CASE When Joan C, a 35-year-old patient whom you’ve known for years, comes in for a physical, you notice that she’s coughing frequently. Upon questioning, Joan says she first noticed the cough several months ago; she also reports that she’s frequently hoarse, but has no other symptoms. Joan is a former smoker, and quit 4 years ago.

If Joan were your patient, would you suspect that she had an upper respiratory infection and prescribe an antibiotic such as azithromycin? Would you include laryngopharyngeal reflux disease in the differential diagnosis?

Laryngopharyngeal reflux disease (LPRD) is a common condition that most primary care physicians encounter frequently. It is also frequently misdiagnosed by clinicians who are unfamiliar with the differences between LPRD and gastroesophageal reflux disease (GERD).

The American Academy of Otolaryngology–Head and Neck Surgery defines laryngopharyngeal reflux as the retrograde movement of gastric contents into the laryngopharynx.¹ Common symptoms include hoarseness/dysphonia, chronic throat clearing, dysphagia, globus pharyngeus, and chronic cough, as well as postnasal drip, paroxysmal laryngospasm, odynophagia, excessive throat mucus, and a strange taste in the mouth.²

The diversity and vagueness of these symptoms, as well as the lack of a gold standard diagnostic test for LPRD, make it difficult to estimate its prevalence. In addition, signs of gastroesophageal reflux can be found in the laryngopharynx of up to 86% of healthy individuals, further complicating the clinical picture.³ To avoid missing this often overlooked reflux disease, you need to know how it develops, what signs and symptoms to look for, and which distinguishing features to keep in mind.

Pathophysiology and distinguishing features

The precise way in which LPRD develops is not known, but there are 2 proposed means of laryngeal injury—direct and indirect. In the first case, chemical irritants in the gastric refluxate enter the laryngopharynx and cause local mucosal injury. In the second, gastric reflux irritates the esophageal tissue enough to evoke laryngeal reflexes without ever reaching the larynx—a vagally mediated response associated with symptoms such as chronic cough, throat-clearing sensations, and bronchoconstriction.⁴

Unlike the esophageal lining, laryngeal epithelium is not protected against chemical injury from gastric acid, as it lacks both the stripping motion of esophageal peristalsis and the neutralizing bicarbonate in saliva.⁴ Thus, while far smaller amounts of gastric reflux make it into the laryngopharynx, the acid remains there longer and may cause greater injury.⁵ In some cases, this occurs as often as 50 times a day, although as few as 3 episodes per week have been known to cause LPRD.⁵

Heartburn is not the rule
Heartburn is a primary complaint of patients with GERD. It is reported by little more than a third (35%) of those with LPRD,^5,6 however, (which is why it is sometimes called the “silent” reflux disease). This is because heartburn is caused by esophagitis due to esophageal dysmotility and lower esophageal sphincter dysfunction,³ while most patients with LPRD have normal esophageal motor function and upper esophageal sphincter dysfunction. The fact that only a minimal amount of reflux enters the laryngopharynx may be part of the reason heartburn is less likely in patients with LPRD.

Onset of symptoms. When reflux occurs is another thing that distinguishes LPRD and GERD. Symptoms of GERD typically worsen when the individual is supine, while laryngopharyngeal reflux usually occurs when he or she is upright.⁷ The frequency with which these 2 conditions overlap is debatable, as there are few studies differentiating LPRD and GERD based on standardized signs and symptoms.⁷

Making sense of signs and symptoms

Most patients with LPRD seek treatment from their primary care physician, typically reporting symptoms that they don’t associate with gastric reflux, such as hoarseness, a chronic cough or sore throat, or the sensation of a lump in the throat (TABLE 1). Less common manifestations include “water brash”—excessive mucus in the mouth caused by a release of salivary bicarbonate to help neutralize acidity⁸—otitis media, sinus disease, and dental caries.⁵

Laryngeal endoscopy may reveal many changes from diffuse irritation. Diffuse erythema, edema, and interarytenoid hypertrophy/cobblestoning are the most useful findings for an LPRD diagnosis.^9,10 But in most cases, only a few nonspecific signs with a number of possible causes (infection, environmental irritants, allergies, temperature/climate change, among others) are seen on endoscopic examination, with little correlation with symptom severity. In fact, 74% of otolaryngologists responding to a recent survey said they relied more on patient symptoms than on laryngeal signs for an LPRD diagnosis.¹⁰

The Reflux Finding Score (RFS), available at http://www.nature.com/gimo/contents/pt1/fig_tab/gimo46_T3.html, is a clinical tool developed to quantify laryngeal inflammation and standardize objective endoscopic findings. The RFS incorporates the following endolaryngeal signs:

• subglottic edema
• ventricular obliteration
• erythema/hyperemia
• vocal cord edema
• diffuse laryngeal edema
• posterior commissure hypertrophy
• granuloma/granulation tissue
• thick endolaryngeal mucus.

A numeric value is assigned to each, based on whether it is present or absent; partial or complete; local or diffuse; or mild or severe. However, the RFS, too, is an imperfect tool. Clinicians who have used the RFS report that a score higher than 7 identifies LPRD with 95% sensitivity.¹¹ But laryngeal findings may be due to other causes, such as infection, autoimmune reaction, or even allergies, and studies have found the RFS to have poor specificity and inter-rater reliability.^12-14

Ambulatory dual probe pH monitoring was considered to be the gold standard test for LPRD at one time, but newer studies have raised questions about its validity and usefulness, especially in patients taking proton-pump inhibitors (PPIs).^1,5,7 Newer advanced probes featuring less invasive data collection and greater sensitivity are under development. Ambulatory 24-hour multichannel intraluminal impedance with pH monitoring is the most promising new diagnostic tool, as it can monitor both acidic and nonacidic reflux and distinguish between gas and liquid.¹⁵

TABLE 1
When to suspect laryngopharyngeal reflux disease^1,5,24

Treatment, like diagnosis, is not clear-cut

LPRD is often called a diagnosis of exclusion, because of the nonspecific nature of its signs and symptoms and the importance of considering a range of other etiologies. The differential diagnosis includes excessive voice use, postnasal drip, upper respiratory infection, habitual throat clearing, allergic rhinitis, environmental irritants, temperature/climate change, chronic or episodic use of alcohol and/or tobacco, and psychological problems related to tics, such as habitual throat clearing or coughing.⁵

Diagnosis is often based on an empiric trial of high-dose PPIs, with confirmation dependent on symptom relief. Because there have been few placebo-controlled trials with PPIs and those that have been completed had conflicting results, diagnosis based on a combination of medical history and endoscopic laryngeal examination may be a better approach.^16,17

Acid suppression therapy with either PPIs or histamine-2 (H2) receptor blockers such as ranitidine or famotidine is the mainstay of treatment for LPRD. But medical societies offer conflicting advice. The American Gastroenterological Association cautions clinicians not to prescribe acid-suppression therapy for patients with LPRD unless they also have GERD.⁶ The American Academy of Otolaryngology–Head and Neck Surgery recommends twice-daily PPI use for ≥6 months.^1,13 The general consensus, based on clinical experience alone, is that patients should be treated with high doses of PPIs (eg, 40 mg omeprazole twice a day) for ≥6 months, with the addition of an H2 receptor blocker to help reduce overnight acid production.^1,18 Prophylactic antacid use is also recommended in anticipation of reflux, such as before exercising and right after a meal.

Symptoms should start to improve within 6 to 8 weeks, and patients should be reassessed in about 3 months. To avoid a rebound effect from the abrupt cessation of medications, we suggest a gradual taper over 16 weeks. For the first 8 weeks, the H2 blocker should be discontinued and the PPI decreased from twice a day to once. If symptoms are still controlled, the PPI dose can be reduced to once every other day for another 8 weeks, then stopped if symptoms do not recur.¹⁸

Lifestyle and dietary changes (TABLE 2), such as smoking cessation, weight loss, and avoidance of alcohol, are an important part of LPRD treatment, and may be used as a first-line therapy before prescribing medication.¹⁹ In fact, some studies have found PPI therapy to be inferior to behavioral/lifestyle modifications.¹⁷

Fundoplication surgery, a procedure in which the gastric fundus of the stomach is wrapped around the lower end of the esophagus and stitched in place to prevent reflux, may be an option for patients who do not respond to, or cannot tolerate, aggressive medical treatment for LPRD. A 2006 prospective controlled study found that surgical fundoplication did not consistently relieve laryngeal symptoms.²⁰ But other studies have found that a carefully selected population with medically unresponsive laryngopharyngeal symptoms can benefit from this procedure.^21,22 One study showed a significant improvement within one month of fundoplication, with continued improvement observed during a 3-year follow-up.²¹ In another prospective study, researchers showed that while LPRD-related laryngeal symptoms such as coughing and throat-clearing improved with both medical therapy and laparoscopic fundoplication, voice quality and endoscopic laryngeal/pharyngeal findings improved significantly only with the surgical procedure.²³

TABLE 2
Recommend these lifestyle modifications¹⁹

CORRESPONDENCE
Shoib Sana, DO, Detroit Medical Center, Otolaryngology-Head and Neck Surgery, 6533 East Jefferson Avenue, Apartment 316, Detroit, MI 48207; [email protected]

CASE When Joan C, a 35-year-old patient whom you’ve known for years, comes in for a physical, you notice that she’s coughing frequently. Upon questioning, Joan says she first noticed the cough several months ago; she also reports that she’s frequently hoarse, but has no other symptoms. Joan is a former smoker, and quit 4 years ago.

If Joan were your patient, would you suspect that she had an upper respiratory infection and prescribe an antibiotic such as azithromycin? Would you include laryngopharyngeal reflux disease in the differential diagnosis?

Laryngopharyngeal reflux disease (LPRD) is a common condition that most primary care physicians encounter frequently. It is also frequently misdiagnosed by clinicians who are unfamiliar with the differences between LPRD and gastroesophageal reflux disease (GERD).

The American Academy of Otolaryngology–Head and Neck Surgery defines laryngopharyngeal reflux as the retrograde movement of gastric contents into the laryngopharynx.¹ Common symptoms include hoarseness/dysphonia, chronic throat clearing, dysphagia, globus pharyngeus, and chronic cough, as well as postnasal drip, paroxysmal laryngospasm, odynophagia, excessive throat mucus, and a strange taste in the mouth.²

The diversity and vagueness of these symptoms, as well as the lack of a gold standard diagnostic test for LPRD, make it difficult to estimate its prevalence. In addition, signs of gastroesophageal reflux can be found in the laryngopharynx of up to 86% of healthy individuals, further complicating the clinical picture.³ To avoid missing this often overlooked reflux disease, you need to know how it develops, what signs and symptoms to look for, and which distinguishing features to keep in mind.

Pathophysiology and distinguishing features

The precise way in which LPRD develops is not known, but there are 2 proposed means of laryngeal injury—direct and indirect. In the first case, chemical irritants in the gastric refluxate enter the laryngopharynx and cause local mucosal injury. In the second, gastric reflux irritates the esophageal tissue enough to evoke laryngeal reflexes without ever reaching the larynx—a vagally mediated response associated with symptoms such as chronic cough, throat-clearing sensations, and bronchoconstriction.⁴

Unlike the esophageal lining, laryngeal epithelium is not protected against chemical injury from gastric acid, as it lacks both the stripping motion of esophageal peristalsis and the neutralizing bicarbonate in saliva.⁴ Thus, while far smaller amounts of gastric reflux make it into the laryngopharynx, the acid remains there longer and may cause greater injury.⁵ In some cases, this occurs as often as 50 times a day, although as few as 3 episodes per week have been known to cause LPRD.⁵

Heartburn is not the rule
Heartburn is a primary complaint of patients with GERD. It is reported by little more than a third (35%) of those with LPRD,^5,6 however, (which is why it is sometimes called the “silent” reflux disease). This is because heartburn is caused by esophagitis due to esophageal dysmotility and lower esophageal sphincter dysfunction,³ while most patients with LPRD have normal esophageal motor function and upper esophageal sphincter dysfunction. The fact that only a minimal amount of reflux enters the laryngopharynx may be part of the reason heartburn is less likely in patients with LPRD.

Onset of symptoms. When reflux occurs is another thing that distinguishes LPRD and GERD. Symptoms of GERD typically worsen when the individual is supine, while laryngopharyngeal reflux usually occurs when he or she is upright.⁷ The frequency with which these 2 conditions overlap is debatable, as there are few studies differentiating LPRD and GERD based on standardized signs and symptoms.⁷

Making sense of signs and symptoms

Most patients with LPRD seek treatment from their primary care physician, typically reporting symptoms that they don’t associate with gastric reflux, such as hoarseness, a chronic cough or sore throat, or the sensation of a lump in the throat (TABLE 1). Less common manifestations include “water brash”—excessive mucus in the mouth caused by a release of salivary bicarbonate to help neutralize acidity⁸—otitis media, sinus disease, and dental caries.⁵

Laryngeal endoscopy may reveal many changes from diffuse irritation. Diffuse erythema, edema, and interarytenoid hypertrophy/cobblestoning are the most useful findings for an LPRD diagnosis.^9,10 But in most cases, only a few nonspecific signs with a number of possible causes (infection, environmental irritants, allergies, temperature/climate change, among others) are seen on endoscopic examination, with little correlation with symptom severity. In fact, 74% of otolaryngologists responding to a recent survey said they relied more on patient symptoms than on laryngeal signs for an LPRD diagnosis.¹⁰

The Reflux Finding Score (RFS), available at http://www.nature.com/gimo/contents/pt1/fig_tab/gimo46_T3.html, is a clinical tool developed to quantify laryngeal inflammation and standardize objective endoscopic findings. The RFS incorporates the following endolaryngeal signs:

• subglottic edema
• ventricular obliteration
• erythema/hyperemia
• vocal cord edema
• diffuse laryngeal edema
• posterior commissure hypertrophy
• granuloma/granulation tissue
• thick endolaryngeal mucus.

A numeric value is assigned to each, based on whether it is present or absent; partial or complete; local or diffuse; or mild or severe. However, the RFS, too, is an imperfect tool. Clinicians who have used the RFS report that a score higher than 7 identifies LPRD with 95% sensitivity.¹¹ But laryngeal findings may be due to other causes, such as infection, autoimmune reaction, or even allergies, and studies have found the RFS to have poor specificity and inter-rater reliability.^12-14

Ambulatory dual probe pH monitoring was considered to be the gold standard test for LPRD at one time, but newer studies have raised questions about its validity and usefulness, especially in patients taking proton-pump inhibitors (PPIs).^1,5,7 Newer advanced probes featuring less invasive data collection and greater sensitivity are under development. Ambulatory 24-hour multichannel intraluminal impedance with pH monitoring is the most promising new diagnostic tool, as it can monitor both acidic and nonacidic reflux and distinguish between gas and liquid.¹⁵

TABLE 1
When to suspect laryngopharyngeal reflux disease^1,5,24

Treatment, like diagnosis, is not clear-cut

LPRD is often called a diagnosis of exclusion, because of the nonspecific nature of its signs and symptoms and the importance of considering a range of other etiologies. The differential diagnosis includes excessive voice use, postnasal drip, upper respiratory infection, habitual throat clearing, allergic rhinitis, environmental irritants, temperature/climate change, chronic or episodic use of alcohol and/or tobacco, and psychological problems related to tics, such as habitual throat clearing or coughing.⁵

Diagnosis is often based on an empiric trial of high-dose PPIs, with confirmation dependent on symptom relief. Because there have been few placebo-controlled trials with PPIs and those that have been completed had conflicting results, diagnosis based on a combination of medical history and endoscopic laryngeal examination may be a better approach.^16,17

Acid suppression therapy with either PPIs or histamine-2 (H2) receptor blockers such as ranitidine or famotidine is the mainstay of treatment for LPRD. But medical societies offer conflicting advice. The American Gastroenterological Association cautions clinicians not to prescribe acid-suppression therapy for patients with LPRD unless they also have GERD.⁶ The American Academy of Otolaryngology–Head and Neck Surgery recommends twice-daily PPI use for ≥6 months.^1,13 The general consensus, based on clinical experience alone, is that patients should be treated with high doses of PPIs (eg, 40 mg omeprazole twice a day) for ≥6 months, with the addition of an H2 receptor blocker to help reduce overnight acid production.^1,18 Prophylactic antacid use is also recommended in anticipation of reflux, such as before exercising and right after a meal.

Symptoms should start to improve within 6 to 8 weeks, and patients should be reassessed in about 3 months. To avoid a rebound effect from the abrupt cessation of medications, we suggest a gradual taper over 16 weeks. For the first 8 weeks, the H2 blocker should be discontinued and the PPI decreased from twice a day to once. If symptoms are still controlled, the PPI dose can be reduced to once every other day for another 8 weeks, then stopped if symptoms do not recur.¹⁸

Lifestyle and dietary changes (TABLE 2), such as smoking cessation, weight loss, and avoidance of alcohol, are an important part of LPRD treatment, and may be used as a first-line therapy before prescribing medication.¹⁹ In fact, some studies have found PPI therapy to be inferior to behavioral/lifestyle modifications.¹⁷

Fundoplication surgery, a procedure in which the gastric fundus of the stomach is wrapped around the lower end of the esophagus and stitched in place to prevent reflux, may be an option for patients who do not respond to, or cannot tolerate, aggressive medical treatment for LPRD. A 2006 prospective controlled study found that surgical fundoplication did not consistently relieve laryngeal symptoms.²⁰ But other studies have found that a carefully selected population with medically unresponsive laryngopharyngeal symptoms can benefit from this procedure.^21,22 One study showed a significant improvement within one month of fundoplication, with continued improvement observed during a 3-year follow-up.²¹ In another prospective study, researchers showed that while LPRD-related laryngeal symptoms such as coughing and throat-clearing improved with both medical therapy and laparoscopic fundoplication, voice quality and endoscopic laryngeal/pharyngeal findings improved significantly only with the surgical procedure.²³

TABLE 2
Recommend these lifestyle modifications¹⁹

CORRESPONDENCE
Shoib Sana, DO, Detroit Medical Center, Otolaryngology-Head and Neck Surgery, 6533 East Jefferson Avenue, Apartment 316, Detroit, MI 48207; [email protected]

CASE When Joan C, a 35-year-old patient whom you’ve known for years, comes in for a physical, you notice that she’s coughing frequently. Upon questioning, Joan says she first noticed the cough several months ago; she also reports that she’s frequently hoarse, but has no other symptoms. Joan is a former smoker, and quit 4 years ago.

If Joan were your patient, would you suspect that she had an upper respiratory infection and prescribe an antibiotic such as azithromycin? Would you include laryngopharyngeal reflux disease in the differential diagnosis?

Laryngopharyngeal reflux disease (LPRD) is a common condition that most primary care physicians encounter frequently. It is also frequently misdiagnosed by clinicians who are unfamiliar with the differences between LPRD and gastroesophageal reflux disease (GERD).

The American Academy of Otolaryngology–Head and Neck Surgery defines laryngopharyngeal reflux as the retrograde movement of gastric contents into the laryngopharynx.¹ Common symptoms include hoarseness/dysphonia, chronic throat clearing, dysphagia, globus pharyngeus, and chronic cough, as well as postnasal drip, paroxysmal laryngospasm, odynophagia, excessive throat mucus, and a strange taste in the mouth.²

The diversity and vagueness of these symptoms, as well as the lack of a gold standard diagnostic test for LPRD, make it difficult to estimate its prevalence. In addition, signs of gastroesophageal reflux can be found in the laryngopharynx of up to 86% of healthy individuals, further complicating the clinical picture.³ To avoid missing this often overlooked reflux disease, you need to know how it develops, what signs and symptoms to look for, and which distinguishing features to keep in mind.

Pathophysiology and distinguishing features

The precise way in which LPRD develops is not known, but there are 2 proposed means of laryngeal injury—direct and indirect. In the first case, chemical irritants in the gastric refluxate enter the laryngopharynx and cause local mucosal injury. In the second, gastric reflux irritates the esophageal tissue enough to evoke laryngeal reflexes without ever reaching the larynx—a vagally mediated response associated with symptoms such as chronic cough, throat-clearing sensations, and bronchoconstriction.⁴

Unlike the esophageal lining, laryngeal epithelium is not protected against chemical injury from gastric acid, as it lacks both the stripping motion of esophageal peristalsis and the neutralizing bicarbonate in saliva.⁴ Thus, while far smaller amounts of gastric reflux make it into the laryngopharynx, the acid remains there longer and may cause greater injury.⁵ In some cases, this occurs as often as 50 times a day, although as few as 3 episodes per week have been known to cause LPRD.⁵

Heartburn is not the rule
Heartburn is a primary complaint of patients with GERD. It is reported by little more than a third (35%) of those with LPRD,^5,6 however, (which is why it is sometimes called the “silent” reflux disease). This is because heartburn is caused by esophagitis due to esophageal dysmotility and lower esophageal sphincter dysfunction,³ while most patients with LPRD have normal esophageal motor function and upper esophageal sphincter dysfunction. The fact that only a minimal amount of reflux enters the laryngopharynx may be part of the reason heartburn is less likely in patients with LPRD.

Onset of symptoms. When reflux occurs is another thing that distinguishes LPRD and GERD. Symptoms of GERD typically worsen when the individual is supine, while laryngopharyngeal reflux usually occurs when he or she is upright.⁷ The frequency with which these 2 conditions overlap is debatable, as there are few studies differentiating LPRD and GERD based on standardized signs and symptoms.⁷

Making sense of signs and symptoms

Most patients with LPRD seek treatment from their primary care physician, typically reporting symptoms that they don’t associate with gastric reflux, such as hoarseness, a chronic cough or sore throat, or the sensation of a lump in the throat (TABLE 1). Less common manifestations include “water brash”—excessive mucus in the mouth caused by a release of salivary bicarbonate to help neutralize acidity⁸—otitis media, sinus disease, and dental caries.⁵

Laryngeal endoscopy may reveal many changes from diffuse irritation. Diffuse erythema, edema, and interarytenoid hypertrophy/cobblestoning are the most useful findings for an LPRD diagnosis.^9,10 But in most cases, only a few nonspecific signs with a number of possible causes (infection, environmental irritants, allergies, temperature/climate change, among others) are seen on endoscopic examination, with little correlation with symptom severity. In fact, 74% of otolaryngologists responding to a recent survey said they relied more on patient symptoms than on laryngeal signs for an LPRD diagnosis.¹⁰

The Reflux Finding Score (RFS), available at http://www.nature.com/gimo/contents/pt1/fig_tab/gimo46_T3.html, is a clinical tool developed to quantify laryngeal inflammation and standardize objective endoscopic findings. The RFS incorporates the following endolaryngeal signs:

• subglottic edema
• ventricular obliteration
• erythema/hyperemia
• vocal cord edema
• diffuse laryngeal edema
• posterior commissure hypertrophy
• granuloma/granulation tissue
• thick endolaryngeal mucus.

A numeric value is assigned to each, based on whether it is present or absent; partial or complete; local or diffuse; or mild or severe. However, the RFS, too, is an imperfect tool. Clinicians who have used the RFS report that a score higher than 7 identifies LPRD with 95% sensitivity.¹¹ But laryngeal findings may be due to other causes, such as infection, autoimmune reaction, or even allergies, and studies have found the RFS to have poor specificity and inter-rater reliability.^12-14

Ambulatory dual probe pH monitoring was considered to be the gold standard test for LPRD at one time, but newer studies have raised questions about its validity and usefulness, especially in patients taking proton-pump inhibitors (PPIs).^1,5,7 Newer advanced probes featuring less invasive data collection and greater sensitivity are under development. Ambulatory 24-hour multichannel intraluminal impedance with pH monitoring is the most promising new diagnostic tool, as it can monitor both acidic and nonacidic reflux and distinguish between gas and liquid.¹⁵

TABLE 1
When to suspect laryngopharyngeal reflux disease^1,5,24

Treatment, like diagnosis, is not clear-cut

LPRD is often called a diagnosis of exclusion, because of the nonspecific nature of its signs and symptoms and the importance of considering a range of other etiologies. The differential diagnosis includes excessive voice use, postnasal drip, upper respiratory infection, habitual throat clearing, allergic rhinitis, environmental irritants, temperature/climate change, chronic or episodic use of alcohol and/or tobacco, and psychological problems related to tics, such as habitual throat clearing or coughing.⁵

Diagnosis is often based on an empiric trial of high-dose PPIs, with confirmation dependent on symptom relief. Because there have been few placebo-controlled trials with PPIs and those that have been completed had conflicting results, diagnosis based on a combination of medical history and endoscopic laryngeal examination may be a better approach.^16,17

Acid suppression therapy with either PPIs or histamine-2 (H2) receptor blockers such as ranitidine or famotidine is the mainstay of treatment for LPRD. But medical societies offer conflicting advice. The American Gastroenterological Association cautions clinicians not to prescribe acid-suppression therapy for patients with LPRD unless they also have GERD.⁶ The American Academy of Otolaryngology–Head and Neck Surgery recommends twice-daily PPI use for ≥6 months.^1,13 The general consensus, based on clinical experience alone, is that patients should be treated with high doses of PPIs (eg, 40 mg omeprazole twice a day) for ≥6 months, with the addition of an H2 receptor blocker to help reduce overnight acid production.^1,18 Prophylactic antacid use is also recommended in anticipation of reflux, such as before exercising and right after a meal.

Symptoms should start to improve within 6 to 8 weeks, and patients should be reassessed in about 3 months. To avoid a rebound effect from the abrupt cessation of medications, we suggest a gradual taper over 16 weeks. For the first 8 weeks, the H2 blocker should be discontinued and the PPI decreased from twice a day to once. If symptoms are still controlled, the PPI dose can be reduced to once every other day for another 8 weeks, then stopped if symptoms do not recur.¹⁸

Lifestyle and dietary changes (TABLE 2), such as smoking cessation, weight loss, and avoidance of alcohol, are an important part of LPRD treatment, and may be used as a first-line therapy before prescribing medication.¹⁹ In fact, some studies have found PPI therapy to be inferior to behavioral/lifestyle modifications.¹⁷

Fundoplication surgery, a procedure in which the gastric fundus of the stomach is wrapped around the lower end of the esophagus and stitched in place to prevent reflux, may be an option for patients who do not respond to, or cannot tolerate, aggressive medical treatment for LPRD. A 2006 prospective controlled study found that surgical fundoplication did not consistently relieve laryngeal symptoms.²⁰ But other studies have found that a carefully selected population with medically unresponsive laryngopharyngeal symptoms can benefit from this procedure.^21,22 One study showed a significant improvement within one month of fundoplication, with continued improvement observed during a 3-year follow-up.²¹ In another prospective study, researchers showed that while LPRD-related laryngeal symptoms such as coughing and throat-clearing improved with both medical therapy and laparoscopic fundoplication, voice quality and endoscopic laryngeal/pharyngeal findings improved significantly only with the surgical procedure.²³

TABLE 2
Recommend these lifestyle modifications¹⁹

CORRESPONDENCE
Shoib Sana, DO, Detroit Medical Center, Otolaryngology-Head and Neck Surgery, 6533 East Jefferson Avenue, Apartment 316, Detroit, MI 48207; [email protected]

CASE 1 A 31-year-old African American woman sought treatment at her local emergency department (ED) for nausea, vomiting, and diarrhea. She reported passing more than 6 yellowish-brown, watery, nonbloody stools during the previous 2 days. She felt weak, feverish, and light-headed and showed signs of dehydration.

The patient had Crohn’s disease and had undergone a partial colectomy 5 years earlier. She told the ED physician that 2 days before visiting the ED she had gone to a “cleansing center” for a colonic cleansing, but was unable to complete the process because she developed cramps 15 minutes into the procedure. Less than an hour later, she developed diarrhea, nausea, and vomiting.

In the ED, her serum potassium was 2.9 mEq/L, blood urea nitrogen was 26 mg/dL, and creatinine was 1.9 mg/dL. She was afebrile, with a blood pressure of 135/75 mm Hg and a heart rate of 113 beats per minute. After receiving 2 liters of normal saline and 90 mEq of potassium chloride replacement, the patient felt better and was later discharged from the ED.

Three days later, the patient came to our residency clinic. She described her stools as being loose, but not watery or bloody, and passed in small amounts, about 4 times daily. She still had some abdominal cramping just before passing stool, but bowel movements relieved that. Her vital signs were within normal limits, and her physical exam was benign. The patient was instructed to follow her normal diet, as tolerated, and drink plenty of fluids to maintain good hydration. Her symptoms resolved by the following week.

CASE 2 A 49-year-old African American man came to our community hospital because of vomiting, diarrhea, and abdominal pain he had been experiencing for 4 days. He linked the symptoms to eating a large fast-food breakfast, followed by a big lunch the day before. He described having multiple episodes of nonbloody, nonbilious vomiting, nonbloody watery diarrhea, and “twisting” abdominal pain that was constant but temporarily relieved with a warm compress or positional maneuvers. He had never had a similar episode and had not taken any antibiotics recently.

Upon further questioning, the patient revealed that he had used a colon cleanser a few days earlier. A review showed that he had lost 24 pounds in 10 days. Vitals were within normal limits. Serum potassium was 2.9 mEq/L, and creatinine was 2.1 mg/dL. A computed tomography scan of the abdomen revealed moderate to moderately severe dilatation of multiple small bowel loops with multiple air fluid levels, suggesting an early or partial small bowel obstruction. We obtained a surgical consultation, but surgery was not required. He was discharged after 2 days.

The patient returned to the hospital 3 days later with similar symptoms and severe weakness associated with dizziness. At that time his serum potassium was 2.4 mEq/L and creatinine was 4.0 mg/dL. Aspartate aminotransferase was 29 U/L, alanine aminotransferase was 80 U/L, lipase was 418 U/L, and amylase was 94 U/L.

The patient was readmitted for dehydration, hypokalemia, and pancreatitis and, following a colonoscopy and biopsy that revealed chronic and acute inflammation, a gastroenterologist made a diagnosis of “herbal intoxication.” The patient was hydrated, his electrolytes were replaced, and his diet was slowly returned to normal. He was discharged after 5 days.

An old practice rediscovered

Colon cleansing has been around since ancient times, when its purported benefits were based on the belief that intestinal waste can poison the body (“autointoxication”).¹ The procedure became popular in the early 1900s, but in a 1919 paper, the American Medical Association discounted the autointoxication theory and condemned the practice.¹ The procedure then fell out of favor, albeit temporarily.² Colon cleansing has staged a comeback in recent years.

Colon cleansing basics
Colon cleansing, also called colonic irrigation or colonic hydrotherapy, is performed by colonic hygienists or colon therapists, or can be self-administered. The procedure works like an enema. The patient generally lies on a table and water (with or without additional herbs or compounds) is pumped through the rectum via a tube.

Unlike enemas, for which a small amount of fluid is used, however, colon cleansing calls for a large volume of fluid—up to 60 liters—to be introduced into the rectum.^3,4 Fluids and waste are expelled through another tube. The procedure may be repeated several times.

Products go by many names
Most colon cleansing products come in the forms of laxatives, teas, powders, and capsules. They can be taken by mouth or inserted into the rectum. They often contain sodium phosphate, coffee, probiotics, enzymes, or any of a variety of herbs.⁵ Some products contain fiber preparations, including psyllium, flaxseed, and laxatives such as cascara, magnesium oxide, cat’s claw, artichoke leaves, burdock root, licorice, and milk thistle.²

With names such as Nature’s Bounty Colon Cleanser Natural Detox Formula, Health Plus Inc. Colon Cleanse, and 7-Day Miracle Cleanse, as well as endorsements by movie stars, these colon cleansing products are actively promoted as a natural way to enhance one’s well-being. Advertisements promising that colon cleansing will alleviate fatigue, headache, weight gain, and low energy are ubiquitous on the Internet and in newspapers and magazines. The ads tout the safety of “herbal” and “natural” preparations. These materials also provide anecdotal support for claims that colon cleansing improves the immune and circulatory systems, enhances cognitive abilities, and aids weight loss through “detoxification.”⁶

Individuals who want to cleanse their own colons can choose among home kits, some of which include disposable tubing, while others have components that can be reused if they are sterilized after each use.^5,7 But many people turn to a “hydrotherapist” for colon irrigation. The services are also increasingly being offered by practitioners who describe themselves as “colon hygienists.”

These individuals sometimes belong to organizations such as the National Board for Colon Hydrotherapy (NBCH) or the International Association for Colon Hydrotherapy (I-ACT).^8,9 These practitioners are not licensed, but they are required to have a high school or equivalent degree plus 3 semesters of postsecondary education and to be certified in cardiopulmonary resuscitation. They also take various seminars and continuing education courses from the NBCH and I-ACT.

How many individuals have used colon cleansing is unclear, although one study suggested that in the United Kingdom, registered practitioners carry out an estimated 5600 procedures every month.¹⁰

Where’s the evidence?

Despite colon cleansing’s long history and current popularity, the literature does not support its purported benefits. Historically, colon cleansing was thought to prevent autointoxication from toxins originating in the colon, but the evidence for this claim is limited.¹¹ A search of the literature using the terms “colon cleansing,” “herbal colon cleanse,” “colon detoxification,” and “colon irrigation,” yielded no scientifically robust studies in support of this practice. One study suggested that lymphocytes might migrate from the gut into the circulation after the procedure, which may “improve colon and immune system function.”¹²

Even though colon cleansing is touted as a commonly used form of holistic, complementary and alternative medicine, the Natural Standard Professional Database concluded in a monograph that there is “limited clinical evidence validating colon therapy as a health promotion practice” and noted a “lack of sufficient evidence” for most of its prescribed uses.¹³

Adverse effects: From cramping to renal failure
Most reports in the literature note a variety of adverse effects of colon cleansing that range from mild (eg, cramping, abdominal pain, fullness, bloating, nausea, vomiting, perianal irritation, and soreness) to severe (eg, electrolyte imbalance and renal failure).^11,14-17 Some herbal preparations have also been associated with aplastic anemia and liver toxicity.¹⁸

Case reports also have noted back and pelvic abscesses after colonic hydrotherapy, fatal aeroportia (gas accumulation in the mesenteric veins) with air emboli, rectal perforations, perineal gangrene, acute water intoxication, coffee enema-associated colitis and septicemia, and deaths due to amebiasis.^2,3,19-21

The FDA has issued many warning letters
The preparations used for colon cleansing are considered dietary supplements, and the US Food and Drug Administration (FDA) requires that they be labeled as such; the FDA does not preapprove these substances, however. The FDA also requires that colonic hydrotherapy and irrigation system devices meet certain requirements, but the agency has never approved any system for general nonmedical purposes, such as colon cleansing.

The devices have an FDA Class III designation, indicating that if a device is used for purposes beyond what is medically indicated (preparation for radiologic and endoscopic procedures), the manufacturer must obtain premarket approval from the FDA, which is based on evaluation of the safety and effectiveness of the device as shown by available scientific evidence and current regulations.²² During the past decade the FDA has issued numerous warning letters to manufacturers for unapproved use of the devices for colon cleansing.^23-26

Raise the issue with patients
Given the current popularity of colon cleansing, it’s important to recognize that some of your patients may engage in, or be thinking about, the practice. (See “4 things to tell patients about colon cleansing”.) Be sure to tell patients about the potential consequences of colon cleansing and to emphasize that there is a lack of evidence to back up supporters’ claims.

CORRESPONDENCE
Ranit Mishori, MD, MHS, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20007; [email protected]

CASE 1 A 31-year-old African American woman sought treatment at her local emergency department (ED) for nausea, vomiting, and diarrhea. She reported passing more than 6 yellowish-brown, watery, nonbloody stools during the previous 2 days. She felt weak, feverish, and light-headed and showed signs of dehydration.

The patient had Crohn’s disease and had undergone a partial colectomy 5 years earlier. She told the ED physician that 2 days before visiting the ED she had gone to a “cleansing center” for a colonic cleansing, but was unable to complete the process because she developed cramps 15 minutes into the procedure. Less than an hour later, she developed diarrhea, nausea, and vomiting.

In the ED, her serum potassium was 2.9 mEq/L, blood urea nitrogen was 26 mg/dL, and creatinine was 1.9 mg/dL. She was afebrile, with a blood pressure of 135/75 mm Hg and a heart rate of 113 beats per minute. After receiving 2 liters of normal saline and 90 mEq of potassium chloride replacement, the patient felt better and was later discharged from the ED.

Three days later, the patient came to our residency clinic. She described her stools as being loose, but not watery or bloody, and passed in small amounts, about 4 times daily. She still had some abdominal cramping just before passing stool, but bowel movements relieved that. Her vital signs were within normal limits, and her physical exam was benign. The patient was instructed to follow her normal diet, as tolerated, and drink plenty of fluids to maintain good hydration. Her symptoms resolved by the following week.

CASE 2 A 49-year-old African American man came to our community hospital because of vomiting, diarrhea, and abdominal pain he had been experiencing for 4 days. He linked the symptoms to eating a large fast-food breakfast, followed by a big lunch the day before. He described having multiple episodes of nonbloody, nonbilious vomiting, nonbloody watery diarrhea, and “twisting” abdominal pain that was constant but temporarily relieved with a warm compress or positional maneuvers. He had never had a similar episode and had not taken any antibiotics recently.

Upon further questioning, the patient revealed that he had used a colon cleanser a few days earlier. A review showed that he had lost 24 pounds in 10 days. Vitals were within normal limits. Serum potassium was 2.9 mEq/L, and creatinine was 2.1 mg/dL. A computed tomography scan of the abdomen revealed moderate to moderately severe dilatation of multiple small bowel loops with multiple air fluid levels, suggesting an early or partial small bowel obstruction. We obtained a surgical consultation, but surgery was not required. He was discharged after 2 days.

The patient returned to the hospital 3 days later with similar symptoms and severe weakness associated with dizziness. At that time his serum potassium was 2.4 mEq/L and creatinine was 4.0 mg/dL. Aspartate aminotransferase was 29 U/L, alanine aminotransferase was 80 U/L, lipase was 418 U/L, and amylase was 94 U/L.

The patient was readmitted for dehydration, hypokalemia, and pancreatitis and, following a colonoscopy and biopsy that revealed chronic and acute inflammation, a gastroenterologist made a diagnosis of “herbal intoxication.” The patient was hydrated, his electrolytes were replaced, and his diet was slowly returned to normal. He was discharged after 5 days.

An old practice rediscovered

Colon cleansing has been around since ancient times, when its purported benefits were based on the belief that intestinal waste can poison the body (“autointoxication”).¹ The procedure became popular in the early 1900s, but in a 1919 paper, the American Medical Association discounted the autointoxication theory and condemned the practice.¹ The procedure then fell out of favor, albeit temporarily.² Colon cleansing has staged a comeback in recent years.

Colon cleansing basics
Colon cleansing, also called colonic irrigation or colonic hydrotherapy, is performed by colonic hygienists or colon therapists, or can be self-administered. The procedure works like an enema. The patient generally lies on a table and water (with or without additional herbs or compounds) is pumped through the rectum via a tube.

Unlike enemas, for which a small amount of fluid is used, however, colon cleansing calls for a large volume of fluid—up to 60 liters—to be introduced into the rectum.^3,4 Fluids and waste are expelled through another tube. The procedure may be repeated several times.

Products go by many names
Most colon cleansing products come in the forms of laxatives, teas, powders, and capsules. They can be taken by mouth or inserted into the rectum. They often contain sodium phosphate, coffee, probiotics, enzymes, or any of a variety of herbs.⁵ Some products contain fiber preparations, including psyllium, flaxseed, and laxatives such as cascara, magnesium oxide, cat’s claw, artichoke leaves, burdock root, licorice, and milk thistle.²

With names such as Nature’s Bounty Colon Cleanser Natural Detox Formula, Health Plus Inc. Colon Cleanse, and 7-Day Miracle Cleanse, as well as endorsements by movie stars, these colon cleansing products are actively promoted as a natural way to enhance one’s well-being. Advertisements promising that colon cleansing will alleviate fatigue, headache, weight gain, and low energy are ubiquitous on the Internet and in newspapers and magazines. The ads tout the safety of “herbal” and “natural” preparations. These materials also provide anecdotal support for claims that colon cleansing improves the immune and circulatory systems, enhances cognitive abilities, and aids weight loss through “detoxification.”⁶

Individuals who want to cleanse their own colons can choose among home kits, some of which include disposable tubing, while others have components that can be reused if they are sterilized after each use.^5,7 But many people turn to a “hydrotherapist” for colon irrigation. The services are also increasingly being offered by practitioners who describe themselves as “colon hygienists.”

These individuals sometimes belong to organizations such as the National Board for Colon Hydrotherapy (NBCH) or the International Association for Colon Hydrotherapy (I-ACT).^8,9 These practitioners are not licensed, but they are required to have a high school or equivalent degree plus 3 semesters of postsecondary education and to be certified in cardiopulmonary resuscitation. They also take various seminars and continuing education courses from the NBCH and I-ACT.

How many individuals have used colon cleansing is unclear, although one study suggested that in the United Kingdom, registered practitioners carry out an estimated 5600 procedures every month.¹⁰

Where’s the evidence?

Despite colon cleansing’s long history and current popularity, the literature does not support its purported benefits. Historically, colon cleansing was thought to prevent autointoxication from toxins originating in the colon, but the evidence for this claim is limited.¹¹ A search of the literature using the terms “colon cleansing,” “herbal colon cleanse,” “colon detoxification,” and “colon irrigation,” yielded no scientifically robust studies in support of this practice. One study suggested that lymphocytes might migrate from the gut into the circulation after the procedure, which may “improve colon and immune system function.”¹²

Even though colon cleansing is touted as a commonly used form of holistic, complementary and alternative medicine, the Natural Standard Professional Database concluded in a monograph that there is “limited clinical evidence validating colon therapy as a health promotion practice” and noted a “lack of sufficient evidence” for most of its prescribed uses.¹³

Adverse effects: From cramping to renal failure
Most reports in the literature note a variety of adverse effects of colon cleansing that range from mild (eg, cramping, abdominal pain, fullness, bloating, nausea, vomiting, perianal irritation, and soreness) to severe (eg, electrolyte imbalance and renal failure).^11,14-17 Some herbal preparations have also been associated with aplastic anemia and liver toxicity.¹⁸

Case reports also have noted back and pelvic abscesses after colonic hydrotherapy, fatal aeroportia (gas accumulation in the mesenteric veins) with air emboli, rectal perforations, perineal gangrene, acute water intoxication, coffee enema-associated colitis and septicemia, and deaths due to amebiasis.^2,3,19-21

The FDA has issued many warning letters
The preparations used for colon cleansing are considered dietary supplements, and the US Food and Drug Administration (FDA) requires that they be labeled as such; the FDA does not preapprove these substances, however. The FDA also requires that colonic hydrotherapy and irrigation system devices meet certain requirements, but the agency has never approved any system for general nonmedical purposes, such as colon cleansing.

The devices have an FDA Class III designation, indicating that if a device is used for purposes beyond what is medically indicated (preparation for radiologic and endoscopic procedures), the manufacturer must obtain premarket approval from the FDA, which is based on evaluation of the safety and effectiveness of the device as shown by available scientific evidence and current regulations.²² During the past decade the FDA has issued numerous warning letters to manufacturers for unapproved use of the devices for colon cleansing.^23-26

Raise the issue with patients
Given the current popularity of colon cleansing, it’s important to recognize that some of your patients may engage in, or be thinking about, the practice. (See “4 things to tell patients about colon cleansing”.) Be sure to tell patients about the potential consequences of colon cleansing and to emphasize that there is a lack of evidence to back up supporters’ claims.

CORRESPONDENCE
Ranit Mishori, MD, MHS, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20007; [email protected]

CASE 1 A 31-year-old African American woman sought treatment at her local emergency department (ED) for nausea, vomiting, and diarrhea. She reported passing more than 6 yellowish-brown, watery, nonbloody stools during the previous 2 days. She felt weak, feverish, and light-headed and showed signs of dehydration.

The patient had Crohn’s disease and had undergone a partial colectomy 5 years earlier. She told the ED physician that 2 days before visiting the ED she had gone to a “cleansing center” for a colonic cleansing, but was unable to complete the process because she developed cramps 15 minutes into the procedure. Less than an hour later, she developed diarrhea, nausea, and vomiting.

In the ED, her serum potassium was 2.9 mEq/L, blood urea nitrogen was 26 mg/dL, and creatinine was 1.9 mg/dL. She was afebrile, with a blood pressure of 135/75 mm Hg and a heart rate of 113 beats per minute. After receiving 2 liters of normal saline and 90 mEq of potassium chloride replacement, the patient felt better and was later discharged from the ED.

Three days later, the patient came to our residency clinic. She described her stools as being loose, but not watery or bloody, and passed in small amounts, about 4 times daily. She still had some abdominal cramping just before passing stool, but bowel movements relieved that. Her vital signs were within normal limits, and her physical exam was benign. The patient was instructed to follow her normal diet, as tolerated, and drink plenty of fluids to maintain good hydration. Her symptoms resolved by the following week.

CASE 2 A 49-year-old African American man came to our community hospital because of vomiting, diarrhea, and abdominal pain he had been experiencing for 4 days. He linked the symptoms to eating a large fast-food breakfast, followed by a big lunch the day before. He described having multiple episodes of nonbloody, nonbilious vomiting, nonbloody watery diarrhea, and “twisting” abdominal pain that was constant but temporarily relieved with a warm compress or positional maneuvers. He had never had a similar episode and had not taken any antibiotics recently.

Upon further questioning, the patient revealed that he had used a colon cleanser a few days earlier. A review showed that he had lost 24 pounds in 10 days. Vitals were within normal limits. Serum potassium was 2.9 mEq/L, and creatinine was 2.1 mg/dL. A computed tomography scan of the abdomen revealed moderate to moderately severe dilatation of multiple small bowel loops with multiple air fluid levels, suggesting an early or partial small bowel obstruction. We obtained a surgical consultation, but surgery was not required. He was discharged after 2 days.

The patient returned to the hospital 3 days later with similar symptoms and severe weakness associated with dizziness. At that time his serum potassium was 2.4 mEq/L and creatinine was 4.0 mg/dL. Aspartate aminotransferase was 29 U/L, alanine aminotransferase was 80 U/L, lipase was 418 U/L, and amylase was 94 U/L.

The patient was readmitted for dehydration, hypokalemia, and pancreatitis and, following a colonoscopy and biopsy that revealed chronic and acute inflammation, a gastroenterologist made a diagnosis of “herbal intoxication.” The patient was hydrated, his electrolytes were replaced, and his diet was slowly returned to normal. He was discharged after 5 days.

An old practice rediscovered

Colon cleansing has been around since ancient times, when its purported benefits were based on the belief that intestinal waste can poison the body (“autointoxication”).¹ The procedure became popular in the early 1900s, but in a 1919 paper, the American Medical Association discounted the autointoxication theory and condemned the practice.¹ The procedure then fell out of favor, albeit temporarily.² Colon cleansing has staged a comeback in recent years.

Colon cleansing basics
Colon cleansing, also called colonic irrigation or colonic hydrotherapy, is performed by colonic hygienists or colon therapists, or can be self-administered. The procedure works like an enema. The patient generally lies on a table and water (with or without additional herbs or compounds) is pumped through the rectum via a tube.

Unlike enemas, for which a small amount of fluid is used, however, colon cleansing calls for a large volume of fluid—up to 60 liters—to be introduced into the rectum.^3,4 Fluids and waste are expelled through another tube. The procedure may be repeated several times.

Products go by many names
Most colon cleansing products come in the forms of laxatives, teas, powders, and capsules. They can be taken by mouth or inserted into the rectum. They often contain sodium phosphate, coffee, probiotics, enzymes, or any of a variety of herbs.⁵ Some products contain fiber preparations, including psyllium, flaxseed, and laxatives such as cascara, magnesium oxide, cat’s claw, artichoke leaves, burdock root, licorice, and milk thistle.²

With names such as Nature’s Bounty Colon Cleanser Natural Detox Formula, Health Plus Inc. Colon Cleanse, and 7-Day Miracle Cleanse, as well as endorsements by movie stars, these colon cleansing products are actively promoted as a natural way to enhance one’s well-being. Advertisements promising that colon cleansing will alleviate fatigue, headache, weight gain, and low energy are ubiquitous on the Internet and in newspapers and magazines. The ads tout the safety of “herbal” and “natural” preparations. These materials also provide anecdotal support for claims that colon cleansing improves the immune and circulatory systems, enhances cognitive abilities, and aids weight loss through “detoxification.”⁶

Individuals who want to cleanse their own colons can choose among home kits, some of which include disposable tubing, while others have components that can be reused if they are sterilized after each use.^5,7 But many people turn to a “hydrotherapist” for colon irrigation. The services are also increasingly being offered by practitioners who describe themselves as “colon hygienists.”

These individuals sometimes belong to organizations such as the National Board for Colon Hydrotherapy (NBCH) or the International Association for Colon Hydrotherapy (I-ACT).^8,9 These practitioners are not licensed, but they are required to have a high school or equivalent degree plus 3 semesters of postsecondary education and to be certified in cardiopulmonary resuscitation. They also take various seminars and continuing education courses from the NBCH and I-ACT.

How many individuals have used colon cleansing is unclear, although one study suggested that in the United Kingdom, registered practitioners carry out an estimated 5600 procedures every month.¹⁰

Where’s the evidence?

Despite colon cleansing’s long history and current popularity, the literature does not support its purported benefits. Historically, colon cleansing was thought to prevent autointoxication from toxins originating in the colon, but the evidence for this claim is limited.¹¹ A search of the literature using the terms “colon cleansing,” “herbal colon cleanse,” “colon detoxification,” and “colon irrigation,” yielded no scientifically robust studies in support of this practice. One study suggested that lymphocytes might migrate from the gut into the circulation after the procedure, which may “improve colon and immune system function.”¹²

Even though colon cleansing is touted as a commonly used form of holistic, complementary and alternative medicine, the Natural Standard Professional Database concluded in a monograph that there is “limited clinical evidence validating colon therapy as a health promotion practice” and noted a “lack of sufficient evidence” for most of its prescribed uses.¹³

Adverse effects: From cramping to renal failure
Most reports in the literature note a variety of adverse effects of colon cleansing that range from mild (eg, cramping, abdominal pain, fullness, bloating, nausea, vomiting, perianal irritation, and soreness) to severe (eg, electrolyte imbalance and renal failure).^11,14-17 Some herbal preparations have also been associated with aplastic anemia and liver toxicity.¹⁸

Case reports also have noted back and pelvic abscesses after colonic hydrotherapy, fatal aeroportia (gas accumulation in the mesenteric veins) with air emboli, rectal perforations, perineal gangrene, acute water intoxication, coffee enema-associated colitis and septicemia, and deaths due to amebiasis.^2,3,19-21

The FDA has issued many warning letters
The preparations used for colon cleansing are considered dietary supplements, and the US Food and Drug Administration (FDA) requires that they be labeled as such; the FDA does not preapprove these substances, however. The FDA also requires that colonic hydrotherapy and irrigation system devices meet certain requirements, but the agency has never approved any system for general nonmedical purposes, such as colon cleansing.

The devices have an FDA Class III designation, indicating that if a device is used for purposes beyond what is medically indicated (preparation for radiologic and endoscopic procedures), the manufacturer must obtain premarket approval from the FDA, which is based on evaluation of the safety and effectiveness of the device as shown by available scientific evidence and current regulations.²² During the past decade the FDA has issued numerous warning letters to manufacturers for unapproved use of the devices for colon cleansing.^23-26

Raise the issue with patients
Given the current popularity of colon cleansing, it’s important to recognize that some of your patients may engage in, or be thinking about, the practice. (See “4 things to tell patients about colon cleansing”.) Be sure to tell patients about the potential consequences of colon cleansing and to emphasize that there is a lack of evidence to back up supporters’ claims.

CORRESPONDENCE
Ranit Mishori, MD, MHS, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20007; [email protected]

As psychiatry’s understanding of borderline personality disorder (BPD) grows, the literature clearly describes the seriousness of BPD, as well as these patients’ high utilization of treatment. Pharmacotherapy for BPD remains controversial. The most recent American Psychiatric Association practice guidelines focus on using symptom domains of this heterogeneous illness to guide medication selection, yet when these guidelines were published, there was a lack of data to support this recommendation.¹

This article evaluates medications for BPD and emerging data supporting matching medications to BPD symptom domains, with an emphasis on making choices that advance clinical practice. We conclude by reviewing studies of combined pharmacotherapy and dialectical behavior therapy (DBT) and describing how a multidisciplinary team approach can enhance BPD treatment.

Early research

Early studies of pharmacotherapy for BPD began after the development of the Diagnostic Interview for Borderlines^2,3 and DSM-III criteria for BPD.⁴ Researchers recruited patients who fulfilled the diagnostic criteria; however, these participants’ symptom profiles were highly heterogeneous. Although such studies can be useful when starting to test new treatments—especially if they are able to show efficacy over placebo or explore safety—they are less helpful in guiding clinical practice.

During the 1980s, low doses of first-generation antipsychotics were evaluated based on hypotheses that BPD was related to schizophrenia. Case series⁵ and placebo-controlled trials^6,7 pointed to symptom reduction over time and greater than placebo for BPD patients. Interestingly, in a small study of BPD inpatients, Soloff et al⁸ compared the first-generation antipsychotic haloperidol to amitriptyline and found amitriptyline led to symptom worsening in some patients. Cowdry and Gardner⁹ compared alprazolam, carbamazepine, trifluoperazine, and tranylcypromine in a double-blind, placebo-controlled crossover trial of 16 female BPD outpatients. They found antipsychotics were not useful. Further, the study found behavioral disinhibition when a benzodiazepine (alprazolam) was used alone in impulsive patients.

These studies provided a basis for the idea that medications could help reduce BPD symptoms. However, some early investigators noted that antipsychotics’ side effects led some patients to discontinue treatment.⁶

Next-generation studies

Antidepressants. Interest in exploring pharmacologic treatments for BPD diminished after the early efficacy trials. Several events led to a reemergence of this interest, including the FDA’s approval of the selective serotonin reuptake inhibitor fluoxetine for depression in 1987. Some investigators hypothesized fluoxetine’s antidepressant properties could help treat BPD symptoms and perhaps the serotonin reuptake action could diminish impulsivity.¹⁰ Case series and a double-blind, placebo-controlled trial¹¹ demonstrated fluoxetine’s efficacy in BPD. In 1 study, Salzman et al¹² found fluoxetine’s greatest impact was on “anger,” a major affective dimension of BPD.

Mood stabilizers. When valproic acid emerged as a successful treatment for bipolar disorder, researchers turned their attention to mood-stabilizing anticonvulsants for BPD. Numerous case series and controlled trials provided evidence of its efficacy.^13,14 This was the first time subtypes of BPD patients were tested prospectively—with the hypothesis that the mood-stabilizing anticonvulsants would diminish impulsivity and aggression. The positive results of Hollander et al¹³ and Frankenburg and Zanarini¹⁴ in assessing divalproex in BPD patients with bipolar II disorder has implications for targeted treatment (discussed below).

Newer antipsychotics. The introduction of second-generation antipsychotics (SGA) led some researchers to explore whether these agents could decrease BPD symptoms. Case series¹⁵ and some (but not all) placebo-controlled trials have demonstrated benefit from SGAs such as olanzapine,^16-18 aripiprazole,¹⁹ and quetiapine.^20,21 Initial research on risperidone²² and ziprasidone also suggested efficacy for BPD. Two placebo-controlled studies of olanzapine examined which symptom groups were most helped; each reported a broad effect.^16,17 However, not all studies of SGAs for BPD patients have been positive.¹⁸ Further, metabolic side effects have been noted for several SGAs, including olanzapine.¹⁸

Omega-3 fatty acids. Some studies examining omega-3 fatty acids have sparked an ongoing interest in this compound. In an 8-week, double-blind, pilot study of 30 women with BPD, Zanarini²³ found omega-3 fatty acids demonstrated efficacy over placebo.

Targeted treatment

Most studies of BPD pharmacotherapy have used a classic clinical trial design, which does not easily translate into recommendations regarding medication selection for individual patients, especially those with BPD and comorbid illnesses. Also, existing trials have not fully explored starting doses, and no maintenance studies have been published. Therefore, many clinical application questions remain unresolved. However, some early treatment recommendations are supported by recent meta-analyses that demonstrate effects of medication classes for specific symptom domains.

Careful identification of comorbid psychiatric disorders is a rational first step. Diagnosing comorbid disorders, such as bipolar disorder, will determine medication choice and impact length of treatment. In a double-blind study of 30 women with BPD and comorbid bipolar II disorder, Frankenburg and Zanarini¹⁴ found divalproex had a statistically significant effect compared with placebo and could be considered for this specific population.

When treating a BPD patient who has a comorbid illness, it is important not to ignore BPD symptoms. The chronic emotional dysregulation and ongoing safety issues require psychiatrists to educate patients about these symptoms and to address them in a multidisciplinary manner.

Clarifying prominent symptom domains can help steer pharmacologic management. Many trials have attempted to focus on specific symptom domains, including cognitive-perceptual disturbances, impulsivity, and affective dysregulation. Table 1²⁴ lists BPD symptom domains and associated characteristics.

Table 1

Symptom domains of BPD

Dosing strategy

Developing a medication management strategy for BPD patients requires a thoughtful approach. When faced with a patient who has overwhelming distress, it is tempting to start with high medication doses; however, clinical experience suggests starting cautiously with lower doses will yield better tolerability and adherence. Based on our clinical experience, patients with BPD tend to be highly perceptive to physiologic stimuli and medication side effects.

Further research is needed to answer clinical questions regarding optimal dosing strategy and treatment, but some studies suggest when using SGAs, doses equivalent to one-third or one-half the dose used for treating schizophrenia may be appropriate.^1,2,17,18 However, for fluoxetine, investigators have espoused using a dosage higher than generally used for depression.¹⁰ For mood-stabilizing anticonvulsants, almost all studies employed the same doses used for bipolar disorder.²⁵ Some studies of valproic acid have verified appropriate blood levels—generally 50 to 100 μg/mL.

Controlled trials have not determined whether medications for patients with BPD should be used briefly during times of stress or for longer periods. Many studies of medication for BPD have been relatively brief trials that explored whether the drug has any potential efficacy. In our opinion, this issue currently is being addressed in clinical practice in a trial-and-error manner.

Clues to targeted treatment

Although pharmacotherapy for BPD subtypes remains controversial, recent meta-analyses by Ingenhoven²⁴ and Nose²⁶ and a Cochrane Review²⁷ (with subsequent online update²⁸) have identified evidence that supports the use of specific medications for treating BPD symptoms. These studies’ authors acknowledge replication studies are required because of the limited nature of the available data. In contrast, a meta-analysis conducted by the National Collaborating Centre for Mental Health²⁹ did not identify sufficient evidence for medication use in BPD on which to base official guidelines to advise health care providers in the United Kingdom. The only medication recommendation in this meta-analysis is to consider prescribing short-term sedative antihistamines during crises; this recommendation is not supported by any clinical trial.

In a meta-analysis of 21 placebo-controlled trials of patients with BPD and/or schizotypal personality disorder, Inghoven et al²⁴ used multiple domains and subdomains, including cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, affective dysregulation, anger, and mood lability, to assess the efficacy of medication use (Table 2).²⁴ They found:

• Antipsychotics seemed to have a moderate effect on cognitive-perceptual symptoms and a moderate-to-large effect on anger.
• Antidepressants had a small effect on anxiety, but no other domains.
• Mood stabilizers had a very large effect on impulsive-behavioral dyscontrol and anger, a large effect on anxiety, and a moderate effect on depressed mood.
• Regarding global functioning, mood stabilizers had a greater effect than antipsychotics. Both led to greater change than antidepressants.

A 2010 Cochrane Review meta-analysis initially conducted by Leib²⁷ with subsequent online update by Stoffers²⁸ included 28 studies with a total of 1,742 patients and also identified symptom-targeted BPD domains. This study analyzed pooled data and found support for the use of specific medications, including certain antipsychotics, mood stabilizers, and antidepressants, for specific BPD symptoms (Table 3).²⁸ The authors recommended data be interpreted cautiously, however, because many of the clinical trials included in their meta-analysis have not been replicated and generalizability from research populations to clinical populations is not well understood.

Table 2

Which medications improve which BPD symptoms?

Table 3

Pharmacotherapy for BPD: Results of a Cochrane review

DBT and pharmacotherapy

As is the case with many studies of psychiatric medications, early efficacy studies of pharmacotherapy for BPD did not include structured psychosocial treatment. In 2 double-blind, placebo-controlled trials with a total of 84 patients receiving DBT, those assigned to olanzapine had better outcomes on objective rating scales than those on placebo.^30,31 Similar trials testing fluoxetine showed no advantage for the drug over placebo.³² In a pilot study by Moen et al,²⁵ 17 patients were assigned to “condensed DBT” before being randomized to divalproex extended release or placebo. Two patients remitted in the first 4 weeks and continued to improve without medication. If replicated, this finding may point to a targeted approach to the timing of medication initiation.

Clinical recommendations

Randomized, placebo-controlled BPD trials have demonstrated striking improvements in patients in placebo groups, which may be attributed to the powerful therapeutic impact of regular, structured, nonjudgmental interactions within a research protocol. Prescribers can enhance a medication’s therapeutic effect by keeping in mind the same principles that apply to treatment of other common psychiatric disorders.

Patients with BPD respond well to validation of their symptoms and their experience. Tell patients you take their BPD symptoms seriously and acknowledge their distress. The goal is to partner with patients to improve function, decrease reactivity, and reduce emotional pain. When working with BPD patients, it is appropriate to communicate a sense of optimism and hopefulness about their prognosis and treatment. Performing this approach in a caring way will better preserve the therapeutic alliance.

Additional suggestions based on our clinical experience include:

• Provide regular medication management visits.
• Consider using a structured symptom rating scale to evaluate symptoms over time, such as the Zanarini Rating Scale for Borderline Personality Disorder³³ or Borderline Evaluation of Severity Over Time.³⁴
• Educate patients with BPD about the disorder by making the appropriate diagnosis and providing reputable educational materials (see Related Resources).
• Do not diagnose a patient with BPD as having bipolar disorder unless they clearly meet criteria for bipolar disorder.
• Communicate your limitations in advance.
• Orient the patient to the possibility of needing to try different medications to determine the most helpful agent or combination.
• Do not de-emphasize risks of medications or side effects. Serious symptoms require medications that bear a risk of side effects; communicate these risks to patients and carefully weigh the risk-benefit profile.
• Inform patients you will be responsive to making appropriate changes if problems arise that are associated with pharmacotherapy and outweigh the benefit of medication.

Multidisciplinary teamwork

Best outcomes for patients with BPD are facilitated by a collaborative team effort. Such an approach addresses both the psychological and biologic underpinnings of the disorder and can significantly decrease the possibility of “splitting” among team members. To determine ways in which a therapist and physician may work together, clinicians should discuss the:

• meaning of medication to the therapist, psychiatrist, and patient
• potential benefits and limitations of medication
• the role of medication in the patient’s overall treatment.³⁵

Patients with BPD experience emotional crisis. At times, prescribing patterns unfortunately reflect the practice of adding medications to address emotional crisis. This practice may partially account for the high rates of polypharmacy in BPD patients.³⁶ Patients with BPD will benefit from interacting with a clinician whose approach is responsive, validating, and non-reactive to the patient’s symptoms and experiences. A comprehensive treatment approach includes screening and treating comorbid conditions, providing education about the diagnosis, and multidisciplinary involvement combined with rational, targeted pharmacotherapy.

Related Resources

• Friedel RO. Borderline personality disorder demystified: an essential guide for understanding and living with BPD. New York, NY: Marlowe & Company; 2004.
• Chapman A, Gratz K. Borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications, Inc; 2007.
• National Education Alliance for Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.

Drug Brand Names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thiothixene • Navane
• Topiramate • Topamax, Topiragen
• Tranylcypromine • Parnate
• Trifluoperazine • Stelazine
• Valproic acid • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Nelson receives research/grant support from the Minnesota Medical Foundation.

Dr. Schulz receives research/grant support from AstraZeneca, Otsuka, and Rules-Based Medicine and is a consultant to Bioavail, Bristol-Myers Squibb, and Eli Lilly and Company.

As psychiatry’s understanding of borderline personality disorder (BPD) grows, the literature clearly describes the seriousness of BPD, as well as these patients’ high utilization of treatment. Pharmacotherapy for BPD remains controversial. The most recent American Psychiatric Association practice guidelines focus on using symptom domains of this heterogeneous illness to guide medication selection, yet when these guidelines were published, there was a lack of data to support this recommendation.¹

This article evaluates medications for BPD and emerging data supporting matching medications to BPD symptom domains, with an emphasis on making choices that advance clinical practice. We conclude by reviewing studies of combined pharmacotherapy and dialectical behavior therapy (DBT) and describing how a multidisciplinary team approach can enhance BPD treatment.

Early research

Early studies of pharmacotherapy for BPD began after the development of the Diagnostic Interview for Borderlines^2,3 and DSM-III criteria for BPD.⁴ Researchers recruited patients who fulfilled the diagnostic criteria; however, these participants’ symptom profiles were highly heterogeneous. Although such studies can be useful when starting to test new treatments—especially if they are able to show efficacy over placebo or explore safety—they are less helpful in guiding clinical practice.

During the 1980s, low doses of first-generation antipsychotics were evaluated based on hypotheses that BPD was related to schizophrenia. Case series⁵ and placebo-controlled trials^6,7 pointed to symptom reduction over time and greater than placebo for BPD patients. Interestingly, in a small study of BPD inpatients, Soloff et al⁸ compared the first-generation antipsychotic haloperidol to amitriptyline and found amitriptyline led to symptom worsening in some patients. Cowdry and Gardner⁹ compared alprazolam, carbamazepine, trifluoperazine, and tranylcypromine in a double-blind, placebo-controlled crossover trial of 16 female BPD outpatients. They found antipsychotics were not useful. Further, the study found behavioral disinhibition when a benzodiazepine (alprazolam) was used alone in impulsive patients.

These studies provided a basis for the idea that medications could help reduce BPD symptoms. However, some early investigators noted that antipsychotics’ side effects led some patients to discontinue treatment.⁶

Next-generation studies

Antidepressants. Interest in exploring pharmacologic treatments for BPD diminished after the early efficacy trials. Several events led to a reemergence of this interest, including the FDA’s approval of the selective serotonin reuptake inhibitor fluoxetine for depression in 1987. Some investigators hypothesized fluoxetine’s antidepressant properties could help treat BPD symptoms and perhaps the serotonin reuptake action could diminish impulsivity.¹⁰ Case series and a double-blind, placebo-controlled trial¹¹ demonstrated fluoxetine’s efficacy in BPD. In 1 study, Salzman et al¹² found fluoxetine’s greatest impact was on “anger,” a major affective dimension of BPD.

Mood stabilizers. When valproic acid emerged as a successful treatment for bipolar disorder, researchers turned their attention to mood-stabilizing anticonvulsants for BPD. Numerous case series and controlled trials provided evidence of its efficacy.^13,14 This was the first time subtypes of BPD patients were tested prospectively—with the hypothesis that the mood-stabilizing anticonvulsants would diminish impulsivity and aggression. The positive results of Hollander et al¹³ and Frankenburg and Zanarini¹⁴ in assessing divalproex in BPD patients with bipolar II disorder has implications for targeted treatment (discussed below).

Newer antipsychotics. The introduction of second-generation antipsychotics (SGA) led some researchers to explore whether these agents could decrease BPD symptoms. Case series¹⁵ and some (but not all) placebo-controlled trials have demonstrated benefit from SGAs such as olanzapine,^16-18 aripiprazole,¹⁹ and quetiapine.^20,21 Initial research on risperidone²² and ziprasidone also suggested efficacy for BPD. Two placebo-controlled studies of olanzapine examined which symptom groups were most helped; each reported a broad effect.^16,17 However, not all studies of SGAs for BPD patients have been positive.¹⁸ Further, metabolic side effects have been noted for several SGAs, including olanzapine.¹⁸

Omega-3 fatty acids. Some studies examining omega-3 fatty acids have sparked an ongoing interest in this compound. In an 8-week, double-blind, pilot study of 30 women with BPD, Zanarini²³ found omega-3 fatty acids demonstrated efficacy over placebo.

Targeted treatment

Most studies of BPD pharmacotherapy have used a classic clinical trial design, which does not easily translate into recommendations regarding medication selection for individual patients, especially those with BPD and comorbid illnesses. Also, existing trials have not fully explored starting doses, and no maintenance studies have been published. Therefore, many clinical application questions remain unresolved. However, some early treatment recommendations are supported by recent meta-analyses that demonstrate effects of medication classes for specific symptom domains.

Careful identification of comorbid psychiatric disorders is a rational first step. Diagnosing comorbid disorders, such as bipolar disorder, will determine medication choice and impact length of treatment. In a double-blind study of 30 women with BPD and comorbid bipolar II disorder, Frankenburg and Zanarini¹⁴ found divalproex had a statistically significant effect compared with placebo and could be considered for this specific population.

When treating a BPD patient who has a comorbid illness, it is important not to ignore BPD symptoms. The chronic emotional dysregulation and ongoing safety issues require psychiatrists to educate patients about these symptoms and to address them in a multidisciplinary manner.

Clarifying prominent symptom domains can help steer pharmacologic management. Many trials have attempted to focus on specific symptom domains, including cognitive-perceptual disturbances, impulsivity, and affective dysregulation. Table 1²⁴ lists BPD symptom domains and associated characteristics.

Table 1

Symptom domains of BPD

Dosing strategy

Developing a medication management strategy for BPD patients requires a thoughtful approach. When faced with a patient who has overwhelming distress, it is tempting to start with high medication doses; however, clinical experience suggests starting cautiously with lower doses will yield better tolerability and adherence. Based on our clinical experience, patients with BPD tend to be highly perceptive to physiologic stimuli and medication side effects.

Further research is needed to answer clinical questions regarding optimal dosing strategy and treatment, but some studies suggest when using SGAs, doses equivalent to one-third or one-half the dose used for treating schizophrenia may be appropriate.^1,2,17,18 However, for fluoxetine, investigators have espoused using a dosage higher than generally used for depression.¹⁰ For mood-stabilizing anticonvulsants, almost all studies employed the same doses used for bipolar disorder.²⁵ Some studies of valproic acid have verified appropriate blood levels—generally 50 to 100 μg/mL.

Controlled trials have not determined whether medications for patients with BPD should be used briefly during times of stress or for longer periods. Many studies of medication for BPD have been relatively brief trials that explored whether the drug has any potential efficacy. In our opinion, this issue currently is being addressed in clinical practice in a trial-and-error manner.

Clues to targeted treatment

Although pharmacotherapy for BPD subtypes remains controversial, recent meta-analyses by Ingenhoven²⁴ and Nose²⁶ and a Cochrane Review²⁷ (with subsequent online update²⁸) have identified evidence that supports the use of specific medications for treating BPD symptoms. These studies’ authors acknowledge replication studies are required because of the limited nature of the available data. In contrast, a meta-analysis conducted by the National Collaborating Centre for Mental Health²⁹ did not identify sufficient evidence for medication use in BPD on which to base official guidelines to advise health care providers in the United Kingdom. The only medication recommendation in this meta-analysis is to consider prescribing short-term sedative antihistamines during crises; this recommendation is not supported by any clinical trial.

In a meta-analysis of 21 placebo-controlled trials of patients with BPD and/or schizotypal personality disorder, Inghoven et al²⁴ used multiple domains and subdomains, including cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, affective dysregulation, anger, and mood lability, to assess the efficacy of medication use (Table 2).²⁴ They found:

• Antipsychotics seemed to have a moderate effect on cognitive-perceptual symptoms and a moderate-to-large effect on anger.
• Antidepressants had a small effect on anxiety, but no other domains.
• Mood stabilizers had a very large effect on impulsive-behavioral dyscontrol and anger, a large effect on anxiety, and a moderate effect on depressed mood.
• Regarding global functioning, mood stabilizers had a greater effect than antipsychotics. Both led to greater change than antidepressants.

A 2010 Cochrane Review meta-analysis initially conducted by Leib²⁷ with subsequent online update by Stoffers²⁸ included 28 studies with a total of 1,742 patients and also identified symptom-targeted BPD domains. This study analyzed pooled data and found support for the use of specific medications, including certain antipsychotics, mood stabilizers, and antidepressants, for specific BPD symptoms (Table 3).²⁸ The authors recommended data be interpreted cautiously, however, because many of the clinical trials included in their meta-analysis have not been replicated and generalizability from research populations to clinical populations is not well understood.

Table 2

Which medications improve which BPD symptoms?

Table 3

Pharmacotherapy for BPD: Results of a Cochrane review

DBT and pharmacotherapy

As is the case with many studies of psychiatric medications, early efficacy studies of pharmacotherapy for BPD did not include structured psychosocial treatment. In 2 double-blind, placebo-controlled trials with a total of 84 patients receiving DBT, those assigned to olanzapine had better outcomes on objective rating scales than those on placebo.^30,31 Similar trials testing fluoxetine showed no advantage for the drug over placebo.³² In a pilot study by Moen et al,²⁵ 17 patients were assigned to “condensed DBT” before being randomized to divalproex extended release or placebo. Two patients remitted in the first 4 weeks and continued to improve without medication. If replicated, this finding may point to a targeted approach to the timing of medication initiation.

Clinical recommendations

Randomized, placebo-controlled BPD trials have demonstrated striking improvements in patients in placebo groups, which may be attributed to the powerful therapeutic impact of regular, structured, nonjudgmental interactions within a research protocol. Prescribers can enhance a medication’s therapeutic effect by keeping in mind the same principles that apply to treatment of other common psychiatric disorders.

Patients with BPD respond well to validation of their symptoms and their experience. Tell patients you take their BPD symptoms seriously and acknowledge their distress. The goal is to partner with patients to improve function, decrease reactivity, and reduce emotional pain. When working with BPD patients, it is appropriate to communicate a sense of optimism and hopefulness about their prognosis and treatment. Performing this approach in a caring way will better preserve the therapeutic alliance.

Additional suggestions based on our clinical experience include:

• Provide regular medication management visits.
• Consider using a structured symptom rating scale to evaluate symptoms over time, such as the Zanarini Rating Scale for Borderline Personality Disorder³³ or Borderline Evaluation of Severity Over Time.³⁴
• Educate patients with BPD about the disorder by making the appropriate diagnosis and providing reputable educational materials (see Related Resources).
• Do not diagnose a patient with BPD as having bipolar disorder unless they clearly meet criteria for bipolar disorder.
• Communicate your limitations in advance.
• Orient the patient to the possibility of needing to try different medications to determine the most helpful agent or combination.
• Do not de-emphasize risks of medications or side effects. Serious symptoms require medications that bear a risk of side effects; communicate these risks to patients and carefully weigh the risk-benefit profile.
• Inform patients you will be responsive to making appropriate changes if problems arise that are associated with pharmacotherapy and outweigh the benefit of medication.

Multidisciplinary teamwork

Best outcomes for patients with BPD are facilitated by a collaborative team effort. Such an approach addresses both the psychological and biologic underpinnings of the disorder and can significantly decrease the possibility of “splitting” among team members. To determine ways in which a therapist and physician may work together, clinicians should discuss the:

• meaning of medication to the therapist, psychiatrist, and patient
• potential benefits and limitations of medication
• the role of medication in the patient’s overall treatment.³⁵

Patients with BPD experience emotional crisis. At times, prescribing patterns unfortunately reflect the practice of adding medications to address emotional crisis. This practice may partially account for the high rates of polypharmacy in BPD patients.³⁶ Patients with BPD will benefit from interacting with a clinician whose approach is responsive, validating, and non-reactive to the patient’s symptoms and experiences. A comprehensive treatment approach includes screening and treating comorbid conditions, providing education about the diagnosis, and multidisciplinary involvement combined with rational, targeted pharmacotherapy.

Related Resources

• Friedel RO. Borderline personality disorder demystified: an essential guide for understanding and living with BPD. New York, NY: Marlowe & Company; 2004.
• Chapman A, Gratz K. Borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications, Inc; 2007.
• National Education Alliance for Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.

Drug Brand Names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thiothixene • Navane
• Topiramate • Topamax, Topiragen
• Tranylcypromine • Parnate
• Trifluoperazine • Stelazine
• Valproic acid • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Nelson receives research/grant support from the Minnesota Medical Foundation.

Dr. Schulz receives research/grant support from AstraZeneca, Otsuka, and Rules-Based Medicine and is a consultant to Bioavail, Bristol-Myers Squibb, and Eli Lilly and Company.

As psychiatry’s understanding of borderline personality disorder (BPD) grows, the literature clearly describes the seriousness of BPD, as well as these patients’ high utilization of treatment. Pharmacotherapy for BPD remains controversial. The most recent American Psychiatric Association practice guidelines focus on using symptom domains of this heterogeneous illness to guide medication selection, yet when these guidelines were published, there was a lack of data to support this recommendation.¹

This article evaluates medications for BPD and emerging data supporting matching medications to BPD symptom domains, with an emphasis on making choices that advance clinical practice. We conclude by reviewing studies of combined pharmacotherapy and dialectical behavior therapy (DBT) and describing how a multidisciplinary team approach can enhance BPD treatment.

Early research

Early studies of pharmacotherapy for BPD began after the development of the Diagnostic Interview for Borderlines^2,3 and DSM-III criteria for BPD.⁴ Researchers recruited patients who fulfilled the diagnostic criteria; however, these participants’ symptom profiles were highly heterogeneous. Although such studies can be useful when starting to test new treatments—especially if they are able to show efficacy over placebo or explore safety—they are less helpful in guiding clinical practice.

During the 1980s, low doses of first-generation antipsychotics were evaluated based on hypotheses that BPD was related to schizophrenia. Case series⁵ and placebo-controlled trials^6,7 pointed to symptom reduction over time and greater than placebo for BPD patients. Interestingly, in a small study of BPD inpatients, Soloff et al⁸ compared the first-generation antipsychotic haloperidol to amitriptyline and found amitriptyline led to symptom worsening in some patients. Cowdry and Gardner⁹ compared alprazolam, carbamazepine, trifluoperazine, and tranylcypromine in a double-blind, placebo-controlled crossover trial of 16 female BPD outpatients. They found antipsychotics were not useful. Further, the study found behavioral disinhibition when a benzodiazepine (alprazolam) was used alone in impulsive patients.

These studies provided a basis for the idea that medications could help reduce BPD symptoms. However, some early investigators noted that antipsychotics’ side effects led some patients to discontinue treatment.⁶

Next-generation studies

Antidepressants. Interest in exploring pharmacologic treatments for BPD diminished after the early efficacy trials. Several events led to a reemergence of this interest, including the FDA’s approval of the selective serotonin reuptake inhibitor fluoxetine for depression in 1987. Some investigators hypothesized fluoxetine’s antidepressant properties could help treat BPD symptoms and perhaps the serotonin reuptake action could diminish impulsivity.¹⁰ Case series and a double-blind, placebo-controlled trial¹¹ demonstrated fluoxetine’s efficacy in BPD. In 1 study, Salzman et al¹² found fluoxetine’s greatest impact was on “anger,” a major affective dimension of BPD.

Mood stabilizers. When valproic acid emerged as a successful treatment for bipolar disorder, researchers turned their attention to mood-stabilizing anticonvulsants for BPD. Numerous case series and controlled trials provided evidence of its efficacy.^13,14 This was the first time subtypes of BPD patients were tested prospectively—with the hypothesis that the mood-stabilizing anticonvulsants would diminish impulsivity and aggression. The positive results of Hollander et al¹³ and Frankenburg and Zanarini¹⁴ in assessing divalproex in BPD patients with bipolar II disorder has implications for targeted treatment (discussed below).

Newer antipsychotics. The introduction of second-generation antipsychotics (SGA) led some researchers to explore whether these agents could decrease BPD symptoms. Case series¹⁵ and some (but not all) placebo-controlled trials have demonstrated benefit from SGAs such as olanzapine,^16-18 aripiprazole,¹⁹ and quetiapine.^20,21 Initial research on risperidone²² and ziprasidone also suggested efficacy for BPD. Two placebo-controlled studies of olanzapine examined which symptom groups were most helped; each reported a broad effect.^16,17 However, not all studies of SGAs for BPD patients have been positive.¹⁸ Further, metabolic side effects have been noted for several SGAs, including olanzapine.¹⁸

Omega-3 fatty acids. Some studies examining omega-3 fatty acids have sparked an ongoing interest in this compound. In an 8-week, double-blind, pilot study of 30 women with BPD, Zanarini²³ found omega-3 fatty acids demonstrated efficacy over placebo.

Targeted treatment

Most studies of BPD pharmacotherapy have used a classic clinical trial design, which does not easily translate into recommendations regarding medication selection for individual patients, especially those with BPD and comorbid illnesses. Also, existing trials have not fully explored starting doses, and no maintenance studies have been published. Therefore, many clinical application questions remain unresolved. However, some early treatment recommendations are supported by recent meta-analyses that demonstrate effects of medication classes for specific symptom domains.

Careful identification of comorbid psychiatric disorders is a rational first step. Diagnosing comorbid disorders, such as bipolar disorder, will determine medication choice and impact length of treatment. In a double-blind study of 30 women with BPD and comorbid bipolar II disorder, Frankenburg and Zanarini¹⁴ found divalproex had a statistically significant effect compared with placebo and could be considered for this specific population.

When treating a BPD patient who has a comorbid illness, it is important not to ignore BPD symptoms. The chronic emotional dysregulation and ongoing safety issues require psychiatrists to educate patients about these symptoms and to address them in a multidisciplinary manner.

Clarifying prominent symptom domains can help steer pharmacologic management. Many trials have attempted to focus on specific symptom domains, including cognitive-perceptual disturbances, impulsivity, and affective dysregulation. Table 1²⁴ lists BPD symptom domains and associated characteristics.

Table 1

Symptom domains of BPD

Dosing strategy

Developing a medication management strategy for BPD patients requires a thoughtful approach. When faced with a patient who has overwhelming distress, it is tempting to start with high medication doses; however, clinical experience suggests starting cautiously with lower doses will yield better tolerability and adherence. Based on our clinical experience, patients with BPD tend to be highly perceptive to physiologic stimuli and medication side effects.

Further research is needed to answer clinical questions regarding optimal dosing strategy and treatment, but some studies suggest when using SGAs, doses equivalent to one-third or one-half the dose used for treating schizophrenia may be appropriate.^1,2,17,18 However, for fluoxetine, investigators have espoused using a dosage higher than generally used for depression.¹⁰ For mood-stabilizing anticonvulsants, almost all studies employed the same doses used for bipolar disorder.²⁵ Some studies of valproic acid have verified appropriate blood levels—generally 50 to 100 μg/mL.

Controlled trials have not determined whether medications for patients with BPD should be used briefly during times of stress or for longer periods. Many studies of medication for BPD have been relatively brief trials that explored whether the drug has any potential efficacy. In our opinion, this issue currently is being addressed in clinical practice in a trial-and-error manner.

Clues to targeted treatment

Although pharmacotherapy for BPD subtypes remains controversial, recent meta-analyses by Ingenhoven²⁴ and Nose²⁶ and a Cochrane Review²⁷ (with subsequent online update²⁸) have identified evidence that supports the use of specific medications for treating BPD symptoms. These studies’ authors acknowledge replication studies are required because of the limited nature of the available data. In contrast, a meta-analysis conducted by the National Collaborating Centre for Mental Health²⁹ did not identify sufficient evidence for medication use in BPD on which to base official guidelines to advise health care providers in the United Kingdom. The only medication recommendation in this meta-analysis is to consider prescribing short-term sedative antihistamines during crises; this recommendation is not supported by any clinical trial.

In a meta-analysis of 21 placebo-controlled trials of patients with BPD and/or schizotypal personality disorder, Inghoven et al²⁴ used multiple domains and subdomains, including cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, affective dysregulation, anger, and mood lability, to assess the efficacy of medication use (Table 2).²⁴ They found:

• Antipsychotics seemed to have a moderate effect on cognitive-perceptual symptoms and a moderate-to-large effect on anger.
• Antidepressants had a small effect on anxiety, but no other domains.
• Mood stabilizers had a very large effect on impulsive-behavioral dyscontrol and anger, a large effect on anxiety, and a moderate effect on depressed mood.
• Regarding global functioning, mood stabilizers had a greater effect than antipsychotics. Both led to greater change than antidepressants.

A 2010 Cochrane Review meta-analysis initially conducted by Leib²⁷ with subsequent online update by Stoffers²⁸ included 28 studies with a total of 1,742 patients and also identified symptom-targeted BPD domains. This study analyzed pooled data and found support for the use of specific medications, including certain antipsychotics, mood stabilizers, and antidepressants, for specific BPD symptoms (Table 3).²⁸ The authors recommended data be interpreted cautiously, however, because many of the clinical trials included in their meta-analysis have not been replicated and generalizability from research populations to clinical populations is not well understood.

Table 2

Which medications improve which BPD symptoms?

Table 3

Pharmacotherapy for BPD: Results of a Cochrane review

DBT and pharmacotherapy

As is the case with many studies of psychiatric medications, early efficacy studies of pharmacotherapy for BPD did not include structured psychosocial treatment. In 2 double-blind, placebo-controlled trials with a total of 84 patients receiving DBT, those assigned to olanzapine had better outcomes on objective rating scales than those on placebo.^30,31 Similar trials testing fluoxetine showed no advantage for the drug over placebo.³² In a pilot study by Moen et al,²⁵ 17 patients were assigned to “condensed DBT” before being randomized to divalproex extended release or placebo. Two patients remitted in the first 4 weeks and continued to improve without medication. If replicated, this finding may point to a targeted approach to the timing of medication initiation.

Clinical recommendations

Randomized, placebo-controlled BPD trials have demonstrated striking improvements in patients in placebo groups, which may be attributed to the powerful therapeutic impact of regular, structured, nonjudgmental interactions within a research protocol. Prescribers can enhance a medication’s therapeutic effect by keeping in mind the same principles that apply to treatment of other common psychiatric disorders.

Patients with BPD respond well to validation of their symptoms and their experience. Tell patients you take their BPD symptoms seriously and acknowledge their distress. The goal is to partner with patients to improve function, decrease reactivity, and reduce emotional pain. When working with BPD patients, it is appropriate to communicate a sense of optimism and hopefulness about their prognosis and treatment. Performing this approach in a caring way will better preserve the therapeutic alliance.

Additional suggestions based on our clinical experience include:

• Provide regular medication management visits.
• Consider using a structured symptom rating scale to evaluate symptoms over time, such as the Zanarini Rating Scale for Borderline Personality Disorder³³ or Borderline Evaluation of Severity Over Time.³⁴
• Educate patients with BPD about the disorder by making the appropriate diagnosis and providing reputable educational materials (see Related Resources).
• Do not diagnose a patient with BPD as having bipolar disorder unless they clearly meet criteria for bipolar disorder.
• Communicate your limitations in advance.
• Orient the patient to the possibility of needing to try different medications to determine the most helpful agent or combination.
• Do not de-emphasize risks of medications or side effects. Serious symptoms require medications that bear a risk of side effects; communicate these risks to patients and carefully weigh the risk-benefit profile.
• Inform patients you will be responsive to making appropriate changes if problems arise that are associated with pharmacotherapy and outweigh the benefit of medication.

Multidisciplinary teamwork

Best outcomes for patients with BPD are facilitated by a collaborative team effort. Such an approach addresses both the psychological and biologic underpinnings of the disorder and can significantly decrease the possibility of “splitting” among team members. To determine ways in which a therapist and physician may work together, clinicians should discuss the:

• meaning of medication to the therapist, psychiatrist, and patient
• potential benefits and limitations of medication
• the role of medication in the patient’s overall treatment.³⁵

Patients with BPD experience emotional crisis. At times, prescribing patterns unfortunately reflect the practice of adding medications to address emotional crisis. This practice may partially account for the high rates of polypharmacy in BPD patients.³⁶ Patients with BPD will benefit from interacting with a clinician whose approach is responsive, validating, and non-reactive to the patient’s symptoms and experiences. A comprehensive treatment approach includes screening and treating comorbid conditions, providing education about the diagnosis, and multidisciplinary involvement combined with rational, targeted pharmacotherapy.

Related Resources

• Friedel RO. Borderline personality disorder demystified: an essential guide for understanding and living with BPD. New York, NY: Marlowe & Company; 2004.
• Chapman A, Gratz K. Borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications, Inc; 2007.
• National Education Alliance for Borderline Personality Disorder. www.borderlinepersonalitydisorder.com.

Drug Brand Names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thiothixene • Navane
• Topiramate • Topamax, Topiragen
• Tranylcypromine • Parnate
• Trifluoperazine • Stelazine
• Valproic acid • Depakote
• Ziprasidone • Geodon

Disclosure

Dr. Nelson receives research/grant support from the Minnesota Medical Foundation.

Dr. Schulz receives research/grant support from AstraZeneca, Otsuka, and Rules-Based Medicine and is a consultant to Bioavail, Bristol-Myers Squibb, and Eli Lilly and Company.

Discuss this article at www.facebook.com/CurrentPsychiatry

Does prescribing stimulants to patients with attention-deficit/hyperactivity disorder (ADHD) increase their risk of future substance abuse? Because ADHD is a common pediatric condition with symptoms that often persist into adulthood, and stimulants are an efficacious first-line therapy, this possible association is a concern for psychiatrists whether they treat children or adults.

Some researchers have expressed concerns that stimulant exposure could predispose patients to future substance abuse.¹ Proponents of the biologic model of “kindling” hypothesize early exposure to stimulants could increase the risk of later substance use disorders (SUDs) by modifying or “priming” the brain, which then becomes more receptive to illicit drug exposure. Although there is some evidence that stimulant use does increase SUD risk, other evidence suggests stimulant use does not increase susceptibility to SUDs^2,3 and some studies have suggested stimulant use in ADHD patients may protect against SUDs.^4,5

This article reviews shared characteristics of ADHD and SUDs and the latest research on the association between the clinical use of stimulants and later development of SUDs. We also offer clinical recommendations for assessing and treating ADHD and comorbid SUD.

ADHD/SUD overlap

Compared with those without the disorder, patients with ADHD have a 6.2 times higher risk of developing an SUD.⁶ Individuals with ADHD experience an earlier age of onset and a longer duration of SUDs.⁷ Several retrospective and prospective studies reveal ADHD is a risk factor for SUDs.⁸ A longitudinal study that tracked teenage males with or without ADHD into young adulthood found SUDs were 4 times more common among those with ADHD.⁹ Up to 45% of adults with ADHD have a history of alcohol abuse or dependence, and up to 30% have a history of illegal drug abuse or dependence.¹⁰

Conversely, an estimated 35% to 71% of alcohol abusers and 15% to 25% of substance-dependent patients have ADHD.¹¹ Adults with ADHD and comorbid SUD report earlier onset¹² and greater severity¹³ of substance abuse than adults without ADHD. Patients with ADHD experience earlier onset and higher rates of tobacco smoking by mid-adolescence.¹⁴

Developmental psychopathology. Longitudinal studies have suggested certain psychopathologic characteristics of ADHD can predispose an individual to SUDs independent of stimulant exposure. For example, inattention, impulsivity, and hyperactivity predispose an individual to develop an SUD and also are core symptoms of ADHD.¹⁵ Another study found impulsivity, impersistence, and difficulty sitting still at age 3 predicted alcohol abuse at age 21.¹⁶ A different longitudinal study found novelty-seeking behavior (restlessness, running/jumping and not keeping still, being squirmy and fidgety) between age 6 to 10 predicted adolescent drug abuse and cigarette smoking.¹⁷ Poor response inhibition is a key characteristic of ADHD and has been linked to adolescent drinking.¹⁸

ADHD may be an independent risk factor for SUD because a common neurobiologic psychopathology may predispose an individual to develop both conditions. The dopamine system has been implicated in SUD, and dysfunction in the dopaminergic circuits—mostly in basal and frontal cortex with consequent defects in executive function and reward system—also has been found in ADHD.¹⁹ Cognitive dysfunction associated with ADHD may decrease a patient’s ability to estimate the negative consequences of substance abuse and to delay immediate gratification from drug or alcohol use.

ADHD patients are more vulnerable to SUDs if they have a comorbid condition, such as oppositional defiant disorder,^13,20 bipolar disorder,^20,21 or conduct disorder (CD).^20,22 Patients with ADHD and comorbid CD are estimated to be 8.8 times more likely to have an SUD before age 18 compared with those with ADHD alone.²³ Comorbid ADHD and CD may increase patients’ predisposition to develop dependence on highly addictive drugs, such as cocaine or methamphetamine.²⁴ Impaired executive function, behavioral dyscontrol, impulsivity, and peer rejection are common in both ADHD and CD and may increase the risk of developing SUDs in individuals who have both conditions.²⁵ Other risk factors for SUDs in patients with ADHD are listed in Table 1.²⁶

Table 1

Risk factors for SUDs in patients with ADHD

Stimulants’ affect on SUD risk

Increased risk. Limited studies suggest exposure to stimulants is a risk factor for developing SUDs. In a longitudinal study, Lambert et al²⁷ followed 218 patients with ADHD and 182 without ADHD into adulthood and found a linear trend between duration of stimulant treatment and prevalence of cocaine dependence. ADHD patients exposed to stimulants for >1 year had the highest prevalence of cocaine abuse (27%), compared with untreated subjects (15%), or those treated with stimulants for <1 year (18%). However, the study did not control for comorbid contributing factors, such as CD.

No change. In a 10-year naturalistic study, Biederman et al²⁸ followed 109 children with ADHD age 7 to 12 into adulthood. These children had a developmental reading disorder but no other psychiatric comorbidities. When comparing patients who were treated with methylphenidate (n = 43) with those who did not receive stimulants (n = 66), Bierderman et al found no significant difference between the 2 groups in the prevalence of SUD for any of the 7 drug categories studied.

Decreased risk. Two meta-analyses found children with ADHD who were treated with stimulants and followed until adolescence were 5.8 times less likely to develop SUDs compared with those who did not receive stimulants.^28,29 This protective effect diminished when patients were followed into adulthood, but individuals treated with stimulants were 1.4 times less likely to develop SUDs than those not treated with stimulants.³⁰ In a prospective case-control, 5-year follow-up study of 114 patients with ADHD treated with stimulants, Wilens et al³¹ found significant protective effects of stimulant treatment on the development of any SUD. They found no effects from time of onset or duration of stimulant therapy on subsequent risk of SUDs or cigarette smoking.

One possible explanation for stimulants’ apparently reduced protective effect among adults is for patients with ADHD, stimulant use might delay but not prevent SUDs. It also is likely that by adulthood, loss of parental supervision leads to poor medication adherence and increased susceptibility to SUDs.³⁰

Other studies have found exposure to stimulants may protect against SUDs. Katusic et al²³ reviewed medical records for documented SUDs in 295 adults with ADHD treated with stimulants and 84 who did not receive stimulants. They found 20% of patients who received stimulants had a documented SUD compared with 27% of those not treated with stimulants. Barkely et al³² followed 98 stimulant-treated and 21 untreated ADHD patients with a mean age of 15 and 21, respectively. They found stimulant treatment did not increase the risk for substance use or abuse in either group.

ADHD and stimulant abuse

The prevalence of stimulant misuse is as high as 9% in patients in grade school and high school and up to 35% in college-age individuals.³³ ADHD patients who misuse stimulants (eg, escalating dose without authorization) or skip stimulant doses to use illicit drugs or alcohol are more likely to sell their medication.³⁴ Immediate-release stimulant formulations are more liable to be abused than extended-release drugs because they achieve earlier peak drug concentrations and dopamine blockade, indicating rapid drug absorption and central drug activity. Close monitoring and use of extended-release formulations are useful deterrents against stimulant abuse.

Clinical recommendations

Detecting and treating SUDs in patients with ADHD can be challenging. Ideally, the best time to assess for ADHD symptoms is after a prolonged abstinence from any influencing substance. However, in most clinical situations this is not practical. A better approach is a longitudinal assessment for ADHD symptoms. Detecting evidence of early childhood onset of ADHD symptoms before the patient began using substances can be helpful in conducting a proper differential diagnosis. Assessing for symptoms of SUDs in early adolescence, along with serial assessment of ADHD symptoms, also can be helpful. Symptoms secondary to ADHD are likely to show a consistent pattern, whereas symptoms secondary to an SUD may be sporadic.

When assessing SUD risk, consider the patient’s clinical condition, history of comorbidities that suggest SUDs, and overall functional status. Collateral information about the patient’s behavior and substance abuse from family members is important. A history of CD, bipolar disorder, or antisocial personality disorder should raise concerns about potential future stimulant abuse or diversion. Close monitoring of patients suspected of having an SUD is essential to detect stimulant abuse or diversion, which often manifests as weight loss, requests for higher doses, requests to switch from long-acting or extended-release formulations to immediate-release formulations, and repeated and suspicious “lost prescriptions.” Close observation for other subtle signs—such as changes in personality or mood and unexplained accidents or injuries—also may be needed.³⁵

Challenges of treating ADHD and co-occurring SUD include poor medication adherence, need for a higher therapeutic stimulant dose, and difficulty in assessing the therapeutic benefit of pharmacotherapy in the presence of an SUD.³⁶ Treating ADHD comorbid with SUD requires a collaborative approach that involves a psychiatrist, family members, and a behavioral care provider in addition to frequent monitoring.³⁴

In the absence of treatment guidelines for treating ADHD with comorbid SUDs, some clinicians prefer to stabilize the SUD before initiating stimulants. Others prefer to use nonstimulants (such as atomoxetine, guanfacine, bupropion, venlafaxine, tricyclic antidepressants, or modafinil) as a first-line treatment. However, nonstimulants have not demonstrated efficacy comparable to that of stimulants for ADHD.³⁵

Table 2 offers clinical recommendations to minimize the risk of SUDs when treating ADHD patients with stimulants. Long-acting stimulant formulations are preferred over short-acting medications because they are less likely to be abused. Psychosocial interventions for treating ADHD and co-occurring SUD disorder include cognitive-behavioral therapy with emphasis on structured skills training and cognitive remediation.

Table 2

Minimizing SUD risk when treating ADHD patients with stimulants

Related Resource

• Faraone SV, Wilens T. Does stimulant treatment lead to substance use disorders? J Clin Psychiatry. 2003;64(suppl 11):9-13.
• Upadhyaya HP, Rose K, Wang W, et al. Attention deficit hyperactivity disorder medication and substance use patterns among adolescents and young adults. J Child Adolesc Psychopharmacol. 2005;15:799-809.
• Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict. 2007;16(suppl 1):45-56.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Guanfacine • Tenex, Intuniv
• Methylphenidate • Ritalin
• Modafinil • Provigil
• Venlafaxine • Effexor

Disclosures

Dr. Shailesh Jain and Dr. Islam report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rakesh Jain has received research support from, is a consultant to, and/or is a speaker for Addrenex Pharmaceuticals, AstraZeneca, Eli Lilly and Company, Forest Pharmaceuticals, Merck, Pamlab, Pfizer Inc., Shionogi Inc., Shire, and Sunovion Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Does prescribing stimulants to patients with attention-deficit/hyperactivity disorder (ADHD) increase their risk of future substance abuse? Because ADHD is a common pediatric condition with symptoms that often persist into adulthood, and stimulants are an efficacious first-line therapy, this possible association is a concern for psychiatrists whether they treat children or adults.

Some researchers have expressed concerns that stimulant exposure could predispose patients to future substance abuse.¹ Proponents of the biologic model of “kindling” hypothesize early exposure to stimulants could increase the risk of later substance use disorders (SUDs) by modifying or “priming” the brain, which then becomes more receptive to illicit drug exposure. Although there is some evidence that stimulant use does increase SUD risk, other evidence suggests stimulant use does not increase susceptibility to SUDs^2,3 and some studies have suggested stimulant use in ADHD patients may protect against SUDs.^4,5

This article reviews shared characteristics of ADHD and SUDs and the latest research on the association between the clinical use of stimulants and later development of SUDs. We also offer clinical recommendations for assessing and treating ADHD and comorbid SUD.

ADHD/SUD overlap

Compared with those without the disorder, patients with ADHD have a 6.2 times higher risk of developing an SUD.⁶ Individuals with ADHD experience an earlier age of onset and a longer duration of SUDs.⁷ Several retrospective and prospective studies reveal ADHD is a risk factor for SUDs.⁸ A longitudinal study that tracked teenage males with or without ADHD into young adulthood found SUDs were 4 times more common among those with ADHD.⁹ Up to 45% of adults with ADHD have a history of alcohol abuse or dependence, and up to 30% have a history of illegal drug abuse or dependence.¹⁰

Conversely, an estimated 35% to 71% of alcohol abusers and 15% to 25% of substance-dependent patients have ADHD.¹¹ Adults with ADHD and comorbid SUD report earlier onset¹² and greater severity¹³ of substance abuse than adults without ADHD. Patients with ADHD experience earlier onset and higher rates of tobacco smoking by mid-adolescence.¹⁴

Developmental psychopathology. Longitudinal studies have suggested certain psychopathologic characteristics of ADHD can predispose an individual to SUDs independent of stimulant exposure. For example, inattention, impulsivity, and hyperactivity predispose an individual to develop an SUD and also are core symptoms of ADHD.¹⁵ Another study found impulsivity, impersistence, and difficulty sitting still at age 3 predicted alcohol abuse at age 21.¹⁶ A different longitudinal study found novelty-seeking behavior (restlessness, running/jumping and not keeping still, being squirmy and fidgety) between age 6 to 10 predicted adolescent drug abuse and cigarette smoking.¹⁷ Poor response inhibition is a key characteristic of ADHD and has been linked to adolescent drinking.¹⁸

ADHD may be an independent risk factor for SUD because a common neurobiologic psychopathology may predispose an individual to develop both conditions. The dopamine system has been implicated in SUD, and dysfunction in the dopaminergic circuits—mostly in basal and frontal cortex with consequent defects in executive function and reward system—also has been found in ADHD.¹⁹ Cognitive dysfunction associated with ADHD may decrease a patient’s ability to estimate the negative consequences of substance abuse and to delay immediate gratification from drug or alcohol use.

ADHD patients are more vulnerable to SUDs if they have a comorbid condition, such as oppositional defiant disorder,^13,20 bipolar disorder,^20,21 or conduct disorder (CD).^20,22 Patients with ADHD and comorbid CD are estimated to be 8.8 times more likely to have an SUD before age 18 compared with those with ADHD alone.²³ Comorbid ADHD and CD may increase patients’ predisposition to develop dependence on highly addictive drugs, such as cocaine or methamphetamine.²⁴ Impaired executive function, behavioral dyscontrol, impulsivity, and peer rejection are common in both ADHD and CD and may increase the risk of developing SUDs in individuals who have both conditions.²⁵ Other risk factors for SUDs in patients with ADHD are listed in Table 1.²⁶

Table 1

Risk factors for SUDs in patients with ADHD

Stimulants’ affect on SUD risk

Increased risk. Limited studies suggest exposure to stimulants is a risk factor for developing SUDs. In a longitudinal study, Lambert et al²⁷ followed 218 patients with ADHD and 182 without ADHD into adulthood and found a linear trend between duration of stimulant treatment and prevalence of cocaine dependence. ADHD patients exposed to stimulants for >1 year had the highest prevalence of cocaine abuse (27%), compared with untreated subjects (15%), or those treated with stimulants for <1 year (18%). However, the study did not control for comorbid contributing factors, such as CD.

No change. In a 10-year naturalistic study, Biederman et al²⁸ followed 109 children with ADHD age 7 to 12 into adulthood. These children had a developmental reading disorder but no other psychiatric comorbidities. When comparing patients who were treated with methylphenidate (n = 43) with those who did not receive stimulants (n = 66), Bierderman et al found no significant difference between the 2 groups in the prevalence of SUD for any of the 7 drug categories studied.

Decreased risk. Two meta-analyses found children with ADHD who were treated with stimulants and followed until adolescence were 5.8 times less likely to develop SUDs compared with those who did not receive stimulants.^28,29 This protective effect diminished when patients were followed into adulthood, but individuals treated with stimulants were 1.4 times less likely to develop SUDs than those not treated with stimulants.³⁰ In a prospective case-control, 5-year follow-up study of 114 patients with ADHD treated with stimulants, Wilens et al³¹ found significant protective effects of stimulant treatment on the development of any SUD. They found no effects from time of onset or duration of stimulant therapy on subsequent risk of SUDs or cigarette smoking.

One possible explanation for stimulants’ apparently reduced protective effect among adults is for patients with ADHD, stimulant use might delay but not prevent SUDs. It also is likely that by adulthood, loss of parental supervision leads to poor medication adherence and increased susceptibility to SUDs.³⁰

Other studies have found exposure to stimulants may protect against SUDs. Katusic et al²³ reviewed medical records for documented SUDs in 295 adults with ADHD treated with stimulants and 84 who did not receive stimulants. They found 20% of patients who received stimulants had a documented SUD compared with 27% of those not treated with stimulants. Barkely et al³² followed 98 stimulant-treated and 21 untreated ADHD patients with a mean age of 15 and 21, respectively. They found stimulant treatment did not increase the risk for substance use or abuse in either group.

ADHD and stimulant abuse

The prevalence of stimulant misuse is as high as 9% in patients in grade school and high school and up to 35% in college-age individuals.³³ ADHD patients who misuse stimulants (eg, escalating dose without authorization) or skip stimulant doses to use illicit drugs or alcohol are more likely to sell their medication.³⁴ Immediate-release stimulant formulations are more liable to be abused than extended-release drugs because they achieve earlier peak drug concentrations and dopamine blockade, indicating rapid drug absorption and central drug activity. Close monitoring and use of extended-release formulations are useful deterrents against stimulant abuse.

Clinical recommendations

Detecting and treating SUDs in patients with ADHD can be challenging. Ideally, the best time to assess for ADHD symptoms is after a prolonged abstinence from any influencing substance. However, in most clinical situations this is not practical. A better approach is a longitudinal assessment for ADHD symptoms. Detecting evidence of early childhood onset of ADHD symptoms before the patient began using substances can be helpful in conducting a proper differential diagnosis. Assessing for symptoms of SUDs in early adolescence, along with serial assessment of ADHD symptoms, also can be helpful. Symptoms secondary to ADHD are likely to show a consistent pattern, whereas symptoms secondary to an SUD may be sporadic.

When assessing SUD risk, consider the patient’s clinical condition, history of comorbidities that suggest SUDs, and overall functional status. Collateral information about the patient’s behavior and substance abuse from family members is important. A history of CD, bipolar disorder, or antisocial personality disorder should raise concerns about potential future stimulant abuse or diversion. Close monitoring of patients suspected of having an SUD is essential to detect stimulant abuse or diversion, which often manifests as weight loss, requests for higher doses, requests to switch from long-acting or extended-release formulations to immediate-release formulations, and repeated and suspicious “lost prescriptions.” Close observation for other subtle signs—such as changes in personality or mood and unexplained accidents or injuries—also may be needed.³⁵

Challenges of treating ADHD and co-occurring SUD include poor medication adherence, need for a higher therapeutic stimulant dose, and difficulty in assessing the therapeutic benefit of pharmacotherapy in the presence of an SUD.³⁶ Treating ADHD comorbid with SUD requires a collaborative approach that involves a psychiatrist, family members, and a behavioral care provider in addition to frequent monitoring.³⁴

In the absence of treatment guidelines for treating ADHD with comorbid SUDs, some clinicians prefer to stabilize the SUD before initiating stimulants. Others prefer to use nonstimulants (such as atomoxetine, guanfacine, bupropion, venlafaxine, tricyclic antidepressants, or modafinil) as a first-line treatment. However, nonstimulants have not demonstrated efficacy comparable to that of stimulants for ADHD.³⁵

Table 2 offers clinical recommendations to minimize the risk of SUDs when treating ADHD patients with stimulants. Long-acting stimulant formulations are preferred over short-acting medications because they are less likely to be abused. Psychosocial interventions for treating ADHD and co-occurring SUD disorder include cognitive-behavioral therapy with emphasis on structured skills training and cognitive remediation.

Table 2

Minimizing SUD risk when treating ADHD patients with stimulants

Related Resource

• Faraone SV, Wilens T. Does stimulant treatment lead to substance use disorders? J Clin Psychiatry. 2003;64(suppl 11):9-13.
• Upadhyaya HP, Rose K, Wang W, et al. Attention deficit hyperactivity disorder medication and substance use patterns among adolescents and young adults. J Child Adolesc Psychopharmacol. 2005;15:799-809.
• Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict. 2007;16(suppl 1):45-56.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Guanfacine • Tenex, Intuniv
• Methylphenidate • Ritalin
• Modafinil • Provigil
• Venlafaxine • Effexor

Disclosures

Dr. Shailesh Jain and Dr. Islam report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rakesh Jain has received research support from, is a consultant to, and/or is a speaker for Addrenex Pharmaceuticals, AstraZeneca, Eli Lilly and Company, Forest Pharmaceuticals, Merck, Pamlab, Pfizer Inc., Shionogi Inc., Shire, and Sunovion Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Does prescribing stimulants to patients with attention-deficit/hyperactivity disorder (ADHD) increase their risk of future substance abuse? Because ADHD is a common pediatric condition with symptoms that often persist into adulthood, and stimulants are an efficacious first-line therapy, this possible association is a concern for psychiatrists whether they treat children or adults.

Some researchers have expressed concerns that stimulant exposure could predispose patients to future substance abuse.¹ Proponents of the biologic model of “kindling” hypothesize early exposure to stimulants could increase the risk of later substance use disorders (SUDs) by modifying or “priming” the brain, which then becomes more receptive to illicit drug exposure. Although there is some evidence that stimulant use does increase SUD risk, other evidence suggests stimulant use does not increase susceptibility to SUDs^2,3 and some studies have suggested stimulant use in ADHD patients may protect against SUDs.^4,5

This article reviews shared characteristics of ADHD and SUDs and the latest research on the association between the clinical use of stimulants and later development of SUDs. We also offer clinical recommendations for assessing and treating ADHD and comorbid SUD.

ADHD/SUD overlap

Compared with those without the disorder, patients with ADHD have a 6.2 times higher risk of developing an SUD.⁶ Individuals with ADHD experience an earlier age of onset and a longer duration of SUDs.⁷ Several retrospective and prospective studies reveal ADHD is a risk factor for SUDs.⁸ A longitudinal study that tracked teenage males with or without ADHD into young adulthood found SUDs were 4 times more common among those with ADHD.⁹ Up to 45% of adults with ADHD have a history of alcohol abuse or dependence, and up to 30% have a history of illegal drug abuse or dependence.¹⁰

Conversely, an estimated 35% to 71% of alcohol abusers and 15% to 25% of substance-dependent patients have ADHD.¹¹ Adults with ADHD and comorbid SUD report earlier onset¹² and greater severity¹³ of substance abuse than adults without ADHD. Patients with ADHD experience earlier onset and higher rates of tobacco smoking by mid-adolescence.¹⁴

Developmental psychopathology. Longitudinal studies have suggested certain psychopathologic characteristics of ADHD can predispose an individual to SUDs independent of stimulant exposure. For example, inattention, impulsivity, and hyperactivity predispose an individual to develop an SUD and also are core symptoms of ADHD.¹⁵ Another study found impulsivity, impersistence, and difficulty sitting still at age 3 predicted alcohol abuse at age 21.¹⁶ A different longitudinal study found novelty-seeking behavior (restlessness, running/jumping and not keeping still, being squirmy and fidgety) between age 6 to 10 predicted adolescent drug abuse and cigarette smoking.¹⁷ Poor response inhibition is a key characteristic of ADHD and has been linked to adolescent drinking.¹⁸

ADHD may be an independent risk factor for SUD because a common neurobiologic psychopathology may predispose an individual to develop both conditions. The dopamine system has been implicated in SUD, and dysfunction in the dopaminergic circuits—mostly in basal and frontal cortex with consequent defects in executive function and reward system—also has been found in ADHD.¹⁹ Cognitive dysfunction associated with ADHD may decrease a patient’s ability to estimate the negative consequences of substance abuse and to delay immediate gratification from drug or alcohol use.

ADHD patients are more vulnerable to SUDs if they have a comorbid condition, such as oppositional defiant disorder,^13,20 bipolar disorder,^20,21 or conduct disorder (CD).^20,22 Patients with ADHD and comorbid CD are estimated to be 8.8 times more likely to have an SUD before age 18 compared with those with ADHD alone.²³ Comorbid ADHD and CD may increase patients’ predisposition to develop dependence on highly addictive drugs, such as cocaine or methamphetamine.²⁴ Impaired executive function, behavioral dyscontrol, impulsivity, and peer rejection are common in both ADHD and CD and may increase the risk of developing SUDs in individuals who have both conditions.²⁵ Other risk factors for SUDs in patients with ADHD are listed in Table 1.²⁶

Table 1

Risk factors for SUDs in patients with ADHD

Stimulants’ affect on SUD risk

Increased risk. Limited studies suggest exposure to stimulants is a risk factor for developing SUDs. In a longitudinal study, Lambert et al²⁷ followed 218 patients with ADHD and 182 without ADHD into adulthood and found a linear trend between duration of stimulant treatment and prevalence of cocaine dependence. ADHD patients exposed to stimulants for >1 year had the highest prevalence of cocaine abuse (27%), compared with untreated subjects (15%), or those treated with stimulants for <1 year (18%). However, the study did not control for comorbid contributing factors, such as CD.

No change. In a 10-year naturalistic study, Biederman et al²⁸ followed 109 children with ADHD age 7 to 12 into adulthood. These children had a developmental reading disorder but no other psychiatric comorbidities. When comparing patients who were treated with methylphenidate (n = 43) with those who did not receive stimulants (n = 66), Bierderman et al found no significant difference between the 2 groups in the prevalence of SUD for any of the 7 drug categories studied.

Decreased risk. Two meta-analyses found children with ADHD who were treated with stimulants and followed until adolescence were 5.8 times less likely to develop SUDs compared with those who did not receive stimulants.^28,29 This protective effect diminished when patients were followed into adulthood, but individuals treated with stimulants were 1.4 times less likely to develop SUDs than those not treated with stimulants.³⁰ In a prospective case-control, 5-year follow-up study of 114 patients with ADHD treated with stimulants, Wilens et al³¹ found significant protective effects of stimulant treatment on the development of any SUD. They found no effects from time of onset or duration of stimulant therapy on subsequent risk of SUDs or cigarette smoking.

One possible explanation for stimulants’ apparently reduced protective effect among adults is for patients with ADHD, stimulant use might delay but not prevent SUDs. It also is likely that by adulthood, loss of parental supervision leads to poor medication adherence and increased susceptibility to SUDs.³⁰

Other studies have found exposure to stimulants may protect against SUDs. Katusic et al²³ reviewed medical records for documented SUDs in 295 adults with ADHD treated with stimulants and 84 who did not receive stimulants. They found 20% of patients who received stimulants had a documented SUD compared with 27% of those not treated with stimulants. Barkely et al³² followed 98 stimulant-treated and 21 untreated ADHD patients with a mean age of 15 and 21, respectively. They found stimulant treatment did not increase the risk for substance use or abuse in either group.

ADHD and stimulant abuse

The prevalence of stimulant misuse is as high as 9% in patients in grade school and high school and up to 35% in college-age individuals.³³ ADHD patients who misuse stimulants (eg, escalating dose without authorization) or skip stimulant doses to use illicit drugs or alcohol are more likely to sell their medication.³⁴ Immediate-release stimulant formulations are more liable to be abused than extended-release drugs because they achieve earlier peak drug concentrations and dopamine blockade, indicating rapid drug absorption and central drug activity. Close monitoring and use of extended-release formulations are useful deterrents against stimulant abuse.

Clinical recommendations

Detecting and treating SUDs in patients with ADHD can be challenging. Ideally, the best time to assess for ADHD symptoms is after a prolonged abstinence from any influencing substance. However, in most clinical situations this is not practical. A better approach is a longitudinal assessment for ADHD symptoms. Detecting evidence of early childhood onset of ADHD symptoms before the patient began using substances can be helpful in conducting a proper differential diagnosis. Assessing for symptoms of SUDs in early adolescence, along with serial assessment of ADHD symptoms, also can be helpful. Symptoms secondary to ADHD are likely to show a consistent pattern, whereas symptoms secondary to an SUD may be sporadic.

When assessing SUD risk, consider the patient’s clinical condition, history of comorbidities that suggest SUDs, and overall functional status. Collateral information about the patient’s behavior and substance abuse from family members is important. A history of CD, bipolar disorder, or antisocial personality disorder should raise concerns about potential future stimulant abuse or diversion. Close monitoring of patients suspected of having an SUD is essential to detect stimulant abuse or diversion, which often manifests as weight loss, requests for higher doses, requests to switch from long-acting or extended-release formulations to immediate-release formulations, and repeated and suspicious “lost prescriptions.” Close observation for other subtle signs—such as changes in personality or mood and unexplained accidents or injuries—also may be needed.³⁵

Challenges of treating ADHD and co-occurring SUD include poor medication adherence, need for a higher therapeutic stimulant dose, and difficulty in assessing the therapeutic benefit of pharmacotherapy in the presence of an SUD.³⁶ Treating ADHD comorbid with SUD requires a collaborative approach that involves a psychiatrist, family members, and a behavioral care provider in addition to frequent monitoring.³⁴

In the absence of treatment guidelines for treating ADHD with comorbid SUDs, some clinicians prefer to stabilize the SUD before initiating stimulants. Others prefer to use nonstimulants (such as atomoxetine, guanfacine, bupropion, venlafaxine, tricyclic antidepressants, or modafinil) as a first-line treatment. However, nonstimulants have not demonstrated efficacy comparable to that of stimulants for ADHD.³⁵

Table 2 offers clinical recommendations to minimize the risk of SUDs when treating ADHD patients with stimulants. Long-acting stimulant formulations are preferred over short-acting medications because they are less likely to be abused. Psychosocial interventions for treating ADHD and co-occurring SUD disorder include cognitive-behavioral therapy with emphasis on structured skills training and cognitive remediation.

Table 2

Minimizing SUD risk when treating ADHD patients with stimulants

Related Resource

• Faraone SV, Wilens T. Does stimulant treatment lead to substance use disorders? J Clin Psychiatry. 2003;64(suppl 11):9-13.
• Upadhyaya HP, Rose K, Wang W, et al. Attention deficit hyperactivity disorder medication and substance use patterns among adolescents and young adults. J Child Adolesc Psychopharmacol. 2005;15:799-809.
• Mariani JJ, Levin FR. Treatment strategies for co-occurring ADHD and substance use disorders. Am J Addict. 2007;16(suppl 1):45-56.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Guanfacine • Tenex, Intuniv
• Methylphenidate • Ritalin
• Modafinil • Provigil
• Venlafaxine • Effexor

Disclosures

Dr. Shailesh Jain and Dr. Islam report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Rakesh Jain has received research support from, is a consultant to, and/or is a speaker for Addrenex Pharmaceuticals, AstraZeneca, Eli Lilly and Company, Forest Pharmaceuticals, Merck, Pamlab, Pfizer Inc., Shionogi Inc., Shire, and Sunovion Pharmaceuticals.

A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

A disease that affects 10%-15% of women of reproductive age, endometriosis is quite prevalent. In 1990, investigators in Belgium first described deep endometriosis to highlight the diagnostic and therapeutic aspects of the disease (Fertil. Steril. 1990;53:978–83). In contrast to superficial disease, deep endometriosis constitutes the most severe form of endometriosis and includes nodules affecting the pouch of Douglas, retrocervical area, bladder, ureter, or the intestinal wall. Less frequently, the rectovaginal septum is involved (Arq. Gastroenterol. 2003;40:192–7). The treatment of bowel endometriosis is challenging, as it is a benign disease that may infiltrate the bowel, requiring a surgical treatment with increased risks.

Preoperative Diagnosis Using Imaging

The definitive diagnosis of deep endometriosis with bowel involvement is reached principally at the time of surgery. However, some clinical characteristics identified by history and physical examination, laboratory tests, and diagnostic imaging may raise suspicion for this form of endometriosis. A surgical approach is still recommended for confirmation and treatment.

Transvaginal ultrasonography (TVUS) still appears to be the superior imaging technique, providing the best cost-benefit ratio for cases of ovarian or deep endometriosis. The presence of a hypoechoic lesion located in the posterior pelvic compartment (see

When performed after complete bowel preparation and during the perimenstrual phase, TVUS carried out by a trained professional provides useful information for therapeutic management.

MRI can be performed to identify deep lesions. (See

Excretory urography or uro-MRI also is useful for evaluating whether the ureters are involved. When urinary tract involvement is suspected, one of these types of imaging should be performed to fully document the state of the urinary tract before surgery.

If we have doubts about the bowel involvement even after TVUS with bowel preparation, we recommend rectal echoendoscopy. (See

Rectal echoendoscopy also permits identification of the distance between the lesion and the rectal lumen, as well as identification of extrinsic compression and lesions of the rectal submucosa. This information can be critical in the preoperative planning of the type of surgery required and the need to have the help of a colorectal surgeon. The chart on page 19 shows the algorithm for preoperative work-up depending on clinical and TVUS findings.

Treatment: Clinical or Surgical?

Medical treatment of deep endometriosis, as opposed to surgical treatment, remains controversial. Dr. Luigi Fedele and his associates in Italy reported a substantial improvement in pain during 6 months of treatment with GnRH analogs (Am. J. Obstet. Gynecol. 2000;183:1462–7). Similar improvements in pain were also observed by our group with both an intrauterine device medicated with levonorgestrel and with a GnRH analog (Hum. Reprod. 2005;20:1993–8). In Dr. Fedele's study, however, an early relapse occurred following discontinuation of treatment. In addition, the endometriotic lesions underwent a discrete but significant reduction in size as detected by TVUS during treatment, but returned to their original size 6 months after suspension of GnRH treatment.

In cases of intractable pain (measured by scores greater than 7 in the visual analog scale) and/or two previously failed IVF cycles, surgical treatment is required. Access for surgical treatment may be by laparotomy or laparoscopy, depending on the surgeon's experience; however, laparoscopy can provide a better visualization of the lesions, allowing a more precise excision.

Surgical Preparation and Technique

Whenever there is clinical suspicion of deep endometriosis, adequate presurgical bowel preparation is indicated. We recommend the use of 3–4 liters of an oral solution of polyethylene glycol (PEG) the day before surgery, followed by one or two Fleet enemas or a mannitol preparation.

Administration of antibiotics should be carried out during anesthetic induction, preferably using a second-generation cephalosporin (2 g intravenously).

When the preoperative rectal ultrasound permits identification of the depth of the lesion, this information can be used to define the type of surgery that will be performed. In the case of unifocal lesions less than 3 cm in size (major diameter) and affecting the serous and external muscular layers of the rectum or sigmoid, resection of the nodule alone may be indicated. This procedure may be done manually or with the help of a circular stapler. (

Our technique approached laparoscopically is as follows:

▸ The lesion on the rectosigmoid is delineated, and adhesions are lysed from contiguous organs such as adnexae, the uterus, or other loops of bowel. We prefer to use scissors or a hook.

▸ To resect the lesion manually (without the use of a disposable stapler), the endometriotic nodule is excised, taking care not to leave any residual disease behind. The defect is then repaired in a double-layer fashion. On the mucosal layer, 3–0 absorbable suture is used in a running and transverse manner to avoid bowel constriction. On the seromuscular layer, 3–0 permanent suture is used in a running manner to imbricate over the first layer.

▸ If a circular stapler is used, the following steps are followed: A stitch is placed in the lesion in order to invaginate it into the stapler. (See

▸ The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

If, on the other hand, the lesion is deeper, affecting the deep muscle or the submucosal or mucosal layers, then segmental resection of the bowel is recommended. Complete surgical resection of endometrial foci has been shown to result in improved quality of life and decreased rates of recurrence (Fertil. Steril. 2004;82:878–84).

Segmental resection of the rectosigmoid can be performed laparoscopically (J. Minim. Invasive Gynecol. 2008;15:280–5). Our technique involves the following steps:

▸ Both ureters are identified (see

▸ The mesosigmoid is divided with an ultrasonic device.

▸ A linear stapler is utilized on the rectosigmoid distal to the lesion.

▸ After excision of all endometriotic implants, the right-lower trocar site is extended to 4 cm in order to remove the surgical specimen(s) and to prepare the proximal stump. (See

▸ An incision is made on the proximal stump in order to insert the anvil of the circular stapler.

▸ A purse-string suture holding the anvil in place is performed prior to replacement of the sigmoid into the abdominal cavity.

▸ The 4-cm fascial incision is closed in order to finish the procedure laparoscopically.

▸ The circular stapler is inserted through the anus in order to complete the end-to-end reanastomosis. The anastomosis is tested by gently injecting air and/or methylene blue through the rectum (with an Asepto, or large bulb syringe) while the surgeon occludes the proximal sigmoid with an atraumatic instrument. Absence of air bubbles and/or methylene blue while the anastomotic site is submerged in sterile water in the pelvis confirms a tight anastomosis.

▸ A large drain is left adjacent to the anastomosis prior to closure of trocar sites. The drain is generally removed 4 days postoperatively.

Deep endometriosis is associated with more severe pain and significantly greater rates of infertility, compared with superficial endometriosis. Because of the high risks of surgical intervention, preoperative diagnosis using imaging modalities can be helpful in planning surgical strategy. Improved outcomes are achieved with complete surgical resection, which can be performed through minimally invasive techniques.

Download a mobile quick response (QR) code reader from your smartphone's app store to view a video by Dr. Abrão, or visit

www.aagl.org/obgynnews

Vitals

Rectal Endometriosis

www.isge.org

www.aagl.org

Deep endometriosis compromising the rectum continues to be a diagnostic and therapeutic challenge. The resultant pelvic pain, dyspareunia, dysmenorrhea, and infertility risk are well documented in literature. Despite the fact that there are numerous studies to evaluate deep endometriosis, including colonoscopy, MRI, vaginal and rectal ultrasound, and barium enema, there continues to be no standard road map for evaluation. In addition, there continues to be debate in the literature when patients should undergo shaving of the endometrioma, discoid resection of the endometrioma, or complete bowel resection.

Since the inception of the Master Class in Gynecologic Surgery, as Editor, I have used only experts who practice within the confines of the United States. However, given the internationally recognized expertise in both the diagnosis and treatment of deep and extensive endometriosis, I believed it was imperative to invite Dr. Mauricio S. Abrão to discuss the diagnosis and treatment of deep endometriosis compromising the rectum.

Dr. Abrão was born in São Paulo, Brazil in 1962, where he went on to complete medical school, and in 1988, his residency in obstetrics and gynecology. In 1989, Dr. Abrão founded the endometriosis division within the department of the teaching hospital of the University of São Paulo School of Medicine, where he currently is Docent Professor.

Since 2007, Dr. Abrão has been president of the Brazilian Society of Endometriosis and Minimally Invasive Endoscopy, and has been a board member of the World Endometriosis Society since 1998. He currently is on the board of trustees of the AAGL and is the chairman of the society's special interest group on endometriosis. Dr. Abrão is leading the AAGL initiative on producing a new classification on endometriosis. A prolific author, Dr. Abrão has nearly 100 papers published in peer-reviewed journals, the majority dealing with endometriosis.

It is with great admiration and respect that I introduce my friend, Dr. Abrão, to this edition of the Master Class in gynecologic surgery.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

They came for a second opinion. They were both in their 50s; she a lawyer, the husband a stockbroker. He had insulin dependent diabetes for 20 years but was otherwise well. She was concerned that her husband would die suddenly just as his father had at age 70. He was without symptoms but had a nuclear exercise stress test at the behest of his local medical doctor because of his diabetes.

The test was said to be abnormal, but three subsequent in-house readers found the results normal. He was advised to have an angiogram by another cardiologist. “What should we do?”

I told her that an angiogram or a stent would not prevent him from dying suddenly. I outlined all the pros and cons and advised against it. The wife was very anxious and wanted an angiogram so that her husband wouldn't die suddenly. They both left my office, never to be seen again.

A recent report by Dr. William B. Borden and colleagues (JAMA 2011;305:1882-9) examined the change in clinical practice in regard to percutaneous coronary intervention before and after the report of the COURAGE trial 4 years ago (N. Engl. J. Med. 2007;356:1503-16), which indicated that there was no mortality or morbidity benefit in patients with stable angina who received PCI when compared to optimal medical therapy.

Dr. Borden and colleagues presumed that the results of the COURAGE trial would transform clinical practice, and that most of the 293,795 patients in their study who went on to PCI in the COURAGE-like population would receive optimal medical therapy before PCI.

In fact, optimal medical therapy (defined as therapy with aspirin, a beta-blocker, an ACE inhibitor, and a statin) was used in 43.4% of the patients before COURAGE and in 45.0% after the COURAGE report. In COURAGE, 32% had diabetes, 12% of the patients were asymptomatic, and 30% had class I angina.

In the most recent analysis by Dr. Borden, one-third of patients (more than 70,000) had no angina prior to PCI. One must wonder what the perceived patient benefit was that led to the performance of a PCI in those patients.

My patient's other cardiologist advised angiography for my patient partly because of a concern for the early identification of ischemic heart disease in diabetic patients. Indeed, this concern had led the American Diabetes Association to recommend that in addition to standard secondary prevention therapy for both diabetes and coronary artery disease, patients with two or more risk factors for coronary artery disease undergo early screening (Diabetes Care 1998;13:1551-9).

These recommendations, however, were not evidence based, but made on the recommendation of an expert panel. The DIAD (Detection of Ischemia in Asymptomatic Diabetics) trial has since provided further insight into the issue of screening asymptomatic diabetic patients (JAMA 2009;301:1547-55), an issue that remains controversial.

Although not a randomized trial, DIAD indicates that the event rate in asymptomatic diabetic patients in general is low, and that a positive myocardial perfusion stress test did not identify patients who were at an increase risk of ischemic events.

Of the 522 asymptomatic patients screened, 409 (78%) had normal results, 50 (10%) had a small perfusion defect, and 33 (6%) had moderate or large perfusion defects. Although there was no significantly increased risk of cardiac events in patients with small defects when they were compared with those who had no perfusion defect, there was a sixfold increase risk in patients with moderate to large defects on myocardial perfusion imaging. Only 4.4% of patients went on to angiography, a decision driven by the clinical judgment of the patient's physician.

Of course, in my example, the greatest pressure for angiography came from the patient's wife, who was convinced that on the basis of conventional wisdom, myocardial perfusion imaging–guided PCI would identify a critical lesion that, when treated with PCI, would prolong her husband's life. And as a matter of fact, in order to prove the absence of coronary artery disease based on the normal perfusion test, I agreed to arrange an angiogram should they need reassurance that the test was normal. What would have eventuated should we have found a lesion remains for your conjecture.

But it is clear that there is an overabundance of angiograms being performed in asymptomatic patients, which more than likely leads to the performance of unnecessary PCIs in asymptomatic patients. Angiography has become the “carpenter's hammer,” with the little regard for its benefit.

A more reasonable and effective approach to diabetes patients (as well as other asymptomatic patients) is the institution of adequate primary prevention, which has been shown to have both morbidity and mortality benefits.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

It’s easy to know whether a critique of some article or other was written by a statistician or a methodologist—it states how badly the study was done and how incompetently the data were analyzed. Indeed, it is extremely easy to criticize any study, no matter how well it was conducted, because all applied research involves compromises of one sort or another. Well, be prepared for a surprise. In this column, we will be discussing a study that we believe was carried out well and analyzed correctly. That’s not to say that we agree with their conclusions (we don’t), but at least the study yields data that people can argue about without dismissing the paper as a whole.

Click on the PDF icon at the top of this introduction to read the full article.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Ying-Kei Hui, MD,1 Thomas Slattery, MD,2 Dale M. Frank, MD,3 Carol Dolinskas, MD,4 and David Henry, MD, FACP5
Departments of 1Internal Medicine, Pennsylvania Hospital; 2Radiology, Pennsylvania Hospital; 3Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania; 4Nuclear Medicine, Diagnostic Radiology, Pennsylvania Hospital; and 5Medicine, Pennsylvania Hospital, Philadelphia, PA

Multiple myeloma (MM) is a neoplastic proliferation of monoclonal plasma cells within the bone marrow, which overproduces immunoglobulin. This disorder accounts for approximately 1% of all reported neoplasms and 12%– 15% of all hematologic malignancies.1 It is the second most common hematologic malignancy diagnosed.2 The etiology is still not fully understood. MM typically affects older patients, ranging from 50–78 years (median, 61 years).3 Common clinical presentations include fatigue, anemia, renal failure, hypercalcemia, bone pain, and pathologic fractures.

Bone involvement in MM may vary at presentation. Most commonly, radiographic findings include multiple small, sharply defined, lytic, “punched-out” lesions without reactive bone formation, arising in the medullary cavity at sites of preserved hematopoiesis in adults (the axial skeleton). The pathophysiology of the bone findings is uncertain, though presumed to be resultant of either inhibition of osteoblastic activity and/ or activation of osteoclastic activity. Involvement of the cortex results in endosteal scalloping, with invasion of the periosteum and occasionally extraosseous extension. Lesions are most commonly seen in the vertebrae, ribs, skull, pelvic bones, and femur, in descending order of prevalence. Distal bone involvement is less common, though cases with predominant involvement in peripheral bones have been described. Uncommon radiographic presentations include diffuse skeletal osteopenia without focal lesions or sclerotic lesions. 4,5 To our knowledge, multiple bone infarcts as a complication of MM have not been reported in the medical literature.

Case presentation
A 47-year-old man with no significant medical history presented after the recent onset of painless hematuria, which spontaneously resolved after 2 days. He complained of left knee pain, which he noted after doing yard work.

Routine laboratory examination showed normocytic normochromic anemia, with a hemoglobin level of 11.5 g/dL and a mildly elevated alkaline phosphatase (ALP) level at 124 units/L. An MRI of the left knee showed increased red bone marrow within the distal femur and proximal tibia/fibula, initially thought to be compatible with anemia from an unexplained inflammatory process. Further urologic and gastroenterologic workup was negative.

Several months later, our patient was noted to have progressive fatigue, with a decrease in hemoglobin level to 10.6 g/dL and a mildly elevated erythrocyte sedimentation rate. Physical examination was otherwise unremarkable. A repeat MRI of both knees showed an extensive marrow infiltrative process, with multiple presumed secondary bone infarcts in the distal femora and proximal tibias, proximal fibulae, and patellae (Figure 1). A tandem skeletal survey showed mild diffuse osteopenia and several small, rounded, lytic foci in the skull (Figure 2), which were suspicious for MM. No focal radiographic lesions were seen (Figure 3).

Bone marrow biopsy from the left posterior iliac crest revealed hypocellular marrow (20%). An expansion of plasmacytoid cells with eccentrically placed, round nuclei, clumped chromatin, occasional nucleoli, and moderate amounts of eosinophilic cytoplasm accounted for 75% of the marrow cellularity. An aspirate smear demonstrated scattered mature plasma cells, accounting for roughly 15% of the total cellularity. Flow cytometry showed no overt evidence of marrow involvement by a lymphocytic clone. Bone biopsy was not performed in the areas of the knees seen to be abnormal on MRI examination.

Serum protein electrophoresis (SPEP) showed a band in the betagamma region. Immunofixation confirmed the presence of a monoclonal paraprotein, consisting predominantly of immunoglobulin A (IgA) heavy chain and kappa light chain. A bone marrow biopsy and aspirate showed replacement of most hematopoietic elements by sheets of mature plasma cells, accounting for 75% of the total marrow cellularity (Figure 4). Confirmatory immunostains were positive for CD138, CD117, and kappa light chain (Figure 5) and negative for CD79a and lambda light chain (Figure 6). A diagnosis of MM was made based on the finding of M protein in the urine, the presence of greater than 10% clonal plasma cells in bone marrow, and related clinical symptomatology (including anemia and hypercalcemia).

The patient was started on immunomodulating therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Autologous stem cell transplantation may be considered after appropriate treatment.

Discussion
We offer the case of a patient with MM who presented with bilateral knee infarcts. Synonyms of bone infarct include osteonecrosis, bone necrosis, avascular necrosis, aseptic necrosis, ischemic bone necrosis, and bone death.6 MRI is the most sensitive imaging modality for evaluation of the bone marrow. It can detect early osteonecrotic changes in bones well before they are visible on radiography7; this fact was exemplified in our case, in which the patient had only mild osteopenia on knee radiographs but extensive osteonecrotic changes on MRI examination.

Bone infarct more commonly involves the hips than the knees.7 Knee involvement can be differentiated into two main categories: primary and secondary. Primary, spontaneous, or idiopathic involvement tends to be unilateral and usually is seen in the elderly, although the recent literature suggests that many of these socalled spontaneous cases are actually secondary to subcortical microfractures, which are then complicated by osteonecrosis.5 Secondary causes tend to present at a younger age, with bilateral and multifocal involvement. Examples of secondary causes include steroid therapy, alcoholism, decompression syndrome, hemoglobinopathies (sickle cell disease), autoimmune disease (lupus and antiphospholipid disease), infections (human immunodeficiency virus), radiation, and trauma.8–15 Other causes, such as chemotherapy toxicity in pediatric leukemia16 and Gaucher disease, have been reported.7 Osteonecrosis of the jaw is a known treatment complication of bisphosphonate therapy in patients with MM17; however, there have been no previous reports describing the presentation of multifocal bone infarcts in both knees in patients with MM.

Although the pathogenesis of bone infarction is unclear, it is thought to be caused by the combined effects of systemic and local factors affecting the blood supply, vascular damage, increased intraosseous pressure, and mechanical stresses. These processes lead to compromise of the bone vasculature, resulting in the death of bone and marrow cells.9 In our case, MRI of both knees revealed an extensive marrow infiltrative process, which may have caused local vasculature damage and diminished blood supply resulting in bone infarctions.

Conclusion
Bone infarction of any joint is not a well-established complication of MM. Physicians should be aware of this potential presentation. Although there is no cure for MM, early recognition of MM can lead to more effective treatment, thus slowing disease progression and improving overall clinical outcomes.

Disclosures
The authors have no conflicts of interest to disclose.

References
1. Phekoo KJ, Schey SA, Richards MA, et al. A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK. Br J Haematol 2004;127:299–304.

 2. Esteve FR, Roodman GD. Pathophysiology of myeloma bone disease. Best Pract Res Clin Haematol 2007;20:613–624.

 3. Jain M, Ascensao J, Schechter GP. Familial myeloma and monoclonal gammopathy: a report of eight African American families. Am J Hematol 2009;84:34–38.

 4. Winterbottom AP, Shaw AS. Imaging patients with myeloma. Clin Radiol 2009;64:1–11.

 5. Resnick D. Diagnosis of Bone and Joint Disorders. Philadelphia, PA: WB Saunders; 2002:2188–2233.

 6. Stoller D, Tirman P, Bredella M, Branstetter R. Diagnostic Imaging: Orthopaedics. Philadelphia, PA: WB Saunders; 2003:82.

 7. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.

 8. Patel DV, Breazeale NM, Behr CT, Warren RF, Wickiewicz TL, O’Brien SJ. Osteonecrosis of the knee: current clinical concepts. Knee Surg Sports Traumatol Arthrosc 1998;6:2–11.

 9. Chang CC, Greenspan A, Gershwin ME. Osteonecrosis: current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 1993;23:47–69.

 10. Jones LC, Mont MA, Le TB, et al. Procoagulants and osteonecrosis. J Rheumatol 2003; 30:783–791.

 11. Saito N, Nadgir RN, Flower EN, Sakai O. Clinical and radiologic manifestations of sickle cell disease in the head and neck. Radiographics 2010;30:1021–1034.

 12. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med 2002;137:17–25.

 13. Mendenhall WM. Mandibular: osteoradionecrosis. J Clin Oncol 2004;22:4867–4868.

 14. Mok MY, Farewell VT, Isenberg DA. Risk factors for avascular necrosis of bone in patients with systemic lupus erythematosus: is there a role for antiphospholipid antibodies? Ann Rheum Dis 2000;59:462–467.

15. Kelman GJ, Williams GW, Colwell CW Jr, Walker RH. Steroid-related osteonecrosis of the knee: two case reports and a literature review. Clin Orthop Relat Res 1990;257:171–176.

 16. Karimova EJ, Wozniak A, Wu J, Neel MD, Kaste SC. How does osteonecrosis about the knee progress in young patients with leukemia? A 2- to 7-year study. Clin Orthop Relat Res 2010;468:2454–2459.

 17. Cafro AM, Barbarano L, Nosari AM, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: definition and management of the risk related to zoledronic acid. Clin Lymphoma Myeloma 2008;8:111–116.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

Fainting in children most often is benign. Often from a history alone, you can determine critical information that will enable you to reassure the patient and family or to consider referral for a specialist evaluation.

The most important thing to determine is the course of events that preceded the syncopal event. That is, if the child just completed a sporting activity on a hot day, was in a hot shower, had a high fever, or was dehydrated before fainting, the level of anxiety about the event should be very low. The same applies if the syncope was triggered by a sudden fright or other strong emotional event.

If the child is old enough to provide a good description of the event, ask if they “knew” that something was about to happen before they fainted. Most patients with routine syncope report an “aura” that includes visual changes (tunnel vision or vision getting dark, for example) and dizziness. Also, witnesses will say that the child “woke up” quickly and without prolonged confusion after the event. Such a description helps to distinguish a simple syncopal event from a seizure or a life-threatening arrhythmia.

With most benign cases of syncope, the pediatrician should counsel the child and the parents about adequate hydration before participation in sports and to be mindful of getting enough salt in the diet.

A normal history and physical examination should reassure you. In most cases, these normal findings will mean that you can treat the child in your office without further referrals.

Don't forget to take the child's blood pressure. Low resting blood pressure, especially in rapidly growing teenagers, can predispose your patients to vasovagal syncope. Patients with low resting blood pressure often have a lower threshold for syncope, compared with children with normal pressure. Recommend addition of some salt to the patient's diet if he has low blood pressure – this can help to reduce the risk of future syncope.

Injury prevention is important, because children who experience syncope often fall unexpectedly. The best strategy to minimize this risk is to review the symptoms that herald the onset of syncope with each patient. Then instruct the child if she experiences any of the warning signs to get to the floor with her legs elevated as soon as possible. This also will reduce the severity and the length of the episode.

Patients and parents will naturally have questions after the child experiences syncope. Although noncardiac conditions such as hypothyroidism or epilepsy can cause a child to faint, fainting is usually a failure of the heart to pump enough blood to the brain. Syncope can result from low blood pressure (dehydration, vasodilation), poor pumping function of the heart, other structural heart issues, and/or from a change in the rhythm that leads to less-efficient pumping. Rhythm changes include both fast and slow heart rates.

In the absence of any structural or electrical abnormality of the heart, the most common reason for fainting is vasovagal syncope. There are two sets of nerves that connect the central nervous system to the heart. The sympathetic system sends the “speed up” signal to the heart and the vagus nerve sends the “slow-down” signal to the heart. Vasovagal syncope occurs when the body sends an erroneous signal to the heart to slow down, insufficient blood is pumped, blood pressure falls, and the child faints.

During a syncopal work-up, most important structural heart issues, which can cause fainting, will be obvious on a physical examination. In almost all cases, children with cardiac disease significant enough to cause syncope will have been diagnosed previously. The exam can feature significant cardiac murmurs, peripheral edema, chest pain, jugular venous distension, hepatomegaly, and absent or diminished pulses. Patients with significant congenital heart disease most often will present with shortness of breath on exertion. If you rule out these findings and the patient has a normal examination, you can be virtually certain that the event is not related to a structural heart problem.

If there is any doubt, an echocardiogram is the definitive test to rule out a subtle structural abnormality. Hypertrophic cardiomyopathies and coronary anomalies are among the conditions that may contribute to syncope and may only be detectable with specialized cardiac imaging.

The child with recurrent syncopal events or with an atypical history most often requires additional evaluation by a specialist, usually to reassure the family. When I see a patient for the first time, I take a thorough history and order an ECG to detect the most common electrical/arrhythmic reasons for syncope. A diagnosis of Wolff-Parkinson-White syndrome, heart block, and long QT syndrome can easily be identified from a routine ECG. Holter evaluations or 30-day home monitoring may be helpful in ruling out arrhythmias. Neurologic evaluation can be helpful to rule out seizure activity which may masquerade as syncope. Rarely, in teenagers and adults, atypical migraine headaches may present with alterations of consciousness. In these patients, there is often a strong family history of migraine. When these episodes recur, they are similar each time, as is stereotypical of other migraine aura.

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."

While most academic hospitalist groups might be struggling with the practicalities of new resident work-hour rules, pediatric hospitalist Glenn Rosenbluth, MD, sees an opportunity if the rules spur a migration from traditional call models to shift-based work.

Dr. Rosenbluth and colleagues at University of California at San Francisco's (UCSF) Benioff Children's Hospital are working on research that shows a shift-based model that complies with Accreditation Council for Graduate Medical Education (ACGME) guidelines can cut costs and reduce length of stay (LOS). The ACGME work-hour rules limit first-year residents to 16-hour shifts.

At UCSF Benioff, the traditional call model (with 30-hour shifts) was replaced by shift work in 2008. Medical inpatient teams now feature four interns working four-week blocks. Three weeks are scheduled as day shifts, with one week of night shifts.

"It's not that I think scheduling is the magic bullet," Dr. Rosenbluth says. "But I think scheduling can be leveraged."

In an abstract published in the Journal of Hospital Medicine, Dr. Rosenbluth and colleagues compared LOS and total cost for admitted patients diagnosed with the hospital's 10 most common pediatric diagnoses during the year before and after the schedule change. When the review was limited to non-ICU patients, LOS was reduced by 18% (rate ratio, 0.82; 95% CI, 0.73-0.93), and total costs were cut 10% (0.90; 95% CI,0.81-0.99). Dr. Rosenbluth says the model also has increased the staff's ownership of night patients, as interns moving from night shift to day shift will often see the same children.

Dr. Rosenbluth hopes to further his research to draw even more evidence-based conclusions. "I think shorter shifts are the way to go and I think our model shows that," he says. "I haven't proven that, but I do believe that. And that’s what we’re looking to study."