Case Reports

Examination

• Patient looks well and is in no distress
• Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
• Normal heart, lung, and abdominal exam. No cervical or other adenopathy.

Medical history

• Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
• Married, with 1 grown son who is healthy
• Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
• Walks 40 minutes 4 times a week
• Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
• Review of systems negative for cough, fever, weight loss, or swollen glands

A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.

The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.¹ The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.¹

Interpreting TB test results

The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.¹ Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).

An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.²

Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).³ It was unavailable in the county where the patient was tested.

TABLE

TST results regarded as positive for tuberculosis, given a patient’s specific risk factors

The patient’s return 48 hours later

A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“

A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.⁴

The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.

The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.

Dealing responsibly with medical errors

A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.

A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.⁵ In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.

Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.⁶

To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.

Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:

• Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
• Report these facts to risk management or to the professional liability carrier, according to internal policies
• Apologize to the patient.

Important features of an apology

• Make the apology promptly
• Be sincere
• Apologize in person
• Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.

The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.

After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.

Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.

Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.⁷ These include:

• Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
• Avoid blame—search for root causes.
• Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
• Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.

In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:

• Create specific written instructions for office procedures
• Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
• Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
• Have regular updates or ”recertification,” particularly for procedures that are done infrequently
• A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
• Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”

Examination

• Patient looks well and is in no distress
• Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
• Normal heart, lung, and abdominal exam. No cervical or other adenopathy.

Medical history

• Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
• Married, with 1 grown son who is healthy
• Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
• Walks 40 minutes 4 times a week
• Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
• Review of systems negative for cough, fever, weight loss, or swollen glands

A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.

The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.¹ The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.¹

Interpreting TB test results

The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.¹ Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).

An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.²

Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).³ It was unavailable in the county where the patient was tested.

TABLE

TST results regarded as positive for tuberculosis, given a patient’s specific risk factors

The patient’s return 48 hours later

A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“

A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.⁴

The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.

The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.

Dealing responsibly with medical errors

A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.

A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.⁵ In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.

Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.⁶

To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.

Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:

• Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
• Report these facts to risk management or to the professional liability carrier, according to internal policies
• Apologize to the patient.

Important features of an apology

• Make the apology promptly
• Be sincere
• Apologize in person
• Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.

The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.

After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.

Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.

Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.⁷ These include:

• Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
• Avoid blame—search for root causes.
• Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
• Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.

In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:

• Create specific written instructions for office procedures
• Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
• Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
• Have regular updates or ”recertification,” particularly for procedures that are done infrequently
• A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
• Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”

Examination

• Patient looks well and is in no distress
• Weight 138 lbs; height 66 inches; body mass index 23; other vitals normal
• Normal heart, lung, and abdominal exam. No cervical or other adenopathy.

Medical history

• Has osteoporosis for which she takes alendronate weekly; also has diet-controlled hyperlipidemia, and is status post-remote hysterectomy for uterine bleeding
• Married, with 1 grown son who is healthy
• Nonsmoker; drinks 2 alcoholic beverages weekly; no illicit drugs
• Walks 40 minutes 4 times a week
• Mother died at age 93 from congestive heart failure; father alive, 92, has bladder cancer
• Review of systems negative for cough, fever, weight loss, or swollen glands

A Mantoux tuberculin skin test (TST) is administered per clinic protocol, and the patient is instructed to return in 48 to 72 hours for a reading of the test result.

The Mantoux TST is the most accurate test for determining tuberculosis (TB) infection.¹ The standard procedure uses 0.1 cc (5 tuberculin units) of purified protein derivative (PPD) in a standard tuberculin syringe (3/8 inch, 26–27 gauge). This is administered on a flexor surface of the forearm, 2 to 4 inches below the elbow, and requires an intradermal injection (needle bevel upward) that raises a wheal 6 to 10 mm in diameter. A previously reported positive TST does not contraindicate repeated administration.¹

Interpreting TB test results

The definition of a positive tuberculin skin test result depends on a person’s risk factors as defined in the TABLE.¹ Read a TST result 48 to 96 (ideally 72) hours after administration. Palpate and measure induration (not redness).

An alternative method is to use a ballpoint pen to draw a line starting at 1 cm from both sides of the skin reaction and moving toward its center. Where you encounter increased resistance, mark that as the border of induration. Then measure the distance between the 2 borders. This method has been reported to be slightly more precise than palpation.²

Another recently developed test for TB infection, the QuantiFERON, is based on quantification of interferon-gamma response in whole blood to TB infection. Its routine use is not recommended by the Centers for Disease Control and Prevention (CDC).³ It was unavailable in the county where the patient was tested.

TABLE

TST results regarded as positive for tuberculosis, given a patient’s specific risk factors

The patient’s return 48 hours later

A nurse examines the patient’s arm and is uncertain how to interpret the test result. The patient’s primary physician is not in the clinic, and one of the other physicians is consulted. He reads the result as “20 mm induration, positive for TB infection.“

A chest X-ray shows no evidence of tuberculosis infection or other abnormality. The patient is referred to the local county health department. In accordance with CDC guidelines, she is diagnosed with latent tuberculosis infection and started on daily isoniazid therapy.⁴

The patient’s family physician learns of the patient’s diagnosis after she starts isoniazid therapy. Because of her low risk of tuberculosis, he wonders if the skin test result might have been misread. He discusses the issue with the physician who read the first skin test and discovers there was uncertainty regarding the redness (as opposed to the induration) of the skin reaction. The patient herself reports that she did not feel a hard “bump” on the skin where the test was administered.

The family physician informs the patient that the tuberculin skin test may have been incorrectly read as positive. He gives her the option of repeating the test at the county health department, whose personnel are experienced in administering and reading tuberculin skin tests. The patient chooses to repeat the TST, which is read as definitely negative. Isoniazid therapy is stopped. The patient is grateful that she does not have to continue unnecessary and potentially harmful therapy.

Dealing responsibly with medical errors

A simple, straightforward explanation and apology is more likely to benefit both patient and physician than is silence or an explanation that is convoluted or places blame.

A growing consensus recommends that when a medical error is made, health care providers should tell patients about the error and apologize.⁵ In part this recommendation stems from accepted ethical principles of respect for patients as autonomous decision-makers, and from the obligation of providers to act with beneficence on the patient’s behalf. If a medical error impacts the patient’s care in some way, the patient is unable to make informed consent about subsequent care or trust the medical provider if the error is not divulged.

Furthermore, others have advocated that an apology after a medical error can reduce the cost or risk of tort litigation for medical malpractice.⁶

To encourage admissions of error, many states now prevent apologies from being used in court as evidence of guilt in malpractice cases.

Although organizations and liability insurance carriers may have specific requirements or guidelines about how to handle medical errors, practitioners may want to consider the following steps:

• Get the key facts of what happened, if possible from those who directly observed or who were involved in the care
• Report these facts to risk management or to the professional liability carrier, according to internal policies
• Apologize to the patient.

Important features of an apology

• Make the apology promptly
• Be sincere
• Apologize in person
• Keep it simple—eg, “I am very sorry for any concern or inconvenience this event caused you.” Avoid blaming others, minimizing the event, or giving an involved explanation about how the problem occurred.

The purpose of the apology is simply that: to apologize. A patient may need to process feelings about what happened, so the apology should be viewed as an important opportunity for the patient to heal.

After apologizing, reassure the patient that you plan to learn from the mishap and prevent further events from happening. Stress that the trust the patient places in you and your team is not misplaced; that you take all mishaps, even minor ones, seriously and have an aggressive program of quality assurance.

Finally, though you cannot undo the event, offering to waive your professional fee for the visit that led to the mishap will help rebuild patient confidence and loyalty.

Learning from errors is a vital way we prevent errors from occurring in the future. Others have described key steps to creating a culture and process of improvement.⁷ These include:

• Establish an atmosphere of quality improvement in your organization by emphasizing that errors are inevitable, are more often caused by faulty systems rather than faulty people, and are opportunities to learn and improve.
• Avoid blame—search for root causes.
• Create a mechanism to report all errors, mishaps, “near-misses,” and unhappy customers, and a method to systematically review these reports to identify areas to improve.
• Incorporate “lessons learned” into system changes designed to prevent recurrence of this and similar mishaps.

In this particular case, a system-based approach to care might have anticipated and prevented this error through the following steps:

• Create specific written instructions for office procedures
• Have the written procedures handy and easily available for staff to reference, if needed, before performing the task
• Make sure during new staff orientation that personnel are trained and documented as proficient in each procedure
• Have regular updates or ”recertification,” particularly for procedures that are done infrequently
• A well-informed patient is often the first protection against mishaps. A patient education sheet given to the patient when the TST test was administered—describing the test, how it is interpreted, and implications of a “positive” test result—may have alerted the patient in the first place that her test had been misread
• Create documentation forms that have built in “decision support”—for instance, instead of having a blank that says: “TST_____,” the form instead could describe: “TST: date applied, date read, mm of induration measured in 2 dimensions.”

You review your outpatient records (you do not have an EMR) and discuss events in more detail with the patient and his wife. One month ago, the patient came to your office for a routine follow-up visit. You were out of town, so he saw one of your colleagues. He recalls that the doctor told him his sugar levels were too high and gave him a prescription, instructing him to take it with-out fail. He already had enough Glucotrol XL at home and had not requested a refill, so he assumed this was a new medication. He does not recall reading the prescription. The outpatient record shows that the patient had admitted to missing doses of his Glucotrol XL and that the covering physician attributed the hyperglycemia to this poor compliance. The physician had therefore decided to keep the dose of Glucotrol XL the same, provided a refill of Glucotrol XL 10 mg daily, and counseled the patient to improve compliance.

The patient took the script to his usual pharmacy, but they had just closed. He went instead to another nearby pharmacy (part of another chain), where he had the prescription filled. The bottle was labeled by the pharmacy: Glipizide XL 10 mg. Since that date he has been taking both Glucotrol and glipizide and, following the physician’s advice, has not missed a dose.

Q: How could this duplication have occurred?

A:___________________________________________________________

Better monitoring systems needed

Therapeutic duplication (referring, in general, to the use of more than one medication from the same class) is a serious problem, as illustrated by this case. A study of 208 elderly patients on 5 or more medications at a general medical clinic in North Carolina found therapeutic duplication in 5.7% of patients.¹ In a Canadian study involving 12,560 elderly patients in primary care settings, the rate was 4%.² Rates in other settings have been found to be higher (21% of 1854 nursing home residents in Sweden,³ and 15% of 259 patients newly enrolled in a home healthcare pro-gram in New York and California.⁴) In this case we have a patient taking 2 different preparations of the same drug. The causes of therapeutic duplication have not been well studied, but potential reasons are outlined in TABLE 1.

Current systems go only so far. Practices that have well-maintained medication lists on paper or as part of an electronic medical record are in a good position to avoid duplicate prescribing. However, tracking systems restricted to an office practice will not prevent duplications made by consultants or hospital physicians.

Pharmacies generally have software that checks for therapeutic duplication, thereby allowing pharmacists to alert physicians of the potential problem. This works well if a patient uses one pharmacy exclusively. But in the case at hand, the patient elected to go to a different pharmacy instead of waiting for his usual pharmacy to reopen the next business day. This innocent action circumvented the safety system, which did not extend to the other pharmacy. Some pharmacy chains have databases integrated across multiple sites, which can help if patients stay loyal to one chain.

Similarly, third-party payers such as many state Medicaid systems have the opportunity to identify and alert physicians to therapeutic duplications. However, I could find no reports in the literature regarding the implementation or effectiveness of such systems.

TABLE 2 offers suggestions for reducing the risk of therapeutic duplication in your practice.

Medication reconciliation is key. As a step toward addressing the larger picture of medication errors, the Joint Commission for Accreditation of Healthcare Organizations (JCAHO) has introduced for the year 2006 the following Patient Safety Goal (Goal #8): “Accurately and completely reconcile medications across the continuum of care,” commonly referred to as “medication reconciliation.”⁵ JCAHO’s adoption of this goal acknowledges, first, that transitions between different parts of the system are a common source of error, and, second, that these transition points (eg, admission to the hospital, or transfer out of the ICU) are opportunities to detect and correct errors. Various tools have been reported in the literature for addressing this issue. ^6-8 The strategies listed in TABLE 2 can also be seen as contributing to this JCAHO goal.

TABLE 1

Have you encountered these causes of therapeutic duplication?

TABLE 2

Strategies for preventing or detecting therapeutic duplication

The story unfolds

You now know the patient has been taking twice the intended dose of his sulphonylurea for about a month, and you ask how he has been feeling during this time. He says he did well initially and did not experience any symptoms of hypoglycemia or hyperglycemia. He has a glucometer at home but did not use it during this period.

Two days ago, his wife expressed concerned that he was seeing several doctors (urologist, medical oncologist, radiation oncologist) for the prostate cancer and wanted to make sure he told them about all his medications. She asked him to make a list of his medications and to keep it in his wallet. He did so (FIGURE 1). That night he went out drinking (in his words, “the whole night”) because he was worried about his upcoming prostate surgery.

The next morning he forgot to take his medications and at noon he experienced transient loss of consciousness. He went to the ED and was found to have a blood sugar of 55. The loss of consciousness was attributed to hypoglycemia secondary to an alcohol binge. The patient says he showed his medication list to one of the ED staff but was not given any advice, except to follow-up with his personal physician. Last night his wife insisted he take his medications since he had missed them in the morning. He did so. This morning he took his medication as prescribed and developed hypoglycemia at about 4 P.M. (while in the car), precipitating this admission.

Q: Why did the patient-carried medication list not seem to help in this case?

A:____________________________________________________________

Why didn’t the list help? A complete, accurate, up-to-date list of a patient’s medications, held by the patient and made available to all healthcare providers to review and update, should be an effective means of tracking medications within and across healthcare settings, thereby reducing risk of errors including duplication. However, in this case, the ED physician did not detect the error even though the patient did have a list that was complete, accurate (except for the misspelling of glipizide), and up-to-date.

The precise circumstances were unclear, but one might speculate that the ED staff were so busy they did not notice the duplication or were unfamiliar with the medications (confounded by the patient’s misspelling of glipizide), or did not take the list seriously because it was poorly written and in poor condition, or were convinced that the hypoglycemia was precipitated by alcohol. Though the ED staff’s failure to recognize the duplication was a missed opportunity, to blame them would be inappropriate and unproductive. Instead, as will be re-emphasized later, we should focus on the underlying system issues that precipitated the failure, including the presence or absence of protocols for medication reconciliation, and the characteristics of the medication list that the patient was using.

Improving patient-carried medication records. These records have been used with varying success.^9-11 Studies show it is difficult to ensure that patients carry records consistently, and to ensure that prescribers update them. Optimal characteristics of such records have yet to be determined, and they will likely vary depending on circumstances. However, the published experiences^9-11 together with review of the present case suggest simple strategies that might help improve the list our patient was carrying.

First, the list should be easy to read and update and be durable.

Second, it should be convenient to carry (wallet-size, for example).

Third, it should include the appropriate amount of information that helps busy practitioners detect errors easily. This issue requires further study, but we might consider using generic names and including information about drug class and indication.

What about electronic media? One proposed solution to paper records is the use of electronic media such as flash memory cards or web-based records.^12-14 Two challenges to widespread implementation of this strategy are cost and compatibility. To deal with the latter issue, current legislative efforts (Wired for Health Care Quality Act S. 1418) are aiming to create standard formats for exchange of electronic health information. Obviously the ability to link to electronic prescribing systems from anywhere would greatly reduce the risk of duplicate prescribing.

In the meantime it may be reasonable, especially for high-risk patients, to provide or encourage the use of paper-based medication lists with the caveat that they need to be kept up to date and shared with all providers.

FIGURE 1 Patient’s medication list

The need for vigilance never ends

The patient is managed appropriately by the inpatient team. His diabetes medications are discontinued and he is placed on a 5% dextrose infusion. He does well. By the following evening, he is off intravenous fluids, is maintaining adequate glucose levels, and is ready for discharge home. The plan calls for him to stop the Glucotrol XL and continue the generic glipizide XL only.

You go to the hospital to check on him and find that he and his wife are about to leave. The nurse has reviewed discharge instructions with them and the patient is holding a copy. You ask to see the instructions. FIGURE 2 shows the medication section of the instruction sheet.

Glucotrol XL appears correctly in the section “Discontinued medications” with the clear instruction “Do NOT take these medications.” However, it is also listed under “Pre-hospital medications to be continued.” When you ask the patient what medications he intends to take at home, he admits that he and his wife are a little confused by the instructions. He says they decided he should continue the same medications he was on before since these are what you and your office colleague prescribed. He adds, by way of explanation, that he trusts you more than he trusts the hospital team because you know him best. You are surprised by his answer but then realize that neither you nor the house staff has explained the duplication error to him. He still believes Glucotrol and glipizide are different medications and does not understand that taking them together caused his symptoms.

Q: Why might you and the house staff have been vague about the cause of the hypoglycemia? What should you say now?

A:_____________________________________________________

Discussing prescribing errors is uncomfortable. In this instance, you the primary doctor may have been reluctant because your office appeared to be most responsible for the mistake. And the residents also may have been reluctant to say anything that might appear critical of the primary doctor’s office. Evidence suggests that most physicians prefer not to discuss the details of errors or even to use the term “error.” They prefer less emotive language.¹⁵ In contrast, there is some evidence to suggest that patients and families would like to be informed when an error occurs in their care.^15,18

As the primary care physician discovered in this case, correcting a medication error often depends on informing the patient. The negative impacts of disclosure (including the possibility of litigation and other sanctions, and the potential for loss of trust) are the subject of much debate.^19-21

Ultimately, the decision to disclose an error must be based on risks and benefits to both patient and physician. If you decide to disclose, choose words carefully. And be careful to avoid apportioning blame. As this case illustrates, adverse events can have many contributing factors, and, in most cases, further investigation is required before a full explanation can be given. Therefore it is generally recommended that when disclosure is made, you should limit the discussion to the known facts. Further disclosure can always be made at a later date if warranted, when more objective information is available.

FIGURE 2 Hospital discharge instructions

A closer examination of what went wrong

In this case, unusual situations, system problems, and errors by individuals combined to cause recurrent hypoglycemia and unnecessary hospitalization. James Reason has provided a framework in which a case such as this may be analyzed systematically. It is called the Adverse Event Trajectory,²² and its application to this case is depicted in FIGURE 3. Each contributing factor is categorized according to the framework and written onto the diagram in such a way as to provide a summary of the whole event. This format has been used successfully as a teaching tool for family medicine residents.²³

The main advantage of this analysis is that it clearly separates human errors (Active Failures) and system problems (Latent Failures, and the lack of Safety Barriers). Often, human error is chiefly blamed for adverse events and little effort is made to look beyond this. However, if we accept that “to err is human”²⁴ and that most errors have roots in systemic problems, then the Adverse Event Trajectory framework can focus our attention on areas more likely to yield workable solutions.

Preventing recurrent errors usually is best assured by (1) correcting latent failures and (2) creating effective safety barriers. The strategies in TABLE 2 that involve changing systems (such as implementing electronic prescribing as part of an electronic medical record) are more likely to be effective than those that change behavior only (such as encouraging patients to use one pharmacy exclusively). However, system strategies also tend to be more expensive and difficult to implement than the latter. Perhaps it is most appropriate to use a combination of approaches listed in TABLE 2.

As implied under “Safety Barriers” in FIGURE 3, an effective patient-carried medication list had the potential to protect this patient from harm. Possible strategies for implementing such a barrier have been discussed above.

Items 2 and 3 under “Latent Failures” apply to the pharmacy level, and solutions would likely require legislation. Restricting access to one pharmacy exclusively would probably have prevented the duplication in our case. However, if such restriction were enforced unilaterally by a payer, it could make that payer less competitive since patients may value the freedom of changing pharmacies at will.

A more realistic alternative is to give pharmacies access to one another’s databases or even to create a central database to which all pharmacies would have access, with the patient’s permission. Clearly confidentiality issues would need to be addressed before such a program was implemented. And there would likely be opposition from the large pharmacy chains who might see this approach as a threat.

FIGURE 3 Adverse event trajectory: Breaking down the process into revealing components

The value of this analytic technique is in identifying and categorizing all factors (not just human error) that potentially contribute to untoward events. Efforts aimed at correcting or improving factors under “Latent Failures” or “Safety Barriers” are usually most fruitful.

The last two issues under “Latent Failures” regard medication name usage. In a free market system, multiple organizations are permitted to market the same active ingredient under their own brand name or under the generic name. If prescribers and pharmacies were permitted to use generic names only, this could have helped avoid the confusion that occurred in the present case. But, again, the legislation necessary to make this happen would likely be opposed by industry. A possible compromise would be to require prominent identification of the generic name on medication bottles and medication lists (whether in paper or electronic form), as well as the drug’s indication so that duplications are easier for both patients and health care workers to identify.

Change is possible. This case that initially seemed simple and could have been easily ignored was found on investigation to be complex. Multiple parties contributed to the problem, which raised issues in communications, information management, ethics, and policy. I hope you will be stimulated to re-examine your own systems and, when faced with errors, will look more deeply to the underlying issues and not be satisfied simply to blame “human error.”

Conflict of interest

The authors have no conflicts of interest to declare.

You review your outpatient records (you do not have an EMR) and discuss events in more detail with the patient and his wife. One month ago, the patient came to your office for a routine follow-up visit. You were out of town, so he saw one of your colleagues. He recalls that the doctor told him his sugar levels were too high and gave him a prescription, instructing him to take it with-out fail. He already had enough Glucotrol XL at home and had not requested a refill, so he assumed this was a new medication. He does not recall reading the prescription. The outpatient record shows that the patient had admitted to missing doses of his Glucotrol XL and that the covering physician attributed the hyperglycemia to this poor compliance. The physician had therefore decided to keep the dose of Glucotrol XL the same, provided a refill of Glucotrol XL 10 mg daily, and counseled the patient to improve compliance.

The patient took the script to his usual pharmacy, but they had just closed. He went instead to another nearby pharmacy (part of another chain), where he had the prescription filled. The bottle was labeled by the pharmacy: Glipizide XL 10 mg. Since that date he has been taking both Glucotrol and glipizide and, following the physician’s advice, has not missed a dose.

Q: How could this duplication have occurred?

A:___________________________________________________________

Better monitoring systems needed

Therapeutic duplication (referring, in general, to the use of more than one medication from the same class) is a serious problem, as illustrated by this case. A study of 208 elderly patients on 5 or more medications at a general medical clinic in North Carolina found therapeutic duplication in 5.7% of patients.¹ In a Canadian study involving 12,560 elderly patients in primary care settings, the rate was 4%.² Rates in other settings have been found to be higher (21% of 1854 nursing home residents in Sweden,³ and 15% of 259 patients newly enrolled in a home healthcare pro-gram in New York and California.⁴) In this case we have a patient taking 2 different preparations of the same drug. The causes of therapeutic duplication have not been well studied, but potential reasons are outlined in TABLE 1.

Current systems go only so far. Practices that have well-maintained medication lists on paper or as part of an electronic medical record are in a good position to avoid duplicate prescribing. However, tracking systems restricted to an office practice will not prevent duplications made by consultants or hospital physicians.

Pharmacies generally have software that checks for therapeutic duplication, thereby allowing pharmacists to alert physicians of the potential problem. This works well if a patient uses one pharmacy exclusively. But in the case at hand, the patient elected to go to a different pharmacy instead of waiting for his usual pharmacy to reopen the next business day. This innocent action circumvented the safety system, which did not extend to the other pharmacy. Some pharmacy chains have databases integrated across multiple sites, which can help if patients stay loyal to one chain.

Similarly, third-party payers such as many state Medicaid systems have the opportunity to identify and alert physicians to therapeutic duplications. However, I could find no reports in the literature regarding the implementation or effectiveness of such systems.

TABLE 2 offers suggestions for reducing the risk of therapeutic duplication in your practice.

Medication reconciliation is key. As a step toward addressing the larger picture of medication errors, the Joint Commission for Accreditation of Healthcare Organizations (JCAHO) has introduced for the year 2006 the following Patient Safety Goal (Goal #8): “Accurately and completely reconcile medications across the continuum of care,” commonly referred to as “medication reconciliation.”⁵ JCAHO’s adoption of this goal acknowledges, first, that transitions between different parts of the system are a common source of error, and, second, that these transition points (eg, admission to the hospital, or transfer out of the ICU) are opportunities to detect and correct errors. Various tools have been reported in the literature for addressing this issue. ^6-8 The strategies listed in TABLE 2 can also be seen as contributing to this JCAHO goal.

TABLE 1

Have you encountered these causes of therapeutic duplication?

TABLE 2

Strategies for preventing or detecting therapeutic duplication

The story unfolds

You now know the patient has been taking twice the intended dose of his sulphonylurea for about a month, and you ask how he has been feeling during this time. He says he did well initially and did not experience any symptoms of hypoglycemia or hyperglycemia. He has a glucometer at home but did not use it during this period.

Two days ago, his wife expressed concerned that he was seeing several doctors (urologist, medical oncologist, radiation oncologist) for the prostate cancer and wanted to make sure he told them about all his medications. She asked him to make a list of his medications and to keep it in his wallet. He did so (FIGURE 1). That night he went out drinking (in his words, “the whole night”) because he was worried about his upcoming prostate surgery.

The next morning he forgot to take his medications and at noon he experienced transient loss of consciousness. He went to the ED and was found to have a blood sugar of 55. The loss of consciousness was attributed to hypoglycemia secondary to an alcohol binge. The patient says he showed his medication list to one of the ED staff but was not given any advice, except to follow-up with his personal physician. Last night his wife insisted he take his medications since he had missed them in the morning. He did so. This morning he took his medication as prescribed and developed hypoglycemia at about 4 P.M. (while in the car), precipitating this admission.

Q: Why did the patient-carried medication list not seem to help in this case?

A:____________________________________________________________

Why didn’t the list help? A complete, accurate, up-to-date list of a patient’s medications, held by the patient and made available to all healthcare providers to review and update, should be an effective means of tracking medications within and across healthcare settings, thereby reducing risk of errors including duplication. However, in this case, the ED physician did not detect the error even though the patient did have a list that was complete, accurate (except for the misspelling of glipizide), and up-to-date.

The precise circumstances were unclear, but one might speculate that the ED staff were so busy they did not notice the duplication or were unfamiliar with the medications (confounded by the patient’s misspelling of glipizide), or did not take the list seriously because it was poorly written and in poor condition, or were convinced that the hypoglycemia was precipitated by alcohol. Though the ED staff’s failure to recognize the duplication was a missed opportunity, to blame them would be inappropriate and unproductive. Instead, as will be re-emphasized later, we should focus on the underlying system issues that precipitated the failure, including the presence or absence of protocols for medication reconciliation, and the characteristics of the medication list that the patient was using.

Improving patient-carried medication records. These records have been used with varying success.^9-11 Studies show it is difficult to ensure that patients carry records consistently, and to ensure that prescribers update them. Optimal characteristics of such records have yet to be determined, and they will likely vary depending on circumstances. However, the published experiences^9-11 together with review of the present case suggest simple strategies that might help improve the list our patient was carrying.

First, the list should be easy to read and update and be durable.

Second, it should be convenient to carry (wallet-size, for example).

Third, it should include the appropriate amount of information that helps busy practitioners detect errors easily. This issue requires further study, but we might consider using generic names and including information about drug class and indication.

What about electronic media? One proposed solution to paper records is the use of electronic media such as flash memory cards or web-based records.^12-14 Two challenges to widespread implementation of this strategy are cost and compatibility. To deal with the latter issue, current legislative efforts (Wired for Health Care Quality Act S. 1418) are aiming to create standard formats for exchange of electronic health information. Obviously the ability to link to electronic prescribing systems from anywhere would greatly reduce the risk of duplicate prescribing.

In the meantime it may be reasonable, especially for high-risk patients, to provide or encourage the use of paper-based medication lists with the caveat that they need to be kept up to date and shared with all providers.

FIGURE 1 Patient’s medication list

The need for vigilance never ends

The patient is managed appropriately by the inpatient team. His diabetes medications are discontinued and he is placed on a 5% dextrose infusion. He does well. By the following evening, he is off intravenous fluids, is maintaining adequate glucose levels, and is ready for discharge home. The plan calls for him to stop the Glucotrol XL and continue the generic glipizide XL only.

You go to the hospital to check on him and find that he and his wife are about to leave. The nurse has reviewed discharge instructions with them and the patient is holding a copy. You ask to see the instructions. FIGURE 2 shows the medication section of the instruction sheet.

Glucotrol XL appears correctly in the section “Discontinued medications” with the clear instruction “Do NOT take these medications.” However, it is also listed under “Pre-hospital medications to be continued.” When you ask the patient what medications he intends to take at home, he admits that he and his wife are a little confused by the instructions. He says they decided he should continue the same medications he was on before since these are what you and your office colleague prescribed. He adds, by way of explanation, that he trusts you more than he trusts the hospital team because you know him best. You are surprised by his answer but then realize that neither you nor the house staff has explained the duplication error to him. He still believes Glucotrol and glipizide are different medications and does not understand that taking them together caused his symptoms.

Q: Why might you and the house staff have been vague about the cause of the hypoglycemia? What should you say now?

A:_____________________________________________________

Discussing prescribing errors is uncomfortable. In this instance, you the primary doctor may have been reluctant because your office appeared to be most responsible for the mistake. And the residents also may have been reluctant to say anything that might appear critical of the primary doctor’s office. Evidence suggests that most physicians prefer not to discuss the details of errors or even to use the term “error.” They prefer less emotive language.¹⁵ In contrast, there is some evidence to suggest that patients and families would like to be informed when an error occurs in their care.^15,18

As the primary care physician discovered in this case, correcting a medication error often depends on informing the patient. The negative impacts of disclosure (including the possibility of litigation and other sanctions, and the potential for loss of trust) are the subject of much debate.^19-21

Ultimately, the decision to disclose an error must be based on risks and benefits to both patient and physician. If you decide to disclose, choose words carefully. And be careful to avoid apportioning blame. As this case illustrates, adverse events can have many contributing factors, and, in most cases, further investigation is required before a full explanation can be given. Therefore it is generally recommended that when disclosure is made, you should limit the discussion to the known facts. Further disclosure can always be made at a later date if warranted, when more objective information is available.

FIGURE 2 Hospital discharge instructions

A closer examination of what went wrong

In this case, unusual situations, system problems, and errors by individuals combined to cause recurrent hypoglycemia and unnecessary hospitalization. James Reason has provided a framework in which a case such as this may be analyzed systematically. It is called the Adverse Event Trajectory,²² and its application to this case is depicted in FIGURE 3. Each contributing factor is categorized according to the framework and written onto the diagram in such a way as to provide a summary of the whole event. This format has been used successfully as a teaching tool for family medicine residents.²³

The main advantage of this analysis is that it clearly separates human errors (Active Failures) and system problems (Latent Failures, and the lack of Safety Barriers). Often, human error is chiefly blamed for adverse events and little effort is made to look beyond this. However, if we accept that “to err is human”²⁴ and that most errors have roots in systemic problems, then the Adverse Event Trajectory framework can focus our attention on areas more likely to yield workable solutions.

Preventing recurrent errors usually is best assured by (1) correcting latent failures and (2) creating effective safety barriers. The strategies in TABLE 2 that involve changing systems (such as implementing electronic prescribing as part of an electronic medical record) are more likely to be effective than those that change behavior only (such as encouraging patients to use one pharmacy exclusively). However, system strategies also tend to be more expensive and difficult to implement than the latter. Perhaps it is most appropriate to use a combination of approaches listed in TABLE 2.

As implied under “Safety Barriers” in FIGURE 3, an effective patient-carried medication list had the potential to protect this patient from harm. Possible strategies for implementing such a barrier have been discussed above.

Items 2 and 3 under “Latent Failures” apply to the pharmacy level, and solutions would likely require legislation. Restricting access to one pharmacy exclusively would probably have prevented the duplication in our case. However, if such restriction were enforced unilaterally by a payer, it could make that payer less competitive since patients may value the freedom of changing pharmacies at will.

A more realistic alternative is to give pharmacies access to one another’s databases or even to create a central database to which all pharmacies would have access, with the patient’s permission. Clearly confidentiality issues would need to be addressed before such a program was implemented. And there would likely be opposition from the large pharmacy chains who might see this approach as a threat.

FIGURE 3 Adverse event trajectory: Breaking down the process into revealing components

The value of this analytic technique is in identifying and categorizing all factors (not just human error) that potentially contribute to untoward events. Efforts aimed at correcting or improving factors under “Latent Failures” or “Safety Barriers” are usually most fruitful.

The last two issues under “Latent Failures” regard medication name usage. In a free market system, multiple organizations are permitted to market the same active ingredient under their own brand name or under the generic name. If prescribers and pharmacies were permitted to use generic names only, this could have helped avoid the confusion that occurred in the present case. But, again, the legislation necessary to make this happen would likely be opposed by industry. A possible compromise would be to require prominent identification of the generic name on medication bottles and medication lists (whether in paper or electronic form), as well as the drug’s indication so that duplications are easier for both patients and health care workers to identify.

Change is possible. This case that initially seemed simple and could have been easily ignored was found on investigation to be complex. Multiple parties contributed to the problem, which raised issues in communications, information management, ethics, and policy. I hope you will be stimulated to re-examine your own systems and, when faced with errors, will look more deeply to the underlying issues and not be satisfied simply to blame “human error.”

Conflict of interest

The authors have no conflicts of interest to declare.

You review your outpatient records (you do not have an EMR) and discuss events in more detail with the patient and his wife. One month ago, the patient came to your office for a routine follow-up visit. You were out of town, so he saw one of your colleagues. He recalls that the doctor told him his sugar levels were too high and gave him a prescription, instructing him to take it with-out fail. He already had enough Glucotrol XL at home and had not requested a refill, so he assumed this was a new medication. He does not recall reading the prescription. The outpatient record shows that the patient had admitted to missing doses of his Glucotrol XL and that the covering physician attributed the hyperglycemia to this poor compliance. The physician had therefore decided to keep the dose of Glucotrol XL the same, provided a refill of Glucotrol XL 10 mg daily, and counseled the patient to improve compliance.

The patient took the script to his usual pharmacy, but they had just closed. He went instead to another nearby pharmacy (part of another chain), where he had the prescription filled. The bottle was labeled by the pharmacy: Glipizide XL 10 mg. Since that date he has been taking both Glucotrol and glipizide and, following the physician’s advice, has not missed a dose.

Q: How could this duplication have occurred?

A:___________________________________________________________

Better monitoring systems needed

Therapeutic duplication (referring, in general, to the use of more than one medication from the same class) is a serious problem, as illustrated by this case. A study of 208 elderly patients on 5 or more medications at a general medical clinic in North Carolina found therapeutic duplication in 5.7% of patients.¹ In a Canadian study involving 12,560 elderly patients in primary care settings, the rate was 4%.² Rates in other settings have been found to be higher (21% of 1854 nursing home residents in Sweden,³ and 15% of 259 patients newly enrolled in a home healthcare pro-gram in New York and California.⁴) In this case we have a patient taking 2 different preparations of the same drug. The causes of therapeutic duplication have not been well studied, but potential reasons are outlined in TABLE 1.

Current systems go only so far. Practices that have well-maintained medication lists on paper or as part of an electronic medical record are in a good position to avoid duplicate prescribing. However, tracking systems restricted to an office practice will not prevent duplications made by consultants or hospital physicians.

Pharmacies generally have software that checks for therapeutic duplication, thereby allowing pharmacists to alert physicians of the potential problem. This works well if a patient uses one pharmacy exclusively. But in the case at hand, the patient elected to go to a different pharmacy instead of waiting for his usual pharmacy to reopen the next business day. This innocent action circumvented the safety system, which did not extend to the other pharmacy. Some pharmacy chains have databases integrated across multiple sites, which can help if patients stay loyal to one chain.

Similarly, third-party payers such as many state Medicaid systems have the opportunity to identify and alert physicians to therapeutic duplications. However, I could find no reports in the literature regarding the implementation or effectiveness of such systems.

TABLE 2 offers suggestions for reducing the risk of therapeutic duplication in your practice.

Medication reconciliation is key. As a step toward addressing the larger picture of medication errors, the Joint Commission for Accreditation of Healthcare Organizations (JCAHO) has introduced for the year 2006 the following Patient Safety Goal (Goal #8): “Accurately and completely reconcile medications across the continuum of care,” commonly referred to as “medication reconciliation.”⁵ JCAHO’s adoption of this goal acknowledges, first, that transitions between different parts of the system are a common source of error, and, second, that these transition points (eg, admission to the hospital, or transfer out of the ICU) are opportunities to detect and correct errors. Various tools have been reported in the literature for addressing this issue. ^6-8 The strategies listed in TABLE 2 can also be seen as contributing to this JCAHO goal.

TABLE 1

Have you encountered these causes of therapeutic duplication?

TABLE 2

Strategies for preventing or detecting therapeutic duplication

The story unfolds

You now know the patient has been taking twice the intended dose of his sulphonylurea for about a month, and you ask how he has been feeling during this time. He says he did well initially and did not experience any symptoms of hypoglycemia or hyperglycemia. He has a glucometer at home but did not use it during this period.

Two days ago, his wife expressed concerned that he was seeing several doctors (urologist, medical oncologist, radiation oncologist) for the prostate cancer and wanted to make sure he told them about all his medications. She asked him to make a list of his medications and to keep it in his wallet. He did so (FIGURE 1). That night he went out drinking (in his words, “the whole night”) because he was worried about his upcoming prostate surgery.

The next morning he forgot to take his medications and at noon he experienced transient loss of consciousness. He went to the ED and was found to have a blood sugar of 55. The loss of consciousness was attributed to hypoglycemia secondary to an alcohol binge. The patient says he showed his medication list to one of the ED staff but was not given any advice, except to follow-up with his personal physician. Last night his wife insisted he take his medications since he had missed them in the morning. He did so. This morning he took his medication as prescribed and developed hypoglycemia at about 4 P.M. (while in the car), precipitating this admission.

Q: Why did the patient-carried medication list not seem to help in this case?

A:____________________________________________________________

Why didn’t the list help? A complete, accurate, up-to-date list of a patient’s medications, held by the patient and made available to all healthcare providers to review and update, should be an effective means of tracking medications within and across healthcare settings, thereby reducing risk of errors including duplication. However, in this case, the ED physician did not detect the error even though the patient did have a list that was complete, accurate (except for the misspelling of glipizide), and up-to-date.

The precise circumstances were unclear, but one might speculate that the ED staff were so busy they did not notice the duplication or were unfamiliar with the medications (confounded by the patient’s misspelling of glipizide), or did not take the list seriously because it was poorly written and in poor condition, or were convinced that the hypoglycemia was precipitated by alcohol. Though the ED staff’s failure to recognize the duplication was a missed opportunity, to blame them would be inappropriate and unproductive. Instead, as will be re-emphasized later, we should focus on the underlying system issues that precipitated the failure, including the presence or absence of protocols for medication reconciliation, and the characteristics of the medication list that the patient was using.

Improving patient-carried medication records. These records have been used with varying success.^9-11 Studies show it is difficult to ensure that patients carry records consistently, and to ensure that prescribers update them. Optimal characteristics of such records have yet to be determined, and they will likely vary depending on circumstances. However, the published experiences^9-11 together with review of the present case suggest simple strategies that might help improve the list our patient was carrying.

First, the list should be easy to read and update and be durable.

Second, it should be convenient to carry (wallet-size, for example).

Third, it should include the appropriate amount of information that helps busy practitioners detect errors easily. This issue requires further study, but we might consider using generic names and including information about drug class and indication.

What about electronic media? One proposed solution to paper records is the use of electronic media such as flash memory cards or web-based records.^12-14 Two challenges to widespread implementation of this strategy are cost and compatibility. To deal with the latter issue, current legislative efforts (Wired for Health Care Quality Act S. 1418) are aiming to create standard formats for exchange of electronic health information. Obviously the ability to link to electronic prescribing systems from anywhere would greatly reduce the risk of duplicate prescribing.

In the meantime it may be reasonable, especially for high-risk patients, to provide or encourage the use of paper-based medication lists with the caveat that they need to be kept up to date and shared with all providers.

FIGURE 1 Patient’s medication list

The need for vigilance never ends

The patient is managed appropriately by the inpatient team. His diabetes medications are discontinued and he is placed on a 5% dextrose infusion. He does well. By the following evening, he is off intravenous fluids, is maintaining adequate glucose levels, and is ready for discharge home. The plan calls for him to stop the Glucotrol XL and continue the generic glipizide XL only.

You go to the hospital to check on him and find that he and his wife are about to leave. The nurse has reviewed discharge instructions with them and the patient is holding a copy. You ask to see the instructions. FIGURE 2 shows the medication section of the instruction sheet.

Glucotrol XL appears correctly in the section “Discontinued medications” with the clear instruction “Do NOT take these medications.” However, it is also listed under “Pre-hospital medications to be continued.” When you ask the patient what medications he intends to take at home, he admits that he and his wife are a little confused by the instructions. He says they decided he should continue the same medications he was on before since these are what you and your office colleague prescribed. He adds, by way of explanation, that he trusts you more than he trusts the hospital team because you know him best. You are surprised by his answer but then realize that neither you nor the house staff has explained the duplication error to him. He still believes Glucotrol and glipizide are different medications and does not understand that taking them together caused his symptoms.

Q: Why might you and the house staff have been vague about the cause of the hypoglycemia? What should you say now?

A:_____________________________________________________

Discussing prescribing errors is uncomfortable. In this instance, you the primary doctor may have been reluctant because your office appeared to be most responsible for the mistake. And the residents also may have been reluctant to say anything that might appear critical of the primary doctor’s office. Evidence suggests that most physicians prefer not to discuss the details of errors or even to use the term “error.” They prefer less emotive language.¹⁵ In contrast, there is some evidence to suggest that patients and families would like to be informed when an error occurs in their care.^15,18

As the primary care physician discovered in this case, correcting a medication error often depends on informing the patient. The negative impacts of disclosure (including the possibility of litigation and other sanctions, and the potential for loss of trust) are the subject of much debate.^19-21

Ultimately, the decision to disclose an error must be based on risks and benefits to both patient and physician. If you decide to disclose, choose words carefully. And be careful to avoid apportioning blame. As this case illustrates, adverse events can have many contributing factors, and, in most cases, further investigation is required before a full explanation can be given. Therefore it is generally recommended that when disclosure is made, you should limit the discussion to the known facts. Further disclosure can always be made at a later date if warranted, when more objective information is available.

FIGURE 2 Hospital discharge instructions

A closer examination of what went wrong

In this case, unusual situations, system problems, and errors by individuals combined to cause recurrent hypoglycemia and unnecessary hospitalization. James Reason has provided a framework in which a case such as this may be analyzed systematically. It is called the Adverse Event Trajectory,²² and its application to this case is depicted in FIGURE 3. Each contributing factor is categorized according to the framework and written onto the diagram in such a way as to provide a summary of the whole event. This format has been used successfully as a teaching tool for family medicine residents.²³

The main advantage of this analysis is that it clearly separates human errors (Active Failures) and system problems (Latent Failures, and the lack of Safety Barriers). Often, human error is chiefly blamed for adverse events and little effort is made to look beyond this. However, if we accept that “to err is human”²⁴ and that most errors have roots in systemic problems, then the Adverse Event Trajectory framework can focus our attention on areas more likely to yield workable solutions.

Preventing recurrent errors usually is best assured by (1) correcting latent failures and (2) creating effective safety barriers. The strategies in TABLE 2 that involve changing systems (such as implementing electronic prescribing as part of an electronic medical record) are more likely to be effective than those that change behavior only (such as encouraging patients to use one pharmacy exclusively). However, system strategies also tend to be more expensive and difficult to implement than the latter. Perhaps it is most appropriate to use a combination of approaches listed in TABLE 2.

As implied under “Safety Barriers” in FIGURE 3, an effective patient-carried medication list had the potential to protect this patient from harm. Possible strategies for implementing such a barrier have been discussed above.

Items 2 and 3 under “Latent Failures” apply to the pharmacy level, and solutions would likely require legislation. Restricting access to one pharmacy exclusively would probably have prevented the duplication in our case. However, if such restriction were enforced unilaterally by a payer, it could make that payer less competitive since patients may value the freedom of changing pharmacies at will.

A more realistic alternative is to give pharmacies access to one another’s databases or even to create a central database to which all pharmacies would have access, with the patient’s permission. Clearly confidentiality issues would need to be addressed before such a program was implemented. And there would likely be opposition from the large pharmacy chains who might see this approach as a threat.

FIGURE 3 Adverse event trajectory: Breaking down the process into revealing components

The value of this analytic technique is in identifying and categorizing all factors (not just human error) that potentially contribute to untoward events. Efforts aimed at correcting or improving factors under “Latent Failures” or “Safety Barriers” are usually most fruitful.

The last two issues under “Latent Failures” regard medication name usage. In a free market system, multiple organizations are permitted to market the same active ingredient under their own brand name or under the generic name. If prescribers and pharmacies were permitted to use generic names only, this could have helped avoid the confusion that occurred in the present case. But, again, the legislation necessary to make this happen would likely be opposed by industry. A possible compromise would be to require prominent identification of the generic name on medication bottles and medication lists (whether in paper or electronic form), as well as the drug’s indication so that duplications are easier for both patients and health care workers to identify.

Change is possible. This case that initially seemed simple and could have been easily ignored was found on investigation to be complex. Multiple parties contributed to the problem, which raised issues in communications, information management, ethics, and policy. I hope you will be stimulated to re-examine your own systems and, when faced with errors, will look more deeply to the underlying issues and not be satisfied simply to blame “human error.”

Conflict of interest

The authors have no conflicts of interest to declare.

History of present illness

• Approximately 4 weeks of generalized extremity pain and weakness; left-sided, nonexertional chest pain, which is much less severe than his extremity pains
• Symptoms are most prominent in the proximal upper extremities, especially with movement; the right side is more effected than the left
• Dyspnea on exertion
• Seen twice in local urgent care facilities in the past 10 days; diagnosed with congestive heart failure; treated with furosemide, digoxin, and an unknown antibiotic without relief
• 20- to 30-pound weight loss over the past year

Other medical history

• No chronic medical problems or medications
• Until this past month, last seen by a physician about 3 or 4 years prior

Review of systems

• Up to the day of admission has been ambulatory and able to care for himself despite his weakness
• No fever, chills, or rash; but has night sweats
• Smokes; does not drink alcohol
• Retired; lives with his wife

Physical examination

• Alert, appears mildly uncomfortable
• Temperature 101°F, respirations 32, blood pressure 164/72, pulse 80
• 3/5 strength in proximal upper and lower extremities (can barely lift arms and legs off the bed; movement also limited by pain)
• Normal distal strength (hand grips and dorsi/plantar flexion of foot)
• Normal sensation, reflexes, cranial nerves, and mental status; no neck weakness
• No abnormal joint findings; has pink discoloration over extensor surface of MCP joint, which patient dismisses as scars from previous abrasions that have been present “for a long time”
• Heart, lungs unremarkable; no peripheral edema

Laboratory studies completed in the emergency department

• ECG: normal
• Chest x-ray: bibasilar peribronchial infiltrates
• Hemoglobin/hematocrit: normal
• White blood count: 27,000 with 92% neutrophils
• Erythrocyte sedimentation rate: normal
• Urinalysis: negative for blood
• Brain natriuretic peptide: normal
• Creatine kinase (CK): 2205 IU/L (normal range 35–232)
• Troponin-I: 0.6 ng/mL.
  [Reference range:
    <0.05=Negative
    0.05–0.09=Equivocal
    0.10–0.49=Suspicious
    0.50=Consistent with myocardial injury]

Is this acute non-ST elevation myocardial infarction (NSTEMI)?

The American College of Cardiology and the American Heart Association define myocardial infarction primarily as elevated cardiac-specific enzymes troponin-I and troponin-T in the appropriate clinical setting.^1,2 Elevated cardiac troponins have a sensitivity approaching 100% for myocardial damage. Specificity is much lower for acute ischemic cardiac disease, however, particularly for patients with a low pretest probability (45% false-positive rate in one series of 1000 consecutive patients presenting to a large urban emergency department with symptoms of acute coronary ischemia).³

Mechanisms other than atherosclerotic coronary artery disease that can elevate cardiac troponins:

• Increased cardiac demand (eg, sepsis, hypovolemia)
• Nonatherosclerotic ischemia (eg, cocaine or other sympathomimetic agents, coronary vasospasm)
• Direct myocardial injury (eg, cardiac contusion, myocarditis)
• Myocardial strain (eg, congestive heart failure, pulmonary embolus)
• Chronic renal insufficiency (mechanism unclear).⁴

In light of this patient’s history and physical exam findings, you doubt he’s having an acute cardiac event. The most remarkable features are his weakness, muscle pain, and markedly elevated CK.

Though you have ruled out anemia and several other possibilities, the differential diagnosis of weakness is still broad. You decide to explore the differential diagnosis of elevated CK, a more specific finding in this case.

Pursuing the differential

You consult UpToDate, searching under “creatine kinase,” and find an article entitled “Muscle enzymes in the evaluation of neuromuscular disease.”⁵ You conclude that the most likely cause of your patient’s problems is an idiopathic inflammatory myopathy: polymyositis, dermatomyositis, or inclusion-body myositis.⁶

Other possibilities include post-viral myositis and myositis associated with connective tissue disease, hypothyroidism, or drug reactions.

D-penicillamine, zidovudine (AZT), and viral or bacterial infection may produce inflammatory myopathy similar to polymyositis.⁷ A history of exposure to myotoxic drugs (such as statins) and toxins has been excluded.

The absence of a family history for neuromuscular disease and the relatively recent onset of symptoms rule out an inherited muscular dystrophy or congenital muscle enzyme deficiency.

Myasthenia gravis presents with extraocular muscle involvement. Guillain-Barré syndrome is characterized by ascending muscle weakness. Lyme disease may cause weakness secondary to peripheral neuropathy but it does not produce evidence of muscle inflammation such as elevation of the CK. West Nile virus encephalitis may present with muscle weakness and flaccid paralysis.⁸ Trichinellosis may also cause muscle inflammation with weakness and elevation of CK, but it is rare in the United States.

You repeat parts of your physical exam and confirm that his proximal upper extremity muscles are much weaker than his distal muscles.

In practice settings where specialty consultation is not always immediately available, your diagnostic skills may be challenged by uncommon presentations of disease. In this case, the challenge is “chest pain and positive cardiac enzymes” in a patient who does not appear to have a primary cardiac problem.

DTaP approach

When confronted with a difficult clinical problem, you may find it useful to organize the management plan according to the acronym “DTaP,” which for this patient would include:

• Diagnostic plan: serial ECGs and cardiac enzymes: an echocardiogram
• Therapeutic plan: pain control; antibiotics for possible pneumonia; consider steroids
• Assistance from consultants (who are you going to ask for help?): physiatrist consult for electromyography (EMG); cardiology consult; neurology consult
• Patient education (explain to the patient and his family the current diagnostic possibilities and your management plan)
• Provider education (learn more about myopathies!).

You request specialty consultations:

Neurology: possible polymyositis; recommends rheumatology consultation, multiple labs (most of which are sent out to a reference lab and return only several days later)

Cardiology: ECG normal; cardiologist does not see evidence for congestive heart failure or coronary artery disease

Physical medicine and rehabilitation: EMG performed; findings consistent with inflammatory myopathy

Rheumatology: recommends proceeding with muscle biopsy to differentiate polymyositis and inclusion-body myositis

Surgery: performs muscle biopsy which is sent to a regional neuropathologist; reveals inflammatory myopathy with prominent perivascular lymphocytic inflammation strongly suggestive of dermatomyositis.

Further case management and resolution

You administer solumedrol intravenously 1 g/d for 3 days, then change to prednisone orally 1 mg/kg/d.

The patient improves steadily with 3 months of oral steroid therapy. He tests positive for anti-Jo antibodies but his pulmonary symptoms resolve. He undergoes an outpatient evaluation for cancer screening. Colonoscopy, esophogastroduodenoscopy and chest/abdominal/pelvic computed tomography scans are negative for evidence of malignancy.

Other ways in which you may encounter inflammatory myopathies

Dermatomyositis usually causes a characteristic rash that facilitates early diagnosis (though it did not appear in this case). As shown in FIGURES 1 AND 2, patients may have either a heliotrope rash (blue-purple to dusky erythematous discoloration on the upper eyelids, with or without edema), or Gottron’s papules (slightly raised violaceous papules and plaques overlying bony prominences, particularly the joints in the fingers and the knuckles).¹⁰

A variety of less specific skin and nail changes can occur. Dermatomyositis may present with skin lesions alone (dermatomyositis sine myositis) or rarely with myopathy alone (dermatomyositis sine dermatitis). In our case, multiple examiners failed to detect any classic dermatologic abnormalities, though the pinkish skin changes over the extensor aspect of the MCP joints were, in retrospect, suggestive of dermatomyositis. The weakness associated with this disease may be mild, moderate, or severe enough to result in quadriparesis. Dermatomyositis usually occurs alone but may be present with scleroderma and mixed connective tissue disease.

Inclusion-body myositis is often misdiagnosed as polymyositis or dermatomyositis until identified by muscle biopsy findings (see How inflammatory myopathies develop), although suspicion is raised with a poor response to steroid therapy.⁹ Some patients report falling as a result of quadriceps weakness. On occasion the weakness can be asymmetric or distal (rare with dermatomyositis or polymyositis). Diagnosis is always made by muscle biopsy. Disease progression is slow but steady and most patients end up requiring a walker or assistive device.

Polymyositis is a sub-acute inflammatory myopathy affecting adults and, rarely, children. In most cases the actual onset of polymyositis is not easily determined as patients tend to delay seeking medical evaluation.

Other muscular disorders, as discussed in the case presentation, need to be excluded.

FIGURE 1 Heliotrope rash

Patients with dermatomyositis often have a characteristic rash on their face.

FIGURE 2 Gottron’s papules

Many patients also have papules and plaques on their hands, typically at the joints.

Commonly associated clinical findings

Extramuscular manifestations of inflammatory myopathies. Dermatomyositis is a systemic inflammatory disorder that may extend beyond the dermatologic and muscular systems, and patients can exhibit such symptoms as fever, malaise, and weight loss.

Arthralgia and Raynaud’s phenomenon may occur with associated connective tissue disease.

Dysphagia indicates involvement of the oropharyngeal striated muscles and the upper esophagus.

Cardiac disturbances include atrioventricular conduction defects, tachyarrhythmias, myocarditis, heart failure, and possibly hypertension from long-term steroid use. The elevated troponin-I seen in our index case may have been evidence of a mild myocarditis, though the echocardiogram was normal.

Calcinosis (deposition of calcium in the skin or muscles) occurs in up to 40% of children with dermatomyositis but is unusual in adults.¹⁰

Pulmonary symptoms may be due to weakness of the thoracic muscles, interstitial lung disease, or aspiration. One retrospective study of 156 consecutive patients with dermatomyositis/polymyositis based on clinical criteria found a 23.1% incidence of interstitial lung disease.¹¹

Malignant disorders. The frequency of cancer is increased in association with these diseases. Studies have placed the highest risk of concomitant malignancy with dermatomyositis and the least risk with polymyositis. (The relative risk for malignancy in dermatomyositis as compared with polymyositis was 2.4.) Malignancy associated with dermatomyositis or polymyositis is twice as likely in women than in men.¹²

Risk of associated malignancy was highest within the first year of diagnosis. Therefore, consider a diagnostic evaluation for malignancy at the time myopathy is diagnosed. The optimal diagnostic regimen in this setting is unknown. In one retrospective French study of 40 consecutive adult patients with inflammatory myopathy (33 with dermatomyositis and 7 with polymyositis) between the years 1981 and 2000, malignancy was present at the time of myopathy diagnosis in 16 patients (13 with dermatomyositis and 3 with polymyositis).¹² An Australian population-based, retrospective cohort study of 537 individuals with biopsy-proven idiopathic inflammatory myopathy from 1981–1995 demonstrated 116 cases of malignancy in 104 patients.¹³ The risk was highest in dermatomyositis (standardized incidence ratio [SIR] 6.2), next highest in inclusion-body myositis (SIR 2.4), and lowest in polymyositis (SIR 2.0).

Diagnosis: What helps, what doesn’t

Suspect inflammatory myopathy by the constellation of clinical findings; confirm it by looking for elevated muscle enzymes and characteristic findings on EMG and muscle biopsy (see How inflammatory myopathies develop).

The most sensitive muscle enzyme for inflammatory myopathy is CK, levels of which usually parallel disease activity and may be used to assess response to therapy.^6,10 Needle EMG demonstrates increased spontaneous activity with fibrillations; complex repetitive discharges; positive sharp waves; and voluntary motor units consisting of low-amplitude polyphasic units of short duration.⁶ EMG findings alone are not diagnostic.

Serologic tests are commonly done but their clinical usefulness is controversial.¹⁰ Antinuclear antibodies are found in about 80% of cases but are nonspecific and not clinically useful.¹⁴ Myositis-specific antibodies (MSAs) have been described in about 30% of idiopathic inflammatory myopathies but are also of uncertain diagnostic and pathogenic importance.¹⁴ The most prevalent MSA, anti-Jo, is present in only about 20% of cases and correlates with interstitial lung disease, but has uncertain usefulness in differentiating between dermatomyositis, polymyositis, and inclusion-body myositis.^{6,10,11,14,15}

Differentiate between the inflammatory myopathies based on characteristic pathological findings on muscle biopsy (previously discussed). Muscle biopsy is the definitive test for establishing the diagnosis. In our case presentation, the regional neuropathologist thought the biopsy result was most consistent with dermatomyositis despite the clinical paucity of skin abnormalities, though our consulting neurologist favored a diagnosis of polymyositis on clinical grounds.

Treatment recommendations

Corticosteroids are the most efficacious treatment for dermatomyositis (strength of recommendation [SOR]: B).¹⁰ One empirical regimen is to give prednisone 1 mg/kg/d as initial therapy; maintain this therapy for 1 month after symptoms and CK have normalized; then slowly taper (SOR: C).¹⁰ Twenty-five percent of patients will not respond to steroids; others will not tolerate the side effects of steroid therapy.¹⁰

Immunosuppressive drugs such as azothioprine, methotrexate, cyclosporine, mycophenolate mofetil and cyclophosphamide may be used as second-line treatment (SOR: C).⁶ Intravenous immunoglobulin may have some efficacy (SOR: B).¹⁶ Plasmapheresis does not appear to be effective (SOR: B).¹⁷

Determinants of prognosis

Most patients will improve over several weeks or months with therapy, although a third or more are left with mild to severe muscle damage. Dermatomyositis responds better than polymyositis; inclusion-body myositis is the most difficult to treat.¹⁰ Poor prognostic factors include older age, association with cancer, pulmonary fibrosis, dysphagia with aspiration pneumonia, cardiac involvement, steroid-resistant disease, and calcinosis in dermatomyositis.^6,10 Studies have demonstrated 5-year survival rates between 77% and 92%.^18,19 The main causes of death were related to malignancy and cardiac or pulmonary complications.

History of present illness

• Approximately 4 weeks of generalized extremity pain and weakness; left-sided, nonexertional chest pain, which is much less severe than his extremity pains
• Symptoms are most prominent in the proximal upper extremities, especially with movement; the right side is more effected than the left
• Dyspnea on exertion
• Seen twice in local urgent care facilities in the past 10 days; diagnosed with congestive heart failure; treated with furosemide, digoxin, and an unknown antibiotic without relief
• 20- to 30-pound weight loss over the past year

Other medical history

• No chronic medical problems or medications
• Until this past month, last seen by a physician about 3 or 4 years prior

Review of systems

• Up to the day of admission has been ambulatory and able to care for himself despite his weakness
• No fever, chills, or rash; but has night sweats
• Smokes; does not drink alcohol
• Retired; lives with his wife

Physical examination

• Alert, appears mildly uncomfortable
• Temperature 101°F, respirations 32, blood pressure 164/72, pulse 80
• 3/5 strength in proximal upper and lower extremities (can barely lift arms and legs off the bed; movement also limited by pain)
• Normal distal strength (hand grips and dorsi/plantar flexion of foot)
• Normal sensation, reflexes, cranial nerves, and mental status; no neck weakness
• No abnormal joint findings; has pink discoloration over extensor surface of MCP joint, which patient dismisses as scars from previous abrasions that have been present “for a long time”
• Heart, lungs unremarkable; no peripheral edema

Laboratory studies completed in the emergency department

• ECG: normal
• Chest x-ray: bibasilar peribronchial infiltrates
• Hemoglobin/hematocrit: normal
• White blood count: 27,000 with 92% neutrophils
• Erythrocyte sedimentation rate: normal
• Urinalysis: negative for blood
• Brain natriuretic peptide: normal
• Creatine kinase (CK): 2205 IU/L (normal range 35–232)
• Troponin-I: 0.6 ng/mL.
  [Reference range:
    <0.05=Negative
    0.05–0.09=Equivocal
    0.10–0.49=Suspicious
    0.50=Consistent with myocardial injury]

Is this acute non-ST elevation myocardial infarction (NSTEMI)?

The American College of Cardiology and the American Heart Association define myocardial infarction primarily as elevated cardiac-specific enzymes troponin-I and troponin-T in the appropriate clinical setting.^1,2 Elevated cardiac troponins have a sensitivity approaching 100% for myocardial damage. Specificity is much lower for acute ischemic cardiac disease, however, particularly for patients with a low pretest probability (45% false-positive rate in one series of 1000 consecutive patients presenting to a large urban emergency department with symptoms of acute coronary ischemia).³

Mechanisms other than atherosclerotic coronary artery disease that can elevate cardiac troponins:

• Increased cardiac demand (eg, sepsis, hypovolemia)
• Nonatherosclerotic ischemia (eg, cocaine or other sympathomimetic agents, coronary vasospasm)
• Direct myocardial injury (eg, cardiac contusion, myocarditis)
• Myocardial strain (eg, congestive heart failure, pulmonary embolus)
• Chronic renal insufficiency (mechanism unclear).⁴

In light of this patient’s history and physical exam findings, you doubt he’s having an acute cardiac event. The most remarkable features are his weakness, muscle pain, and markedly elevated CK.

Though you have ruled out anemia and several other possibilities, the differential diagnosis of weakness is still broad. You decide to explore the differential diagnosis of elevated CK, a more specific finding in this case.

Pursuing the differential

You consult UpToDate, searching under “creatine kinase,” and find an article entitled “Muscle enzymes in the evaluation of neuromuscular disease.”⁵ You conclude that the most likely cause of your patient’s problems is an idiopathic inflammatory myopathy: polymyositis, dermatomyositis, or inclusion-body myositis.⁶

Other possibilities include post-viral myositis and myositis associated with connective tissue disease, hypothyroidism, or drug reactions.

D-penicillamine, zidovudine (AZT), and viral or bacterial infection may produce inflammatory myopathy similar to polymyositis.⁷ A history of exposure to myotoxic drugs (such as statins) and toxins has been excluded.

The absence of a family history for neuromuscular disease and the relatively recent onset of symptoms rule out an inherited muscular dystrophy or congenital muscle enzyme deficiency.

Myasthenia gravis presents with extraocular muscle involvement. Guillain-Barré syndrome is characterized by ascending muscle weakness. Lyme disease may cause weakness secondary to peripheral neuropathy but it does not produce evidence of muscle inflammation such as elevation of the CK. West Nile virus encephalitis may present with muscle weakness and flaccid paralysis.⁸ Trichinellosis may also cause muscle inflammation with weakness and elevation of CK, but it is rare in the United States.

You repeat parts of your physical exam and confirm that his proximal upper extremity muscles are much weaker than his distal muscles.

In practice settings where specialty consultation is not always immediately available, your diagnostic skills may be challenged by uncommon presentations of disease. In this case, the challenge is “chest pain and positive cardiac enzymes” in a patient who does not appear to have a primary cardiac problem.

DTaP approach

When confronted with a difficult clinical problem, you may find it useful to organize the management plan according to the acronym “DTaP,” which for this patient would include:

• Diagnostic plan: serial ECGs and cardiac enzymes: an echocardiogram
• Therapeutic plan: pain control; antibiotics for possible pneumonia; consider steroids
• Assistance from consultants (who are you going to ask for help?): physiatrist consult for electromyography (EMG); cardiology consult; neurology consult
• Patient education (explain to the patient and his family the current diagnostic possibilities and your management plan)
• Provider education (learn more about myopathies!).

You request specialty consultations:

Neurology: possible polymyositis; recommends rheumatology consultation, multiple labs (most of which are sent out to a reference lab and return only several days later)

Cardiology: ECG normal; cardiologist does not see evidence for congestive heart failure or coronary artery disease

Physical medicine and rehabilitation: EMG performed; findings consistent with inflammatory myopathy

Rheumatology: recommends proceeding with muscle biopsy to differentiate polymyositis and inclusion-body myositis

Surgery: performs muscle biopsy which is sent to a regional neuropathologist; reveals inflammatory myopathy with prominent perivascular lymphocytic inflammation strongly suggestive of dermatomyositis.

Further case management and resolution

You administer solumedrol intravenously 1 g/d for 3 days, then change to prednisone orally 1 mg/kg/d.

The patient improves steadily with 3 months of oral steroid therapy. He tests positive for anti-Jo antibodies but his pulmonary symptoms resolve. He undergoes an outpatient evaluation for cancer screening. Colonoscopy, esophogastroduodenoscopy and chest/abdominal/pelvic computed tomography scans are negative for evidence of malignancy.

Other ways in which you may encounter inflammatory myopathies

Dermatomyositis usually causes a characteristic rash that facilitates early diagnosis (though it did not appear in this case). As shown in FIGURES 1 AND 2, patients may have either a heliotrope rash (blue-purple to dusky erythematous discoloration on the upper eyelids, with or without edema), or Gottron’s papules (slightly raised violaceous papules and plaques overlying bony prominences, particularly the joints in the fingers and the knuckles).¹⁰

A variety of less specific skin and nail changes can occur. Dermatomyositis may present with skin lesions alone (dermatomyositis sine myositis) or rarely with myopathy alone (dermatomyositis sine dermatitis). In our case, multiple examiners failed to detect any classic dermatologic abnormalities, though the pinkish skin changes over the extensor aspect of the MCP joints were, in retrospect, suggestive of dermatomyositis. The weakness associated with this disease may be mild, moderate, or severe enough to result in quadriparesis. Dermatomyositis usually occurs alone but may be present with scleroderma and mixed connective tissue disease.

Inclusion-body myositis is often misdiagnosed as polymyositis or dermatomyositis until identified by muscle biopsy findings (see How inflammatory myopathies develop), although suspicion is raised with a poor response to steroid therapy.⁹ Some patients report falling as a result of quadriceps weakness. On occasion the weakness can be asymmetric or distal (rare with dermatomyositis or polymyositis). Diagnosis is always made by muscle biopsy. Disease progression is slow but steady and most patients end up requiring a walker or assistive device.

Polymyositis is a sub-acute inflammatory myopathy affecting adults and, rarely, children. In most cases the actual onset of polymyositis is not easily determined as patients tend to delay seeking medical evaluation.

Other muscular disorders, as discussed in the case presentation, need to be excluded.

FIGURE 1 Heliotrope rash

Patients with dermatomyositis often have a characteristic rash on their face.

FIGURE 2 Gottron’s papules

Many patients also have papules and plaques on their hands, typically at the joints.

Commonly associated clinical findings

Extramuscular manifestations of inflammatory myopathies. Dermatomyositis is a systemic inflammatory disorder that may extend beyond the dermatologic and muscular systems, and patients can exhibit such symptoms as fever, malaise, and weight loss.

Arthralgia and Raynaud’s phenomenon may occur with associated connective tissue disease.

Dysphagia indicates involvement of the oropharyngeal striated muscles and the upper esophagus.

Cardiac disturbances include atrioventricular conduction defects, tachyarrhythmias, myocarditis, heart failure, and possibly hypertension from long-term steroid use. The elevated troponin-I seen in our index case may have been evidence of a mild myocarditis, though the echocardiogram was normal.

Calcinosis (deposition of calcium in the skin or muscles) occurs in up to 40% of children with dermatomyositis but is unusual in adults.¹⁰

Pulmonary symptoms may be due to weakness of the thoracic muscles, interstitial lung disease, or aspiration. One retrospective study of 156 consecutive patients with dermatomyositis/polymyositis based on clinical criteria found a 23.1% incidence of interstitial lung disease.¹¹

Malignant disorders. The frequency of cancer is increased in association with these diseases. Studies have placed the highest risk of concomitant malignancy with dermatomyositis and the least risk with polymyositis. (The relative risk for malignancy in dermatomyositis as compared with polymyositis was 2.4.) Malignancy associated with dermatomyositis or polymyositis is twice as likely in women than in men.¹²

Risk of associated malignancy was highest within the first year of diagnosis. Therefore, consider a diagnostic evaluation for malignancy at the time myopathy is diagnosed. The optimal diagnostic regimen in this setting is unknown. In one retrospective French study of 40 consecutive adult patients with inflammatory myopathy (33 with dermatomyositis and 7 with polymyositis) between the years 1981 and 2000, malignancy was present at the time of myopathy diagnosis in 16 patients (13 with dermatomyositis and 3 with polymyositis).¹² An Australian population-based, retrospective cohort study of 537 individuals with biopsy-proven idiopathic inflammatory myopathy from 1981–1995 demonstrated 116 cases of malignancy in 104 patients.¹³ The risk was highest in dermatomyositis (standardized incidence ratio [SIR] 6.2), next highest in inclusion-body myositis (SIR 2.4), and lowest in polymyositis (SIR 2.0).

Diagnosis: What helps, what doesn’t

Suspect inflammatory myopathy by the constellation of clinical findings; confirm it by looking for elevated muscle enzymes and characteristic findings on EMG and muscle biopsy (see How inflammatory myopathies develop).

The most sensitive muscle enzyme for inflammatory myopathy is CK, levels of which usually parallel disease activity and may be used to assess response to therapy.^6,10 Needle EMG demonstrates increased spontaneous activity with fibrillations; complex repetitive discharges; positive sharp waves; and voluntary motor units consisting of low-amplitude polyphasic units of short duration.⁶ EMG findings alone are not diagnostic.

Serologic tests are commonly done but their clinical usefulness is controversial.¹⁰ Antinuclear antibodies are found in about 80% of cases but are nonspecific and not clinically useful.¹⁴ Myositis-specific antibodies (MSAs) have been described in about 30% of idiopathic inflammatory myopathies but are also of uncertain diagnostic and pathogenic importance.¹⁴ The most prevalent MSA, anti-Jo, is present in only about 20% of cases and correlates with interstitial lung disease, but has uncertain usefulness in differentiating between dermatomyositis, polymyositis, and inclusion-body myositis.^{6,10,11,14,15}

Differentiate between the inflammatory myopathies based on characteristic pathological findings on muscle biopsy (previously discussed). Muscle biopsy is the definitive test for establishing the diagnosis. In our case presentation, the regional neuropathologist thought the biopsy result was most consistent with dermatomyositis despite the clinical paucity of skin abnormalities, though our consulting neurologist favored a diagnosis of polymyositis on clinical grounds.

Treatment recommendations

Corticosteroids are the most efficacious treatment for dermatomyositis (strength of recommendation [SOR]: B).¹⁰ One empirical regimen is to give prednisone 1 mg/kg/d as initial therapy; maintain this therapy for 1 month after symptoms and CK have normalized; then slowly taper (SOR: C).¹⁰ Twenty-five percent of patients will not respond to steroids; others will not tolerate the side effects of steroid therapy.¹⁰

Immunosuppressive drugs such as azothioprine, methotrexate, cyclosporine, mycophenolate mofetil and cyclophosphamide may be used as second-line treatment (SOR: C).⁶ Intravenous immunoglobulin may have some efficacy (SOR: B).¹⁶ Plasmapheresis does not appear to be effective (SOR: B).¹⁷

Determinants of prognosis

Most patients will improve over several weeks or months with therapy, although a third or more are left with mild to severe muscle damage. Dermatomyositis responds better than polymyositis; inclusion-body myositis is the most difficult to treat.¹⁰ Poor prognostic factors include older age, association with cancer, pulmonary fibrosis, dysphagia with aspiration pneumonia, cardiac involvement, steroid-resistant disease, and calcinosis in dermatomyositis.^6,10 Studies have demonstrated 5-year survival rates between 77% and 92%.^18,19 The main causes of death were related to malignancy and cardiac or pulmonary complications.

History of present illness

• Approximately 4 weeks of generalized extremity pain and weakness; left-sided, nonexertional chest pain, which is much less severe than his extremity pains
• Symptoms are most prominent in the proximal upper extremities, especially with movement; the right side is more effected than the left
• Dyspnea on exertion
• Seen twice in local urgent care facilities in the past 10 days; diagnosed with congestive heart failure; treated with furosemide, digoxin, and an unknown antibiotic without relief
• 20- to 30-pound weight loss over the past year

Other medical history

• No chronic medical problems or medications
• Until this past month, last seen by a physician about 3 or 4 years prior

Review of systems

• Up to the day of admission has been ambulatory and able to care for himself despite his weakness
• No fever, chills, or rash; but has night sweats
• Smokes; does not drink alcohol
• Retired; lives with his wife

Physical examination

• Alert, appears mildly uncomfortable
• Temperature 101°F, respirations 32, blood pressure 164/72, pulse 80
• 3/5 strength in proximal upper and lower extremities (can barely lift arms and legs off the bed; movement also limited by pain)
• Normal distal strength (hand grips and dorsi/plantar flexion of foot)
• Normal sensation, reflexes, cranial nerves, and mental status; no neck weakness
• No abnormal joint findings; has pink discoloration over extensor surface of MCP joint, which patient dismisses as scars from previous abrasions that have been present “for a long time”
• Heart, lungs unremarkable; no peripheral edema

Laboratory studies completed in the emergency department

• ECG: normal
• Chest x-ray: bibasilar peribronchial infiltrates
• Hemoglobin/hematocrit: normal
• White blood count: 27,000 with 92% neutrophils
• Erythrocyte sedimentation rate: normal
• Urinalysis: negative for blood
• Brain natriuretic peptide: normal
• Creatine kinase (CK): 2205 IU/L (normal range 35–232)
• Troponin-I: 0.6 ng/mL.
  [Reference range:
    <0.05=Negative
    0.05–0.09=Equivocal
    0.10–0.49=Suspicious
    0.50=Consistent with myocardial injury]

Is this acute non-ST elevation myocardial infarction (NSTEMI)?

The American College of Cardiology and the American Heart Association define myocardial infarction primarily as elevated cardiac-specific enzymes troponin-I and troponin-T in the appropriate clinical setting.^1,2 Elevated cardiac troponins have a sensitivity approaching 100% for myocardial damage. Specificity is much lower for acute ischemic cardiac disease, however, particularly for patients with a low pretest probability (45% false-positive rate in one series of 1000 consecutive patients presenting to a large urban emergency department with symptoms of acute coronary ischemia).³

Mechanisms other than atherosclerotic coronary artery disease that can elevate cardiac troponins:

• Increased cardiac demand (eg, sepsis, hypovolemia)
• Nonatherosclerotic ischemia (eg, cocaine or other sympathomimetic agents, coronary vasospasm)
• Direct myocardial injury (eg, cardiac contusion, myocarditis)
• Myocardial strain (eg, congestive heart failure, pulmonary embolus)
• Chronic renal insufficiency (mechanism unclear).⁴

In light of this patient’s history and physical exam findings, you doubt he’s having an acute cardiac event. The most remarkable features are his weakness, muscle pain, and markedly elevated CK.

Though you have ruled out anemia and several other possibilities, the differential diagnosis of weakness is still broad. You decide to explore the differential diagnosis of elevated CK, a more specific finding in this case.

Pursuing the differential

You consult UpToDate, searching under “creatine kinase,” and find an article entitled “Muscle enzymes in the evaluation of neuromuscular disease.”⁵ You conclude that the most likely cause of your patient’s problems is an idiopathic inflammatory myopathy: polymyositis, dermatomyositis, or inclusion-body myositis.⁶

Other possibilities include post-viral myositis and myositis associated with connective tissue disease, hypothyroidism, or drug reactions.

D-penicillamine, zidovudine (AZT), and viral or bacterial infection may produce inflammatory myopathy similar to polymyositis.⁷ A history of exposure to myotoxic drugs (such as statins) and toxins has been excluded.

The absence of a family history for neuromuscular disease and the relatively recent onset of symptoms rule out an inherited muscular dystrophy or congenital muscle enzyme deficiency.

Myasthenia gravis presents with extraocular muscle involvement. Guillain-Barré syndrome is characterized by ascending muscle weakness. Lyme disease may cause weakness secondary to peripheral neuropathy but it does not produce evidence of muscle inflammation such as elevation of the CK. West Nile virus encephalitis may present with muscle weakness and flaccid paralysis.⁸ Trichinellosis may also cause muscle inflammation with weakness and elevation of CK, but it is rare in the United States.

You repeat parts of your physical exam and confirm that his proximal upper extremity muscles are much weaker than his distal muscles.

In practice settings where specialty consultation is not always immediately available, your diagnostic skills may be challenged by uncommon presentations of disease. In this case, the challenge is “chest pain and positive cardiac enzymes” in a patient who does not appear to have a primary cardiac problem.

DTaP approach

When confronted with a difficult clinical problem, you may find it useful to organize the management plan according to the acronym “DTaP,” which for this patient would include:

• Diagnostic plan: serial ECGs and cardiac enzymes: an echocardiogram
• Therapeutic plan: pain control; antibiotics for possible pneumonia; consider steroids
• Assistance from consultants (who are you going to ask for help?): physiatrist consult for electromyography (EMG); cardiology consult; neurology consult
• Patient education (explain to the patient and his family the current diagnostic possibilities and your management plan)
• Provider education (learn more about myopathies!).

You request specialty consultations:

Neurology: possible polymyositis; recommends rheumatology consultation, multiple labs (most of which are sent out to a reference lab and return only several days later)

Cardiology: ECG normal; cardiologist does not see evidence for congestive heart failure or coronary artery disease

Physical medicine and rehabilitation: EMG performed; findings consistent with inflammatory myopathy

Rheumatology: recommends proceeding with muscle biopsy to differentiate polymyositis and inclusion-body myositis

Surgery: performs muscle biopsy which is sent to a regional neuropathologist; reveals inflammatory myopathy with prominent perivascular lymphocytic inflammation strongly suggestive of dermatomyositis.

Further case management and resolution

You administer solumedrol intravenously 1 g/d for 3 days, then change to prednisone orally 1 mg/kg/d.

The patient improves steadily with 3 months of oral steroid therapy. He tests positive for anti-Jo antibodies but his pulmonary symptoms resolve. He undergoes an outpatient evaluation for cancer screening. Colonoscopy, esophogastroduodenoscopy and chest/abdominal/pelvic computed tomography scans are negative for evidence of malignancy.

Other ways in which you may encounter inflammatory myopathies

Dermatomyositis usually causes a characteristic rash that facilitates early diagnosis (though it did not appear in this case). As shown in FIGURES 1 AND 2, patients may have either a heliotrope rash (blue-purple to dusky erythematous discoloration on the upper eyelids, with or without edema), or Gottron’s papules (slightly raised violaceous papules and plaques overlying bony prominences, particularly the joints in the fingers and the knuckles).¹⁰

A variety of less specific skin and nail changes can occur. Dermatomyositis may present with skin lesions alone (dermatomyositis sine myositis) or rarely with myopathy alone (dermatomyositis sine dermatitis). In our case, multiple examiners failed to detect any classic dermatologic abnormalities, though the pinkish skin changes over the extensor aspect of the MCP joints were, in retrospect, suggestive of dermatomyositis. The weakness associated with this disease may be mild, moderate, or severe enough to result in quadriparesis. Dermatomyositis usually occurs alone but may be present with scleroderma and mixed connective tissue disease.

Inclusion-body myositis is often misdiagnosed as polymyositis or dermatomyositis until identified by muscle biopsy findings (see How inflammatory myopathies develop), although suspicion is raised with a poor response to steroid therapy.⁹ Some patients report falling as a result of quadriceps weakness. On occasion the weakness can be asymmetric or distal (rare with dermatomyositis or polymyositis). Diagnosis is always made by muscle biopsy. Disease progression is slow but steady and most patients end up requiring a walker or assistive device.

Polymyositis is a sub-acute inflammatory myopathy affecting adults and, rarely, children. In most cases the actual onset of polymyositis is not easily determined as patients tend to delay seeking medical evaluation.

Other muscular disorders, as discussed in the case presentation, need to be excluded.

FIGURE 1 Heliotrope rash

Patients with dermatomyositis often have a characteristic rash on their face.

FIGURE 2 Gottron’s papules

Many patients also have papules and plaques on their hands, typically at the joints.

Commonly associated clinical findings

Extramuscular manifestations of inflammatory myopathies. Dermatomyositis is a systemic inflammatory disorder that may extend beyond the dermatologic and muscular systems, and patients can exhibit such symptoms as fever, malaise, and weight loss.

Arthralgia and Raynaud’s phenomenon may occur with associated connective tissue disease.

Dysphagia indicates involvement of the oropharyngeal striated muscles and the upper esophagus.

Cardiac disturbances include atrioventricular conduction defects, tachyarrhythmias, myocarditis, heart failure, and possibly hypertension from long-term steroid use. The elevated troponin-I seen in our index case may have been evidence of a mild myocarditis, though the echocardiogram was normal.

Calcinosis (deposition of calcium in the skin or muscles) occurs in up to 40% of children with dermatomyositis but is unusual in adults.¹⁰

Pulmonary symptoms may be due to weakness of the thoracic muscles, interstitial lung disease, or aspiration. One retrospective study of 156 consecutive patients with dermatomyositis/polymyositis based on clinical criteria found a 23.1% incidence of interstitial lung disease.¹¹

Malignant disorders. The frequency of cancer is increased in association with these diseases. Studies have placed the highest risk of concomitant malignancy with dermatomyositis and the least risk with polymyositis. (The relative risk for malignancy in dermatomyositis as compared with polymyositis was 2.4.) Malignancy associated with dermatomyositis or polymyositis is twice as likely in women than in men.¹²

Risk of associated malignancy was highest within the first year of diagnosis. Therefore, consider a diagnostic evaluation for malignancy at the time myopathy is diagnosed. The optimal diagnostic regimen in this setting is unknown. In one retrospective French study of 40 consecutive adult patients with inflammatory myopathy (33 with dermatomyositis and 7 with polymyositis) between the years 1981 and 2000, malignancy was present at the time of myopathy diagnosis in 16 patients (13 with dermatomyositis and 3 with polymyositis).¹² An Australian population-based, retrospective cohort study of 537 individuals with biopsy-proven idiopathic inflammatory myopathy from 1981–1995 demonstrated 116 cases of malignancy in 104 patients.¹³ The risk was highest in dermatomyositis (standardized incidence ratio [SIR] 6.2), next highest in inclusion-body myositis (SIR 2.4), and lowest in polymyositis (SIR 2.0).

Diagnosis: What helps, what doesn’t

Suspect inflammatory myopathy by the constellation of clinical findings; confirm it by looking for elevated muscle enzymes and characteristic findings on EMG and muscle biopsy (see How inflammatory myopathies develop).

The most sensitive muscle enzyme for inflammatory myopathy is CK, levels of which usually parallel disease activity and may be used to assess response to therapy.^6,10 Needle EMG demonstrates increased spontaneous activity with fibrillations; complex repetitive discharges; positive sharp waves; and voluntary motor units consisting of low-amplitude polyphasic units of short duration.⁶ EMG findings alone are not diagnostic.

Serologic tests are commonly done but their clinical usefulness is controversial.¹⁰ Antinuclear antibodies are found in about 80% of cases but are nonspecific and not clinically useful.¹⁴ Myositis-specific antibodies (MSAs) have been described in about 30% of idiopathic inflammatory myopathies but are also of uncertain diagnostic and pathogenic importance.¹⁴ The most prevalent MSA, anti-Jo, is present in only about 20% of cases and correlates with interstitial lung disease, but has uncertain usefulness in differentiating between dermatomyositis, polymyositis, and inclusion-body myositis.^{6,10,11,14,15}

Differentiate between the inflammatory myopathies based on characteristic pathological findings on muscle biopsy (previously discussed). Muscle biopsy is the definitive test for establishing the diagnosis. In our case presentation, the regional neuropathologist thought the biopsy result was most consistent with dermatomyositis despite the clinical paucity of skin abnormalities, though our consulting neurologist favored a diagnosis of polymyositis on clinical grounds.

Treatment recommendations

Corticosteroids are the most efficacious treatment for dermatomyositis (strength of recommendation [SOR]: B).¹⁰ One empirical regimen is to give prednisone 1 mg/kg/d as initial therapy; maintain this therapy for 1 month after symptoms and CK have normalized; then slowly taper (SOR: C).¹⁰ Twenty-five percent of patients will not respond to steroids; others will not tolerate the side effects of steroid therapy.¹⁰

Immunosuppressive drugs such as azothioprine, methotrexate, cyclosporine, mycophenolate mofetil and cyclophosphamide may be used as second-line treatment (SOR: C).⁶ Intravenous immunoglobulin may have some efficacy (SOR: B).¹⁶ Plasmapheresis does not appear to be effective (SOR: B).¹⁷

Determinants of prognosis

Most patients will improve over several weeks or months with therapy, although a third or more are left with mild to severe muscle damage. Dermatomyositis responds better than polymyositis; inclusion-body myositis is the most difficult to treat.¹⁰ Poor prognostic factors include older age, association with cancer, pulmonary fibrosis, dysphagia with aspiration pneumonia, cardiac involvement, steroid-resistant disease, and calcinosis in dermatomyositis.^6,10 Studies have demonstrated 5-year survival rates between 77% and 92%.^18,19 The main causes of death were related to malignancy and cardiac or pulmonary complications.

Other medical history

• Enuresis, recurrent perioral rash around age 7 with annual recurrences
• No chronic infections or illness
• Premenarchal
• Negative trauma history, including abuse
• Bike riding 2 days earlier but no falls
• Taking acyclovir as prescribed by ED; acetaminophen/ibuprofen for fever
• No known allergies

Family and social history

• Parents alive and well; no siblings
• Straight-A student
• Involved in JROTC (was on a retreat 2 weeks ago)
• No use of tobacco, alcohol, street drugs, or suspicious substances
• Denies any sexual activity

Physical examination

• Review of systems: Positive for chills, fever, dysuria, and perineal pain; otherwise negative
• Temperature 101.6°F, pulse 112, respiratory rate 22, blood pressure 110/70 mm Hg, weight 94 lb
• Alert female in no distress, normal neurologic exam
• HEENT: normal exam with clear oropharynx without lesions
• Skin/integument: no rashes, including arms, legs, hands, feet, and trunk
• Heart, lungs, and abdomen: tachycardia, otherwise normal
• Reproductive examination (chaperone present): Tanner stage III; perineal edema with marked purple ecchymoses located bilaterally at posterior introitus; multiple lacerations also noted as well as tenderness; some scabbed areas noted; no periurethral or perianal lesions or bruising; no vaginal discharge; speculum and bimanual exam were deferred due to pain.

You are concerned about abuse. You interview the patient alone and she again denies any type of sexual encounter. She has never used tampons. She does report that she is a heavy sleeper and that she recently went on a retreat where she and a girlfriend slept in the same room. As far as she knows, there was no intruder. She tearfully says, “If anything happened, I can’t remember.”

You also interview the father alone. He says he and his wife “keep a tight rein” on their daughter. She has been out of their supervision only for the recent retreat. He is concerned that his daughter may have been given a “date-rape” drug and requests testing. His demeanor seems appropriate during the conversations both in the presence and absence of his daughter.

According to state law, you notify the Department of Social Services of unexplained perineal trauma. You also contact the local sexual abuse/rape experts in your area, who have arranged for an evaluation the following day. The father assists in making the arrangements for the evaluation while he is still in your office.

Department of Social Services forensic interview and medical examination

The next day, the patient and her family undergo a comprehensive evaluation by local medical and investigative professionals from the Department of Social Services.

The differential diagnosis for genital ulcers in a sexually inexperienced female includes sexual abuse, herpes simplex virus, Behçet’s disease, Epstein Barr infection, pilonidal disease, Crohn’s disease, and hidradenitis suppurativa. Definitive diagnosis can be difficult (TABLE 1).

One retrospective series reviewed the case of 9 adolescent females with vulvar ulcers and found that 6 had no formal diagnosis. Most important, the initial presentation should prompt healthcare professionals to take steps to ensure a patient’s safety.

After performing a physical examination, the abuse experts report that the patient’s presentation is consistent with Behçet’s disease. A genital culture was obtained, and the patient was given pain medication and azithromycin.

The expert also stated that the father’s reaction to the situation was appropriate and not that of an abusive father. Most perpetrators are very hostile and defensive, whereas this father was extremely concerned and cooperative. Still, a report to Child Protective Services had to be made because of the unexplained physical findings, especially in the genital area.

Further consideration

Additional information on Behçet’s disease is found in an article in the New England Journal of Medicine from 1999: “Behçet’s disease is an inflammatory disorder of unknown cause, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions.”

You ponder this information and note that your patient has no oral lesions currently but apparently has a history of some oral lesions. You review your records indicating a history of recurrent perioral rash but do not find a history of oral lesions. However, the consultant remains constant in his diagnosis.

You review the results of the ED laboratory evaluation:

• Gonorrhea/chlamydia DNA probe negative
• Herpes culture and herpes immunoglobulin M (IgM) negative
• Rapid plasma reagin (RPR) nonreactive
• Serum pregnancy negative
• Urine drug screen negative for PCP, benzodiazepines, amphetamines, THC, opiates, barbiturates, methadone, tricyclic antidepressants
• Complete blood count normal; white blood count 9600 with a normal differential

As the family physician, you interpret these results and support the clinical plan for this patient, pending further changes in the clinical picture.

TABLE 1

Differential diagnosis of vulvar ulcers in sexually inexperienced females

Next contact—ED visit 2 days later

The patient’s vaginal pain is worsening and she cannot void. Large ulcers with adhered pus are on the left labia; a smaller lesion is on the right labia. There are also questionable lacerations of the posterior fourchette. She is catheterized and 300 mL urine is emptied from the bladder. A gynecology consultation is obtained by the ED physician with your concurrence.

Details of Behçet’s disease

Behçet’s disease is most common in the third or fourth decade of life. It has an association with the human leukocyte antigen HLA-B51 and HLA-B5 allele. Vascular injuries, hyperfunction of neutrophils, and autoimmune responses lead to the clinical findings. Behçet’s disease is presumed to be an autoimmune disease, with the primary lesion being related to the vasculitis.

Clinical criteria of Behçet’s

Diagnosis of Behçet’s disease is based on clinical criteria. No single test can determine if a patient has Behçet’s.

An International Study Group of physicians was convened to develop a set of guidelines to diagnose Behçet’s disease. These criteria include recurrent, painful oral ulceration with at least 2 other symptoms (recurrent genital ulcers, eye lesions, skin lesions, and positive pathergy test) (TABLE 2). These diagnostic criteria may be accessed at the website of the American Behçet’s Disease Association, www.behcets.com.

Prevalence of signs

Oral ulcerations are the presenting signs in about 70% of cases. These ulcers may remain for as long as 3 weeks. In women, the genital lesions are often present in the vulvovaginal region; in men, they often appear in the scrotal area. Ocular complaints occur in about one-half of patients, sometimes with photophobia, watering, and blurred vision. The most common skin lesions are pseudofolliculitis and erythema nodosum.

The pathergy test uses a sterile needle to make a skin prick. The test result is positive if an aseptic erythematous nodule or pustule (>2 mm in diameter) occurs within 24 to 48 hours, indicating neutrophil hyperfunction.

Differential diagnosis

Skin, joint, gastrointestinal, vascular, and central nervous systems may also be involved. The differential diagnosis includes chronic oral aphthosis, herpes simplex virus infection, Sweet’s syndrome, ankylosing spondylitis, inflammatory bowel disease, and multiple sclerosis (TABLE 3).

Laboratory findings and treatment

Examination of the blood can reveal nonspecific findings consistent with inflammation, including elevated C-reactive protein, erythrocyte sedimentation rate, and positive markers for autoimmune diseases.

Treatmentdepends upon the particular symptoms and clinical findings and must be coordinated with the various specialists involved.

Topical steroids are used for oral and genital ulcers as well as ocular lesions.

Oral steroids are useful for gastrointestinal and neurological symptoms but may also help with skin, joint, vascular, and ocular symptoms.

Colchicine may help alleviate oral and genital ulcers as well as skin, ocular, and joint problems.

Topical tetracycline may be used to treat oral ulcers.

Anticoagulants may be indicated for vascular disturbances and progressive central nervous system lesions.

Cytotoxic and antirheumatic agents may treat vascular, ocular, neurological, and joint manifestations.

TABLE 2

Diagnostic criteria of Behçet’s disease

TABLE 3

Differential diagnosis of Behçet’s disease

Gynecology consultation

The gynecologist recommends that the patient be admitted to the hospital for examination under anesthesia. This examination found an ulcerated area of perineum, cellulitis, and edema, without a palpable abscess. Necrotic tissue is debrided.

Biopsies are obtained for herpes, aerobic, and anaerobic cultures. Repeat gonorrhea and chlamydia polymerase chain reaction (PCR) probes are obtained as well. The patient is started on ampicillin/sulbactam (Unasyn) after the debridement.

Further laboratory testing is also done at admission, including a throat culture, cryoglobulin, hepatitis screen, antinuclear antibody (ANA), HIV, lupus anticoagulant, cardiolipin, herpes IgG, antithrombin III level, immune complex detection panel for C1q, and tissue transgluttin AB4 IgA. All results are negative. A possible rheumatology consultation is also discussed.

Culture results from the previous sexual abuse evaluation show strep and gramnegative rods. Initial cultures from exam under anesthesia reveal grampositive cocci, grampositive rods, and gramnegative rods on the Gram’s stain with final report pending. An infectious disease consultation is recommended. The family physician agreed.

Infectious disease consultation

The consultant believes streptococcal infection is the most likely culprit and recommends changing the IV antibiotic from ampicillin/sulbactam to piperacillin/tazobactam (Zosyn) with the addition of clindamycin for broad-spectrum coverage. Later, the final culture results from the sexual abuse evaluation show heavy Enterococcus colonization. Surgical culture results reveal moderate Escherichia coli, moderate Enterococcus, light Staphylococcus epidermidis, heavy bacteroides, and moderate Lactobacillus. All are susceptible to the piperacillin/tazobactam.

The patient does well and is successfully switched to oral amoxicillin/clavulanate (Augmentin) with no recurrent fever and continued healing of vaginal ulcers. She is sent home to continue to heal.

One week later, the patient is seen in follow-up with continued healing and no further lesions. A few months later, the patient has healed completely and no other lesions have occurred. Incidental discussions included recent menarche. The family physician, patient, and patient’s family do a final review of all clinical and pathological findings.

The pathology report shows inflammation and necrosis. In addition, the vulvar biopsy reveals “multiple hair follicles adjacent to the inflammation and necrosis, raising the possibility of infected hair follicles and pilonidal disease.”

Unlike the implications with the presumed Behçet’s, the patient’s localized disease process has no long-term health consequences. She is discharged with a diagnosis of labial ulcers with cellulitis, resolved urinary retention, and a pathological diagnosis of pilonidal disease.

Pilonidal disease

Pilonidal disease, this patient’s final diagnosis, is more common than Behçet’s disease. Men are affected more often than women, and ages range from puberty to the third decade of life with decreased frequency after the age of 45.

Pilonidal disease becomes a problem when “nests of hair” become infected. It is mostly found in the natal cleft but can present in almost any hairy area, mostly in the midline. Other examples include the umbilicus and scalp. There are also reports of acquired pilonidal disease from trauma in the hands of barbers, hair dressers, sheep shearers, and animal groomers. It is important to distinguish pilonidal disease from other disorders in the same region, such as anal fistulas, perirectal abscesses, and hidradenitis suppurativa.

Recurrences of pilonidal disease are quite common, with painful inflamed masses, abscesses, or sinus tracts. An acute abscess must be incised and drained. Hair removal by laser may prevent the growth of hair temporarily. For recurring infections, the definitive treatment is surgical. Procedures range from simple incision and curettage to excision of the area with plastic flap reconstruction. Antibiotics are not routinely needed, but they may be appropriate when cultures indicate specific microbes, when significant cellulitis is present, or for perioperative prophylaxis.

Could it be hidradenitis suppurativa?

Hidradenitis suppurativa is a possibility, but the clinical and pathological findings make pilonidal disease more likely. Hidradenitis suppurativa similar to pilonidal disease, but it usually is located in the axillary, perineal, or inguinal areas. Incidence is as high as 1 in 300, and it frequently begins with puberty.

Hidradenitis suppurativa differs from pilonidal disease in that the hair follicle becomes occluded due to a defect in the epithelium of the follicle’s terminal ends. This defect leads to trapping of bacteria and formation of firm, peasized nodules or cysts. Some associations between hidradenitis suppurativa and sex hormones have been proposed, but hormonal states of pregnancy, menstruation, and menopause have not shown clear association with hidradenitis suppurativa. Initial symptoms of hidradenitis suppurativa may be pruritus, erythema, and hyperhidrosis. Recurrences are common. Treatment includes medications such as antibiotics, antiandrogens, and retinoids, as well as surgical excision.

Acknowledgements

The author would like to thank Jessie Junker, MD, Albert Meyer, MD, and Barbara Walker, DO, at New Hanover Regional Medical Center, Residency in Family Medicine, Wilmington, NC; and Beth Deaton, FNP, at Wilmington Health Access for Teens, Wilmington, NC.

Conflict Of Interest

The author has no conflicts of interest to declare.

Other medical history

• Enuresis, recurrent perioral rash around age 7 with annual recurrences
• No chronic infections or illness
• Premenarchal
• Negative trauma history, including abuse
• Bike riding 2 days earlier but no falls
• Taking acyclovir as prescribed by ED; acetaminophen/ibuprofen for fever
• No known allergies

Family and social history

• Parents alive and well; no siblings
• Straight-A student
• Involved in JROTC (was on a retreat 2 weeks ago)
• No use of tobacco, alcohol, street drugs, or suspicious substances
• Denies any sexual activity

Physical examination

• Review of systems: Positive for chills, fever, dysuria, and perineal pain; otherwise negative
• Temperature 101.6°F, pulse 112, respiratory rate 22, blood pressure 110/70 mm Hg, weight 94 lb
• Alert female in no distress, normal neurologic exam
• HEENT: normal exam with clear oropharynx without lesions
• Skin/integument: no rashes, including arms, legs, hands, feet, and trunk
• Heart, lungs, and abdomen: tachycardia, otherwise normal
• Reproductive examination (chaperone present): Tanner stage III; perineal edema with marked purple ecchymoses located bilaterally at posterior introitus; multiple lacerations also noted as well as tenderness; some scabbed areas noted; no periurethral or perianal lesions or bruising; no vaginal discharge; speculum and bimanual exam were deferred due to pain.

You are concerned about abuse. You interview the patient alone and she again denies any type of sexual encounter. She has never used tampons. She does report that she is a heavy sleeper and that she recently went on a retreat where she and a girlfriend slept in the same room. As far as she knows, there was no intruder. She tearfully says, “If anything happened, I can’t remember.”

You also interview the father alone. He says he and his wife “keep a tight rein” on their daughter. She has been out of their supervision only for the recent retreat. He is concerned that his daughter may have been given a “date-rape” drug and requests testing. His demeanor seems appropriate during the conversations both in the presence and absence of his daughter.

According to state law, you notify the Department of Social Services of unexplained perineal trauma. You also contact the local sexual abuse/rape experts in your area, who have arranged for an evaluation the following day. The father assists in making the arrangements for the evaluation while he is still in your office.

Department of Social Services forensic interview and medical examination

The next day, the patient and her family undergo a comprehensive evaluation by local medical and investigative professionals from the Department of Social Services.

The differential diagnosis for genital ulcers in a sexually inexperienced female includes sexual abuse, herpes simplex virus, Behçet’s disease, Epstein Barr infection, pilonidal disease, Crohn’s disease, and hidradenitis suppurativa. Definitive diagnosis can be difficult (TABLE 1).

One retrospective series reviewed the case of 9 adolescent females with vulvar ulcers and found that 6 had no formal diagnosis. Most important, the initial presentation should prompt healthcare professionals to take steps to ensure a patient’s safety.

After performing a physical examination, the abuse experts report that the patient’s presentation is consistent with Behçet’s disease. A genital culture was obtained, and the patient was given pain medication and azithromycin.

The expert also stated that the father’s reaction to the situation was appropriate and not that of an abusive father. Most perpetrators are very hostile and defensive, whereas this father was extremely concerned and cooperative. Still, a report to Child Protective Services had to be made because of the unexplained physical findings, especially in the genital area.

Further consideration

Additional information on Behçet’s disease is found in an article in the New England Journal of Medicine from 1999: “Behçet’s disease is an inflammatory disorder of unknown cause, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions.”

You ponder this information and note that your patient has no oral lesions currently but apparently has a history of some oral lesions. You review your records indicating a history of recurrent perioral rash but do not find a history of oral lesions. However, the consultant remains constant in his diagnosis.

You review the results of the ED laboratory evaluation:

• Gonorrhea/chlamydia DNA probe negative
• Herpes culture and herpes immunoglobulin M (IgM) negative
• Rapid plasma reagin (RPR) nonreactive
• Serum pregnancy negative
• Urine drug screen negative for PCP, benzodiazepines, amphetamines, THC, opiates, barbiturates, methadone, tricyclic antidepressants
• Complete blood count normal; white blood count 9600 with a normal differential

As the family physician, you interpret these results and support the clinical plan for this patient, pending further changes in the clinical picture.

TABLE 1

Differential diagnosis of vulvar ulcers in sexually inexperienced females

Next contact—ED visit 2 days later

The patient’s vaginal pain is worsening and she cannot void. Large ulcers with adhered pus are on the left labia; a smaller lesion is on the right labia. There are also questionable lacerations of the posterior fourchette. She is catheterized and 300 mL urine is emptied from the bladder. A gynecology consultation is obtained by the ED physician with your concurrence.

Details of Behçet’s disease

Behçet’s disease is most common in the third or fourth decade of life. It has an association with the human leukocyte antigen HLA-B51 and HLA-B5 allele. Vascular injuries, hyperfunction of neutrophils, and autoimmune responses lead to the clinical findings. Behçet’s disease is presumed to be an autoimmune disease, with the primary lesion being related to the vasculitis.

Clinical criteria of Behçet’s

Diagnosis of Behçet’s disease is based on clinical criteria. No single test can determine if a patient has Behçet’s.

An International Study Group of physicians was convened to develop a set of guidelines to diagnose Behçet’s disease. These criteria include recurrent, painful oral ulceration with at least 2 other symptoms (recurrent genital ulcers, eye lesions, skin lesions, and positive pathergy test) (TABLE 2). These diagnostic criteria may be accessed at the website of the American Behçet’s Disease Association, www.behcets.com.

Prevalence of signs

Oral ulcerations are the presenting signs in about 70% of cases. These ulcers may remain for as long as 3 weeks. In women, the genital lesions are often present in the vulvovaginal region; in men, they often appear in the scrotal area. Ocular complaints occur in about one-half of patients, sometimes with photophobia, watering, and blurred vision. The most common skin lesions are pseudofolliculitis and erythema nodosum.

The pathergy test uses a sterile needle to make a skin prick. The test result is positive if an aseptic erythematous nodule or pustule (>2 mm in diameter) occurs within 24 to 48 hours, indicating neutrophil hyperfunction.

Differential diagnosis

Skin, joint, gastrointestinal, vascular, and central nervous systems may also be involved. The differential diagnosis includes chronic oral aphthosis, herpes simplex virus infection, Sweet’s syndrome, ankylosing spondylitis, inflammatory bowel disease, and multiple sclerosis (TABLE 3).

Laboratory findings and treatment

Examination of the blood can reveal nonspecific findings consistent with inflammation, including elevated C-reactive protein, erythrocyte sedimentation rate, and positive markers for autoimmune diseases.

Treatmentdepends upon the particular symptoms and clinical findings and must be coordinated with the various specialists involved.

Topical steroids are used for oral and genital ulcers as well as ocular lesions.

Oral steroids are useful for gastrointestinal and neurological symptoms but may also help with skin, joint, vascular, and ocular symptoms.

Colchicine may help alleviate oral and genital ulcers as well as skin, ocular, and joint problems.

Topical tetracycline may be used to treat oral ulcers.

Anticoagulants may be indicated for vascular disturbances and progressive central nervous system lesions.

Cytotoxic and antirheumatic agents may treat vascular, ocular, neurological, and joint manifestations.

TABLE 2

Diagnostic criteria of Behçet’s disease

TABLE 3

Differential diagnosis of Behçet’s disease

Gynecology consultation

The gynecologist recommends that the patient be admitted to the hospital for examination under anesthesia. This examination found an ulcerated area of perineum, cellulitis, and edema, without a palpable abscess. Necrotic tissue is debrided.

Biopsies are obtained for herpes, aerobic, and anaerobic cultures. Repeat gonorrhea and chlamydia polymerase chain reaction (PCR) probes are obtained as well. The patient is started on ampicillin/sulbactam (Unasyn) after the debridement.

Further laboratory testing is also done at admission, including a throat culture, cryoglobulin, hepatitis screen, antinuclear antibody (ANA), HIV, lupus anticoagulant, cardiolipin, herpes IgG, antithrombin III level, immune complex detection panel for C1q, and tissue transgluttin AB4 IgA. All results are negative. A possible rheumatology consultation is also discussed.

Culture results from the previous sexual abuse evaluation show strep and gramnegative rods. Initial cultures from exam under anesthesia reveal grampositive cocci, grampositive rods, and gramnegative rods on the Gram’s stain with final report pending. An infectious disease consultation is recommended. The family physician agreed.

Infectious disease consultation

The consultant believes streptococcal infection is the most likely culprit and recommends changing the IV antibiotic from ampicillin/sulbactam to piperacillin/tazobactam (Zosyn) with the addition of clindamycin for broad-spectrum coverage. Later, the final culture results from the sexual abuse evaluation show heavy Enterococcus colonization. Surgical culture results reveal moderate Escherichia coli, moderate Enterococcus, light Staphylococcus epidermidis, heavy bacteroides, and moderate Lactobacillus. All are susceptible to the piperacillin/tazobactam.

The patient does well and is successfully switched to oral amoxicillin/clavulanate (Augmentin) with no recurrent fever and continued healing of vaginal ulcers. She is sent home to continue to heal.

One week later, the patient is seen in follow-up with continued healing and no further lesions. A few months later, the patient has healed completely and no other lesions have occurred. Incidental discussions included recent menarche. The family physician, patient, and patient’s family do a final review of all clinical and pathological findings.

The pathology report shows inflammation and necrosis. In addition, the vulvar biopsy reveals “multiple hair follicles adjacent to the inflammation and necrosis, raising the possibility of infected hair follicles and pilonidal disease.”

Unlike the implications with the presumed Behçet’s, the patient’s localized disease process has no long-term health consequences. She is discharged with a diagnosis of labial ulcers with cellulitis, resolved urinary retention, and a pathological diagnosis of pilonidal disease.

Pilonidal disease

Pilonidal disease, this patient’s final diagnosis, is more common than Behçet’s disease. Men are affected more often than women, and ages range from puberty to the third decade of life with decreased frequency after the age of 45.

Pilonidal disease becomes a problem when “nests of hair” become infected. It is mostly found in the natal cleft but can present in almost any hairy area, mostly in the midline. Other examples include the umbilicus and scalp. There are also reports of acquired pilonidal disease from trauma in the hands of barbers, hair dressers, sheep shearers, and animal groomers. It is important to distinguish pilonidal disease from other disorders in the same region, such as anal fistulas, perirectal abscesses, and hidradenitis suppurativa.

Recurrences of pilonidal disease are quite common, with painful inflamed masses, abscesses, or sinus tracts. An acute abscess must be incised and drained. Hair removal by laser may prevent the growth of hair temporarily. For recurring infections, the definitive treatment is surgical. Procedures range from simple incision and curettage to excision of the area with plastic flap reconstruction. Antibiotics are not routinely needed, but they may be appropriate when cultures indicate specific microbes, when significant cellulitis is present, or for perioperative prophylaxis.

Could it be hidradenitis suppurativa?

Hidradenitis suppurativa is a possibility, but the clinical and pathological findings make pilonidal disease more likely. Hidradenitis suppurativa similar to pilonidal disease, but it usually is located in the axillary, perineal, or inguinal areas. Incidence is as high as 1 in 300, and it frequently begins with puberty.

Hidradenitis suppurativa differs from pilonidal disease in that the hair follicle becomes occluded due to a defect in the epithelium of the follicle’s terminal ends. This defect leads to trapping of bacteria and formation of firm, peasized nodules or cysts. Some associations between hidradenitis suppurativa and sex hormones have been proposed, but hormonal states of pregnancy, menstruation, and menopause have not shown clear association with hidradenitis suppurativa. Initial symptoms of hidradenitis suppurativa may be pruritus, erythema, and hyperhidrosis. Recurrences are common. Treatment includes medications such as antibiotics, antiandrogens, and retinoids, as well as surgical excision.

Acknowledgements

The author would like to thank Jessie Junker, MD, Albert Meyer, MD, and Barbara Walker, DO, at New Hanover Regional Medical Center, Residency in Family Medicine, Wilmington, NC; and Beth Deaton, FNP, at Wilmington Health Access for Teens, Wilmington, NC.

Conflict Of Interest

The author has no conflicts of interest to declare.

Other medical history

• Enuresis, recurrent perioral rash around age 7 with annual recurrences
• No chronic infections or illness
• Premenarchal
• Negative trauma history, including abuse
• Bike riding 2 days earlier but no falls
• Taking acyclovir as prescribed by ED; acetaminophen/ibuprofen for fever
• No known allergies

Family and social history

• Parents alive and well; no siblings
• Straight-A student
• Involved in JROTC (was on a retreat 2 weeks ago)
• No use of tobacco, alcohol, street drugs, or suspicious substances
• Denies any sexual activity

Physical examination

• Review of systems: Positive for chills, fever, dysuria, and perineal pain; otherwise negative
• Temperature 101.6°F, pulse 112, respiratory rate 22, blood pressure 110/70 mm Hg, weight 94 lb
• Alert female in no distress, normal neurologic exam
• HEENT: normal exam with clear oropharynx without lesions
• Skin/integument: no rashes, including arms, legs, hands, feet, and trunk
• Heart, lungs, and abdomen: tachycardia, otherwise normal
• Reproductive examination (chaperone present): Tanner stage III; perineal edema with marked purple ecchymoses located bilaterally at posterior introitus; multiple lacerations also noted as well as tenderness; some scabbed areas noted; no periurethral or perianal lesions or bruising; no vaginal discharge; speculum and bimanual exam were deferred due to pain.

You are concerned about abuse. You interview the patient alone and she again denies any type of sexual encounter. She has never used tampons. She does report that she is a heavy sleeper and that she recently went on a retreat where she and a girlfriend slept in the same room. As far as she knows, there was no intruder. She tearfully says, “If anything happened, I can’t remember.”

You also interview the father alone. He says he and his wife “keep a tight rein” on their daughter. She has been out of their supervision only for the recent retreat. He is concerned that his daughter may have been given a “date-rape” drug and requests testing. His demeanor seems appropriate during the conversations both in the presence and absence of his daughter.

According to state law, you notify the Department of Social Services of unexplained perineal trauma. You also contact the local sexual abuse/rape experts in your area, who have arranged for an evaluation the following day. The father assists in making the arrangements for the evaluation while he is still in your office.

Department of Social Services forensic interview and medical examination

The next day, the patient and her family undergo a comprehensive evaluation by local medical and investigative professionals from the Department of Social Services.

The differential diagnosis for genital ulcers in a sexually inexperienced female includes sexual abuse, herpes simplex virus, Behçet’s disease, Epstein Barr infection, pilonidal disease, Crohn’s disease, and hidradenitis suppurativa. Definitive diagnosis can be difficult (TABLE 1).

One retrospective series reviewed the case of 9 adolescent females with vulvar ulcers and found that 6 had no formal diagnosis. Most important, the initial presentation should prompt healthcare professionals to take steps to ensure a patient’s safety.

After performing a physical examination, the abuse experts report that the patient’s presentation is consistent with Behçet’s disease. A genital culture was obtained, and the patient was given pain medication and azithromycin.

The expert also stated that the father’s reaction to the situation was appropriate and not that of an abusive father. Most perpetrators are very hostile and defensive, whereas this father was extremely concerned and cooperative. Still, a report to Child Protective Services had to be made because of the unexplained physical findings, especially in the genital area.

Further consideration

Additional information on Behçet’s disease is found in an article in the New England Journal of Medicine from 1999: “Behçet’s disease is an inflammatory disorder of unknown cause, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions.”

You ponder this information and note that your patient has no oral lesions currently but apparently has a history of some oral lesions. You review your records indicating a history of recurrent perioral rash but do not find a history of oral lesions. However, the consultant remains constant in his diagnosis.

You review the results of the ED laboratory evaluation:

• Gonorrhea/chlamydia DNA probe negative
• Herpes culture and herpes immunoglobulin M (IgM) negative
• Rapid plasma reagin (RPR) nonreactive
• Serum pregnancy negative
• Urine drug screen negative for PCP, benzodiazepines, amphetamines, THC, opiates, barbiturates, methadone, tricyclic antidepressants
• Complete blood count normal; white blood count 9600 with a normal differential

As the family physician, you interpret these results and support the clinical plan for this patient, pending further changes in the clinical picture.

TABLE 1

Differential diagnosis of vulvar ulcers in sexually inexperienced females

Next contact—ED visit 2 days later

The patient’s vaginal pain is worsening and she cannot void. Large ulcers with adhered pus are on the left labia; a smaller lesion is on the right labia. There are also questionable lacerations of the posterior fourchette. She is catheterized and 300 mL urine is emptied from the bladder. A gynecology consultation is obtained by the ED physician with your concurrence.

Details of Behçet’s disease

Behçet’s disease is most common in the third or fourth decade of life. It has an association with the human leukocyte antigen HLA-B51 and HLA-B5 allele. Vascular injuries, hyperfunction of neutrophils, and autoimmune responses lead to the clinical findings. Behçet’s disease is presumed to be an autoimmune disease, with the primary lesion being related to the vasculitis.

Clinical criteria of Behçet’s

Diagnosis of Behçet’s disease is based on clinical criteria. No single test can determine if a patient has Behçet’s.

An International Study Group of physicians was convened to develop a set of guidelines to diagnose Behçet’s disease. These criteria include recurrent, painful oral ulceration with at least 2 other symptoms (recurrent genital ulcers, eye lesions, skin lesions, and positive pathergy test) (TABLE 2). These diagnostic criteria may be accessed at the website of the American Behçet’s Disease Association, www.behcets.com.

Prevalence of signs

Oral ulcerations are the presenting signs in about 70% of cases. These ulcers may remain for as long as 3 weeks. In women, the genital lesions are often present in the vulvovaginal region; in men, they often appear in the scrotal area. Ocular complaints occur in about one-half of patients, sometimes with photophobia, watering, and blurred vision. The most common skin lesions are pseudofolliculitis and erythema nodosum.

The pathergy test uses a sterile needle to make a skin prick. The test result is positive if an aseptic erythematous nodule or pustule (>2 mm in diameter) occurs within 24 to 48 hours, indicating neutrophil hyperfunction.

Differential diagnosis

Skin, joint, gastrointestinal, vascular, and central nervous systems may also be involved. The differential diagnosis includes chronic oral aphthosis, herpes simplex virus infection, Sweet’s syndrome, ankylosing spondylitis, inflammatory bowel disease, and multiple sclerosis (TABLE 3).

Laboratory findings and treatment

Examination of the blood can reveal nonspecific findings consistent with inflammation, including elevated C-reactive protein, erythrocyte sedimentation rate, and positive markers for autoimmune diseases.

Treatmentdepends upon the particular symptoms and clinical findings and must be coordinated with the various specialists involved.

Topical steroids are used for oral and genital ulcers as well as ocular lesions.

Oral steroids are useful for gastrointestinal and neurological symptoms but may also help with skin, joint, vascular, and ocular symptoms.

Colchicine may help alleviate oral and genital ulcers as well as skin, ocular, and joint problems.

Topical tetracycline may be used to treat oral ulcers.

Anticoagulants may be indicated for vascular disturbances and progressive central nervous system lesions.

Cytotoxic and antirheumatic agents may treat vascular, ocular, neurological, and joint manifestations.

TABLE 2

Diagnostic criteria of Behçet’s disease

TABLE 3

Differential diagnosis of Behçet’s disease

Gynecology consultation

The gynecologist recommends that the patient be admitted to the hospital for examination under anesthesia. This examination found an ulcerated area of perineum, cellulitis, and edema, without a palpable abscess. Necrotic tissue is debrided.

Biopsies are obtained for herpes, aerobic, and anaerobic cultures. Repeat gonorrhea and chlamydia polymerase chain reaction (PCR) probes are obtained as well. The patient is started on ampicillin/sulbactam (Unasyn) after the debridement.

Further laboratory testing is also done at admission, including a throat culture, cryoglobulin, hepatitis screen, antinuclear antibody (ANA), HIV, lupus anticoagulant, cardiolipin, herpes IgG, antithrombin III level, immune complex detection panel for C1q, and tissue transgluttin AB4 IgA. All results are negative. A possible rheumatology consultation is also discussed.

Culture results from the previous sexual abuse evaluation show strep and gramnegative rods. Initial cultures from exam under anesthesia reveal grampositive cocci, grampositive rods, and gramnegative rods on the Gram’s stain with final report pending. An infectious disease consultation is recommended. The family physician agreed.

Infectious disease consultation

The consultant believes streptococcal infection is the most likely culprit and recommends changing the IV antibiotic from ampicillin/sulbactam to piperacillin/tazobactam (Zosyn) with the addition of clindamycin for broad-spectrum coverage. Later, the final culture results from the sexual abuse evaluation show heavy Enterococcus colonization. Surgical culture results reveal moderate Escherichia coli, moderate Enterococcus, light Staphylococcus epidermidis, heavy bacteroides, and moderate Lactobacillus. All are susceptible to the piperacillin/tazobactam.

The patient does well and is successfully switched to oral amoxicillin/clavulanate (Augmentin) with no recurrent fever and continued healing of vaginal ulcers. She is sent home to continue to heal.

One week later, the patient is seen in follow-up with continued healing and no further lesions. A few months later, the patient has healed completely and no other lesions have occurred. Incidental discussions included recent menarche. The family physician, patient, and patient’s family do a final review of all clinical and pathological findings.

The pathology report shows inflammation and necrosis. In addition, the vulvar biopsy reveals “multiple hair follicles adjacent to the inflammation and necrosis, raising the possibility of infected hair follicles and pilonidal disease.”

Unlike the implications with the presumed Behçet’s, the patient’s localized disease process has no long-term health consequences. She is discharged with a diagnosis of labial ulcers with cellulitis, resolved urinary retention, and a pathological diagnosis of pilonidal disease.

Pilonidal disease

Pilonidal disease, this patient’s final diagnosis, is more common than Behçet’s disease. Men are affected more often than women, and ages range from puberty to the third decade of life with decreased frequency after the age of 45.

Pilonidal disease becomes a problem when “nests of hair” become infected. It is mostly found in the natal cleft but can present in almost any hairy area, mostly in the midline. Other examples include the umbilicus and scalp. There are also reports of acquired pilonidal disease from trauma in the hands of barbers, hair dressers, sheep shearers, and animal groomers. It is important to distinguish pilonidal disease from other disorders in the same region, such as anal fistulas, perirectal abscesses, and hidradenitis suppurativa.

Recurrences of pilonidal disease are quite common, with painful inflamed masses, abscesses, or sinus tracts. An acute abscess must be incised and drained. Hair removal by laser may prevent the growth of hair temporarily. For recurring infections, the definitive treatment is surgical. Procedures range from simple incision and curettage to excision of the area with plastic flap reconstruction. Antibiotics are not routinely needed, but they may be appropriate when cultures indicate specific microbes, when significant cellulitis is present, or for perioperative prophylaxis.

Could it be hidradenitis suppurativa?

Hidradenitis suppurativa is a possibility, but the clinical and pathological findings make pilonidal disease more likely. Hidradenitis suppurativa similar to pilonidal disease, but it usually is located in the axillary, perineal, or inguinal areas. Incidence is as high as 1 in 300, and it frequently begins with puberty.

Hidradenitis suppurativa differs from pilonidal disease in that the hair follicle becomes occluded due to a defect in the epithelium of the follicle’s terminal ends. This defect leads to trapping of bacteria and formation of firm, peasized nodules or cysts. Some associations between hidradenitis suppurativa and sex hormones have been proposed, but hormonal states of pregnancy, menstruation, and menopause have not shown clear association with hidradenitis suppurativa. Initial symptoms of hidradenitis suppurativa may be pruritus, erythema, and hyperhidrosis. Recurrences are common. Treatment includes medications such as antibiotics, antiandrogens, and retinoids, as well as surgical excision.

Acknowledgements

The author would like to thank Jessie Junker, MD, Albert Meyer, MD, and Barbara Walker, DO, at New Hanover Regional Medical Center, Residency in Family Medicine, Wilmington, NC; and Beth Deaton, FNP, at Wilmington Health Access for Teens, Wilmington, NC.

Conflict Of Interest

The author has no conflicts of interest to declare.

Other medical history

• Diabetes mellitus type II
• Diabetic retinopathy
• Hypertension
• Erectile dysfunction
• Obesity
• Pes planus

Family history

• Diabetes and hypertension in father and paternal grandmother. Father had 2 myocardial infarctions and died at age 62. Mother is healthy. Sister has borderline diabetes.

Social history

• Nonsmoker
• 4 to 5 beers per week
• Divorced
• Works as a baker

Review of systems

• Negative except for increased swelling of right foot

Physical exam

• Alert male in no distress
• Blood pressure 135/68 mm Hg, temperature 37.5 °C, respiratory rate 14, heart rate 80, weight 236 pounds
• Heart, lung, and abdominal exam unremarkable
• Right 3rd toe has erythema at the metatarsophalangeal joint, with a draining ulcer on the plantar surface. Foot is edematous with erythema spreading proximally toward lower extremity. Erythema is <2 cm from ulcer rim. Pedal pulses are 1+, and capillary refill is <2 seconds. Monofilament testing reveals insensitivity at more than 4 sites.

Important elements of the history and exam

Assess vascular integrity. Arterial insufficiency is suggested by a history of cardiac or cerebrovascular disease, leg claudication, impotence, or pain in the distal foot when the patient is supine. Exam may reveal diminished or absent pulses, pallor on elevation, redness of the foot on lowering the leg, delayed capillary refill in toes, and thickened nails or absence of toe hair. With diabetes or renal impairment, the pulse exam may be unreliable due to arterial calcification.

Helpful studies may include segmental limb pressures, pulse-volume wave form, transcutaneous oxygen pressure, and ankle brachial index (which can be normal with significant calcinosis). Obtain a vascular surgery consultation immediately if you suspect arterial insufficiency, as revascularization may be necessary.¹

Evaluate for musculoskeletal problems. Examine gait, look for foot deformities, and test joint range of motion. If a mechanical basis of the ulceration is found, eliminate or reduce foot pressure with shoes, inserts, orthoses, etc. Reconstructive foot surgery may be an option for some patients.

Gauge neurologic status. Most foot ulcers develop because of loss of protective sensation; therefore, screen all patients with diabetes annually for loss of protective sensation, using a 10-g nylon monofilament. Press the monofilament against the plantar skin until it buckles, hold it there for 1 second, and remove it.² The neurologic exam can also include testing for motor strength, deeptendon reflexes, and vibratory (128-Hz tuning fork), proprioceptive, and protective sensation.

Measure the wound, watch for infection. When examining an ulcer, assess location, size, and depth. When caring for wounds, document at each visit the length and width of the wound.³ Note any signs of infection (warmth, redness, pain, tenderness, induration, pus) or gangrene. Observe for fever, chills, and leukocytosis, but do not rely on systemic symptoms as indicators of infection. Assess the severity of infection, and explore the wound for foreign or necrotic material with a sterile metal instrument.

Examine toenails for fungal infection, as this may be a significant contributor to the initiation and continuation of a foot ulcer. Callus formation, especially with hemorrhage, may be evidence of an impending ulcer.³

M.N.’s physician was increasingly concerned about the lack of healing of his ulcer. The differential diagnosis for this patient’s swollen foot includes cellulitis, osteomyelitis, gout, foreign body, arthritis, trauma, deep venous thrombosis, pseudogout, and venous insufficiency. Many of these were excluded by the physical exam. A bone scan was ordered.

Referral to plastic surgeon

When M.N. returns to the clinic with worsening drainage, edema, and spreading erythema, the decision is made to admit him to the hospital, start intravenous ampicillin/sulbactam (Unasyn) and ciprofloxacin (Cipro), and consult with a plastic surgeon.

Following the examination and review of the bone scan results, which show osteomyelitis, the surgeon recommends surgical therapy of the affected toe. He advocates aggressive debridement, and also thinks that this wound could require a staged surgical approach or amputation.

Further primary care evaluation

Laboratory:

• Complete blood count, normal
• Erythrocyte sedimentation rate (ESR), 38
• C-reactive protein (CRP), 2.1
• Lipid panel: HDL 32 mg/dL, LDL 96 mg/dL, triglycerides 116 mg/dL
• Hemoglobin A1c, 6.0

Details of foot ulcers

Statistics

About 50% to 60% of serious foot infections are complicated by osteomyelitis, and 10% to 20% of mild to moderate infections likely involve the bone. Twenty-five percent of foot infections in persons with diabetes will spread to subcutaneous tissues or bone. Up to 50% of those with a foot infection will experience a recurrence within a few years.² Approximately 10% to 30% with a diabetic foot ulcer will eventually require amputation. Infected foot ulcers precede 60% of amputations. Two thirds of patients with a diabetic foot ulcer have peripheral vascular disease, and 80% have lost protective sensation. Infections most commonly involve the forefoot, usually plantar surface.²

Pathophysiology

Ulcers develop from breaks in the dermal barrier with subsequent erosion of subcutaneous tissue. Healing is inhibited when wound-repair mechanisms are corrupted by impaired perfusion, infection, or repeated trauma. Ulceration progresses due to impaired arterial supply, neuropathy, or musculoskeletal deformities.¹

Risk of ulceration correlates with number of risk factors. The risk is increased by 1.7 in persons with isolated peripheral neuropathy (TABLE 1), by 12 in those with neuropathy and foot deformity, and by 36 in those with peripheral neuropathy, deformity, and previous amputation.¹

Pathology usually mixed. The feet have sensory and motor neuropathies that cause the patient to put abnormal stresses on them, resulting in trauma that may lead to infection. Immunologic impairment due to hyperglycemia also plays a role; this can include reduced function of neutrophils, monocytes, and complement. Skin and nail disorders are more common among persons with diabetes than in the general population, and these may also increase the rate of infection.²

TABLE 1

Risk factors predisposing to foot ulcers and inhibiting healing

Management of ulcers

Optimal management should involve a multidisciplinary group of consultants. Mechanical debridement, systemic antibiotic therapy, and measures to reduce weight bearing are the main elements of effective care. Foot soaks and whirlpool therapy may be detrimental and lead to further skin breakdown, but moist dressings on granulating wounds may help.

Debridement a must. Remove nonviable, infected tissue to achieve a border of healthy, bleeding soft tissue and uninfected bone. Debridement improves the outcome of foot ulcers.³

When hospitalization is indicated. Determine whether or not the patient requires hospitalization based on the presence of a severe infection (TABLE 2) and need for surgical intervention, fluid resuscitation, IV antibiotics, or control of metabolic derangements.² Consider hospitalization also if there is concern about the patient’s ability or willingness to comply with wound care, antibiotic therapy, or off-loading of the affected area.

Consider need for off-loading. Most diabetic wounds develop because of unperceived trauma, and likely do not heal because of ongoing trauma. Total contact casting, whereby loading levels to a foot ulcer are drastically reduced, has been shown to be effective in healing ulcers in about 6 weeks.⁴ This suggests that healing of neuropathic ulcers must include mechanical off-loading of the ulcer. Total contact casting has several limitations, and new modalities are being investigated.⁵

Obtain cultures. Wound culture results can greatly assist in determining appropriate antimicrobials. Gram stain can help direct therapy, and culture results are consistent with Gram staining in 95% of cases. Gram-stained smear is 70% sensitive for identifying organisms that grow on culture, and is much better for gram-positive organisms than for gram-negative bacilli.

Deep tissue specimens collected aseptically at surgery contain the true pathogens more often than more superficial samples. Curettage, involving tissue scraping with a scalpel from the base of a debrided ulcer, is more accurate than a wound swab. Wound swabs are likely to miss key pathogens as well as include nonpathogenic bacteria that confuse the antibiotic choice.²

When antibiotics are needed. In gross infections and cellulitis, topical antibiotics may reduce bacterial loads, but there are few published data about their efficacy in diabetic foot infections. The Wagner ulcer grading system (TABLE 3) is most widely used for tracking diabetic foot ulcers, but it does not allow for identification of superficial infection and has not been validated as an effective tool.⁶ An alternate method of classifying foot ulcers, taken from Lipsky et al, is shown in TABLE 4.

Currently systemic antibiotics are recommended only for established infection, although one study suggested that antibiotic therapy in clinically uninfected foot ulcers may significantly improve healing.⁷

Optimal duration of antibiotic therapy has not been studied, but convention has found 1 to 2 weeks to be effective for mild to moderate infections, at least 2 weeks for serious infections, and at least 6 weeks for osteomyelitis.²

Oral antibiotics are indicated when the ulcer is believed to be infected, and they should cover the usual pathogens, streptococci or staphylococci⁷ (TABLE 5). Treat severe infections with intravenous broad-spectrum antibiotics, covering for gramnegative and gram-positive aerobes and anaerobes.

Studies have shown similar therapeutic outcomes between high-dose oral fluoroquinolones and intravenous cephalosporin therapy. Oral fluoroquinolones cause fewer side effects and reduce hospitalizationrelated costs compared with cephalosporins, penicillinase-resistant penicillins, and vancomycin.⁸ Clindamycin or metronidazole may be added to fluoroquinolones to cover anaerobic organisms in severe or limb-threatening infections.⁹ One study found that patients treated with vancomycin had a greater rate of recurrence.⁵

Staphylococcus aureus is the most important pathogen in diabetic foot infections and may cause disease in isolation or as part of a mixed infection. Gram-negative rods, usually Enterobacteriaceae, are found in patients with chronic or previously treated infections. Pseudomonas species may be isolated from wounds that have been soaked or treated with wet dressings. Enterococci are more likely to be cultured from patients previously treated with a cephalosporin. Suspect anaerobes in cases of ischemic necrosis or deep tissue infections.²

When a person with diabetes has peripheral vascular disease, therapeutic antibiotic concentrations are often not achieved in infected tissues even with adequate serum levels.² Novel methods of antibiotic delivery are being experimented with in an effort to solve this problem.

Surgery. Surgical options may include plastic reconstruction involving debridement and either primary closure or flap coverage. Optimally, vascular-bypass is performed to allow either primary healing or surgical reconstruction. If revascularization is not possible, amputation may be required.

If osteomyelitis complicates the picture. No validated or well-accepted guidelines exist for diagnosing or treating diabetic foot osteomyelitis. Factors that may suggest osteomyelitis: long-standing ulcers (>4 weeks), large (>2 cm) or deep ulcers (>3 mm), elevated ESR (>70 mm/h).²

Laboratory assays for diagnosing osteomyelitis can include measurements of erythrocyte sedimentation rate or C-reactive protein, though there are insufficient studies to assess their usefulness. One study found that 100% of patients with an ESR >70 mm/hr had osteomyelitis, despite lack of physical signs of inflammation. In diabetic patients with noninflamed foot ulcers, ESR can have a specificity of 100% and sensitivity of 28%. With inflamed ulcers, the sensitivity decreases to 23%.⁸ Some believe that the ESR can be used to follow osteomyelitis, and a persistent elevation or rise after initial fall would suggest osteomyelitis. Studies are inadequate to support this, however.⁵

Imaging for osteomyelitis can begin with plain films, which may show softtissue swelling, disruption of the bone cortex, and periosteal elevation. The American College of Radiology suggests this in the guidelines.¹⁰ However, 50% of the bone may be destroyed before these changes are evident. Plain films have a sensitivity of 28% to 100% and a specificity of 69% to 92%. If initial films yield normal results, it may be useful to repeat them in 2 to 4 weeks.⁹

MRI is highly sensitive (>90%) and specific (>80%), and may be even better with gadolinium. MRI is more sensitive for forefoot osteomyelitis than a leukocyte scan.¹¹ Positron-emission tomography (PET) scans and high-resolution ultrasound may be helpful in the future.

Some studies suggest probing of sinuses and deep ulcers may be more sensitive than imaging. Palpable bone found at the base of an ulcer, with no overlying soft tissue, is highly predictive of osteomyelitis.¹ Visible bone in a nontraumatic wound suggests osteomyelitis, with a sensitivity of 32% and specificity of 100%.¹² The gold standard for diagnosis of osteomyelitis is obtaining a specimen of bone for pathology and culture.⁹

Antibiotic choice should be based on bone culture, as soft-tissue or sinus tract cultures do not accurately predict bone pathogens. When empiric therapy is necessary, coverage should always include S aureus. Cure of osteomyelitis has traditionally been thought to require removal of infected bone, but studies are showing that antibiotics may be adequate in two thirds of cases, especially those with good bioavailability. When bone is removed, shorter antibiotic therapy may be sufficient.²

Additional treatment options may include revascularization in an ischemic foot, which has been shown to salvage up to 98% of limbs. Hyperbaric oxygen may provide benefit, but data are insufficient to document this measure. Edema control may be beneficial for wound healing. Promising adjuvant therapies include granulocyte colony-stimulating factor (G-CSF), antibiotic-impregnated beads or orthopedic implants, and “biosurgery” with fly larvae.²

TABLE 2

Clinical characteristics of a severe infection

TABLE 3

Wagner ulcer grading system

TABLE 4

Clinical classification of diabetic foot infections

Case resolution

The family physician and M.N. discuss the options. The specialist recommends surgery, but the patient does not want to undergo this procedure. As his physician explains his concerns about the chronic, nonhealing ulcer and osteomyelitis, M.N. says he will negotiate a change in his work situation that would allow him to decrease the time spent on his feet and thus improve healing.

The patient has small clinical improvement of his ulcer while hospitalized, and a peripherally inserted central catheter (PICC) line is placed to administer long-term antibiotics on an outpatient basis. The ulcer heals gradually in coming weeks and months. Laboratory results show improvement as well, with normalization of the ESR and CRP. Given the clinical improvement and a steady decrease in inflammatory markers, a bone scan is not repeated. The patient now has a job that allows him to sit instead of being on his feet all day.

Other medical history

• Diabetes mellitus type II
• Diabetic retinopathy
• Hypertension
• Erectile dysfunction
• Obesity
• Pes planus

Family history

• Diabetes and hypertension in father and paternal grandmother. Father had 2 myocardial infarctions and died at age 62. Mother is healthy. Sister has borderline diabetes.

Social history

• Nonsmoker
• 4 to 5 beers per week
• Divorced
• Works as a baker

Review of systems

• Negative except for increased swelling of right foot

Physical exam

• Alert male in no distress
• Blood pressure 135/68 mm Hg, temperature 37.5 °C, respiratory rate 14, heart rate 80, weight 236 pounds
• Heart, lung, and abdominal exam unremarkable
• Right 3rd toe has erythema at the metatarsophalangeal joint, with a draining ulcer on the plantar surface. Foot is edematous with erythema spreading proximally toward lower extremity. Erythema is <2 cm from ulcer rim. Pedal pulses are 1+, and capillary refill is <2 seconds. Monofilament testing reveals insensitivity at more than 4 sites.

Important elements of the history and exam

Assess vascular integrity. Arterial insufficiency is suggested by a history of cardiac or cerebrovascular disease, leg claudication, impotence, or pain in the distal foot when the patient is supine. Exam may reveal diminished or absent pulses, pallor on elevation, redness of the foot on lowering the leg, delayed capillary refill in toes, and thickened nails or absence of toe hair. With diabetes or renal impairment, the pulse exam may be unreliable due to arterial calcification.

Helpful studies may include segmental limb pressures, pulse-volume wave form, transcutaneous oxygen pressure, and ankle brachial index (which can be normal with significant calcinosis). Obtain a vascular surgery consultation immediately if you suspect arterial insufficiency, as revascularization may be necessary.¹

Evaluate for musculoskeletal problems. Examine gait, look for foot deformities, and test joint range of motion. If a mechanical basis of the ulceration is found, eliminate or reduce foot pressure with shoes, inserts, orthoses, etc. Reconstructive foot surgery may be an option for some patients.

Gauge neurologic status. Most foot ulcers develop because of loss of protective sensation; therefore, screen all patients with diabetes annually for loss of protective sensation, using a 10-g nylon monofilament. Press the monofilament against the plantar skin until it buckles, hold it there for 1 second, and remove it.² The neurologic exam can also include testing for motor strength, deeptendon reflexes, and vibratory (128-Hz tuning fork), proprioceptive, and protective sensation.

Measure the wound, watch for infection. When examining an ulcer, assess location, size, and depth. When caring for wounds, document at each visit the length and width of the wound.³ Note any signs of infection (warmth, redness, pain, tenderness, induration, pus) or gangrene. Observe for fever, chills, and leukocytosis, but do not rely on systemic symptoms as indicators of infection. Assess the severity of infection, and explore the wound for foreign or necrotic material with a sterile metal instrument.

Examine toenails for fungal infection, as this may be a significant contributor to the initiation and continuation of a foot ulcer. Callus formation, especially with hemorrhage, may be evidence of an impending ulcer.³

M.N.’s physician was increasingly concerned about the lack of healing of his ulcer. The differential diagnosis for this patient’s swollen foot includes cellulitis, osteomyelitis, gout, foreign body, arthritis, trauma, deep venous thrombosis, pseudogout, and venous insufficiency. Many of these were excluded by the physical exam. A bone scan was ordered.

Referral to plastic surgeon

When M.N. returns to the clinic with worsening drainage, edema, and spreading erythema, the decision is made to admit him to the hospital, start intravenous ampicillin/sulbactam (Unasyn) and ciprofloxacin (Cipro), and consult with a plastic surgeon.

Following the examination and review of the bone scan results, which show osteomyelitis, the surgeon recommends surgical therapy of the affected toe. He advocates aggressive debridement, and also thinks that this wound could require a staged surgical approach or amputation.

Further primary care evaluation

Laboratory:

• Complete blood count, normal
• Erythrocyte sedimentation rate (ESR), 38
• C-reactive protein (CRP), 2.1
• Lipid panel: HDL 32 mg/dL, LDL 96 mg/dL, triglycerides 116 mg/dL
• Hemoglobin A1c, 6.0

Details of foot ulcers

Statistics

About 50% to 60% of serious foot infections are complicated by osteomyelitis, and 10% to 20% of mild to moderate infections likely involve the bone. Twenty-five percent of foot infections in persons with diabetes will spread to subcutaneous tissues or bone. Up to 50% of those with a foot infection will experience a recurrence within a few years.² Approximately 10% to 30% with a diabetic foot ulcer will eventually require amputation. Infected foot ulcers precede 60% of amputations. Two thirds of patients with a diabetic foot ulcer have peripheral vascular disease, and 80% have lost protective sensation. Infections most commonly involve the forefoot, usually plantar surface.²

Pathophysiology

Ulcers develop from breaks in the dermal barrier with subsequent erosion of subcutaneous tissue. Healing is inhibited when wound-repair mechanisms are corrupted by impaired perfusion, infection, or repeated trauma. Ulceration progresses due to impaired arterial supply, neuropathy, or musculoskeletal deformities.¹

Risk of ulceration correlates with number of risk factors. The risk is increased by 1.7 in persons with isolated peripheral neuropathy (TABLE 1), by 12 in those with neuropathy and foot deformity, and by 36 in those with peripheral neuropathy, deformity, and previous amputation.¹

Pathology usually mixed. The feet have sensory and motor neuropathies that cause the patient to put abnormal stresses on them, resulting in trauma that may lead to infection. Immunologic impairment due to hyperglycemia also plays a role; this can include reduced function of neutrophils, monocytes, and complement. Skin and nail disorders are more common among persons with diabetes than in the general population, and these may also increase the rate of infection.²

TABLE 1

Risk factors predisposing to foot ulcers and inhibiting healing

Management of ulcers

Optimal management should involve a multidisciplinary group of consultants. Mechanical debridement, systemic antibiotic therapy, and measures to reduce weight bearing are the main elements of effective care. Foot soaks and whirlpool therapy may be detrimental and lead to further skin breakdown, but moist dressings on granulating wounds may help.

Debridement a must. Remove nonviable, infected tissue to achieve a border of healthy, bleeding soft tissue and uninfected bone. Debridement improves the outcome of foot ulcers.³

When hospitalization is indicated. Determine whether or not the patient requires hospitalization based on the presence of a severe infection (TABLE 2) and need for surgical intervention, fluid resuscitation, IV antibiotics, or control of metabolic derangements.² Consider hospitalization also if there is concern about the patient’s ability or willingness to comply with wound care, antibiotic therapy, or off-loading of the affected area.

Consider need for off-loading. Most diabetic wounds develop because of unperceived trauma, and likely do not heal because of ongoing trauma. Total contact casting, whereby loading levels to a foot ulcer are drastically reduced, has been shown to be effective in healing ulcers in about 6 weeks.⁴ This suggests that healing of neuropathic ulcers must include mechanical off-loading of the ulcer. Total contact casting has several limitations, and new modalities are being investigated.⁵

Obtain cultures. Wound culture results can greatly assist in determining appropriate antimicrobials. Gram stain can help direct therapy, and culture results are consistent with Gram staining in 95% of cases. Gram-stained smear is 70% sensitive for identifying organisms that grow on culture, and is much better for gram-positive organisms than for gram-negative bacilli.

Deep tissue specimens collected aseptically at surgery contain the true pathogens more often than more superficial samples. Curettage, involving tissue scraping with a scalpel from the base of a debrided ulcer, is more accurate than a wound swab. Wound swabs are likely to miss key pathogens as well as include nonpathogenic bacteria that confuse the antibiotic choice.²

When antibiotics are needed. In gross infections and cellulitis, topical antibiotics may reduce bacterial loads, but there are few published data about their efficacy in diabetic foot infections. The Wagner ulcer grading system (TABLE 3) is most widely used for tracking diabetic foot ulcers, but it does not allow for identification of superficial infection and has not been validated as an effective tool.⁶ An alternate method of classifying foot ulcers, taken from Lipsky et al, is shown in TABLE 4.

Currently systemic antibiotics are recommended only for established infection, although one study suggested that antibiotic therapy in clinically uninfected foot ulcers may significantly improve healing.⁷

Optimal duration of antibiotic therapy has not been studied, but convention has found 1 to 2 weeks to be effective for mild to moderate infections, at least 2 weeks for serious infections, and at least 6 weeks for osteomyelitis.²

Oral antibiotics are indicated when the ulcer is believed to be infected, and they should cover the usual pathogens, streptococci or staphylococci⁷ (TABLE 5). Treat severe infections with intravenous broad-spectrum antibiotics, covering for gramnegative and gram-positive aerobes and anaerobes.

Studies have shown similar therapeutic outcomes between high-dose oral fluoroquinolones and intravenous cephalosporin therapy. Oral fluoroquinolones cause fewer side effects and reduce hospitalizationrelated costs compared with cephalosporins, penicillinase-resistant penicillins, and vancomycin.⁸ Clindamycin or metronidazole may be added to fluoroquinolones to cover anaerobic organisms in severe or limb-threatening infections.⁹ One study found that patients treated with vancomycin had a greater rate of recurrence.⁵

Staphylococcus aureus is the most important pathogen in diabetic foot infections and may cause disease in isolation or as part of a mixed infection. Gram-negative rods, usually Enterobacteriaceae, are found in patients with chronic or previously treated infections. Pseudomonas species may be isolated from wounds that have been soaked or treated with wet dressings. Enterococci are more likely to be cultured from patients previously treated with a cephalosporin. Suspect anaerobes in cases of ischemic necrosis or deep tissue infections.²

When a person with diabetes has peripheral vascular disease, therapeutic antibiotic concentrations are often not achieved in infected tissues even with adequate serum levels.² Novel methods of antibiotic delivery are being experimented with in an effort to solve this problem.

Surgery. Surgical options may include plastic reconstruction involving debridement and either primary closure or flap coverage. Optimally, vascular-bypass is performed to allow either primary healing or surgical reconstruction. If revascularization is not possible, amputation may be required.

If osteomyelitis complicates the picture. No validated or well-accepted guidelines exist for diagnosing or treating diabetic foot osteomyelitis. Factors that may suggest osteomyelitis: long-standing ulcers (>4 weeks), large (>2 cm) or deep ulcers (>3 mm), elevated ESR (>70 mm/h).²

Laboratory assays for diagnosing osteomyelitis can include measurements of erythrocyte sedimentation rate or C-reactive protein, though there are insufficient studies to assess their usefulness. One study found that 100% of patients with an ESR >70 mm/hr had osteomyelitis, despite lack of physical signs of inflammation. In diabetic patients with noninflamed foot ulcers, ESR can have a specificity of 100% and sensitivity of 28%. With inflamed ulcers, the sensitivity decreases to 23%.⁸ Some believe that the ESR can be used to follow osteomyelitis, and a persistent elevation or rise after initial fall would suggest osteomyelitis. Studies are inadequate to support this, however.⁵

Imaging for osteomyelitis can begin with plain films, which may show softtissue swelling, disruption of the bone cortex, and periosteal elevation. The American College of Radiology suggests this in the guidelines.¹⁰ However, 50% of the bone may be destroyed before these changes are evident. Plain films have a sensitivity of 28% to 100% and a specificity of 69% to 92%. If initial films yield normal results, it may be useful to repeat them in 2 to 4 weeks.⁹

MRI is highly sensitive (>90%) and specific (>80%), and may be even better with gadolinium. MRI is more sensitive for forefoot osteomyelitis than a leukocyte scan.¹¹ Positron-emission tomography (PET) scans and high-resolution ultrasound may be helpful in the future.

Some studies suggest probing of sinuses and deep ulcers may be more sensitive than imaging. Palpable bone found at the base of an ulcer, with no overlying soft tissue, is highly predictive of osteomyelitis.¹ Visible bone in a nontraumatic wound suggests osteomyelitis, with a sensitivity of 32% and specificity of 100%.¹² The gold standard for diagnosis of osteomyelitis is obtaining a specimen of bone for pathology and culture.⁹

Antibiotic choice should be based on bone culture, as soft-tissue or sinus tract cultures do not accurately predict bone pathogens. When empiric therapy is necessary, coverage should always include S aureus. Cure of osteomyelitis has traditionally been thought to require removal of infected bone, but studies are showing that antibiotics may be adequate in two thirds of cases, especially those with good bioavailability. When bone is removed, shorter antibiotic therapy may be sufficient.²

Additional treatment options may include revascularization in an ischemic foot, which has been shown to salvage up to 98% of limbs. Hyperbaric oxygen may provide benefit, but data are insufficient to document this measure. Edema control may be beneficial for wound healing. Promising adjuvant therapies include granulocyte colony-stimulating factor (G-CSF), antibiotic-impregnated beads or orthopedic implants, and “biosurgery” with fly larvae.²

TABLE 2

Clinical characteristics of a severe infection

TABLE 3

Wagner ulcer grading system

TABLE 4

Clinical classification of diabetic foot infections

Case resolution

The family physician and M.N. discuss the options. The specialist recommends surgery, but the patient does not want to undergo this procedure. As his physician explains his concerns about the chronic, nonhealing ulcer and osteomyelitis, M.N. says he will negotiate a change in his work situation that would allow him to decrease the time spent on his feet and thus improve healing.

The patient has small clinical improvement of his ulcer while hospitalized, and a peripherally inserted central catheter (PICC) line is placed to administer long-term antibiotics on an outpatient basis. The ulcer heals gradually in coming weeks and months. Laboratory results show improvement as well, with normalization of the ESR and CRP. Given the clinical improvement and a steady decrease in inflammatory markers, a bone scan is not repeated. The patient now has a job that allows him to sit instead of being on his feet all day.

Other medical history

• Diabetes mellitus type II
• Diabetic retinopathy
• Hypertension
• Erectile dysfunction
• Obesity
• Pes planus

Family history

• Diabetes and hypertension in father and paternal grandmother. Father had 2 myocardial infarctions and died at age 62. Mother is healthy. Sister has borderline diabetes.

Social history

• Nonsmoker
• 4 to 5 beers per week
• Divorced
• Works as a baker

Review of systems

• Negative except for increased swelling of right foot

Physical exam

• Alert male in no distress
• Blood pressure 135/68 mm Hg, temperature 37.5 °C, respiratory rate 14, heart rate 80, weight 236 pounds
• Heart, lung, and abdominal exam unremarkable
• Right 3rd toe has erythema at the metatarsophalangeal joint, with a draining ulcer on the plantar surface. Foot is edematous with erythema spreading proximally toward lower extremity. Erythema is <2 cm from ulcer rim. Pedal pulses are 1+, and capillary refill is <2 seconds. Monofilament testing reveals insensitivity at more than 4 sites.

Important elements of the history and exam

Assess vascular integrity. Arterial insufficiency is suggested by a history of cardiac or cerebrovascular disease, leg claudication, impotence, or pain in the distal foot when the patient is supine. Exam may reveal diminished or absent pulses, pallor on elevation, redness of the foot on lowering the leg, delayed capillary refill in toes, and thickened nails or absence of toe hair. With diabetes or renal impairment, the pulse exam may be unreliable due to arterial calcification.

Helpful studies may include segmental limb pressures, pulse-volume wave form, transcutaneous oxygen pressure, and ankle brachial index (which can be normal with significant calcinosis). Obtain a vascular surgery consultation immediately if you suspect arterial insufficiency, as revascularization may be necessary.¹

Evaluate for musculoskeletal problems. Examine gait, look for foot deformities, and test joint range of motion. If a mechanical basis of the ulceration is found, eliminate or reduce foot pressure with shoes, inserts, orthoses, etc. Reconstructive foot surgery may be an option for some patients.

Gauge neurologic status. Most foot ulcers develop because of loss of protective sensation; therefore, screen all patients with diabetes annually for loss of protective sensation, using a 10-g nylon monofilament. Press the monofilament against the plantar skin until it buckles, hold it there for 1 second, and remove it.² The neurologic exam can also include testing for motor strength, deeptendon reflexes, and vibratory (128-Hz tuning fork), proprioceptive, and protective sensation.

Measure the wound, watch for infection. When examining an ulcer, assess location, size, and depth. When caring for wounds, document at each visit the length and width of the wound.³ Note any signs of infection (warmth, redness, pain, tenderness, induration, pus) or gangrene. Observe for fever, chills, and leukocytosis, but do not rely on systemic symptoms as indicators of infection. Assess the severity of infection, and explore the wound for foreign or necrotic material with a sterile metal instrument.

Examine toenails for fungal infection, as this may be a significant contributor to the initiation and continuation of a foot ulcer. Callus formation, especially with hemorrhage, may be evidence of an impending ulcer.³

M.N.’s physician was increasingly concerned about the lack of healing of his ulcer. The differential diagnosis for this patient’s swollen foot includes cellulitis, osteomyelitis, gout, foreign body, arthritis, trauma, deep venous thrombosis, pseudogout, and venous insufficiency. Many of these were excluded by the physical exam. A bone scan was ordered.

Referral to plastic surgeon

When M.N. returns to the clinic with worsening drainage, edema, and spreading erythema, the decision is made to admit him to the hospital, start intravenous ampicillin/sulbactam (Unasyn) and ciprofloxacin (Cipro), and consult with a plastic surgeon.

Following the examination and review of the bone scan results, which show osteomyelitis, the surgeon recommends surgical therapy of the affected toe. He advocates aggressive debridement, and also thinks that this wound could require a staged surgical approach or amputation.

Further primary care evaluation

Laboratory:

• Complete blood count, normal
• Erythrocyte sedimentation rate (ESR), 38
• C-reactive protein (CRP), 2.1
• Lipid panel: HDL 32 mg/dL, LDL 96 mg/dL, triglycerides 116 mg/dL
• Hemoglobin A1c, 6.0

Details of foot ulcers

Statistics

About 50% to 60% of serious foot infections are complicated by osteomyelitis, and 10% to 20% of mild to moderate infections likely involve the bone. Twenty-five percent of foot infections in persons with diabetes will spread to subcutaneous tissues or bone. Up to 50% of those with a foot infection will experience a recurrence within a few years.² Approximately 10% to 30% with a diabetic foot ulcer will eventually require amputation. Infected foot ulcers precede 60% of amputations. Two thirds of patients with a diabetic foot ulcer have peripheral vascular disease, and 80% have lost protective sensation. Infections most commonly involve the forefoot, usually plantar surface.²

Pathophysiology

Ulcers develop from breaks in the dermal barrier with subsequent erosion of subcutaneous tissue. Healing is inhibited when wound-repair mechanisms are corrupted by impaired perfusion, infection, or repeated trauma. Ulceration progresses due to impaired arterial supply, neuropathy, or musculoskeletal deformities.¹

Risk of ulceration correlates with number of risk factors. The risk is increased by 1.7 in persons with isolated peripheral neuropathy (TABLE 1), by 12 in those with neuropathy and foot deformity, and by 36 in those with peripheral neuropathy, deformity, and previous amputation.¹

Pathology usually mixed. The feet have sensory and motor neuropathies that cause the patient to put abnormal stresses on them, resulting in trauma that may lead to infection. Immunologic impairment due to hyperglycemia also plays a role; this can include reduced function of neutrophils, monocytes, and complement. Skin and nail disorders are more common among persons with diabetes than in the general population, and these may also increase the rate of infection.²

TABLE 1

Risk factors predisposing to foot ulcers and inhibiting healing

Management of ulcers

Optimal management should involve a multidisciplinary group of consultants. Mechanical debridement, systemic antibiotic therapy, and measures to reduce weight bearing are the main elements of effective care. Foot soaks and whirlpool therapy may be detrimental and lead to further skin breakdown, but moist dressings on granulating wounds may help.

Debridement a must. Remove nonviable, infected tissue to achieve a border of healthy, bleeding soft tissue and uninfected bone. Debridement improves the outcome of foot ulcers.³

When hospitalization is indicated. Determine whether or not the patient requires hospitalization based on the presence of a severe infection (TABLE 2) and need for surgical intervention, fluid resuscitation, IV antibiotics, or control of metabolic derangements.² Consider hospitalization also if there is concern about the patient’s ability or willingness to comply with wound care, antibiotic therapy, or off-loading of the affected area.

Consider need for off-loading. Most diabetic wounds develop because of unperceived trauma, and likely do not heal because of ongoing trauma. Total contact casting, whereby loading levels to a foot ulcer are drastically reduced, has been shown to be effective in healing ulcers in about 6 weeks.⁴ This suggests that healing of neuropathic ulcers must include mechanical off-loading of the ulcer. Total contact casting has several limitations, and new modalities are being investigated.⁵

Obtain cultures. Wound culture results can greatly assist in determining appropriate antimicrobials. Gram stain can help direct therapy, and culture results are consistent with Gram staining in 95% of cases. Gram-stained smear is 70% sensitive for identifying organisms that grow on culture, and is much better for gram-positive organisms than for gram-negative bacilli.

Deep tissue specimens collected aseptically at surgery contain the true pathogens more often than more superficial samples. Curettage, involving tissue scraping with a scalpel from the base of a debrided ulcer, is more accurate than a wound swab. Wound swabs are likely to miss key pathogens as well as include nonpathogenic bacteria that confuse the antibiotic choice.²

When antibiotics are needed. In gross infections and cellulitis, topical antibiotics may reduce bacterial loads, but there are few published data about their efficacy in diabetic foot infections. The Wagner ulcer grading system (TABLE 3) is most widely used for tracking diabetic foot ulcers, but it does not allow for identification of superficial infection and has not been validated as an effective tool.⁶ An alternate method of classifying foot ulcers, taken from Lipsky et al, is shown in TABLE 4.

Currently systemic antibiotics are recommended only for established infection, although one study suggested that antibiotic therapy in clinically uninfected foot ulcers may significantly improve healing.⁷

Optimal duration of antibiotic therapy has not been studied, but convention has found 1 to 2 weeks to be effective for mild to moderate infections, at least 2 weeks for serious infections, and at least 6 weeks for osteomyelitis.²

Oral antibiotics are indicated when the ulcer is believed to be infected, and they should cover the usual pathogens, streptococci or staphylococci⁷ (TABLE 5). Treat severe infections with intravenous broad-spectrum antibiotics, covering for gramnegative and gram-positive aerobes and anaerobes.

Studies have shown similar therapeutic outcomes between high-dose oral fluoroquinolones and intravenous cephalosporin therapy. Oral fluoroquinolones cause fewer side effects and reduce hospitalizationrelated costs compared with cephalosporins, penicillinase-resistant penicillins, and vancomycin.⁸ Clindamycin or metronidazole may be added to fluoroquinolones to cover anaerobic organisms in severe or limb-threatening infections.⁹ One study found that patients treated with vancomycin had a greater rate of recurrence.⁵

Staphylococcus aureus is the most important pathogen in diabetic foot infections and may cause disease in isolation or as part of a mixed infection. Gram-negative rods, usually Enterobacteriaceae, are found in patients with chronic or previously treated infections. Pseudomonas species may be isolated from wounds that have been soaked or treated with wet dressings. Enterococci are more likely to be cultured from patients previously treated with a cephalosporin. Suspect anaerobes in cases of ischemic necrosis or deep tissue infections.²

When a person with diabetes has peripheral vascular disease, therapeutic antibiotic concentrations are often not achieved in infected tissues even with adequate serum levels.² Novel methods of antibiotic delivery are being experimented with in an effort to solve this problem.

Surgery. Surgical options may include plastic reconstruction involving debridement and either primary closure or flap coverage. Optimally, vascular-bypass is performed to allow either primary healing or surgical reconstruction. If revascularization is not possible, amputation may be required.

If osteomyelitis complicates the picture. No validated or well-accepted guidelines exist for diagnosing or treating diabetic foot osteomyelitis. Factors that may suggest osteomyelitis: long-standing ulcers (>4 weeks), large (>2 cm) or deep ulcers (>3 mm), elevated ESR (>70 mm/h).²

Laboratory assays for diagnosing osteomyelitis can include measurements of erythrocyte sedimentation rate or C-reactive protein, though there are insufficient studies to assess their usefulness. One study found that 100% of patients with an ESR >70 mm/hr had osteomyelitis, despite lack of physical signs of inflammation. In diabetic patients with noninflamed foot ulcers, ESR can have a specificity of 100% and sensitivity of 28%. With inflamed ulcers, the sensitivity decreases to 23%.⁸ Some believe that the ESR can be used to follow osteomyelitis, and a persistent elevation or rise after initial fall would suggest osteomyelitis. Studies are inadequate to support this, however.⁵

Imaging for osteomyelitis can begin with plain films, which may show softtissue swelling, disruption of the bone cortex, and periosteal elevation. The American College of Radiology suggests this in the guidelines.¹⁰ However, 50% of the bone may be destroyed before these changes are evident. Plain films have a sensitivity of 28% to 100% and a specificity of 69% to 92%. If initial films yield normal results, it may be useful to repeat them in 2 to 4 weeks.⁹

MRI is highly sensitive (>90%) and specific (>80%), and may be even better with gadolinium. MRI is more sensitive for forefoot osteomyelitis than a leukocyte scan.¹¹ Positron-emission tomography (PET) scans and high-resolution ultrasound may be helpful in the future.

Some studies suggest probing of sinuses and deep ulcers may be more sensitive than imaging. Palpable bone found at the base of an ulcer, with no overlying soft tissue, is highly predictive of osteomyelitis.¹ Visible bone in a nontraumatic wound suggests osteomyelitis, with a sensitivity of 32% and specificity of 100%.¹² The gold standard for diagnosis of osteomyelitis is obtaining a specimen of bone for pathology and culture.⁹

Antibiotic choice should be based on bone culture, as soft-tissue or sinus tract cultures do not accurately predict bone pathogens. When empiric therapy is necessary, coverage should always include S aureus. Cure of osteomyelitis has traditionally been thought to require removal of infected bone, but studies are showing that antibiotics may be adequate in two thirds of cases, especially those with good bioavailability. When bone is removed, shorter antibiotic therapy may be sufficient.²

Additional treatment options may include revascularization in an ischemic foot, which has been shown to salvage up to 98% of limbs. Hyperbaric oxygen may provide benefit, but data are insufficient to document this measure. Edema control may be beneficial for wound healing. Promising adjuvant therapies include granulocyte colony-stimulating factor (G-CSF), antibiotic-impregnated beads or orthopedic implants, and “biosurgery” with fly larvae.²

TABLE 2

Clinical characteristics of a severe infection

TABLE 3

Wagner ulcer grading system

TABLE 4

Clinical classification of diabetic foot infections

Case resolution

The family physician and M.N. discuss the options. The specialist recommends surgery, but the patient does not want to undergo this procedure. As his physician explains his concerns about the chronic, nonhealing ulcer and osteomyelitis, M.N. says he will negotiate a change in his work situation that would allow him to decrease the time spent on his feet and thus improve healing.

The patient has small clinical improvement of his ulcer while hospitalized, and a peripherally inserted central catheter (PICC) line is placed to administer long-term antibiotics on an outpatient basis. The ulcer heals gradually in coming weeks and months. Laboratory results show improvement as well, with normalization of the ESR and CRP. Given the clinical improvement and a steady decrease in inflammatory markers, a bone scan is not repeated. The patient now has a job that allows him to sit instead of being on his feet all day.