the likely cause of the side effects often
seen with prolonged therapy.
Artemisinin Derivatives Artesunate, artemether, arteether, and the
parent compound artemisinin are sesquiterpene lactones derived from
the wormwood plant Artemisia annua. 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; thus, they have be-
come first-line agents for the treatment of severe falciparum malaria in
some areas where multidrug resistance is a major problem. However,
to limit the development of resistance, the World Health Organization
(WHO) has recommended that artemisinin and its derivatives be used
only in areas where there is proven multidrug resistance. Artemether
appears to be effective for the treatment of schistosomiasis and is being
evaluated for community-based treatment programs.
The artemisinin compounds are rapidly effective against the asexu-
al blood forms of Plasmodium spp. but are not active against intrahe-
patic forms. Artemisinin and its derivatives are highly lipid soluble
and readily cross both host and parasite cell membranes. 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.
The antimalarial effect of these agents results primarily from dihy-
droartemisinin, a compound to which artemether and artesunate are
both converted. In the presence of heme or molecular iron, the endo-
peroxide moiety of dihydroartemisinin decomposes, generating free
radicals and other metabolites that damage parasite proteins. Long
treatment courses are required. When these agents are used alone, re-
crudescence may occur. The compounds are available for oral, rectal,
IV, or IM administration, depending on the derivative. Artemisinin
and its derivatives are cleared rapidly from the circulation. Their
short half-lives limit their value for prophylaxis and monotherapy. A
combined formulation of artemether and lumefantrine has been de-
 e120 veloped for the treatment of acute uncomplicated falciparum malaria
in areas where Plasmodium falciparum is resistant to chloroquine and
antifolates.
Atovaquone Atovaquone is a hydroxynaphthoquinone that exerts
broad-spectrum antiprotozoal activity via selective inhibition of parasite
mitochondrial electron transport. This agent exhibits potent activity
against toxoplasmosis and babesiosis when used with pyrimethamine
and azithromycin, respectively. Atovaquone possesses a novel mode of
action against Plasmodium spp., inhibiting the electron transport system
at the level of the cytochrome bc1 complex. The drug is active against
both the erythrocytic and the exoerythrocytic stages of Plasmodium
spp.; however, because it does not eradicate hypnozoites from the liver,
patients with Plasmodium vivax or Plasmodium ovale infections must be
given radical prophylaxis.
Malarone is a fixed-dose combination of atovaquone and proguanil
used for malaria prophylaxis as well as for the treatment of acute, un-
complicated P. falciparum malaria. Malarone has been shown to be ef-
fective in regions with multidrug-resistant P. falciparum. Resistance to
atovaquone has yet to be reported.
The bioavailability of atovaquone varies considerably. Absorption
after a single oral dose is slow, increases two- to threefold with a fatty
meal, and is dose-limited above 750 mg. The elimination half-life is
PART 7
increased in patients with moderate hepatic impairment. Because of
the potential for drug accumulation, the use of atovaquone is contra-
indicated in persons with severe renal impairment (creatinine clear-
ance rate < 30 mL/min). No dosage adjustments are needed in patients
with mild to moderate renal impairment. It is unknown if atovaquone
is dialyzable.
Infectious Diseases
Azithromycin See Table 201-1 and Chap. 127.
Azoles See Table 201-1 and Chap. 191.
Benznidazole This oral nitroimidazole derivative is used to treat
Chagas’ disease, with cure rates of 80–90% recorded in acute infec-
tions. Benznidazole is believed to exert its trypanocidal effects by gen-
erating oxygen radicals to which the parasites are more sensitive than
mammalian cells because of a relative deficiency in antioxidant en-
zymes. Benznidazole also appears to alter the balance between pro-
and anti-inflammatory mediators by downregulating the synthesis of
nitrite, interleukin (IL) 6, and IL-10 in macrophages. Benznidazole is
highly lipophilic and readily absorbed. The drug is extensively metab-
olized; only 5% of the dose is excreted unchanged in the urine.
Bithionol Bithionol is a chlorinated bisphenol with activity against
trematodes. Fasciola hepatica uses fumarate reduction coupled to
rhodoquinone for anaerobic energy metabolism. Bithionol competi-
tively inhibits electron transfer to fumarate by rhodoquinone; the re-
sult is impaired anaerobic energy metabolism and trematode death.
Bithionol is parasite specific for two reasons: (1) Fumarate reductase
catalyzes the reverse of the reaction of mammalian succinic dehydro-
genase in the Krebs cycle. (2) The rhodoquinone respiratory chain link
is unique to the parasite. In the mammalian respiratory chain, the
quinone electron carrier is ubiquinone. Bithionol is readily absorbed
from the GI tract. It is no longer produced, but limited supplies are
available from the CDC.
Chloroquine This 4-aminoquinoline has marked, rapid schizontocidal
and gametocidal activity against blood forms of P. ovale and Plasmodi-
um malariae and against susceptible strains of P. vivax and P. falci-
parum. It is not active against intrahepatic forms (P. vivax and P. ovale).
Parasitized erythrocytes accumulate chloroquine in significantly great-
er concentrations than do normal erythrocytes. Chloroquine, a weak
base, concentrates in the food vacuoles of intraerythrocytic parasites
because of a relative pH gradient between the extracellular space and
the acidic food vacuole. Once it enters the acidic food vacuole, chloro-
quine is rapidly converted to a membrane-impermeable protonated
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
form and is trapped. 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 high accumulation of chloro-
quine results in an increase in pH within the food vacuole to a level
above that required for the acid proteases’ optimal activity, inhibiting
parasite heme polymerase; as a result, the parasite is effectively killed
with its own metabolic waste. Compared with susceptible strains, chlo-
roquine-resistant plasmodia transport chloroquine out of intraparasit-
ic compartments more rapidly and maintain lower chloroquine
concentrations in their acid vesicles. Hydroxychloroquine, a congener
of chloroquine, is equivalent to chloroquine in its antimalarial efficacy
but is preferred to chloroquine for the treatment of autoimmune disor-
ders because it produces less ocular toxicity when used in high doses.
Chloroquine is well absorbed. However, because it exhibits exten-
sive tissue binding, a loading dose is required to yield effective plasma
concentrations. A therapeutic drug level in plasma is reached 2–3 h af-
ter oral administration (the preferred route). Chloroquine can be ad-
ministered IV, but excessively rapid parenteral administration can
result in seizures and death from cardiovascular collapse. The mean
half-life of chloroquine is 4 days, but the rate of excretion decreases as
plasma levels decline, making once-weekly administration possible for
prophylaxis in areas with sensitive strains. About half of the parent
drug is excreted in urine, but the dose should not be reduced for per-
sons with acute malaria and renal insufficiency.
Ciprofloxacin See Table 201-1 and Chap. 127.
Clindamycin See Table 201-1 and Chap. 127.
Dapsone See Table 201-1 and Chap. 161.
Dehydroemetine Emetine is an alkaloid derived from ipecac; dehy-
droemetine is synthetically derived from emetine and is considered less
toxic. Both agents are active against Entamoeba histolytica and appear
to work by blocking peptide elongation and thus inhibiting protein
synthesis. Emetine is rapidly absorbed after parenteral administration,
rapidly distributed throughout the body, and slowly excreted in the
urine in unchanged form. Both agents are contraindicated in patients
with renal disease.
Diethylcarbamazine* A derivative of the antihelminthic agent pipera-
zine with a long history of successful use, diethylcarbamazine (DEC) re-
mains the treatment of choice for lymphatic filariasis and loiasis and has
also been used for visceral larva migrans. While piperazine itself has no
antifilarial activity, the piperazine ring of DEC is essential for the drug’s
activity. Although DEC was shown to be an effective agent for treatment
of lymphatic filariasis in 1947, its mechanism of action remains to be
fully defined. Proposed mechanisms include immobilization due to in-
hibition of parasite cholinergic muscle receptors, disruption of microtu-
bule formation, and alteration of helminthic surface membranes
resulting in enhanced killing by the host’s immune system. In addition,
DEC enhances adherence properties of eosinophils. The development of
resistance under drug pressure (i.e., a progressive decrease in efficacy
when the drug is used widely in human populations) has not been ob-
served, although DEC’s effect is variable when administered to persons
with filariasis. Monthly administration provides effective prophylaxis
against both bancroftian filariasis and loiasis.
DEC is well absorbed after oral administration, with peak plasma
concentrations reached within 1–2 h. No parenteral form is available.
The drug is eliminated largely by renal excretion, with <5% found in
feces. If more than one dose is to be administered to an individual with
renal dysfunction, the dose should be reduced commensurate with the
reduction in creatinine clearance rate. Alkalinization of the urine pre-
vents renal excretion and increases the half-life of DEC. Use in patients
with onchocerciasis can precipitate a Mazzotti reaction, with pruritus,
fever, and arthralgias. Like other piperazines, DEC is active against As-
caris spp. Patients co-infected with this nematode may expel live but
paralyzed worms after treatment.
Diloxanide Furoate Diloxanide furoate, a substituted acetanilide, is a
luminally active agent used to eradicate the cysts of E. histolytica. After
ingestion, diloxanide furoate is hydrolyzed by enzymes in the lumen or
mucosa of the intestine, releasing furoic acid and the ester diloxanide;
the latter acts directly as an amebicide.
Diloxanide furoate is given alone to asymptomatic cyst passers. For
patients with active amebic infections, diloxanide is generally adminis-
tered in combination with a 5-nitroimidazole such as metronidazole
or tinidazole. Diloxanide furoate is rapidly absorbed after oral admin-
istration. When coadministered with a 5-nitroimidazole, only dilox-
anide appears in the systemic circulation; levels peak within 1 h and
disappear within 6 h. About 90% of an oral dose is excreted in the
urine within 48 h, chiefly as the glucuronide metabolite. Diloxanide
furoate is contraindicated in pregnant and breast-feeding women and
in children <2 years of age.
Eflornithine† Eflornithine (difluoromethylornithine, or DFMO) is a
fluorinated analogue of the amino acid ornithine. Although originally
designed as an antineoplastic agent, eflornithine has proven effective
against some trypanosomatids. At one point, the production of this ef-
fective agent ceased despite the increasing incidence of human African
trypanosomiasis; however, production resumed after eflornithine was
discovered to be an effective cosmetic depilatory agent.
Eflornithine has specific activity against all stages of infection with
Trypanosoma brucei gambiense; however, it is inactive against T. b.
rhodesiense. The drug acts as an irreversible suicide inhibitor of orni-
thine decarboxylase, the first enzyme in the biosynthesis of the
polyamines putrescine and spermidine. Polyamines are essential for
the synthesis of trypanothione, an enzyme required for the mainte-
nance of intracellular thiols in the correct redox state and in the re-
moval of reactive oxygen metabolites. However, polyamines are also
essential for cell division in eukaryotes, and ornithine decarboxylase is
similar in trypanosomes and mammals. The selective antiparasitic ac-
tivity of eflornithine is partly explained by the structure of the try-
panosomal enzyme, which lacks a 36-amino-acid C-terminal sequence
found on mammalian ornithine decarboxylase. This difference results
in a lower turnover of ornithine decarboxylase and a more rapid de-
crease of polyamines in trypanosomes than in the mammalian host.
The diminished effectiveness of eflornithine against T. b. rhodesiense
appears to be due to the parasite’s ability to replace the inhibited en-
zyme more rapidly than T. b. gambiense.
Eflornithine is less toxic but more costly than conventional therapy.
Eflornithine HCl can be administered IV or PO; however, its bioavail-
ability after oral administration is only 54%. Eflornithine readily
crosses the blood-brain barrier; CSF levels are highest in persons with
the most severe central nervous system (CNS) involvement. The kid-
ney excretes >80% of the drug dose; therefore, the dosage should be
reduced in patients with renal failure.
Fumagillin Fumagillin is a water-insoluble antibiotic that is derived
from the fungus Aspergillus fumigatus and is active against microspo-
ridia. This drug is effective when used topically to treat ocular infec-
tions due to Encephalitozoon spp. When given systemically, fumagillin
was effective but caused thrombocytopenia in all recipients in the sec-
ond week of treatment; this side effect was readily reversed when ad-
ministration of the drug was stopped. The mechanisms by which
fumagillin inhibits microsporidial replication are poorly understood,
although the drug may inhibit methionine aminopeptidase 2 by irre-
versibly blocking the active site.
Furazolidone This nitrofuran derivative is an effective alternative
agent for the treatment of giardiasis and also exhibits activity against
Isospora belli. Since it is the only agent active against Giardia that is
available in liquid form, it is often used to treat young children. Fura-
zolidone undergoes reductive activation in Giardia lamblia trophozo-
ites—an event that, unlike the reductive activation of metronidazole,
involves an NADH oxidase. The killing effect correlates with the toxic-
ity of reduced products, which damage important cellular compo-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
nents, including DNA. Although furazolidone had been thought to be e121
largely unabsorbed when administered orally, the occurrence of sys-
temic adverse reactions indicates that this is not the case. More than
65% of the drug dose can be recovered from the urine as colored me-
tabolites. Omeprazole reduces the oral bioavailability of furazolidone.
Furazolidone is a monoamine oxidase (MAO) inhibitor; thus cau-
tion 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 treat-
ment. However, hypertensive crises have not been reported in patients
receiving furazolidone, and it has been suggested that—since furazoli-
done inhibits MAO gradually over several days—the risks are small if
treatment is limited to a 5-day course. Because hemolytic anemia can
occur in patients with glucose-6-phosphate dehydrogenase (G6PD)
deficiency and glutathione instability, furazolidone treatment is con-
traindicated in mothers who are breast-feeding and in neonates.
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. Its activity is be-
lieved to be similar to that of chloroquine, although it is an oral alter-
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
native for the treatment of malaria due to chloroquine-resistant P.
falciparum. Although the mechanism of action is poorly understood,
halofantrine is thought to share mechanism(s) with the 4-aminoquin-
olines, forming a complex with ferriprotoporphyrin IX and interfering
with the degradation of hemoglobin.
Halofantrine exhibits erratic bioavailability, but its absorption is
significantly enhanced when it is taken with a fatty meal. The elimina-
tion half-life of halofantrine is 1–2 days; it is excreted mainly in feces.
Halofantrine is metabolized into N-debutyl-halofantrine by the cyto-
chrome P450 enzyme CYP3A4. Grapefruit juice should be avoided
during treatment because it increases both halofantrine’s bioavailabili-
ty and halofantrine-induced QT interval prolongation by inhibiting
CYP3A4 at the enterocyte level.
Iodoquinol Iodoquinol (diiodohydroxyquin), a hydroxyquinoline, is
an effective luminal agent for the treatment of amebiasis, balantidiasis,
and infection with Dientamoeba fragilis. Its mechanism of action is
unknown. It is poorly absorbed. Because the drug contains 64% or-
ganically bound iodine, it should be used with caution in patients with
thyroid disease. Iodine dermatitis occurs occasionally during io-
doquinol treatment. Protein-bound serum iodine levels may be in-
creased during treatment and can interfere with certain tests of thyroid
function. These effects may persist for as long as 6 months after dis-
continuation of therapy. Iodoquinol is contraindicated in patients
with liver disease. Most serious are the reactions related to prolonged
high-dose therapy (optic neuritis, peripheral neuropathy), which
should not occur if the recommended dosage regimens are followed.
Ivermectin Ivermectin (22,23-dihydroavermectin) is a derivative of
the macrocyclic lactone avermectin produced by the soil-dwelling ac-
tinomycete Streptomyces avermitilis. Ivermectin is active at low doses
against a wide range of helminths and ectoparasites. It is the drug of
choice for the treatment of onchocerciasis, strongyloidiasis, cutaneous
larva migrans, and scabies. Ivermectin is highly active against microfi-
lariae of the lymphatic filariases but has no macrofilaricidal activity.
When ivermectin is used in combination with other agents such as
DEC or albendazole for treatment of lymphatic filariasis, synergistic
activity is seen. While active against the intestinal helminths Ascaris
lumbricoides and Enterobius vermicularis, ivermectin is only variably
effective in trichuriasis and is ineffective against hookworms. Wide-
spread use of ivermectin for treatment of intestinal nematode infec-
tions in sheep and goats has led to the emergence of drug resistance in
veterinary practice; this development may portend problems in hu-
man medical use.
Recent data suggest that ivermectin acts by opening the neuromus-
cular membrane-associated, glutamate-dependent chloride channels.
The influx of chloride ions results in hyperpolarization and muscle pa-
 e122 ralysis—particularly of the nematode pharynx, with consequent
blockage of the oral ingestion of nutrients. Because these chloride
channels are present only in invertebrates, the paralysis is seen only in
the parasite.
Ivermectin is available only as an oral formulation. The drug is
highly protein bound; it is almost completely excreted in feces. The ef-
fect of food on bioavailability is unknown. Ivermectin is distributed
widely throughout the body; animal studies indicate that it accumu-
lates at the highest concentration in adipose tissue and liver, with little
accumulation in the brain. Few data exist to guide therapy in hosts
with conditions that may influence drug pharmacokinetics.
Ivermectin is generally administered as a single dose of 150–200 μg/
kg. In the absence of parasitic infection, the adverse effects of ivermec-
tin in therapeutic doses are minimal. Adverse effects in patients with
filarial infections include fever, myalgia, malaise, lightheadedness, and
(occasionally) postural hypotension. The severity of such side effects is
related to the intensity of parasite infection, with more symptoms in
individuals with a heavy parasite burden. In onchocerciasis, skin ede-
ma, pruritus, and mild eye irritation may also occur. The adverse ef-
fects are generally self-limiting and only occasionally require
symptom-based treatment with antipyretics or antihistamines. More
severe complications of ivermectin therapy for onchocerciasis include
encephalopathy in patients heavily infected with Loa loa. This reaction
PART 7
has led to the suspension of ivermectin distribution for this indication
in regions where the two filarial infections are coendemic.
Levamisole Levamisole is the levo-isomer of tetramisole and is used
to treat ascariasis and hookworm infection. Levamisole appears to act
by binding to a distinctive ion channel that forms a nicotinic acetyl-
choline receptor on nematode muscle. This event causes sustained de-
Infectious Diseases
polarization of the muscle membrane and results in paralysis of the
worm. Levamisole is rapidly absorbed from the GI tract and is exten-
sively metabolized in the liver; the metabolites are excreted in the
urine. The use of this drug is contraindicated in patients with preexist-
ing blood disorders (e.g., agranulocytosis) or Sjögren’s syndrome.
When used for the treatment of helminthic infections, levamisole is
well tolerated, with side effects usually limited to GI disturbances.
Lumefantrine Lumefantrine (benflumetol), a fluorene (benzindene)
derivative synthesized in the 1970s by the Chinese Academy of Mili-
tary Medical Sciences (Beijing), has marked blood schizontocidal ac-
tivity against a wide range of plasmodia. This agent conforms
structurally and in mode of action to the arylaminoalcohol group of
antimalarial drugs, including quinine, mefloquine, and halofantrine.
Lumefantrine exerts its antimalarial effect as a consequence of its in-
teraction with heme, a degradation product of hemoglobin metabo-
lism. Although its antimalarial activity is slower than that of the
artemisinin-based drugs, the recrudescence rate with the recommend-
ed lumefantrine regimen is lower. The pharmacokinetic properties of
lumefantrine are reminiscent of those of halofantrine, with variable
oral bioavailability, considerable augmentation of oral bioavailability
by concomitant fat intake, and a terminal elimination half-life of ~4–5
days in patients with malaria.
Artemether and lumefantrine have synergistic activity, and clinical
studies in China on several hundred patients show the combination to
be safe and well tolerated. The combined formulation of artemether
and lumefantrine has been developed for the treatment of falciparum
malaria in areas where P. falciparum is resistant to chloroquine and
antifolates.
Mebendazole This benzimidazole is a broad-spectrum antiparasitic
agent widely used to treat intestinal helminthiases. Its mechanism of
action is similar to that of albendazole; however, it is a more potent
inhibitor of parasite malic dehydrogenase and exhibits a more specif-
ic and selective effect against intestinal nematodes than the other
benzimidazoles.
Mebendazole is available only in oral form but is poorly absorbed
from the GI tract; only 5–10% of a standard dose is measurable in
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
plasma. The proportion absorbed from the GI tract is extensively me-
tabolized in the liver. Metabolites appear in the urine and bile; im-
paired liver or biliary function results in higher plasma mebendazole
levels in treated patients. No dose reduction is warranted in patients
with renal function impairment. Because mebendazole is poorly ab-
sorbed, its incidence of side effects is low. Transient abdominal pain
and diarrhea sometimes occur, usually in persons with massive para-
site burdens.
Mefloquine Mefloquine is the preferred drug for prophylaxis of chlo-
roquine-resistant malaria; high doses can be used for treatment. De-
spite the development of drug-resistant strains of P. falciparum in
parts of Africa and Southeast Asia, mefloquine is an effective drug
throughout most of the world. Cross-resistance of mefloquine with
halofantrine and with quinine has been documented in limited areas.
Like quinine and chloroquine, this quinoline is active only against the
asexual erythrocytic stages of malarial parasites. Unlike quinine, how-
ever, mefloquine has a relatively poor affinity for DNA and, as a result,
does not inhibit the synthesis of parasitic nucleic acids and proteins.
Although both mefloquine and chloroquine inhibit hemozoin forma-
tion and heme degradation, mefloquine differs in that it forms a com-
plex with heme that may be toxic to the parasite.
Mefloquine HCl is poorly water soluble and intensely irritating
when given parenterally; thus it is available only in tablet form. Its ab-
sorption is adversely affected by vomiting and diarrhea but is signifi-
cantly enhanced when the drug is administered with or after food.
About 98% of the drug binds to protein. Mefloquine is excreted main-
ly in the bile and feces; therefore, no dose adjustment is needed in per-
sons with renal insufficiency. The drug and its main metabolite are not
appreciably removed by hemodialysis. No special chemoprophylactic
dosage adjustments are indicated for the achievement of plasma con-
centrations in dialysis patients that are similar to those in healthy per-
sons. Pharmacokinetic differences have been detected among various
ethnic populations. In practice, however, these distinctions are of mi-
nor importance compared with host immune status and parasite sen-
sitivity. In patients with impaired liver function, the elimination of
mefloquine may be prolonged, leading to higher plasma levels.
Mefloquine should be used with caution by individuals participat-
ing in activities requiring alertness and fine-motor coordination. If the
drug is to be administered for a prolonged period, periodic evalua-
tions are recommended, including liver function tests and ophthalmic
examinations. Sleep abnormalities (insomnia, abnormal dreams) have
occasionally been reported. Psychosis and seizures occur rarely; meflo-
quine should not be prescribed to patients with neuropsychiatric con-
ditions, including depression, generalized anxiety disorder, psychosis,
schizophrenia, and seizure disorder. If acute anxiety, depression, rest-
lessness, or confusion develops during prophylaxis, these psychiatric
symptoms may be considered prodromal to a more serious event, and
the drug should be discontinued.
Concomitant use of quinine, quinidine, or drugs producing β-adren-
ergic blockade may cause significant electrocardiographic abnormalities
or cardiac arrest. 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. No data exist on
mefloquine use after halofantrine use. Administration of mefloquine
with quinine or chloroquine may increase the risk of convulsions. Me-
floquine may lower plasma levels of anticonvulsants. Caution should be
exercised with regard to concomitant antiretroviral therapy, since meflo-
quine has been shown to exert variable effects on ritonavir pharmacoki-
netics that are not explained by hepatic CYP3A4 activity or ritonavir
protein binding. Vaccinations with attenuated live bacteria should be
completed at least 3 days before the first dose of mefloquine.
Women of childbearing age who are traveling to areas where malar-
ia is endemic should be warned against becoming pregnant and en-
couraged to practice contraception during malaria prophylaxis with
mefloquine and for up to 3 months thereafter. However, in the case of
unplanned pregnancy, use of mefloquine is not considered an indica-
tion for pregnancy termination.
Melarsoprol* Melarsoprol has been used since 1949 for the treatment
of human African trypanosomiasis (HAT). This trivalent arsenical
compound is indicated for the treatment of HAT with neurologic in-
volvement and for the treatment of early HAT that is resistant to
suramin or pentamidine. The changing view on the mode of action of
arsenicals is well documented. Melarsoprol, like other drugs contain-
ing heavy metals, interacts with thiol groups of several different pro-
teins; however, its antiparasitic effects appear to be more specific.
Trypanothione reductase is a key enzyme involved in the oxidative
stress management of both Trypanosoma and Leishmania spp., helping
to maintain an intracellular reducing environment by reduction of di-
sulfide trypanothione to its dithiol derivative dihydrotrypanothione.
Melarsoprol sequesters dihydrotrypanothione, depriving the parasite
of its main sulfhydryl antioxidant, and inhibits trypanothione reduc-
tase, depriving the parasite of the essential enzyme system that is re-
sponsible for keeping trypanothione reduced. These effects are
synergistic. The selectivity of arsenical action against trypanosomes is
due at least in part to the greater melarsoprol affinity of reduced try-
panothione than of other monothiols (e.g., cysteine) on which the
mammalian host depends for maintenance of high thiol levels. Melar-
soprol enters the parasite via an adenosine transporter; drug-resistant
strains lack this transport system.
Melarsoprol is always administered IV. A small but therapeutically
significant amount of the drug enters the CSF. The compound is ex-
creted rapidly, with ~80% of the arsenic found in feces.
Melarsoprol is highly toxic. The most serious adverse reaction is re-
active encephalopathy, which affects 6% of treated individuals and
usually develops within 4 days of the start of therapy, with an average
case-fatality rate of 50%. Glucocorticoids are administered with
melarsoprol to prevent this development. Because melarsoprol is in-
tensely irritating, care must be taken to avoid infiltration of the drug.
Metrifonate Metrifonate has selective activity against Schistosoma
haematobium. This organophosphorous compound is a prodrug that
is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dime-
thylphosphate, DDVP), a highly active chemical that irreversibly in-
hibits the acetylcholinesterase enzyme. Schistosomal cholinesterase is
more susceptible to dichlorvos than is the corresponding human en-
zyme. The exact mechanism of action of metrifonate is uncertain, but
the drug is believed to inhibit tegumental acetylcholine receptors that
mediate glucose transport.
Metrifonate is administered in a series of three doses at 2-week in-
tervals. After a single oral dose, metrifonate produces a 95% decrease
in plasma cholinesterase activity within 6 h, with a fairly rapid return
to normal. However, 2.5 months are required for erythrocyte cholin-
esterase levels to return to normal. Treated persons should not be
exposed to neuromuscular blocking agents or organophosphate insec-
ticides for at least 48 h after treatment.
Metronidazole and Other Nitroimidazoles See Table 201-1 and Chap.
127.
Miltefosine In the early 1990s, miltefosine (hexadecylphosphocho-
line), originally developed as an antineoplastic agent, was discovered to
have significant antiproliferative activity against Leishmania spp., Try-
panosoma cruzi, and T. brucei parasites in vitro and in experimental an-
imal models. In 1995, Tropical Disease Research, a program sponsored
by the WHO and other international groups, entered into an agree-
ment with the company now known as ASTA Medica/Zentaris to devel-
op miltefosine for the treatment of visceral leishmaniasis in India.
Miltefosine is the first oral drug that has proved to be highly effective
and comparable to amphotericin B against visceral leishmaniasis in In-
dia, where antimonial-resistant cases are prevalent. Miltefosine is also
effective in previously untreated visceral infections. Cure rates in cuta-
neous leishmaniasis are comparable to those obtained with antimony.
The activity of miltefosine is attributed to interaction with cell sig-
nal transduction pathways and inhibition of phospholipid and sterol
biosynthesis. Resistance to miltefosine has not been observed clinical-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
ly. The drug is readily absorbed from the GI tract, is widely distribut- e123
ed, and accumulates in several tissues. The efficacy of a 28-day
treatment course in Indian visceral leishmaniasis is equivalent to that
of amphotericin B therapy; however, it appears that a shortened course
of 21 days may be equally efficacious.
General recommendations for the use of miltefosine are limited by
the exclusion of specific groups from the published clinical trials: per-
sons <12 or >65 years of age, persons with the most advanced disease,
breast-feeding women, HIV-infected patients, and individuals with
significant renal or hepatic insufficiency.
Niclosamide Niclosamide is active against a wide variety of adult
tapeworms but not against tissue cestodes. It is also a molluscacide
and is used in snail-control programs. The drug uncouples oxidative
phosphorylation in parasite mitochondria, thereby blocking the up-
take of glucose by the intestinal tapeworm and resulting in the para-
site’s death. Niclosamide rapidly causes spastic paralysis of intestinal
cestodes in vitro. Its use is limited by its side effects, the necessarily
long duration of therapy, the recommended use of purgatives, and—
most important—limited availability (i.e., on a named-patient basis
from the manufacturer).
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
Niclosamide is poorly absorbed. Tablets are given on an empty
stomach in the morning after a liquid meal the night before, and this
dose is followed by another 1 h later. For treatment of hymenolepiasis,
the drug is administered for 7 days. A second course is often pre-
scribed. The scolex and proximal segments of the tapeworms are killed
on contact with niclosamide and may be digested in the gut. However,
disintegration of the adult tapeworm results in the release of viable
ova, which theoretically can result in autoinfection. Although fears of
the development of cysticercosis in patients with Taenia solium infec-
tions have proved unfounded, it is still recommended that a brisk pur-
gative be given 2 h after the first dose.
Nifurtimox* This nitrofuran compound is a cheap and effective oral
agent for the treatment of acute Chagas’ disease. Trypanosomes lack
catalase and have very low levels of peroxidase; as a result, they are very
vulnerable to by-products of oxygen reduction. When nifurtimox is
reduced in the trypanosome, a nitro anion radical is formed and un-
dergoes autooxidation, resulting in the generation of the superoxide
anion O2–, hydrogen peroxide (H2O2), hydroperoxyl radical (HO2),
and other highly reactive and cytotoxic molecules. Despite the abun-
dance of catalases, peroxidases, and superoxide dismutases that neu-
tralize these destructive radicals in mammalian cells, nifurtimox has a
poor therapeutic index. Prolonged use is required, but the course may
have to be interrupted because of drug toxicity, which develops in 40–
70% of recipients. Nifurtimox is well absorbed and undergoes rapid
and extensive biotransformation; <0.5% of the original drug is excret-
ed in urine.
Nitazoxanide Nitazoxanide is a 5-nitrothiazole compound used for
the treatment of cryptosporidiosis and giardiasis; it is active against
other intestinal protozoa as well. The drug is approved for use in chil-
dren 1–11 years of age.
The antiprotozoal activity of nitazoxanide is believed to be due to
interference with the pyruvate-ferredoxin oxidoreductase (PFOR) en-
zyme–dependent electron transfer reaction that is essential to anaero-
bic energy metabolism. Studies have shown that the PFOR enzyme
from G. lamblia directly reduces nitazoxanide by transfer of electrons
in the absence of ferredoxin. The DNA-derived PFOR protein se-
quence of Cryptosporidium parvum appears to be similar to that of G.
lamblia. Interference with the PFOR enzyme–dependent electron
transfer reaction may not be the only pathway by which nitazoxanide
exerts antiprotozoal activity.
After oral administration, nitazoxanide is rapidly hydrolyzed to an
active metabolite, tizoxanide (desacetyl-nitazoxanide). Tizoxanide then
undergoes conjugation, primarily by glucuronidation. It is recom-
mended that nitazoxanide be taken with food; however, no studies
have been conducted to determine whether the pharmacokinetics of
 e124 tizoxanide and tizoxanide glucuronide differ in fasted versus fed sub-
jects. Tizoxanide is excreted in urine, bile, and feces, and tizoxanide
glucuronide is excreted in urine and bile. The pharmacokinetics of ni-
tazoxanide in patients with impaired hepatic and/or renal function
have not been studied. Tizoxanide is highly bound to plasma protein
(>99.9%). Therefore, caution should be used when administering this
agent concurrently with other highly plasma protein–bound drugs
with narrow therapeutic indices, as competition for binding sites may
occur.
Oxamniquine This tetrahydroquinoline derivative is an effective alter-
native agent for the treatment of Schistosoma mansoni, although suscep-
tibility to this drug exhibits regional variation. Oxamniquine exhibits
anticholinergic properties, but its primary mode of action seems to rely
on ATP-dependent enzymatic drug activation generating an intermedi-
ate that alkylates essential macromolecules, including DNA. In treated
adult schistosomes, oxamniquine produces marked tegumental alter-
ations that are similar to those seen with praziquantel but that develop
less rapidly, becoming evident 4–8 days after treatment.
Oxamniquine is administered orally as a single dose and is well ab-
sorbed. Food retards absorption and reduces bioavailability. About
70% of an administered dose is excreted in urine as a mixture of phar-
macologically inactive metabolites. Patients should be warned that
PART 7
their urine might have an intense orange-red color. Side effects are un-
common and usually mild, although hallucinations and seizures have
been reported.
Paromomycin (Aminosidine) First isolated in 1956, this aminoglyco-
side is an effective oral agent for the treatment of infections due to in-
testinal protozoa. Parenteral paromomycin appears to be effective
Infectious Diseases
against visceral leishmaniasis in India.
Paromomycin inhibits protozoan protein synthesis by binding to
the 30S ribosomal RNA in the aminoacyl-tRNA site, causing misread-
ing of mRNA codons. Paromomycin is less active against G. lamblia
than standard agents; however, like other aminoglycosides, paromo-
mycin is poorly absorbed from the intestinal lumen, and the high lev-
els of drug in the gut compensate for this relatively weak activity. If
absorbed or administered systemically, paromomycin can cause oto-
toxicity and nephrotoxicity. However, systemic absorption is very lim-
ited, and toxicity should not be a concern in persons with normal
kidneys. Topical formulations are not generally available.
Pentamidine Isethionate This diamidine is an effective alternative
agent for some forms of leishmaniasis and trypanosomiasis. It is avail-
able for parenteral and aerosolized administration. While its mecha-
nism of action remains undefined, it is known to exert a wide range of
effects, including interaction with trypanosomal kinetoplast DNA; in-
terference with polyamine synthesis by a decrease in the activity of or-
nithine decarboxylase; and inhibition of RNA polymerase, ribosomal
function, and the synthesis of nucleic acids and proteins.
Pentamidine isethionate is well absorbed, is highly tissue bound, and
is excreted slowly over several weeks, with an elimination half-life of 12
days. No steady-state plasma concentration is attained in persons given
daily injections; the result is extensive accumulation of pentamidine in
tissues, primarily the liver, kidney, adrenal, and spleen. Pentamidine does
not penetrate well into the CNS. Pulmonary concentrations of pentami-
dine are increased when the drug is delivered in aerosolized form.
Piperazine The antihelminthic activity of piperazine is confined to
ascariasis and enterobiasis. Piperazine acts as an agonist at extrasynap-
tic γ-aminobutyric acid (GABA) receptors, causing an influx of chlo-
ride ions in the nematode somatic musculature. The ultimate effect is
flaccid paralysis of the muscle fibers, leading to the expulsion of live
but mostly paralyzed worms. Patients should be warned, as this occur-
rence can be unsettling.
Praziquantel This heterocyclic pyrazinoisoquinoline derivative is
highly active against a broad spectrum of trematodes and cestodes. It
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
is the mainstay of treatment for schistosomiasis and is a critical part of
community-based control programs.
All of the effects of praziquantel can be attributed either directly or
indirectly to an alteration of intracellular calcium concentrations. Al-
though the exact mechanism of action remains unclear, the major
mechanism is disruption of the parasite tegument, causing tetanic
contractures with loss of adherence to host tissues and, ultimately, dis-
integration or expulsion. Praziquantel induces changes in the antige-
nicity of the parasite by causing the exposure of concealed antigens.
Praziquantel also produces alterations in schistosomal glucose metab-
olism, including decreases in glucose uptake, lactate release, glycogen
content, and ATP levels.
Praziquantel exerts its parasitic effects directly and does not need to
be metabolized to be effective. It is well absorbed but undergoes exten-
sive first-pass hepatic clearance. Levels of the drug are increased when
it is taken with food, particularly carbohydrates, or with cimetidine.
Serum levels are reduced by glucocorticoids, chloroquine, carbamaze-
pine, and phenytoin. Praziquantel is completely metabolized in hu-
mans, with 80% of the dose recovered as metabolites in urine within 4
days. It is not known to what extent praziquantel crosses the placenta.
Patients with schistosomiasis who have heavy parasite burdens may
develop abdominal discomfort, nausea, headache, dizziness, and drows-
iness. Symptoms begin 30 min after ingestion, may require spasmolytics
for relief, and usually disappear spontaneously after a few hours.
Primaquine Phosphate Primaquine, an 8-aminoquinoline, has a
broad spectrum of activity against all stages of plasmodial develop-
ment in humans but has been used most effectively for eradication of
the hepatic stage of these parasites. Despite its toxicity, it remains the
drug of choice for radical cure of P. vivax infections. Primaquine must
be metabolized by the host to be effective. It is, in fact, rapidly metabo-
lized; only a small fraction of the dose of the parent drug is excreted
unchanged. Although the parasiticidal activity of the three oxidative
metabolites remains unclear, they are believed to affect both pyrimi-
dine synthesis and the mitochondrial electron transport chain. The
metabolites appear to have significantly less antimalarial activity than
primaquine; however, their hemolytic activity is greater than that of
the parent drug.
Primaquine causes marked hypotension after parenteral adminis-
tration and therefore is given only by the oral route. It is rapidly and
almost completely absorbed from the GI tract.
Patients should be tested for G6PD deficiency before they receive
primaquine. The drug may induce the oxidation of hemoglobin into
methemoglobin, irrespective of the G6PD status of the patient. Pri-
maquine is otherwise well tolerated.
Proguanil (Chloroguanide) Proguanil inhibits plasmodial dihydrofo-
late reductase and is used with atovaquone for oral treatment of uncom-
plicated malaria or with chloroquine for malaria prophylaxis in parts of
Africa without widespread chloroquine-resistant P. falciparum.
Proguanil exerts its effect primarily by means of the metabolite cy-
cloguanil, whose inhibition of dihydrofolate reductase in the parasite
disrupts deoxythymidylate synthesis, thus interfering with a key path-
way involved in the biosynthesis of pyrimidines required for nucleic
acid replication. There are no clinical data indicating that folate sup-
plementation diminishes drug efficacy; women of childbearing age for
whom atovaquone/proguanil is prescribed should continue taking
folate supplements to prevent neural-tube birth defects.
Proguanil is extensively absorbed regardless of food intake. The
drug is 75% protein-bound. The main routes of elimination are hepat-
ic biotransformation and renal excretion; 40–60% of the proguanil
dose is excreted by the kidneys. Drug levels are increased and elimina-
tion is impaired in patients with hepatic insufficiency.
Pyrantel Pamoate Pyrantel is a tetrahydropyrimidine formulated as
pamoate. This safe, well-tolerated, inexpensive drug is used to treat a
variety of intestinal nematode infections but is ineffective in trichuria-
sis. Pyrantel pamoate is usually effective in a single dose. Like levami-
sole, the drug has as its target the nicotinic acetylcholine receptor on
the surface of nematode somatic muscle. Pyrantel depolarizes the neu-
romuscular junction of the nematode, resulting in its irreversible pa-
ralysis and allowing the natural expulsion of the worm.
Pyrantel pamoate is poorly absorbed from the intestine; >85% of
the dose is passed unaltered in feces. The absorbed portion is metabo-
lized and excreted in urine. Piperazine, which produces hyperpolariza-
tion of muscle cells in intestinal helminths, is antagonistic to pyrantel
pamoate and should not be used concomitantly.
Pyrantel pamoate has minimal toxicity at the oral doses used to
treat intestinal helminthic infection. It is not recommended for preg-
nant women or for children <12 months old.
Pyrimethamine When combined with short-acting sulfonamides,
this diaminopyrimidine is effective in malaria, toxoplasmosis, and
isosporiasis. Unlike mammalian cells, the parasites that cause these in-
fections cannot utilize preformed pyrimidines obtained through sal-
vage pathways but rather rely completely on de novo pyrimidine
synthesis, for which folate derivatives are essential cofactors. The effi-
cacy of pyrimethamine is increasingly limited by the development of
resistant strains of P. falciparum and P. vivax. Single amino acid substi-
tutions to parasite dihydrofolate reductase confer resistance to py-
rimethamine by decreasing the enzyme’s binding affinity for the drug.
Pyrimethamine is well absorbed; the drug is 87% bound to human
plasma proteins. In healthy volunteers, drug concentrations remain at
therapeutic levels for up to 2 weeks; drug levels are lower in patients
with malaria.
At the usual dosage, pyrimethamine alone causes little toxicity ex-
cept for occasional skin rashes and, more rarely, blood dyscrasias.
Bone marrow suppression sometimes occurs at the higher doses used
for toxoplasmosis; at these doses, the drug should be administered
with folinic acid.
Quinacrine* First introduced as an antimalarial agent in 1930, quina-
crine is the only drug approved by the FDA for the treatment of giar-
diasis. Its production was discontinued in 1992. Although not
commercially available, quinacrine can be obtained from alternative
sources through the CDC Drug Service. The antiprotozoal mechanism
of quinacrine has not been fully elucidated. The drug inhibits NADH
oxidase—the same enzyme that activates furazolidone. The differing
relative quinacrine uptake rate between human cells and G. lamblia
may explain the selective toxicity of the drug. Resistance correlates
with decreased drug uptake.
Quinacrine is rapidly absorbed from the intestinal tract and is
widely distributed in body tissues. Alcohol is best avoided due to a di-
sulfiram-like effect.
Quinine and Quinidine When combined with another agent, the cin-
chona alkaloid quinine is effective for the oral treatment of both un-
complicated, chloroquine-resistant malaria and babesiosis. Quinine
acts rapidly against the asexual blood stages of all forms of human ma-
laria. For severe malaria, only quinidine (the dextroisomer of quinine)
is available in the United States. Quinine concentrates in the acidic
food vacuoles of Plasmodium spp. The drug inhibits the nonenzymatic
polymerization of the highly reactive, toxic heme molecule into the
nontoxic polymer pigment hemozoin.
Quinine is readily absorbed when given orally. In patients with ma-
laria, the elimination half-life of quinine increases according to the se-
verity of the infection. However, toxicity is avoided by an increase in the
concentration of plasma glycoproteins. The cinchona alkaloids are ex-
tensively metabolized, particularly by CYP3A4; only 20% of the dose is
excreted unchanged in urine. The drug’s metabolites are also excreted in
urine and may be responsible for toxicity in patients with renal failure.
Renal excretion of quinine is decreased when cimetidine is taken and in-
creased when the urine is acidic. The drug readily crosses the placenta.
Quinidine is both more potent as an antimalarial and more toxic
than quinine. Its use requires cardiac monitoring. Dose reduction is
necessary in persons with severe renal impairment.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Spiramycin† This macrolide is used to treat acute toxoplasmosis in e125
pregnancy and congenital toxoplasmosis. While the mechanism of ac-
tion is similar to that of other macrolides, the efficacy of spiramycin in
toxoplasmosis appears to stem from its rapid and extensive intracellu-
lar penetration, which results in macrophage drug concentrations 10–
20 times greater than serum concentrations.
Spiramycin is rapidly and widely distributed throughout the body
and reaches concentrations in the placenta up to five times those in se-
rum. This agent is excreted mainly in bile. Indeed, in humans, the uri-
nary excretion of active compounds represents only 20% of the
administered dose.
Serious reactions to spiramycin are rare. Of the available mac-
rolides, spiramycin appears to have the lowest risk of drug interac-
tions. Complications of treatment are rare but, in neonates, can
include life-threatening ventricular arrhythmias that disappear with
drug discontinuation.
Sulfonamides See Table 201-1 and Chap. 127.
Suramin* This derivative of urea is the drug of choice for the early
stage of African trypanosomiasis. The drug is polyanionic and acts by
CHAPTER e17 Pharmacology of Agents Used to Treat Parasitic Infections
forming stable complexes with proteins, thus inhibiting multiple en-
zymes essential to parasite energy metabolism. Suramin appears to in-
hibit all trypanosome glycolytic enzymes more effectively than it
inhibits the corresponding host enzymes.
Suramin is parenterally administered. It binds to plasma proteins
and persists at low levels for several weeks after infusion. Its metabo-
lism is negligible. This drug does not penetrate the CNS.
Tafenoquine Tafenoquine is an 8-aminoquinoline with causal pro-
phylactic activity. Its prolonged half-life (2–3 weeks) allows longer
dosing intervals when the drug is used for prophylaxis. Tafenoquine
has been well tolerated in clinical trials. When tafenoquine is taken
with food, its absorption is increased by 50% and the most commonly
reported adverse event—mild GI upset—is diminished. Like pri-
maquine, tafenoquine is a potent oxidizing agent, causing hemolysis
in patients with G6PD deficiency as well as methemoglobinemia.
Tetracyclines See Table 201-1 and Chap. 127.
Thiabendazole Discovered in 1961, thiabendazole remains one of the
most potent of the numerous benzimidazole derivatives. However, its
use has declined significantly because of a higher frequency of adverse
effects than is seen with other, equally effective agents.
Thiabendazole is active against most intestinal nematodes that infect
humans. Although the exact mechanism of its antihelminthic activity
has not been fully elucidated, it is likely to be similar to that of other
benzimidazole drugs: namely, inhibition of polymerization of parasite
β-tubulin. The drug also inhibits the helminth-specific enzyme fuma-
rate reductase. In animals, thiabendazole has anti-inflammatory, anti-
pyretic, and analgesic effects, which may explain its usefulness in
dracunculiasis and trichinosis. Thiabendazole also suppresses egg and/
or larval production by some nematodes and may inhibit the subse-
quent development of eggs or larvae passed in feces. Despite the emer-
gence and global spread of thiabendazole-resistant trichostrongyliasis
among sheep, there have been no reports of drug resistance in humans.
Thiabendazole is available in tablet form and as an oral suspension.
The drug is rapidly absorbed from the GI tract but can also be ab-
sorbed through the skin. Thiabendazole should be taken after meals.
This agent is extensively metabolized in the liver before ultimately be-
ing excreted; most of the dose is excreted within the first 24 h. The
usual dose of thiabendazole is determined by the patient’s weight, but
some treatment regimens are parasite specific. No particular adjust-
ments are recommended in patients with renal or hepatic failure; only
cautious use is advised.
Coadministration of thiabendazole in patients taking theophylline
can result in an increase in theophylline levels by >50%. Therefore, se-
rum levels of theophylline should be monitored closely in this situation.
 e126 Tinidazole This nitroimidazole is effective for the treatment of ame-
biasis, giardiasis, and trichomoniasis. Like metronidazole, tinidazole
must undergo reductive activation by the parasite’s metabolic system
before it can act on protozoal targets. Tinidazole inhibits the synthesis
of new DNA in the parasite and causes degradation of existing DNA.
The reduced free-radical derivatives alkylate DNA, with consequent
cytotoxic damage to the parasite. This damage appears to be produced
by short-lived reduction intermediates, resulting in helix destabiliza-
tion and strain breakage of DNA. The mechanism of action and side
effects of tinidazole are similar to those of metronidazole, but adverse
events appear to be less frequent and severe with tinidazole. In addi-
tion, the significantly longer half-life of tinidazole (>12 h) offers po-
tential cure with a single dose.
Triclabendazole While most benzimidazoles have broad-spectrum an-
tihelminthic activity, they exhibit minimal or no activity against F. he-
patica. In contrast, the antihelminthic activity of triclabendazole is
highly specific for Fasciola spp. and Paragonimus spp., with little activity
against nematodes, cestodes, and other trematodes. Triclabendazole is
effective against all stages of Fasciola spp. The active sulfoxide metabolite
of triclabendazole binds to fluke tubulin by assuming a unique nonpla-
nar configuration and disrupts microtubule-based processes. Resistance
to triclabendazole in veterinary use has been reported in Australia and
PART 7
Europe; however, no resistance has been documented in humans.
Triclabendazole is rapidly absorbed after oral ingestion; administra-
tion with food enhances its absorption and shortens the elimination
half-life of the active metabolite. Both the sulfoxide and the sulfone
Infectious Diseases
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
metabolites are highly protein bound (>99%). Treatment with tricla-
bendazole is typically given in one or two doses. No clinical data are
available regarding dose adjustment in renal or hepatic insufficiency;
however, given the short course of therapy and extensive hepatic me-
tabolism of triclabendazole, dose adjustment is unlikely to be neces-
sary. No information exists on drug interactions.
Trimethoprim-Sulfamethoxazole See Table 201-1 and Chap. 127.
FURTHER READINGS
ABRAMOWICZ M (ed): Drugs for parasitic infections. Med Lett Drugs
Ther 46:1, 2004
MOORE TA, MCCARTHY JS: Benzimidazoles (albendazole, mebenda-
zole, thiabendazole, triclabendazole), in Antimicrobial Therapy and
Vaccines, 2d ed, VL Yu et al (eds). Pittsburgh, ESun Technologies,
2005, pp 1021–1036
SHAPIRO TA, GOLDBERG DE: Drugs used in the chemotherapy of pro-
tozoal infections: Malaria, in Goodman and Gilman’s The Pharma-
cological Basis of Therapeutics, 11th ed, L Brunton et al (eds). New
York, McGraw-Hill, 2005, pp 1021–1048
WARD SA et al: Antimalarial drugs and pregnancy: Safety, pharmaco-
kinetics, and pharmacovigilance. Lancet Infect Dis 7:136, 2007
WINSTANLEY P, WARD S: Malaria chemotherapy. Adv Parasitol 61:47,
2006
WORLD HEALTH ORGANIZATION: Model Prescribing Information: Drugs
Used in Parasitic Diseases, 2d ed. Geneva, WHO, 1995
 supravital dyes (e.g., Giemsa’s, Field’s, Wright’s, Leishman’s). The e127

e18 Atlas of Blood Smears of

Malaria and Babesiosis
Nicholas J. White, Joel G. Breman
Four species of blood protozoan parasites cause human malaria: the
potentially lethal and often drug-resistant Plasmodium falciparum; the
relapsing parasites P. vivax and P. ovale; and P. malariae, which can
persist at low densities for years. Occasional infections in individuals
who have been in tropical forests may be caused by monkey para-
sites—notably, P. knowlesi.
The malaria parasites are readily seen under the microscope
(×1000 magnification) in thick and thin blood smears stained with
morphologic characteristics of the parasites are summarized in Table
e18-1. In the thick film, lysis of red blood cells by water leaves the
stained white cells and parasites, allowing detection of densities as
low as 50 parasites/μL. This degree of sensitivity is up to 100 times
greater than that of the thin film, in which the red cells are fixed and
the malaria parasites are seen inside the cells. The thin film is better
for speciation and provides useful prognostic information in severe
falciparum malaria. Several findings are associated with increased
mortality risk: high parasite counts, more mature parasites (>20%
containing visible malaria pigment), and phagocytosed malaria pig-
ment in >5% of neutrophils.
Babesia microti appears as a small ring form resembling P. falci-
parum. Unlike Plasmodium, Babesia does not cause the production of
pigment in parasites, nor are schizonts or gametocytes formed.

TABLE e18-1 MORPHOLOGIC CHARACTERISTICS OF HUMAN MALARIA PARASITES

P. falciparum P. vivax P. ovale P. malariae
Asexual Usually only fine blue ring forms Irregular, large, fairly thick rings Regular, dense ring enlarges to Dense, thick rings mature
parasites (some resembling stereo headsets) become highly pleomorphic as compact, blue, mature tro- to dense, round tropho-

CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis

are seen. Parasitemia level may
exceed 2%.
Schizonts Rare in peripheral blood; 8–32 mero-
zoites, dark brown-black pigment
Gameto- Banana-shaped; male: light blue;
cytes female: darker blue; a few scattered
blue-black pigment granules in
cytoplasm
RBC changes RBCs are normal in size. As the para-
site matures, the RBC cytoplasm
becomes pale, the cells become
crenated, and a few small red dots
may appear over the cytoplasm
(Maurer’s clefts).
Note: RBC, red blood cell.
the parasite grows. Parasitemia
level is low.
Common; 12–18 merozoites,
orange-brown pigment
Round or oval; male: round, pale
blue; female: oval, dark blue; tri-
angular nucleus, a few orange
pigment granules
RBCs are enlarged. Pale red
Schüffner’s dots increase in
number as the parasite
matures.
phozoite (rectangular or
band-form). Parasitemia level
is low.
8–14 merozoites, brown or
black pigment
Large, round, dense, and blue
(like P. malariae), but promi-
nent James’s dots; brown
pigment
RBCs become oval with tufted
ends. Red James’s dots are
prominent.
zoites. Parasitemia level
is low.
8–10 merozoites, dark
brown or black pigment
Large, oval; male: pale
blue; female: dense
blue; large black pig-
ment granules
RBCs are normal in size
and shape. No red dots
are seen.

FIGURE e18-1 Thin blood films of Plas-

modium falciparum. A. Young tropho-
zoites. B. Old trophozoites. C. Pigment in
polymorphonuclear cells and trophozo-
ites. D. Mature schizonts. E. Female game-
tocytes. F. Male gametocytes. (Reproduced
from Bench Aids for the Diagnosis of Malaria
Infections, 2d ed, with the permission of the
World Health Organization.)

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

 e128
PART 7

FIGURE e18-2 Thin blood films of Plasmodium vivax. A. Young trophozoites. B. Old trophozoites.
Infectious Diseases

C. Mature schizonts. D. Female gametocytes. E. Male gametocytes. (Reproduced from Bench Aids for
the Diagnosis of Malaria Infections, 2d ed, with the permission of the World Health Organization.)

FIGURE e18-3 Thin blood films of Plasmodium ovale. A. Old tro- FIGURE e18-4 Thin blood films of Plasmodium malariae. A. Old
phozoites. B. Mature schizonts. C. Male gametocytes. D. Female ga- trophozoites. B. Mature schizonts. C. Male gametocytes. D. Female ga-
metocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria metocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria In-
Infections, 2d ed, with the permission of the World Health Organization.) fections, 2d ed, with the permission of the World Health Organization.)

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

 e129

FIGURE e18-5 Thick blood films of Plasmodium falciparum.

A. Trophozoites. B. Gametocytes. (Reproduced from Bench Aids
for the Diagnosis of Malaria Infections, 2d ed, with the permission
of the World Health Organization.)

CHAPTER e18 Atlas of Blood Smears of Malaria and Babesiosis

FIGURE e18-6 Thick blood films of Plasmodium vivax. A. Trophozoites. B. Schizonts. C. Game-
tocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permis-
sion of the World Health Organization.)

FIGURE e18-7 Thick blood films of Plasmodium ovale. A. Trophozoites. B. Schizonts. C. Game-
tocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the permis-
sion of the World Health Organization.)

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

 e130

FIGURE e18-8 Thick blood films of Plasmodium malariae. A. Trophozoites. B. Schizonts. C. Ga-
metocytes. (Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d ed, with the per-
mission of the World Health Organization.)

FURTHER READINGS
WARHURST C, WILLIAMS JE: Laboratory procedures for diagnosis of
malaria, in Abdalla SH, Pasvol G (series eds): Malaria: A Hemato-
logical Perspective. G Pasvol, SL Hoffman (eds): Tropical Medicine:
Science and Practice, vol 4. London, Imperial College Press, 2004
PART 7

FIGURE e18-9 Thin blood film showing trophozoites of Babesia.

(Reproduced from Bench Aids for the Diagnosis of Malaria Infections, 2d
Infectious Diseases

ed, with the permission of the World Health Organization.)

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

 e131

e19 Atlas of Electrocardiography

CHAPTER e19 Atlas of Electrocardiography

Ary L. Goldberger

The electrocardiograms (ECGs) in this Atlas supplement those illus-

trated in Chap. 221. The interpretations emphasize findings of specific
teaching value.
All of the figures are from ECG Wave-Maven, Copyright 2003, Beth
Israel Deaconess Medical Center, http://ecg.bidmc.harvard.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,
aVL, V3–V6) in a patient with LVH (increased voltage in V2–V5).

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

 e132 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e19-2 Acute anterolateral wall ischemia with ST elevations in V4–V6. Probable old inferior
MI with Q waves in leads II, III and aVF.

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 de-
pressions inferiorly (II, III, and aVF). Ischemic ST depressions also in V3 and V4. Left atrial abnormality.

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

 I aVR V1 V4 e133

CHAPTER e19 Atlas of Electrocardiography

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-4 Sinus tachycardia. Marked ischemic ST-segment eleva- acute inferolateral MI, and prominent ST-segment depressions with
tions in inferior limb leads (II, III, aVF) and laterally (V6) suggestive of upright T waves in V1–V4 consistent with acute posterior MI.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-5 Acute MI with marked ST elevations in I, aVL, V1–V6 and small pathologic Q waves in
V3–V6. Marked reciprocal ST-segment depressions in III and aVF.

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

 e134 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

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. RBBB; pathologic Q waves and ST elevation due
to acute anterior/septal MI in V1–V3.

Copyright © 2008 The McGraw-Hill Companies. 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, V1).

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, III,
aVF, tall R waves in V1,V2, and Q waves in V5, V6). T-wave abnormalities in leads I and aVL, V5, and V6.

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

 e136 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e19-10 NSR with PR prolongation (“1st degree AV block”), aVL with ST elevations (a chronic finding in this patient). Findings com-
left atrial abnormality, LVH, and RBBB. Pathologic Q waves in V1–V5 and patible with old anterolateral MI and LV aneurysm.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-11 Old inferior-posterior MI. Wide (0.04 s) Q waves in Absence of right-axis deviation and the presence of upright T waves in
the inferior leads (II, III, aVF); broad R wave in V1 (a Q wave equivalent). V1–V2 are also against RVH.

Copyright © 2008 The McGraw-Hill Companies. 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 disease with echocardiogram showing septal dyskinesis and apical
anterior hemiblock, pathologic anterior Q waves in V1–V3 with slow R akinesis.
wave progression. Patient had severe multivessel coronary artery

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

 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, II, III, aVF, V3–V6, without T-wave
inversions. Also PR-segment elevation in aVR and PR depression in the inferolateral leads.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-14 Sinus tachycardia; diffuse ST elevations (I, II, aVL, aVF, V4–V6); borderline low voltage. Q-wave and T-wave inversions in II, III,
V2–V6) with associated PR deviations (elevated PR in aVR; depressed in and aVF. Diagnosis is acute pericarditis with inferior Q wave MI.

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

VALVULAR HEART DISEASE AND HYPERTROPHIC CARDIOMYOPATHY e139

I aVR V1 V4

CHAPTER e19 Atlas of Electrocardiography

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-15 NSR, left atrial abnormality (see l, II, V1), right-axis deviation and RVH (Rr' in V1) in a patient with mitral stenosis.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-16 NSR, left atrial abnormality, and LVH by voltage criteria regurgitation (LVH). Prominent precordial T-wave inversions and QT
with borderline right-axis deviation in a patient with mixed mitral prolongation also present.
stenosis (left atrial abnormality and right-axis deviation) and mitral

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

 e140
I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e19-17 Coarse AF, tall R in V2 with vertical QRS axis (positive R in aVF) indicating RVH. Tall R in
V4 may be due to concomitant LVH. Patient had severe mitral stenosis with moderate mitral
regurgitation.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-18 NSR; first-degree A-V block (P-R prolongation); LVH (tall R in aVL); RBBB (Rr') and left anterior
fascicular block in a patient with HCM. Deep Q waves in I and aVL consistent with septal hypertrophy.

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 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.

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 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 inver- consistent with acute RV overload in a patient with pulmonary
sion in III), incomplete RBBB, and right precordial T-wave inversions emboli.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-21 Sinus tachycardia, right-axis deviation, RVH with tall R in V1 and deep S in V6 and in-
verted T waves in II, III, aVF, and V1–V5 in a patient with atrial septal defect and severe pulmonary
hypertension.

Copyright © 2008 The McGraw-Hill Companies. 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 V1 with narrow QRS; (3) delayed precordial transition, with terminal S
chronic obstructive lung disease: (1) peaked P waves in II; (2) QR in waves in V5/V6; (4) superior axis deviation with an S1-S2-S3 pattern.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-23 (1) Low voltage; (2) incomplete RBBB (rsr' in V1–V3); V3; (5) prominent S waves in V6; and (6) atrial premature beats. This
(3) borderline peaked P waves in lead II with vertical P-wave axis combination is seen typically in severe chronic obstructive lung
(probable right atrial overload); (4) slow R-wave progression in V1– disease.

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 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, III, V4–V6) with Q-TU prolongation in a patient with severe hypokalemia.

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, V4, aVL, and V5) in a patient with hypercalcemia. High take-off of ST segment in V2/V3.

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

 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, left atrial abnormality, and tall peaked T interval in a patient with renal failure, hypertension, and hyper-
waves in the precordial leads with inferolateral ST depressions (II, III, kalemia; prolonged QT is secondary to associated hypocalcemia.
aVF, and V6); left anterior fascicular block and borderline prolonged QT

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

 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. Vertical QRS axis
(+90°) and early precordial transition between V2 and V3 are normal findings in children.

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.

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

 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 21- V4. Precordial QRS voltages are prominent, but within normal limits for
year-old male (commonly referred to as early repolarization pattern). ST a young adult. No evidence of left atrial abnormality or ST depression/
elevations exhibit upward concavity and are most apparent in V3 and T wave inversions to go along with LVH.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-30 NSR with first-degree AV block (PR interval = 0.24 s), and complete left bundle branch block.

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

 e148 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e19-31 Dextrocardia with: (1) inverted P waves in I and aVL; (2) negative QRS complex and
T wave in I; and (3) progressively decreasing voltage across the precordium.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e19-32 Sinus tachycardia; intraventricular conduction delay tricyclic antidepressant overdose. Terminal S wave (rS) in I, and
with a rightward QRS axis. QT interval is prolonged for the rate. The terminal R wave (qR) in aVR are also seen in this condition.
triad of sinus tachycardia, a wide QRS complex, and a long QT suggest

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

 If you have downloaded this PDF to your computer, you will not be able to view the videos using the links in the PDF. e149
Please visit the Video Bank on the DVD to view the videos.
VIDEO e20-1 Real-time echocardiographic images of a patient with

CHAPTER e20 Atlas of Noninvasive Cardiac Imaging

e20 Atlas of Noninvasive a normal heart. A. (Play video) Parasternal long axis view. B. (Play
video) Parasternal short axis view. C. (Play video) Apical four-cham-
Cardiac Imaging ber view. There is symmetric contraction of the ventricles, evidenced
Rick Nishimura, Raymond J. Gibbons, by a decrease in cavity size and an increase in wall thickness during
James F. Glockner, A. Jamil Tajik systole.
Echocardiographic imaging is performed from multiple acoustic
windows with different transducer rotations so that the entire heart
Noninvasive cardiac imaging is essential to the diagnosis and manage- and great vessels can be displayed in various planes. Most information
ment of patients with known or suspected cardiovascular disease. from a study is obtained from a visual analysis of the two-dimensional
Chapter 222 describes the principles and clinical applications of these images, although objective measurements of cardiac dimensions can
important techniques. This atlas supplements Chap. 222. It provides be made (see Fig. e20-1).
“real time” image clips, as they are viewed in clinical practice, as well as
additional static images.

FIGURE e20-1 Still frame images of an echocardiogram in diastole (left) and systole (right).
Apical four-chamber view (top) and apical two-chamber view (bottom) comprise two orthogonal
views. This illustrates the quantitative assessment of ejection fraction. The endocardial area is out-
lined and is used for calculation of ejection fraction.
With quantitative two-dimensional echocardiography, endocardial outlines of the left ventricle
(LV) cavity are traced in systole and diastole and the LV cavity areas are then fitted to computer mod-
els of the LV to obtain systolic and diastolic volumes. The presence or absence of regional wall mo-
tion abnormalities can be assessed by examining endocardial motion as well as wall thickening.

VIDEO e20-2 Real-time echocardiographic images of a patient VIDEO e20-4 Real-time echocardiographic images of a patient
with a severe decrease in left ventricular systolic function. The with mitral stenosis. There is diastolic doming and restricted
estimated ejection fraction is 20%. A. (Play video) Parasternal long leaflet opening secondary to fusion of the commissures. A. (Play
axis view. B. (Play video) Parasternal short axis view. video) Parasternal long axis. B. (Play video) Parasternal short axis.
VIDEO e20-3 Real-time echocardiographic images of a patient
with hypertrophic cardiomyopathy, demonstrating an increase in
wall thickness during systole. A. (Play video) Parasternal long axis
view. B. (Play video) Parasternal short axis view.

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 e150
PART 9
Disorders of the Cardiovascular System

FIGURE e20-2 Continuous wave Doppler (DOPP) echocardio-

graphic tracings across the mitral valve in a patient with mitral
stenosis with simultaneous pressures in the left atrium (LA) and left
ventricle (LV). The velocity of flow is high in early diastole, followed by
a prolonged deceleration of transmitral mitral flow velocity, and a re-
acceleration during atrial systole (A). There is a mean gradient of 10
mmHg derived from the Doppler tracing, which corresponds to the si-
multaneous transmitral gradient of 11 mmHg derived from cardiac
catheterization. These are consistent with the diagnosis of moderate
mitral stenosis. LA, left atrial pressure; LV, left ventricular pressure; a,
atrial contraction wave. (From RA Nishimura et al: J Am Coll Cardiol
24:152, 1994.)

FIGURE e20-3 Continuous-wave Doppler echocardiogram across the mitral valve of a pa-
tient with mitral stenosis. In the resting state (left) there is a mean gradient of 8 mmHg. During
exercise (right), the mean gradient rises to 29 mmHg, indicating hemodynamically significant mitral
stenosis.

VIDEO e20-5 Real-time images with color-flow Doppler imaging
of a patient with mitral regurgitation due to ruptured chordae
tendinae. A. (Play video) Gray scale image showing a thickened re-
dundant posterior leaflet with loss of coaptation. B. (Play video)
Color-flow imaging showing the regurgitation as a high-velocity tur-
bulence (mosaic pattern) regurgitating into the left atrium during sys-
tole. C. (Play video) Color-flow imaging of a patient with a normal
mitral valve showing no regurgitation into the left atrium.
VIDEO e20-6 (Play video) Real-time transesophageal echocardio-
graphic images of a patient with severe mitral regurgitation
due to a flail posterior leaflet. The posterior mitral valve leaflet is com-
pletely unsupported and moves into the left atrium during systole.
VIDEO e20-7 Real-time echocardiographic images from the
parasternal long axis view of a patient with mitral valve pro-
lapse. Both leaflets prolapse into the left atrium during systole. A. (Play
video) Black and white images demonstrating leaflet morphology
and motion. B. (Play video) Color-flow imaging demonstrating a late
systolic blue-colored jet of mitral regurgitation.
Annular dilatation, prolapse, flail leaflets, vegetation, and rheumatic
involvement can all be diagnosed and the LV response to volume
overload assessed by two-dimensional echocardiography.

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

VIDEO e20-8 (Play video) Real-time two-dimensional echocar- VIDEO e20-9 (Play video) Real-time two-dimensional parasternal e151
diographic images of a patient with a vegetation on the mitral long axis echocardiographic images from a patient with aortic
valve. There is a mobile echo density attached directly to the mitral stenosis. The aortic valve is calcified with restricted opening.

CHAPTER e20 Atlas of Noninvasive Cardiac Imaging

valve apparatus.

FIGURE e20-4 Continuous-wave Doppler tracings across the aor-

tic valve in a patient with aortic stenosis. There is an increase in
velocity to 3 m/s, with a mean transvalvular gradient calculated to be
24 mmHg. This corresponds to the simultaneous catheterization gra-
dient of 24 mmHg between left ventricle (LV) and aorta (Ao).

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. Left. At baseline, there
is a mean left ventricular (LV)-aortic (Ao) gradient of 24 mmHg (by Doppler) with a calculated aortic
valve area (AVA) of 0.5 cm2. 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, in which
there is not enough force to open fully a mildly stenotic aortic valve. Right. During dobutamine infu-
sion, there is an increase in the transvalvular pressure gradient to 55 mmHg, with normalization of
the stroke volume. This indicates the presence of severe aortic stenosis.

VIDEO e20-10 Real-time echocardiographic images showing a is a large echo-dense mass in the left atrium that is attached to the
close-up view of the atrial septum in a patient with a large se- atrial septum. The mass moves across the mitral valve in diastole.
cundum atrial septal defect. A. (Play video) Gray scale image Although an echocardiographic examination cannot provide
showing a questionable “drop-out” in the atrial septum. B. (Play pathologic confirmation of the etiology of a mass, in many instances
video) Color-flow imaging confirms flow across the atrial septum. the diagnosis can be suspected from the appearance, mobility, attach-
VIDEO e20-11 (Play video) Real-time transesophageal echocar- ments, and concomitant abnormalities.
diographic images of a patient with a left atrial myxoma. There
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e152 VIDEO e20-12 (Play video) Real-time two-dimensional echocar-
diographic images of a patient with a pericardial effusion. The
effusion is shown as black echo-free space surrounding the heart.
PART 9
Disorders of the Cardiovascular System

FIGURE e20-6 Pulsed-wave Doppler echocardiogram of transmi-

tral flow recorded simultaneously with pulmonary artery wedge pres-
sure (PAWP) and left ventricular (LV) pressure in a patient with
constrictive pericarditis. There is a dissociation of intrathoracic and in- FIGURE e20-8 High-fidelity left ventricular pressure (LV) curve
tracardiac pressures so that the PAWP has a larger inspiratory (INSP) fall superimposed on a mitral inflow velocity curve obtained by Doppler
than the LV pressure, causing a decrease in the driving force across the echocardiography in a patient with stage I diastolic dysfunction. There
mitral valve. This results in a fall in the transmitral flow velocity. The op- is a decrease in the early diastolic filling and an increase with filling at
posite occurs during expiration (EXP). atrial contraction, resulting in a low E:A ratio and prolonged decelera-
tion time (DT). The LV diastolic pressure is normal at 12 mmHg.
VIDEO e20-13 (Play video) Real-time two-dimensional echocar-
diographic images from the parasternal long axis view of a pa-
tient with a large aneurysm of the ascending aorta.

FIGURE e20-9 High-fidelity left ventricular (LV) and right ventric-

ular (RV) pressure tracings superimposed on a Doppler mitral in-
flow velocity tracing in a patient with stage III diastolic dysfunction.
There is a restriction to filling, in which there is a high early diastolic ve-
FIGURE e20-7 Pulsed-wave Doppler tracings of the mitral valve locity [rapid filling wave (RFW)] and low velocity of atrial contraction
inflow velocities superimposed on left atrial (LA) and left ventricular resulting in a high E:A ratio with a short (150 ms) deceleration time
(LV) pressures. The initial (early diastolic) velocity of mitral inflow (E) (DT). Both ventricular diastolic pressures (*) are elevated.
correlates with the driving pressure across the mitral valve. The decel-
eration time (DT) indicates the relative change in LA and LV pressures
as blood begins to fill the LV. This increases LV pressure, which rises to
meet the LA pressure. The A velocity on the mitral flow velocity curve
is a reacceleration of flow due to atrial contraction. Normally, the E ve-
locity exceeds the A velocity. In this patient, they are equal, suggestive
of mild diastolic dysfunction (see Fig. e20-8).

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

VIDEO e20-14 Real-time two-dimensional stress echocardiogram VIDEO e20-15 Real-time two-dimensional stress echocardiogram of e153
in a normal subject. The studies at rest are shown on the left and a patient with coronary artery disease. The studies at rest are shown
the studies during peak exercise are on the right. A. (Play video) on the left and the studies during peak exercise are on the right. A. (Play

CHAPTER e20 Atlas of Noninvasive Cardiac Imaging

Parasternal long axis (top) and short axis (bottom) views. B. (Play video)
Apical four-chamber (top) and two-chamber (bottom) views. At rest,
there is contraction of all segments of the myocardium. During exer-
cise, there are increases in contractility and in the thickening of all seg-
ments of the myocardium.
video) Parasternal long axis (top) and short axis (bottom) views. B. (Play
video) Apical four-chamber (top) and two-chamber views (bottom). The
images during peak exercise show regional wall motion abnormalities in
the anteroapical distribution indicative of myocardial ischemia.

FIGURE e20-10 Strain rate images from

a patient with severe left ventricular
dysfunction illustrating dyssynchro-
nous contraction.
Strain rate is a measure of regional
deformation (or contraction). Strain rates
can be used to examine the degree of
dyssynchronous contraction of the ven-
tricle, which may help in determining
patients who would benefit from biven-
tricular pacing. Shown are the different
strain rates over time of the basal sep-
tum (yellow line), mid septum (blue
line), and apical septum (red line).

FIGURE e20-11 Still frame images dem-

onstrating regional wall motion
abnormalities during an exercise
echocardiogram in a patient with
known coronary artery disease. Left. The
systolic frames in the resting state show
symmetric contraction of all segments
of the myocardium. The upper frame is
from the apical four-chamber view and
the lower frame is from the apical two-
chamber view. Right. The systolic frames
immediately after exercise show re-
gional wall motion abnormalities in the
anterior and apical segments (arrows).
LV, left ventricle; RV, right ventricle
(From JK Oh et al: The Echo Manual, 2d ed.
Philadelphia, Lippincott Williams & Wilkins,
1999, with permission.)

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

 e154 TABLE e20-1 RELATIVE ADVANTAGES OF THALLIUM 201 AND
TECHNETIUM 99M
Thallium
PART 9

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)
FIGURE e20-12 Anterior planar thallium images following stress, Ventricular function assessment (gated SPECT)
Disorders of the Cardiovascular System

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. It reflects increased pulmonary capillary wedge pressure and
occurs in the presence of severe coronary artery disease and/or left
ventricular dysfunction. It provides important adverse prognostic in-
formation that is incremental to other clinical, stress, and coronary an-
giographic variables.
Shorter imaging time
Shorter imaging protocols (patient/scheduling convenience)
Acute imaging in myocardial infarction and unstable angina
Superior quantification
SPECT, single photon emission computed tomography.
VIDEO e20-16 (Play video) MRI scan in real-time of a patient with
a large left ventricular apical aneurysm. The long axis view dem-
onstrates a thin dyskinetic apical aneurysm with preserved systolic
function of the basal anterior and basal inferior wall.

FIGURE e20-13 Adenosine 99mTc sestamibi scan in a 50-year-old

male with a previous anterior infarct. The stress images (left)
show a large defect involving the apex and anterior walls (white ar-
rows) with little change from the rest images (white arrows), signifying
a fixed defect without further ischemia during stress. SA, short axis in
the middle of the left ventricle; VLA, vertical long axis; HLA, horizontal
long axis.
The relative advantage of 201Tl and 99mTc are detailed in Table
e20-1. The better image quality and assessment of ventricular function
permitted by 99mTc compounds have contributed to their more com-
mon use for stress imaging, although both 201Tl- and 99mTc-labeled
compounds provide clinically useful myocardial perfusion images in
the majority of patients. A “dual-isotope” protocol is employed in
some centers. This uses 201Tl for the initial rest image and a 99mTc-la-
beled compound for the subsequent stress image, primarily for pa-
tient and scheduling convenience.

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


VIDEO e20-17 (Play video) Three-dimensional reconstruction of
an MR angiogram, showing a severe coarctation of the descending
aorta. The large collateral vessels as a result of the coarctation are
shown.
FIGURE e20-15 MR scan with delayed enhancement of a patient
with an apical left ventricular infarction (top). Imaging the heart
10–20 min after gadolinium injection demonstrates enhancement of
the infarcted tissue (visible as dense white image), as the tissue retains
contrast by virtue of its large extracellular volume.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e155
CHAPTER e20 Atlas of Noninvasive Cardiac Imaging
FIGURE e20-14 MR images with con-
trast enhancement of a patient with
constrictive pericarditis, demonstrat-
ing abnormal pericardial thickening.
VIDEO e20-18 (Play video) Cine MR scan of a patient with a di-
lated ascending aorta (annulo-aortic ectasia). There is a thin central
jet of aortic regurgitation going into the left ventricular outflow tract.
FIGURE e20-16 MR image of a patient with a right ventricular
myxoma, which is shown as a bright oblong structure in the right
ventricular outflow tract.
 e156
PART 9
Disorders of the Cardiovascular System

FIGURE e20-17 Noncontrast image from electron beam CT reveal-

ing two small foci of calcification in the left anterior descending artery FIGURE e20-18 CT coronary angiogram showing a normal right cor-
(arrows). onary artery.

VIDEO e20-19 (Play video) CT coronary angiogram showing a

normal right coronary artery. The movie highlights multiple thin
slices through the right coronary artery.

FIGURE e20-19 Three-dimensional reconstruction of a CT angiogram demonstrating three

saphenous vein coronary artery bypass grafts in different views. In the upper left panel is an anterior-
posterior view of the heart and grafts. 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.
RCA, saphenous vein graft to the right coronary artery; CX, saphenous vein graft to the circumflex ar-
tery; DIAG, saphenous vein graft to the diagonal artery.

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 e157

CHAPTER e20 Atlas of Noninvasive Cardiac Imaging

FIGURE e20-20 Cardiac CT images demonstrating a calcified mass chronic thrombus. Calcification is seen as a bright signal in both the
in the right ventricle, which at pathologic examination was a noncontrast (upper) and contrast-enhanced (lower) images.

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

 The abbreviations used in this chapter are as follows:
\

e159

e21 Atlas of Cardiac Arrhythmias AF—atrial fibrillation

CHAPTER e21 Atlas of Cardiac Arrhythmias

Ary L. Goldberger AV—atrioventricular
AVRT—atrioventricular reentrant tachycardia
LBBB—left bundle branch block
The electrocardiograms in this Atlas supplement those illustrated in LV—left ventricular
Chaps. 225 and 226. The interpretations emphasize findings of specific LVH—left ventricular hypertrophy
teaching value. MI—myocardial infarction
All of the figures are from ECG Wave-Maven, Copyright 2003, Beth NSR—normal sinus rhythm
Israel Deaconess Medical Center, http://ecg.bidmc.harvard.edu. RBBB—right bundle branch block
VT—ventricular tachycardia
WPW—Wolff-Parkinson-White

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-1 Respiratory sinus arrhythmias, a physiologic finding the beginning of the strip during expiration, then accelerates during
in a healthy young woman. The rate of the sinus pacemaker is slow at inspiration and slows again with expiration.

I aVR 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 = 0.28 s). The P wave
is visible after the ST-T wave in V1–V3. Atrial tachycardia may produce a similar pattern.

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 e160
I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e21-3 Sinus rhythm (pulse rate about 62/min) with 2:1 AV block causing marked bradycardia.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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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 I aVR V1 V4 e161

CHAPTER e21 Atlas of Cardiac Arrhythmias

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-5 Marked junctional bradycardia (25 beats/min). Rate waves. Patient was on atenolol, with possible underlying sick sinus
is regular, flat baseline between narrow QRS complexes without P syndrome.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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.

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

 e162 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e21-7 Sinus rhythm at a rate of 90/min with third degree 60/min, with an occasional dropped beat, in a patients with Lyme
(complete) AV block and an A-V junctional pacemaker at a rate of carditis.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-8 Multifocal atrial tachycardia with varying P-wave layed transition in precordial leads in patient with severe obstructive
morphologies and P-P intervals; right atrial overload with peaked P lung disease.
waves in II, III, and aVF; superior axis; poor R-wave progression with de-

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

 e163
I aVR V1 V4

CHAPTER e21 Atlas of Cardiac Arrhythmias

II aVL V2 V5

III aVF V3 V6

II

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.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-10 Atrial tachycardia with atrial rate 200/min (note lead present: LVH with intraventricular conduction defect and slow precor-
V1), 2:1 AV block, and one premature ventricular complex. Also dial R-wave progression (cannot rule out old MI).

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

 e164 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

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.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-12 Atrial tachycardia [180/min with 2:1 AV block (see lead V1)]. LVH by left precor-
dial voltage. Slow R-wave progression (V1–V4) compatible with old anteroseptal MI.

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

 I aVR V1 V4 e165

CHAPTER e21 Atlas of Cardiac Arrhythmias

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-13 AV nodal reentrant tachycardia (AVNRT) at a rate of 150/min.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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.

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

 e166 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e21-15 Atrial flutter with atrial rate 300/min and 2:1 or 3:1 conduction. Flutter waves best seen in lead II.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

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 e167

CHAPTER e21 Atlas of Cardiac Arrhythmias

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-17 AF with LBBB. The ventricular rhythm is irregularly irregular.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-18 AF with complete heart block and a junctional es- min). The QRS complexes show intraventricular conduction defect
cape mechanism causing a slow regular ventricular response (45/ with left-axis deviation and LVH. Q-T (U) prolongation.

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

 e168
I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e21-19 AF with right-axis deviation and LVH. Tracing suggests biventricular hypertrophy
in a patient with mitral stenosis and aortic valve disease.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-20 WPW pre-excitation pattern, with triad of short PR, in lead II and lateral chest leads) consistent with a right-sided bypass
wide QRS, and delta waves. Polarity of the delta waves (most positive tract.

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

 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 ante- tachycardia. Rhythm is “irregularly irregular” and rate is extremely rapid
grade conduction down the bypass tract leading to a wide complex (about 230/min). Not all beats are pre-excited.

I aVR 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. ST elevations in the precordial leads from underlying acute MI.

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

 e170 I aVR V1 V4
PART 9

II aVL V2 V5
Disorders of the Cardiovascular System

III aVF V3 V6

II

FIGURE e21-23 Prolonged (0.60 s) QT interval in a patient with hereditary long-QT syndrome.

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

II

FIGURE e21-24 Monomorphic VT at rate of 170/min. The RBBB mor- heart, near the base (RBBB with inferior/rightward axis). Baseline arti-
phology in V1 and the R:S ratio < 1 in V6 are both suggestive of VT. The fact is present also in leads V1–V3.
morphology of the VT is suggestive of origin from the left side of the

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

 If you have downloaded this PDF to your computer, you will not be able to view the videos using the links in the PDF.
Please visit the Video Bank on the DVD to view the videos.
e22 Atlas of Atherosclerosis
Peter Libby
We have learned a great deal about the biology of human atherosclero-
sis in recent years, with new information about the risk factors for ath-
erosclerosis expanding considerably. The application of vascular
biology to human atherosclerosis has revealed many new insights into
the mechanisms that promote clinical events. The series of animated
video presentations presented here illustrates some of the evolving in-
formation regarding risk factors for atherosclerosis and the patho-
physiology of clinical events.
We have long appreciated the importance of blood pressure as a risk
factor for atherosclerosis and cardiovascular events. More recent clini-
cal information has highlighted the importance of pulse pressure, that
is, the difference between the systolic pressure and minimum diastolic
arterial pressure, as a prognostic indicator of cardiovascular risk. The
video clip on pulse pressure explains the pathophysiology of this readi-
ly measured clinical variable.
We possess a great deal of knowledge regarding the role of choles-
terol in the prediction of atherosclerosis and its complications; howev-
er, our knowledge of the mechanism that links hypercholesterolemia
to cardiovascular events has lagged the epidemiologic and observa-
tional findings. Low-density lipoprotein (LDL) provides an example of
a well-understood cardiovascular risk factor. 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. We now pos-
sess useful tools for modulating LDL. Yet, other aspects of dyslipide-
mia are on the rise and provide a growing challenge to the practitioner.
In particular, low levels of high-density lipoprotein (HDL) and elevat-
ed levels of triglycerides characterize the constellation of findings de-
noted by some as “metabolic syndrome.” In the wake of increasing
obesity worldwide, these features of the lipoprotein profile require re-
newed focus. 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.
Our traditional approach to atherosclerosis focused on arterial
stenoses as a cause of ischemia and cardiovascular events. We now pos-
sess effective revascularization modalities for addressing flow-limiting
stenoses, but we recognize that atherosclerotic plaques that do not
cause stenoses may nonetheless precipitate clinical events, such as un-
stable angina or acute myocardial infarction. Thus we must add to our
traditional focus on stenosis an enlarged appreciation of the pathobi-
ology of atherosclerosis that underlies many acute coronary syn-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e171
dromes. The animation on the development and complication of the
CHAPTER e22 Atlas of Atherosclerosis
atherosclerotic plaque explains some of these emerging concepts in
plaque activation as they apply to the precipitation of thrombotic
complications of atherosclerosis.
VIDEO e22-1 (Play video) Pulse pressure. Considerable evidence sug-
gests that pulse pressure serves as an important risk factor for future car-
diovascular events. This video clip explains the derivation of pulse
pressure and some of the pathophysiology that determines this param-
eter. (With permission from the Academy for Health Care Education.)
VIDEO e22-2 (Play video) Plaque instability. We currently under-
stand that most coronary thromboses result from a physical disruption
of the atherosclerotic plaque. This video animation explains some of
the current concepts of the pathophysiology of atherosclerotic plaque
disruption and how it triggers arterial thrombosis.
VIDEO e22-3 (Play video) Lipoprotein menagerie. The lipid profile
confers important information regarding cardiovascular risk and the
effects of therapies; understanding lipoprotein metabolism provides
insight into the pathophysiology of arterial disease. This video anima-
tion presents the rudiments of the metabolism of lipoproteins impor-
tant in clinical medicine.
VIDEO e22-4 (Play video) Formation and complication of athero-
sclerotic plaques. We now understand the generation of atheroscle-
rotic plaques as a dynamic process involving an interchange between
cells of the artery wall, inflammatory cells recruited from blood, and
risk factors such as lipoproteins. 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. This presenta-
tion also discusses the importance of inflammation in these processes,
and portrays the role of inflammation in plaque disruption and throm-
bosis. Finally, this animation depicts the concept of stabilization of ath-
erosclerotic plaques by intervention such as lipid lowering.
VIDEO e22-5 (Play video) Atherogenesis. This video clip highlights
some of the current thinking about mechanisms of atherogenesis.
VIDEO e22-6 (Play video) Metabolic syndrome. A number of im-
portant cardiovascular risk factors tend to cluster in a pattern described
by some as the “metabolic syndrome.” While controversy persists re-
garding whether cardiovascular risk due to these factors is additive or
synergistic, their clinical importance is growing. This animation dis-
cusses some of the metabolic derangements that underlie the “meta-
bolic syndrome.”
(From Peter Libby, MD: Changes and Challenges in Cardiovascular
Protection, A Special CME Activity for Physicians. Created under an
unrestricted educational grant from Merck & Co., Inc. Copyright ©
2002, Cardinal Health; used with permission.)
 If you have downloaded this PDF to your computer, you will not be able to view the videos using the links in the PDF. e173
Please visit the Video Bank on the DVD to view the videos.

CHAPTER e23 Atlas of Percutaneous Revascularization

e23 Atlas of Percutaneous
Revascularization
Donald S. Baim*

As indicated in Chap. 240, percutaneous coronary intervention (PCI)

has assumed a major role in the management of coronary artery dis-
ease. It is used most commonly in patients with chronic stable angina,
unstable angina, and primary therapy in acute ST segment elevation
myocardial infarction.
This chapter illustrates some complex uses of percutaneous tech-
niques, including management of cardiogenic shock, stent thrombo-
sis, management of distal coronary vascular disease, and stenting of a
chronic totally occluded vessel. In addition, pressure tracings obtained
at left heart catheterization in the diagnosis of obstructive hyper-
trophic cardiomyopathy are shown, as is the percutaneous insertion of
an experimental aortic valve. The latter has not yet been approved for FIGURE e23-2 Cardiogenic shock is present. The mean pulmonary cap-
clinical use but demonstrates one of the future extensions of percuta- illary wedge (PCW) pressure is elevated at 23 mmHg, with prominent v
neous techniques. waves (peaking after the ECG T wave), suggestive of mitral regurgita-
tion. Arterial pressure is reduced (91/55 mmHg) despite dopamine in-
fusion, and the respiratory rate (24/min) plus arterial desaturation
CASE 1: CARDIOGENIC SHOCK WITH LEFT MAIN (93%) on 100% O2 suggest incipient pulmonary edema.
CORONARY ARTERY OBSTRUCTION
(Figs. e23-1 to e23-5; Videos e23-1 to e23-10) VIDEO e23-2 (Play video) As seen also in this right anterior oblique
projection.
• A 93-year-old man presented to the emergency room with 9 h of
VIDEO e23-3 (Play video) There is also significant stenosis in the mid-
dyspnea and a sense of “dread”
portion of the dominant right coronary artery.
• Prior subendocardial MI 2 months earlier managed medically (no
VIDEO e23-4 (Play video) Intraaortic balloon pump placed via contra-
catheterization done)
lateral groin. 8 Fr guiding catheter is used to place separate wires into
• Entry systolic pressure 70 mmHg, rales 2/3 way up, cool clammy ex-
the left anterior descending (LAD) and circumflex (CX) arteries.
tremities, arterial saturation 85% on 100% oxygen rebreathing
VIDEO e23-5 (Play video) Simultaneous inflation of two 3.0-mm adja-
mask
cent “kissing” balloons.
• Brought emergently to the catheterization laboratory—right heart
VIDEO e23-6 (Play video) Simultaneous kissing stent deployment in
catheterization performed
the LAD and Cx.
VIDEO e23-1 (Play video) Baseline left coronary angiogram shows se- VIDEO e23-7 (Play video) Post-stent result.
vere ulcerated stenosis of the distal left main coronary artery. VIDEO e23-8 (Play video) Post-stent result.

FIGURE e23-1 Presenting ECG—marked inferior and anterolateral ST depression.

*At the time that Dr. Baim prepared this chapter, he was a Professor of
Medicine at Harvard Medical School and Senior Physician at Brigham and
Women’s Hospital. Since then, he has assumed the position of Chief Medi-
cal and Scientific Officer at Boston Scientific Co.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 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 1.4 (L/min)/m2,
confirming the cardiogenic shock state.
VIDEO e23-9 (Play video) Shock persists, so the right coronary artery
lesion was also stented.
VIDEO e23-10 (Play video) Result.
LEFT MAIN CORONARY ARTERY STENOSIS WITH CARDIOGENIC SHOCK
• Cardiogenic shock requires emergent revascularization
• Right heart catheterization is useful to assess and monitor hemody-
namics, in this case showing profound shock and probable ischem-
ic mitral regurgitation
FIGURE e23-4 Estimation of risk of mortality of percutaneous coronary intervention (PCI). (From M Singh et al:
J Am Coll Cardiol 40:387, 2002.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
FIGURE e23-5 The PCW fell from 34 mmHg preintervention to 20
mmHg post-intervention with resolution of the tall v waves, and PA
saturation increased from 32 to 52%, while cardiac index (CI) rose from
1.4 to 2.1 (L/min)/m2.
• 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, and double wire, “kissing” balloon and kissing stent implan-
tation were performed via 8 Fr guide
• Because of ongoing shock, RCA stenting also performed
• This stabilized hemodynamics with PCW falling to 10 mmHg, and
cardiac output normalizing over first 8 h in CCU
• Patient recovered despite a peak CPK of 2300, CKMB 274
• Discharged on day 7, despite a pre-procedure 85% estimated PCI
mortality!
Estimated PCI
mortality 85%
CASE 2: INFERIOR MI WITH CARDIOGENIC SHOCK
(Figs. e23-6 and e23-7; 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 coro-
nary shows unexpected distal left main bifurcation stenosis with possi-
ble superimposed thrombus.
VIDEO e23-12 (Play video) The right coronary artery is occluded prox-
imally.
VIDEO e23-13 (Play video) Guidewire passage restores antegrade
flow, exposing extensive linear thrombus and stenosis in the mid-RCA.
Elapsed time since arrival in the catheterization laboratory—10 min.
VIDEO e23-14 (Play video) Some improvement in the filling defect
after suction thrombectomy.
VIDEO e23-15 (Play video) Positioning a 3.5 × 32 mm drug-eluting
stent to cover the culprit lesion.
VIDEO e23-16 (Play video) Stent deployment.
VIDEO e23-17 (Play video) Post-stent.
VIDEO e23-18 (Play video) Post-stent in shallow RAO cranial projec-
tion shows brisk flow in a very dominant right coronary artery. Elapsed
time since catheterization laboratory arrival < 20 min.
VIDEO e23-19 (Play video) Sheath injection shows entry into the
common femoral artery just above a moderate lesion. An intraaortic
balloon pump was placed to stabilize the patient for bypass surgery of
the left coronary artery the following day. Peak CPK was 337 (upper
limit of normal = 200), indicating an aborted myocardial infarction
with this very early reperfusion.
INFERIOR MI WITH CARDIOGENIC SHOCK
• Inferior MIs are usually more benign than anterior MIs
• When there is hypotension in an inferior MI, 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, how-
ever, suggest associated global ischemia due to the left main disease
• The patient was clinically stable after the intervention on the right
coronary artery, and an intraaortic balloon was placed preparatory
to bypass surgery of the left system
• The very early presentation and rapid intervention virtually com-
pletely aborted this life-threatening MI
FIGURE e23-6 ECG shows sinus bradycardia, an accelerated idioven-
tricular rhythm and isorhythmic dissociation, and profound inferior
ST elevation.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e175
CHAPTER e23 Atlas of Percutaneous Revascularization
FIGURE e23-7 Top: Preintervention. Bottom: Postintervention. As soon
as flow was restored, rhythm returned to normal sinus, ST elevation re-
solved, blood pressure rose to 152/84 mmHg despite discontinuation of
dopamine, and oxygen saturation normalized (not shown). Right heart
catheterization post-stent (not shown) revealed normal hemodynamics
with wedge pressure of 12 mmHg and cardiac index of 2.4 (L/min)/m2.
CASE 3: ANTERIOR MI STENT, 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, 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. A. (Play video) B. (Play video)
VIDEO e23-21 Rheolytic thrombectomy, with post-thrombectomy re-
sult. A. (Play video) B. (Play video)
VIDEO e23-22 Simultaneous drug-eluting stenting of the LAD-diagonal
bifurcation (A) (Play video), with an excellent result (B) (Play video).
VIDEO e23-23 (Play video) The patient self-discontinued clopidogrel
at 2 months after stenting, and developed recurrent pain 10 days later.
Emergency coronary angiography shows recurrent LAD occlusion due
to subacute stent thrombosis.
VIDEO e23-24 The stent thrombosis was crossed with wires into the
distal LAD and diagonal (A) (Play video), restoring flow but showing
filling defects representing thrombus. This was again treated with
thrombectomy (B) (Play video).
VIDEO e23-25 (Play video) The result after thrombectomy was again
excellent, although a small filling defect remains.
MYOCARDIAL INFARCTION STENTING, WITH STENT THROMBOSIS
• Coronary occlusions causing myocardial infarction usually con-
tain some thrombus
• Although routine thrombectomy has not been shown to produce
benefit, large thrombi respond well to thrombectomy
• The underlying, 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, since early discontinuation increases the
risk of subacute stent thrombosis (SAT)
• In this case, as in most, SAT was associated with a substantial myo-
cardial infarction
This case was contributed by Dr. James Kirshenbaum, Brigham and
Women’s Hospital, Boston; with permission.
 e176 CASE 4: DISTAL CORONARY DISEASE IN A DIABETIC PATIENT • Using stiff (3.0–9 g) specialty guidewires, double injection, and
(Videos e23-26 to e23-32) painstaking technique, roughly 70% of these lesions can be crossed
and, once crossed, stented with good long-term results.
• This 67-year-old non-insulin dependent diabetic developed refrac- • This patient declined to return for an attempt on the occluded Cx
tory angina
PART 9

• The culprit lesions were in the posterior descending and posterolat-
eral branches of the dominant right coronary artery
• While bypass surgery is still the standard of care in diabetic patients
with multivessel coronary disease, drug-eluting stenting may be an
option in selected patients
• They present challenges for intervention because of distal location,
Disorders of the Cardiovascular System
and did well for 10 months. Then he returned with a patent RCA
and progressive disease in the LAD, which was in turn stented.
• If the RCA had not been opened, and the stents had not remained
patent, the consequences of the severe LAD lesion progression
might well have been more risky.
See Chaps. 22, 24, and 29.

small vessel diameter, diffuse disease, and a high restenosis rate due
to diabetes mellitus CASE 6: HYPERTROPHIC CARDIOMYOPATHY (HCM)
VIDEO e23-26 (Play video) Baseline angiogram in the shallow right WITH OBSTRUCTION
anterior oblique view with cranial angulation shows the culprit lesions. HYPERTROPHIC CARDIOMYOPATHY (HCM) WITH OBSTRUCTION
VIDEO e23-27 (Play video) Dilation of the posterior descending artery (Figs. e23-8 to e23-11)
(PDA) with a 2-mm balloon.
VIDEO e23-28 (Play video) Post-angioplasty result shows significant • Asymmetric hypertrophy of the upper septum can cause an intra-
residual stenosis. cavitary gradient within the LV due to contact of the anterior leaflet
VIDEO e23-29 Positioning a 2.5 × 24 mm drug-eluting stent in the dis- with the septum during systole
tal posterior descending artery (PDA) (A) (Play video) and a 2.5 × 16
mm stent in the proximal PDA (B) (Play video).
VIDEO e23-30 (Play video) After documenting an excellent result in
the PDA, the guidewire is relocated to the posterolateral branch,
which is also predilated with a 2-mm balloon.
VIDEO e23-31 (Play video) Stent deployment.
VIDEO e23-32 (Play video) Excellent result in both vessels poststenting.

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, poor prospects for a favorable outcome with sur-
gery swung the balance to PCI
• The availability of flexible stents for small vessels has made treat-
ment of such vessels possible
• Drug-eluting stents also reduce the incidence of restenosis (in-
creased in patients with diabetes) to roughly 7% compared to
roughly 25% with bare metal stents
FIGURE e23-8 Simultaneous recording of the left ventricular (yellow)
and femoral artery (orange) pressures shows a 60 mmHg pressure gra-
CASE 5: CHRONIC TOTAL OCCLUSION STIFF GUIDEWIRE dient. This could represent aortic stenosis, but this patient had a nor-
(Videos e23-33 to e23-41) mal aortic valve on echo and asymmetric thickening of the upper left
ventricular septum.
• 75-year-old man with angina and inferior ischemia on exercise
thallium-201 scan
• Catheterization shows moderate left anterior descending (LAD)
coronary artery lesion, and chronic total occlusion of the circum-
flex (Cx) and right coronary arteries (RCA)
VIDEO e23-33 (Play video) Baseline left coronary injection shows LAD dis-
ease and occluded Cx-OM, plus left-to-right collaterals from AV groove Cx.
VIDEO e23-34 (Play video) Double (also known as “simultaneous”) injec-
tion of the left and right coronaries demonstrates area of distal occlusion.
VIDEO e23-35 (Play video) Stiff guidewire slightly below trajectory.
VIDEO e23-36 (Play video) Stiff guidewire now across the occlusion
and in a small branch of the PDA.
VIDEO e23-37 (Play video) After stenting, the RCA is widely patent,
and now supplies right to left collaterals to the Cx.
VIDEO e23-38 (Play video) Poststenting view in AP cranial projection.
VIDEO e23-39 (Play video) Return of angina 10 months later—re-
study shows widely patent RCA.
VIDEO e23-40 (Play video) Progression of the proximal LAD lesion,
with slow flow at the apex.
VIDEO e23-41 (Play video) Post LAD stenting.
FIGURE e23-9 A spontaneous ventricular premature beat is followed
TOTAL OCCLUSION—STIFF WIRES
by an augmented sinus beat marked by increased LV pressure and LV-
• The presence of one or more chronic total occlusions often leads to Ao gradient, but a decrease in femoral artery pulse pressure, consistent
referral to surgery with HCM with obstruction (Braunwald-Brockenbrough sign).
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 CASE 7: PERCUTANEOUS AORTIC VALVE REPLACEMENT e177
(Figs. e23-12 to e23-15)

CHAPTER e23 Atlas of Percutaneous Revascularization

• The preferred treatment for severe aortic stenosis is surgical re-
placement of the aortic valve
• Although the average surgical mortality for this procedure is ~4%,
some patients are at significantly higher risk due to advanced age,
poor LV function, or other comorbidities
• Percutaneous balloon valvuloplasty was evaluated in the late 1980s,
and provided limited benefit
• A new class of investigational percutaneous aortic valve replace-
ment techniques, using pericardial valves mounted in an outer
stent, are now under investigation
The case and data shown here were provided by Dr. Eberhard
Grube of Sieburg, Germany; with permission.

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.

FIGURE e23-12 Self-expanding AV prosthesis: the CoreValve. A pericar-

dium tissue valve fixed to the frame in a surgical manner.

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.
Note that the femoral artery systolic pressure is slightly higher than the
central aortic pressure due to peripheral augmentation.

• While the LV-Ao pressure gradient may look superficially like that
FIGURE e23-13 CoreValve delivery by sheath withdrawal.
seen in aortic stenosis, the characteristic decrease in aortic or pe-
ripheral 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 re-
cording this dynamic gradient, and intracavitary localization of the
gradient during pull-back
• The diagnosis and evaluation of this disease, however, is more
often made by echocardiography in current practice

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

 e178
140

120
p<0.0001
PART 9

100

mmHg
80

60

40
Disorders of the Cardiovascular System

20

0
Pre Post 30 Days

Mean Mean Mean

69.90 ± 22.96 mmHg 22.23 ± 8.23 mmHg 22.48 ± 8.40 mmHg

FIGURE e23-15 CoreValve study: Peak pressure gradients.

FIGURE e23-14 CoreValve follow-up: Post-implant morphologic assess-

ment by CT scan.

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

 e179

e24 Atlas of Chest Imaging

Patricia Kritek, John J. Reilly, Jr.

This atlas of chest imaging is a collection of interesting chest radio-

graphs and computed tomograms of the chest. The readings of the
films are meant to be illustrative of specific, major findings. The associ-
ated text is not intended as a comprehensive assessment of the images.

EXAMPLES OF NORMAL IMAGING

CHAPTER e24
Atlas of Chest Imaging
FIGURE e24-1 Normal chest radio-
graph—review of anatomy. 1. Trachea.
2. Carina. 3. Right atrium. 4. Right hemi-
diaphragm. 5. Aortic knob. 6. Left hilum.
7. Left ventricle. 8. Left hemi-diaphragm
(with stomach bubble). 9. Retrosternal
clear space. 10. Right ventricle. 11. Left
hemi-diaphragm (with stomach bub-
ble). 12. Left upper lobe bronchus.

FIGURE e24-2 Normal chest to-

mogram—note anatomy. 1. Supe-
rior vena cava. 2. Trachea. 3. Aortic
arch. 4. Ascending aorta. 5. Right
mainstem bronchus. 6. Descending
aorta. 7. Left mainstem bronchus.
8. Main pulmonary artery. 9. Heart.
10. Esophagus. 11. Pericardium.
12. Descending aorta.

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

 e180 VOLUME LOSS
PART 10
Disorders of the Respiratory System

FIGURE e24-3 CT scan demonstrating left upper lobe collapse.
The patient was found to have an endobronchial lesion (not visible on
the CT scan) resulting in this finding. The superior vena cava (black ar-
row) is partially opacified by intravenous contrast.
FIGURE e24-5 Left upper lobe scarring with hilar retraction with
less prominent scarring in right upper lobe as well. Findings consistent
with previous tuberculosis infection in an immigrant from Ecuador.

FIGURE e24-6 Apical scarring, traction bronchiectasis (red ar-

row), and decreased lung volume consistent with previous tuber-
culosis infection. Findings most significant in left lung.
FIGURE e24-4 CT scan revealing chronic left lower lobe collapse.
Note dramatic volume loss with minimal aeration. There is subtle me-
diastinal shift to the left.

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

 e181

CHAPTER e24
Atlas of Chest Imaging
FIGURE e24-7 Chest x-ray (CXR) demonstrating right upper lobe
collapse (yellow arrow). Note the volume loss as demonstrated by the
elevated right hemi-diaphragm as well as mediastinal shift to the right.
Also apparent on the film are an endotracheal tube (red arrow) and a
central venous catheter (black arrow).

LOSS OF PARENCHYMA

FIGURE e24-8 Emphysema with in-

creased lucency, flattened diaphragms
(black arrows), increased AP diameter,
and increased retrosternal clear space
(red arrow).

FIGURE e24-9 CT scan of diffuse, bilateral emphysema.

Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e182
PART 10
Disorders of the Respiratory System

FIGURE e24-10 CT scan of bullous emphysema.

FIGURE e24-13 CT scan of parenchymal cavity.

FIGURE e24-11 Multiple, thin-walled cysts consistent with lymphan-

gioleiomyomatosis.

FIGURE e24-12 Two cavities on posteroanterior (PA) and lateral CXR. Cavities and air-fluid levels
identified by red arrows. 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 lo-
cated between the minor (red arrow) and major fissures. There is an area of consolidation associated
with the cavity in the right lower lobe.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
INTERSTITIAL PROCESSES e183

CHAPTER e24
Atlas of Chest Imaging
FIGURE e24-15 Pulmonary edema. Note indistinct vasculature, peri-
hilar opacities, and peripheral interstitial reticular opacities. While this
is an anteroposterior film making cardiac size more difficult to assess,
the cardiac silhouette still appears enlarged.
FIGURE e24-14 Mild congestive heart failure. Note the Kerley B lines
(black arrow) and perivascular cuffing (yellow arrow) as well as the pul-
monary vascular congestion (red arrow).

FIGURE e24-16 CXR demonstrates reticular nodular opacities bi-

laterally with small lung volumes consistent with usual interstitial
pneumonitis (UIP) on pathology. Clinically, UIP is used interchangeably
with idiopathic pulmonary fibrosis (IPF).

FIGURE e24-17 CT scan of usual inter-

stitial pneumonitis (UIP), also known
as idiopathic pulmonary fibrosis (IPF).
Classic findings include traction bron-
chiectasis (black arrow) and honey-
combing (red arrows). Note subpleural,
basilar predominance of the honey-
combing.
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 e184

FIGURE e24-18 Sarcoid—CXR of stage

PART 10

I (hilar lymphadenopathy without pa-

renchymal infiltrates).
Disorders of the Respiratory System

FIGURE e24-19 Sarcoid—CT scan of stage I demonstrating bulky FIGURE e24-21 Sarcoid—CT scan of stage II (calcified lymphade-
hilar and mediastinal lymphadenopathy (red arrows) without paren- nopathy, parenchymal infiltrates).
chymal infiltrates.

FIGURE e24-22 Sarcoid—CT scan of stage II (nodular opacities track-

ing along bronchovascular bundles).

FIGURE e24-20 Sarcoid—CXR of stage II (lymphadenopathy with pa-

renchymal changes). Note apical predominance of disease. The dia-
phragms are also flattened, suggesting hyperinflation.
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 e185

CHAPTER e24
FIGURE e24-24 Sarcoid—stage IV (fibrotic lung disease).

Atlas of Chest Imaging

FIGURE e24-23 Sarcoid—stage III with nodular parenchymal infil-
trates (yellow arrows), no lymphadenopathy. Also note large pulmo-
nary artery (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.

FIGURE e24-26 Right lower lobe pneumonia—subtle opacity on PA

film (red arrow), while the lateral film illustrates the “spine sign” (black
arrow) where the lower spine does not become more lucent.
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 e186
PART 10

FIGURE e24-27 CT scan of diffuse, bilateral “ground-glass” infil-

Disorders of the Respiratory System

trates. This finding is consistent with fluid density in the alveolar space.

FIGURE e24-28 CXR reveals diffuse, bilateral alveolar infiltrates

without pleural effusions, consistent with acute respiratory distress syn-
drome (ARDS). Note that the patient has an endotracheal tube (red ar-
row) and has a central venous catheter (black arrow).

FIGURE e24-29 CT scan of ARDS demonstrates ground-glass infil-

trates with more consolidated areas in the dependent lung zones.
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 e187

CHAPTER e24
Atlas of Chest Imaging

FIGURE e24-30 Three examples of air bronchograms (red arrows) on

chest CT.

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 e188 BRONCHIECTASIS
PART 10
Disorders of the Respiratory System

FIGURE e24-31 Cystic fibrosis with bronchiectasis, apical disease.

FIGURE e24-32 CT scan of diffuse, cystic bronchiectasis (red ar-

rows) in a patient with cystic fibrosis.

FIGURE e24-34 “Tree in bud” opacities (red arrows) and bron-

chiectasis (yellow arrow) consistent with atypical mycobacterial in-
fection. “Tree in bud” refers to small nodules clustered around the
centrilobular arteries as well as increased prominence of the centrilob-
ular branching. These findings are consistent with bronchiolitis.

FIGURE e24-33 CT scan of focal right middle lobe and lingular

bronchiectasis (yellow arrows). Note that there is near total collapse
of the right middle lobe (red arrow).
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PLEURAL ABNORMALITIES e189

CHAPTER e24
Atlas of Chest Imaging
FIGURE e24-37 CT scan of large right-sided pneumothorax. Note
significant collapse of right lung with adhesion to anterior chest wall.
FIGURE e24-35 Large right pneumothorax with near complete
Pleural reflection highlighted with red arrows. The patient has severe
collapse of right lung. Pleural reflection highlighted with red arrows.
underlying emphysema.

FIGURE e24-36 Basilar pneumothorax with visible pleural reflec-

tion (red arrows). Also note, patient has subcutaneous emphysema
(yellow arrow).

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 e190
PART 10

FIGURE e24-38 Small right pleural effusion (red arrows highlight blunted right costophrenic an-
gles) with associated pleural thickening. Note fluid in the major fissure (black arrow) visible on the lat-
eral film as well as the meniscus of the right pleural effusion.
Disorders of the Respiratory System

FIGURE e24-39 Left pleural effusion with clear meniscus seen on both PA and lateral chest radio-
graphs.

FIGURE e24-40 Asbestosis. Note calcified pleural plaques (red ar-

rows); pleural thickening (black arrow) and subpleural atelectasis
(green arrows).

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NODULES AND MASSES e191

CHAPTER e24
Atlas of Chest Imaging
FIGURE e24-41 Left upper lobe mass, which biopsy revealed to be squamous cell carcinoma.

FIGURE e24-43 Metastatic sarcoma. Note the multiple, well-circum-

FIGURE e24-42 Solitary pulmonary nodule on the right (red arrow) scribed nodules of different size.
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).

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 e192
PART 10

FIGURE e24-46 Mycetoma. Fungal ball (red arrow) growing in preex-

isting cavity on the left. Right upper lobe has a large bulla (black ar-
Disorders of the Respiratory System

row).

FIGURE e24-44 Left lower lobe lung mass (red arrow) abutting
pleura. Biopsy demonstrated small cell lung cancer.

FIGURE e24-45 CT scan of soft tissue mass encircling the trachea

(red arrow) and invading tracheal lumen. Biopsy demonstrated ade-
noid cystic carcinoma (cylindroma).

Copyright © 2008 The McGraw-Hill Companies. 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. Note
the markedly enlarged pulmonary arteries (red arrow).

FIGURE e24-47 Pulmonary arteriovenous malformation (AVM)

demonstrated on reformatted CT angiogram (red arrow).

FIGURE e24-48 Large bilateral pulmonary emboli (intravascular filling defects in contrast scan
identified by red arrows).

FIGURE e24-49 CXR of a patient with severe pulmonary hypertension. Note the enlarged pul-
monary arteries (red arrows) visible on both PA and lateral films.

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

 If you have downloaded this PDF to your computer, you will not be able to view the videos using the links in the PDF. e195
Please visit the Video Bank on the DVD to view the videos.
ic findings in a variety of gastrointestinal infectious, inflammatory,

CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy

e25 Video Atlas of
Gastrointestinal Endoscopy
Louis Michel Wong-Kee-Song, Mark Topazian
vascular, and neoplastic conditions. Cancer screening and prevention
are common indications for gastrointestinal endoscopy, and the pre-
malignant conditions of Barrett’s esophagus and colonic polyps are il-
lustrated. Endoscopic treatment modalities for gastrointestinal
bleeding, polyps, and biliary stones are demonstrated in video clips.
Gastrointestinal endoscopy is an increasingly important method for The images shown in this Atlas are also found in Chap. 285 of the
diagnosis and treatment of disease. This atlas demonstrates endoscop- book.

FIGURE e25-1 Duodenal ulcers. A. Ulcer with a clean base. B. Ulcer FIGURE e25-2 Gastric ulcers. A. Benign gastric ulcer. B. Malignant
with a visible vessel (arrow) in a patient with recent hemorrhage. gastric ulcer involving greater curvature of stomach.

FIGURE e25-3 Barrett’s esophagus. A. Pink tongues of Bar-

rett’s mucosa extending proximally from the gastro-esoph-
ageal junction. B. Barrett’s esophagus with a suspicious
nodule (arrow) identified during endoscopic surveillance.
C. Histologic finding of intramucosal adenocarcinoma in
the endoscopically resected nodule. Tumor extends into
the esophageal submucosa (arrow). D. Barrett’s esophagus
with locally advanced adenocarcinoma.

FIGURE e25-4 Causes of colitis. A. Chronic ulcerative colitis with dif- branes. D. Ischemic colitis with patchy mucosal edema, subepithelial
fuse ulcerations and exudates. B. Severe Crohn’s colitis with deep ulcers. hemorrhage, and cyanosis.
C. Pseudomembranous colitis with yellow, adherent pseudomem-

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 e196
PART 13
Disorders of the Gastrointestinal System

FIGURE e25-5 Colonic polyps. A. Pedunculated colon polyp on a

thick stalk covered with normal mucosa (arrow). B. Sessile rectal polyp.

FIGURE e25-10 Endoscopic sphincterotomy. A. A normal-appearing

ampulla of Vater. B. Sphincterotomy is performed with electrocautery.
FIGURE e25-6 Colon adenocarci- FIGURE e25-7 Capsule endos- C. Bile duct stones are extracted with a balloon catheter. D. Final ap-
noma growing into the lumen. copy image of jejunal vascu- pearance of the sphincterotomy.
lar ectasia.

FIGURE e25-8 Radiograph of a

double-balloon enteroscope
in the small intestine. (Image
courtesy of Dr. Ananya Das; with
permission.)

FIGURE e25-9 Endoscopic retrograde

cholangiopancreatography (ERCP)
for bile duct stones with cholangi-
tis. A. Faceted bile duct stones are
demonstrated in the common bile duct.
B. After endoscopic sphincterotomy,
the stones are extracted with a Dormia
basket. A small abscess communicates
with the left hepatic duct.

Copyright © 2008 The McGraw-Hill Companies. Copyright © 2008 by Louis Michel Wong-Kee-Song, MD, and Mark Topazian, MD, for all Videos. All rights reserved.
 e197

CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy

FIGURE e25-11 Endoscopic diagnosis, staging, and palliation of
hilar cholangiocarcinoma. A. ERCP in a patient with obstructive
jaundice demonstrates a malignant appearing stricture of the biliary
confluence extending into the left and right intrahepatic ducts. B. In-
traductal ultrasound of the biliary stricture demonstrates marked bile
duct wall thickening due to tumor (T) with partial encasement of the
hepatic artery (arrow). C. Intraductal biopsy obtained during ERCP
demonstrates malignant cells infiltrating the submucosa of the bile
duct wall (arrow). D. Endoscopic placement of bilateral self-expanding
metal stents relieves the biliary obstruction.

FIGURE e25-12 Bile leak (arrow)

from a duct of Luschka after lap-
aroscopic cholecystectomy. Con-
trast leaks from a small right
intrahepatic duct into the gallblad-
der fossa, then flows into the pigtail
of a percutaneous drainage catheter.

FIGURE e25-13 Local staging of gastrointestinal cancers with en- cer. The tumor does not invade the mp. B. T2 esophageal cancer. The
doscopic ultrasound. In each example the white arrowhead marks tumor invades the mp. C. T3 esophageal cancer. The tumor extends
the primary tumor and the black arrow indicates the muscularis pro- through the mp into the surrounding tissue, and focally abuts the
pria (mp) of the intestinal wall. “AO” indicates aorta. A. T1 gastric can- aorta.

FIGURE e25-14 Endoscopic ultra-

sound (EUS)–guided fine-needle
aspiration (FNA). A. Ultrasound
image of a 22-gauge needle passed
through the duodenal wall and posi-
tioned in a hypoechoic pancreatic
head mass. B. Micrograph of aspi-
rated malignant cells. (Image B cour-
tesy of Dr. Mary S. Chacho; with
permission.)

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 e198
PART 13
Disorders of the Gastrointestinal System

FIGURE e25-15 Stigmata of hem-

orrhage in peptic ulcers. A. Gas-
tric antral ulcer with a clean base.
B. Duodenal ulcer with flat pig-
mented spots. C. Duodenal ulcer
with a dense adherent clot. D. Gas-
tric ulcer with a pigmented protu-
berance/visible vessel. E. Duodenal
ulcer with active spurting (arrow).

VIDEO e25-1 (Play video) Actively bleeding duodenal ulcer treated VIDEO e25-4 (Play video) Dieulafoy’s lesion treated endoscopically.
with endoscopic epinephrine injection, thermal probe application, and
hemoclips. (Video courtesy of Dr. Navtej Buttar; with permission.)

FIGURE e25-18 Mallory-Weiss

tear at the gastroesopha-
FIGURE e25-16 Esophageal geal junction.
varices.

VIDEO e25-2 (Play video) Actively bleeding varices treated with

endoscopic band ligation.
VIDEO e25-3 (Play video) Large, actively bleeding gastric varix
treated with endoscopic cyanoacrylate injection.

FIGURE e25-17 Dieulafoy’s lesion. A. Actively spurting jejunal Dieu-

lafoy’s lesion. There is no underlying mucosal lesion. B. Histology of a
gastric Dieulafoy’s lesion. A persistent caliber artery (arrows) is present
in the gastric submucosa, immediately beneath the mucosa.

Copyright © 2008 The McGraw-Hill Companies. Copyright © 2008 by Louis Michel Wong-Kee-Song, MD, and Mark Topazian, MD, for all Videos. All rights reserved.
 e199
FIGURE e25-19 Gastrointestinal vas-

CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy

cular ectasias. A. Gastric antral vascu-
lar ectasias, or ”watermelon stomach,”
characterized by prominent flat or
raised red angioectatic stripes radiating
in a spoke-like fashion from the pylorus
to the antrum. B. Cecal vascular ecta-
sias. C. Radiation-induced vascular ec-
tasias of the rectum in a patient
previously treated for prostate cancer.

VIDEO e25-5 (Play video) Actively bleeding colon diverticulum

treated with dilute epinephrine injection.

FIGURE e25-20 Sigmoid volvulus with

the characteristic radiological appear-
ance of a “bent inner tube.”

FIGURE e25-21 Obstructing colonic carcinoma. A. Colonic adeno-

carcinoma causing marked luminal narrowing of the descending colon.
B. Endoscopic placement of a self-expanding metal stent. C. Radio-
graph of expanded stent across the obstructing tumor with a residual
waist (arrow). (Image A courtesy of Dr. Glenn Alexander; with permission.)

Copyright © 2008 The McGraw-Hill Companies. Copyright © 2008 by Louis Michel Wong-Kee-Song, MD, and Mark Topazian, MD, for all Videos. All rights reserved.
 e200
PART 13
Disorders of the Gastrointestinal System

FIGURE e25-22 Methods of bile duct imaging. Arrows mark bile terisk marks the portal vein. A. Endoscopic ultrasound (EUS). B. Mag-
duct stones. Arrowheads indicate the common bile duct, and the as- netic resonance cholangiopancreatography (MRCP). C. CT.

VIDEO e25-6 (Play video) Impacted biliary stones removed during

endoscopic retrograde cholangiopancreatography.

FIGURE e25-24 Peptic esophageal stricture associated with ulcer-

ation and scarring of the distal esophagus.

FIGURE e25-23 Causes of esophagitis. A. Severe reflux esophagitis

with mucosal ulceration and friability. B. Cytomegalovirus esophagitis.
FIGURE e25-25 Schatzki’s ring at the gastro-esophageal junction.
C. Herpes simplex virus esophagitis with numerous shallow ulcer-
ations. D. Candida esophagitis with white plaques adherent to the
esophageal mucosa.

FIGURE e25-26 Eosinophilic esophagitis with multiple circular rings

of the esophagus creating a corrugated appearance, and an impacted
grape at the narrowed esophagogastric junction. The diagnosis re-
quires biopsy with histologic finding of ≥20 eosinophils/high power
field.
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 e201

CHAPTER e25 Video Atlas of Gastrointestinal Endoscopy

FIGURE e25-27 Scalloped duodenal folds in a patient with celiac FIGURE e25-30 Virtual colonoscopy image of a colon polyp (ar-
sprue. row). (Image courtesy of Dr. Jeff Fidler; with permission.)

FIGURE e25-28 Capsule endoscopy images of a mildly scalloped

jejunal fold (left) and an ileal tumor (right) in a patient with celiac
sprue. (Images courtesy of Dr. Elizabeth Rajan; with permission.)

VIDEO e25-7 (Play video) Pedunculated colonic polyp removed FIGURE e25-31 Internal hemorrhoids with bleeding (arrow) as seen
with snare cautery during colonoscopy. on a retroflexed view of the rectum.

VIDEO e25-8 (Play video) Organized pancreatic necrosis treated

by transduodenal endoscopic drainage.

FIGURE e25-29 Innumerable colon polyps of various sizes in a pa-

tient with familial adenomatous polyposis syndrome.

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 e203

e26 Atlas of Liver Biopsies

CHAPTER e26 Atlas of Liver Biopsies

Jules L. Dienstag, Atul K. Bhan

Although clinical and laboratory features yield clues to the extent of

inflammatory processes (disease grade), the degree of scarring and ar-
chitectural distortion (disease stage), and the nature of the disease
process, the liver biopsy is felt to represent the “gold standard” for as-
sessing the degree of liver injury and fibrosis. Examination of liver his-
tology 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.
A normal liver lobules consists of portal, lobular, and central zones.
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). The lobular area contains cords of liver cells surrounded by
vascular sinusoids, and the central zone consists of the central vein
(CV), the terminal branch of the hepatic vein (see figure below). FIGURE e26-1 Acute hepatitis with lobular inflammation and hepato-
cellular ballooning (H&E, 10×).

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, some in-
volving the lobular areas (e.g., the lobular inflammatory changes of
acute hepatitis, apoptotic hepatocyte degeneration in acute and chron-
ic hepatitis, virus antigen localization in hepatocyte cytoplasm and/or
nuclei, viral inclusion bodies), and others involving the portal tracts FIGURE e26-2 Acute hepatitis, higher magnification, showing lobu-
(e.g., the portal mononuclear infiltrate that expands and spills over be- lar inflammation, hepatocellular ballooning, and acidophilic bodies
yond the border of periportal hepatocytes in chronic hepatitis C, au- (arrows) (H&E, 20×).
toimmune hepatitis, and liver allograft rejection). Other histologic
features of importance include hepatic steatosis (observed in alcoholic
liver injury, in nonalcoholic fatty liver disorders, in metabolic disor-
ders—including mitochondrial injury—and in patients with chronic
viral hepatitis); injury of bile ducts in the portal tract, an important
diagnostic hallmark of primary biliary cirrhosis as well as of liver al-
lograft rejection; plasma cell infiltration common in autoimmune
hepatitis; and portal inflammation affecting portal veins (“endotheli-
alitis”) in liver allograft rejection.

ACKNOWLEDGMENTS
The authors wish to thank Zachary Goodman, MD, Armed Forces Insti-
tute of Pathology, Washington, DC, and Joseph Misdraji, MD, Depart-
ment of Pathology, Massachusetts General Hospital, Boston, for their
assistance and sharing of liver biopsies.

FIGURE e26-3 Chronic hepatitis C with portal lymphoid infiltrate and

lymphoid follicle containing germinal center (H&E, 10×).

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 e204
PART 13
Disorders of the Gastrointestinal System

FIGURE e26-4 Chronic hepatitis C with portal and lobular inflamma-

tion and steatosis (H&E, 10×). FIGURE e26-7 Chronic hepatitis B with hepatocellular cytoplasmic
staining for hepatitis B surface antigen (immunoperoxidase, 20×).

FIGURE e26-5 Chronic hepatitis C with portal inflammation and in-

terface hepatitis (erosion of the limiting plate of periportal hepato- FIGURE e26-8 Chronic hepatitis B with hepatocellular nuclear stain-
cytes by infiltrating mononuclear cells) (H&E, 20×). ing for hepatitis B core antigen (immunoperoxidase, 20×).

FIGURE e26-9 Autoimmune hepatitis with portal and lobular inflam-

mation, interface hepatitis, and cholestasis (H&E, 10×).
FIGURE e26-6 Lobular inflammation with acidophilic body (apop-
totic body) surrounded by lymphoid cells (H&E, 40×).

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


FIGURE e26-10 Autoimmune hepatitis, higher magnification, show-
ing dense plasma cell infiltrate in the portal and periportal regions
(H&E, 40×).
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, 40×).
FIGURE e26-12 Chronic hepatitis C with bridging fibrosis (arrow)
(Masson trichrome, 10×).
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e205
CHAPTER e26 Atlas of Liver Biopsies
FIGURE e26-13 Cirrhosis with architectural alteration resulting
from fibrosis and nodular hepatocellular regeneration (Masson
trichrome, 2×).
FIGURE e26-14 Acute cellular rejection of orthotopic liver al-
lograft demonstrating a mixed inflammatory cell infiltrate (lymphoid
cells, eosinophils, neutrophils) of the portal tract as well as endotheli-
alitis 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×).
 e207

e27 Primary Immunodeficiencies

Associated with or Secondary
to Other Diseases
Max D. Cooper, Harry W. Schroeder, Jr.

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. Table e27-1 categorizes conditions in which the immu-
nodeficiency is an integral component or a secondary consequence.

CHAPTER e27 Primary Immunodeficiencies Associated with or Secondary to Other Diseases

Gene mutations have now been identified as the cause of many pri-
mary immunodeficiencies. Table e27-2 categorizes currently recog-
nized aberrant genes according to the predominant immunologic
deficit or well-defined syndrome.

TABLE e27-1 IMMUNODEFICIENCIES ASSOCIATED WITH OR SECONDARY TO OTHER CONDITIONS a

Chromosomal Instability or Defective Repair Hypercatabolism of Immunoglobulin

Ataxia-telangiectasia (ATM) Familial hypercatabolism

Bloom syndrome (BLM helicase) Intestinal lymphangiectasia
DNA ligase IV deficiency (LIG4)
Immunodeficiency with Dermatologic Defects
Fanconi anemia (multiple complementation groups)
Immunodeficiency-centromeric instability-facial anomalies (ICF) syn- Dyskeratosis congenita
drome (DNMT3B DNA methyltransferase, other) Autosomal dominant (TERC)
Nijmegen breakage syndrome (Nibrin) Autosomal recessive
Seckel syndrome (ATR) X-linked, Zinsser-Cole-Engman syndrome (dyskerin)
Xeroderma pigmentosum (multiple complementation groups) Ectodermal dysplasia, anhidrotic, with T cell deficiency, autosomal domi-
nant (NFKBIA)
Chromosomal Defects Ectrodactyly-ectodermal dysplasia-clefting syndrome
Griscelli syndrome, partial albinism (RAB27A)
Deletions or rings of chromosome 18 (18p– and 18q–)
Netherton syndrome (SPINK5)
Down syndrome (trisomy 21)
Trichothiodystrophy, congenital ichthyosis (ERCC2/XPD or ERCC3/XPB)
Monosomy 22
Trisomy 8
Immunodeficiency with Generalized Growth Retardation
Turner syndrome (X chromosome monosomy)

Drug-Induced Hypogammaglobulinemia Schimke immuno-osseous dysplasia (SMARCAL1)

Dubowitz syndrome
Kyphomelic dysplasia with SCID
Antimalarial agents
Mulibrey nanism (TRIM37 )
Captopril
Progeria (Hutchinson-Gilford syndrome) (LMNA)
Carbamazepine
Thumb agenesis, short stature, and immunodeficiency
Glucocorticoids
X-linked agammaglobulinemia with growth hormone deficiency (BTK )
Fenclofenac
Gold salts
Infectious Diseases
Lamotrigine
Penicillamine Congenital rubella
Phenytoin Congenital infection with cytomegalovirus
Sulfasalazine Congenital infection with Toxoplasma gondii
Epstein-Barr virus
Hereditary Defects of T Cell Regulation Human immunodeficiency virus
Autoimmune Lymphoproliferative Syndrome (ALPS) Malignancy
ALPS 1A (CD95)
ALPS 1B (CD95L) Chronic lymphocytic leukemia
ALPS2A (CASP10) Immunodeficiency with thymoma
ALPS2B (CASP8)
Autoimmune polyendocrinopathy syndrome (APECED), type 1 (AIRE ) Other
Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
(IPEX) (FOXP3) Cartilage-hair hypoplasia (endoribonuclease RMRP)
Chronic mucocutaneous candidiasis
Hereditary or congenital hyposplenia or asplenia (Ivemark syndrome)
Hereditary Metabolic Defects Liver transplantation
Mannose binding lectin deficiency (MBL2)
α-Mannosidosis (MAN2B1)
Omenn syndrome (AIRE, Artemis, IL7RA, RAG 1/2)
Acrodermatitis enteropathica, zinc deficiency type (SLC39A4)
Propionyl-CoA carboxylase, beta subunit, deficiency (PCCB)
Chédiak-Higashi syndrome (CHS1)
Glycogen storage disease, type 1b (G6PT1)
Hyperzincemia with functional zinc depletion
Orotic aciduria I (UMPS)
Transcobalamin 2 deficiency (TCN2)
aMutant genes are indicated in parentheses.

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

 e208 TABLE e27-2 GENES OR GENETIC LOCI ASSOCIATED WITH PRIMARY IMMUNODEFICIENCIES
Gene or Gene or
Disorder Locus Chromosome Disorder Locus Chromosome
Severe Combined Immunodeficiency (SCID) Predominantly Antibody Deficiencies

Adenosine deaminase deficiency ADA 20q13.11 IgA deficiency/common variable MHC 6p21.3
Artemis deficiency (SCIDA) ARTEMIS 10p immunodeficiency
DNA ligase IV deficiency LIG4 13q22-q34 TACI deficiency (autosomal TNFRSF13B 17p11.2
CD45 deficiency CD45 1q31-32 dominant)
DNA-dependent protein kinase deficiency PRKDC 8q11 Common variable immunodeficiency
Interleukin receptor γ chain deficiency IL2RG Xq13 ICOS deficiency (autosomal recessive) ICOS 2q33
Janus-associated kinase 3 deficiency JAK3 19p13.1 BAFF-R TNFRSF13C 22q13.1-
Recombinase activating gene deficiency RAG1, RAG2 11p13 q13.31
CD19 deficiency (autosomal recessive) CD19 16p11.2
PART 14

Primary T Cell Immunodeficiency

Hyper-IgM syndrome
Activation-induced cytidine HIGM2 12p13
Antigen peptide transporter deficiency TAP1, TAP2 6p21.3 deaminase deficiency
CD8 deficiency CD8 2p12 CD40 deficiency HIGM3 20q12-q13.2
diGeorge syndrome DGCR1 22q11 Uracil-DNA glycosylase (UNG) HIGM5 12q23-q24.1
DGCR2 10p13 deficiency
Interleukin 7 receptor α deficiency IL7R 5p13 X-linked hyper-IgM syndrome (XHM) HIGM1 Xq26
LCK deficiency LCK 1p34.3-1p35 XHM with ectodermal dysplasia IKBKG, NEMO Xq28
Disorders of the Immune System, Connective Tissue, and Joints

Nude syndrome WHN 17q11-q12 (XHM-ED)

T cell receptor deficiency Immunoglobulin-associated beta (Igβ) CD79B 17q23
CD3γ CD3G 7q35 deficiency
CD3δ, CD3ε CD3D, CD3E 11q23 Immunoglobulin heavy chain deficiencies IGHG1 14q32.33
CD3ζ CD3Z 1q22-q23 BLNK deficiency BLNK 10q23.2
MHC class II deficiency Surrogate light chain deficiency IGLL1 22q11.21
MHC class II transactivator (group A) CIITA 16p13 LRRC8 truncation LRRC8 9q34.13
Regulatory factor X, ankyrin repeat– RFXANK 19p12 X-linked agammaglobulinemia BTK Xq21.3-q22
containing (group B)
Regulatory factor X, 5 (group C) RFX5 1q21.1-q21.3 Other Well-Defined Immunodeficiency Syndromes
Regulatory factor X–associated pro- RFXAP 13q14
tein (group D) Atypical mycobacteriosis, familial
Zeta chain–associated protein kinase ZAP70 2q12 Interferon γ receptor 1 deficiency IFNGR1 6q23-q24
deficiency Interferon γ receptor 2 deficiency IFNGR2 21q22.1-22.2
Purine nucleotide phosphorylase NP 14q13.1 Interleukin 12 deficiency IL12B 5q31-q33
deficiency Interleukin 12 receptor deficiency IL12RB1 19p13.1
STAT1 deficiency STAT1 2q32
Interleukin 1 receptor–associated kinase IRAK4 12q12
4 deficiency
WHIM syndrome CXCR4 2q21
Wiskott-Aldrich syndrome WAS Xp11.23-
p11.22
X-linked lymphoproliferative syndrome SH2D1A/SAP Xq25

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


e28 Atlas of Clinical Imaging
of the Vasculitic Diseases
Carol A. Langford, Anthony S. Fauci
Diagnostic imaging represents a critical assessment tool in patients who
are known or suspected to have a systemic vasculitic disease. Imaging
contributes unique information about the patient that, when taken to-
gether with the history, physical examination, and laboratory determina-
tions, can guide the differential diagnosis and the subsequent assessment
or treatment plan. A diverse range of imaging techniques are utilized in
the assessment of vasculitis including plain radiography, ultrasonogra-
phy, CT, MRI, positron emission tomography, and catheter-directed dye
arteriography. These procedures have specific utilities that can allow dif-
fering perspectives on the spectrum and severity of vasculitis.
For vasculitic diseases that involve the large- or medium-sized
blood vessels, arteriography provides information regarding blood
vessel stenoses or aneurysms that can support the diagnosis. Catheter-
directed dye arteriography offers the most precise information regard-
FIGURE e28-1 Bilateral nodular infiltrates seen on computed to-
mography of the chest in a 40-year-old woman with Wegener’s granu-
lomatosis.
FIGURE e28-2 Computed tomography of the chest in two patients
with Wegener’s granulomatosis demonstrating (A) single and (B) mul-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
ing the vessel lumen but carries risks related to dye exposure and the e209
invasive nature of the procedure. Advancements in MR and CT arteri-
ography have brought about noninvasive options to view the lumen
and vessel wall, thus enhancing the ability to perform serial studies for
patient monitoring.
Although vasculitis involving the small blood vessels cannot be di-
rectly visualized, diagnostic imaging plays an essential role in detecting
tissue injury that occurs as result of blood vessel and tissue inflamma-
tion. In Wegener’s granulomatosis, 80% of patients may have pulmo-
nary involvement during their disease course. Chest imaging should
be obtained whenever active disease is suspected, as up to one-third of
patients with radiographic abnormalities are asymptomatic. Pulmo-
CHAPTER e28 Atlas of Clinical Imaging of the Vasculitic Diseases
nary imaging is also important to detect complications of vasculitis
therapy such as opportunistic pneumonias as well as medication-relat-
ed 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.
With the rapid growth in precision and techniques, the role of diag-
nostic imaging will continue to enhance the ability of physicians to de-
tect, monitor, and diagnose vasculitis noninvasively.
tiple cavitary lung lesions.
 e210
PART 14
Disorders of the Immune System, Connective Tissue, and Joints

FIGURE e28-3 Bilateral ground-glass infiltrates due to alveolar This manifestation can occur in Wegener’s granulomatosis or micro-
hemorrhage from pulmonary capillaritis as seen in the same scopic polyangiitis.
patient by (A) chest radiograph and (B) computed tomography.

FIGURE e28-5 Computed tomography of the orbits in a patient

with Wegener’s granulomatosis who presented with right eye
proptosis. The image demonstrates inflammatory tissue extending
FIGURE e28-4 Computed tomography of the chest demonstrat-
from the ethmoid sinus through the lamina papyracea and filling the
ing a dense infiltrate with air bronchograms involving a seg-
orbital space.
ment of the right upper lobe due to bacterial pneumonia in an
immunosuppressed patient with Wegener’s granulomatosis.
Collapse of the left upper lobe secondary to endobronchial stenosis
from Wegener’s granulomatosis also is seen on this image.

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 pa- (B) Osteitis with obliteration of the left maxillary sinus in a patient with
tients with Wegener’s granulomatosis. (A) Mucosal thickening of long-standing sinus disease.
the bilateral maxillary sinuses and a perforation of the nasal septum.

FIGURE e28-8 Arteriogram of a 40-year-old man with polyarteritis

nodosa demonstrating microaneurysms in the hepatic circulation.
FIGURE e28-7 Computed tomography of the chest demonstrat-
ing a large pericardial effusion in a patient with Churg-Strauss
syndrome. Cardiac involvement is an important cause of morbidity
and mortality in Churg-Strauss syndrome and can include myocarditis,
endocarditis, and pericarditis.

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 e212
PART 14
Disorders of the Immune System, Connective Tissue, and Joints

FIGURE e28-9 Cerebral arteriogram demonstrating beading along

branches of the internal carotid artery in a patient with isolated central FIGURE e28-11 Magnetic resonance imaging demonstrating ex-
nervous system vasculitis. tensive aneurysmal disease of the thoracic aorta in an 80-year-
old female. The patient had been diagnosed with biopsy-proven
giant cell arteritis 10 years prior to presenting with this aneurysm.

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.

FIGURE e28-12 Arteriogram of the aortic arch demonstrating

complete occlusion of the left common carotid artery just after
its origin from the aorta. This 20-year-old female presented with
syncope and was subsequently diagnosed with Takayasu’s arteritis.

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

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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 ab-

dominal aorta in a 25-year-old female with Takayasu’s arteritis.

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

 e215

e29 ofAtlasMetabolic
of Clinical Manifestations
Diseases
J. Larry Jameson

The term metabolism is derived from the Greek metabol, to change. It

includes the broad array of chemical pathways that are necessary for
normal development and homeostasis. In practice, clinicians generally
use the term metabolism in reference to energy utilization for anabo-
lism or catabolism. Alternatively, intermediary metabolism describes
the myriad cellular pathways that convert energy sources from one
form to another (e.g., citric acid cycle). The emerging field of metabo-
lomics is based on the premise that the identification and measure-
ment of metabolic products will enhance our understanding of
physiology and disease.
Over the years, the classification of metabolic diseases has extended FIGURE e29-1 “Gauntlet” of pellagra (niacin deficiency). Indu-
beyond traditional pathways involved in fuel metabolism to include rated, lichenified, pigmented, and scaly skin on the dorsa of the hands.
disorders such as lysosomal storage diseases or connective tissue dis- See Chap. 71.
eases. Thus, metabolic diseases really reflect disorders of cell biology.

CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases

For example, lysosomal storage diseases (Chap. 355) result from a va-
riety of defects, usually in a lysosomal enzyme, causing accumulation
of a substrate within the lysosome. Certain lipodystrophies and car-
diomyopathies can be caused by mutations in lamin A, a structural
protein in the nuclear envelope. Membrane defects (Chap. 359), usual-
ly involving transporters of amino acids, sugars, or ions, cause dis-
orders such as cystinuria, Hartnup disease, or Wilson disease.
Connective tissue diseases (Chap. 357) frequently involve defects in
collagen synthesis or structure (osteogenesis imperfecta, Ehlers-Dan-
los syndrome, Alport syndrome) or in other extracellular matrix
structural proteins such as fibrillin (Marfan syndrome). Many meta-
bolic disorders originate from defects in enzymes involved in the syn-
thesis or degradation of amino acids, carbohydrates, lipids, purines, or
pyrimidines. (Chaps. 353, 356, 358). Lipoprotein disorders (Chap.
350) are caused by defects in a wide array of cellular pathways includ-
ing membrane receptors (LDL-R), enzyme defects (lipoprotein lip-
ase), carrier proteins (apoB100), or transporters (ABCA1). In some
instances, metabolic abnormalities induce compensatory physiologic
responses that reflect the interactions of multiple different metabolic
pathways. For example, the metabolic syndrome (Chap. 236) includes
a constellation of clinical features (central obesity, hypertriglyceride-
mia, low HDL cholesterol, hyperglycemia, and hypertension). It likely
has multiple genetic and environmental origins. Cushing syndrome
reflects the metabolic effects of excess cortisol on multiple tissues
(Chap. 336).
This broader definition results in a plethora of metabolic diseases,
numbering in the thousands. Fortunately, comprehensive reference
sources exist, such as the Online Metabolic and Molecular Bases of In-
herited Disease (OMMBID): (http://genetics.accessmedicine.com/) and
the Online Mendelian Inheritance in Man (OMIM): (http://www.ncbi.
nlm.nih.gov/entrez/query.fcgi?db=OMIM). The study of metabolic dis-
eases has been invaluable for advancing our understanding of human
genetics by providing insight into principles such as patterns of inher-
itance, variable expressivity, phenotypic variation, and novel ap-
proaches to therapy, including screening programs, blood and organ
transplantation, gene therapy, and enzyme replacement (Chap. 62).
This atlas provides a visual survey of selected metabolic disorders FIGURE e29-2 Scurvy (vitamin C deficiency). Perifollicular hemor-
with references to the topics elsewhere in the text. The authors encour- rhage on the leg. The follicles are often plugged by keratin (perifollicu-
age submission of additional illustrations that might be used to facili- lar hyperkeratosis). This eruption occurred in a 46-year-old alcoholic,
tate learning among our peers and thereby enhance the recognition homeless male, who also had bleeding gums and loose teeth. See
and care of patients with these disorders. Chap. 71.

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

 e216

FIGURE e29-5 Gout. The finger is an unusual site for gouty arthritis. Ex-
amination of the synovial fluid confirmed the diagnosis. See Chaps.
327 and 353. (Courtesy of Alan B. Storrow, MD; with permission.)
PART 15

FIGURE e29-3 Podagra with gouty inflammation of the first

Endocrinology and Metabolism

metatarsophalangeal (MTP) joint. Note the swelling and erythema

of the left first MTP. See Chaps. 327 and 353. (Courtesy of Kevin J. Knoop,
MD, MS; with permission.)

FIGURE e29-6 Cushing’s syndrome. Plethoric moon facies with ery-

thema and telangiectases of cheek and forehead; the face and neck
and supraclavicular areas (not depicted here) show increased deposi-
tion of fat. See Chap. 336.

FIGURE e29-4 Gout. Large tophi of gout located in and around the
right knee. See Chaps. 327 and 353. (Courtesy of Daniel L. Savitt, MD;
with permission.)

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

 e217

CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases

FIGURE e29-8 Patient with multiple endocrine neoplasia 2B syn-
drome. Note the multiple neuromas on the lips and tongue and the
marfanoid facies. See Chap. 345.
FIGURE e29-7 Necrobiosis lipoidica diabeticorum. A large, sym-
metric plaque with active tan-pink, well-demarcated, raised, firm bor-
ders and a yellow center in the pretibial regions of a 28-year-old
diabetic female. The central parts of the lesions are depressed with
atrophic changes of epidermal thinning and telangiectasis against yel-
low background. See Chap. 338.

FIGURE e29-9 Early and late radiographs of Paget disease of the

tibia, taken when the male patient was 45 years of age (A) and when
he was 65 years of age (B). See Chap. 349.

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 e218

FIGURE e29-11 Tendinous xanthomas. Large subcutaneous tumors

adherent to the Achilles tendons. See Chap. 350.
PART 15
Endocrinology and Metabolism

FIGURE e29-10 Bone scan of patient with severe Paget disease of

the skull, ribs, spine, pelvis, right femur, and acetabulum. Note
localization of bone-seeking isotope (99mTc-labeled bisphospho-
nate) in these areas. See Chap. 349.

FIGURE e29-12 Papular eruptive xanthomas. A. Multiple, discrete,

red-to-yellow papules becoming confluent on the elbow of an indi-
vidual with uncontrolled diabetes mellitus; lesions were present on
both elbows and buttocks. B. Papular eruptive xanthomas on the el-
bows and lower arms in an African American. This image is shown to
demonstrate the color of xanthomas in black skin. See Chap. 350.

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 e219

CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases

FIGURE e29-13 Forms of xanthomas and other lipid de-
posits frequently seen in familial hypercholesterolemia
homozygotes. A. Arcus corneae. B, C, E, and F. Cutaneous
planar xanthomas, which usually have a bright orange hue.
C and D. Tuberous xanthomas on the elbows. H. Tendon
and tuberous xanthomas. (Panel H reproduced through the
courtesy of Dr. A. Khachadurian; with permission.) See Chap.
350.

FIGURE e29-14 Examples of xanthomas in type III hyperlipo-

proteinemic subjects. A. Tuberoeruptive xanthomas of the elbows.
B. Tuberous xanthomas of the digits and xanthomas of the palmar
creases (xanthoma striata palmaris) (arrows). (Courtesy of Dr. Thomas P.
Bersot; with permission.) See Chap. 350.

FIGURE e29-15 A 17-year-old patient with abetalipoproteinemia

with generalized weakness, kyphoscoliosis, and lordosis. (Courtesy of
Drs. Peter Herbert, Gerd Assmann, Antonio M. Gotto, Jr., and Donald Fre-
drickson; with permission.) See Chap. 350.

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 e220

FIGURE e29-16 Porphyria cutanea tarda. Periorbital and malar viola-

ceous coloration, hyperpigmentation, and hypertrichosis on the face; bul-
lae, crusts, and scars on the dorsa of the hands. See Chap. 352.
PART 15
Endocrinology and Metabolism

FIGURE e29-18 Growth and development in two patients with

type Ia glycogen storage disease. A. Patient at age 7 years and at
39 years old. B. Another type Ia patient at age 10 years, and follow-up
at age 33 years. Both patients survive despite their disease not being
adequately treated. Note that the abdomen is less protuberant with
age. Hypoglycemia also improves with age. In adulthood, however,
both patients continue to be short, and both have gout, multiple liver
adenomas, and a progressive renal disease. See Chap. 356.

FIGURE e29-17 Mucopolysaccharidosis type IH (Hurler syndrome) in

a 4-year-old boy. Diagnosis was made at the age of 15 months, at which
time he had developmental delay, hepatomegaly, and skeletal involve-
ment. At the time of the picture, the patient had short stature, an enlarged
tongue, persistent nasal discharge, stiff joints, and hydrocephalus. Verbal
language skills consisted of four to five words. The patient had a severe
hearing loss and wore hearing aids. See Chap. 355.

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 e221

CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases

FIGURE e29-19 Progressive myopathy in a patient with type IIIa
glycogen storage disease. The patient has a debrancher deficiency
in both liver and muscle (subtype IIIa). As a child, he had hepatomeg-
aly, hypoglycemia, and growth retardation. After puberty, he no FIGURE e29-20 Skeletal features of Marfan syndrome in a 16-
longer had hepatomegaly, and his final height is normal. Note the year-old girl. Note the long limbs that are associated with dispropor-
muscle wasting in the lower legs and both hands at age 44 years (left tionate tall stature, long fingers, scoliosis, and genu valgum. See Chap.
panel); this progressed to a pronounced muscle atrophy at age 53 357.
years (two right panels). See Chap. 356.

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 e222
PART 15
Endocrinology and Metabolism

FIGURE e29-21 Marfan’s syndrome. A. Long, narrow face. B. Arach-

nodactyly and positive wrist sign. C. High-arched palate. D. Ectopia
lentis associated with aortic aneurysm and severe aortic regurgitation
in a teenage girl. See Chap. 357.

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


FIGURE e29-22 Ochronotic pigmentation of the femur of a 56-
year-old alkaptonuric patient. (Courtesy of Dr. H. W. Edmonds of the
Washington Hospital Center, Washington, DC; with permission.) See
Chap. 358.
FIGURE e29-23 Clusters of dark-red to blue angiokeratomas (te-
langiectases) on the buttocks (A) and in the umbilical area (B) of a
hemizygote with Fabry disease. See Chap. 355.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e223
CHAPTER e29 Atlas of Clinical Manifestations of Metabolic Diseases
FIGURE e29-24 Two patients with type B Niemann-Pick disease
(NPD). A. A 4.7-year-old patient with type B NPD. (From DS Fredrickson,
HR Sloan, in JB Stanbury et al: The Metabolic Basis of Inherited Disease, 3d
ed. New York, McGraw-Hill, 1972. Used by permission.) B. A 44-year-old
patient with type B NPD. See Chap. 355.
FIGURE e29-25 “Cherry red” spot in the eye of a Tay-Sachs patient.
See Chap. 355. (From http://www.nei.nih.gov/resources/eyegene.asp.)
FIGURE e29-26 Kayser-Fleischer ring. This develops in Wilson’s dis-
ease from copper deposition in Descemet’s membrane, producing
brownish discoloration of the peripheral cornea. It should not be con-
fused with the yellow-white lipid ring of arcus senilis, which is com-
mon in the elderly and occasionally signifies hyperlipidemia, especially
when it appears at a young age. See Chap. 354. (Courtesy of Jonathan
C. Horton, MD, PhD; with permission.)
 e224

FIGURE e29-27 Anterior view of patients with different forms of lipodys-

PART 15

trophy. A. Congenital generalized lipodystrophy: a 16-year-old girl with gener-

alized loss of fat, acromegaloid features, severe acanthosis nigricans affecting
axillae and abdomen, umbilical hernia. B. Familial partial lipodystrophy, Dunni-
gan 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, chin, supraclavic-
ular area, and labia majora. C. 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. D. Acquired partial lipodystrophy: a 30-
Endocrinology and Metabolism

year-old woman with onset of lipodystrophy at age 14 years shows loss of fat
from the face, neck, upper limbs, trunk, and anterior thighs. There is accumula-
tion of excess fat in the hips and other regions of lower limbs. (A from A Garg et
al: J Clin Endocrinol Metab 84:3390, 1999; with permission. B, from JM Peters et al: Nat
Genet 18;292, 1998; with permission.)

SOURCES FOR FIGURES

Figures e29-1; e29-2; e29-6; e29-7; e29-11; e29-12; e29-16: K Wolff,
RA Johnson, D Suurmond: Fitzpatrick’s Color Atlas & Synopsis of
Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.
www.accessmedicine.com

Figures e29-3; e29-4; e29-5: JE Tintinalli, GD Kelen, JS Stapcynski

(eds): Tintinalli’s Emergency Medicine: A Comprehensive Guide, 6th ed.
New York, McGraw-Hill, 2004. www.accessmedicine.com

Figures e29-8; e29-10: DG Gardner, D Shoback (eds): Greenspan’s Ba-

sic & Clinical Endocrinology, 8th ed. New York, McGraw-Hill, 2006.
www.accessmedicine.com

Figure e29-9: HB Skinner: Current Diagnosis & Treatment in Orthope-

dics, 4th ed. New York, McGraw-Hill, 2007. www.accessmedicine.com

Figures e29-13 to e29-15; e29-17 to e29-20; e29-22 to e29-24: CR

Scriver, AL Beaudet, WS Sly, D Valle (eds): The Metabolic and Molecu-
lar Bases of Inherited Disease online, 8th ed. New York, McGraw-
Hill.com. www.ommbid.com

Figure e29-21: V Fuster, RW Alexander, RA O’Rourke, et al (eds):

Hurst’s The Heart, 11th ed. New York, McGraw-Hill, 2004.
www.accessmedicine.com

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 e225

e30 Atlas of Neuroimaging

Andre Furtado, William P. Dillon

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-1 Limbic encephalitis (Chap. 97) poral lobes (arrowheads) including the hippocampi (left greater than
Coronal (A, B), axial FLAIR (C, D), and axial T2-weighted (E) MR images right) without significant mass effect (arrows). There was no enhance-
demonstrate abnormal high signal involving the bilateral mesial tem- ment on post-gadolinium images (not shown). (continued)

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 e226

FIGURE e30-1 (Continued )

PART 16
Neurologic Disorders

FIGURE e30-2 CNS tuberculosis (Chap. 158) Axial T1-weighted MR images post-gadolinium (B, C) demonstrate
Axial T2-weighted MRI (A) demonstrates multiple lesions (arrows) with ring enhancement of the lesions (arrows) and additional lesions in the
peripheral high signal and central low signal, located predominantly in subarachnoid space (arrowheads). (continued)
the cortex and subcortical white matter, as well as in the basal ganglia.

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 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).
Sagittal T1-weighted MR image post-gadolinium of the cer-
vical spine (E) demonstrates enhancement of the lesion in
the subarachnoid space at the level of T5 (arrow).

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 e228
PART 16
Neurologic Disorders

FIGURE e30-3 Neurosyphilis (Chap. 162) abnormal high signal in the basal ganglia bilaterally and in a wedge-
Case I shaped distribution in the right parietal lobe (arrows).
Axial T2-weighted MR images (A, B) demonstrate well-defined areas of Axial (C, D) T1-weighted images post-gadiolinium. (continued)

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 e229

FIGURE e30-3 (Continued )

Coronal (E, F) T1-weighted images post-gadolinium demonstrate irregular ring enhancement of the
lesions (arrows).

CHAPTER e30 Atlas of Neuroimaging

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

 e230
PART 16
Neurologic Disorders

FIGURE e30-4 Neurosyphilis (Chap. 162)

Case II
Axial T2-weighted MRI (A) demonstrates a dural-based, peripherally
hyperintense and centrally hypointense lesion located lateral to the
left frontal lobe (arrows).
Axial (B) and coronal (C) T1-weighted MR images post-gadolinium
demonstrate peripheral enhancement of the lesion (arrows).

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 e231

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-5 Histoplasmosis of the pons (Chap. 192)
Axial FLAIR (A) and T2-weighted (B) MR images demonstrate a low sig-
nal mass in the right pons (arrow) with surrounding vasogenic edema.
Axial T1-weighted MR image post-gadolinium (C) demonstrates ring
enhancement of the lesion in the right pons (arrows). Of note, there
was no evidence of restricted diffusion (not shown).

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 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 peri-
mesencephalic cisterns (arrows), as well as the sylvian and interhemi-
spheric fissures.

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 e233

FIGURE e30-7 Candidiasis in a newborn (Chap. 196)

CHAPTER e30 Atlas of Neuroimaging
Axial T2-weighted MR image (A) demonstrates multiple punctate foci of
low signal diffusely distributed in the brain parenchyma (arrowheads).
Axial T1-weighted MR images post-gadolinium (B, C) demonstrate
marked enhancement of the lesions (arrowheads).
ADC map (D, E) demonstrates restricted diffusion of water molecules
in the lesions (arrowheads).

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 e234
PART 16
Neurologic Disorders

FIGURE e30-8 CNS aspergillosis (Chap. 197) Axial T2-weighted MR images (C, D) demonstrate intrinsic low signal in
Axial FLAIR MR images (A, B) demonstrate multiple areas of abnormal the lesions (arrows), suggesting the presence of blood products. Some
high signal in the basal ganglia as well as cortex and subcortical white of the lesions also show vasogenic edema. (continued)
matter (arrows). There is also abnormal high signal in the subarach-
noid space adjacent to the lesions (arrowhead) that can correspond to
blood or high protein content.

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 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. 197) B. T1-weighted image pre-gadolinium demonstrates enhancement of
Axial T2-weighted MR image (A) demonstrates an irregularly shaped lesion (arrow). (continued)
low signal lesion involving the left orbital apex (arrow).

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 e236

FIGURE e30-9 (Continued )

C. T1-weighted image post-gadolinium demonstrates enhancement
of lesion (arrow).
PART 16
Neurologic Disorders

FIGURE e30-10 Behçet’s disease (Chap. 320)

Axial FLAIR MRI demonstrates abnormal high signal involving the an-
terior pons (arrow); following gadolinium administration, the lesion
was nonenhancing (not shown). Brainstem lesions are typical of Beh-
çet’s disease, caused primarily by vasculitis and in some cases demye-
linating lesions.

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 e237

FIGURE e30-11 Neurosarcoid (Chap. 322) suppression demonstrate a homogeneously enhancing well circum-
Case I scribed mass centered in the left Meckel’s cave (arrows).
Axial (A) and coronal (B) T1-weighted images post-gadolinium with fat

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-12 Neurosarcoid (Chap. 322) fat suppression demonstrate a homogeneously enhancing mass in-
Case II volving the hypothalamus and the pituitary stalk (arrows). (continued)
Axial (A, B) and sagittal (C) T1-weighted images post-gadolinium with

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 e238

FIGURE e30-12 (Continued )

PART 16
Neurologic Disorders

FIGURE e30-13 Neurosarcoid (Chap. 322) expansion in the midbrain, dorsal pons, and pineal region (arrows)
Case III without significant mass effect. (continued)
Axial FLAIR images (A–E) demonstrate abnormal high signal and slight

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 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, dorsal pons,
and pineal region (arrows).

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PART 16
Neurologic Disorders

FIGURE e30-14 Neurosarcoid (Chap. 322) sule and globus pallidus, bilateral cerebral peduncles, bilateral gyrus
Case IV rectus, right frontal lobe periventricular white matter, and patchy areas
Axial T2-weighted images (A–D) demonstrate numerous areas of ab- in bilateral temporal lobes. (continued)
normal hyperintensity involving the corpus callosum, left internal cap-

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 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.

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 e242
PART 16

FIGURE e30-15 Histiocytosis (Chap. 334)

Sagittal T1-weighted image (A) demonstrates enlargement of the pi-
tuitary stalk (arrow) and absence of the posterior pituitary intrinsic T1
hyperintensity (arrowhead).
Sagittal and coronal T1-weighted images post-gadolinium (B, C)
demonstrate enhancement of the pituitary stalk and infundibulum
(arrows).
Neurologic Disorders

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 e243

FIGURE e30-16 Middle cerebral artery stenosis (Chap. 364)

Time-of-flight (TOF) MR angiography (MRA) (A, B) reveals narrowing
within the left M1 segment that is likely secondary to atherosclerosis
(arrows).

CHAPTER e30 Atlas of Neuroimaging

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 e244
PART 16
Neurologic Disorders
FIGURE e30-17 Lacunar infarction (Chap. 364)
Axial noncontrast CT (A) demonstrates abnormal hypodensity involv-
ing the left anterior putamen and anterior limb of internal capsule
with ex-vacuo dilatation of the adjacent frontal horn of the left lateral
ventricle, suggestive of an old infarction (arrow). A small area of slight
hypodensity is also seen in the posterior limb of the right internal cap-
sule that can correspond to an acute infarct (arrowhead).
Axial FLAIR MRI (B) demonstrates abnormal high signal involving the
left anterior putamen and anterior limb of internal capsule with ex-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
vacuo dilatation of the adjacent frontal horn of the left lateral ventricle,
suggestive of an old infarction (arrow). A small area of slight hyperin-
tensity is also seen in the posterior limb of the right internal capsule
that can correspond to an acute lacunar infarct (arrowhead).
Diffusion-weighted image (C) and apparent diffusion coefficient (ADC)
map (D) demonstrate restricted water motion in the lesion of the pos-
terior limb of the right internal capsule, strongly suggestive for an
acute lacunar infarct (arrowhead). There is no evidence of restricted
diffusion in the old infarct (arrow).
 e245

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-18 Cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL) (Chap.
364)
Axial T2-weighted MR images (A, B) demonstrate multiple patchy areas
of abnormal high signal in the periventricular white matter (arrows).
Coronal FLAIR MRI (C, D) demonstrates multiple patchy areas of abnor-
mal high signal in the periventricular white matter bilaterally, includ-
ing the temporal lobes (arrows). In some of these areas, there are small
areas of tissue loss (encephalomalacia) (arrowheads).

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 e246
PART 16

FIGURE e30-19 CNS vasculitis (Chap. 364)

Axial noncontrast CT (A) demonstrates a large hyperdense intraparen-
chymal hematoma surrounded by hypodense vasogenic edema in
the right parietal lobe.
Neurologic Disorders

Axial T2-weighted MRI (B) demonstrates a large hypointense intra-

parenchymal hematoma surrounded by hyperintense vasogenic
edema in the right parietal lobe.
Conventional angiography (C) demonstrates multiple segments of in-
tracranial arterial narrowing, some of which have associated adjacent
areas of focal arterial dilatation. These abnormalities are suggestive of
vasculitis.

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FIGURE e30-20 Superior sagittal sinus thrombosis (Chap. 364)
Noncontrast CT of the head (A) demonstrates increased density in the
superior sagittal sinus, suggestive of thrombosis (arrow), and small lin-
ear hyperdensities in some temporal lobe sulci, suggestive of sub-
arachnoid hemorrhage (arrowheads).
Axial T1-weighted MRI (B) demonstrates absence of flow void in the
superior sagittal sinus, suggestive of thrombosis.
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e247
CHAPTER e30 Atlas of Neuroimaging
Coronal FLAIR images (C, D) demonstrate areas of abnormal high sig-
nal involving the gray and the subcortical white matter of the right
frontal and left parietal lobes, as well as the adjacent sulci. These find-
ings are suggestive of vasogenic edema with subarachnoid hemor-
rhage (arrowheads). (continued)
 e248
PART 16
Neurologic Disorders

FIGURE e30-20 (Continued)

Diffusion-weighted images (E, F) and ADC maps (G, H) demonstrate restricted diffusion of the abnormal
areas on FLAIR, suggestive of infarct. (continued)

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 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, and
left transverse sinus and jugular vein.
Axial (J) and coronal (K) T1-weighted images post-gadolinium demon-
strate a filling defect in the superior sagittal sinus, suggestive of throm-
bosis.

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 e250

FIGURE e30-21 Multiple system atrophy (Chap. 366) Sagittal T1-weighted MR image (B) demonstrates pontine atrophy and
Axial T2-weighted MR image (A) reveals symmetric poorly circum- enlarged cerebellar fissures as a result of cerebellar atrophy (arrows).
scribed abnormal high signal in the middle cerebellar peduncles bilat-
erally (arrowheads).
PART 16
Neurologic Disorders

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

 e251

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-22 Huntington’s disease (Chap. 367)
Axial noncontrast CT (A) demonstrates symmetric bilateral severe atro-
phy involving the caudate nuclei, putamen, and globus pallidi bilater-
ally with consequent enlargement of the frontal horns of the lateral
ventricles (arrows). There is also diffuse prominence of the sulci indi-
cating generalized cortical atrophy.
Axial (B) and coronal (C) FLAIR images demonstrate bilateral symmet-
ric 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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 e252
PART 16
Neurologic Disorders

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 evi-
dence 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). Al-
though these findings are highly suggestive of Bell’s palsy, the diagno-
sis is established on clinical grounds.

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 e253

FIGURE e30-24 Spinal cord infarction (Chap. 372) onstrates mild enhancement (arrow).
Sagittal T2-weighted MR image of the lumbar spine (A) demonstrates Sagittal diffusion-weighted MR image of the lumbar spine (C) demon-
poorly defined areas of abnormal high signal in the conus medullaris strates restricted diffusion (arrow) in the areas of abnormal high signal
and mild cord expansion (arrow). on the T2-weighted image (A).

CHAPTER e30 Atlas of Neuroimaging

T1-weighted MR image of the lumbar spine post-gadolinium (B) dem-

FIGURE e30-25 Acute transverse myelitis (Chap. 372) Sagittal T1-weighted MR image post-gadolinium (B) demonstrates ab-
Sagittal T2-weighted MR image (A) demonstrates abnormal high sig- normal enhancement in the posterior half of the cord from C2 to T1
nal in the cervical cord extending from C1 to T1 with associated cord (arrows).
expansion (arrows).

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 e254
PART 16
Neurologic Disorders

FIGURE e30-26 Acute disseminated encephalomyelitis (ADEM)
(Chap. 375)
Axial T2-weighted (A) and coronal FLAIR (B) images demonstrate ab-
normal 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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 e255

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-27 Balo’s concentric sclerosis (a variant of multiple scle-
rosis) (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 ventri-
cles, and with little mass effect.
Axial (B) and sagittal (C–E) T2-weighted MR images demonstrate mul-
tiple 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 sclero-
sis (arrows). (continued)

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 e256
PART 16
Neurologic Disorders

FIGURE e30-27 (Continued) demonstrate abnormal enhancement of all lesions with some of the
Sagittal (F) and axial (G, H) T1-weighted MR images post-gadolinium lesions demonstrating concentric ring enhancement (arrows).

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 e257

CHAPTER e30 Atlas of Neuroimaging

FIGURE e30-28 Hashimoto’s encephalopathy (Chap. 376)
Axial FLAIR (A) demonstrates focal area of abnormal high signal involv-
ing the gray and white matter in the left frontal lobe. There is also a
small area of abnormal high signal in the precentral gyrus.
Axial T1-weighted images (B, C) pre- and post-gadolinium demon-
strate cortical/pial enhancement in the region of high signal on FLAIR.

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 e258
PART 16
Neurologic Disorders

FIGURE e30-29 Brachial plexopathy (Chap. 379) mal high signal involving the right C6, C7, and C8 nerve roots, and
Axial (A), sagittal (B), and coronal (C, D) short tau inversion recovery the trunks and divisions that originate from these roots (arrows).
(STIR) MR images demonstrate abnormal enlargement and abnor- (continued)

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

 e259

FIGURE e30-29 (Continued)

Diffusion-weighted MR imaging (E) demonstrates abnormal reduced
diffusion within the right C6, C7, C8 nerve roots and their correspond-
ing trunks and divisions (arrow). These findings are compatible with ra-
diation-induced brachial plexopathy.

CHAPTER e30 Atlas of Neuroimaging

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

 commonly include hyperventilation (for 3 or 4 min), photic stimula- e261

e31 Electrodiagnostic Studies

of Nervous System
Disorders: EEG, Evoked
tion, sleep, and sleep deprivation on the night prior to the recording.
Electroencephalography is relatively inexpensive and may aid clini-
cal management in several different contexts.

THE EEG AND EPILEPSY

Potentials, and EMG The EEG is most useful in evaluating patients with suspected epilepsy.
Michael J. Aminoff The presence of electrographic seizure activity—i.e., of abnormal, repet-
itive, rhythmic activity having an abrupt onset and termination and a
characteristic evolution—clearly establishes the diagnosis. The absence
of such electrocerebral accompaniment does not exclude a seizure disor-
ELECTROENCEPHALOGRAPHY der, however, 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. With generalized ton-
is easily recorded from electrodes placed on the scalp. The potential ic-clonic seizures, however, the EEG is always abnormal during the ep-
difference between pairs of electrodes on the scalp (bipolar derivation) isode. It is often not possible to obtain an EEG during clinical events
or between individual scalp electrodes and a relatively inactive com- that may represent seizures, especially when such events occur unpre-
mon reference point (referential derivation) is amplified and displayed dictably or infrequently. Continuous monitoring for prolonged peri-
on a computer monitor, oscilloscope, or paper. 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. The of portable equipment to record the EEG continuously on cassettes for
rhythmic activity normally recorded represents the postsynaptic po- 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. Monitoring
is characterized by its frequency. In normal awake adults lying quietly by these means is sometimes helpful in confirming that seizures are
with the eyes closed, an 8- to 13-Hz alpha rhythm is seen posteriorly in occurring, characterizing the nature of clinically equivocal episodes,
the EEG, intermixed with a variable amount of generalized faster (be- and determining the frequency of epileptic events.
ta) activity (>13 Hz); the alpha rhythm is attenuated when the eyes are The EEG findings may also be helpful in the interictal period by
opened (Fig. e31-1). During drowsiness, the alpha rhythm is also at- showing certain abnormalities that are strongly supportive of a diag-
tenuated; with light sleep, slower activity in the theta (4–7 Hz) and nosis of epilepsy. Such epileptiform activity consists of bursts of abnor-
delta (<4 Hz) ranges becomes more conspicuous. mal discharges containing spikes or sharp waves. The presence of
The EEG is best recorded from several different electrode arrange- epileptiform activity is not specific for epilepsy, but it has a much
ments (montages) in turn, and activating procedures are generally un- greater prevalence in epileptic patients than in normal individuals.

CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders

dertaken in an attempt to provoke abnormalities. Such procedures However, even in an individual who is known to have epilepsy, the ini-
tial routine interictal EEG may be nor-
mal up to 60% of the time. Thus, the
Eyes open EEG cannot establish the diagnosis of
Fp1-F3 F3-C3 epilepsy in many cases.
The EEG findings have been used in
F3-C3 C3-P3
classifying seizure disorders and select-
C3-P3 P3-O1 ing appropriate anticonvulsant medica-
P3-O1 F4-C4 tion for individual patients (Fig. e31-2).
Fp2-F4 C4-P4
The episodic generalized spike-wave ac-
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
P4-O2 CZ-T4 epileptiform discharges or ictal patterns
A B found in patients with complex partial
seizures. These latter seizures may have
no correlates in the scalp-recorded EEG
F3-A1 or may be associated with abnormal
Fp1-F3
C3-A1 F3-C3 rhythmic activity of variable frequency, a
C3-P3
localized or generalized distribution,
P3-A1
and a stereotyped pattern that varies
O1-A1 P3-O1
with the patient. Focal or lateralized epi-
Fp2-F4
F4-A2 leptogenic lesions are important to
F4-C4 recognize, especially if surgical treat-
C4-A2
C4-P4 ment is contemplated. Intensive long-
P4-A2 P4-O2 term monitoring of clinical behavior
O2-A2 and the EEG is required for operative
candidates, however, and this generally
C D
also involves recording from intracrani-
FIGURE e31-1 A. Normal EEG showing a posteriorly situated 9-Hz alpha rhythm that attenuates with ally placed electrodes (which may be
eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient with en- subdural, extradural, or intracerebral in
cephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a location).
patient with a right parietal glioma. D. Periodic complexes occurring once every second in a patient The findings in the routine scalp-
with Creutzfeldt-Jakob disease. Horizontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV in recorded EEG may indicate the prog-
other panels. (From Aminoff, 1999.) In this and the following figure, electrode placements are indicated nosis of seizure disorders: in general, a
at the left of each panel and accord with the international 10:20 system. A, earlobe; C, central; F, frontal; normal EEG implies a better prognosis
Fp, frontal polar; P, parietal; T, temporal; O, occipital. Right-sided placements are indicated by even than otherwise, whereas an abnormal
numbers, left-sided placements by odd numbers, and midline placements by Z. background or profuse epileptiform
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e262 A continuing in a comatose patient. In patients treated by pentobarbital-
F3-C3 induced coma for refractory status epilepticus, the EEG findings are
useful in indicating the level of anesthesia and whether seizures are oc-
C3-P3
curring. During status epilepticus, the EEG shows repeated electro-
P3-O1 graphic seizures or continuous spike-wave discharges. In nonconvulsive
F4-C4 status epilepticus, a disorder that may not be recognized unless an EEG
is performed, the EEG may also show continuous spike-wave activity
C4-P4
(“spike-wave stupor”) or, less commonly, repetitive electrographic sei-
P4-O2 zures (complex partial status epilepticus).
T3-CZ
THE EEG AND COMA
CZ-T4
In patients with an altered mental state or some degree of obtunda-
tion, the EEG tends to become slower as consciousness is depressed,
regardless of the underlying cause (Fig. e31-1). Other findings may
B
also be present and may suggest diagnostic possibilities, as when elec-
Fp1-F7 trographic seizures are found or there is a focal abnormality indicating
F7-T3 a structural lesion. The EEG generally slows in metabolic encephalop-
athies, and triphasic waves may be present. The findings do not permit
T3-T5 differentiation of the underlying metabolic disturbance but help to ex-
T5-O1 clude other encephalopathic processes by indicating the diffuse extent
of cerebral dysfunction. The response of the EEG to external stimula-
Fp2-F8 tion is helpful prognostically because electrocerebral responsiveness
F8-T4
implies a lighter level of coma than a nonreactive EEG. Serial records
provide a better guide to prognosis than a single record and supple-
T4-T6 ment the clinical examination in following the course of events. As the
T6-O2 depth of coma increases, the EEG becomes nonreactive and may show
a burst-suppression pattern, with bursts of mixed-frequency activity
separated by intervals of relative cerebral inactivity. In other instances
C there is a reduction in amplitude of the EEG until eventually activity
Fp1-A1 cannot be detected. Such electrocerebral silence does not necessarily
reflect irreversible brain damage, because it may occur in hypothermic
F7-A1 patients or with drug overdose. The prognosis of electrocerebral si-
PART 16

T3-A1 lence, when recorded using an adequate technique, depends upon the
clinical context in which it is found. In patients with severe cerebral
T5-A1
anoxia, for example, electrocerebral silence in a technically satisfactory
Fp2-A2 record implies that useful cognitive recovery will not occur.
In patients with clinically suspected brain death, an EEG, when re-
F8-A2
corded using appropriate technical standards, may be confirmatory by
T4-A2 showing electrocerebral silence. However, complicating disorders that
Neurologic Disorders

may produce a similar but reversible EEG appearance (e.g., hypother-

T6-A2
FIGURE e31-2 Electrographic seizures. A. Onset of a tonic seizure show-
ing generalized repetitive sharp activity with synchronous onset over
both hemispheres. B. Burst of repetitive spikes occurring with sudden
onset in the right temporal region during a clinical spell characterized by
transient impairment of external awareness. C. Generalized 3-Hz spike-
wave activity occurring synchronously over both hemispheres during an
absence (petit mal) attack. Horizontal calibration: 1 s; vertical calibration:
400 μV in A, 200 μV in B, and 750 μV in C. (From Aminoff, 1999.)
activity suggests a poor outlook. The EEG findings are not helpful in de-
termining which patients with head injuries, stroke, or brain tumors will
go on to develop seizures, because in such circumstances epileptiform
activity is commonly encountered regardless of whether seizures occur.
The EEG findings are sometimes used to determine whether anticonvul-
sant medication can be discontinued in epileptic patients who have been
seizure-free for several years, but the findings provide only a general
guide to prognosis: further seizures may occur after withdrawal of anti-
convulsant medication despite a normal EEG or, conversely, may not oc-
cur despite a continuing EEG abnormality. The decision to discontinue
anticonvulsant medication is made on clinical grounds, 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.
The EEG has no role in the management of tonic-clonic status epi-
lepticus except when there is clinical uncertainty whether seizures are
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
mia or drug intoxication) must be excluded. The presence of residual
EEG activity in suspected brain death fails to confirm the diagnosis
but does not exclude it. 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.
THE EEG IN OTHER NEUROLOGIC DISORDERS
In the developed countries, CT scanning and MRI have taken the place
of EEG as a noninvasive means of screening for focal structural abnor-
malities of the brain, such as tumors, infarcts, or hematomas (Fig. e31-
1). Nonetheless, the EEG is still used for this purpose in many parts of
the world, although infratentorial or slowly expanding lesions may fail
to cause any abnormalities. Focal slow-wave disturbances, a localized
loss of electrocerebral activity, or more generalized electrocerebral dis-
turbances are common findings but provide no reliable indication
about the nature of the underlying pathology.
In patients with an acute encephalopathy, focal or lateralized peri-
odic slow-wave complexes, sometimes with a sharpened outline, sug-
gest a diagnosis of herpes simplex encephalitis, and periodic
lateralized epileptiform discharges (PLEDs) are commonly found with
acute hemispheric pathology such as a hematoma, abscess, or rapidly
expanding tumor. The EEG findings in dementia are usually nonspe-
cific and do not distinguish between the different causes of cognitive
decline except in rare instances when, for example, the presence of
complexes occurring with a regular repetition rate (so-called periodic
complexes) supports a diagnosis of Creutzfeldt-Jakob disease (Fig.
e31-1) or subacute sclerosing panencephalitis. In most patients with
dementias, the EEG is normal or diffusely slowed, and the EEG find-
ings alone cannot indicate whether a patient is demented or distin-
guish between dementia and pseudodementia.
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 in-
dicate the pathologic basis of lesions involving them. Such evoked po-
tentials (EPs) are so small compared to the background EEG activity
that the responses to a number of stimuli have to be recorded and av-
eraged with a computer in order to permit their recognition and defi-
nition. The background EEG activity, which has no fixed temporal
relationship to the stimulus, is averaged out by this procedure.
Visual evoked potentials (VEPs) are elicited by monocular stimula-
tion with a reversing checkerboard pattern and are recorded from the
occipital region in the midline and on either side of the scalp. The
component of major clinical importance is the so-called P100 re-
sponse, a positive peak having a latency of approximately 100 ms. Its
presence, latency, and symmetry over the two sides of the scalp are
noted. Amplitude may also be measured, but changes in size are much
less helpful for the recognition of pathology. VEPs are most useful in
detecting dysfunction of the visual pathways anterior to the optic chi-
asm. In patients with acute severe optic neuritis, the P100 is frequently
lost or grossly attenuated; as clinical recovery occurs and visual acuity
improves, the P100 is restored but with an increased latency that gen-
erally remains abnormally prolonged indefinitely. The VEP findings
are therefore helpful in indicating previous or subclinical optic neuri-
tis. They may also be abnormal with ocular abnormalities and with
other causes of optic nerve disease, such as ischemia or compression
by a tumor. Normal VEPs may be elicited by flash stimuli in patients
with cortical blindness.
Brainstem auditory evoked potentials (BAEPs) are elicited by mon-
aural stimulation with repetitive clicks and are recorded between the
vertex of the scalp and the mastoid process or earlobe. A series of po-
tentials, designated by roman numerals, occurs in the first 10 ms after
the stimulus and represents in part the sequential activation of differ-
ent structures in the pathway between the auditory nerve (wave I) and
the inferior colliculus (wave V) in the midbrain. The presence, latency,
and interpeak latency of the first five positive potentials recorded at the
vertex are evaluated. The findings are helpful in screening for acoustic
neuromas, detecting brainstem pathology, and evaluating comatose
patients. The BAEPs are normal in coma due to metabolic/toxic disor-
ders or bihemispheric disease but abnormal in the presence of brain-
stem pathology.
Somatosensory evoked potentials (SEPs) are recorded over the scalp
and spine in response to electrical stimulation of a peripheral (mixed
or cutaneous) nerve. The configuration, polarity, and latency of the re-
sponses depend on the nerve that is stimulated and on the recording
arrangements. SEPs are used to evaluate proximal (otherwise inacces-
sible) portions of the peripheral nervous system and the integrity of
the central somatosensory pathways.
Clinical Utility of SEPs EP studies may detect and localize lesions in af-
ferent pathways in the central nervous system (CNS). They have been
used particularly to investigate patients with suspected multiple sclero-
sis (MS), the diagnosis of which requires the recognition of lesions in-
volving several different regions of the central white matter. In patients
with clinical evidence of only one lesion, the electrophysiologic recog-
nition of abnormalities in other sites helps to suggest or support the di-
agnosis but does not establish it unequivocally. Multimodality EP
abnormalities are not specific for MS; they may occur in AIDS, Lyme
disease, systemic lupus erythematosus, neurosyphilis, spinocerebellar
degenerations, familial spastic paraplegia, and deficiency of vitamin E
or B12, among other disorders. The diagnostic utility of the electro-
physiologic findings therefore depends on the circumstances in which
they are found. Abnormalities may aid in the localization of lesions to
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
broad areas of the CNS, but attempts at precise localization on electro- e263
physiologic grounds are misleading because the generators of many
components of the EP are unknown.
The EP findings are sometimes of prognostic relevance. Bilateral
loss of SEP components that are generated in the cerebral cortex im-
plies that cognition may not be regained in posttraumatic or postan-
oxic coma, and EP studies may also be useful in evaluating patients
with suspected brain death. In patients who are comatose for uncer-
tain reasons, preserved BAEPs suggest either a metabolic-toxic etiolo-
gy or bihemispheric disease. In patients with spinal cord injuries, SEPs
have been used to indicate the completeness of the lesion. The pres-
ence 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 other-
wise. In surgery, 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 avert-
ed or minimized.
Visual and auditory acuity may be determined using EP techniques
in patients whose age or mental state precludes traditional ophthalmo-
logic or audiologic examinations.
COGNITIVE EVOKED POTENTIALS
Certain EP components depend on the mental attention of the subject
and the setting in which the stimulus occurs, rather than simply on the
physical characteristics of the stimulus. 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. For clinical pur-
poses, attention has been directed particularly at the so-called P3 com-
CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders
ponent of the ERP, 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. The P3 component is pro-
longed in latency in many patients with dementia, whereas it is generally
normal in patients with depression or other psychiatric disorders that
might be mistaken for dementia. ERPs are therefore sometimes helpful
in making this distinction when there is clinical uncertainty, although a
response of normal latency does not exclude dementia.
MOTOR EVOKED POTENTIALS
The electrical potentials recorded from muscle or the spinal cord fol-
lowing stimulation of the motor cortex or central motor pathways are
referred to as motor evoked potentials. For clinical purposes such re-
sponses are recorded most often as the compound muscle action po-
tentials elicited by transcutaneous magnetic stimulation of the motor
cortex. A strong but brief magnetic field is produced by passing a cur-
rent through a coil, and this induces stimulating currents in the subja-
cent neural tissue. The procedure is painless and apparently safe.
Abnormalities have been described in several neurologic disorders
with clinical or subclinical involvement of central motor pathways, in-
cluding MS and motor neuron disease. In addition to a possible role in
the diagnosis of neurologic disorders or in evaluating the extent of
pathologic involvement, the technique provides information of prog-
nostic relevance (e.g., in suggesting the likelihood of recovery of motor
function after stroke) and is useful as a means of monitoring intraop-
eratively the functional integrity of central motor tracts.
ELECTROPHYSIOLOGIC STUDIES OF MUSCLE AND NERVE
The motor unit is the basic element subserving motor function. It is
defined as an anterior horn cell, its axon and neuromuscular junc-
tions, and all the muscle fibers innervated by the axon. The number of
motor units in a muscle ranges from approximately 10 in the extraoc-
ular muscles to several thousand in the large muscles of the legs. There
is considerable variation in the average number of muscle fibers within
the motor units of an individual muscle, i.e., in the innervation ratio
of different muscles. Thus the innervation ratio is <25 in the human
external rectus or platysma muscle and between 1600 and 1700 in the
 e264
A 100 µV
10 ms
B 100 µV
100 ms
100 µV
C D E may also be abnormal, depending on the duration of the neuropathic
10 ms
FIGURE e31-3 Activity recorded during EMG. A. Spontaneous fibrilla-
tion potentials and positive sharp waves. B. Complex repetitive dis-
charges recorded in partially denervated muscle at rest. C. Normal
triphasic motor unit action potential. D. Small, short-duration,
polyphasic motor unit action potential such as is commonly encoun-
tered in myopathic disorders. E. Long-duration polyphasic motor unit
action potential such as may be seen in neuropathic disorders.
medial head of the gastrocnemius muscle. The muscle fibers of indi-
vidual motor units are divided into two general types by distinctive
contractile properties, histochemical stains, and characteristic re-
sponses to fatigue. Within each motor unit, all of the muscle fibers are
of the same type.
ELECTROMYOGRAPHY
PART 16
The pattern of electrical activity in muscle [i.e., the electromyogram
(EMG)], both at rest and during activity, may be recorded from a nee-
dle electrode inserted into the muscle. The nature and pattern of ab-
normalities relate to disorders at different levels of the motor unit.
Relaxed muscle normally is electrically silent except in the end plate
region, but abnormal spontaneous activity (Fig. e31-3) occurs in vari-
ous neuromuscular disorders, especially those associated with denerva-
Neurologic Disorders
tion or inflammatory changes in affected muscle. 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 cer-
tain myopathic disorders, especially inflammatory disorders such as
polymyositis. After an acute neuropathic lesion, they are found earlier in
proximal rather than distal muscles and sometimes do not develop dis-
tally in the extremities for 4–6 weeks; once present, they may persist in-
definitely unless reinnervation occurs or the muscle degenerates so
completely that no viable tissue remains. Fasciculation potentials (which
reflect the spontaneous activity of individual motor units) are character-
istic of slowly progressive neuropathic disorders, especially those with
degeneration of anterior horn cells (such as amyotrophic lateral sclero-
sis). Myotonic discharges—high-frequency discharges of potentials de-
rived 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, rarer, disorders.
Slight voluntary contraction of a muscle leads to activation of a
small number of motor units. 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. e31-3). The parameters of normal mo-
tor unit action potentials depend on the muscle under study and age
of the patient, but their duration is normally between 5 and 15 ms,
amplitude is between 200 μV and 2 mV, and most are bi- or triphasic.
The number of units activated depends on the degree of voluntary ac-
tivity. 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. With a full contraction, so many
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
motor units are normally activated that individual motor unit action
potentials can no longer be distinguished, and a complete interference
pattern is said to have been produced.
The incidence of small, short-duration, polyphasic motor unit ac-
tion potentials (i.e., having more than four phases) is usually increased
in myopathic muscle, and an excessive number of units is activated for
a specified degree of voluntary activity. By contrast, 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 in-
crease in their firing rate, i.e., there is an incomplete or reduced inter-
ference pattern. The configuration and dimensions of the potentials
process and on whether reinnervation has occurred. The surviving
motor units are initially normal in configuration but, as reinnervation
occurs, they increase in amplitude and duration and become polypha-
sic (Fig. e31-3).
Action potentials from the same motor unit sometimes fire with a
consistent temporal relationship to each other, so that double, triple,
or multiple discharges are recorded, especially in tetany, hemifacial
spasm, or myokymia.
Electrical silence characterizes the involuntary, sustained muscle
contraction that occurs in phosphorylase deficiency, which is desig-
nated a contracture.
EMG enables disorders of the motor units to be detected and char-
acterized as either neurogenic or myopathic. In neurogenic disorders,
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, limb
plexus, and peripheral nerve to their terminal arborizations. The find-
ings do not enable a specific etiologic diagnosis to be made, however,
except in conjunction with the clinical findings and results of other
laboratory studies.
The findings may provide a guide to the severity of an acute disor-
der of a peripheral or cranial nerve (by indicating whether denerva-
tion 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. Such information is
important for prognostic purposes.
Various quantitative EMG approaches have been developed. The
most common is to determine the mean duration and amplitude of 20
motor unit action potentials using a standardized technique. The tech-
nique 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.
Scanning EMG is a computer-based technique that has been used to
study the topography of motor unit action potentials and, in particular,
the spatial and temporal distribution of activity in individual units. The
technique of single-fiber EMG is discussed separately below.
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. e31-4) per-
mits conduction velocity to be determined in the fastest-conducting
motor fibers between the points of stimulation. The latency and am-
plitude of the electrical response of muscle (i.e., 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. Sensory
nerve conduction studies are performed by determining the conduc-
tion 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. In adults, conduction
velocity in the arms is normally between 50 and 70 m/s, and in the legs
is between 40 and 60 m/s.
Nerve conduction studies complement the EMG examination, en-
abling the presence and extent of peripheral nerve pathology to be de-
termined. 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, peripheral sensory conduction
studies will be normal) and whether neuromuscular dysfunction relates
 Recording
electrodes
Reference Ground
Active
Cathode
Anode
Stimulating Stimulating
electrodes electrodes
Stimulation
site
Wrist
Below
elbow
Above
elbow
Axilla 5 mV
10 ms
FIGURE e31-4 Arrangement for motor conduction studies of the ulnar
nerve. Responses are recorded with a surface electrode from the abduc-
tor digiti minimi muscle to supramaximal stimulation of the nerve at dif-
ferent sites, and are shown in the lower panel. (From Aminoff, 1998.)
to peripheral nerve disease. In patients with a mononeuropathy, they
are invaluable as a means of localizing a focal lesion, determining the
extent and severity of the underlying pathology, providing a guide to
prognosis, and detecting subclinical involvement of other peripheral
nerves. They enable a polyneuropathy to be distinguished from a
mononeuropathy multiplex when this is not possible clinically, an im-
portant distinction because of the etiologic implications. Nerve con-
duction 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. They may suggest the un-
derlying pathologic basis in individual cases. Conduction velocity is of-
ten markedly slowed, terminal motor latencies are prolonged, and
compound motor and sensory nerve action potentials may be dis-
persed in the demyelinative neuropathies (such as in Guillain-Barré
syndrome, chronic inflammatory polyneuropathy, metachromatic leu-
kodystrophy, or certain hereditary neuropathies); conduction block is
frequent in acquired varieties of these neuropathies. By contrast, con-
duction velocity is normal or slowed only mildly, sensory nerve action
potentials are small or absent, and there is EMG evidence of denerva-
tion in axonal neuropathies such as occur in association with metabolic
or toxic disorders.
The utility and complementary role of EMG and nerve conduction
studies are best illustrated by reference to a common clinical problem.
Numbness and paresthesia of the little finger and associated wasting of
the intrinsic muscles of the hand may result from a spinal cord lesion,
C8/T1 radiculopathy, brachial plexopathy (lower trunk or medial
cord), or a lesion of the ulnar nerve. If sensory nerve action potentials
can be recorded normally at the wrist following stimulation of the digi-
tal fibers in the affected finger, the pathology is probably proximal to
the dorsal root ganglia, i.e., there is a radiculopathy or more central le-
sion; absence of the sensory potentials, by contrast, suggests distal pa-
thology. EMG examination will indicate whether the pattern of affected
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
muscles conforms to radicular or ulnar nerve territory, or is more ex- e265
tensive (thereby favoring a plexopathy). Ulnar motor conduction stud-
ies 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 sev-
eral 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, with
stimulation at a particular site. The electrophysiologic findings thus
permit a definitive diagnosis to be made and specific treatment institut-
ed in circumstances where there is clinical ambiguity.
F WAVE STUDIES
Stimulation of a motor nerve causes impulses to travel antidromically
(i.e., toward the spinal cord) as well as orthodromically (to the nerve
terminals). Such antidromic impulses cause a few of the anterior horn
cells to discharge, producing a small motor response that occurs con-
siderably later than the direct response elicited by nerve stimulation.
The F wave so elicited is sometimes abnormal (absent or delayed) with
proximal pathology of the peripheral nervous system, such as a radic-
ulopathy, and may therefore be helpful in detecting abnormalities
when conventional nerve conduction studies are normal. In general,
however, the clinical utility of F wave studies has been disappointing,
except perhaps in Guillain-Barré syndrome, where they are often ab-
sent or delayed.
H REFLEX STUDIES
The H reflex is easily recorded only from the soleus muscle (S1) in
normal adults. It is elicited by low-intensity stimulation of the tibial
nerve and represents a monosynaptic reflex in which spindle (Ia) affer-
CHAPTER e31 Electrodiagnostic Studies of Nervous System Disorders
ent fibers constitute the afferent arc and alpha motor axons the effer-
ent pathway. The H reflexes are often absent bilaterally in elderly
patients or with polyneuropathies and may be lost unilaterally in S1
radiculopathies.
MUSCLE RESPONSE TO REPETITIVE NERVE STIMULATION
The size of the electrical response of a muscle to supramaximal electri-
cal stimulation of its motor nerve relates to the number of muscle fi-
bers that are activated. Neuromuscular transmission can be tested by
several different protocols, but the most helpful is to record with sur-
face 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.
There is normally little or no change in size of the compound mus-
cle action potential following repetitive stimulation of a motor nerve
at 2–3 Hz with stimuli delivered at intervals after voluntary contrac-
tion of the muscle for about 20–30 s, 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. 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. In disorders of neuromuscular trans-
mission this safety factor is reduced. Thus in myasthenia gravis, repet-
itive stimulation, particularly at a rate of between 2 and 5 Hz, may lead
to a depression of neuromuscular transmission, with a decrement in
size of the response recorded from affected muscles. Similarly, imme-
diately after a period of maximal voluntary activity, single or repetitive
stimuli of the motor nerve may elicit larger muscle responses than be-
fore, indicating that more muscle fibers are responding. This postacti-
vation facilitation of neuromuscular transmission is followed by a
longer-lasting period of depression, maximal between 2 and 4 min af-
ter the conditioning period and lasting for as long as 10 min or so,
during which responses are reduced in size.
Decrementing responses to repetitive stimulation at 2–5 Hz are com-
mon in myasthenia gravis but may also occur in the congenital myas-
thenic syndromes. In Lambert-Eaton myasthenic syndrome, in which
there is defective release of acetylcholine at the neuromuscular junction,
the compound muscle action potential elicited by a single stimulus is
 e266 generally very small. With repetitive stimulation at rates of up to 10 Hz,
the first few responses may decline in size, but subsequent responses in-
crease. If faster rates of stimulation are used (20–50 Hz), the increment
may be dramatic so that the amplitude of compound muscle action po-
tentials eventually reaches a size that is several times larger than the ini-
tial response. In patients with botulism, the response to repetitive
stimulation is similar to that in Lambert-Eaton syndrome, although the
findings are somewhat more variable and not all muscles are affected.
SINGLE-FIBER ELECTROMYOGRAPHY
This technique is particularly helpful in detecting disorders of neuro-
muscular transmission. A special needle electrode is placed within a
muscle and positioned to record action potentials from two muscle fi-
bers belonging to the same motor unit. The time interval between the
two potentials will vary in consecutive discharges; this is called the
neuromuscular jitter. The jitter can be quantified as the mean differ-
ence between consecutive interpotential intervals and is normally be-
tween 10 and 50 μs. This value is increased when neuromuscular
transmission is disturbed for any reason, and in some instances im-
pulses in individual muscle fibers may fail to occur because of impulse
blocking at the neuromuscular junction. Single-fiber EMG is more
sensitive than repetitive nerve stimulation or determination of acetyl-
choline receptor antibody levels in diagnosing myasthenia gravis.
Single-fiber EMG can also be used to determine the mean fiber
density of motor units (i.e., mean number of muscle fibers per motor
unit within the recording area) and to estimate the number of motor
units in a muscle, but this is of less immediate clinical relevance.
PART 16
Neurologic Disorders
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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. The trigem-
inal and facial nerves constitute the afferent and efferent arcs of the re-
flex, respectively. Abnormalities of either nerve or intrinsic lesions of
the medulla or pons may lead to uni- or bilateral loss of the response,
and the findings may therefore be helpful in identifying or localizing
such pathology.
FURTHER READINGS
AMINOFF MJ: Electromyography in Clinical Practice: Electrodiagnostic
Aspects of Neuromuscular Disease, 3d ed. New York, Churchill Liv-
ingstone, 1998
——— (ed): Electrodiagnosis in Clinical Neurology, 5th ed. New York,
Churchill Livingstone, 2005
BROWN WF et al (eds): Neuromuscular Function and Disease. Philadel-
phia, Saunders, 2002
EBERSOLE JS, PEDLEY TA (eds): Current Practice of Clinical Electroen-
cephalography, 3d ed. Philadelphia, Lippincott Williams & Wilkins,
2003
HOLMES GL et al: Clinical Neurophysiology of Infancy, Childhood, and
Adolescence. Philadelphia, Butterworth Heinemann, 2006
KIMURA J: Electrodiagnosis in Diseases of Nerve and Muscle, 3d ed. New
York, Oxford University Press, 2001

e32 Technique of Lumbar Puncture
Elizabeth Robbins, Stephen L. Hauser
In experienced hands, lumbar puncture (LP) is usually a safe proce-
dure. Major complications are extremely uncommon but can include
cerebral herniation, injury to the spinal cord or nerve roots, hemor-
rhage, or infection. Minor complications occur with greater frequency
and can include backache, post-LP headache, and radicular pain or
numbness.
IMAGING AND LABORATORY STUDIES PRIOR TO LP
Patients with an altered level of consciousness, a focal neurologic deficit,
new-onset seizure, papilledema, or an immunocompromised state are at
increased risk for potentially fatal cerebellar or tentorial herniation fol-
lowing LP. Neuroimaging should be obtained in these patients prior to
LP to exclude a focal mass lesion or diffuse swelling. Imaging studies
should include the spine in patients with symptoms suggesting cord
compression, such as back pain, leg weakness, urinary retention, or in-
continence. In patients with suspected meningitis who require neuroim-
aging prior to diagnostic LP, administration of antibiotics, preferably
following blood culture, should precede the neuroimaging study.
Patients receiving therapeutic anticoagulation or those with coagu-
lation defects including thrombocytopenia are at increased risk of
post-LP spinal subdural or epidural hematomas, either of which can
produce permanent nerve injury and/or paralysis. If a bleeding disor-
der is suspected, the platelet count, international normalized ratio
(INR), and partial thromboplastin time should be checked prior to
lumbar puncture. There are no data available to assess the safety of LP
in patients with low platelet counts; a count of <20,000/μL is consid-
ered to be a contraindication to LP. Bleeding complications rarely oc-
cur in patients with platelet counts ≥ 50,000/μL and an INR ≤ 1.5.
Patients receiving low-molecular-weight heparin are at increased risk
of post-LP spinal or epidural hematoma, and doses should be held for
24 h before the procedure.
LP should not be performed through infected skin as organisms can
be introduced into the subarachnoid space (SAS).
ANALGESIA
Anxiety and pain can be minimized prior to beginning the procedure.
Anxiety can be allayed by the use of lorazepam, 1–2 mg given PO 30
min prior to the procedure or IV 5 min prior to the procedure. Topical
anesthesia can be achieved by the application of a lidocaine-based
cream. Lidocaine 4% is effective when applied 30 min prior to the pro-
cedure; lidocaine/prilocaine requires 60–120 min. The cream should
be applied in a thick layer so that it completely covers the skin; an oc-
clusive dressing is used to keep the cream in place.
POSITIONING
Proper positioning of the patient is essential. The procedure should be
performed on a firm surface; if the procedure is to be performed at the
bedside, the patient should be positioned at the edge of the bed and
not in the middle. The patient is asked to lie on his or her side, facing
away from the examiner, and to “roll up into a ball.” The neck is gently
ante-flexed and the thighs pulled up toward the abdomen; the shoul-
ders and pelvis should be vertically aligned without forward or back-
ward tilt (Fig. e32-1). The spinal cord terminates at approximately the
L1 vertebral level in 94% of individuals. In the remaining 6%, the co-
nus extends to the L2-L3 interspace. LP is therefore performed at or
below the L3-L4 interspace. A useful anatomic guide is a line drawn
between the posterior superior iliac crests, which corresponds closely
to the level of the L3-L4 interspace. The interspace is chosen following
gentle palpation to identify the spinous processes at each lumbar level.
An alternative to the lateral recumbent position is the seated posi-
tion. The patient sits at the side of the bed, with feet supported on a
chair. The patient is instructed to curl forward, trying to touch the nose
to the umbilicus. It is important that the patient not simply lean for-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Vertical alignment of e267
shoulders and pelvis
L3-L4
inner space
FIGURE e32-1 Proper positioning of a patient in the lateral decu-
bitus position. Note that the shoulders and hips are in a vertical
plane; the torso is perpendicular to the bed. (From Straus et al.)
ward onto a bedside table top, as this is not an optimal position for
opening up the spinous processes. LP is sometimes more easily per-
formed in obese patients if they are sitting. A disadvantage of the seated
position is that measurement of opening pressure may not be accurate.
In situations in which LP is difficult using palpable spinal landmarks,
bedside ultrasound to guide needle placement may be employed.
TECHNIQUE
Once the desired target for needle insertion has been identified, the ex-
aminer should put on sterile gloves. After cleansing the skin with pov-
idone-iodine or similar disinfectant, the area is draped with a sterile
cloth; the needle insertion site is blotted dry using a sterile gauze pad.
CHAPTER e32 Technique of Lumbar Puncture
Proper local disinfection reduces the risk of introducing skin bacteria
into the SAS or other sites. Local anesthetic, typically 1% lidocaine, 3–
5 mL total, is injected into the subcutaneous tissue; in nonemergency
situations a topical anesthetic cream can be applied (see above). When
time permits, pain associated with the injection of lidocaine can be
minimized by slow, serial injections, each one progressively deeper
than the last, over a period of ~5 min. Approximately 0.5–1 mL of li-
docaine is injected at a time; the needle is not usually withdrawn be-
tween injections. A pause of ~15 s between injections helps to
minimize the pain of the subsequent injection. The goal is to inject
each mini-bolus of anesthetic into an area of skin that has become
numb from the preceding injection. Approximately 5–10 mini-boluses
are injected, using a total of ~5 mL of lidocaine.
If possible, the LP should be delayed for 10–15 min following the
completion of the injection of anesthetic; this significantly decreases
and can even eliminate pain from the procedure. Even a delay of 5 min
will help to reduce pain.
The LP needle (typically 20- to 22-gauge) is inserted in the midline,
midway between two spinous processes, and slowly advanced. The
bevel of the needle should be maintained in a horizontal position, par-
allel to the direction of the dural fibers and with the flat portion of the
bevel pointed upward; this minimizes injury to the fibers as the dura is
penetrated. When lumbar puncture is performed in patients who are
sitting, the bevel should be maintained in the vertical position. In
1
most adults, the needle is advanced 4–5 cm (1 --2 –2 in.) before the SAS is
reached; the examiner usually recognizes entry as a sudden release of
resistance, a “pop.” If no fluid appears despite apparently correct nee-
dle placement, then the needle may be rotated 90°–180°. If there is still
no fluid, the stylet is reinserted and the needle is advanced slightly.
Some examiners halt needle advancement periodically to remove the
stylet and check for flow of cerebrospinal fluid (CSF). If the needle
cannot be advanced because it hits bone, if the patient experiences
sharp radiating pain down one leg, or if no fluid appears (“dry tap”),
the needle is partially withdrawn and reinserted at a different angle. If
on the second attempt the needle still hits bone (indicating lack of suc-
cess in introducing it between the spinous processes), then the needle
should be completely withdrawn and the patient should be reposi-
tioned. The second attempt is sometimes more successful if the patient
 e268 straightens the spine completely prior to repositioning. The needle can
then be reinserted at the same level or at an adjacent one.
Once the SAS is reached, a manometer is attached to the needle and
the opening pressure measured. The examiner should look for normal
oscillations in CSF pressure associated with pulse and respirations.
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.
CSF is allowed to drip into collection tubes; it should not be with-
drawn with a syringe. Depending on the clinical indication, fluid is then
obtained for studies including: (1) cell count with differential, (2) pro-
tein and glucose concentrations, (3) culture (bacterial, fungal, myco-
bacterial, viral), (4) smears (e.g., Gram’s and acid-fast stained smears),
(5) antigen tests (e.g., latex agglutination) (6) polymerase chain reaction
(PCR) amplification of DNA or RNA of microorganisms (e.g., herpes
simplex virus, enteroviruses), (7) antibody levels against microorgan-
isms, (8) immunoelectrophoresis for determination of γ-globulin level
and oligoclonal banding, and (9) cytology. Although 15 mL of CSF is
sufficient to obtain all of the listed studies, the yield of fungal and myco-
bacterial cultures and cytology increases when larger volumes are sam-
pled. In general 20–30 mL may be safely removed from adults.
A bloody tap due to penetration of a meningeal vessel (a “traumat-
ic tap”) may result in confusion with subarachnoid hemorrhage
(SAH). In these situations a specimen of CSF should be centrifuged
immediately after it is obtained; clear supernatant following CSF cen-
trifugation supports the diagnosis of a bloody tap, whereas xantho-
chromic supernatant suggests SAH. In general, bloody CSF due to the
penetration of a meningeal vessel clears gradually in successive tubes,
whereas blood due to SAH does not. In addition to SAH, xanthochro-
mic CSF may also be present in patients with liver disease and when
the CSF protein concentration is markedly elevated [>1.5–2.0 g/L
(150–200 mg/dL)].
PART 16
Prior to removing the LP needle, the stylet is reinserted to avoid the
possibility of entrapment of a nerve root in the dura as the needle is
being withdrawn; entrapment could result in a dural CSF leak, causing
headache. Some practitioners question the safety of this maneuver,
with its potential risk of causing a needle-stick injury to the examiner.
Injury is unlikely, however, given the flexibility of the small-diameter
stylet, which tends to bend, rather than penetrate, on contact. Follow-
Neurologic Disorders
ing LP, the patient is customarily positioned in a comfortable, recum-
bent position for 1 h before rising, although recent data suggests that
assuming a recumbent position may be unnecessary as it does not ap-
pear to affect the development of headache (see below).
POST-LP HEADACHE
The principal complication of LP is headache, occurring in 10–30% of
patients. Younger age and female gender are associated with an in-
creased risk of post-LP headache. Headache usually begins within 48 h
but may be delayed for up to 12 days. Head pain is dramatically posi-
tional; it begins when the patient sits or stands upright; there is relief
upon reclining or with abdominal compression. The longer the pa-
tient is upright, the longer the latency before head pain subsides. The
pain is usually a dull ache but may be throbbing; its location is occipi-
tofrontal. Nausea and stiff neck often accompany headache, and occa-
sionally, patients report blurred vision, photophobia, tinnitus, and
vertigo. Symptoms usually resolve over a few days but may on occasion
persist for weeks to months.
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 sub-
arachnoid space. Loss of CSF volume decreases the brain’s supportive
cushion, so that when a patient is upright there is probably dilation
and tension placed on the brain’s anchoring structures, the pain-sensi-
tive dural sinuses, resulting in pain. Although intracranial hypoten-
sion is the usual explanation for severe LP headache, the syndrome can
occur in patients with normal CSF pressure.
Post-LP headache usually resolves without specific treatment, and
care is largely supportive with oral analgesics [acetaminophen, nonster-
oidal anti-inflammatory drugs, opioids (Chap. 12)] and antiemetics.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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. For some
patients beverages with caffeine can provide temporary pain relief.
For patients with persistent pain, treatment with IV caffeine (500
mg in 500 mL saline administered over 2 h) may be effective; atrial fi-
brillation is an uncommon side effect. For patients who do not re-
spond to caffeine, an epidural blood patch accomplished by injection
of 15 mL of autologous whole blood is usually effective. This proce-
dure is usually performed by a pain specialist or anesthesiologist. The
mechanism for these treatment effects is not straightforward. The
blood patch has an immediate effect, making it unlikely that sealing
off a dural hole with blood clot is its sole mechanism of action.
Strategies to decrease the incidence of post-LP headache are listed in
Table e32-1. Use of a smaller caliber needle is associated with a lower risk:
in one study, the risk of headache following use of a 20- or 22-gauge stan-
dard (Quinke) needle was 20–40%, compared to 5–12% when a 24- to 27-
gauge needle was used. The smallest gauge needles usually require the use
of an introducer needle and are associated with a slower CSF flow rate.
Use of an “atraumatic” (Sprotte, “pencil point,” or “non-cutting”) needle
also reduces the incidence of moderate to severe headache compared with
standard LP (Quinke, or “traumatic”) needles (Fig. e32-2). However, be-
cause atraumatic needles are more difficult to use, more attempts may be
required to perform the LP, particularly in overweight patients. It may also
be necessary to use an introducer with the atraumatic needle, which does
not have the customary cutting, beveled tip. There is a low risk of needle
damage, e.g., breakage, with the Sprotte atraumatic needle.
Another strategy to decrease the incidence of headache is to replace
the stylet before removing the LP needle. Studies comparing mobiliza-
tion immediately following LP with bed rest for up to 4 h show no sig-
nificant differences in the incidence of headache, suggesting that the
customary practice of remaining in a recumbent position post-LP may
be unnecessary.
NORMAL VALUES
(See Table e32-2) In uninfected CSF, the normal white blood cell count is
fewer than five mononuclear cells (lymphocytes and monocytes) per μL.
Polymorphonuclear leukocytes (PMNs) are not found in normal uncon-
centrated CSF; however, rare PMNs can be found in centrifuged or con-
centrated CSF specimens such as those utilized for cytologic examination.
FIGURE e32-2 Comparison of the standard (“traumatic” or
Quinke) LP needle with the “atraumatic” (Sprotte). The “atrau-
matic” needle has its opening on the top surface of the needle, a de-
sign intended to reduce the chance of cutting dural fibers that, by
protruding through the dura, could be responsible for subsequent
CSF fluid leak and post-LP headache. (From Thomas et al.)
TABLE e32-2 CEREBROSPINAL FLUID a Red blood cells (RBC) are not normally present in CSF; if RBC are present e269
from a traumatic tap, their number decreases as additional CSF is collect-
Constituent SI Units Conventional Units
ed. CSF glucose concentrations <2.2 mmol/L (<40 mg/dL) are abnormal.
Glucose 2.22–3.89 mmol/L 40–70 mg/dL
Lactate 1–2 mmol/L 10–20 mg/dL
Total protein FURTHER READINGS
Lumbar 0.15–0.5 g/L 15–50 mg/dL
Cisternal 0.15–0.25 g/L 15–25 mg/dL
ARMON C, EVANS RW: Addendum to assessment: Prevention of post-
Ventricular 0.06–0.15 g/L 6–15 mg/dL lumbar puncture headaches: Report of the Therapeutics and Tech-
Albumin 0.066–0.442 g/L 6.6–44.2 mg/dL nology Assessment Subcommittee of the American Academy of
IgG 0.009–0.057 g/L 0.9–5.7 mg/dL Neurology. Neurology 65:510, 2005
IgG indexb 0.29–0.59 ELLENBY MS et al: Lumbar puncture (video). N Engl J Med 355:e12, 2006
Oligoclonal bands <2 bands not present EVANS RW et al: Assessment: Prevention of post-lumbar puncture
(OGB) in matched serum
sample
headaches: Report of the Therapeutics and Technology Assessment
Ammonia 15–47 μmol/L 25–80 μg/dL Subcommittee of the American Academy of Neurology. Neurology
CSF pressure 50–180 mmH2O 55:909, 2000
CSF volume (adult) ∼150 mL LAVI R et al: Standard vs atraumatic Whitacre needle for diagnostic
Red blood cells 0 0 lumbar puncture: A randomized trial. Neurology 67:1492, 2006
Leukocytes PETERSON MA, ABELE J: Bedside ultrasound for difficult lumbar punc-
Total 0–5 mononuclear
cells per mm3
ture. J Emerg Med 28:197, 2005
Differential RICHMAN JM et al: Bevel direction and postdural puncture headache:
Lymphocytes 60–70% A meta-analysis. Neurologist 12:224, 2006
Monocytes 30–50% STRAUS SE et al: How do I perform a lumbar puncture and analyze the
Neutrophils None results to diagnose bacterial meningitis? JAMA 296:2012, 2006
aSince cerebrospinal fluid concentrations are equilibrium values, measurements of the STRUPP M et al: Incidence of post-lumbar puncture syndrome re-
same parameters in blood plasma obtained at the same time are recommended. duced by reinserting the stylet: A randomized prospective study of
However, there is a time lag in attainment of equilibrium, and cerebrospinal levels of 600 patients. J Neurol 245:589, 1998
plasma constituents that can fluctuate rapidly (such as plasma glucose) may not THOMAS SF et al: Randomised controlled trial of atraumatic versus
achieve stable values until after a significant lag phase. standard needles for diagnostic lumbar puncture. BMJ 321:986, 2000
bIgG index = CSF IgG(mg/dL) × serum albumin(g/dL)/Serum IgG(g/dL)
TURNBULL DK, SHEPHERD DB: Post-dural puncture headache: Patho-
× CSF albumin(mg/dL).
genesis, prevention and treatment. Br J Anaesth 91:718, 2003

CHAPTER e32 Technique of Lumbar Puncture

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

\
e33 Special Issues in Inpatient
Neurologic Consultation
S. Andrew Josephson, Martin A. Samuels
Inpatient neurologic consultations usually involve questions about spe-
cific disease processes or prognostication after various cerebral injuries.
Common reasons for neurologic consultation include stroke (Chap.
364), seizures (Chap. 363), altered mental status (Chap. 26), headache
(Chap. 15), and management of coma and other critical conditions
(Chaps. 268 and 269). This chapter focuses on additional common rea-
sons for consultation that are not addressed elsewhere in the text.
CONSULTATIONS REGARDING
CENTRAL NERVOUS SYSTEM DYSFUNCTION
HYPERPERFUSION STATES
A group of neurologic disorders shares the common feature of hyper-
perfusion playing a key role in pathogenesis. These seemingly diverse
syndromes include hypertensive encephalopathy, eclampsia, post-ca-
rotid endarterectomy syndrome, and toxicity from calcineurin-inhibi-
tor medications. Modern imaging techniques and experimental
models suggest that vasogenic edema is usually the primary process
leading to neurologic dysfunction; therefore prompt recognition and
management of this condition should allow for clinical recovery if su-
perimposed hemorrhage or infarction has not occurred.
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. In patients with
chronic hypertension, this cerebral autoregulation curve is shifted, re-
sulting in autoregulation working over a much higher range of pres-
sures (e.g., 70–175 mmHg). In these hypertensive patients, cerebral
blood flow is kept steady at higher MAP, but a rapid lowering of pres-
sure can more easily lead to ischemia on the lower end of the autoregu-
latory curve. This autoregulatory phenomenon is achieved through
both myogenic and neurogenic influences causing small arterioles to
contract and dilate. When the systemic blood pressure exceeds the lim-
its of this mechanism, breakthrough of autoregulation occurs, resulting
in hyperperfusion via increased cerebral blood flow, capillary leakage
into the interstitium, and resulting edema. 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 autoregulato-
ry breakthrough in the posterior circulation.
While elevated or relatively elevated blood pressure is common in
many of these disorders, some hyperperfusion states such as cal-
cineurin-inhibitor toxicity occur with no apparent pressure rise. In
these cases, vasogenic edema is likely due primarily to dysfunction of
the capillary endothelium itself, leading to breakdown of the blood-
brain barrier. 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). In reality, both of these pathophysiologic processes are likely
playing some role in each of these disorders.
The clinical presentation of the hyperperfusion syndromes is simi-
lar, with prominent headaches, seizures, or focal deficits. Headaches
have no specific characteristics, range from mild to severe, and may be
accompanied by alterations in consciousness ranging from confusion
to coma. Seizures may be present, and these can be of multiple types
depending on the severity and location of the edema. Nonconvulsive
seizures have been described in hyperperfusion states; therefore a low
threshold for obtaining an electroencephalogram (EEG) in these pa-
tients should be maintained. The typical focal deficit in hyperperfu-
sion states is cortical visual loss, given the tendency of the process to
involve the occipital lobes. However, any focal deficit can occur de-
pending on the area affected, as evidenced by patients who, after carot-
id endarterectomy, exhibit neurologic dysfunction in the ipsilateral
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TABLE e33-1 SOME COMMON ETIOLOGIES OF e271
HYPERPERFUSION SYNDROME
Disorders in which increased capillary pressure dominates the pathophysiology
Hypertensive encephalopathy, including secondary causes such as
renovascular hypertension, pheochromocytoma, cocaine use, etc.
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.g., cytarabine, azathioprine,
5-fluorouracil, cisplatin, methotrexate)
Glucocorticoids
Erythropoietin
HELLP syndrome (hemolysis, elevated liver enzyme levels, low platelet count)
Thrombotic thrombocytopenic purpura (T TP)
Hemolytic uremic syndrome (HUS)
Systemic lupus erythematosus (SLE)
Wegener’s granulomatosis
newly reperfused hemisphere. In conditions where increased cerebral
blood flow plays a role, examination of the inpatient vital signs record
will usually reveal a systemic blood pressure that is increased above
baseline. It appears as if the rapidity of rise rather than the absolute
value of pressure is the most important risk factor.
The diagnosis in all of these conditions is clinical. The symptoms of
these disorders are common and nonspecific, so a long differential di-
agnosis should be entertained, including consideration of other causes
of confusion, focal deficits, headache, and seizures. MRI has improved
the ability of clinicians to diagnose hyperperfusion syndromes, al-
though cases have been reported with normal imaging. Patients classi-
CHAPTER e33 Special Issues in Inpatient Neurologic Consultation
cally exhibit the high T2 signal of edema primarily in the posterior
occipital lobes, not respecting any single vascular territory (Fig. e33-1).
Diffusion-weighted images are typically normal, emphasizing the va-
sogenic rather than cytotoxic nature of this edema. Imaging with CT is
less sensitive but may show a pattern of patchy hypodensity in the in-
volved territory. Previously this classic radiographic appearance had
been termed reversible posterior leukoencephalopathy (RPLE). Howev-
er, this term has fallen out of favor because none of its elements are
completely accurate: the radiographic and clinical changes are not al-
ways reversible, the territory involved is not uniquely posterior, and
gray matter may be affected as well, rather than purely white matter as
the word “leukoencephalopathy” intimates. Other ancillary studies
such as cerebrospinal fluid (CSF) analysis often yield nonspecific re-
sults. It should be noted that many of the substances that have been
implicated, such as cyclosporine, can cause this syndrome even at low
doses or after years of treatment. Therefore, normal serum levels of
these medications do not exclude them as inciting agents.
In cases of hyperperfusion syndromes, treatment should commence
urgently once the diagnosis is considered. Hypertension plays a key
role commonly, and judicious lowering of the blood pressure with IV
agents such as labetolol or nicardipine is advised along with continu-
ous cardiac and blood pressure monitoring, often through an arterial
line. It is reasonable to lower mean arterial pressure by ~20% initially,
as further lowering of the pressure may cause secondary ischemia as
pressure drops below the lower range of the patient’s autoregulatory
capability. In cases where there is an identified cause of the syndrome,
these etiologies should be treated promptly, including discontinuation
of offending substances such as calcineurin inhibitors in toxic process-
es, treatment of immune-mediated disorders such as thrombotic
thrombocytopenic purpura (TTP), and prompt delivery of the fetus in
eclampsia. Seizures must be identified and controlled, often necessitat-
ing continuous EEG monitoring. Anticonvulsants are effective, but in
the special case of eclampsia, there is good evidence to support the use
of magnesium sulfate for seizure control.
POST-CARDIAC BYPASS BRAIN INJURY
Central nervous system (CNS) injuries following open heart or coro-
nary artery bypass grafting (CABG) surgery are common and include
 e272
FIGURE e33-1 Axial fluid-attenuated inversion recovery (FLAIR)
MRI of the brain in a patient taking cyclosporine after liver trans-
plantation who presented with seizures, headache, and cortical blind-
ness. Increased signal is seen bilaterally in the occipital lobes
predominantly involving the white matter, consistent with a hyperper-
fusion state secondary to calcineurin-inhibitor exposure.
acute encephalopathy, stroke, and a chronic syndrome of cognitive im-
pairment, which is now increasingly recognized. Hypoperfusion and
embolic disease are frequently involved in the pathogenesis of these
syndromes, although multiple mechanisms may be involved in these
critically ill patients who are at risk for various metabolic and poly-
pharmaceutical complications.
The frequency of hypoxic injury secondary to inadequate blood
flow intraoperatively has been markedly decreased by the use of mod-
ern surgical and anesthetic techniques. Despite these advances, some
patients still experience neurologic complications from cerebral hy-
PART 16
poperfusion or may suffer focal ischemia from tight carotid or focal
intracranial stenoses in the setting of regional hypoperfusion. Postop-
erative infarcts in the border zones between vascular territories com-
monly are blamed on systemic hypotension although some have
suggested that these infarcts can also result from embolic disease (Fig.
e33-2).
Embolic disease is likely the predominant mechanism of cerebral
Neurologic Disorders
injury during cardiac surgery as evidenced by diffusion-weighted MRI
and intraoperative transcranial Doppler studies. 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; therefore,
a negative MRI after surgery does not exclude the diagnosis of emboli-
related complications. Thrombus in the heart itself as well as athero-
mas in the aortic arch can become dislodged during cardiac surgeries,
FIGURE e33-2 Coronal fluid-attenuated inversion recovery (FLAIR)
MRI of the brain in a patient presenting with altered mental sta-
tus after an episode of hypotension during coronary artery bypass graft-
ing (CABG). Increased signal is seen in the border zones bilaterally
between the middle cerebral artery and anterior cerebral artery territo-
ries. Diffusion-weighted MRI sequences demonstrated restricted diffu-
sion in these same locations, suggesting acute infarction.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
releasing a shower of particulate matter into the cerebral circulation.
Cross-clamping of the aorta, manipulation of the heart, extracorpore-
al circulation techniques (“bypass”), arrhythmias such as atrial fibril-
lation, and introduction of air through suctioning have all been
implicated as potential sources of emboli. Histologic studies indicate
that literally millions of tiny emboli may be released, even using mod-
ern surgical techniques.
This shower of microemboli results in a number of clinical syn-
dromes. Occasionally, a single large embolus leads to an isolated large-
vessel stroke that presents with obvious clinical focal deficits. More
commonly, the emboli released are multiple and smaller. When there
is a high burden of these small emboli, an acute encephalopathy can
occur postoperatively, presenting as either a hyperactive or hypoactive
confusional state, the latter of which is frequently and incorrectly as-
cribed to depression. When the burden of microemboli is lower, no
acute syndrome is recognized, but the patient may suffer a chronic
cognitive deficit. Cardiac surgery can be viewed, like delirium, as a
“stress test for the brain.” Some patients with a low cerebral reserve
due to underlying cerebrovascular disease or an early neurodegenera-
tive process will develop a chronic, cognitive deficit, whereas others
with higher reserves may remain asymptomatic despite a similar dose
of microemboli. In this manner, cardiac surgery may serve to unmask
the early manifestations of disorders such as vascular dementia and
Alzheimer’s disease.
Since modern techniques have successfully minimized hypoperfusion
complications during these surgeries, much attention is now focused on
reducing this inevitable shower of microemboli. Off-pump CABG sur-
geries have the advantages of reducing length of stay and perioperative
complications; however, some recent data suggests that off-pump CABG
does not preserve cognitive function compared with on-pump CABG.
Filters placed in the aortic arch may have some promise in capturing
these emboli, although convincing evidence is currently lacking. Devel-
opment of successful endovascular operative approaches may provide a
reasonable alternative to conventional CABG procedures, especially for
patients at high risk of developing cognitive dysfunction after surgery
due to advanced age, previous stroke, or severe atheromatous disease of
the carotid arteries or aortic arch.
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. 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.
Immunosuppressive medications are administered in high doses to
patients after solid organ transplant, and many of these compounds
have well-described neurologic complications. In patients with head-
ache, seizures, or focal neurologic deficits taking calcineurin inhibi-
tors, the diagnosis of hyperperfusion syndrome should be considered,
as discussed above. This neurotoxicity occurs mainly with cyclospor-
ine and tacrolimus and can present even in the setting of normal se-
rum drug levels. Treatment primarily involves lowering the drug
dosage or discontinuing the drug. A related newer agent, sirolimus,
has very few recorded cases of neurotoxicity and may be a reasonable
alternative for some patients. Other examples of immunosuppressive
medications and their neurologic complications include OKT3-associ-
ated akinetic mutism and the leukoencephalopathy seen with metho-
trexate, especially when it is administered intrathecally or with
concurrent radiotherapy. In any solid organ transplant patient with
neurologic complaints, a careful examination of the medication list is
required to search for these possible drug effects.
Cerebrovascular complications of solid organ transplant are often first
recognized in the immediate postoperative period. Border zone territory
infarctions can occur, especially in the setting of systemic hypotension
during cardiac transplant surgery. Embolic infarctions classically compli-
cate cardiac transplantation, but all solid organ transplant procedures
place patients at risk for systemic emboli. When cerebral embolization
accompanies renal or liver transplantation surgery, a careful search for
right-to-left shunting should include evaluation of the heart with agitat-
ed saline echocardiography, as well as looking for intrapulmonary shunt-
ing. Renal and some cardiac transplant patients often have advanced
atherosclerosis, providing yet another mechanism for stroke. Imaging
with CT or MRI with diffusion is advised when cerebrovascular compli-
cations are suspected to confirm the diagnosis and to exclude intracere-
bral hemorrhage, which most often occurs in the setting of coagulopathy
secondary to liver failure or after cardiac bypass procedures.
Given that patients with solid organ transplants are chronically im-
munosuppressed, infections are a common concern (Chap. 126). In
any transplant patient with new CNS signs or symptoms such as sei-
zure, confusion, or focal deficit, the diagnosis of a nervous system in-
fection should be considered and evaluated through imaging (usually
MRI) and possibly lumbar puncture. The most common pathogens
responsible for CNS infections in these patients vary based on time
since transplant. In the first month posttransplant, common patho-
gens include the usual bacterial organisms associated with surgical
procedures and indwelling catheters. Starting in the second month
posttransplant, opportunistic infections of the CNS become more
common, including Nocardia and Toxoplasma species as well as fungal
infections such as aspergillosis. Viral infections that can affect the
brain of the immunosuppressed patient, such as herpes simplex virus,
cytomegalovirus, and varicella, also become more common after the
first month posttransplant. After 6 months posttransplant, immuno-
suppressed patients still remain at risk for these opportunistic bacteri-
al, fungal, 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.
COMMON NEUROLOGIC COMPLICATIONS
OF ELECTROLYTE DISTURBANCES
A wide variety of neurologic conditions can result from abnormalities
in serum electrolytes, and consideration of electrolyte disturbances
should be part of any inpatient neurologic consultation. A complete
general discussion of fluid and electrolyte imbalance and homeosta-
sis can be found in Chap. 46.
HYPERNATREMIA AND HYPEROSMOLALITY
The normal range of serum osmolality is around 275–295 mOsm/kg,
but neurologic manifestations are usually seen only at levels >325
mOsm/kg. Hyperosmolality is usually due to hypernatremia, hyper-
glycemia, azotemia, or the addition of extrinsic osmoles such as man-
nitol, which is commonly used in critically ill neurologic patients.
Hyperosmolality itself can lead to a generalized encephalopathy that is
nonspecific and without focal findings; however, an underlying lesion
such as a mass can become symptomatic under the metabolic stress of
a hyperosmolar state, producing focal signs. Some patients with hy-
perosmolality from severe hyperglycemia can present, for unclear rea-
sons, with generalized seizures or unilateral movement disorders,
which usually respond to lowering of the serum glucose. The treat-
ment 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.
Hypernatremia leads to the loss of intracellular water, leading to cell
shrinkage. In the cells of the brain, solutes such as glutamine and urea
are generated under these conditions in order to minimize this shrink-
age. Despite this corrective mechanism, when hypernatremia is severe
[serum sodium > 160 mmol/L (>160 meq/L)] or occurs rapidly, cellu-
lar metabolic processes fail and encephalopathy will result. There are
many etiologies of hypernatremia including, most commonly, renal
and extrarenal losses of water. Causes of neurologic relevance include
central diabetes insipidus, where hyperosmolality is accompanied by
submaximal urinary concentration due to inadequate release of anti-
diuretic hormone (ADH) from the posterior pituitary, resulting often
from pituitary injury in the setting of surgery, hemorrhage, infiltrative
processes, or cerebral herniation.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
HYPONATREMIA e273
Hyponatremia is commonly defined as a serum sodium < 135 mmol/L
(<135 meq/L). Neurologic symptoms occur at different levels of low so-
dium, depending not only on the absolute value but also on the rate of
fall. In patients with hyponatremia that develops over hours, life-threat-
ening seizures and cerebral edema may occur at values as high as 125
mmol/L. In contrast, some patients with more chronic hyponatremia
that has slowly developed over months to years may be asymptomatic
even with serum levels < 110 mmol/L. Correction of hyponatremia, es-
pecially when chronic, must take place slowly in order to avoid additional
neurologic complications. Cells in the brain swell in hypotonic hy-
ponatremic states but may compensate over time by excreting solute into
the extracellular space, leading to restoration of cell volume when water
follows the solute out of the cells. If treatment of hyponatremia results in
a rapid rise in serum sodium, cells in the brain may quickly shrink, lead-
ing to osmotic demyelination, a process that previously was thought to
be limited exclusively to the brainstem (central pontine myelinolysis; see
Fig. 269-6), but now has been described elsewhere in the CNS.
Treatment of hyponatremia is dependent on the cause. Hypertonic
hyponatremia treatment focuses on the underlying condition, such as
hyperglycemia. Isovolemic hyponatremia (syndrome of inappropriate
antidiuretic hormone, SIADH) is managed with water restriction or
administration of ADH antagonists. The management of choice for
patients with hypervolemic hypotonic hyponatremia is free-water re-
striction and treatment of the underlying edematous disorder, such as
nephrotic syndrome or congestive heart failure. Finally, in hypovole-
mic hypotonic hyponatremia, volume is replaced with isotonic saline
while underlying conditions of the kidneys, adrenals, and gastrointes-
tinal tract are addressed.
One neurologic cause of hypovolemic hypotonic hyponatremia is
CHAPTER e33 Special Issues in Inpatient Neurologic Consultation
the cerebral salt-wasting syndrome that accompanies subarachnoid
hemorrhage and, less commonly, other cerebral processes such as
meningitis or stroke. In these cases, the degree of renal sodium excre-
tion can be remarkable, and large amounts of saline, hypertonic saline,
or oral sodium may need to be given in a judicious fashion in order to
avoid complications from cerebral edema.
HYPOKALEMIA
Hypokalemia, defined as a serum potassium level < 3.5 mmol/L (<3.5
meq/L), occurs either because of excessive potassium losses (from the kid-
neys or gut) or due to an abnormal potassium distribution between the
intracellular and extracellular spaces. At very low levels (<1.5 mmol/L),
hypokalemia may be life threatening due to the risk of cardiac arrhythmia
and may present neurologically with severe muscle weakness and paraly-
sis. Hypokalemic periodic paralysis is a rare disorder caused by excessive
intracellular potassium uptake in the setting of a calcium or sodium chan-
nel mutation. 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.g., eliminat-
ing β2-adrenergic agonist medications).
HYPERKALEMIA
Hyperkalemia is defined as a serum potassium level > 5.5 mmol/L
(>5.5 meq/L) and can neurologically present as muscle weakness with
or without paresthesias. Hyperkalemia becomes life threatening when
it produces electrocardiographic abnormalities such as peaked T waves
or a widened QRS complex. In these cases, prompt treatment is essen-
tial and consists of strategies that protect the heart against arrhythmias
(calcium gluconate administration), promote potassium redistribu-
tion into cells (with glucose, insulin, and β2-agonist medications), and
increase potassium removal (through sodium polystyrene sulfonate,
loop diuretics, or hemodialysis).
CALCIUM DISTURBANCES
Hypercalcemia usually occurs in the setting of either hyperparathyroidism
or systemic malignancy. Neurologic manifestations include encephalopa-
thy as well as muscle weakness due to reduced neuromuscular excitability.
Seizures can occur but are more common in states of low calcium.
 e274 A B
Radial nerve Ulnar nerve
Sensory distribution
of the radial nerve
Lateral cutaneous
nerve of arm
Posterior cutaneous
nerve of arm
Posterior cutaneous
nerve of forearm Sensory distribution of the ulnar nerve
Superficial branch
D E
Sensory distribution
of the femoral nerve Anterior femoral
cutaneus nerve Lateral femoral
cutaneus nerve
Medial femoral
cutaneus nerve
Saphenous nerve
PART 16
FIGURE e33-3 Sensory distribution of peripheral nerves com-
monly affected by entrapment neuropathies. A. Radial nerve.
Hypocalcemia in adults often follows surgical treatment of the thy-
Neurologic Disorders
roid or parathyroid. Seizures and altered mental status dominate the
neurologic picture and usually resolve with calcium repletion. Tetany
is due to spontaneous, repetitive action potentials in peripheral nerves
and remains the classic sign of symptomatic hypocalcemia.
MAGNESIUM DISTURBANCES
Disorders of magnesium are difficult to correlate with serum levels be-
cause a very small amount of total-body magnesium is located in the
extracellular space. Hypomagnesemia presents neurologically with sei-
zures, tremor, and myoclonus. When intractable seizures occur in the
setting of hypomagnesemia, only administration of magnesium will
lead to resolution. High levels of magnesium, in contrast, lead to CNS
depression. Hypermagnesemia usually only occurs in the setting of renal
failure and can lead to confusion and muscular paralysis when severe.
CONSULTATIONS REGARDING PERIPHERAL
NERVOUS SYSTEM DYSFUNCTION
ENTRAPMENT NEUROPATHIES
Polyneuropathy is a common cause of outpatient neurologic consulta-
tion (Chap. 379). In the inpatient setting, however, mononeuropathies
are more frequent, especially the entrapment neuropathies that com-
plicate many surgical procedures and medical conditions. Median
neuropathy at the wrist (carpal tunnel syndrome) is the most frequent
entrapment neuropathy by far, but it is rarely a cause for inpatient
consultation. Mechanisms for perioperative mononeuropathy include
traction, compression, and ischemia of the nerve. Imaging with MR
neurography may allow these causes to be distinguished definitively. In
all cases of mononeuropathy, the diagnosis can be made through the
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
C
Peroneal nerve
Sensory distribution of
the peroneal nerve
Lateral cutaneous
nerve of calf
Superficial peroneal nerve
Deep peroneal
nerve
B. Ulnar nerve. C. Peroneal nerve. D. Femoral nerve. E. Lateral femo-
ral cutaneous nerve.
clinical examination and then confirmed with electrodiagnostic stud-
ies in the subacute period, if necessary. Treatment consists mainly of
avoidance of repetitive trauma but may also include surgical ap-
proaches to relieve pressure on the nerve.
Radial Neuropathy Radial nerve injury classically presents with weak-
ness of extension of the wrist and fingers (“wrist drop”) with or without
more proximal weakness of extensor muscles of the upper extremity, de-
pending on the site of injury. Sensory loss is in the distribution of the ra-
dial nerve, which includes the dorsum of the hand (Fig. e33-3A).
Compression at the level of the axilla, e.g., resulting from use of crutch-
es, includes weakness of the triceps, brachioradialis, and supinator mus-
cles in addition to wrist drop. 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”). Sparing of the triceps is the rule when the
nerve is injured in this location. Because extensors of the upper extremi-
ty are injured preferentially in radial nerve injury, these lesions may be
mistaken for the pyramidal distribution of weakness that accompanies
upper motor neuron lesions from brain or spinal cord processes.
Ulnar Neuropathy Compression of the ulnar nerve is the second most
common entrapment neuropathy after carpal tunnel syndrome. The
most frequent site of compression is at the elbow where the nerve
passes superficially in the ulnar groove. Symptoms usually begin with
tingling in the ulnar distribution, including the fourth and fifth digits
of the hand (Fig. e33-3B). Sensory symptoms may be worsened by el-
bow flexion due to increased pressure on the nerve, hence the tenden-
cy of patients to complain of increasing paresthesias at night when the
arm is flexed at the elbow during sleep. Motor dysfunction can be dis-
abling and involves most of the intrinsic hand muscles, limiting dex-
terity and strength of grasp and pinch. Etiologies of ulnar entrapment
include trauma to the nerve (hitting the “funny bone”), malposition-
ing during anesthesia for surgical procedures, and chronic arthritis of
the elbow. When a perioperative ulnar nerve injury is considered,
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. If the clinical examination is equivocal, elec-
trodiagnostic studies can definitively distinguish between plexus and
ulnar nerve lesions a few weeks after the injury. Conservative methods
of treatment are often the first step, but a variety of surgical approach-
es may be effective, including anterior ulnar nerve transposition and
release of the flexor carpi ulnaris aponeurosis.
Peroneal Neuropathy The peroneal nerve winds around the head of
the fibula in the leg below the lateral aspect of the knee, and its super-
ficial location at this site makes it vulnerable to trauma. Patients
present with weakness of foot dorsiflexion (“foot drop”) as well as
with weakness in eversion but not inversion at the ankle. Sparing of
inversion, which is a function of muscles innervated by the tibial
nerve, helps to distinguish peroneal neuropathies from L5 radiculopa-
thies. Sensory loss involves the lateral aspect of the leg as well as the
dorsum of the foot (Fig. e33-3C). Fractures of the fibular head may be
responsible for peroneal neuropathies, but in the perioperative setting
poorly applied braces exerting pressure on the nerve while the patient
is unconscious are more often responsible. Tight-fitting stockings or
casts of the upper leg can also cause a peroneal neuropathy, and thin
individuals and those with recent weight loss are at increased risk.
Proximal Femoral Neuropathy Lesions of the proximal femoral nerve
are relatively uncommon but may present dramatically with weakness
of hip flexion, quadriceps atrophy, weakness of knee extension (often
manifesting with leg-buckling falls), and an absent patellar reflex. Ad-
duction of the thigh is spared as these muscles are supplied by the ob-
turator nerve, thereby distinguishing a femoral neuropathy from a
more proximal lumbosacral plexus lesion. The sensory loss found is in
the distribution of the femoral nerve sensory branches on the anterior
part of the thigh (Fig. e33-3D). Compressive lesions from retroperito-
neal hematomas or masses are common, and a CT of the pelvis should
be obtained in all cases of femoral neuropathy to exclude these condi-
tions. Bleeding into the pelvis resulting in hematoma can occur spon-
taneously, following trauma, or after intrapelvic surgeries such as renal
transplantation. In intoxicated or comatose patients, stretch injuries to
the femoral nerve are seen following prolonged, extreme hip flexion or
extension. Rarely, attempts at femoral vein or arterial puncture can be
complicated by injury to this nerve.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Lateral Femoral Cutaneous Nerve The symptoms of lateral femoral e275
cutaneous nerve entrapment, commonly known as “meralgia pares-
thetica,” include sensory loss, pain, and dysesthesia in part of the
area supplied by the nerve (Fig. e33-3E). There is no motor compo-
nent to the nerve, and therefore weakness is not a part of this syn-
drome. Symptoms often are worsened by standing or walking.
Compression of the nerve occurs where it enters the leg near the in-
guinal ligament, usually in the setting of tight-fitting belts, pants,
corsets, or recent weight gain, including that of pregnancy. The dif-
ferential diagnosis of these symptoms includes hip problems such as
trochanteric bursitis.
OBSTETRIC NEUROPATHIES
Pregnancy and delivery place women at special risk for a variety of
nerve injuries. Radiculopathy due to a herniated lumbar disc is not
common during pregnancy, but compressive injuries of the lumbosa-
cral plexus do occur secondary to either the fetal head passing through
the pelvis or the use of forceps during delivery. 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 lithot-
omy position during delivery. Other compressive mononeuropathies
of pregnancy include meralgia paresthetica, carpal tunnel syndrome,
femoral neuropathy when the thigh is abducted severely in an effort to
facilitate delivery of the fetal shoulder, and obturator neuropathy dur-
ing lithotomy positioning. The latter presents with medial thigh pain
that may be accompanied by weakness of thigh adduction. There is
also a clear association between pregnancy and an increased frequency
of idiopathic facial palsy (Bell’s palsy).
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. Circulation 113:2784, 2006
JILLAPALLI D, SHEFNER JM: Electrodiagnosis in common mononeuro-
pathies and plexopathies. Semin Neurol 25:196, 2005
KARNAD DR, GUNTUPALLI KK: Neurologic disorders in pregnancy.
Crit Care Med 33:S362, 2005
KUMAR S et al: Central pontine myelinolysis, an update. Neurol Res
28:360, 2006
LAMY C et al: Neuroimaging in posterior reversible encephalopathy
syndrome. J Neuroimaging 14:89, 2004
VAN DIJK D et al: Cognitive and cardiac outcomes 5 years after off-
pump vs. on-pump coronary artery bypass graft surgery. JAMA
297;701, 2007
 levels of exposure. Others, such as lead and mercury, are xenobiotic e277

e34 Heavy Metal Poisoning

Howard Hu
Metals pose a significant threat to health through occupational as well
as environmental exposures. One indication of their importance rela-
tive to other potential hazards is their ranking by the U.S. Agency for
Toxic Substances and Disease Registry, which lists all hazards present
in toxic waste sites according to their prevalence and the severity of
their toxicity. The first, second, third, and sixth hazards on the list are
heavy metals: lead, mercury, arsenic, and cadmium, respectively. Spe-
and theoretically are capable of exerting toxic effects at any level of ex-
posure. Indeed, much research is currently focused on the contribu-
tion of low-level xenobiotic metal exposure to chronic diseases and to
subtle changes in health that may have significant public health conse-
quences. Genetic factors also may modify the impact of metals on
health and thereby account, at least in part, for individual susceptibili-
ty to metal effects.
The most important component of treatment for metal toxicity is
the termination of exposure. Chelating agents are used to bind metals
into stable cyclic compounds with relatively low toxicity and to en-
hance their excretion. The principal chelating agents are dimercaprol

CHAPTER e34 Heavy Metal Poisoning

cific information pertaining to each of these metals, including sources
and metabolism, toxic effects produced, diagnosis, and the appropri-
ate treatment for poisoning, is summarized in Table e34-1.
Metals are inhaled primarily as dusts and fumes (the latter defined as
tiny particles generated by combustion). Metal poisoning can also re-
sult from exposure to vapors (e.g., mercury vapor in creating dental
amalgams). When metals are ingested in contaminated food or drink
or by hand-to-mouth activity (implicated especially in children), their
gastrointestinal absorption varies greatly with the specific chemical
form of the metal and the nutritional status of the host. Once a metal is
absorbed, blood is the main medium for its transport, with the precise
kinetics dependent on diffusibility, protein binding, rates of biotrans-
formation, availability of intracellular ligands, and other factors. Some
organs (e.g., bone, liver, and kidney) sequester metals in relatively high
concentrations for years. Most metals are excreted through renal clear-
ance and gastrointestinal excretion; some proportion is also excreted
through salivation, perspiration, exhalation, lactation, skin exfoliation,
and loss of hair and nails. The intrinsic stability of metals facilitates
tracing and measurement in biologic material, although the clinical sig-
nificance of the levels measured is not always clear.
Some metals, such as copper and selenium, are essential to normal
metabolic function as trace elements (Chap. 71) but are toxic at high
(British Anti-Lewisite, BAL), edetate (EDTA), succimer (DMSA,
dimercaptosuccinic acid), and penicillamine; their specific use de-
pends on the metal involved and the clinical circumstances. Activated
charcoal does not bind metals and thus is of limited usefulness in cases
of acute metal ingestion.
In addition to the information provided in Table e34-1, several oth-
er aspects of exposure, toxicity, or management are worthy of discus-
sion with respect to the four most hazardous toxicants (arsenic,
cadmium, lead, and mercury).
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. Contamination was formerly considered only a prob-
lem with deep wells; however, the geology of this region allows most
residents only a few alternatives for potable drinking water.
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, so named because of cadmium-in-
duced bone toxicity that led to painful bone fractures. Modest expo-
sures from environmental contamination near a smelter in Belgium
were recently associated with a lower bone density, a higher incidence
of fractures, and a faster decline in height in both men and women, ef-

TABLE e34-1 HEAVY METALS

Main Sources Metabolism Toxicity Diagnosis Treatment
Arsenic

Smelting and mi- Organic arsenic (arse-
croelectronics nobentaine, arsenocho-
industries; wood line) is ingested in
preservatives, seafood and fish, but is
pesticides, nontoxic; inorganic ar-
herbicides, senic is readily absorbed
fungicides; (lung and GI); sequesters
contaminant in liver, spleen, kidneys,
of deep-water lungs, and GI tract; resi-
wells; folk reme- dues persist in skin, hair,
dies; and coal; and nails; biomethyla-
incineration of tion results in detoxifica-
these products tion, but this process
saturates.
Acute arsenic poisoning results in
necrosis of intestinal mucosa
with hemorrhagic gastroenteri-
tis, fluid loss, hypotension, de-
layed cardiomyopathy, acute
tubular necrosis, and hemolysis.
Chronic arsenic exposure causes
diabetes, vasospasm, peripheral
vascular insufficiency and gan-
grene, peripheral neuropathy,
and cancer of skin, lung, liver (an-
giosarcoma), bladder, kidney.
Lethal dose: 120–200 mg (adults);
2 mg/kg (children).
Cadmium
Nausea, vomiting, diarrhea, abdominal
pain, delirium, coma, seizures; garlicky
odor on breath; hyperkeratosis, hy-
perpigmentation, exfoliative dermati-
tis, and Mees’ lines (transverse white
striae of the fingernails); sensory and
motor polyneuritis, distal weakness.
Radiopaque sign on abdominal x-ray;
ECG–QRS broadening, QT prolonga-
tion, ST depression, T-wave flattening;
24-h urinary arsenic >67 μmol/d or 50
μg/d; (no seafood × 24 h); if recent ex-
posure, serum arsenic >0.9 μmol/L (7
μg/dL). High arsenic in hair or nails.
If acute ingestion, ipecac to
induce vomiting, gastric la-
vage, activated charcoal
with a cathartic. Supportive
care in ICU.
Dimercaprol 3–5 mg/kg IM
q4h × 2 days; q6h × 1 day,
then q12h × 10 days; alter-
native: oral succimer.

Metal-plating, pig- Absorbed through inges-
ment, smelting, tion or inhalation;
battery, and bound by metallothion-
plastics indus- ein, filtered at the glom-
tries; tobacco; erulus, but reabsorbed
incineration of by proximal tubules
these products; (thus, poorly excreted).
ingestion of Biologic 1/2 life: 10–30 y.
food that con- Binds cellular sulfhydryl
centrates cad- groups, competes with
mium (grains, zinc, calcium for binding
cereals). sites. Concentrates in
liver and kidneys.
Acute cadmium inhalation caus-
es pneumonitis after 4–24 h;
acute ingestion causes gastro-
enteritis.
Chronic exposure causes
anosmia, yellowing of teeth,
emphysema, minor LFT eleva-
tions, microcytic hypochromic
anemia unresponsive to iron
therapy, proteinuria, increased
urinary β2- microglobulin, calci-
uria, leading to chronic renal fail-
ure, osteomalacia, and fractures.
With inhalation: pleuritic chest pain,
dyspnea, cyanosis, fever, tachycardia,
nausea, noncardiogenic pulmonary
edema. With ingestion: nausea, vom-
iting, cramps, diarrhea. Bone pain,
fractures with osteomalacia. If recent
exposure, serum cadmium >500
nmol/L (5 μg/dL). Urinary cadmium
>100 nmol/L (10 μg/g creatinine)
and/or urinary β2-microglobulin
>750 μg/g creatinine (but urinary β2-
microglobulin also increased in other
renal diseases such as pyelonephritis).
There is no effective treat-
ment for cadmium poison-
ing (chelation not useful;
dimercaprol can exacer-
bate nephrotoxicity).
Avoidance of further expo-
sure, supportive therapy, vi-
tamin D for osteomalacia.

(continued)

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

 e278 TABLE e34-1 HEAVY METALS (CONTINUED)
Main Sources Metabolism Toxicity Diagnosis Treatment
Lead

Manufacturing of Absorbed through inges- Acute exposure with blood lead lev- Abdominal pain, irritability, lethargy, Identification and correction
auto batteries, tion or inhalation; or- els (BPb) of > 60–80 μg/dL can anorexia, anemia, Fanconi’s syn- of exposure sources is criti-
lead crystal, ce- ganic lead (e.g., cause impaired neurotransmis- drome, pyuria, azotemia in children cal. In some U.S. states,
ramics, fishing tetraethyl lead) ab- sion and neuronal cell death (with with blood lead level (BPb) >80 μg/ screening and reporting to
weights, etc.; sorbed dermally. In central and peripheral nervous dL; may also see epiphyseal plate local health boards of chil-
demolition or blood, 95–99% seques- system effects); impaired hemato- “lead lines” on long bone x-rays. Con- dren with BPb > 10 μg/dL
sanding of lead- tered in RBCs—thus, poiesis and renal tubular dysfunc- vulsions, coma at BPb > 120 μg/dL. and workers with BPb > 40
painted houses, must measure lead in tion. At higher levels of exposure Noticeable neurodevelopmental de- μg/dL is required. In the
bridges; stained whole blood (not se- (e.g., BPb > 80–120 μg/dL), acute lays at BPb of 40–80 μg/dL; may also highly exposed individual
glass making, rum). Distributed widely encephalopathy with convul- see symptoms associated with high- with symptoms, chelation is
PART 17

plumbing, sol- in soft tissue, with 1/2 sions, coma, and death may oc- er BPb levels. In the U.S., screening of recommended with oral
dering; environ- life ~30 days; 15% of cur. Subclinical exposures in all children when they begin to crawl DMSA (succimer); if acutely
mental dose sequestered in children (BPb 25–60 μg/dL) are (∼6 months) is recommended by the toxic, hospitalization and IV
exposure to bone with 1/2 life of >20 associated with anemia; mental CDC; source identification and inter- or IM chelation with eden-
paint chips, years. Excreted mostly retardation; and deficits in lan- vention is begun if the BPb > 10 μg/ tate calcium disodium
house dust (in in urine, but also ap- guage, motor function, balance, dL. In adults, acute exposure causes (CaEDTA) may be required,
home built pears in other fluids in- hearing, behavior, and school per- similar symptoms as in children as with the addition of dimer-
<1975), firing cluding breast milk. formance. Impairment of IQ ap- well as headaches, arthralgias, myal- caprol to prevent worsen-
Poisoning, Drug Overdose, and Envenomation

ranges (from Interferes with mito- pears to occur at even lower levels gias, depression, impaired short-term ing of encephalopathy. It is
bullet dust), chondrial oxidative of exposure with no measurable memory, loss of libido. Physical exam uncertain whether children
food or water phosphorylation, threshold above the limit of de- may reveal a “lead line” at the gingi- with asymptomatic lead ex-
from improperly ATPases, calcium-de- tection in most assays of 1 μg/dL. va-tooth border, pallor, wrist drop, posure (e.g., BPb 20–40 μg/
glazed ceramics, pendent messengers; In adults, chronic subclinical ex- and cognitive dysfunction (e.g., de- dL) benefit from chelation.
lead pipes; con- enhances oxidation and posures (BPb > 40 μg/dL) are clines on the mini-mental status ex- Correction of dietary defi-
taminated herb- cell apoptosis. associated with an increased am); lab tests may reveal a ciencies in iron, calcium,
al remedies, risk of anemia, demyelinating normocytic, normochromic anemia, magnesium, and zinc will
candies; expo- peripheral neuropathy (mainly basophilic stippling, an elevated lower lead absorption and
sure to the com- motor), impairments of reac- blood protoporphyrin level (free may also improve toxicity.
bustion of tion time, hypertension, ECG erythrocyte or zinc), and motor de- Vitamin C is a weak but nat-
leaded fuels. conduction delays, interstitial lays on nerve conduction. In the U.S., ural chelating agent.
nephritis and chronic renal fail- OSHA requires regular testing of
ure, diminished sperm counts, lead-exposed workers with removal
spontaneous abortions. if BPb > 40 μg/dL.
Mercury

Metallic, mercu- Elemental mercury (Hg°) Acute inhalation of Hg° vapor caus- Chronic exposure to metallic mercu- Treat acute ingestion of mer-
rous, and mer- is not well absorbed; es pneumonitis and noncardio- ry vapor produces a characteristic curic salts with induced
curic mercury however, it will volatil- genic pulmonary edema leading intention tremor and mercurial ere- emesis or gastric lavage
(Hg°, Hg+, Hg2+) ize into highly absorb- to death, CNS symptoms, and thism: excitability, memory loss, in- and polythiol resins (to bind
exposures occur able vapor. Inorganic polyneuropathy. somnia, timidity, and delirium mercury in the GI tract).
in some chemi- mercury is absorbed Chronic high exposure causes CNS (“mad as a hatter”). On neurobe- Chelate with dimercaprol
cal, metal-pro- through the gut and toxicity (mercurial erethism; see di- havioral tests: decreased motor (up to 24 mg/kg per day IM
cessing, skin. Organic mercury is agnosis); lower exposures impair speed, visual scanning, verbal in divided doses), DMSA
electrical-equip- well absorbed through renal function, motor speed, and visual memory, visuomotor (succimer), or penicil-
ment, automo- inhalation and inges- memory, coordination. coordination. lamine, with 5-day courses
tive industries; tion. Elemental and or- Acute ingestion of inorganic mer- Children exposed to mercury in any separated by several days of
they are also in ganic mercury cross the cury causes gastroenteritis, the form may develop acrodynia (“pink rest. If renal failure occurs,
thermometers, blood-brain barrier and nephritic syndrome, or acute re- disease”): flushing, itching, swell- treat with peritoneal dialy-
dental amal- placenta. Mercury is ex- nal failure, hypertension, tachy- ing, tachycardia, hypertension, ex- sis, hemodialysis, or extra-
gams, batteries. creted in urine and fe- cardia, and cardiovascular cessive salivation or perspiration, corporeal regional
Mercury is dis- ces and has a 1/2 life in collapse, with death at a dose of irritability, weakness, morbilliform complexing hemodialysis
persed by waste blood of ∼60 days; how- 10–42 mg/kg. rashes, desquamation of palms and and succimer.
incineration. En- ever, deposits will re- Ingestion of organic mercury caus- soles. Chronic inorganic mercury
vironmental main in the kidney and es gastroenteritis, arrhythmias, Toxicity from elemental or inorganic poisoning is best treated
bacteria con- brain for years. Expo- and lesions in the basal ganglia, mercury exposure begins when with N-acetyl penicillamine.
vert inorganic to sure to mercury stimu- gray matter, and cerebellum at blood levels >180 nmol/L (3.6 μg/
organic mercu- lates the kidney to doses >1.7 mg/kg. dL) and urine levels >0.7 μmol/L
ry, which then produce metallothion- High exposure during pregnancy (15 μg/dL). Exposures that ended
bioconcen- ein, which provides causes derangement of fetal neu- years ago may result in a >20-μg in-
trates up the some detoxification ronal migration resulting in se- crease in 24-h urine after a 2-g dose
aquatic food benefit. Mercury binds vere mental retardation. of succimer.
chain to con- sulfhydryl groups and Mild exposures during pregnancy Organic mercury exposure is best
taminate tuna, interferes with a wide (from fish consumption) are asso- measured by levels in blood (if re-
swordfish, and variety of critical enzy- ciated with declines in neurobe- cent) or hair (if chronic); CNS toxici-
other pelagic matic processes. havioral performance in offspring. ty in children may derive from fetal
fish. Dimethylmercury, a compound exposures associated with mater-
only found in research labs, is “su- nal hair Hg > 30 nmol/g (6 μg/g).
pertoxic”—a few drops of expo-
sure via skin absorption or inhaled
vapor can cause severe cerebellar
degeneration and death.
Note: GI, gastrointestinal; ECG, electrocardiogram; ICU, intensive care unit; LFT, liver Control and Prevention; OSHA, Occupational Safety and Health Administration; CNS,
function tests; RBC, red blood cell; IQ, intelligence quotient; CDC, Centers for Disease central nervous system.

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

fects that may be related to cadmium’s calciuric effect on the kidney.
Such research is creating concern that cadmium exposure may be con-
tributing significantly to morbidity and mortality from osteoporosis
in the general population.
Advances in our understanding of lead toxicity have recently bene-
fited by the development of K-x-ray fluorescence (KXRF) instruments
for making safe in vivo measurements of lead levels in bone (which, in
turn, reflect cumulative exposure over many years, as opposed to
blood lead levels, which mostly reflect recent exposure). High bone
lead levels measured by KXRF have been linked to increased risk of hy-
pertension in both men and women from an urban population. In ad-
dition, high maternal bone lead levels were found to predict lower
birth weight, head circumference, birth length, and neurodevelop-
mental performance in offspring by age 2.
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-contaminat-
ed fish. However, current evidence has not supported the recent con-
tention that ethyl mercury, used as a preservative in multiuse vaccines
administered in early childhood, has played a significant role in caus-
ing neurodevelopmental problems such as autism.
A few additional metals deserve brief mention but are not covered
in Table e34-1 because of the relative rarity of their being clinically en-
countered, or the uncertainty regarding their potential toxicities. Alu-
minum contributes to the encephalopathy in patients with severe renal
disease who are undergoing dialysis (Chap. 347). High levels of alumi-
num are found in the neurofibrillary tangles in the cerebral cortex and
hippocampus of patients with Alzheimer’s disease, as well as in the
drinking water and soil of areas with an unusually high incidence of
Alzheimer’s. The experimental and epidemiologic evidence for the
aluminum–Alzheimer’s disease link is so far relatively weak, however,
and it cannot be concluded that aluminum is a causal agent or a con-
tributing factor in neurodegenerative disease. Hexavalent chromium is
corrosive and sensitizing. Workers in the chromate and chrome pig-
ment production industries have consistently had a greater risk of lung
cancer. The introduction of cobalt chloride as a fortifier in beer led to
outbreaks of fatal cardiomyopathy among heavy consumers. Occupa-
tional exposure (e.g., of miners, dry-battery manufacturers, and arc
welders) to manganese can cause a Parkinsonian syndrome within 1–2
years, including gait disorders; postural instability; a masked, expres-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
sionless face; tremor; and psychiatric symptoms. With the introduc- e279
tion of methylcyclopentadienyl manganese tricarbonyl (MMT) as a
gasoline additive, there is concern for the toxic potential of environ-
mental manganese exposure. Nickel exposure induces an allergic re-
sponse, and inhalation of nickel compounds with low aqueous
solubility (e.g., nickel subsulfide and nickel oxide) in occupational set-
tings is associated with an increased risk of lung cancer. Overexposure
to selenium may cause local irritation of the respiratory system and
eyes, gastrointestinal irritation, liver inflammation, loss of hair, depig-
mentation, and peripheral nerve damage. Workers exposed to certain
organic forms of tin (particularly trimethyl and triethyl derivatives)
have developed psychomotor disturbances, including tremor, convul-
CHAPTER e34 Heavy Metal Poisoning
sions, hallucinations, and psychotic behavior.
Thallium, which is a component of some insecticides, metal alloys,
and fireworks, is absorbed through the skin as well as by ingestion and
inhalation. Severe poisoning follows a single ingested dose of >1 g or
>8 mg/kg. Nausea and vomiting, abdominal pain, and hematemesis
precede confusion, psychosis, organic brain syndrome, and coma.
Thallium is radiopaque. Induced emesis or gastric lavage is indicated
within 4–6 h of acute ingestion; Prussian blue prevents absorption and
is given orally at 250 mg/kg in divided doses. Unlike other types of
metal poisoning, thallium poisoning may be less severe when activated
charcoal is used to interrupt its enterohepatic circulation. Other mea-
sures include forced diuresis, treatment with potassium chloride
(which promotes renal excretion of thallium), and peritoneal dialysis.
FURTHER READINGS
BRODKIN E et al: Lead and mercury exposures: Interpretation and ac-
tion. CMAJ 176(1):59, 2007
CENTENO JA et al: Pathology related to chronic arsenic exposure. En-
viron Health Perspect 110(Suppl 5):883, 2002
JÄRUP L: Hazards of heavy metal contamination. Br Med Bull 68:167,
2003
MISRA UK: Thallium poisoning: Emphasis on early diagnosis and re-
sponse to haemodialysis. Postgrad Med J 79:103, 2003
PARK S, JOHNSON MA: Awareness of fish advisories and mercury ex-
posure in women of childbearing age. Nutr Rev 64:250, 2006
SAPER RB et al: Heavy metal content of ayurvedic herbal medicine
products. JAMA 292: 2868, 2004

e35 Poisoning and
Drug Overdosage
Christopher H. Linden, Michael J. Burns,
Mark B. Mycyk
Poisoning refers to the development of dose-related adverse effects fol-
lowing exposure to chemicals, drugs, or other xenobiotics. To para-
phrase Paracelsus, the dose makes the poison. In excessive amounts,
substances that are usually innocuous, such as oxygen and water, can
cause poisoning. Conversely, in small doses, substances commonly re-
garded as poisons, such as arsenic and cyanide, can be consumed with-
out ill effect. There is, however, substantial individual variability in the
response to, and disposition of, a given dose. Some of this variability is
genetic, and some is acquired on the basis of enzyme induction or in-
hibition, or because of tolerance. Poisoning may be local (e.g., skin,
eyes, or lungs) or systemic depending on the chemical and physical
properties of the poison, its mechanism of action, and the route of ex-
posure. The severity and reversibility of poisoning also depend on the
functional reserve of the individual or target organ, which is influ-
enced by age and preexisting disease.
EPIDEMIOLOGY
About 5 million poison exposures occur in the United States each year.
Most are acute, accidental (unintentional), involve a single agent, oc-
cur in the home, result in minor or no toxicity, and involve children
under 6 years of age. Pharmaceuticals are involved in 47% of expo-
sures and 84% of serious or fatal poisonings. Unintentional exposures
can result from the improper use of chemicals at work or play; product
mislabeling; label misreading; mistaken identification of unlabeled
chemicals; uninformed self-medication; and dosing errors by nurses,
parents, pharmacists, physicians, and the elderly. Excluding the recre-
ational use of ethanol, attempted suicide (deliberate self-harm) is the
most common reason for intentional exposure. Unintended poison-
ings may result from the recreational use of prescribed and over-the-
counter drugs for psychotropic or euphoric effects (abuse) or excessive
self-dosing (misuse).
About 25% of exposures require health professional evaluation, and
5% of all exposures require hospitalization. Poisonings account for 5–
10% of all ambulance transports, emergency department visits, and
intensive care unit admissions. Up to 30% of psychiatric admissions
are prompted by attempted suicide via overdosage. Overall, the mor-
tality rate is low: 0.4% of all exposures. It is much higher (1–2%) in
hospitalized patients with intentional (suicidal) overdose, who ac-
count for the majority of serious poisonings. Acetaminophen is the
pharmaceutical agent most often implicated in fatal poisoning. Over-
all, carbon monoxide is the leading cause of death from poisoning, but
this is not reflected in hospital or poison center statistics because pa-
tients with such poisoning are typically dead when discovered and are
referred directly to medical examiners.
DIAGNOSIS
Although poisoning can mimic other illnesses, the correct diagnosis
can usually be established by the history, physical examination, rou-
tine and toxicologic laboratory evaluations, and characteristic clinical
course. The history should include the time, route, duration, and cir-
cumstances (location, surrounding events, and intent) of exposure;
the name and amount of each drug, chemical, or ingredient involved;
the time of onset, nature, and severity of symptoms; the time and type
of first aid measures provided; and the medical and psychiatric history.
In many cases the victim is confused, comatose, unaware of an ex-
posure, or unable or unwilling to admit to one. Suspicious circum-
stances include unexplained illness in a previously healthy person; a
history of psychiatric problems (particularly depression); recent
changes in health, economic status, or social relationships; and onset
of illness while working with chemicals or after ingesting food, drink
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
(especially ethanol), or medications. Patients who become ill soon af- e281
ter arriving from a foreign country or being arrested for criminal ac-
tivity should be suspected of “body packing” or “body stuffing”
(ingesting or concealing illicit drugs in a body cavity). Relevant history
may be available from family, friends, paramedics, police, pharmacists,
physicians, and employers, who should be questioned regarding the
patient’s habits, hobbies, behavior changes, available medications, and
antecedent events. A search of clothes, belongings, and place of discov-
ery may reveal a suicide note or a container of drugs or chemicals. 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, a computerized database, the manufac-
CHAPTER e35 Poisoning and Drug Overdosage
turer, or a regional poison information center. Occupational expo-
sures require review of available MSDS (Material Safety Data Sheets)
from the worksite.
The physical examination should focus initially on the vital signs,
cardiopulmonary system, and neurologic status. The neurologic ex-
amination should include documentation of neuromuscular abnor-
malities such as dyskinesia, dystonia, fasciculations, myoclonus,
rigidity, tremors. The patient should also be examined for evidence of
trauma and underlying illnesses. Focal neurologic findings are uncom-
mon in poisoning, and their presence should prompt evaluation for a
structural central nervous system (CNS) lesion. Examination of the
eyes (for nystagmus, pupil size and reactivity), abdomen (for bowel
activity and bladder size), and skin (for burns, bullae, color, warmth,
moisture, pressure sores, and puncture marks) may reveal findings of
diagnostic value. When the history is unclear, all orifices should be ex-
amined for the presence of chemical burns and drug packets. The odor
of breath or vomitus and the color of nails, skin, or urine may provide
diagnostic clues.
The diagnosis of poisoning in cases of unknown etiology primarily
relies on pattern recognition. The first step is to assess the pulse, blood
pressure, respiratory rate, temperature, and neurologic status and
characterize the overall physiologic state as stimulated, depressed, dis-
cordant, or normal (Table e35-1). Obtaining a complete set of vital
signs and reassessing them frequently are critical. Measuring core tem-
perature is especially important, even in difficult or combative pa-
tients, since temperature elevation is the most reliable prognosticator
of poor outcome in poisoning. The next step is to consider the under-
lying causes of the observed physiologic state and attempt to identify a
pathophysiologic pattern or toxic syndrome (toxidrome) based on fur-
ther analysis of the vital signs, neurologic status, and other physical
findings. 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. The final step is to attempt to identify the
particular agent involved by looking for unique or relatively poison-
specific physical or ancillary test abnormalities. This approach is sum-
marized below.
Increased pulse, blood pressure, respiratory rate, temperature, and
neuromuscular activity characterize the stimulant toxidromes: sympa-
thetic, antimuscarinic (anticholinergic), hallucinogen poisoning and
drug withdrawal (Table e35-1). Other features are noted in Table e35-2.
Mydriasis, a characteristic feature of all stimulant toxidromes, is most
marked in antimuscarinic (anticholinergic) poisoning since pupillary
reactivity relies on muscarinic control; in sympathetic poisoning (e.g.,
cocaine), pupils are also enlarged but some reactivity to light is ob-
served. The anticholinergic (antimuscarinic) toxidrome is also distin-
guished by the presence of hot, dry, flushed skin; decreased bowel
sounds; and urinary retention (Table e35-1). Other stimulant tox-
idromes increase sympathetic activity and cause diaphoresis, pallor,
and increased bowel activity with varying degrees of nausea, vomiting,
abnormal distress, and occasionally diarrhea. The absolute and relative
degree of vital sign changes and neuromuscular hyperactivity can help
distinguish among stimulant toxidromes. Since sympathetics stimulate
the peripheral nervous system more directly than do hallucinogens or
drug withdrawal, markedly increased vital signs and organ ischemia
suggest sympathetic poisoning. Findings helpful in suggesting the par-
ticular drug or class causing physiologic stimulation include reflex
 e282 TABLE e35-1 DIFFERENTIAL DIAGNOSIS OF POISONING BASED ON PHYSIOLOGIC STATE
Stimulated Depressed Discordant Normal
Sympathetics Sympatholytics Asphyxiants Nontoxic exposure
Sympathomimetics α1-Adrenergic antagonists Cytochrome oxidase inhibitors Psychogenic illness
Ergot alkaloids α2-Adrenergic agonists Inert gases Toxic time-bombs
Methylxanthines ACE inhibitors Irritant gases Slow absorption
Monoamine oxidase inhibitors Angiotensin receptor blockers Methemoglobin inducers Anticholinergics
Thyroid hormones Antipsychotics Oxidative phosphorylation Carbamazepine
Anticholinergics β-adrenergic blockers inhibitors Concretion formers
Antihistamines Calcium channel blockers AGMA inducers Dilantin Kapseals
Antiparkinsonian agents Cardiac glycosides Alcohol (ketoacidosis) Drug packets
Antipsychotics Cyclic antidepressants Ethylene glycol Enteric-coated pills
Antispasmodics Cholinergics Iron Lomotil
Belladonna alkaloids Acetylcholinesterase inhibitors Methanol Opioids
PART 17

Cyclic antidepressants Muscarinic agonists Salicylate Salicylates

Muscle relaxants Nicotinic agonists Toluene Sustained-release pills
Mushrooms and plants Opioids CNS syndromes Slow distribution
Hallucinogens Analgesics Extrapyramidal reactions Cardiac glycosides
Cannabinoids (marijuana) GI antispasmodics Hydrocarbon inhalation Lithium
LSD and analogues Heroin Isoniazid Metals
Mescaline and analogues Sedative-hypnotics Lithium Salicylate
Mushrooms Alcohols Neuroleptic malignant syndrome Toxic metabolite
Poisoning, Drug Overdose, and Envenomation

Phencyclidine and analogues Anticonvulsants Serotonin syndrome Acetaminophen

Withdrawal syndromes Barbiturates Strychnine Carbon tetrachloride
Barbiturates Benzodiazepines Membrane-active agents Cyanogenic glycosides
Benzodiazepines GABA precursors Amantidine Ethylene glycol
Ethanol Muscle relaxants Antiarrhythmics Methanol
Opioids Other agents Antihistamines Methemoglobin inducers
Sedative-hypnotics GHB Products Antipsychotics Mushroom toxins
Sympatholytics Carbamazepine Organophosphate insecticides
Cyclic antidepressants Paraquat
Local anesthetics Metabolism disruptors
Opioids (some) Antineoplastic agents
Orphenadrine Antiviral agents
Quinoline antimalarials Colchicine
Hypoglycemic agents
Immunosuppressive agents
MAO inhibitors
Metals
Salicylate
Warfarins

Note: ACE, angiotensin-converting enzyme; AGMA, anion-gap metabolic alkalosis; GHB, ethylamide; GABA, γ-aminobutyric acid; MAO; monoamine oxidase; GHB, γ-hydroxy-
γ-hydroxybutyric; GI, gastrointestinal; CNS, central nervous system; LSD, lysergic acid di- butyric.

bradycardia from selective α-adrenergic stimulants (e.g., deconges-
tants), hypotension from selective β-adrenergic stimulants (e.g., as-
thma therapeutics), limb ischemia from ergot alkaloids, nystagmus
from phencyclidine and ketamine (the only physiologic stimulants that
cause this finding), and delayed cardiac conduction from high doses of
cocaine and some anticholinergic agents (e.g., antihistamines, cyclic
antidepressants, and antipsychotics). Seizures suggest a sympathetic
etiology, an anticholinergic agent with membrane-active properties
(e.g., cyclic antidepressants, orphenadrine, phenothiazines), or a with-
drawal syndrome. Other manifestations of grade 4 physiologic stimula-
tion (Table e35-2) are likely only in sympathetic poisoning. Close
attention to core temperature is critical in these patients.
Decreased pulse, blood pressure, respiratory rate, temperature, 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), cholinergic (mus-
carinic and nicotinic) agents, opioids, and sedative-hypnotic γ-ami-
nobutyric acid (GABA)-ergic] agents (Tables e35-1 and e35-2). Miosis
is also common and most pronounced in opioid and cholinergic poi-
soning. The latter is distinguished from other depressant toxidromes
by the presence of muscarinic and nicotinic signs and symptoms (Ta-
ble e35-1). Pronounced cardiovascular depression in the absence of
significant CNS depression suggests a direct or peripherally acting
sympatholytic. In contrast, in opioid and sedative-hypnotic poisoning,
vital sign changes are secondary to depression of CNS cardiovascular
and respiratory centers (or consequent hypoxemia) and significant ab-
normalities in these parameters do not occur until there is a marked
decrease in the level of consciousness (grade 3 or 4 physiologic depres-
sion, Table e35-2). Other clues that suggest the cause of physiologic
depression include cardiac arrhythmias and conduction disturbances
(due to antiarrhythmics, β-adrenergic antagonists, calcium-channel
blockers, digitalis glycosides, propoxyphene, and cyclic antidepres-
sants), mydriasis [due to tricyclic antidepressants, some antiarrhyth-
mics, meperidine, and diphenoxylate-atropine (Lomotil)], nystagmus
(due to sedative-hypnotics), and seizures (due to cholinergic agents,
propoxyphene, cyclic antidepressants).
Discordant or mixed vital sign and neuromuscular abnormalities are
characteristic of poisoning by asphyxiants, CNS syndromes, mem-
brane-active agents, and anion-gap metabolic acidosis (AGMA) induc-
ers (Table e35-1). In these conditions, manifestations of physiologic
stimulation and physiologic depression occur together or at different
times during the clinical course. For example, membrane-active agents
can cause simultaneous coma, seizures, hypotension, and tachyar-
rhythmias. Alternatively, vital signs may be normal but the patient has
altered mental status or is obviously sick or clearly symptomatic. Early,
pronounced vital sign and mental status changes suggest asphyxiant or
membrane-active agent poisoning; the lack of such abnormalities sug-
gests an AGMA inducer, and marked neuromuscular dysfunction with-
out significant vital sign abnormalities suggests a CNS syndrome. As
noted below, AGMA inducer poisoning can be distinguished from oth-
er causes of AGMA by the serum lactate concentration.
A normal physiologic status and physical examination may be due
to a nontoxic exposure, psychogenic illness, or poisoning by “toxic
time-bombs,” agents that are slowly absorbed, slowly distributed to

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

TABLE e35-2 SEVERITY OF PHYSIOLOGIC STIMULATION AND DEPRESSION
IN POISONING AND DRUG WITHDRAWAL
Physiologic Stimulation
Grade 1 Anxious, irritable, tremulous; vital signs normal; diaphoresis,
flushing or pallor, mydriasis, and hyperreflexia may be present
Grade 2 Agitated; may have confusion or hallucinations but is able to
converse and follow commands; vital signs mildly to moder-
ately increased
Grade 3 Delirious; unintelligible speech, uncontrollable motor hyper-
activity; moderately to markedly increased vital signs; tachy-
arrhythmias possible
Grade 4 Coma, seizures, cardiovascular collapse
Physiologic Depression
Grade 1 Awake, lethargic, or sleeping but arousable by voice or tactile
stimulation; able to converse and follow commands; may be
confused
Grade 2 Responds to pain but not voice; can vocalize but not con-
verse; spontaneous motor activity present; brainstem re-
flexes intact
Grade 3 Unresponsive to pain; spontaneous motor activity absent;
brainstem reflexes depressed; motor tone, respirations, and
temperature decreased
Grade 4 Unresponsive to pain; flaccid paralysis; brainstem reflexes and
respirations absent; cardiovascular vital signs decreased
their sites of action, require metabolic activation, or disrupt metabolic
processes (Table e35-1). Because so many medications are now refor-
mulated in a once-a-day form for patient convenience and adherance,
“toxic time-bombs” are increasingly common. 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 be-
tween exposure and peak toxicity. Psychogenic illness (fear of being
poisoned, mass hysteria) may also occur after a nontoxic exposure and
should be considered when symptoms are inconsistent with the expo-
sure history. 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 peri-
od of observation.
Laboratory assessment may be helpful in the differen-
tial diagnosis (Fig. e35-1). An increased AGMA is char-
Increased
acteristic of advanced methanol, ethylene glycol, and
salicylate intoxication but can occur with other agents
(Table e35-1) and in any poisoning that results in hepat- Lactate level
ic, renal, or respiratory failure; seizures; or shock. The se-
rum lactate concentration is low (less than the anion
gap) in the former and high (nearly equal to the anion High
gap) in the latter. An abnormally low anion gap can be
due to elevated blood levels of bromide, calcium, iodine,
lithium, magnesium, or nitrate. An increased osmolal
gap—a difference between the serum osmolality (meas-
ured by freezing point depression) and that calculated
from the serum sodium, glucose, and blood urea nitro-
gen of >10 mmol/L—suggests the presence of a low-mo- Asphyxiants Propylene Formaldehyde Alcoholic
Biguanides
lecular-weight solute such as acetone, an alcohol (benzyl, Liver failure
ethanol, isopropanol, methanol), a glycol (diethylene, Seizures
ethylene, propylene), ether (ethyl, glycol), or an “unmea- Severe
agitation
sured” cation (calcium, magnesium) or sugar (glycerol, Shock
mannitol, sorbitol). Ketosis suggests acetone, isopropyl
alcohol, or salicylate poisoning. Hypoglycemia may be
due to poisoning with β-adrenergic blockers, ethanol, Normal
insulin, oral hypoglycemic agents, quinine, and salicyl-
ates, whereas hyperglycemia can occur in poisoning with
acetone, β-adrenergic agonists, caffeine, calcium channel
blockers, iron, theophylline, or N-3-pyridylmethyl-N′-p-
nitrophenylurea (PNU, Vacor). Hypokalemia can be FIGURE e35-1 Differential diagnosis of poisoning based on the results of routine
caused by barium, β-adrenergic agonists, caffeine, di- laboratory tests.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
uretics, theophylline, or toluene; hyperkalemia suggests poisoning e283
with an α-adrenergic agonist, a β-adrenergic blocker, cardiac glyco-
sides, or fluoride. Hypocalcemia may be seen in ethylene glycol, fluo-
ride, and oxalate poisoning.
The electrocardiogram (ECG) can sometimes be useful for rapid di-
agnostic purposes. Bradycardia and atrioventricular block may occur
in patients poisoned by α-adrenergic agonists, antiarrhythmic agents,
beta blockers, calcium channel blockers, cholinergic agents (carbam-
ate and organophosphate insecticides), cardiac glycosides, lithium,
magnesium, or tricyclic antidepressants. QRS- and QT-interval pro-
longation may be caused by hyperkalemia and by membrane-active
drugs (Table e35-1). Ventricular tachyarrhythmias may be seen in poi-
CHAPTER e35 Poisoning and Drug Overdosage
soning with cardiac glycosides, fluorides, membrane-active drugs, meth-
ylxanthines, sympathomimetics, and agents that cause hyperkalemia
or potentiate the effects of endogenous catecholamines (e.g., chloral
hydrate, aliphatic and halogenated hydrocarbons).
Radiologic studies may also be useful. Pulmonary edema (adult res-
piratory distress syndrome, or ARDS) can be caused by poisoning with
carbon monoxide, cyanide, an opioid, paraquat, phencyclidine, a sed-
ative-hypnotic, or salicylate; by inhalation of irritant gases, fumes, or
vapors (acids and alkali, ammonia, aldehydes, chlorine, hydrogen sul-
fide, isocyanates, metal oxides, mercury, phosgene, polymers); or by
prolonged anoxia, hyperthermia, or shock. Aspiration pneumonia is
common in patients with coma, seizures, and petroleum distillate in-
gestion. The presence of radiopaque densities on abdominal x-rays
suggests the ingestion of calcium salts, chloral hydrate, chlorinated hy-
drocarbons, heavy metals, illicit drug packets, iodinated compounds,
potassium salts, psychotherapeutic agents, lithium, phenothiazines,
enteric-coated tablets, or salicylates.
Toxicologic analysis of urine and blood (and occasionally of gastric
contents and chemical samples) can sometimes confirm or rule out sus-
pected poisoning. Interpretation of laboratory data requires knowledge
of the tests used for screening and confirmation (thin-layer, gas-liquid,
or high-performance liquid chromatography; colorimetric and fluoro-
metric assays; enzyme-multiplied, fluorescence polarization, and radio-
Anion Gap
with metabolic acidosis Normal Decreased
Low Ketosis Iron Bromide
Iodine
Lithium
Absent Toluene Nitrate
Present
Ethylene Ethanol Calcium
glycol Kidney failure ketoacidosis glycol Magnesium
Paraldehyde Acetone Methanol
Phosphates Isopropanol
Salicylates Valproic
Sulfur/sulfate acid
Increased
Osmolal Gap
 e284 immunoassays; gas chromatography; mass spectrometry), their sensitiv- TABLE e35-3 FUNDAMENTALS OF POISONING MANAGEMENT
ity (limit of detection) and specificity, the preferred biologic specimen
for analysis, and the optimal time of specimen sampling. Personal com- Supportive Care
munication with the laboratory is essential. A negative result may mean Airway protection Treatment of seizures
the substance is not detectable by the test used or that its concentration Oxygenation/ventilation Correction of temperature abnormalities
is too low for detection at the time of sampling. In the latter case, repeat- Treatment of arrhythmias Correction of metabolic derangements
ing the test at a later time may yield a positive result. Hemodynamic support Prevention of secondary complications
Although rapid qualitative screening tests for a limited number of Prevention of Further Poison Absorption
drugs of abuse are available, comprehensive screening tests require 2–6
h for completion. Thus, immediate management must often be based Gastrointestinal decontamination Decontamination of other sites
Syrup of ipecac–induced Eye decontamination
on the history, physical examination, and routine bedside ancillary emesis Skin decontamination
tests (e.g., ECG). In addition, when the patient is asymptomatic, or Gastric lavage Body cavity evacuation
when the clinical picture is consistent with the reported history, quali- Activated charcoal
PART 17

tative screening is neither clinically useful nor cost-effective. It is of Whole-bowel irrigation

greatest value in patients with severe or unexplained toxicity such as Catharsis
coma, seizures, cardiovascular instability, metabolic or respiratory aci- Dilution
Endoscopic/surgical removal
dosis, and non-sinus cardiac rhythms. Quantitative analysis is useful
for poisoning with acetaminophen (Chap. 299), acetone, alcohols (in- Enhancement of Poison Elimination
cluding ethylene glycol and methanol), antiarrhythmics, anticonvul- Multiple-dose activated charcoal Extracorporeal removal
sants, barbiturates, digoxin, heavy metals, lithium, salicylate, and Diuresis Peritoneal dialysis
Poisoning, Drug Overdose, and Envenomation

theophylline, as well as for carboxyhemoglobin and methemoglobin. Alteration of urinary pH Hemodialysis

Results can often be available within an hour. Chelation Hemoperfusion
The response to antidotes may be useful for diagnostic purposes. Hemofiltration
Resolution of altered mental status and abnormal vital signs within Plasmapheresis
Exchange transfusion
minutes of IV administration of dextrose, naloxone, or flumazenil is Hyperbaric oxygenation
virtually diagnostic of hypoglycemia, narcotic poisoning, and benzo-
diazepine intoxication, respectively. The prompt reversal of dystonic Administration of Antidotes
(extrapyramidal) signs and symptoms following an IV dose of benz- Neutralization by antibodies Metabolic antagonism
tropine or diphenhydramine confirms a drug etiology. Although com- Neutralization by chemical binding Physiologic antagonism
plete reversal of both central and peripheral manifestations of Prevention of Reexposure
anticholinergic poisoning by physostigmine is diagnostic of this con-
dition, physostigmine may cause some arousal in patients with CNS Adult education Notification of regulatory agencies
depression of any etiology. Child-proofing Psychiatric referral

POISONING AND DRUG OVERDOSE
GENERAL PRINCIPLES Treatment goals include support of vital
signs, prevention of further poison absorption, enhancement of poison
elimination, administration of specific antidotes, and prevention of reexpo-
sure (Table e35-3). Specific treatment depends on the identity of the poi-
son, the route and amount of exposure, the time of presentation relative to
the time of exposure, and the severity of poisoning. Knowledge of the of-
fending agents’ pharmacokinetics and pharmacodynamics is essential.
During the pretoxic phase, prior to the onset of poisoning, decontamina-
tion is the highest priority, and treatment is based solely on the history. The
maximum potential toxicity based on the greatest possible exposure
should be assumed. Since decontamination is more effective when ac-
complished soon after exposure, the initial history and physical examina-
tion should be focused and brief. It is also advisable to establish IV access
and initiate cardiac monitoring, particularly in patients with potentially se-
rious ingestions or unclear histories.
When an accurate history is not obtainable and a poison causing de-
layed toxicity or irreversible damage is suspected, blood and urine should
be sent for toxicologic screening and, if indicated, for quantitative analysis.
During absorption and distribution, blood levels may be greater than
those in tissue and may not correlate with toxicity. However, high blood
levels of agents whose metabolites are more toxic than the parent com-
pound (acetaminophen, ethylene glycol, or methanol) may indicate the
need for additional interventions (antidotes, dialysis).
Most patients who remain or become asymptomatic 4–6 h after inges-
tion will not develop subsequent toxicity and can be discharged safely.
Longer observation will likely be necessary for patients who have ingested
toxic time-bombs, agents that are slowly absorbed, slowly distributed to
their sites of action, require metabolic activation, or disrupt metabolic pro-
cesses (Table e35-1). During the toxic phase, the time between the onset of
poisoning and the peak effects, management is based primarily on clinical
and laboratory findings. Effects after an overdose usually begin sooner, peak
later, and last longer than they do after a therapeutic dose. 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-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
dose. Resuscitation and stabilization are the first priority. Symptomatic pa-
tients should have an IV line, oxygen saturation determination, cardiac
monitoring, and continuous observation. Baseline laboratory, ECG, and x-
ray evaluation may also be appropriate. Intravenous glucose (unless the se-
rum level is documented to be normal), naloxone, and thiamine should be
considered in patients with altered mental status, particularly those with
coma or seizures. Decontamination should also be considered, but it is less
likely to be effective during this phase than during the pretoxic one.
Measures that enhance poison elimination may shorten the duration of
toxicity and lessen its severity. However, they are not without risk, which
must be weighed against the potential benefit. Diagnostic certainty (usu-
ally via laboratory confirmation) is generally a prerequisite. Intestinal (or
“gut”) dialysis with repetitive doses of activated charcoal is usually safe and
can enhance the elimination of selected poisons. Urinary alkalinization and
chelation therapy enhance the elimination of a relatively small number of
poisons, and their use is associated with potential complications. Extracor-
poreal elimination methods are effective for many poisons, but their ex-
pense and risk make their use reasonable only in patients who would
otherwise have an unfavorable outcome.
During the resolution phase of poisoning, supportive care and monitor-
ing should continue until clinical, laboratory, and ECG abnormalities have
resolved. Since chemicals are eliminated sooner from the blood than from
tissues, blood levels are usually lower than tissue levels during this phase
and again may not correlate with toxicity. This is particularly true when ex-
tracorporeal elimination procedures are used. Redistribution from tissues
may cause a rebound increase in the blood level after termination of these
procedures. When a metabolite is responsible for toxic effects, continued
treatment might be necessary in the absence of clinical toxicity or abnor-
mal laboratory studies.
SUPPORTIVE CARE The goal of supportive therapy is to maintain
physiologic homeostasis until detoxification is accomplished and to pre-
vent and treat secondary complications such as aspiration, bedsores, cere-
bral and pulmonary edema, pneumonia, rhabdomyolysis, renal failure,
sepsis, thromboembolic disease, coagulopathy, and generalized organ
dysfunction due to hypoxia or shock.
 Admission to an intensive care unit is indicated for the following: patients
with severe poisoning (coma, respiratory depression, hypotension, cardiac
conduction abnormalities, cardiac arrhythmias, hypothermia or hyperther-
mia, seizures); those needing close monitoring, antidotes, or enhanced elim-
ination therapy; those showing progressive clinical deterioration; and those
with significant underlying medical problems. Patients with mild to moder-
ate toxicity can be managed on a general medical service, intermediate care
unit, or emergency department observation area, depending on the antici-
pated duration and level of monitoring needed (intermittent clinical obser-
vation versus continuous clinical, cardiac, and respiratory monitoring).
Patients who have attempted suicide require continuous observation and
measures to prevent self-injury until they are no longer suicidal.
Respiratory Care Endotracheal intubation for protection against the
aspiration of gastrointestinal contents is of paramount importance in pa-
tients with CNS depression or seizures as this complication can increase
morbidity and mortality. Mechanical ventilation may be necessary for pa-
tients with respiratory depression or hypoxia and to facilitate therapeutic
sedation or paralysis in order to prevent or treat hyperthermia, acidosis,
and rhabdomyolysis associated with neuromuscular hyperactivity. Since
clinical assessment of respiratory function can be inaccurate, the need for
oxygenation and ventilation is best determined by continuous pulse oxim-
etry or arterial blood-gas analysis. The gag reflex is not a reliable indicator
of the need for intubation. A patient with CNS depression may maintain
airway patency while being stimulated but not if left alone. Those who
cannot respond to voice or who are unable to sit and drink fluids without
assistance are best managed by prophylactic intubation.
Drug-induced pulmonary edema is usually noncardiac rather than car-
diac in origin, although profound CNS depression and cardiac conduction
abnormalities suggest the latter. Measurement of pulmonary artery pres-
sure may be necessary to establish the cause and direct appropriate therapy.
Extracorporeal measures (membrane oxygenation, venoarterial perfusion,
cardiopulmonary bypass) and partial liquid (perfluorocarbon) ventilation
may be appropriate for severe but reversible respiratory failure.
Cardiovascular Therapy Maintenance of normal tissue perfusion is
critical for complete recovery to occur once the offending agent has been
eliminated. If hypotension is unresponsive to volume expansion, treatment
with norepinephrine, epinephrine, or high-dose dopamine may be neces-
sary. Intraaortic balloon pump counterpulsation and venoarterial or cardio-
pulmonary perfusion techniques should be considered for severe but
reversible cardiac failure. Bradyarrhythmias associated with hypotension
generally should be treated as described in Chap. 225. Glucagon, calcium,
and high-dose insulin with dextrose may be effective in both beta blocker
and calcium channel blocker poisoning. Antibody therapy may be indicat-
ed for cardiac glycoside poisoning.
Supraventricular tachycardia associated with hypertension and CNS ex-
citation is almost always due to agents that cause generalized physiologic
excitation (Table e35-1). Most cases are mild or moderate in severity and
require only observation or nonspecific sedation with a benzodiazepine. In
severe cases or those associated with hemodynamic instability, chest pain,
or ECG evidence of ischemia, specific therapy is indicated. When the etiolo-
gy is sympathetic hyperactivity, treatment with a benzodiazepine should
be prioritized. Further treatment with a combined alpha and beta blocker
(labetalol), a calcium channel blocker (verapamil or diltiazem), or a combi-
nation of a beta blocker and a vasodilator (esmolol and nitroprusside) may
be considered for cases refractory to high doses of benzodiazepines. Treat-
ment with an α-adrenergic antagonist (phentolamine) alone may sometimes
be appropriate. If the cause is anticholinergic poisoning, physostigmine is the
treatment of choice. Supraventricular tachycardia without hypertension is
generally secondary to vasodilation or hypovolemia and responds to fluid
administration.
For ventricular tachyarrhythmias due to tricyclic antidepressants and
probably other membrane-active agents (Table e35-1), sodium bicarbon-
ate is indicated, whereas class IA, IC, and III antiarrhythmic agents are con-
traindicated because of similar electrophysiologic effects. Although
lidocaine and phenytoin are historically safe for ventricular tachyarrhyth-
mias of any etiology, sodium bicarbonate should be considered first for
any ventricular arrhythmia suspected to have a toxicologic etiology. Beta
blockers can be hazardous if the arrhythmia is due to sympathetic hyper-
activity. Magnesium sulfate and overdrive pacing (by isoproterenol or a
pacemaker) may be useful in patients with torsades des pointes and pro-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
longed QT intervals. Magnesium and anti-digoxin antibodies should be e285
considered in patients with severe cardiac glycoside poisoning. Invasive
(esophageal or intracardiac) ECG recording may be necessary to determine
the origin (ventricular or supraventricular) of wide-complex tachycardias
(Chap. 226). If the patient is hemodynamically stable, however, it is reason-
able to simply observe them rather than to administer another potentially
proarrhythmic agent. Arrhythmias may be resistant to drug therapy until
underlying acid-base, electrolyte, oxygenation, and temperature derange-
ments are corrected.
Central Nervous System Therapies Neuromuscular hyperactivity and
seizures can lead to hyperthermia, lactic acidosis, and rhabdomyolysis, with
their attendant complications, and should be treated aggressively. Seizures
CHAPTER e35 Poisoning and Drug Overdosage
caused by excessive stimulation of catecholamine receptors (sympathomi-
metic or hallucinogen poisoning and drug withdrawal) or decreased activi-
ty of GABA (isoniazid poisoning) or glycine (strychnine poisoning) receptors
are best treated with agents that enhance GABA activity, such as benzodiaz-
epine or barbiturates. Since benzodiazepines and barbiturates act by slight-
ly different mechanisms (the former increases the frequency and the latter
increases the duration of chloride channel opening in response to GABA),
therapy with both may be effective when neither is effective alone. Seizures
caused by isoniazid, which inhibits the synthesis of GABA at several steps by
interfering with the cofactor pyridoxine (vitamin B6), may require high dos-
es of supplemental pyridoxine. Seizures resulting from membrane destabili-
zation (beta blocker or cyclic antidepressant poisoning) require GABA
enhancers (benzodiazepines first, barbiturates second). Phenytoin is contra-
indicated in toxicologic seizures: animal and human data demonstrate
worse outcomes after phenytoin loading, especially in theophylline over-
dose. For poisons with central dopaminergic effects (phencyclidine) mani-
fested by psychotic behavior, a dopamine receptor antagonist, such as
haloperidol, may be useful. In anticholinergic and cyanide poisoning, spe-
cific antidotal therapy may be necessary. The treatment of seizures second-
ary to cerebral ischemia or edema or to metabolic abnormalities should
include correction of the underlying cause. Neuromuscular paralysis is indi-
cated in refractory cases. Electroencephalographic monitoring and continu-
ing treatment of seizures are necessary to prevent permanent neurologic
damage. Serotonergic receptor overstimulation in serotonin syndrome may
be treated with cyproheptadine.
Other Measures Temperature extremes, metabolic abnormalities, he-
patic and renal dysfunction, and secondary complications should be treat-
ed by standard therapies.
PREVENTION OF POISON ABSORPTION Gastrointestinal
Decontamination Whether or not to perform gastrointestinal decon-
tamination, and which procedure to use, depends on the time since inges-
tion; the existing and predicted toxicity of the ingestant; the availability,
efficacy, and contraindications of the procedure; and the nature, severity,
and risk of complications. The efficacy of activated charcoal, gastric lavage,
and syrup of ipecac decreases with time, and there are insufficient data to
support or exclude a beneficial effect when they are used >1 h after inges-
tion. The average time from ingestion to presentation for treatment is >1 h
for children and >3 h for adults. Most patients will recover from poisoning
uneventfully with good supportive care alone, but complications of gas-
trointestinal decontamination, particularly aspiration, can prolong this pro-
cess. Hence, gastrointestinal decontamination should be performed
selectively, not routinely, in the management of overdose patients. It is
clearly unnecessary when predicted toxicity is minimal or the time of ex-
pected maximal toxicity has passed without significant effect.
Activated charcoal has comparable or greater efficacy, fewer contraindi-
cations and complications, and is less aversive and invasive than ipecac or
gastric lavage; thus it is the preferred method of gastrointestinal decon-
tamination in most situations. Activated charcoal suspension (in water) is
given orally via a cup, straw, or small-bore nasogastric tube. The recom-
mended dose is 1 g/kg body weight. Palatability may be increased by add-
ing a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola
syrup) to the suspension. Charcoal adsorbs ingested poisons within the
gut lumen, allowing the charcoal-toxin complex to be evacuated with
stool. In vitro, charcoal adsorbs ≥90% of most substances when given in an
amount equal to 10 times the weight of the substance. Charged (ionized)
chemicals such as mineral acids, alkalis, and highly dissociated salts of cya-
nide, fluoride, iron, lithium, and other inorganic compounds are not well
 e286 adsorbed by charcoal. In animal and human volunteer studies, charcoal
decreases the absorption of ingestants by an average of 73% when given
within 5 min of ingestant administration, 51% when given at 30 min, and
36% at 60 min. Side effects of charcoal include nausea, vomiting, and diar-
rhea or constipation. Charcoal may also prevent the absorption of orally
administered therapeutic agents. Complications include mechanical ob-
struction of the airway, aspiration, vomiting, and bowel obstruction and in-
farction caused by inspissated charcoal. Charcoal is not recommended for
patients who have ingested corrosives because it obscures endoscopy.
Gastric lavage is performed by sequentially administering and aspirating
~5 mL fluid per kilogram of body weight through a no. 40 French orogastric
tube (no. 28 French tube for children). Except for infants, where normal sa-
line is recommended, tap water is acceptable. The patient should be placed
in Trendelenburg and left lateral decubitus positions to prevent aspiration
PART 17
(even if an endotracheal tube is in place). Lavage decreases ingestant ab-
sorption by an average of 52% if performed within 5 min of ingestion ad-
ministration, 26% if performed at 30 min, and 16% if performed at 60 min.
Its efficacy is similar to that of ipecac. Significant amounts of ingested drug
are recovered in ~10% of patients. Aspiration is a common complication
(occurring in up to 10% of patients), especially when lavage is perfomed im-
properly. Serious complications (esophageal and gastric perforation, tube
Poisoning, Drug Overdose, and Envenomation
misplacement in the trachea) occur in ~1% of patients. For this reason, the
physician should personally insert the lavage tube and confirm its place-
ment, and the patient must be cooperative or adequately restrained (with
pharmacologic sedation if necessary) during the procedure. Gastric lavage
is contraindicated in corrosive or petroleum distillate ingestions because of
the respective risks of gastroesophageal perforation and aspiration pneu-
monitis. 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. Finally, gastric lavage is absolutely
contraindicated in combative patients or those who refuse, as most pub-
lished complications involve patient resistance to the procedure.
Syrup of ipecac, once the most commonly used decontamination proce-
dure, has no role in the hospital setting. Even the American Academy of Pedi-
atrics (AAP), traditionally the strongest proponent of ipecac, issued a policy
statement in 2003 recommending that ipecac should no longer be used in
poisoning treatment. Some argue it can still be considered for the home
management of patients with unintentional ingestions, reliable histories,
and mild predicted toxicity when transport to a hospital site is prolonged. Ip-
ecac irritates the stomach and stimulates the central chemoreceptor trigger
zone. Vomiting usually occurs about 20 min after administration. Nausea and
vomiting from ipecac may prevent use of other, more effective decontami-
nation procedures. Chronic ipecac use (by patients with anorexia nervosa or
bulimia) may cause electrolyte and fluid abnormalities, cardiac toxicity, and
myopathy. Except for aspiration, serious complications (e.g., gastric or esoph-
ageal tears and perforations) are rare. Ipecac is contraindicated in patients
with recent gastrointestinal surgery, CNS depression, or seizures, and in
those who have ingested corrosives or rapidly acting CNS poisons (camphor,
cyanide, tricyclic antidepressants, propoxyphene, strychnine).
Whole-bowel irrigation is performed by administering a bowel-cleansing
solution containing electrolytes and polyethylene glycol (Golytely, Colyte)
orally or by gastric tube at a rate of 2.0 L/h (0.5 L/h in children) until rectal
effluent is clear. The patient must be in a sitting position. Although data are
limited, whole-bowel irrigation appears to be as effective as other decon-
tamination procedures. It is most appropriate for those who have ingested
foreign bodies, packets of illicit drugs, slow-release or enteric-coated medi-
cations, and agents that are poorly adsorbed by charcoal (e.g., heavy met-
als). It is contraindicated in patients with bowel obstruction, ileus,
hemodynamic instability, and compromised unprotected airways.
Cathartics are salts (disodium phosphate, magnesium citrate and sulfate,
sodium sulfate) or saccharides (mannitol, sorbitol) that promote the rectal
evacuation of gastrointestinal contents. The most effective cathartic is sor-
bitol in a dose of 1–2 g/kg of body weight. Alone, cathartics do not prevent
ingestant absorption and should not be used as a method of gut decon-
tamination. Their primary use is to prevent constipation following a single
dose of charcoal. Abdominal cramps, nausea, and occasional vomiting are
side effects. Complications of repeated dosing include hypermagnesemia
(from magnesium salts) and excessive diarrhea. Cathartics are contraindica-
ted in patients who have ingested corrosives and in those with preexisting
diarrhea. Magnesium-containing cathartics should not be used in patients
with renal failure.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Dilution (i.e., drinking 5 mL/kg of body weight of water or another clear
liquid) is recommended only after the ingestion of corrosives (acids, alkali). It
may increase the dissolution rate (and hence absorption) of capsules, tablets,
and other solid ingestants and should not be used in these circumstances.
Endoscopic or surgical removal of poisons may be useful in rare situa-
tions, such as ingestion of a potentially toxic foreign body that fails to tran-
sit the gastrointestinal tract, a potentially lethal amount of a heavy metal
(arsenic, iron, mercury, thallium), or agents that have coalesced into gastric
concretions or bezoars (barbiturates, glutethimide, heavy metals, lithium,
meprobamate, salicylates, sustained-release preparations). Patients who
become toxic from cocaine due to its leakage from ingested drug packets
require immediate surgical intervention.
Decontamination of Other Sites Immediate, copious flushing with
water, saline, or another available clear, drinkable liquid is the initial treat-
ment for topical exposures (exceptions include alkali metals, calcium oxide,
phosphorus). Saline is preferred for eye irrigation. A triple wash (water,
soap, water) may be best for dermal decontamination. Inhalational expo-
sures should be treated initially with fresh air or oxygen. The removal of liq-
uids from body cavities such as the vagina or rectum is best accomplished
by irrigation. Solids (drug packets, pills) should be removed manually, pref-
erably under direct visualization.
ENHANCEMENT OF POISON ELIMINATION Although the elimi-
nation of most poisons can be accelerated by therapeutic interventions,
the pharmacokinetic efficacy (removal of drug at a rate greater than that
accomplished by intrinsic elimination) and clinical benefit (shortened du-
ration of toxicity or improved outcome) of such interventions are often
more theoretical than proven. Hence, the decision to use such measures
should be based on the actual or predicted toxicity and the potential effi-
cacy, cost, and risks of therapy.
Multiple-Dose Activated Charcoal Repetitive oral dosing with char-
coal can enhance the elimination of previously absorbed substances by
binding them within the gut as they are excreted in the bile, secreted by
gastrointestinal cells, or passively diffuse into the gut lumen (reverse ab-
sorption or enterocapillary exsorption). Doses of 0.5–1 g/kg body weight
every 2–4 h, adjusted downward to avoid regurgitation in patients with de-
creased gastrointestinal motility, are generally recommended. Pharmacoki-
netic efficacy approaches that of hemodialysis for some agents (e.g.,
phenobarbital, theophylline). Multiple-dose therapy should be considered
only for selected agents (theophylline, phenobarbital, carbamazepine, dap-
sone, quinine) and is not effective in accelerating elimination of chlorpropa-
mide, tobramycin, or agents that adsorb poorly to charcoal. Complications
include intestinal obstruction, pseudoobstruction, and nonocclusive intesti-
nal infarction in patients with decreased gut motility. Sorbitol and other ca-
thartics are absolutely contraindicated when administering multiple doses
of activated charcoal because of electrolyte and fluid shifts.
Urinary Alkalinization Ion trapping via alteration of urine pH may pre-
vent the renal reabsorption of poisons that undergo excretion by glomeru-
lar filtration and active tubular secretion. Since membranes are more
permeable to nonionized molecules than to their ionized counterparts,
acidic (low-pKa) poisons are ionized and trapped in alkaline urine, whereas
basic ones become ionized and trapped in acid urine. Urinary alkalinization
(producing a urine pH ≥7.5 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, chlorpropamide, diflunis-
al, fluoride, methotrexate, phenobarbital, sulfonamides, and salicylates.
Contraindications include congestive heart failure, renal failure, and cere-
bral edema. Acid-base, fluid, and electrolyte parameters should be moni-
tored carefully. While making theoretical sense for some overdoses
(amphetamines), acid diuresis is never indicated and is potentially harmful.
Extracorporeal Removal Peritoneal dialysis, hemodialysis, charcoal or
resin hemoperfusion, hemofiltration, plasmapheresis, and exchange trans-
fusion are capable of removing any toxin from the bloodstream. Agents
most amenable to enhanced elimination by dialysis have low molecular
mass (<500 Da), high water solubility, low protein binding, small volumes
of distribution (<1 L/kg body weight), prolonged elimination (long half-
life), and high dialysis clearance relative to total-body clearance. Molecular
weight, water solubility, or protein binding do not limit the efficacy of the
other forms of extracorporeal removal.
 Dialysis should be considered in cases of severe poisoning due to acetone,
barbiturates, bromide, carbamazepine, chloral hydrate, ethanol, ethylene gly-
col, isopropyl alcohol, lithium, methanol, procainamide, theophylline, salicyl-
ates, and valproate. Although hemoperfusion may be more effective in
removing some of these poisons, it does not correct associated acid-base and
electrolyte abnormalities, and most hospitals no longer have hemoperfusion
cartridges readily available. Fortunately, recent advances in hemodialysis
technology make it useful for removing poisons such as caffeine, carbamaze-
pine, carbon tetrachloride, chloramphenicol, dapsone, disopyramide, hyp-
notic-sedatives (barbiturates, ethchlorvynol, glutethimide, meprobamate,
methaqualone), methotrexate, mushrooms (amatoxin-containing), paraquat,
phenytoin, procainamide, theophylline, and valproate. Both techniques re-
quire central venous access and systemic anticoagulation and often result in
those with potentially prolonged, irreversible, or fatal toxicity; those with e287
dangerous blood levels of toxins; those who lack the capacity for self-
detoxification because of liver or renal failure; and those with a serious un-
derlying illness or complication that will adversely affect recovery.
Other Techniques The elimination of heavy metals can be enhanced
by chelation, and the removal of carbon monoxide can be increased by hy-
perbaric oxygenation.
ADMINISTRATION OF ANTIDOTES Antidotes counteract the ef-
fects of poisons by neutralizing them (e.g., antibody-antigen reactions,
chelation, chemical binding) or by antagonizing their physiologic effects
(e.g., activation of opposing nervous system activity, provision of competi-

CHAPTER e35 Poisoning and Drug Overdosage

transient hypotension. Hemoperfusion may also cause hemolysis, hypocalce-
mia, and thrombocytopenia. Peritoneal dialysis and exchange transfusion are
less effective but may be used when other procedures are either not available,
contraindicated, or technically difficult (e.g., in infants). Exchange transfu-
sion may be indicated in the treatment of severe arsine- or sodium chlorate–
induced hemolysis, methemoglobinemia, and sulfhemogloginemia. Although
hemofiltration can enhance elimination of aminoglycosides, vancomycin,
and metal-chelate complexes, the roles of hemofiltration and plasmapheresis
in the treatment of poisoning are not yet defined.
Candidates for extracorporeal removal therapies include patients with
severe toxicity who deteriorate despite aggressive supportive therapy;
tive metabolic or receptor substrate). Poisons or conditions with specific
antidotes include acetaminophen, anticholinergic agents, anticoagulants,
benzodiazepines, beta blockers, calcium channel blockers, carbon monox-
ide, cardiac glycosides, cholinergic agents, cyanide, drug-induced dystonic
reactions, ethylene glycol, fluoride, heavy metals, hydrogen sulfide, hy-
poglycemic agents, isoniazid, membrane-active agents, methemoglobin-
emia, opioids, sympathomimetics, and a variety of envenomations.
Antidotes can significantly reduce morbidity and mortality but are poten-
tially toxic if used for inappropriate reasons. Since their safe use requires
correct identification of a specific poisoning or syndrome, details of anti-
dotal therapy are discussed with the conditions for which they are indicat-
ed (Table e35-4).

TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS
Physiologic
Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments
Stimulated

Sympathetics (see also Chap. 389)

Sympathomimetics α1-Adrenergic agonists
(decongestants): phenyl-
ephrine, phenylpropano-
lamine
β2-Adrenergic agonists
(bronchodilators): al-
buterol, terbutaline
Nonspecific adrenergic
agonists: amphetamines,
cocaine, ephedrine
Ergot alkaloids Ergotamine, methysergide,
bromocriptine, pergolide
Methylxanthines Caffeine, theophylline
Stimulation of central and
peripheral sympathetic
receptors directly or indi-
rectly (by promoting the
release or inhibiting the
reuptake of norepineph-
rine and sometimes
dopamine)
Stimulation and inhibition
of serotonergic and α-ad-
renergic receptors; stimu-
lation of dopamine
receptors
Inhibition of adenosine syn-
thesis and adenosine re-
ceptor antagonism;
stimulation of epineph-
rine and norepinephrine
release; inhibition of
phosphodiesterase result-
ing in increased intracellu-
lar cyclic adenosine and
quanosine monophos-
phate
Physiologic stimulation (Ta-
ble e35-2); reflex brady-
cardia can occur with
selective α1 agonists; β
agonists can cause hypo-
tension and hypokalemia.
Physiologic stimulation (Ta-
ble e35-2); formication;
vasospasm with limb (iso-
lated or generalized), my-
ocardial, and cerebral
ischemia progressing to
gangrene or infarction;
hypotension, bradycardia,
and involuntary move-
ments can also occur.
Physiologic stimulation (Ta-
ble e35-2); pronounced
gastrointestinal symp-
toms and β agonist ef-
fects (see above). Toxicity
occurs at lower drug lev-
els in chronic poisoning
than in acute poisoning.
Phentolamine, a nonselective α1-
adrenergic receptor antagonist,
for severe hypertension due to
α1-adrenergic agonists; propran-
olol, a nonselective β blocker, for
hypotension and tachycardia
due to β2 agonists; labetalol, a β
blocker with α-blocking activity,
or phentolamine with esmolol,
metoprolol, or other cardioselec-
tive β blocker for hypertension
with tachycardia due to nonse-
lective agents (β blockers, if used
alone, can exacerbate hyperten-
sion and vasospasm due to un-
opposed α stimulation);
benzodiazepines; propofol.
Nitroprusside or nitroglycerine for
severe vasospasm; prazocin (an
α1 blocker), captopril, nifedi-
pine, and cyproheptidene (a se-
rotonin receptor antagonist) for
mild to moderate limb is-
chemia; dopamine receptor an-
tagonists (antipsychotics) for
hallucinations and movement
disorders
Propranolol, a nonselective β
blocker, for tachycardia with hy-
potension; any β blocker for su-
praventricular or ventricular
tachycardia without hypoten-
sion; elimination enhanced by
multiple-dose charcoal, hemo-
perfusion, and hemodialysis; in-
dications for hemoperfusion or
hemodialysis include unstable
vital signs, seizures, and a theo-
phylline level of 80−100 μg/mL
after acute overdose and 40−60
μg/mL with chronic exposure.
(continued)

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

 e288 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED)
Physiologic
Condition, Causes Examples
Monoamine oxidase Phenelzine, tranylcyprom-
inhibitors ine, selegiline
Anticholinergics
Antihistamines Diphenhydramine, doxy-
lamine, pyrilamine
Antiparkinsonian Amantidine,
PART 17
agents trihexiphenydyl
Antipsychotics Chlorpromazine, olanza-
pine, quetiapine,
thioridazine
Antispasmotics Clinidium, dicyclomine
Belladonna alkaloids Atropine, hyoscyamine,
scopolamine
Cyclic antidepressants Amitriptyline, doxepin,
Poisoning, Drug Overdose, and Envenomation
imipramine
Muscle relaxants Cyclobenzaprine,
orphenadrine
Mushrooms and Amanita muscaria and A.
plants pantherina, henbane,
jimson weed, nightshade
Depressed
Sympatholytics
α2-Adrenergic Clonidine, guanabenz, tet-
agonists rahydrozoline and other
imidazoline deconges-
tants, tizanidine and other
imidazoline muscle
relaxants
Antipsychotics Chlorpromazine, clozapine,
haloperidol, risperidone,
thioridazine
β-Adrenergic Cardioselective (β1) block-
blockers ers: atenolol, esmolol,
metoprolol
Nonselective (β1 and β2)
blockers: nadolol, pro-
pranolol, timolol
Partial β agonists: acebu-
tolol, pindolol
α1 Antagonists: carvedilol,
labetalol
Membrane-active agents:
acebutolol, propranolol,
sotalol
Calcium channel Diltiazem, nifedipine and
blockers other dihydropyridine de-
rivatives, verapamil
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Mechanism of Action
Inhibition of monoamine
oxidase resulting in im-
paired metabolism of
endogenous catechol-
amines and exogenous
sympathomimetic agents
Inhibition of central and
postganglionic parasym-
pathetic muscarinic cho-
linergic receptors. At high
doses, amantidine, di-
phenhydramine, or-
phenadrine,
phenothiazines, and tri-
cyclic antidepressants
have additional nonanti-
cholinergic activity (see
below).
Stimulation of α2-adrener-
gic receptors leading to in-
hibition of CNS
sympathetic outflow; ac-
tivity at nonadrenergic imi-
dazoline binding sites also
contributes to CNS effects.
Inhibition of α-adrenergic,
dopaminergic, histamin-
ergic, muscarinic, and se-
rotonergic receptors.
Some agents also inhibit
sodium, potassium, and
calcium channels.
Inhibition of β-adrenergic
receptors (class II antiar-
rhythmic effect). Some
agents have activity at ad-
ditional receptors or have
membrane effects (see
below).
Inhibition of slow (type L)
cardiovascular calcium
channels (class IV antiar-
rhythmic effect).
Clinical Features
Delayed or slowly progres-
sive physiologic stimula-
tion (Table e35-2); terminal
hypotension and bradycar-
dia in severe cases.
Physiologic stimulation (Ta-
ble e35-2); dry skin and
mucous membranes, de-
creased bowel sounds,
flushing, and urinary re-
tention; myoclonus and
picking activity. Central ef-
fects may occur without
significant autonomic
dysfunction.
Physiologic depression (Ta-
ble e35-2), miosis. Tran-
sient initial hypertension
may be seen.
Physiologic depression (Ta-
ble e35-2), miosis, anticho-
linergic effects (see above),
extrapyramidal reactions
(see below), tachycardia.
Cardiac conduction delays
(increased PR, QRS, JT, and
QT intervals) with ventricu-
lar tachydysrhythmias, in-
cluding torsades des
pointes, can sometimes
develop.
Physiologic depression (Ta-
ble e35-2), atrioventricu-
lar block, hypoglycemia,
hyperkalemia, seizures.
Partial agonists can cause
hypertension and tachy-
cardia. Sotalol can cause
increased QT interval and
ventricular tachydysrhyth-
mias. Onset may be de-
layed after sotalol and
sustained-release formu-
lation overdose.
Physiologic depression (Table
e35-2), atrioventricular
block, organ ischemia and
infarction, hyperglycemia,
seizures. Hypotension is
usually due to decreased
vascular resistance rather
than to decreased cardiac
output. Onset may be de-
layed for ≥12 h after over-
dose of sustained-release
formulations.
Specific Treatments
Short-acting agents (e.g., nitro-
prusside, esmolol) for severe hy-
pertension and tachycardia;
direct-acting sympathomimet-
ics (e.g., norepinephrine, epi-
nephrine) for hypotension and
bradycardia
Physostigmine, an acetylcho-
linesterase inhibitor (see be-
low) for delirium, hallucinations,
and neuromuscular hyperactiv-
ity. Contraindications include
nonanticholinergic cardiovas-
cular toxicity (e.g., cardiac con-
duction abnormalities,
hypotension, and ventricular
arrhythmias).
Dopamine and norepinephrine
for hypotension. Atropine for
symptomatic bradycardia.
Naloxone for CNS depression
(inconsistently effective).
Sodium bicarbonate and lido-
caine for ventricular tachydys-
rhythmias associated with QRS
prolongation. Magnesium, iso-
proterenol, and overdrive pac-
ing for torsades de pointes.
Avoid class IA, IC, and III antiar-
rhythmics.
Glucagon and calcium for hy-
potension and symptomatic
bradycardia. Atropine, isopro-
terenol, amrinone, dopamine,
dobutamine, epinephrine, and
norepinephrine may some-
times be effective. High-dose
insulin (with glucose and potas-
sium to maintain euglycemia
and normokalemia), electrical
pacing, and mechanical cardio-
vascular support for refractory
cases.
Calcium and glucagon for hy-
potension and symptomatic
bradycardia. Dopamine, epineph-
rine, norepinephrine, atropine,
and isoproterenol are less often
effective but can be used adjunc-
tively. Amrinone, high-dose insu-
lin (with glucose and potassium
to maintain euglycemia and
normokalemia), electrical pacing,
and mechanical cardiovascular
support for refractory cases.
(continued)
TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED)
Physiologic
Condition, Causes Examples
Cardiac glycosides Digoxin, endogenous car-
dioactive steroids, fox-
glove and other plants,
toad skin secretions (Bu-
fonidae sp.)
Cyclic Amitriptyline, doxepin,
antidepressants imipramine
Cholinergics
Acetylcholinesterase Carbamate insecticides (al-
inhibitors dicarb, carbaryl, pro-
poxur) and medicinals
(neostigmine, physostig-
mine, tacrine); nerve
gases (sarin, soman,
tabun, VX) organophos-
phate insecticides (diazi-
non, chlopyriphos,
malathion)
Muscarinic agonists Bethanecol, mushrooms
(Boletus, Clitocybe, Inocybe
sp.), pilocarpine
Nicotinic agonists Lobeline, nicotine (tobacco)
Sedative-hypnotics (see also Chap. 388)
Anticonvulsants Carbamazepine, ethosuxi-
mide, felbamate, gaba-
pentin, lamotrigine,
levetiracetam, oxcarba-
zepine, phenytoin, tiagab-
ine, topiramate, valproate,
zonisamide
Barbiturates Short-acting: butabarbital,
pentobarbital, secobarbital
Long-acting: phenobar-
bital, primadone
Benzodiazepines Ultrashort-acting:
estazolam, midazolam,
temazapam, triazolam
Short-acting: alprazolam,
flunitrazepam, lorazepam,
oxazepam
Long-acting: chlordiazep-
oxide, clonazepam, diaz-
epam, flurazepam
Pharmacologically related
agents: zaleplon, zolpidem
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Mechanism of Action
Inhibition of cardiac Na+, K+-
ATPase membrane pump.
Inhibition of α-adrenergic
dopaminergic, GABA-ergic,
histaminergic, muscarinic,
and serotonergic recep-
tors; inhibition of sodium
channels (see membrane-
active agents); inhibition of
norepinephrine and sero-
tonin reuptake.
Inhibition of acetylcho-
linesterase leading to in-
creased synaptic
acetylcholine at musca-
rinic and nicotinic cholin-
ergic receptor sites
Stimulation of CNS and
postganglionic parasym-
pathetic cholinergic (mus-
carinic) receptors
Stimulation of pregangli-
onic sympathetic and
parasympathetic and stri-
ated muscle (neuromus-
cular junction) cholinergic
(nicotine) receptors
Potentiation of the inhibi-
tory effects of GABA by
binding to the neuronal
GABA-A chloride channel
receptor complex and in-
creasing the frequency or
duration of chloride chan-
nel opening in response to
GABA stimulation. Baclo-
fen and, to some extent,
GHB act at the GABA-B
rector complex; meproba-
mate, its metabolite cari-
soprodol, felbamate, and
orphenidrine antagonize
N-methyl-D-aspartate
(NDMA) excitatory recep-
tors; ethosuximide, val-
proate, and zonisamide
decrease conduction
through T-type calcium
channels; valproate
Clinical Features
Physiologic depression (Ta-
ble e35-2); gastrointesti-
nal, psychiatric, and visual
symptoms; atrioventricu-
lar block with or without
concomitant supraven-
tricular tachyarrhythmia;
ventricular tachyarrhyth-
mias. Hyperkalemia in
acute poisoning. Toxicity
occurs at lower drug levels
in chronic poisoning than
in acute poisoning.
Physiologic depression (Table
e35-2), seizures, tachycar-
dia, cardiac conduction de-
lays (increased PR, QRS, JT,
and QT intervals; terminal
QRS right axis deviation)
with aberrancy and ventric-
ular tachydysrhythmias. An-
ticholinergic toxidrome
(see above).
Physiologic depression (Ta-
ble e35-2). Muscarinic
signs and symptoms: sei-
zures, excessive secretions
(lacrimation, salivation,
bronchorrhea and wheez-
ing, diaphoresis), and in-
creased bowel and
bladder activity with nau-
sea, vomiting, diarrhea,
abdominal cramps, and
incontinence of feces and
urine. Nicotinic signs and
symptoms: hypertension,
tachycardia, muscle
cramps, fasciculations,
weakness, and paralysis.
Death is usually due to
respiratory failure. Cholin-
esterase activity in plasma
and red cells <50% of nor-
mal in acetylcholinest-
erase inhibitor poisoning.
Physiologic depression (Ta-
ble e35-2), nystagmus.
Delayed absorption can
occur with carbamaze-
pine, phenytoin, and val-
proate. Myoclonus,
seizures, hypertension,
and tachyarrhythmias
can occur with baclofen,
carbamazepine, and
orphenadrine.
Tachyarrhythias can also
occur with chloral hy-
drate. AGMA, hypernatre-
mia, hyperosmolality,
hyperammonemia, chemi-
cal hepatitis, and hypo-
glycemia can be seen in
valproate poisoning. Car-
bamazepine and oxcarba-
zepine may produce
hyponatremia from SIADH.
e289
Specific Treatments
Digoxin-specific antibody frag-
ments for hemodyamically com-
promising dysrhythmias, Mobitz II
or third-degree atrioventricular
block, hyperkalemia (>5.5 meq/L;
in acute poisoning only). Tempo-
rizing measures include atropine,
dopamine, epinephrine, pheny-
toin, and external cardiac pacing
CHAPTER e35 Poisoning and Drug Overdosage
for bradydysrhythmias and mag-
nesium, lidocaine, phenytoin, and
bretylium for ventricular tachydys-
rhythmias. Internal cardiac pacing
and cardioversion can increase
ventricular irritability and should
be reserved for refractory cases.
Hypertonic sodium bicarbonate
(or hypertonic saline) and lido-
caine for ventricular tachydys-
rhythmias associated with QRS
prolongation. Use of phenytoin
is controversial. Avoid class IA,
IC, and III antiarrhythmics.
Atropine for muscarinic signs and
symptoms. Pralidoxime (2-
PAM), a cholinesterase reactiva-
tor, for nicotinic signs and
symptoms due to organophos-
phates, nerve gases, or an un-
known anticholinesterase.
Flumazenil for benzodiazepine
and zolpidem poisoning. Ben-
zodiazepines and barbiturates
for seizures. Elimination of phe-
nobarbital and possibly other
long-acting agents enhanced
by multiple-dose charcoal. He
modialysis and hemoperfusion
may be indicated for severe
poisoning by some agents (see
Extracorporeal Removal, in text).
See above and below for treat-
ment of anticholinergic and so-
dium channel (membrane)
blocking effects.
(continued)
 e290 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED)
Physiologic
Condition, Causes Examples
GABA precursors γ-Hydroxybutyrate (so-
dium oxybate; GHB), γ-
butyrolactone (GBL), 1,4-
butanediol.
Muscle relaxants Baclofen, carisoprodol, cy-
clobenzaprine, etomidate,
metaxalone, methocar-
bamol, orphenadrine, pro-
pafol, tizanidine and other
imidazoline muscle
relaxants.
PART 17
Other agents Chloral hydrate, ethclorvynol,
glutethimide, meproba-
mate, methaqualone,
methyprylon
Discordant
Asphyxiants
Cytochrome oxi- Carbon monoxide, cya-
Poisoning, Drug Overdose, and Envenomation
dase inhibitors nide, hydrogen sulfide
Methemoglobin Aniline derivatives, dap-
inducers sone, local anesthetics,
nitrates, nitrites, nitrogen
oxides, nitro- and ni-
trosohydrocarbons,
phenazopyridine, pri-
maquine-type antimalari-
als, sulfonamides.
AGMA inducers Ethylene glycol
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Mechanism of Action
decreases GABA degrada-
tion, and tiagabine blocks
GABA reuptake; carba-
mazepine, lamotrigine,
oxcarbazepine, phenytoin,
topiramate, valproate, and
zonisamide slow the rate
of recovery of inactivated
sodium channels. Some
agents also have α2 ago-
nist, anticholinergic, and
sodium channel blocking
activity (see above and
below).
Inhibition of mitochron-
drial cytochrome oxi-
dase, thereby blocking
electron transport and
oxidative metabolism.
Carbon monoxide also
binds to hemoglobin
and myoglobin and pre-
vents oxygen binding,
transport, and tissue up-
take (binding to hemo-
globin shifts the oxygen
dissociation curve to the
left).
Oxidation of hemoglobin
iron from ferrous (Fe2+)
to ferric (Fe3+) state pre-
vents oxygen binding,
transport, and tissue up-
take (methemoglobin-
emia shifts oxygen
dissociation curve to the
left). Oxidation of hemo-
globin protein causes he-
moglobin precipitation
and hemolytic anemia
(manifest as Heinz bod-
ies and “bite cells” on pe-
ripheral blood smear).
Ethylene glycol causes CNS
depression and in-
creased serum osmolal-
ity. Metabolites (primarily
glycolic acid) cause
AGMA, CNS depression,
and renal failure. Precipi-
tation of oxalic acid me-
tabolite as calcium salt in
tissues and urine results
in hypocalcemia, tissue
edema, and crystalluria.
Clinical Features
Some agents can cause anticho-
linergic and sodium channel
(membrane) blocking effects
(see above and below).
Signs and symptoms of hypoxia
with initial physiologic stimula-
tion and subsequent depression
(Table e35-2); lactic acidosis; nor-
mal PO2 and calculated oxygen
saturation but decreased oxy-
gen saturation by co-oximetry
(that measured by pulse oxime-
try is falsely elevated but is less
than normal and less than the
calculated value). Headache and
nausea are common with car-
bon monoxide. Sudden col-
lapse may occur with cyanide
and hydrogen sulfide exposure.
A bitter almond breath odor
may be noted with cyanide in-
gestion, and hydrogen sulfide
smells like rotten eggs.
Signs and symptoms of hypoxia
with initial physiologic stimula-
tion and subsequent depres-
sion (Table e35-2), gray-brown
cyanosis unresponsive to oxy-
gen at methemoglobin frac-
tions > 15–20%, headache,
lactic acidosis (at methemoglo-
bin fractions > 45%), normal PO2
and calculated oxygen satura-
tion but decreased oxygen sat-
uration 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).
Initial ethanol-like intoxication,
nausea, vomiting, increased
osmolar gap, calcium oxylate
crystalluria. Delayed AGMA,
back pain, renal failure. Coma,
seizures, hypotension, ARDS
in severe cases.
Specific Treatments
High-dose oxygen. Inhaled amyl ni-
trite and IV sodium nitrite and so-
dium thiosulfate (Lilly cyanide
antidote kit) for coma, metabolic
acidosis, and cardiovascular dys-
function in cyanide poisoning.
Amyl and sodium nitrite (without
thiosulfate) for similar toxicity in
hydrogen sulfide poisoning. Hy-
perbaric oxygen for moderate to
severe carbon monoxide poison-
ing and for cyanide or hydrogen
sulfide poisoning unresponsive to
other measures.
High-dose oxygen. Intravenous
methylene blue for methemoglo-
bin fraction > 30%, symptomatic
hypoxia, or ischemia (contraindica-
ted in G6PD deficiency). Exchange
transfusion and hyperbaric oxygen
for severe or refractory cases.
Gastric aspiration for recent ingestions.
Sodium bicarbonate to correct acide-
mia. Thiamine, folinic acid, magne-
sium, and high-dose pyridoxine to
facilitate metabolism. Ethanol or fo-
mepizole for AGMA, crystalluria or
renal dysfunction, ethylene glycol
level > 3 mmol/L (20 mg/dL), and for
ethanol-like intoxication or increased
osmolal gap if level not readily ob-
tainable. Hemodialysis for persistent
AGMA, lack of clinical improvement,
and renal dysfunction. Hemodialysis
also useful for enhancing ethylene
glycol elimination and shortening
duration of treatment when ethylene
glycol level > 8 mmol/L (50 mg/dL).
(continued)
TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED)
Physiologic
Condition, Causes Examples Mechanism of Action
AGMA inducers Iron Hydration of ferric (Fe3+) ion
generates H+. Non-trans-
ferrin-bound iron cata-
lyzes formation of free
radicals that cause mito-
chondrial injury, lipid per-
oxidation, increased
capillary permeability,
vasodilation, and organ
toxicity.
Methanol Methanol causes ethanol-
like CNS depression and
increased serum osmolal-
ity. Formic acid metabo-
lite causes AGMA and
retinal toxicity.
Salicylate Increased sensitivity of CNS
respiratory center to
changes in PO2 and PCO2
stimulates respiration. Un-
coupling of oxidative
phosphorylation, inhibi-
tion of Kreb’s cycle en-
zymes, and stimulation of
carbohydrate and lipid
metabolism generate un-
measured endogenous
anions and cause AGMA.
CNS syndromes
Extrapyramidal Antipsychotics (see above), Decreased CNS dopaminer-
reactions some cyclic antidepres- gic activity with relative ex-
sants and antihistamines. cess of cholinergic activity.
Isoniazid Interference with activation
and supply of pyridoxal-5-
phosphate, a cofactor for
glutamic acid decarboxy-
lase, which converts
glutamic acid to GABA, re-
sults in decreased levels of
this inhibitory CNS neu-
rotransmitter; complex-
ation with and depletion
of pyridoxine itself; inhibi-
tion of nicotine-adenine
dinucleotide dependent
lactate and hydroxybu-
tyrate dehydrogenases re-
sulting in substrate
accumulation.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Clinical Features
Initial nausea, vomiting, ab-
dominal pain, diarrhea.
AGMA, cardiovascular and
CNS depression, hepatitis,
coagulopathy, and sei-
zures in severe cases. Radi-
opaque iron tablets may
be seen on abdominal
x-ray.
Initial ethanol-like intoxica-
tion, nausea, vomiting, in-
creased osmolar gap.
Delayed AGMA, visual
(clouding, spots, blind-
ness) and retinal (edema,
hyperemia) abnormali-
ties. Coma, seizures, car-
diovascular depression in
severe cases. Possible
pancreatitis.
Initial nausea, vomiting, hy-
perventilation, alkalemia, al-
kaluria. Subsequent
alkalemia with both respira-
tory alkalosis and AGMA,
and paradoxical aciduria.
Late acidemia with CNS
and respiratory depression.
Cerebral and pulmonary
edema in severe cases. Hy-
poglycemia, hypocalce-
mia, hypokalemia, and
seizures can occur.
Akathisia, dystonia,
parkinsonism
Nausea, vomiting, agita-
tion, confusion; coma, res-
piratory depression,
seizures, lactic and ke-
toacidosis in severe cases.
e291
Specific Treatments
Whole-bowel irrigation for large
ingestions. Endoscopy and gas-
trostomy if clinical toxicity and
large number of tablets still visi-
ble on x-ray. IV hydration. Sodi-
um bicarbonate for acidemia. IV
deferoxamine for systemic tox-
icity, iron level > 90 μmol/L (500
μg/dL).
CHAPTER e35 Poisoning and Drug Overdosage
Gastric aspiration for recent inges-
tions. Sodium bicarbonate to cor-
rect acidemia. High-dose folinic
acid or folate to facilitate metabo-
lism. Ethanol or fomepizole for
AGMA, visual symptoms, metha-
nol level > 6 mmol/L (20 mg/dL),
and for ethanol-like intoxication
or increased osmolal gap if level
not readily obtainable. Hemodial-
ysis for persistent AGMA, lack of
clinical improvement, and renal
dysfunction. Hemodialysis also
useful for enhancing methanol
elimination and shortening dura-
tion of treatment when metha-
nol level > 15 mmol/L (50 mg/dL).
IV hydration and supplemental
glucose. Sodium bicarbonate to
correct acidemia. Alkaline diure-
sis for systemic toxicity. Hemo-
dialysis for coma, cerebral
edema, seizures, pulmonary
edema, renal failure, progres-
sive acid-base disturbances or
clinical toxicity, salicylate level
> 7 mmol/L (100 mg/dL) fol-
lowing acute overdose.
Oral or parenteral anticholinergic
agent such as benztropine or
diphenhydramine.
High-dose intravenous pyridox-
ine (vitamin B6 ) for agitation,
confusion, coma, and seizures.
Diazepam or barbiturates for
seizures.
(continued)
 e292 TABLE e35-4 PATHOPHYSIOLOGIC FEATURES AND TREATMENT OF SPECIFIC TOXIC SYNDROMES AND POISONINGS (CONTINUED)
Physiologic
Condition, Causes Examples Mechanism of Action
Lithium Interference with cell mem-
brane ion transport,
adenylate cyclase and
Na+, K+-ATPase activity,
and neurotransmitter
release.
PART 17
Clinical Features
Nausea, vomiting, diarrhea,
ataxia, choreoathetosis,
encephalopathy, hyperre-
flexia, myoclonus, nystag-
mus, nephrogenic
diabetes insipidus, falsely
elevated serum chloride
with low anion gap,
tachycardia. Coma, sei-
zures, arrhythmias, hyper-
thermia, and prolonged
Specific Treatments
Whole-bowel irrigation for large
ingestions. Consider endo-
scopic removal if high and ris-
ing drug level with progressive
clinical toxicity. IV hydration.
Hemodialysis for coma, sei-
zures, severe, progressive, or
persistent encephalopathy or
neuromuscular dysfunction,
peak lithium level > 8 meq/L
(mmol/L) following acute

or permanent encepha- overdose.

lopathy and movement
disorders in severe cases.
Delayed onset after acute
overdose, particularly with
delayed-release forma-
tions. Toxicity occurs at
lower drug levels in
Poisoning, Drug Overdose, and Envenomation

chronic poisoning than in

Serotonin syndrome Amphetamines, cocaine,
dextromethorphan, mep-
eridine, MAO inhibitors,
selective serotonin (5HT)
reuptake inhibitors, tricyc-
lic antidepressants, trama-
dol, triptans, tryptophan.
Membrane-active Amantidine, antiarrhyth-
agents mics (class I and III agents;
some β blockers), antipsy-
chotics (see above), anti-
histamines (particularly
diphenhydramine), carba-
mazepine, local anesthet-
ics (including cocaine),
opioids (meperidine,
propoxyphene), orphen-
adrine, quinoline anti-
malarials (chloroquine,
hydroxychloroquine, qui-
nine), cyclic antidepres-
sants (see above).
Promotion of serotonin re-
lease, inhibition of seroto-
nin reuptake, or direct
stimulation of CNS and
peripheral serotonin re-
ceptors (primarily 5HT-1a
and 5HT-2), alone or in
combination.
Blockade of fast sodium
membrane channels pro-
longs phase 0 (depolariza-
tion) of the cardiac action
potential, which prolongs
the QRS duration and pro-
motes reentrant (mono-
morphic) ventricular
tachycardia. Class Ia, Ic,
and III antiarrhythmics
also block potassium
channels during phases 2
and 3 (repolarization) of
the action potential, pro-
longing the JT interval
and promoting early after-
depolarizations and poly-
morphic (torsades des
pointes) ventricular tachy-
cardia. Similar effects on
neuronal membrane
channels cause CNS dys-
function. Some agents
also block α-adrenergic
and cholinergic receptors
or have opioid effects (see
above and Chap. 388).
acute poisoning.
Altered mental status (agita- Serotonin receptor antagonist
tion, confusion, mutism, such as cyproheptadine or
coma, seizures), neuro- chlorpromazine.
muscular hyperactivity
(hyperreflexia, myoclo-
nus, rigidity, tremors), and
autonomic dysfunction
(abdominal pain, diar-
rhea, diaphoresis, fever,
flushing, labile hyperten-
sion, mydriasis, tearing,
salivation, tachycardia).
Complications include hy-
perthermia, lactic acido-
sis, rhabdomyolysis, and
multisystem organ failure.
QRS and JT prolongation (or Hypertonic sodium bicarbonate
both) with hypotension, (or hypertonic saline) for cardiac
ventricular tachyarrhyth- conduction delays and mono-
mias, CNS depression, sei- morphic ventricular tachycardia.
zures. Anticholinergic Lidocaine for monomorphic
effects with amantidine, ventricular tachycardia (except
antihistamines, carbamaz- when due to class Ib antiar-
epine, disopyramide, anti- rhythmics). Magnesium, isopro-
psychotics, and cyclic terenol, and overdrive pacing
antidepressants (see for polymorphic ventricular
above). Opioid effects with tachycardia. Physostigmine for
meperidine and pro- anticholinergic effects (see
poxyphene (see Chap. above). Naloxone for opioid ef-
388). Cinchonism (hearing fects (see Chap. 388). Extracor-
loss, tinnitus, nausea, vom- poreal removal for some agents
iting, vertigo, ataxia, head- (see text).
ache, flushing, diaphoresis)
and blindness with quino-
line antimalarials.

Note: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; dehydrogenase; MAO, monoamine oxidase; SIADH, syndrome of inappropriate antidi-
CNS, central nervous system; GABA, γ-aminobutyric acid; G6PD, glucose-6-phosphate uretic hormone.

PREVENTION OF REEXPOSURE Poisoning is a preventable illness. cations. Adults with unintentional exposures should be instructed regarding
Unfortunately, some adults and children are poison-prone, and recurrences the safe use of medications and chemicals (according to labeling instruc-
are common. Unintentional polypharmacy poisoning has become especially tions). Confused patients may need assistance with the administration of
common among adults with developmental delays and among the growing their medications. Errors in dosing by health care providers may require edu-
population of geriatric patients who are prescribed a large number of medi- cational efforts. Patients should be advised to avoid circumstances that result
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
in chemical exposure or poisoning. Appropriate agencies and health depart-
ments should be notified in cases of environmental or workplace exposure.
The best approach with young children and patients with intentional over-
dose (deliberate self-harm or suicide) is to limit their access to poisons. In
households where children live or visit, alcoholic beverages, medications,
household products (automotive, cleaning, fuel, pet-care, toiletry products),
nonedible plants, and vitamins should be kept out of reach or in locked or
child-proof cabinets. Depressed or psychotic patients should receive psychi-
atric assessment, disposition, and follow-up. They should be given prescrip-
tions for a limited supply of drugs and with a limited number of refills and be
monitored for compliance and response to therapy.
SPECIFIC TOXIC SYNDROMES AND POISONINGS
Table e35-4 summarizes the pathophysiology, clinical features, and
treatment of toxidromes and poisonings that are common, produce
life-threatening toxicity, or require unique therapeutic interventions.
In all cases, treatment should include attending to the general princi-
ples discussed above, particularly supportive care. Details regarding
specific therapies can be found in the references cited here and at
harrisonsonline.com. Poisonings not covered in this chapter are dis-
cussed in the referenced texts. Alcohol, cocaine, hallucinogen, and
opioid poisoning and alcohol and opioid withdrawal are discussed
in Chaps. 387 to 390; acetaminophen poisoning is discussed in
Chap. 299; the neuroleptic malignant syndrome is discussed in
Chap. 366; and heavy metal poisoning is discussed in Chap. e34.
FURTHER READINGS
AMERICAN ACADEMY OF CLINICAL TOXICOLOGY/EUROPEAN ASSOCIATION
OF POISONS CENTERS AND CLINICAL TOXICOLOGISTS: Position State-
ments on Gastrointestinal Decontamination: Introduction; Ipecac
syrup; Gastric lavage; Single-dose activated charcoal; Cathartics; Whole
bowel irrigation. Clin Toxicol 35:695, 699, 711, 721, 743, 753, 1997
BOSSE GM, MATYUNAS NJ: Delayed toxidromes. J Emerg Med 17:679, 1999
BRUNTON L et al (eds): Goodman and Gilman’s The Pharmacologic
Basis of Therapeutics, 11th ed. New York, McGraw-Hill, 2005
KLAASSEN CD (ed): Casarett and Doull’s Toxicology: The Basic Science
of Poisons, 6th ed. New York, McGraw-Hill, 2001
LAI MW et al: 2005 Annual Report of the American Association of
Poison Control Centers National Poisoning and Exposure Data-
base. Clin Toxicol 44(6-7):803, 2006
SZTAJNKRYCER MD et al: Development and implementation of an
emergency department observation unit protocol for deliberate
drug ingestion in adults—preliminary results. Clin Toxicol (Phila)
45(5):499, 2007
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of roofing fumes. Ann Emerg Med 15:826, 1986
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MILLS KC, CURRY SC: Acute iron poisoning. Emerg Med Clin North
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e36 Pulmonary Biomarkers in COPD
Peter J. 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). COPD
involves a specific pattern of inflammation in the respiratory tract and
lung parenchyma, with increased production of multiple inflammato-
ry mediators.1
A biomarker refers to the measurement of any molecule or material
(cells, tissue) that reflects the disease process. In COPD, several types
of biomarker have been measured that are related to disease pathobiol-
ogy and the inflammatory and destructive process in the lung. Here,
biomarkers in bronchial biopsies, sputum, bronchoalveolar lavage
(BAL), and exhaled breath are considered. Unfortunately, few of these
biomarkers have been validated, and there is little information about
their reproducibility and the relationship to disease severity or pro-
gression.2 A meta-analysis of biomarker measurements in 150,000 pa-
tients with COPD revealed the poor sensitivity of current biomarkers
to define clinical status and quantify the effect of treatment. Only spu-
tum neutrophils, interleukin (IL) 8, serum tumor necrosis factor
(TNF) α, and C-reactive protein (CRP) showed any trend towards
separating different stages of COPD.3 More research in this area is now
needed with repeated measurements in carefully phenotyped patients.
With the development of many new drugs that target inflammation in
COPD, there is a pressing need to identify reliable biomarkers that
may indicate whether an anti-inflammatory therapy is likely to have
clinical benefit. A major barrier is the lack of any “gold standard” anti-
inflammatory therapy that is effective in COPD, as are inhaled gluco-
corticoids in asthma, as a yardstick to compare potential therapies.
Many inflammatory cells, mediators, and enzymes are involved in
the complex pathobiology of COPD, and, as a result, there are many
possible biomarkers to study with a high degree of redundancy.1 Pul-
monary inflammation in COPD appears to increase with disease pro-
gression and increases during exacerbations. It is likely that some
biomarkers will prove to be much more useful than others in terms of
reproducibility of measurement, ease of assay, relationship to disease
severity, and predictability for assessing therapeutic efficacy. Some
biomarkers are more easily measurable and reliable than others and
are more easily applied in clinical studies, especially in multicenter
studies involving large numbers of patients. New assays may have
greater sensitivity and assay reproducibility; in addition, many novel
biomarkers may be identified by genomic and proteomic analyses of
COPD samples in the future.
BRONCHIAL BIOPSIES
Although the inflammation in COPD involves predominantly lung
parenchyma and small airways, bronchial biopsies appear to reflect at
least some of the cellular abnormalities described in peripheral lung
tissue. Bronchial biopsies are useful for documenting the structural
changes, cellular patterns, and expression of inflammatory proteins in
patients with COPD.4 In stable COPD, there is increased infiltration of
macrophages and activated T lymphocytes, particularly of CD8+ T
lymphocytes, which express interferon (IFN) γ, CXCL10 (IP-10), and
IL-9, and the pattern of inflammation differs substantially from that
described in asthma (Table e36-1). Moreover, these lymphocytes ex-
press chemokine receptors associated with a type 1 response, such as
CXCR3, in contrast to lymphocytes in asthma, which express chemo-
kine receptors typical of a type 2 response (chemokine receptor
CCR4). There is also a reduction in T cells expressing CCR5 in COPD.
While a prominent neutrophilia is present in the airway lumen of sta-
ble patients with COPD, it is not observed at the tissue level, except in
patients with severe airflow limitation. During exacerbations of the
disease, an increased recruitment of eosinophils and neutrophils has
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TABLE e36-1 MORPHOLOGIC CHANGES IN BRONCHIAL BIOPSIES e297
OF PATIENTS WITH COPD AND ASTHMA
Reticular basement
COPD
Within normal range
Asthma
Increased
membrane thickness
Inflammatory cell Macrophages Eosinophils, mast cells
infiltrate CD8+ T lymphocytes CD4+ T lymphocytes
Eosinophils and neu- Eosinophils and neu-
trophils during trophils during
exacerbations exacerbations
Neutrophils in severe Neutrophils in severe
disease disease
Cytokines, chemo- IFN-γ, CXCL10, IL-9, IL-4, IL-5, IL-9, IL-13,
kines, and receptors CXCR3 CCR4
Abbreviations: IFN, interferon; IL, interleukin; CXCL, CXC chemokine ligand; CCR, CC
chemokine receptor.
been described, which is associated with upregulation of specific
chemoattractants, such as CCL5 (RANTES) and CXCL5 (ENA-78).
Bronchial biopsies may give some insights into disease pathogene-
sis. For example, there is increased activation of the transcription fac-
CHAPTER e36 Pulmonary Biomarkers in COPD
tor nuclear factor-κB (NF-κB) in bronchial epithelial cells of COPD
patients, which increases with disease severity.5 There is also a reduc-
tion in histone deacetylase (HDAC) activity and HDAC2 expression in
bronchial biopsies of COPD patients compared to normal smokers
and nonsmokers, and this change is correlated with a reduction in NF-
κB activity and increased expression of inflammatory genes.6 These
changes in bronchial biopsies reflect the changes in NF-κB and HDAC
found in lung parenchyma.
Several studies have assessed the potential anti-inflammatory ef-
fects of treatments in bronchial biopsies of patients with COPD. These
studies usually involve either a baseline biopsy and then a second biop-
sy after a defined period of treatment, or a single biopsy at the end of
active treatment with a biopsy in a parallel group of patients taking
placebo therapy. Overall, inhaled glucocorticoids seem to have little ef-
fect on the airway inflammation typical of COPD, although they are
able to reduce mast cells, an effect associated with a reduction in the
frequency of exacerbations. 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 long-
acting β2-agonist, but these changes have not been related to function-
al or clinical improvements. However, further studies are required to
establish whether the airway inflammation in COPD can be success-
fully suppressed (as with glucocorticoids in asthma) and whether this
would result in significant clinical improvement.
The main advantage of endobronchial biopsies is that they directly
sample airway tissue, maintaining the spatial relationships of structur-
al components that may be important for functional changes. Unlike
sputum and BAL, bronchial biopsies provide an assessment of struc-
tural components of the airway wall, such as epithelium, basement
membrane, vessels, connective tissue, and, on occasion, smooth mus-
cle and submucosal glands. This means that biomarkers of structural
modification, apoptosis or uncontrolled proliferation, can be meas-
ured. Moreover, the different inflammatory cell subtypes can be iden-
tified by immunohistochemistry in their microenvironment, thus
allowing investigation of interactions between inflammatory and resi-
dent cells. Finally, individual structural components can be dissected
from the biopsies and studied in isolation using techniques recently
developed, such as laser microdissection.
Problems There are, however, several limitations to analysis of bron-
chial biopsies to assess outcome in COPD. Since this is an invasive pro-
cedure, it may be difficult to recruit patients, especially in studies
investigating treatment effects that require two biopsies (pre- and
posttreatment). The biopsy of proximal airways may not closely reflect
all the pathologic changes present in peripheral airways and lung pa-
renchyma, the primary sites responsible for airflow limitation in
COPD. Moreover, it may not be possible to apply this procedure to pa-
 e298 tients with more severe disease, complicated by cardiac comorbid con-
ditions and often associated with significant oxygen desaturation and
hypercapnia. There is also a relatively high variability in baseline mea-
surements of inflammatory cells, which necessitates multiple biopsies.
Finally, since studies evaluating the effect of treatment should be de-
signed to provide a power of at least 80%, a large number of patients
for each treatment group is usually required.
BRONCHOALVEOLAR LAVAGE
BAL has the advantage, unlike bronchial biopsies, of sampling inflam-
mation in the lung periphery. BAL can generally be safely performed,
provided careful assessment is performed and guidelines are followed.
In general, fluid recovery is greater in patients with less extensive em-
physema as assessed by diffusion capacity.7 BAL may be performed in
the same patients as bronchial biopsy, thus providing additional and
complementary information.
Cellular Composition The cellular composition in individuals with
COPD is predominantly (>80%) alveolar macrophages, with some neu-
trophils and T lymphocytes, and some patients having increased num-
bers of eosinophils. The percentages of macrophages and neutrophils
are usually higher than in healthy nonsmokers and healthy smokers.
PART 18
Studies investigating individuals with COPD, healthy smokers, and ex-
smokers show that smoking is generally associated with increased num-
bers of neutrophils. Numbers of lymphocytes are generally higher in
ex-smokers than in smokers, with or without COPD. Moreover, some
studies have shown that patients with COPD have higher eosinophil
percentages than healthy smokers. Alveolar macrophages, which may be
separated by adhesion and cultured in vitro for functional studies, from
e-Chapters from International Advisory Editors
COPD patients behave abnormally in tissue culture, with increased ex-
pression of inflammatory proteins, such as TNF-α, IL-8, and matrix
metalloproteinase (MMP) 9. Alveolar macrophages also show a reduc-
tion in expression and activity of HDAC2, which modulates the expres-
sion of inflammatory genes, with progressive reduction with disease
severity. The reduction in HDAC2 is associated with increased activa-
tion of the NF-κB. It may be possible in the future to study the effects of
treatment in patients on cellular behavior in vitro.
Mediators and Proteases Several inflammatory mediators can be
measured in BAL fluid. Levels of eosinophil cationic protein (ECP),
myeloperoxidase (MPO), and IL-8 are increased in COPD patients
and in healthy smokers, compared to healthy nonsmokers, suggesting
that smoking induces the changes, rather than COPD itself. Studies in-
vestigating other mediators have not been replicated and are not dis-
cussed here. 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,
confirming the imbalance between proteases and antiproteases.
Effect of Smoking and Disease Severity In one study, ex-smokers with
COPD had lower mast cell numbers in BAL than ex-smokers without
COPD. No other studies have compared smokers and ex-smokers
with COPD. Only one study has investigated the association between
the severity of COPD and BAL inflammation, 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. This in-
flammation seems to be the result of macrophage and neutrophil acti-
vation, as assessed by mediators measured in BAL. In contrast, in a
healthy population, the number of inflammatory cells did not corre-
late with lung function decline over a 4-year follow-up; however, high-
er levels of neutrophil elastase-α1 protease inhibitor complexes in BAL
fluid have been significantly associated with accelerated decline in
FEV1. This also suggests that the number or percentage of cells is not a
prerequisite for development or progression of emphysema, but that
the activation state of these cells with accompanying mediator release
may be important.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
Effects of Therapy There are few published studies of the effects of
treatments on cellular and mediator components of BAL. Three studies,
one open label and two double-blind, assessed the effect of different
types of inhaled glucocorticoids, for various periods of treatment on in-
flammatory cell counts and mediators in BAL.2 Although the numbers
of patients involved were small, precluding firm conclusions, these stud-
ies suggest that there may be a reduction in percentages of neutrophils
and lymphocytes with inhaled glucocorticoid treatment; however, long-
term studies in larger populations are needed. Some studies have inves-
tigated the effects of smoking cessation on BAL composition, showing
inconsistent decreases in cell numbers, particularly macrophages.
Problems BAL is an invasive procedure and may cause more discom-
fort to the patients than bronchial biopsy; it may also cause transient
fever. The recovery of fluid is often reduced in COPD patients, result-
ing in samples that are inadequate for analysis. Quantification of bio-
markers in supernatant is a problem as there is no satisfactory marker
to account for the dilutional effect of the saline lavage. This is one of
the factors that may contribute to the variability in measurements and
the necessity for relatively large numbers of patients.
SPUTUM
Many COPD patients produce suitable sputum spontaneously, but
spontaneously produced sputum may contain a high proportion of
dead cells, which potentially give misleading cell counts and mediator
measurements. For this reason, induced sputum has usually been the
procedure of choice.8 It should be recognized that “sputum” obtained
after inhaling nebulized hypertonic saline may have a different com-
position than mucus and may be more similar to proximal airway
washings. The procedure is tolerated by patients with FEV1 >30% pre-
dicted; however, airflow obstruction is often observed and cannot be
prevented by premedication with β2-agonists.
Cells There is an abnormal pattern of inflammatory cells in COPD
patients, with an increase in the number of total inflammatory cells
and in the percentage of neutrophils, and, in some patients, eosino-
phils (the latter predicting a greater likelihood of response to glucocor-
ticoids). CD8+ T cells are increased in the induced sputum of COPD
patients. An increased number of eosinophils may indicate concomi-
tant asthma and appears to predict the patients who show a larger
bronchodilator response and improvement with glucocorticoids.
There is little information about the reproducibility of differential cell
counts in induced sputum of COPD patients, but there appears to be a
reasonably good reproducibility of cells and mediators in long-term
repeatability studies.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. Several studies have re-
ported the effects of drugs on sputum neutrophils. Most studies have
shown no change in inflammatory cells with inhaled or oral glucocor-
ticoids. A significant reduction in neutrophils with low-dose oral theo-
phylline has been reported.
Mediators Many mediators have been reported to be increased in the
sputum supernatant of COPD patients, and most show a greater in-
crease in COPD than in smokers without COPD, with a further in-
crease during exacerbations; few have been related to disease severity
or progression.2 Sputum IL-8 has been studied most extensively, is in-
creased in COPD patients compared to smokers, is related to disease
severity (FEV1 % predicted), and may be further increased with exac-
erbations. Sputum concentrations are unaffected by glucocorticoids
but are reduced by theophylline. Increased concentrations of TNF-α
and soluble TNF receptors are found in sputum of COPD patients
compared to that in normal smokers. Higher concentrations of in-
flammatory cytokines, including TNF-α, IL-8, and IL-6, are reported
in patients with more severe compared to less severe COPD. Leptin is
detectable in the induced sputum of COPD patients and is correlated
with other inflammatory markers, including TNF-α and CRP.
 Increased concentrations of proteases have been reported in the
sputum of patients with COPD, including neutrophil elastase, MMP-
8, MMP-9, and MMP-12. 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.10 Sputum mark-
ers of structural changes in the airways have been difficult to identify.
Hyaluronan, a component of extracellular matrix, is found in higher
concentration in the sputum of COPD patients than in the sputum of
smokers without COPD and nonsmokers, especially in patients with
the lowest FEV1 values; this suggests increased degradation of extracel-
lular matrix in COPD. 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, although
there was a reduction in tachykinins noted during exacerbations of
COPD in one study.
Problems Although induced sputum samples are relatively easy to
obtain in COPD patients and give a lot of information about inflam-
matory cells and mediators, there are several problems that need to be
addressed. Induced sputum samples predominantly derive from large
airways and may not reflect the peripheral inflammation that may be
important for clinical outcomes in COPD. Sputum induction with hy-
pertonic saline promotes neutrophilic inflammation that persists for
24 h and, thus, repeated sampling within this period is not possible.
Solubilization of sputum with dithiothreitol (DTT), which disrupts
sulfhydryl bonds, may alter proteins so that they are not recognized by
antibodies; this is a particular problem with several cytokines and che-
mokines. Furthermore, proteases in sputum, particularly in COPD,
may degrade certain protein mediators. Recent studies using dialysis
to remove DTT and protease inhibitors show that it is possible to in-
crease markedly the concentrations of several cytokines in induced
sputum of COPD patients. More work is needed on long-term repro-
ducibility in COPD patients, studying the effect and duration of exac-
erbations and correlating individual biomarkers with disease severity
and progression.
EXHALED GASES
Measuring biomarkers in the breath is a very attractive approach to
monitoring inflammation in COPD as it is noninvasive and makes re-
peated sampling possible.11 However, there are important issues about
reproducibility and sensitivity that need to be addressed before this
approach can be recommended as a routine outcome measurement.
Nitric Oxide Exhaled nitric oxide (FENO) has been extensively investi-
gated in asthma and shown to correlate with airway inflammation and
to be reduced by glucocorticoid therapy. The measurement is highly
reproducible in normal and asthmatic subjects if careful attention is
paid to technique. In COPD, however, conventionally measured FENO
is less useful as the levels are usually normal or only slightly elevated,
except during exacerbations; this is likely to be due to the increase in
oxidative stress, resulting in formation of peroxynitrite and nitrate so
that NO is removed from the gaseous phase. This observation also ex-
plains why FENO is reduced in normal smokers. An increase in FENO in
COPD patients is correlated with increased numbers of eosinophils,
an increased bronchodilator response, and steroid responsiveness, and
thus may be useful in detecting associated asthma. Recently, the mea-
surement of FENO has been extended by making measurements of
exhaled NO at different flows, so that it is possible to partition airway-
derived NO, which is flow-independent, from peripheral NO derived
from endothelium via the alveoli and probably from small airways.
Using this technique it is possible to show that while airway NO is low
or normal in COPD, there is an increase in peripheral NO that is relat-
ed to disease severity.12 This may reflect the increase in inducible NO
synthase in the lung periphery of patients with COPD. Peripheral NO
may prove to be a useful noninvasive biomarker of COPD inflamma-
tion, but further studies on reproducibility, relationship to disease se-
verity, and the effects of treatment are now needed.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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 measure-
ment as FENO. Exhaled CO is elevated in patients with COPD, but it is
also elevated in normal smokers owing to the high CO content in ciga-
rette smoke; however, exhaled CO is elevated to a greater extent in
COPD patients than in matched smokers without COPD, and it re-
mains elevated in sustained ex-smokers. Importantly, the signal is low
and the measurement is also confounded by highly variable environ-
mental CO levels and the effects of passive smoking.
Hydrocarbons Volatile hydrocarbons, such as ethane and pentane, have
been detected in exhaled breath and are biomarkers of lipid peroxida-
tion as a result of oxidative stress. Concentrations of ethane are elevated
in patients with COPD and correlate with disease severity. Measurement
of ethane by gas chromatography–mass spectrometry offline is difficult
and thus unlikely to be useful in clinical trials; smaller and more sensi-
tive detectors for hydrocarbons are now in development.
EXHALED BREATH CONDENSATE
Many mediators have now been detected in exhaled breath condensate
CHAPTER e36 Pulmonary Biomarkers in COPD
(EBC), which has the advantage that it is easy to perform and com-
pletely noninvasive.11 Several factors affect the measurement, and rec-
ommendations have recently been formulated by an ERS/ATS task
force. A limitation of the technique is the variability of the measure-
ment and the low concentrations of mediators (often close to the lim-
its of detection).
Oxidative/Nitrative Stress Hydrogen peroxide (H2O2) is increased in
EBC of COPD patients, is further increased during exacerbations, and
is related to disease severity. Exhaled H2O2 is reported to be reproduc-
ible in repeated measurements over 3 days. 8-Isoprostane is a stable
marker of oxidative stress and is also increased in EBC of COPD pa-
tients. The isoprostanes represent a family of isomers that are derived
from the nonoxidative metabolism of arachidonic acid and are stable
biomarkers of oxidative stress.13 Concentrations of 8-isoprostane are
greater in COPD patients than in smokers without COPD, are related
to disease severity, and are further increased during exacerbations.
Certain aldehydes resulting from lipid peroxidation are also increased
in COPD patients, but only malondialdehyde is increased in COPD
patients compared to smokers without COPD. Increased nitrative
stress in COPD is indicated by increased concentrations of nitrite and
S-nitrosothiols in EBC.
Mediators Inflammation is associated with tissue acidification, and
there is a decrease in pH in EBC of COPD patients. There is consider-
able variability in exhaled pH in COPD patients, which is greater than
in normal subjects, and the lower pH has been ascribed to increased
acidity of salivary contaminants. There is an increase in the concentra-
tion of leukotriene (LT) B4 in COPD patients, which is further in-
creased during exacerbations. Increased prostaglandin E2 and IL-6
have also been reported in COPD patients. It is not yet clear how most
of these biomarkers relate to disease severity. Most proteins, including
cytokines and enzymes, cannot reliably be measured in EBC. A recent
study reported increases in the concentrations of proinflammatory cy-
tokines, including IL-1β, IL-6, and TNF-α, during exacerbations of
COPD, but reproducibility was not reported. Chemokines cannot be
reliably measured in EBC.
Problems There is a relative high variability in repeated measurements
of EBC biomarkers, and this may relate (1) to the extensive variable di-
lution that occurs from water vapor during condensation, and (2) the
low concentrations that may be near to the detection limits of the assays
used. Further work is needed to optimize these measurements and to
determine the causes of variability. Correction for the variable dilution
is one approach. Assays are usually performed using enzyme-linked im-
munosorbent assay, and these assays have been validated using gas chro-
matography–mass spectrometry for some mediators.
 e300 USE OF BIOMARKERS TO ASSESS RESPONSE TO THERAPY
Many drugs are now in development as potential anti-inflammatory
therapies for COPD. Because no effective anti-inflammatory treat-
ments for COPD currently exist, it is not certain how much and how
rapidly clinical parameters will change in patients. This uncertainty
makes it important to develop reliable biomarkers to quantify inflam-
mation in COPD patients and to validate these against some other
measure of disease activity and progression. For assessment of anti-in-
flammatory treatments, it is important to identify biomarkers that in-
dicate the efficacy of the drug on components of the inflammatory
process before proceeding to large and prolonged clinical trials. Bio-
markers can facilitate drug development in a number of ways, such as
providing evidence that a drug can reach its target and modify that
target in some positive way, identifying criteria for dose selection for
phase 2 and phase 3 studies, providing “go/no-go” decisions at early
stages of the drug development process, identifying populations that
are more likely to benefit from a drug, and predicting safety problems.
There are several types of drugs that can be developed for COPD
based on whether the drug is intended to improve airflow obstruction,
provide symptom relief, modify or prevent exacerbations, alter disease
progression, or modify lung structure. The efficacy endpoints that are
currently used in phase 3 studies to support registration of a drug for
PART 18
COPD are based on measures that translate to direct benefit of some
aspects of the disease that is clinically meaningful to patients, such as
improvement of symptoms, functional capacity, or survival. Examples
of such endpoints include pulmonary function tests; test of exercise
capacity, e.g., treadmill or cycle ergometry; activity scales, e.g., Medi-
cal Research Council dyspnea score, Borg scale, Mahler baseline dysp-
nea index (BDI)/transitional dyspnea index (TDI); health-related
e-Chapters from International Advisory Editors
quality-of-life (QOL) instruments, e.g., St. George’s respiratory ques-
tionnaire (SGRQ), chronic respiratory disease questionnaire (CRQ);
scores based on patient- or physician-reported symptom severity; and
death. With the possible exception of a drug that is intended to im-
prove airflow obstruction, whose efficacy can be relatively easily as-
sessed by measuring FEV1 in short-term studies, drugs of other types
will likely require prolonged studies, often extending to many years.
These studies become rather risky expensive endeavors, and this fur-
ther underscores the need of development of biomarkers.
The biomarkers described elsewhere in this chapter are not sufficient-
ly validated to date for use as evidence of efficacy in phase 3 studies or
for supporting specific labeling claims. Nevertheless, these biomarkers
are reflective of the disease and have potential use for regulatory purpos-
es. Carefully selected biomarkers, with or without a patient-centered
clinically meaningful endpoint, can be used in early phase studies, such
as proof-of-action or proof-of-concept studies, based on which a ratio-
nal decision can be made on further development of the drug. Biomark-
ers can also be used in either early phase studies or phase 3 studies to
support the drug’s putative mode of action. In addition, use of the bio-
markers in phase 3 studies in conjunction with clinically meaningful
endpoints may help validate the use of the biomarker, or even help ele-
vate a biomarker to a surrogate endpoint status.
OVERVIEW
Many biomarkers of inflammation and oxidative/nitrative stress have
now been measured in the airways of patients with COPD using a va-
riety of techniques of differing invasiveness. Bronchial biopsies pro-
vide valuable information about inflammatory cells and mediators, as
well as the spatial relationships between the inflammatory process in
the airway wall. However, they may not reflect all pathologic changes
in the periphery of the lung that appear to be more important in
COPD, and its invasiveness precludes repeated measurements. BAL
may provide more information about peripheral inflammation, but
there are problems of quantification of mediators because of variable
dilution and the same problems as with biopsies in reproducibility. In-
duced sputum is a valuable procedure giving information about cells,
mediators, and markers of oxidative/nitrative stress, but standardiza-
tion of the technique is important to reduce the high variability in the
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
biomarkers. The technique probably samples more proximal airways
and thus may not reflect the inflammatory process in the lung periph-
ery. Exhaled biomarkers are noninvasive and may be repeated but are
technique-dependent and have a relatively high variability. For all of
these biomarkers, there is a relative lack of information about how
they relate to disease severity, how reproducible they are, and how they
may be affected by concurrent therapies. In addition, there is little in-
formation at present about how they relate to other outcome measure-
ments in COPD, such as rate of decline in FEV1, exacerbation
frequency, and mortality. There is a need for comparison of all pulmo-
nary biomarkers in COPD patients with those in smokers without air-
flow limitation but matched for smoke exposure (pack-years) and also
with those in age-matched nonsmoking control subjects. The effect of
smoking itself is rarely documented, and ex-smokers may have a dif-
ferent profile of biomarkers than active smokers. Patients with mixed
asthma and COPD and patients who have COPD without smoking
also need to be characterized.
COPD involves small airway inflammation and fibrosis as well as al-
veolar destruction. It is not yet clear whether pulmonary biomarkers
will be able to discriminate these two pathophysiologic processes. 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 paren-
chymal disease from small-airway involvement.10 How other biomark-
ers relate to the phenotype of COPD deserves further investigation.
Clinical Perspective Although many pulmonary biomarkers have
been described in COPD patients, their clinical relevance is far from
certain. None of the approaches described in this chapter are in rou-
tine use for the diagnosis of COPD, for predicting disease progression,
or for predicting response to therapy. However, progress is now being
made in asthma, where monitoring sputum eosinophils and FENO ap-
pears to improve control of asthma and at the same time reduce ster-
oid requirements. Similar studies have not been done in COPD
patients, as these patients do not respond well to glucocorticoids.
However, 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 bronchodi-
lators and inhaled glucocorticoids. When more effective anti-inflam-
matory treatments become available for COPD patients, it is possible
that inflammatory cells in sputum may be used to monitor the re-
sponse to treatment, which may be difficult using physiologic parame-
ters that are likely to improve only very slowly. 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, ideally with detailed lung
function assessments (including lung volumes and gas transfer), exer-
cise performance, measurement of free fat mass, and high-resolution
CT scanning.
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. Bronchial biopsies and BAL provide
important information about cellular composition but cannot be re-
peated, whereas induced sputum and exhaled markers are repeatable.
The biomarkers selected for measurement will depend on the nature
of the study. For example, assessment of an anti-inflammatory drug
will require the measurement of inflammatory cells and specific in-
flammatory mediators, whereas assessment of an antioxidant may re-
quire measurements of oxidative stress and an antiprotease will
require measurement of protease activity. Prediction of steroid re-
sponsiveness may be given by increased FENO and sputum eosinophils.
In the future it is possible that patterns of pulmonary biomarkers may
predict exacerbations, as they do in asthma, and may reflect different
mechanisms of exacerbations, discriminating between bacterial, viral,
and noninfective mechanisms.
This is an active research area, and further studies addressing several
of the issues raised in this chapter are already in progress. Correlation of
pulmonary biomarkers with other outcome measures is essential for the
future assessment of the inflammatory destructive process and for mea-
suring the effects of the new anti-inflammatory drugs that are now in
development for the treatment of COP, as well as for understanding how
disease mechanisms relate to clinical outcomes.
REFERENCES
1. Barnes PJ et al: Chronic obstructive pulmonary disease: Molecu-
lar and cellular mechanisms. Eur Respir J 22:672, 2003
2. Barnes PJ et al: Pulmonary biomarkers in chronic obstructive pul-
monary disease. Am J Respir Crit Care Med 174:6, 2006
3. Franciosi LG et al: Markers of disease severity in chronic obstruc-
tive pulmonary disease. Pulm Pharmacol Ther 19:189, 2006
4. Jeffery PK et al: Methods for the assessment of endobronchial bi-
opsies in clinical research. Application to studies of pathogenesis
and the effects of treatment. Am J Respir Crit Care Med 168:S1,
2003
5. Di Stefano A et al: Increased expression of NF-κB in bronchial bi-
opsies from smokers and patients with COPD. Eur Resp J 20:556,
2002
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6. Ito K et al: Decreased histone deacetylase activity in chronic ob- e301
structive pulmonary disease. N Engl J Med 352:1967, 2005
7. Lofdahl JM et al: Bronchoalveolar lavage in COPD: Fluid recovery
correlates with the degree of emphysema. Eur Respir J 25:275,
2005
8. Tsoumakidou M et al: Induced sputum in the investigation of air-
way inflammation of COPD. Respir Med 97:863, 2003
9. Beeh KM et al: Long-term repeatability of induced sputum cells
and inflammatory markers in stable, moderately severe COPD.
Chest 123:778, 2003
10. Boschetto P et al: Association between markers of emphysema
and more severe chronic obstructive pulmonary disease. Thorax
61:1037, 2006
11. Kharitonov SA, Barnes PJ: Exhaled biomarkers. Chest 130:1541,
2006
12. Brindicci C et al: Exhaled nitric oxide from lung periphery is in-
creased in COPD. Eur Respir J 26:52, 2005
13. Montuschi P et al: Isoprostanes: Markers and mediators of oxida-
tive stress. FASEB J 18:1791, 2004
14. Celli BR, Barnes PJ: Exacerbations of chronic obstructive pulmo-
nary disease. Eur Resp J 29:1224, 2007
CHAPTER e36 Pulmonary Biomarkers in COPD

e37 Chagas’ Disease:
Advances in Diagnosis
and Management
Andrei C. Sposito, Jose A. F. Ramires
INTRODUCTION
Chagasic cardiomyopathy is the major complication resulting from in-
fection by Trypanosoma cruzi, occurring in up to 30% of individuals
who have a positive specific serology. The T. cruzi infection is related to
the close proximity between humans and triatomines carrying T. cruzi
and extends from the Southern United States11 and Mexico to the
south of Argentina. According to the World Health Organization Tech-
nical Report, among individuals living in Latin American countries,
5–6 million are infected and 25 million are at risk of contracting the
infection (Chap. 206).
It usually takes 10–20 years for the infection to manifest the disease
in a broad range of clinical presentations including heart failure, cardi-
ac arrhythmias, thromboembolism, and sudden death. Once estab-
lished, the signs of heart failure result in life expectancy being reduced
to ≤5 years. Therefore, strategies to identify the disease in the early
phase and characterize predictive signs and potential therapeutic tar-
gets have been intensely pursued. In this chapter, we discuss the results
from recent, novel research on the diagnosis and management of Cha-
gas’ disease.
LABORATORY DIAGNOSIS
Parasitemia During the acute phase of the disease, parasites can easi-
ly be found by microscopic observation of fresh blood. Morphologic
characteristics of the parasite and differentiation from T. rangeli can
also be determined by staining the blood smears. When parasitemia is
low, procedures for parasite concentration or indirect methods (xeno-
diagnosis and hemoculture) can be used instead. Parasite concentra-
tion could be obtained either by microhematocrit or by the Strout
method. In the microhematocrit, blood is centrifuged and the buffy
coat examined by microscopy to visualize trypomastigote movements.
In the Strout method, blood cells are first eliminated by precipitation
and centrifugation. The supernatant is then submitted to a second
centrifugation and the precipitate is examined as fresh blood.
The xenodiagnostic method consists of feeding uninfected triatom-
inae with blood from the patient under examination and then investi-
gating the intestinal contents of the insects some days later to search
for metacyclic trypomastigotes. Artificial xenodiagnosis is preferred to
avoid inconveniences from direct contact between the triatomines and
patients’ skin. Recently, amplification of T. cruzi DNA target sequences
by polymerase chain reaction (PCR) has become a preferred method
for the detection of parasites in blood and tissues. Such PCR tech-
niques are especially helpful for the follow-up of chemotherapy for T.
cruzi. However, despite being more sensitive than xenodiagnosis and
hemoculture, this sensitivity is equally dependent on the magnitude of
the parasitemia.
Immunodiagnosis Infected individuals soon develop antibodies, ini-
tially IgM and later IgG, against several epitopes of T. cruzi allowing the
indirect diagnosis of Chagas’ disease. Conventional immunodiagnostic
tests are available worldwide and are based on three main techniques:
hemagglutination, immunofluorescence, and ELISA. Nonconventional
tests using recombinant chimeric proteins, synthetic peptides, or puri-
fied antigens have been developed to increase specificity and reduce
cross-reactivity with other infections and with autoimmune diseases.
In general, conventional tests have elevated sensitivity, and a positive
result in two conventional tests is sufficient to diagnose the infection. In
parallel with PCR for detecting T. cruzi parasitemia, conventional sero-
logic tests could also be used for the follow-up of patients undergoing
chemotherapy.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
ANATOMIC DIAGNOSIS e303
Myocardial Fibrosis and Inflammation T. cruzi can be easily detected
in muscle cells and interstitial histiocytes of individuals in the acute
phase of Chagas’ disease. However, such a finding is rare in the chronic
phase of the disease. Hence, the main finding in the hearts of patients
with chronic Chagas’ disease is the presence of inflammatory infil-
trates. Chagas’ myocarditis lesions are spread out over both ventricles
and in a large spectrum of severity, transforming myofibers into fi-
brous tissue and featuring the changes in heart structure and function.
Accordingly, myocardial fibrosis caused by Chagas’ disease is a strong
marker of clinical impairment and ventricular dysfunction.
The histopathologic evaluation of myocardial fibrosis and inflam-
mation can be obtained through a percutaneous and transvenous en-
domyocardial biopsy of the right ventricle. This diagnostic procedure
has been proved to be a powerful tool for both the prediction of clini-
cal outcome and estimation of the severity of myocardial damage in
Chagas’ disease and in other primary and secondary cardiac diseases.
In patients with Chagas’ disease who undergo heart transplantation,
endomyocardial biopsy is considered the “gold standard” technique in
the differentiation between allograft rejection and reactivation of the
disease. In such patients, however, the use of endomyocardial biopsy
CHAPTER e37 Chagas’ Disease: Advances in Diagnosis and Management
has been limited by the mild, albeit significant, intrinsic risk of the
procedure and the lack of evidence-based parameters that may guide
clinical decisions. Consequently, noninvasive methods have been de-
veloped to explore potential clinical benefits from assessing the degree
of myocardial inflammation and fibrosis in patients with Chagas’ disease.
In our group, the histopathologic findings of myocardial inflammation
via endomyocardial biopsy were compared with two noninvasive tech-
niques, gallium-67 myocardial uptake scintigraphy and MRI. Despite
both noninvasive techniques detecting Chagas’ myocarditis, MRI was
more accurate due to the higher spatial resolution.
Myocardial delayed enhancement by MRI has been proved to be ef-
ficient in detecting myocardial fibrosis in ischemic and nonischemic
myocardial disease. In Chagas’ disease, delayed enhanced MRI can de-
tect even traces of myocardial fibrosis in individuals in the indetermi-
nate phase, that is, the period before presentation of cardiac electrical
or mechanical abnormalities.3 Such refined accuracy would potential-
ly be helpful for characterization and treatment of arrhythmogenic
foci in patients with Chagas’ disease. Moreover, the severity of myo-
cardial fibrosis detected by MRI is proportional to the severity of myo-
cardial dysfunction and clinical symptoms.
In patients in the chronic phase of the disease, myocardial fibrosis is
found particularly at the apex and inferolateral regions of the left ven-
tricle. Ischemia, inflammation, mechanical factors, and parasympa-
thetic nerve cell destruction are considered among potential
underlying mechanisms for these lesions. In these affected regions,
ventricular wall aneurysms would develop in a later stage of Chagas’
cardiomyopathy, constituting a classic sign of the disease. Figure e37-1
shows the typical apex lesion with severe myocardial fibrosis in a heart
examined at autopsy.
Myocardial Perfusion Myocardial ischemia has been frequently re-
ported in patients with Chagas’ disease and normal coronary angio-
grams. In fact, these patients have chest pain associated with
electrocardiographic signs of ischemia simulating obstructive coro-
nary artery disease. From a pathophysiologic standpoint, vascular dys-
autonomia due to denervation and inflammatory damage of the
microcirculation is considered the leading cause of myocardial is-
chemia in these patients. Figure e37-2 shows myocardial denervation
and ischemia by scintigraphic imaging; the denervation demonstrated
by the reduced cardiac uptake of 123I-metaiodobenzylguanidine
(MIBG) is concordant with the perfusion deficit, but is much larger,
suggesting that denervation is the initiating event.
In angiographic studies, endothelium-dependent and -independent
impairment in coronary vasodilation have been observed in patients
with Chagas’ disease.4 With scintigraphic perfusion imaging using
thallium-201, transient and permanent myocardial perfusion abnor-
malities have been described in patients with the disease (Chaps. 222
 e304
PART 18
FIGURE e37-1 Photo of a heart from a patient with chronic chagasic
cardiac disease, exhibiting a typical lesion at the left ventricle.
and e20). These studies demonstrate an elevated topographic correla-
tion between perfusion and wall motion abnormalities. Even though
e-Chapters from International Advisory Editors
prospective cohorts demonstrating a temporal association between
perfusion defects and the development of wall motion dysfunction are
lacking, it is plausible to consider that such perfusion defects would
represent an early sign of Chagas’ cardiomyopathy. In addition, these
radionuclide studies also indicate that the perfusion defects are pre-
dominantly in the apex and inferolateral regions, which are those most
affected by the inflammatory damage and the autonomic denervation.
From a clinical perspective, 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’ dis-
ease. Actually, both the endothelium-dependent and -independent va-
sodilatory responses of coronary resistance vessels are also affected in
patients with idiopathic dilated cardiomyopathy and angiographically
normal coronary arteries. These patients have impairment of the vasodi-
lator responses to both metabolic and pharmacologic stimuli and an in-
creased sensitivity to vasoconstrictors. 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. Whether such perfusion disturbances also con-
tribute to the detriment of ventricular wall motion is presently unknown.
FIGURE e37-2 Myocardial denervation and ischemia detected by
scintigraphic imaging. Above. The denervation is demonstrated by
the reduced cardiac uptake of 123l-metaiodobenzylguanidine (MIBG)
(arrows). Below. A permanent perfusion deficit with smaller size as
compared with the denervation is demonstrated by scintigraphic per-
fusion with 99mTc-sestamibi (MIBI).
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FIGURE e37-3 Echocardiographic analysis of mitral inflow by
pulse-wave Doppler showing diastolic function in a patient with Cha-
gas’ disease. Normally, the early flow velocity (E) is higher than the late
flow velocity (A), which is related to atrial contraction. In this case,
there is an inverted E/A relation, indicating the impairment of left ven-
tricular relaxation.
Myocardial Wall Motion In the acute phase of the disease, pericardial
effusion and occasionally myocardial wall motion abnormalities have
been described. By definition, in the indeterminate phase, chronically
infected individuals remain a parasite reservoir without being affected
by the disease and consequently have a normal life expectancy. Hence,
the appearance of an abnormality of the ventricular wall reflects pro-
gression of the disease and must be considered, accordingly, as the on-
set of the chronic phase of Chagas’ disease.
In the chronic phase, thinning, aneurysm formation, and wall mo-
tion dysfunction are the most frequent findings detected on echocar-
diography. In keeping with necropsy, scintigraphic, and MRI studies,
these echocardiographic findings are mostly observed in the apex and
inferobasal regions of the left ventricle. The segmental thinning of the
ventricular wall, particularly at the apex, promotes remodeling of the
left ventricle, which may increase mechanical tension and contribute
to aneurysm formation in this area. Nevertheless, abnormalities of
other left ventricular segments can also be found.
As the disease progresses, the affected segments of the ventricular
wall become hypokinetic, akinetic, or even dyskinetic. Frequently, dia-
stolic dysfunction occurs in an early phase of the disease, as shown in
Fig. e37-3. The thinning of the apex becomes an aneurysm, and the
global systolic function of the left and right ventricles deteriorates. Ini-
tially, the systolic dysfunction may be apparent only under pharmaco-
logic stress by dobutamine or phenylephrine, characterizing the
reduction of systolic reserve. Echocardiography or MRI can accurately
detect these characteristics.
The right ventricle is first and predominantly affected in the major-
ity of patients with Chagas’ disease. This may occur even in the ab-
sence of any detectable abnormality in the left ventricle. Accordingly,
in these patients, the development of heart failure is typically mani-
fested with a predominance of systemic over pulmonary congestion.
Because echocardiography has a low accuracy for detecting right ven-
tricular dysfunction, radionuclide angiography or MRI is preferred for
evaluation of this chamber.
CHAGAS’ DISEASE
ETIOLOGIC TREATMENT Nitrofurans and nitroimidazole derivatives
(nifurtimox and benznidazole respectively) have been the cornerstones of
trypanosomicidal treatment in recent decades. These compounds seem to
exert their trypanosomicidal action by the generation of superoxide radi-
cals causing oxidative stress and cell death in susceptible parasites.
From the clinical point of view, the activity of treatment with both com-
pounds is evident in terms of parasite load reduction and serologic conver-
sion to negative in the acute phase of Chagas’ disease and in congenital
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 to-
gether 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 anti-
body titers in individuals in the indeterminate phase. Whether this treat-
ment will prevent the development of cardiac or digestive complications
of the disease is still unclear. Large randomized controlled trials are re-
quired to define this issue.
The effect of trypanosomicidal therapies on parasite load or disease pro-
gression 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 pro-
gression. Hence, the ideal therapeutic schema or duration for such chronic
patients is unknown. In addition, several adverse reactions, such as peripher-
al neuropathy and skin disorders, have been reported in a large proportion
of patients treated with both nifurtimox and benznidazole. Thus, there is in-
sufficient 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 in-
vestigated 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 ben-
efits have not been proved thus far.
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 combi-
nation with benznidazole has been demonstrated to be effective in atten-
uating 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 atten-
uate symptoms and prevent complications. The most relevant cardiac com-
plications 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 Cha-
gas’ 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-convert-
ing 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 spirono-
lactone 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 at-
tenuate 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 pa-
tients with Chagas’ disease who also have heart failure is indicated.
There is some evidence that amiodarone can prevent complex arrhyth-
mias in patients with heart failure irrespective of the cause. In small studies
in patients with Chagas’ disease with sustained ventricular tachyarrhyth-
mias, amiodarone provided longer intervals free of arrhythmic events com-
pared 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 sur-
gical 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-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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 elec-
trophysiologic mapping. Alternatively, interpapillary endomyocardial cryo-
ablation 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 surgi-
cal risk is low, and when other surgical procedures, such as aneurysmecto-
my, 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 epicar-
dial, this combined approach provides a higher efficacy for treating recur-
rent 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 high-
risk bradyarrhythmia is frequently manifested in these patients. Thus, im-
plantation of an ICD with pacing capability is often indicated. ICDs are
CHAPTER e37 Chagas’ Disease: Advances in Diagnosis and Management
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, antiar-
rhythmic therapy, and catheter ablation appears to be ideal in these
patients.
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 develop-
ment 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 pa-
tients with Chagas’ heart disease. Am Heart J 129:995, 1995
5. Marin-Neto JA et al: Pathogenesis of chronic Chagas’ heart dis-
ease. Circulation 115:1109, 2007
6. Acquatella H et al: Limited myocardial contractile reserve and
chronotropic incompetence in patients with chronic Chagas’ dis-
ease: 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: Experimen-
tal evidence of the efficacy of near infrared lasers for catheter abla-
tion of Chagas’ VT. J Interv Cardiol Electrophysiol 7:23, 2002
10. Sosa E et al: Radiofrequency catheter ablation of ventricular tachy-
cardia guided by nonsurgical epicardial mapping in chronic Cha-
gasic 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

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 modi-
fying one or more of them provide opportunities for reducing the risk
of CVD through actions that impact on populations or directly on in-
dividuals. 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 ob-
servational studies, especially from large and long-term cohorts, has de-
fined 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 con-
verged because of accumulating new knowledge. For example, in the
seventh U.S. Joint National Committee report on hypertension, the def-
inition of normal blood pressure was lowered to <120/80 mmHg from
<130/85 mmHg in the sixth report. Similarly, the target goals of low-
density 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 pro-
posed 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 di-
abetes; abdominal obesity; psychological factors; and lack of daily con-
sumption of fruits and vegetables, regular alcohol intake, and regular
physical activity] account for ~90% of CVD risk globally, cutting across
all major ethnic populations. Interven-
tions, directed toward lowering many of
these risk factors, have been shown to 1 Four elements
lower the risk of subsequent CVD events.
Drugs that act on critical steps in the
Survival after STEMI
pathogenesis of atherothrombotic events, 0.9
either by reducing risk factors (e.g., stat-
ins) or preventing pathologic processes
(e.g., aspirin), have been shown to reduce 0.8
vascular events. Both lifestyle measures
and pharmacotherapy have been demon-
strated to prevent or delay the onset of 0.7
CVD-related clinical events in persons
with high levels of one or more risk fac- p-logrank < .0001
tors (primary prevention). They have also 0.6
been shown to reduce the risk of recur- 0 2
rent events and to extend survival in per-
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 re-
secondary 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. Repro-
sin-converting enzyme (ACE) inhibitors, duced from Sleight et al.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
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 revas-
cularization 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 high-
dose 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, prava-
statin, 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
CHAPTER e38 The Polypill
by 26%. While these benefits persist for many years on continuing ther-
apy, they disappear on discontinuing therapy. Despite these proven ben-
efits, 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 ob-
served that beta blockers were not prescribed to nearly two-thirds of eli-
gible 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 dys-
function, have also been demonstrated. The HOPE study, which in-
cluded patients with CVD or diabetes and at least one cardiovascular
risk factor but the absence of left ventricular dysfunction, demonstrat-
ed 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
Three elements
Two elements
One element
No element
4 6 8 10 12
Months after discharge
 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 stat-
ins 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 re-
ceived none to two drugs.
However, the protective role of combinations of these drugs for pri-
mary 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 pharmaco-
therapy are lacking.
POLYPILL STUDY MODELS
PART 18
bination pharmacotherapy in reducing CVD in low-income and
middle-income countries. Using a Markov model to assess cost-effec-
tiveness, the authors used a combination of four drugs—aspirin, a cal-
cium 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 smok-
ing status. The authors estimated that a nearly 50–60% reduction in
CVD-related events could be expected if all patients with a 10-year ab-
solute risk >5% were treated. This would lead to at least a 2-year in-
crease in life expectancy in those above the age of 35 years. Using the
secondary prevention strategy, the authors predicted a 10–15% reduc-
tion in lifetime risk of death due to CVD.
Using this model, the authors reported that the incremental cost-ef-
fectiveness 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 abso-
lute 10-year cardiovascular risk, as more patients needed to be treated

to achieve a similar reduction in CVD events, leading to higher expen-

Two studies have attempted to define the possible benefits of pharma- diture and lower cost-effectiveness. However, incremental cost-effec-
cologic treatment of multiple risk factors in reducing cardiovascular tiveness was still favorable for all primary prevention strategies, except
events by modeling potentially achievable risk reduction with the use for the strategy of treating all patients >55 years. For secondary pre-
of multiple drugs. Wald and Law, in 2003, combined six drugs to mod- vention, incremental cost-effectiveness of the polypill was most favor-
el reduction of four cardiovascular risk factors—LDL cholesterol, able, at US$306–388 per QALY gained.
blood pressure, serum homocysteine, and platelet function. The com-
bined formulation included a statin (atorvastatin, 10 mg, or simvastat- LIMITATIONS OF THE POLYPILL
e-Chapters from International Advisory Editors

in, 40 mg), three blood pressure–lowering drugs (a thiazide diuretic, a Despite the perceived advantages associated with the delivery of multi-
beta blocker, and an ACE inhibitor, all at half the standard dose), folic ple drugs in a single pill, including convenience of delivery, ensuring in-
acid (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 pharmaco-
model, 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 dys-
off 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. Aspi-
the combined effect of the four drugs would be an 88% reduction in rin also does not have a well-established role in preventing cardiovas-
ischemic 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 as-
pirin reduces the advantage of the
polypill by only 5 percentage points to TABLE e38-1 EFFECT OF POLYPILL ON RISK OF ISCHEMIC HEART DISEASE (IHD) AND STROKE, AS
83%. These benefits accrued with a low ESTIMATED BY WALD AND LAW, AFTER 2 YEARS OF TREATMENT AT THE AGE 55–64 YEARS
incidence of projected side effects. It % Reduction in Risk (95% CI)
was estimated that only 15% of patients Reduction in
would be expected to have adverse ef- Risk Factor Agent Risk Factor IHD Event Stroke
fects due to the formulation, mostly as- LDL cholesterol a Statin b 1.8 mmol/L (70 mg/ 61 (51–71) 17 (9–25)
cribable to aspirin. If all people >55 dL) reduction
years used the pill, it was estimated that Blood pressure Three classes of drugs 11 mmHg diastolic 46 (39–53) 63 (55–70)
one in three people would benefit di- at half standard dose
Serum 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 com-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 The projected benefits of these combinations of drugs have been as-
sumed 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 reduc-
tion 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 assump-
tions therefore need to be verified by an actual clinical trial. This is es-
pecially important in the case of primary prevention.
In secondary prevention trials, the sequential evaluation of cardio-
protective 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 vari-
ables (risk factor levels) may suffice. Even in secondary prevention,
some questions remain: Are beta blockers useful for secondary preven-
tion 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 inhibi-
tors, 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 dis-
continue 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 ex-
posed to the adverse effects of combination multidrug therapy. On the
other hand, there would be high-risk patients who would be under-
treated and might not reach the desired therapeutic goals. Without ap-
propriate risk profiling, the latter patients would be diligently taking
drugs but not accruing the maximum benefits. Although the popula-
tion 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 educa-
tion campaigns, and economic considerations are among the many
factors that impact adherence positively and are unaffected by combi-
nation 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. Long-
term 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 mul-
tiple risk factors simultaneously is that there are no clear demarcations
between “normal” and “abnormal” levels of risk factors. They pro-
posed, 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 inter-
ventions to modify risk factors should be guided by a person’s level of
absolute cardiovascular risk rather than the level of individual risk fac-
tors. Thus, patients with what is currently considered borderline eleva-
tion 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 individu-
als with at least one preexisting major cardiovascular risk factor. Clus-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
tering of these risk factors is frequently observed in individuals and e309
contributes to high level of absolute risk of CVD. Therefore, it is im-
portant to screen the population for these risk factors and then treat
individuals at a high absolute risk with the combination pharmaco-
therapy, rather than treat the entire population >55 years with a blan-
ket 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 interven-
tion 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 manage-
ment of these chronic diseases, may not be treated with the seriousness
that they deserve. The polypill will not reduce the number of individu-
als acquiring a high-risk status in any population—it can only avert
their future risk, if detected and treated. On the other hand, popula-
tion-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
CHAPTER e38 The Polypill
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.
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 cardio-
vascular 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 high-
risk primary preventions. It overcomes the problems of inadvertent
drug omission by under-informed physician and provides the oppor-
tunity to include generic drugs such as lovastatin or simvastatin, enal-
april, 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 signifi-
cantly, 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-ef-
fect 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 coun-
tries would need to place even greater emphasis on policies and educa-
tional 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 high-
risk primary prevention. However, its role is presently speculative and
needs to be assessed in randomized trials. It should not distract clini-
cians 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
 e310 would continue to yield equal dividends. They would also be applica-
ble to the wider population, with greater safety.
FURTHER READINGS
COMBINATION PHARMACOTHERAPY AND PUBLIC HEALTH RESEARCH
WORKING GROUP: Combination pharmacotherapy for cardiovas-
cular 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 multi-
drug regimen in the developing world: A cost-effectiveness analy-
sis. Lancet 368:679, 2006
PART 18
e-Chapters from International Advisory Editors
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
REDDY KS: The preventive polypill—much promise, insufficient evi-
dence. 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 myocar-
dial infarction in 52 countries (the INTERHEART study): Case-
control study. Lancet 364:937, 2004
 TABLE e39-1 FUNCTIONS OF MITOCHONDRIA e311

e39 Heritable
Mitochondrial DNA and
Traits and Diseases
Karl Skorecki, Hanna Mandel
All cells and tissues
Oxidative phosphorylation
Apoptosis (programmed cell death)
Tissue- or cell-specific
Cholesterol metabolism
Amino and organic acid metabolism
Mitochondria are cytoplasmic organelles whose major function is to Fatty acid beta oxidation
generate ATP by the process of oxidative phosphorylation under aero- Sex steroid synthesis
bic conditions. This process is mediated by the respiratory electron Heme synthesis
Hepatic ammonia detoxification
transport chain (ETC) multiprotein enzyme complexes I–V, and the Neurotransmitter metabolism
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 cell- mechanisms of mtDNA differ from the corresponding mechanisms in
type specific functions (Table e39-1). The efficiency of the mitochon- the nuclear genome, whose nucleosomal packaging and structure is
drial ETC in ATP production is a major determinant of overall body more complex. In terms of mtDNA replication, at least two major
energy balance and thermogenesis. In addition, mitochondria serve as models have been proposed, which differ principally in whether the
the predominant source for the generation of reactive oxygen species two strands of the mtDNA double helix replicate simultaneously or
(ROS), whose rate of production also relates to the coupling of ATP consecutively. Since each mitochondrion contains many copies of
production to oxygen consumption. Given the centrality of oxidative mtDNA, and because the number of mitochondrion per cell can vary
phosphorylation to the normal activities of almost all cells, it is not during the lifetime of a cell through the processes of fission, fusion, and

CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases

surprising that mitochondrial dysfunction can affect almost any organ mitochondrial biogenesis, mtDNA copy number per mitochondrion
system (Fig. e39-1). Thus, physicians in many specialties might en- and per cell can also vary within the lifetime of a cell, and it is not di-
counter patients with mitochondrial diseases and should be aware of rectly coordinated with the cell cycle. Thus, it is not surprising that vast
their existence and characteristics. differences in mtDNA copy number are observed between different cell
The integrated activity of several hundred proteins is required for types and tissues and during the lifetime of a cell. Another important
normal mitochondrial biogenesis, function, and integrity. Most of feature of the mtDNA replication process is a greatly reduced stringen-
these are encoded by nuclear genes and thus follow the rules and pat- cy of proofreading and replication error correction, leading to a much
terns of nuclear genomic inheritance (see Part 3, Genetics and Disease). greater degree of sequence variation compared to the nuclear genome.
These nuclear-encoded proteins are synthesized in the cell cytoplasm Some of these sequence variants are silent polymorphisms that do not
and imported to their location of activity in mi-
tochondria through a complex biochemical
process. In addition, the mitochondria them- Heart Eye
selves have their own genome consisting of Conduction disorder Optic neuropathy
Wolff-Parkinson-White Ophthalmoplegia
numerous copies (polyploidy) per mitochon-
syndrome Retinopathy
drion of a circular, double-strand mitochon- Cardiomyopathy
drial DNA (mtDNA) molecule consisting of a
16,569-nucleotide sequence. This mtDNA se-
quence contains a total of 37 genes, of which 13
encode mitochondrial protein components of Liver
the ETC (Fig. e39-2). The remaining 22 tRNA- Hepatopathy
and 2 rRNA-encoding genes are dedicated to Skeletal muscle
Weakness
the process of translation of the 13 mtDNA-en- ATP
Fatigue
coded proteins. This dual genetic control of mi- Myopathy
tochondrial function can result in fascinating Neuropathy
patterns of inheritance, which may be challeng-
ing to unravel. The current chapter focuses on Nuclear Subunits Oxidative
diseases and heritable traits related to the DNA phosphorylation Kidney
mtDNA component of the dual genetic control Fanconi's syndrome
of mitochondrial function. The reader is re- Glomerulopathy
ferred elsewhere for consideration of mitochon- Brain
Seizures
drial disease originating from mutations in the
Myoclonus
nuclear genome. The latter include (1) nuclear Ataxia
genomic mutations that disrupt the integrity of Stroke Mitochondrial
the mitochondrial genome itself (mtDNA dele- Dementia DNA Pancreas
tion and depletion states), (2) disorders due to Migraine Diabetes mellitus
mutations in nuclear genes encoding structural
components or assembly factors of the oxidative
phosphorylation complexes, and (3) mitochon- Nuclear DNA
Blood
drial disorders due to mutations in nuclear Pearson's syndrome
genes encoding proteins indirectly related to
oxidative phosphorylation. Inner ear
Sensorineural
Colon hearing loss
MITOCHONDRIAL DNA (mtDNA) Pseudo-obstruction
STRUCTURE AND FUNCTION FIGURE e39-1 Dual genetic control and multiple organ system manifestations of mito-
As a result of its circular structure and extranu- chondrial disease. (Reproduced with permission from DR Johns: Mitochondrial DNA and dis-
clear location, the replication and transcription ease. N Engl J Med 333:638, 1995.)
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
 e312
D-loop region

A 12S Phe Pro Cyt b

Val Thr
16S
Leu (UUR)
ND1 Glu
ND6
IIe
Gln
Met

ND2 ND5

Trp
Ala
Asn Leu (CUN)
Cys Ser (AGY)
Tyf His

COXI ND4
Ser (UCN)
Asp
Arg
Lys Gly ND4L
COXII
ND3
A8 A6
PART 18

COXIII

B ND1, ND2, ND3, ND4 Cyt b COXI, COXII, ATPase 6

ND4L, ND5, ND6 Sporadic myopathy COX III NARP
LHON Encephalomyopathy Sporadic anemia MILS
MELAS Septo-optic dysplasia Sporadic myopathy FBSN
LHON and dystonia Cardiomyopathy Encephalomyopathy
Sporadic myopathy ALS-like syndrome
H+ H+ H+ H+
e-Chapters from International Advisory Editors

Matrix Succinate Fumarate O2 H2O ADP ATP

COXI
Inner ND1 ND2 ND3
Cyt b COXII A8
mitochondrial ND6 ND4L e− COXIII A6
membrane ND5 ND4 e− e−
CoQ
Intermembrane Cyt c
space
Complex I Complex II Complex III Complex IV Complex V
NDUFS1, NDUFS2 SDHA, SDHB BCS1L COX10, COX15
NDUFS4, NDUFS7 SDHC, SDHD Leigh’s SCO1, SCO2, SURF1
NDUFS8, NDUFV1 Leigh’s syndrome Leigh’s syndrome
Leigh’s syndrome syndrome GRACILE Hepatopathy
Leukodystrophy Paraganglioma syndrome Cardioencephalomyopathy
Pheochromocytoma Leukodystrophy and tubulopathy
No. of mtDNA-
encoded subunits 7 0 1 3 2
No. of nDNA-
encoded subunits -39 4 10 10 14

FIGURE e39-2 Mitochondrial DNA (mtDNA) and the mitochon-
drial respiratory chain. A. The map of the human mitochondrial ge-
nome. The protein-coding genes—seven subunits of complex I (ND),
three subunits of cytochrome-c oxidase (COX), the cytochrome-b sub-
unit of complex III (Cyt b), and two subunits of adenosine triphosphate
(ATP) synthase (A6 and A8)—are shown in red. The protein-synthesis
genes—the 12S and 16S ribosomal RNAs and the 22 transfer RNAs
(three-letter amino acid symbols)—are shown in blue. The D-loop re-
gion controls the initiation of replication and transcription of mtDNA.
B. 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. As electrons (e–) flow along the electron-transport chain,
protons (H+) are pumped from the matrix to the intermembrane
space through complexes I, III, and IV and then back into the matrix
through complex V, to produce ATP. Coenzyme Q (CoQ) and cyto-
chrome-c (Cyt c) are electron-transfer carriers. Genes responsible for
the indicated respiratory-chain disorders are also shown. ATPase 6
denotes ATP synthase 6; BCS1L, cytochrome b–c complex assembly
protein (complex III); NDUF, NADH dehydrogenase–ubiquinone oxi-
doreductase; SCO, synthesis of cytochrome oxidase; SDHA, SDHB,
SDHC, and SDHD, succinate dehydrogenase subunits; SURF1, surfeit
gene 1; FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary
optic neuropathy; MELAS, mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes; MILS, maternally inherited Leigh’s
syndrome; NARP, neuropathy, ataxia, and retinitis pigmentosa; GRACILE,
growth retardation, aminoaciduria, lactic acidosis, and early death; and
ALS, amyotrophic lateral sclerosis. (Reproduced with permission from
DiMauro and Schon.)

have the potential for a phenotypic or pathogenic effect, whereas others kilobases (kb) of noncoding DNA, thought to have a major role in rep-
may be considered pathogenic mutations. lication and transcription initiation. The mutation rate is considerably
With respect to transcription, initiation can occur on both strands higher in the control region, which contains a displacement, or D, loop,
and proceeds through the production of an intronless polycistronic in turn containing two adjacent hypervariable regions (HVR-I and
precursor RNA that is then processed to produce the 13 individual HVR-II) that give rise to large interindividual variability within the hu-
mRNA and 24 individual tRNA and rRNA products. The 37 mtDNA man population. Indeed mtDNA sequence variants at both the coding
genes comprise fully 93% of the 16,569 nucleotides of the mtDNA in and control regions are more highly partitioned across geographically
what is known as the coding region. The control region consists of ~1.1 defined populations than sequence variants in other parts of the ge-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
nome, and combinations of these sequence variants define phylogeo-
graphic mtDNA haplogroups and haplotypes. A major active research
question is whether or not differences in these haplotypes are of medi-
cal significance in terms of disease predisposition. The foregoing struc-
tural 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. Intensive research during the
past two decades has confirmed that this is, indeed, the case.
MATERNAL INHERITANCE AND LACK OF RECOMBINATION
The nuclear genome is characterized by homologous pairs of chromo-
somes of biparental origin. With the exception of the nonrecombining
region of the Y chromosome in males, these homologous pairs under-
go meiotic recombination during gametogenesis, which, together with
mutation, serves as the source of universal genetic diversity. In con-
trast, mtDNA molecules do not undergo recombination, such that
mutational events represent the only source of mtDNA genetic diversi-
fication. Moreover, with very rare exceptions, it is only the maternal
DNA that is transmitted to the offspring. The fertilized oocyte de-
grades mtDNA carried from the sperm in a complex process involving
the ubiquitin proteasome system. Thus, while mothers transmit their
mtDNA to both their sons and daughters, only the daughters are able
to transmit the inherited mtDNA to future generations. Accordingly,
mtDNA sequence variation and associated phenotypic traits and dis-
eases are inherited exclusively along maternal lines.
As will be noted below, because of the complex relationship be-
tween mtDNA mutations and disease expression, sometimes this ma-
ternal inheritance is difficult to recognize at the clinical or pedigree
level. However, evidence of paternal transmission can almost certainly
rule out an mtDNA genetic origin of phenotypic variation or disease;
conversely, a disease affecting both sexes without evidence of paternal
transmission strongly suggests a heritable mtDNA disorder (Fig. e39-3).
One interesting consequence of uniparental inheritance and lack of re-
combination is the utility of mtDNA marker and sequence analysis in
tracing matrilineal ancestry in phylogenetic research.
MULTIPLE COPY NUMBER (POLYPLOIDY), MITOTIC SEGREGATION,
AND HIGH MUTATION RATE
Each aerobic cell in the body has multiple mitochondria, often
numbering many hundreds or more in cells with extensive en-
ergy production requirements. Furthermore, the number of
copies of mtDNA within each mitochondrion varies from sev-
eral to hundreds; this is true of both somatic as well as germ
cells, including oocytes in females. In the case of somatic cells,
this means that the impact of each individual, newly acquired
somatic mutation is likely to be very small in terms of total cellu-
lar or organ system function; however, because of the manyfold
higher mutation rate during mtDNA replication, numerous dif-
ferent mutations may accumulate with the aging of the organ-
ism. 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, contributing to
age-related reduction in the efficiency of oxidative phosphory-
lation and increased production of damaging ROS. According to
this formulation, 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. The potential contribution of such acquired
somatic mtDNA mutations to aging and to common age-relat-
ed disturbances, such as metabolic syndrome and diabetes, can-
cer, neurodegenerative, and cardiovascular disease, will be
considered in greater detail below.
It is evident that just as in the case of acquired somatic mu-
tations in the nuclear genome, so, too, the somatic mutations
in mtDNA are not carried forward to the next generation.
Therefore, in terms of heritable traits and disease, it is impor-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
e313
I
II
III
FIGURE e39-3 Maternal inheritance of mtDNA disorders and heri-
table traits. Affected women (filled circles) transmit the trait to their
children. Affected men (filled square) do not transmit the trait to any
of their offspring.
tant to focus on the consequence of mtDNA polyploidy within the
germ cells of the female reproductive system. The multiple mtDNA
copy number within the maternal germ cells result in the phenome-
non of heteroplasmy of inherited mtDNA mutations. Heteroplasmy
for a given mtDNA sequence variant or mutation arises as a result of
the coexistence within the oocyte of mtDNA molecules bearing both
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
versions of the sequence variant (Fig. e39-4). In the case of pathogenic
mutations, this means coexistence within the oocyte of both the wild-
type and mutant versions. For each oocyte, the percentage of mtDNA
molecules bearing each version of the polymorphic sequence vari-
ant or mutation depends on stochastic events related to partitioning
of mtDNA molecules during the process of oogenesis itself. Thus,
oocytes differ from each other in the degree of heteroplasmy for that
sequence variant or mutation. In turn, the heteroplasmic state is car-
ried forward to the zygote and then, to varying degrees, depending on
mitotic segregation of mtDNA molecules, during organ system devel-
opment and maintenance.
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. The particular mtDNA sequence variant
may be entirely silent in terms of phenotype or disease predisposition
Oocyte maturation
Fertilization
and mtDNA amplification
Mutant mitochondrion
Normal mitochondrion
Nucleus High level of mutation
(affected offspring)
Intermediate level
of mutation (mildly
affected offspring)
Primordial germ
cell containing
mutant mtDNA Low level of mutation
(unaffected offspring)
Primary oocytes
Mature oocytes
FIGURE e39-4 Heteroplasmy and the mitochondrial genetic bottleneck.
During the production of primary oocytes, a selected number of mitochon-
drial DNA (mtDNA) molecules are transferred into each oocyte. Oocyte matu-
ration is associated with the rapid replication of this mtDNA population. This
restriction-amplification event can lead to a random shift of mtDNA muta-
tional load between generations and is responsible for the variable levels of
mutated mtDNA observed in affected offspring from mothers with patho-
genic mtDNA mutations. Mitochondria that contain mutated mtDNA are
shown in red, and those with normal mtDNA are shown in green. (Reproduced
with permission from Taylor and Turnbull.)
 e314 and only detectable upon mtDNA sequencing. By contrast, the mtDNA
sequence variant may affect one or more aspects of mitochondrial
function in a manner that gives rise to a phenotypic effect or predis-
poses to a disease. 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), but also of its distribution among the multiple copies of
mtDNA in the various mitochondria, cells, and tissues of the affected
individual. This leads to the notion of a “threshold” effect, wherein the
actual expression of disease depends upon the relative percentage of
mitochondria whose function is disrupted by mtDNA mutations.
Consequently, there is tremendous heterogeneity in disease pene-
trance and severity, as well as complexity of organ system involvement
among the offspring of women with pathogenic heteroplasmic muta-
tions. This heterogeneity arises from differences in the degree of het-
eroplasmy among oocytes and with subsequent mitotic segregation of
the pathogenic mutation during tissue and organ development, and
throughout the lifetime of the individual. This may create difficulty in
recognizing a maternal pattern of inheritance and making the diagno-
sis of an mtDNA genetic cause of disease.
During the course of human evolution, certain heteroplasmic
PART 18
mtDNA sequence variants may drift to a state of homoplasmy, where-
in all of the mtDNA molecules in the organism contain the new se-
quence variant. This arises due to a “bottleneck” effect followed by
genetic drift during the very process of oogenesis itself (Fig. e39-4). In
other words, during certain stages of oogenesis, the mtDNA copy
number becomes substantially reduced, such that the particular mtDNA
species bearing the novel or derived sequence variant may become the
increasingly predominant, and eventually exclusive, version of the
e-Chapters from International Advisory Editors
mtDNA for that particular nucleotide site. The offspring of a woman
bearing an mtDNA sequence variant or mutation that has become ho-
moplasmic will also be homoplasmic for that variant, and the female
offspring will transmit it forward in subsequent generations; this pro-
cess establishes a new mtDNA haplotype in the human population.
Considerations of reproductive fitness limit the evolutionary or
population emergence of homoplasmic mutations that are lethal or
cause severe disease in infancy or childhood. Thus, with a number of
notable exceptions (e.g., mtDNA mutations causing Leber hereditary
optic neuropathy; see below), most homoplasmic mutations were con-
sidered to be neutral markers of human evolution—useful and inter-
esting in the population genetics analysis of shared maternal ancestry
but with little significance in human phenotypic variation or disease
predisposition. However, recent research and clinical attention have
focused on the potential for certain of these homoplasmic mtDNA se-
quence variants to contribute to the evolutionary adaptation of popu-
lations to their climatic environment or to predispose to heritable late
postreproductive and age-associated disease predisposition.
MITOCHONDRIAL DNA DISEASE
The true prevalence of mtDNA disease is difficult to estimate because
of the phenotypic heterogeneity that occurs as a function of hetero-
plasmy, the challenge of detecting and assessing heteroplasmy in dif-
ferent affected tissues, and the other unique features of mtDNA
function and inheritance described above. Very rough estimates sug-
gest that heteroplasmic germ-line pathogenic mtDNA mutations may
affect up to approximately 1 in 5000 individuals. The true overall im-
pact of mtDNA mutation in human health and disease is certainly
much greater, if the potential contribution of homoplasmic mtDNA
sequence variation to common complex diseases appearing in the
postreproductive age is also considered. Only when the ability to dis-
tinguish a completely neutral sequence variant from a true phenotype-
modifying or pathogenic mutation is achieved, and when an accurate
assessment of heteroplasmy can be determined with fidelity, will the
true extent and contribution of mtDNA sequence variation to human
traits and health be determined. In addition, the combination of inter-
actions of mtDNA sequence variation with mutations in the nuclear
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
genome also complicates our ability to ascertain the extent of contri-
bution of heritable mtDNA mutations to human illness. Finally, as-
sessment of the impact of the accumulation of acquired somatic
mtDNA mutations on late-onset common disease predisposition, or
on diseases arising from exposure to metabolic stress, also needs to be
considered in order to appreciate the full impact of mtDNA in human
health and disease.
OVERVIEW OF CLINICAL AND PATHOLOGIC FEATURES
OF HUMAN mtDNA DISEASE
Given the vital roles of mitochondria in all nucleated cells, it is not
surprising that mtDNA mutations can affect numerous tissues with
pleiotropic effects. More than 200 different disease-causing mtDNA
mutations have been described to date, all affecting ETC function. Fig-
ure e39-5 provides an mtDNA map of some of the better characterized
disorders. A number of clues can increase the index of suspicion for
mtDNA mutation as an etiology of a heritable trait or disease, includ-
ing (1) familial clustering with absence of paternal transmission; (2) ad-
herence 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 muta-
tion category; (3) a complex of laboratory and pathologic abnormali-
ties that reflect disruption in cellular energetics (e.g., lactic acidosis and
neurodegenerative and myodegenerative symptoms with the finding of
ragged red fibers, reflecting the accumulation of abnormal mitochon-
dria under the muscle sarcolemmal membrane); or (4) a mosaic pat-
tern reflecting a heteroplasmic state.
Heteroplasmy can sometimes be elegantly demonstrated at the tis-
sue level using histochemical staining for enzymes in the oxidative
phosphorylation pathway, with a mosaic pattern indicating heteroge-
neity of the genotype for the coding region for the mtDNA-encoded
enzyme. Complex II, CoQ, and cytochrome-c are exclusively encoded
by nuclear DNA. In contrast, complexes I, III, IV, and V contain at
least some subunits encoded by mtDNA. Just 3 of the 13 subunits of
the ETC complex IV enzyme, cytochrome-c oxidase, are encoded by
mtDNA, and, therefore, this enzyme has the lowest threshold for dys-
function when a threshold of mutated mtDNA is reached. Histochem-
ical staining for cytochrome-c oxidase activity in tissues of patients
affected with heteroplasmic inherited mtDNA mutations (or with the
somatic accumulation of mtDNA mutations, see below) can show a
mosaic pattern of reduced histochemical staining in comparison with
histochemical staining for the complex II enzyme, succinate dehydro-
genase (Fig. e39-6). Heteroplasmy can also be detected at the genetic
level through direct mtDNA genotyping under special conditions. 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 sequenc-
ing or genotyping approaches.
Clinically, the most striking overall characteristic of mitochondrial
genetic disease is the phenotypic heterogeneity associated with mtDNA
mutations. This extends to intrafamilial phenotypic heterogeneity for
the same mtDNA pathogenic mutation and, conversely, to the overlap of
phenotypic disease manifestations with distinct mutations. Thus, while
fairly consistent and well-defined “classic” syndromes have been at-
tributed to specific mutations, frequently “nonclassic” combinations
of disease phenotypes ranging from isolated myopathy to extensive mul-
tisystem disease are often encountered, rendering genotype-phenotype
correlation challenging. In both classic and nonclassic mtDNA disor-
ders, there is often a clustering of some combination of abnormalities
affecting the neurologic system (including optic nerve atrophy, pigment
retinopathy, sensorineural hearing loss), cardiac and skeletal muscle
(including extraocular muscles), and endocrine and metabolic systems
(including diabetes mellitus). Additional organ systems that may be af-
fected include the hematopoietic, renal, hepatic, and gastrointestinal
systems, though these are more frequently involved in infants and chil-
dren. Disease-causing mtDNA coding region mutations can affect either
one of the 13 protein encoding genes, or one of the 24 protein synthetic
 Parkinsonism, e315
aminoglycoside-induced deafness
LS, MELAS, MELAS Myopathy,
multisystem disease myoglobinuria PEO
Cardiomyopathy Cardiomyopathy
PEO, LHON, MELAS, ECM ECM, LHON, myopathy,
myopathy, cardiomyopathy, 12s F PT cardiomyopathy, MELAS
V
diabetes and deafness 16S and parkinsonism
Cyt b
Myopathy, LHON L1 Cardiomyopathy
cardiomyopathy, PEO E ECM
ND1
Myopathy, MELAS ND6 LHON, MELAS,
I diabetes,
Myopathy, lymphoma Q
M LHON and dystonia
Cardiomyopathy
LHON ND5 LS, MELAS
LS, ataxia, ND2
chorea, myopathy W Cardiomyopathy, ECM
PEO A L2 PEO, myopathy,
N sideroblastic anemia
Myopathy, C S2
PEO Y H
ECM Diabetes and deafness
PEO COXI ND4
Myoglobinuria, LHON, myopathy,
motor neuron disease, S1 LHON and dystonia

CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases

sideroblastic anemia D ND4L
COXII
ND3 R
PPK, deafness, A8
Cardiomyopathy K A6 COXIII G LHON
MERRF-MELAS myoclonus
Progressive myoclonus,
Myopathy, epilepsy, and optic atrophy
multisystem disease, NARP, MILS, Cardiomyopathy,
encephalomyopathy FBSN
SIDS, ECM
Cardiomyopathy, LS, ECM,
PEO, MERRF, myoglobinuria
MELAS, deafness

FIGURE e39-5 Mutations in the human mitochondrial genome
known to cause disease. Disorders that are frequently or promi-
nently associated with mutations in a particular gene are shown in
boldface. Diseases due to mutations that impair mitochondrial protein
synthesis are shown in blue. Diseases due to mutations in protein-cod-
ing genes are shown in red. ECM denotes encephalomyopathy; FBSN,
familial bilateral striatal necrosis; LHON, Leber hereditary optic neurop-
athy; LS, Leigh’s syndrome; MELAS, mitochondrial encephalomyopa-
thy, lactic acidosis, and stroke-like episodes; MERRF, myoclonic
epilepsy with ragged red fibers; MILS, maternally inherited Leigh’s syn-
drome; NARP, neuropathy, ataxia, and retinitis pigmentosa; PEO, pro-
gressive external ophthalmoplegia; PPK, palmoplantar keratoderma;
and SIDS, sudden infant death syndrome. (Reproduced with permission
from DiMauro and Schon.)

genes. Clinical manifestations do not readily distinguish these two cate-
gories, though lactic acidosis and muscle pathologic findings tend to be
more prominent in the latter. In all cases, either defective ATP produc-
tion due to disturbances in the ETC or enhanced generation of reactive
oxygen species has been invoked as the mediating biochemical mecha-
nism between mtDNA mutation and disease manifestation.
mtDNA DISEASE PRESENTATIONS
The clinical presentation of adult patients with mtDNA disease can be
divided into three categories: (1) clinical features suggestive of mito-
chondrial disease (Table e39-2), but not a well-defined classic syn-
drome; (2) classic mtDNA syndromes; and (3) clinical presentation
confined to one organ system (e.g., isolated sensorineural deafness,
cardiomyopathy, or diabetes mellitus).
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 molecu-
lar pathogenesis, inheritance, and clinical presentation. The first five of
these syndromes result from heritable point mutations in either pro-
tein encoding or protein synthetic mtDNA genes; the other three re-
sult from rearrangements or deletions that usually do not involve the
germ line.
Leber hereditary optic neuropathy (LHON) is a common cause of
maternally inherited visual failure. LHON typically presents during
young adulthood with subacute painless loss of vision in one eye, with
symptoms developing in the other eye 6–12 weeks after the initial on-
set. In some instances, cerebellar ataxia, peripheral neuropathy, and
cardiac conduction defects are observed. In >95% of cases, LHON is
due to one of three homoplasmic point mutations of mtDNA that af-
fect genes encoding different subunits of complex I of the mitochon-
drial ETC; however, not all individuals who inherit a primary LHON
mtDNA mutation develop optic neuropathy, indicating that addition-
al environmental (e.g., tobacco exposure) or genetic factors are impor-
tant in the etiology of the disorder. Both the nuclear as well as
mitochondrial genomic background modify disease penetrance. Thus,
for example, LHON has a greater penetrance and severity in men than
in women, pointing to an epistatic interaction with the nuclear ge-
nome. Moreover, disease susceptibility for a given mutation is modu-
lated by mtDNA haplotype background, with certain haplotypes being
protective. Of interest, patients with this syndrome are often ho-
moplasmic for the disease-causing mutation. The somewhat later on-
set in young adulthood and modifying effect of genetic background
may have enabled homoplasmic pathogenic mutations to have escaped
evolutionary censoring.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-
like episodes (MELAS) is probably the most common mtDNA dis-
ease, consisting of a progressive encephalomyopathy characterized
by repeated stroke-like events involving mainly posterior cerebral ar-
eas. Of note, brain lesions do not respect the distribution of vascular
territories. Recurrent migraine-like headache and vomiting, exercise
intolerance, seizures, short stature, and lactic acidosis are other fre-
quent clinical features. The most commonly described pathogenic
point mutations are A3243G and T3271C in the gene encoding the
leucine tRNA.
Myoclonic epilepsy with ragged red fibers (MERRF) is a multisystem
disorder characterized by myoclonus, seizures, ataxia, and myopathy
with ragged red fibers. Hearing loss, exercise intolerance, neuropathy,
and short stature are often present. Almost all MERRF patients have

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

 e316 arrangements of mtDNA are thought to
result from clonal amplification of a
single sporadic mutational event, oc-
curring in the maternal oocyte or dur-
ing early embryonic development. Since
germ line involvement is rare, most cas-
es are sporadic rather than inherited.
KSS is characterized by the triad of
onset before age 20, chronic progressive
external ophthalmoplegia, and pigmen-
tary retinopathy. Cerebellar syndrome,
heart block, increased cerebrospinal flu-
id protein content, diabetes, and short
stature are also part of the syndrome.
Single deletions/duplication can also re-
sult in milder phenotypes such as PEO,
characterized by late-onset progressive
external ophthalmoplegia, proximal my-
opathy, and exercise intolerance. In both
KSS and PEO, diabetes mellitus and hear-
ing loss are frequent accompaniments.
FIGURE e39-6 Cytochrome-c oxidase deficiency in mitochondrial DNA–associated disease. Pearson syndrome is also characterized
PART 18

Transverse tissue sections that are reacted for both cytochrome-c oxidase (COX) and succinate dehy- by diabetes mellitus from pancreatic in-
drogenase (SDH) activities sequentially, with COX-positive cells shown in brown and COX-deficient sufficiency, together with pancytopenia
cells shown in blue. A. Skeletal muscle from a patient with a heteroplasmic mitochondrial tRNA point and lactic acidosis, caused by the large-
mutation. The section shows a typical “mosaic” pattern of COX activity, with many muscle fibers har- scale sporadic deletion of several mtDNA
boring levels of mutated mtDNA that are above the crucial threshold to produce a functional en- genes.
zyme complex. B. Cardiac tissue (left ventricle) from a patient with a homoplasmic tRNA mutation
that causes hypertrophic cardiomyopathy, whichdemonstrates an absence of COX in most cells. C. A THE INVESTIGATION OF SUSPECTED
mtDNA DISEASE
e-Chapters from International Advisory Editors

section of cerebellum from a patient with mtDNA rearrangement that highlights the presence of
COX-deficient neurons. D, E. Tissues that show COX deficiency due to clonal expansion of somatic The clinical presentations of classic syn-
mtDNA mutations within single cells—a phenomenon that is seen in both postmitotic cells (D; ex- dromes, groupings of disease manifesta-
traocular muscles) and rapidly dividing cells (E; colonic crypt) in aging humans. (Reproduced with per- tions in multiple organ systems, or
mission from Taylor and Turnbull.) unexplained isolated presentations of
one of the disease features of a classic
mtDNA syndrome should prompt a
mutation in the mtDNA tRNAlys gene and the A8344G mutation in systematic clinical investigation as outlined in Fig. e39-7. Despite the
the mtDNA gene encoding the lysine amino acid tRNA is responsible centrality of disruptive oxidative phosphorylation, an elevated blood
for 80–90% of MERRF cases. lactate level is neither specific nor sensitive because there are many
Neurogenic weakness, ataxia, and retinitis pigmentosa (NARP) is causes of blood lactic acidosis, and many patients with mtDNA defects
characterized by moderate diffuse cerebral and cerebellar atrophy and presenting in adulthood have normal blood lactate. A raised cere-
symmetric lesions of the basal ganglia on MRI. A heteroplasmic brospinal fluid lactate is a more specific test for mitochondrial disease
T8993G mutation in the gene ATPase 6 subunit gene has been identi- if there is central neurologic involvement. The serum creatine kinase
fied as causative. Ragged red fibers are not observed in muscle biopsy. may be elevated but is often normal, even in the presence of a proxi-
When >95% of mtDNA molecules are mutant, a more severe clinical, mal myopathy. Urine organic and amino acids may also be abnormal.
neuroradiologic and neuropathologic picture (Leigh’s syndrome) Every patient with seizures or cognitive decline should have an electro-
emerges. Point mutations in the mtDNA gene encoding the 12S rRNA encephalogram. A brain CT scan may show calcified basal ganglia or
result in heritable nonsyndromic hearing loss. One such mutation bilateral hypodense regions with cortical atrophy. MRI is indicated in
causes heritable ototoxic susceptibility to aminoglycoside antibiotics, patients with brain stem signs or stroke-like episodes.
which opens a pathway for a simple pharmacogenetic test in the ap- For some mitochondrial diseases, it is possible to obtain an accurate
propriate clinical settings. diagnosis with a simple molecular genetic screen. For examples, 95%
Kearns-Sayre syndrome (KSS), sporadic progressive external oph- of patients with LHON harbor one of three mtDNA point mutations
thalmoplegia (PEO), and Pearson syndrome are three disease pheno- (A11778G, A3460G, and T14484C). These patients have very high lev-
types caused by large-scale mtDNA rearrangements including partial els of mutated mtDNA in peripheral blood cells, and it is, therefore,
deletions or partial duplication. The majority of single large-scale re- appropriate to send a blood sample for molecular genetic analysis by
polymerase chain reaction (PCR) or restriction fragment length poly-
morphism. The same is true for most MERRF patients who harbor a
TABLE e39-2 COMMON FEATURES OF mtDNA-ASSOCIATED point mutation in the lysine tRNA gene at position 8344. In contrast,
DISEASES IN ADULTS patients with the A3243G MELAS mutation often have low levels of
mutated mtDNA in blood. If clinical suspicion is strong enough to
Neurologic: stroke, epilepsy, migraine headache, peripheral neuropathy, cranial
neuropathy (optic atrophy, sensorineural deafness, dysphagia, dysphasia)
warrant peripheral blood testing, then patients with a negative result
Skeletal myopathy: ophthalmoplegia, exercise intolerance, myalgia should be investigated further by performing a skeletal muscle biopsy.
Cardiac: conduction block, cardiomyopathy Muscle biopsy histochemical analysis is the cornerstone for investi-
Respiratory: hypoventilation, aspiration pneumonitis gation of patients with suspected mitochondrial disease. Histochemi-
Endocrine: diabetes mellitus, premature ovarian failure, hypothyroidism, cal analysis may show subsarcolemmal accumulation of mitochondria
hypoparathyroidism with the appearance of ragged red fibers. Electron microscopy might
Ophthalmologic: cataracts, pigment retinopathy, neurologic and myopathic
(optic atrophy, ophthalmoplegia)
show abnormal mitochondria with paracrystalline inclusions. Muscle
histochemistry may show cytochrome-c oxidase (COX)–deficient fi-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TABLE e39-3 MITOCHONDRIAL DISEASES DUE TO mtDNA POINT MUTATIONS AND LARGE-SCALE REARRANGEMENTS e317
Most Frequent Homoplasmy or
Disease Phenotype mtDNA Mutations Heteroplasmy Inheritance
Leber hereditary optic Loss of central vision leading to blindness in G1778A, T14484C, G3460A Homoplasmic Maternal
neuropathy (LHON) young adult life (usually)
NARP, Leigh’s disease Neuropathy, ataxia, retinitis pigmentosa, Point mutation in ATPase Heteroplasmic Maternal
developmental delay, mental retardation, subunit 6 gene
lactic acidemia
MELAS Mitochondrial encephalomyopathy, lactic Point mutation in tRNAleu Heteroplasmic Maternal
acidosis, and stroke-like episodes; may
manifest only as diabetes
MERRF Myoclonic epilepsy, ragged red f ibers in Point mutation in tRNAlys Heteroplasmic Maternal
muscle, ataxia, increased CSF protein,
sensorineural deafness, dementia
Deafness Progressive sensorineural deafness, often A1555G mutation in 12S rRNA Homoplasmic Maternal
induced by aminoglycoside antibiotics.
Nonsyndromic sensorineural deafness A7445G mutation in 12S rRNA Homoplasmic Maternal
Chronic progressive external Late-onset bilateral ptosis and ophthalmo- Single deletions or duplications Heteroplasmic Mostly sporadic,
ophthalmoplegia (PEO) plegia, proximal muscle weakness, and somatic mutations
exercise intolerance
Pearson syndrome Pancreatic insufficiency, pancytopenia, Large deletion Heteroplasmic Sporadic, somatic
lactic acidosis mutations
Kearn-Sayre syndrome (KSS) External ophthalmoplegia, heart-block, The 5-kb “common deletion” Heteroplasmic Sporadic, somatic

CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases

retinal pigmentation, ataxia mutations
Note: CSF, cerebrospinal fluid.

bers, which indicate mitochondrial dysfunction (Fig. e39-6). Respira- A much broader extrapolation of the foregoing mechanism states
tory chain complex assays may also show a deficiency. Either of these that many homoplasmic mtDNA mutations affect human health in
two abnormalities confirm that a patient has mitochondrial disease, the postreproductive age only and therefore escaped evolutionary cen-
and this should lead to in-depth molecular genetic analysis. soring altogether. In the modern era of increased median life span,
such mutations are thought to account for a considerable burden of
age-associated common complex disease. Mean life expectancy has
IMPACT OF HOMOPLASMIC SEQUENCE VARIATION risen from ~47 years to ~77 years during the past century alone; there-
ON HERITABLE TRAITS AND DISEASE
The relationship among the degree of heteroplasmy, tissue distribu-
tion of the mutant mtDNA, and disease phenotype simplifies infer- CLINICAL AND LABORATORY INVESTIGATION
ence of a clear causative relationship between heteroplasmic mutation OF SUSPECTED MTDNA DISORDER
and disease. With the exception of certain mutations (e.g., those caus-
ing most cases of LHON), drift to homoplasmy of such mutations Clinical investigations
would be precluded normally by the severity of impaired oxidative Blood: creatine kinase, liver functions,
glucose, lactate
phosphorylation and the consequent reduction in reproductive fit- Urine: organic and amino acids
ness. Therefore, it has been previously thought that sequence variants CSF: glucose, protein, lactate
that have reached homoplasmy should be neutral in terms of human Cardiac x-ray, ECG, ECHO
evolution and useful only for tracing human evolution, demography, EEG, EMG, nerve conduction
and migration; however, recent studies have suggested that some ho- Brain CT/MRI
moplasmic mtDNA sequence variants may affect heritable traits or
health through one or more mechanisms.
The first such mechanism relates to locally adaptive evolutionary Yes
Specific point mutation syndrome: PCR/RFLP analysis of
forces. As noted above, homoplasmic mtDNA sequence variants that e.g., MELAS, MERRF, and LHON blood for known mutations
partition population groups are designated as defining maternal “hap-
logroups.” Striking discontinuities have been observed in mtDNA No
haplogroup distribution among climatic zones across the globe. For
example, of the extensive mtDNA sequence diversity in Africa, only a
limited number of haplogroups and their derivative lineages success- Histochemistry Muscle biopsy Study of respiratory-
fully colonized all of Eurasia and then the Americas. Furthermore, it chain complexes
was shown that ancient missense mutations that define these haplo- activities
groups alter amino acids that are as highly conserved in evolution as
are those known to result from pathogenic mutations. Retention of Molecular genetic analysis
mutations altering such highly conserved amino acids, over many tens rearrangements
of thousands of years, suggests that they must be adaptive since they PCR/RFLP for common point mutation
mtDNA automated sequencing
could not have been maintained if they were pathogenic and destruc-
tive to reproductive fitness. This phenomenon has been attributed to
adaptive differences in the efficiency of oxidative phosphorylation and FIGURE e39-7 Clinical and laboratory investigation of suspected
consequent thermogenesis, according to differences in prevailing cli- mtDNA disorder. CSF, cerebrospinal fluid; ECG, electrocardiogram;
mates in different global geographic regions during much of human EEG, electroencephalogram; EMG, electromyogram; MELAS, mito-
evolution. A potential health implication of this finding is the possibil- chondrial encephalomyopathy, lactic acidosis, and stoke-like episodes;
ity that these same mutations might result in deleterious effects on en- MERFF, myoclonic epilepsy with ragged red fibers; LHON, Leber hered-
ergy metabolism and caloric balance in the current era of human itary optic neuropathy; PCR, polymerase chain reaction; RFLP, restric-
transglobal migration or climate control. tion fragment length polymorphism.

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

 e318 fore, late-onset effects of a subset of homoplasmic mtDNA mutations
may contribute significantly to the burden of human illness only in the
current era when a relatively higher percentage of the population is
surviving beyond reproductive age. Many homoplasmic mtDNA vari-
ants have been and will continue to be identified by whole mtDNA se-
quencing in various global populations. The challenge is to identify
the subsets that modify mtDNA function and contribute to late-onset,
common complex disease. Indeed, given the finding that global popu-
lations are more differentiated at the level of mtDNA than they are at
the level of the nuclear genome, it also attractive to postulate that pop-
ulation differences in the predisposition to certain late-onset common
complex metabolic diseases may be attributed in part to population-
based mtDNA sequence variation. The diseases that have been of par-
ticular interest are those that affect the very organ systems familiar
from the known classic mtDNA syndromes described above.
METABOLIC SYNDROME AND TYPE 2 DIABETES MELLITUS (T2DM)
Insulin release by pancreatic beta cells is modulated in response to ATP
metabolism, and insulin action is perturbed by metabolites of mito-
chondrial fatty acid oxidation. This has led investigators to consider
mtDNA itself as a potential genomic locus for susceptibility to T2DM.
A rather clear-cut case is that of a mutation in mtDNA nucleotide 3243
PART 18
encoding the mitochondrial tRNA for the amino acid leucine. Even a
low level of heteroplasmy for a particular point mutation in the mtDNA
tRNA gene encoding the leucine tRNA is thought to contribute to the
pathogenesis of up to 1% of all cases of T2DM. This and other findings
at the biochemical and population genetics levels have motivated the
search for more definitive evidence of the role of homoplasmic variants
in the predisposition to metabolic syndrome and T2DM. Such evi-
dence has been obtained with the finding of significant segregation of a
e-Chapters from International Advisory Editors
homoplasmic mtDNA tRNA mutation (T→ C transition in the nucleo-
tide immediately 5′ to the isoleucine tRNA anticodon) with metabolic
syndrome phenotypes in a large Caucasian kindred.
Since the metabolic syndrome is so common, and can result from
numerous different genetic susceptibility loci and environmental causes,
and since its pathogenesis involves a large number of recently identi-
fied genetic susceptibility loci coupled with environmental factors—
additional features in this particular reported kindred—researchers
were able to tease out affected from unaffected individuals for purpos-
es of the association study. The affected individuals had signs of hypo-
magnesemia, hypertension, and hypercholesterolemia. This finding
highlights the problem of underdiagnosing homoplasmic mtDNA se-
quence variants as pathogenic causes of common symptoms and syn-
dromes. This particular mutation in a tRNA-encoding mtDNA gene
also highlights the expected difference in the phenotypic impact of
mutations in genomic regions encoding tRNAs in the mitochondrial
versus the nuclear genome.
In the case of the mitochondrial genome, mutations affecting
mtDNA-encoded tRNAs perturb the translation of only up to 13 pro-
tein products and may be compatible with life. In contrast, severe loss
of function of nuclear genome–encoded tRNA might be expected to
perturb the function of a much greater array of nuclear-encoded pro-
teins. It is also of interest to contrast the anticipated effects of point
mutations in one of the 13 protein-coding genes of mtDNA with those
of the 24 genes encoding tRNAs and rRNAs. Whereas the former
would disrupt the function of a single protein product, the latter
group would perturb translation of up to all 13 of the mtDNA-encod-
ed proteins. Under these circumstances, a tolerable loss of function of
all 13 proteins might be compatible with life, although it would be ex-
pected to cause a pleiotropic multiorgan heritable syndrome, as was
indeed observed for the mtDNA isoleucine tRNA mutation causing an
extended metabolic syndrome phenotype. At the population level, the
finding of an apparent excess of maternal inheritance in T2DM sug-
gests the potential involvement of mtDNA. A common variant mtDNA
sequence variant (T16189C) has been related to both low birth weight,
impaired glucose tolerance, and metabolic syndrome in specific popu-
lations. However, rigorous population-based association studies using
case-control designs have not yet provided definitive evidence for a re-
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
lationship between mtDNA haplogroups and susceptibility to T2DM
or its complications.
NEURODEGENERATIVE DISEASE
The prominence of neurologic injury in classic mtDNA diseases, to-
gether with the presumed role of reactive oxygen species in neuronal
injury and late age of onset of neurodegenerative diseases, have led in-
vestigators to consider the possibility that homoplasmic variants in
mtDNA sequence that define population haplogroups might also
modify the susceptibility to neurodegenerative diseases such as Par-
kinson’s and Alzheimer’s disease. Thus, for example, particular config-
urations of mtDNA sequence polymorphisms that define population
haplogroups designated in phylogenetics by the labels J, T, U, and K
have been reported to be potentially protective against Parkinson’s
disease in different populations. In the case of Alzheimer’s disease,
some studies have shown haplogroup J to increase risk, with haplo-
group D decreasing risk. Mutations located in the mtDNA control re-
gion do not produce defective polypeptide products but affect both
the light and heavy strand promoters, as well as the heavy strand ori-
gin of replication, and thus may modulate mtDNA replication and
transcription. Mitochondrial DNA control region sequence variants
(e.g., T414G) have been identified in Alzheimer’s disease brains in as-
sociation with a significant reduction in mtDNA copy number and
reduction in specific transcripts. A number of studies have focused on
the interaction of mtDNA haplogroup–designating mutations with
the well-established Alzheimer’s disease risk alleles at the nuclear
APOE4 locus. From these studies it was postulated that ETC-uncou-
pling mutations that minimize ROS production are those that confer
protection against neuronal injury, but definitive proof of this postu-
late awaits further studies.
OTHER DISEASES AND NONDISEASE HERITABLE TRAITS
Consideration of the potential contribution of mtDNA mutations to
numerous heritable traits and common complex diseases requires con-
sideration of the common variant–common phenotype model (includ-
ing disease phenotype) versus the rare variant–common phenotype
model, which are also applicable to the nuclear genome. According to
the common variant–common phenotype model, DNA sequence vari-
ants inherited identically by descent and present in large numbers of
individuals within one or more populations, may predispose to com-
mon phenotypes. In the rare variant–common phenotype model, dif-
ferent mutations within one or more genetic loci involved in a
particular molecular pathway may predispose to a common phenotype
or disease. In this regard, the entire mtDNA can be considered as a sin-
gle genomic locus. Genome-wide association studies have been utilized
to try to map common variants responsible for common diseases, using
case-control or multiplex family approaches. These approaches have
been applied to common variants in mtDNA sequence as well, as noted
above for metabolic syndrome and neurodegenerative disease. Addi-
tional examples include the variable length of an mtDNA control re-
gion polycytosine stretch (16189 variant) as a contributing genomic
influence in the onset of age-related cardiomyopathy with T2DM. An
association of mtDNA haplogroup T, and a polymorphism at position
13368 with hypertrophic cardiomyopathy has been reported in a Euro-
pean population, and a number of studies have suggested an associa-
tion between mtDNA mutations and mitochondrial dysfunction in
heart failure predisposition. In the case of age-related cancers as well,
the association of a number of heritable homoplasmic mtDNA muta-
tions with certain cancers has been reported, including prostate, kid-
ney, and breast cancer.
The association of mtDNA haplogroups with at least two nondisease
heritable traits has also been studied. These are life expectancy and ex-
ercise endurance. Several mtDNA control region mutations, including
the C150T mutation that shifts the heavy chain origin of replication,
have been reported to accumulate with age in specific tissues, including
lymphocytes of centenarians and their twins. The relationship between
the C150T mutation and longevity has been replicated in Italian, Finn-
ish, and Japanese populations—suggesting a common ancient origin.
The alternative of evolutionary convergence of this mutation for lon-
gevity seems less likely, as trait does not confer reproductive advantage.
The association of haplogroup J and its sub-haplogroups with longevi-
ty has been demonstrated in north Italian, north Irish, and Finnish
sample sets. At least in the Italian study, this association was shown to
be population specific, since it was not reproduced in sample sets of
southern Italian communities. Furthermore, in the case of the north
Italian communities, an additional interaction of the mtDNA haplo-
group designated as J2 with several different mutations adjacent to rep-
lication origins, including the aforementioned C150T, has been noted.
The functional importance of one or more of the mutations desig-
nated as haplogroup J is further strengthened by the finding of the in-
teresting interaction with the mtDNA mutations causing LHON, as
noted previously. Reduced disease predilection suggests that one or
more of the ancient sequence variants designated as haplogroup J ap-
pear to attenuate predisposition to degenerative disease, in the face of
other risk factors. It has been proposed that the mtDNA haplogroups
associated with exceptional longevity favor a relatively uncoupled state
of the ETC, with reduced efficiency of production of ATP and ROS
and increased thermogenesis. While this has not been demonstrated
biochemically, the notion is strengthened by the finding of a relative
paucity of these mtDNA haplogroups among successful endurance
athletes, for whom maximum efficiency of oxidative phosphorylation
confers an athletic competitive advantage.
It should be noted that not all studies have replicated associations of
mtDNA haplogroups with longevity, athletic performance, or other
heritable phenotypes. Most of these studies are limited by small sam-
ple sizes and the possibility of population stratification or ethnic an-
cestry bias. Since mtDNA haplogroups are so prominently partitioned
along phylogeographic lines, it is difficult to rule out the possibility
that a haplogroup for which an association has been found is simply a
marker for differences in populations with a societal or environmental
difference or with different allele frequencies at other genomic loci,
which are actually causally related to the heritable trait or disease of
interest. The difficulty in generating cellular or animal models to test
the functional influence of homoplasmic sequence variants (as a result
of mtDNA polyploidy) further compounds the challenge. The most
likely formulation is that different mtDNA haplogroup–defining ho-
moplasmic mutations serve to provide different “risk backgrounds”
for common age-related diseases whose major molecular pathogenesis
emanates from a combination of mutations in the nuclear genome, to-
gether with environmental influences. Progress in minimizing poten-
tially misleading associations in mtDNA heritable trait and disease
studies should include ensuring adequate sample size taken from a
large sample recruitment base, together with the use of carefully
matched controls, and analysis that takes into account the interaction
with other genomic loci and environmental factors.
IMPACT OF ACQUIRED SOMATIC mtDNA MUTATION
ON HUMAN HEALTH AND DISEASE
Studies on aging humans and animals have shown a potentially im-
portant correlation of age with the accumulation of heterogeneous
mtDNA mutations, especially in those organ systems that undergo the
most prominent age-related degenerative tissue phenotype. Sequenc-
ing of PCR-amplified single mtDNA molecules has demonstrated an
average of two to three point mutations per molecule in elderly sub-
jects when compared with younger ones. Point mutations observed in-
clude those responsible for known heritable heteroplasmic mtDNA
disorders, such as the A3344G and A3243G mutations responsible for
the MERRF and MELAS syndromes, respectively. However, the cumu-
lative burden of these acquired somatic point mutations with age was
observed to remain well below the threshold expected for phenotypic
expression (<2%). Point mutations at other sites not normally in-
volved in inherited mtDNA disorders have also been shown to accu-
mulate to much higher levels in some tissues of elderly individuals,
with the description of tissue-specific “hot spots” for mtDNA point
mutations. Along the same lines, an age-associated and tissue-specific
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
accumulation of mtDNA deletions has been observed, including dele- e319
tions involved in known heritable mtDNA disorders, as well as others.
The accumulation of functional mtDNA deletions in a given tissue is
expected to be associated with mitochondrial dysfunction, as reflected
in an age-associated patchy and reduced cytochrome-c oxidase activity
upon histochemical staining, especially in skeletal and cardiac muscle
and brain. A particularly well studied and potentially important exam-
ple is the accumulation of mtDNA deletions and cytochrome-c oxi-
dase deficiency observed in neurons of the substantia nigra in
Parkinson’s disease patients.
The progressive accumulation of ROS has been proposed as the key
factor connecting mtDNA mutations with aging and age-related dis-
ease pathogenesis (Fig. e39-8). As noted above, ROS are a byproduct of
oxidative phosphorylation and are removed by detoxifying antioxi-
dants into less harmful moieties; however, exaggerated production of
ROS or impaired removal results in their accumulation. One of the
main targets for ROS-mediated injury is DNA, and mtDNA is particu-
larly vulnerable because of its lack of protective histones and less effi-
cient injury repair systems compared with nuclear DNA. In turn,
accumulation of mtDNA mutations results in inefficient oxidative
phosphorylation, with the potential for excessive production of ROS,
CHAPTER e39 Mitochondrial DNA and Heritable Traits and Diseases
generating a “vicious cycle” of cumulative mtDNA damage. Indeed,
measurement of the oxidative stress biomarker 8-hydroxy-2-deoxygua-
nosine has been used to measure age-dependent increases in mtDNA
oxidative damage at a rate exceeding that of nuclear DNA. It should be
noted that mtDNA mutation can potentially occur in postmitotic cells
as well, since mtDNA replication is not synchronized with the cell cycle.
Two other proposed links between mtDNA mutation and aging, be-
sides ROS-mediated tissue injury, are the perturbations in efficiency of
oxidative phosphorylation with disturbed cellular aerobic function and
perturbations in apoptotic pathways, whose execution steps involve mi-
tochondrial activity.
Genetic intervention studies in animal models have sought to clarify
the potential causative relationship between acquired somatic mtDNA
mutation and the aging phenotype, and the role of ROS in particular.
Damaged
mitochondrial Error-prone
Mutant proteins DNA Pol-γ Decreased
mitochondrial DNA repair
proteins
O2
X
O2−
DNA X
H2O2 mutations
H2O OH
ROS
Nuclear
DNA damage Apoptosis
Aging
FIGURE e39-8 Multiple pathways of DNA damage and aging. Mi-
tochondrial DNA damage and aging. Multiple factors may impinge on
the integrity of mitochondria that lead to loss of cell function, apopto-
sis, and aging. The classic pathway is indicated with blue arrows; the
generation of ROS (superoxide anion, hydrogen peroxide, and hydroxyl
radicals), as a by-product of mitochondrial oxidative phosphorylation,
results in damage to mitochondrial macromolecules including the
mtDNA, the latter leading to deleterious mutations. When these factors
damage the mitochondrial energy-generating apparatus beyond a
functional threshold, proteins are released from the mitochondria that
activate the caspase pathway leading to apoptosis, cell death, and ag-
ing. (Reproduced with permission from Loeb L et al.)
 e320 Replication of the mitochondrial genome is mediated by the activity of
the nuclear-encoded polymerase gamma gene. A transgenic homozy-
gous mouse knock-in mutation of this gene renders the polymerase en-
zyme deficient in proofreading and results in a three- to fivefold increase
in mtDNA mutation rate. Such mice develop a premature aging pheno-
type, which includes subcutaneous lipoatrophy, alopecia, kyphonia, and
weight loss with premature death. However, not all animal models of
enhanced mtDNA mutation rate have shown a similar accelerated aging
phenotype. Furthermore, it has been difficult to demonstrate a consistent
relationship between rates of mtDNA mutation and ROS production.
While the finding of increased in mtDNA mutation and mitochondrial
dysfunction with age has been solidly established, the causative role and
specific contribution of mitochondrial ROS to aging and age-related
disease has yet to be proved. Similarly, while many tumors display high-
er levels of heterogeneous mtDNA mutations, a causal relationship to
tumorigenesis has not been proved.
Besides the age-dependent acquired accumulation in somatic cells
of heterogeneous point mutations and deletions, a quite different ef-
fect of nonheritable and acquired mtDNA mutation has been de-
scribed affecting tissue stem cells. In particular, disease phenotypes
attributed to acquired mtDNA mutation have been observed in spo-
radic and apparently nonfamilial cases involving a single individual or
PART 18
even tissue, usually skeletal muscle. The presentation consists of de-
creased exercise tolerance and myalgias, sometimes progressing to
rhabdomyolysis. As in the case of the sporadic heteroplasmic large-
scale deletion classic syndromes of chronic PEO, Pearson syndrome,
and KSS, the absence of a maternal inheritance pattern, together with
the finding of limited tissue distribution, suggests a molecular patho-
genic mechanism emanating from mutations arising de novo in mus-
cle stem cells after germ-line differentiation (somatic mutations that
e-Chapters from International Advisory Editors
are not sporadic and occur in tissue-specific stem cells during fetal de-
velopment or in the postnatal maintenance or postinjury repair stage).
Such mutations would be expected to be propagated only within the
progeny of that stem cell and affect a particular tissue within a given
individual, without evidence of heritability.
PROSPECTS FOR PREVENTION AND
TREATMENT OF mtDNA DISEASE
GENETIC COUNSELING IN mtDNA DISORDERS
The provision of accurate genetic counseling and reproductive options
to families with mtDNA mutations is complicated by the unique ge-
netic features of mtDNA that distinguish it from Mendelian genetics.
While there is no risk of disease transmission from an affected male,
the risk of maternal transmission of disease phenotypes associated
with heteroplasmic mutations is a function of differential segregation
and copy number of mutant mtDNA during oogenesis and subse-
quently, following tissue and organ development in the offspring. This
is rarely predictable with any degree of accuracy. In addition, interac-
tions with the mtDNA haplotype background or nuclear human ge-
nome (as in the case of LHON) serve as an additional important
determinant of disease penetrance. Environmental interactions are
also of importance, as in the case of ototoxic susceptibility to ami-
noglycosides in the case of the A1555G mutation of the 12SrRNA en-
coding gene.
The value of prenatal genetic testing is also questionable, partly ow-
ing to the absence of data on the rules that govern the segregation of
wild-type and mutant mtDNA species (heteroplasmy) among tissue in
the developing embryo. Three factors are required to ensure the reliabil-
ity of prenatal testing: (1) a close correlation between the mutant load
and the disease severity, (2) a uniform distribution of mutant load
among tissues, and (3) no major change in mutant load with time.
These criteria are suggested to be fulfilled for the NARP T8993G muta-
tion but do not seem to apply to other mtDNA disorders. In fact, the
level of mutant mtDNA in a chorionic villous or amniotic fluid sample
may be very different from the level in the fetus, and it would be difficult
to deduce whether the mutational load in the prenatal samples provide
clinically useful information regarding the postnatal and adult state.
Copyright © 2008 The McGraw-Hill Companies. All rights reserved.
TREATMENT OF mtDNA DISORDERS
The polyploid nature of the mitochondrial genome, the inability to
deliver therapeutic nucleic acids to the organelle through mitochon-
drial transfection, and the phenomenon of heteroplasmy coupled
with the relative unavailability of useful preclinical experimental
models have hampered progress in the development of curative treat-
ments for mtDNA disease. One possible approach to “diluting” or
even entirely eliminating the mutant mtDNA is applicable only in the
earliest embryonic state and in effect represents a form of germ-line
preventive therapy. This would involve cytoplasmic transfer of nor-
mal mitochondria into the oocyte of a woman affected with the hetero-
plasmic mtDNA mutation or, more radically, the use of a normal
donor oocyte that has been enucleated and into which the nucleus of
the affected recipient mother has been introduced. These approaches
have not yet been met with widely reported clinical success. On the
hopeful side, the threshold effect suggests that even a small increase in
nonmutant mtDNA copies or limited amelioration of metabolic dys-
function might greatly improve the disease phenotype and benefit pa-
tient health. Therefore counteracting the most damaging metabolic
changes currently represents the mainstay of treatment. Combined
treatment strategies include dietary intervention and removal of toxic
metabolites. Cofactors and vitamin supplements are widely used in
the treatment of diseases of mitochondrial oxidative phosphoryla-
tion, although there is little evidence, apart from anecdotal reports, to
support their use. This includes administration of artificial electron
acceptors, including vitamin K3, vitamin C, and ubiquinone (coen-
zyme Q10); administration of cofactors (coenzymes) including ribo-
flavin, carnitine, and creatine; and use of oxygen radical scavengers,
such as vitamin E, copper, selenium, ubiquinone, and idebenone.
Drugs that could interfere with mitochondrial defects, such as the
anesthetic agent propofol, barbiturates, and high doses of valproate,
should be avoided. Supplementation with the nitric oxide synthase
substrate, L-arginine, has been advocated as a vasodilator treatment
during stroke-like episodes.
In the case of homoplasmic mtDNA variants that predispose to
late-onset common complex disease, it is more realistic to think of us-
ing their identification in a given patient as a nonmodifiable risk fac-
tor, which guides the aggressiveness of medical intervention for the
associated modifiable risk factors for the same disorder. For example,
the identification of a haplogroup-defining homoplasmic mtDNA
mutation that confers added risk for metabolic syndrome should trig-
ger intensive dietary, lifestyle, and medical intervention to reduce oth-
er factors that promote the metabolic syndrome and its complications.
In the case of acquired somatic mutations—to the extent that a vicious
cycle of ROS production with mtDNA mutation plays a role—effective
antioxidant and ROS scavenging therapeutic strategies may prove to
be of benefit.
FURTHER READINGS
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DIMAURO S: Mitochondrial DNA medicine. Biosci Rep 27:5, 2007
———, SCHON E: Mitochondrial respiratory-chain diseases. N Engl J
Med 348:2656, 2003
FILOSTO M, MANUSCO M: Mitochondrial diseases: A nosological up-
date. Acta Neurol Scand 115:211, 2007
HUDSON G et al: Clinical expression of Leber hereditary optic neurop-
athy is affected by the mitochondrial DNA-haplogroup back-
ground. Am J Hum Genet 81:228, 2007
LEOB L et al: The mitochondrial theory of aging and its relationship to
reactive oxygen species damage and somatic mtDNA mutations.
Proc Natl Acad Sci USA 102:18769, 2005.
MANCUSO M et al: Mitochondrial DNA-related disorders. Natural se-
lection shaped regional mtDNA variation in humans. Biosci Rep
27:31, 2007
MISHMAR D et al: Natural selection shaped regional mtDNA variation
in humans. Proc Natl Acad Sci USA 100:171, 2003
NEIMI AK, MAJAMAA K: Mitochondrial DNA and ACTN3 genotypes
in Finnish elite endurance and sprint athletes. Euro J Hum Genet
13:965, 2005
SALAS A et al: A critical reassessment of the role of mitochondria in tu-
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TAYLOR R, TURNBULL D: Mitochondrial DNA mutations in human
disease. Nature Reviews: Genetics 6:389, 2005
THORBURN DR, DAHL HH: Mitochondrial disorders: Genetics, coun-
seling, prenatal diagnosis and reproductive options. Am J Med
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WALLACE D: The mitochondrial genome in human adaptive radiation
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and disease: On the road to therapeutics and performance en- e321
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———: Why do we still have a maternally inherited mitochondrial
DNA? Insights from evolutionary medicine. Annu Rev Biochem
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156 Actinomycosis 25
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