Reviews

Tuberculosis rates in the United States are at an all-time low, which is good news for public health. However, as clinicians see fewer cases of tuberculosis, their skill at making this diagnosis rapidly diminishes.

In 2012, for the first time, fewer than 10,000 tuberculosis cases were reported in the United States to the Centers for Disease Control and Prevention (CDC),¹ for a case rate of 3.2 per 100,000. This is in sharp contrast to the worldwide burden of tuberculosis: the World Health Organization² estimated that there were 8.6 million new cases of tuberculosis in 2012. As a result of travel and immigration, clinicians in the United States will continue to see sporadic cases of active tuberculosis in their hospitals and clinics.

This review describes the clinical and radiographic clues to the diagnosis of pulmonary tuberculosis, discusses the use and discontinuation of respiratory isolation, and reviews the use of new diagnostic technologies.

CASE 1: A COLLEGE STUDENT WITH FATIGUE

A 23-year-old graduate student presents to the student health clinic with vague symptoms of fatigue and several pounds of weight loss over the past 3 months. When asked about coughing, he says he thinks he has had a mild, nonproductive cough for about a month. On examination he is thin, appears comfortable, and has faint rales in the right middle lung zone.

The clinician thinks that the symptoms are likely related to stress, lack of sleep, and difficulty adapting to graduate school life. However, in view of the pulmonary finding on examination, the physician obtains a complete blood cell count (CBC) and a chest radiograph. The CBC is normal. The radiograph (Figure 1) reveals a patchy, somewhat nodular infiltrate in the right upper lobe. The radiologist reviews the results, noting that tuberculosis is high on the list of possible diagnoses. The clinician calls the student and obtains the following additional history.

The patient was born in Thailand and arrived in the United States 3 months ago. Soon after his arrival, he had a tuberculin skin test with purified protein derivative in the student health department, which produced an induration 18 mm in diameter. The patient dismissed this finding as a false-positive result, attributing it to having received BCG vaccine in his native country, and he therefore did not follow up as recommended for a chest radiograph. He denies having fever, night sweats, or hemoptysis.

Since the patient lives in a college dormitory and has four roommates, the clinician admits him to the hospital for further evaluation and for airborne infection isolation. Sputum smears are positive for acid-fast bacilli, and samples ultimately grow Mycobacterium tuberculosis. He is started on standard antituberculosis treatment with isoniazid, rifampin, ethambutol, and pyrazinamide and discharged about 1 week later. He does well. Approximately 50 of his classmates are tested for possible exposure to tuberculosis.

CASE 2: A MAN WITH ACUTE-ONSET SYMPTOMS

A 35-year-old man presents to the emergency department for evaluation of cough with sputum production, fever, nausea, vomiting, and diarrhea. The symptoms began suddenly 1 week previously. He has no medical history, was born in the United States, and works in computer sales. On examination he looks uncomfortable, is slightly tachypneic, and has a temperature of 101°F (38.3°C).

Given his complaint of cough, chest radiography and a CBC are ordered. The white blood cell count is 18.0 × 10⁹/L (reference range 4.5–11.0), with 50% bands (reference range 3%–5%). The chest radiograph (Figure 2) shows a dense infiltrate in the right upper lobe, with air bronchograms and possible right hilar fullness.

The patient is diagnosed with community-acquired pneumonia, and because his oral intake is poor, he is admitted to the hospital and started on azithromycin and ceftriaxone. Blood cultures the next day grow Streptococcus pneumoniae. He fully recovers. A follow-up radiograph is performed 6 weeks later because of the right hilar fullness, and it is normal.

COMMENT

These two cases demonstrate the importance of clinical, demographic, laboratory, and radiographic clues to raise or lower our suspicion for pulmonary tuberculosis. Both patients had right-upper-lobe infiltrates on radiography, yet the diagnosis of tuberculosis was considered only in the first patient.

CLINICAL CLUES TO PULMONARY TUBERCULOSIS

Symptoms of tuberculosis are generally indolent in onset, often so much so that the patient does not realize that he or she is sick until after starting treatment and beginning to improve. In addition, the symptoms can be vague, including only mild fatigue and cough. The classic symptoms of prolonged nonproductive cough, hemoptysis, weight loss, and fever often do not appear until the disease is quite advanced in the lung and the patient has been sick for months.

Since the symptoms of tuberculosis can be nonspecific, the patient’s social and demographic characteristics are important in assessing the likelihood that his or her current illness is tuberculosis.

Foreign birth

Almost two-thirds of all reported tuberculosis cases in the United States are in people who were born outside of the United States.¹ The highest risk of reactivation appears to be within the first 5 years after immigration to the United States.³

Other risk factors

• Extensive travel to tuberculosis-endemic regions of the world
• Previous incarceration
• Intravenous drug use
• Work in health care
• Homelessness
• Known exposure to tuberculosis in the past.

Certain medical conditions predispose to reactivation of tuberculosis and should be considered when evaluating someone for active tuberculosis. These include human immunodeficiency virus infection and immunosuppression from tumor necrosis factor inhibitors, steroids, and medications used in organ transplantation. Other risk factors include diabetes requiring insulin, end-stage renal disease, and hematologic malignancies.⁴ Absence of these risk factors does not exclude tuberculosis, but it decreases the likelihood.

Findings on physical examination and laboratory testing are generally nonspecific in active tuberculosis. In particular, fever is present in 40% to 80% of patients. The white blood cell count is generally normal or only slightly elevated.

Radiographic signs

While the presenting symptoms and physical findings can be nonspecific, there are definite clues to the diagnosis of tuberculosis on chest radiography. In adults, most cases of tuberculosis are reactivation-type, which means the patient was exposed to tuberculosis many months to years in the past.

Reactivation-type tuberculosis usually occurs in the upper lobes, classically in the apical and posterior segments. The infiltrates tend to be patchy rather than densely consolidated. Cavitation, when present, increases the likelihood of tuberculosis. Intrathoracic lymphadenopathy, which occurs in primary tuberculosis, is generally not seen in adults with typical reactivation pulmonary tuberculosis.

However, adults who are highly immunosuppressed, such as those with advanced human immunodeficiency virus infection, organ transplant recipients, or those taking tumor necrosis factor inhibitors, may have radiographic features that are atypical for tuberculosis. For example, they may present with hilar adenopathy or lower-lobe infiltrates.⁵

Are there clinical prediction rules for tuberculosis?

Because tuberculosis rates have been declining and most hospitals have a limited number of rooms for airborne infection isolation, several studies have evaluated clinical prediction rules for diagnosing pulmonary tuberculosis.

Reactivation-type tuberculosis usually occurs in the upper lobes

In general, the signs and symptoms that predict tuberculosis are similar to those discussed above, including chronic symptoms, immunosuppression, birth in a region with a high incidence of the disease, a chest radiograph showing upper-zone findings, a positive tuberculin skin test, and fever.^6–8 The studies that identified these factors are limited in generalizability as they were performed and validated in single institutions, and the prediction rules have not been widely adopted. Yet they provide a straightforward way to determine which patients should be prioritized for isolation.

RETURN TO THE CASES

The student in case 1 had several features suggesting tuberculosis: indolent and nonspecific symptoms, normal CBC, patchy upper-lobe infiltrates, birth in a country that has a high incidence of tuberculosis, and a positive skin test.

In contrast, the man in case 2 had features that made tuberculosis much less likely: acute symptoms, markedly elevated white blood cell count, and densely consolidated infiltrate. He was also born in the United States and had no additional risk factors for tuberculosis exposure.

EVALUATION OF SUSPECTED TUBERCULOSIS

Who should be admitted to the hospital for evaluation?

In general, a patient with suspected tuberculosis can be evaluated as an outpatient. However, there are a number of reasons to consider hospital admission for the initial workup and for starting treatment:

• Clinical instability requiring inpatient care: eg, hypoxia, unstable vital signs, inability to tolerate oral intake
• Residence in a congregate setting such as a homeless shelter, nursing home, or college dormitory, where there is an ongoing risk of transmitting the infection to others
• Concern that the patient might be lost to follow-up if discharged from the emergency department or clinic
• Vulnerable contacts living in the home with the patient (eg, newborn infants, severely immunosuppressed people)
• Lack of resources in the community to provide prompt evaluation and initiation of treatment; most urban areas have tuberculosis clinics with outreach staff available to provide support for patients, but these resources are scarcer in rural regions.

When should a patient be placed in airborne infection isolation?

Patients with suspected active pulmonary tuberculosis should be placed in airborne infection isolation (also called respiratory or negative-pressure isolation). The purpose of this isolation method is to prevent transmission to other patients and to health care workers. Isolation and other environmental and personal controls such as ultraviolet light and N-95 masks are highly effective in preventing transmission.⁹

However, there are disadvantages to placing patients in isolation. Only 1 out of every 10 to 25 patients isolated actually has tuberculosis,¹⁰ and patients typically remain in isolation for 4 to 7 days. Therefore, unnecessary isolation can delay diagnostic testing for other illnesses and may waste already-limited health care resources. In addition, isolation carries the potential for decreased contact with providers.

When can a patient be released from isolation?

One of the problems with airborne infection isolation is determining when it is safe to discontinue it, especially when the diagnosis of tuberculosis appears less likely.

Traditionally, we have used the requirement of three negative sputum smears for acid-fast bacilli on 3 separate days, as well as low clinical suspicion for tuberculosis. The use of three sputum smears for acid-fast bacilli is based on studies^11,12 in populations that have a high prevalence of tuberculosis. These studies found that after three sputum smears were obtained, additional sputum smears were unlikely to improve the sensitivity of the test. The studies focused on maximizing the sensitivity of the test and detecting all potential cases.^11,12 However, in US hospitals today, the focus is on rapidly excluding the diagnosis of tuberculosis to minimize hospital length of stay and to allow evaluation for alternative diagnoses.

A problem with isolation is when to discontinue it

Several studies have called into question the need for three negative sputum smears to discontinue isolation.^13–16 Mathew et al¹³ found a negative predictive value of 97.8% with a single negative sputum smear for the diagnosis of culture-positive tuberculosis. Each additional sputum increased the negative predictive value by only 0.2%. The authors suggested that one or two negative sputum smears are sufficient to discontinue isolation in a region that has a low incidence of tuberculosis. These studies were all performed at single institutions in the United States and Canada, and their findings are relevant to regions that have a low incidence of tuberculosis.

The CDC continues to recommend that airborne infection isolation be discontinued only when either another diagnosis is made that explains the clinical syndrome or the patient has three negative acid-fast bacilli sputum smear results or two negative acid-fast bacilli smears and one negative nucleic amplification test (discussed below). These should be done at least 8 hours apart and should include at least one early-morning specimen.⁹

In a minority of cases, empiric treatment for tuberculosis is indicated despite negative sputum smears, based on clinical and radiographic manifestations. Patients receiving empiric treatment for pulmonary tuberculosis should remain in airborne infection isolation during the initiation of treatment (if a hospital stay is required) until cleared by a specialist in infectious disease or tuberculosis.

Can molecular techniques help in rapidly diagnosing tuberculosis?

Additional tests for tuberculosis that are performed on clinical specimens have been available for the past 10 years.

Nucleic acid amplification can detect tuberculosis directly in sputum, bronchoscopy specimens, or other clinical specimens. It is available at reference laboratories, large hospitals, and many state laboratories, often with 24-hour turnaround. Both commercial and in-house tests are performed. The CDC considers nucleic acid amplification to be very helpful and underutilized. An important limitation of the test is that it performs best in smear-positive specimens, with a sensitivity of 96.8%, whereas its sensitivity in smear-negative samples is only 73%.¹⁷ For this reason, nucleic acid amplification is still not widely used in US hospitals.

The CDC recommends nucleic acid amplification testing in all patients in whom the diagnosis of tuberculosis is being considered but is not yet confirmed.¹⁸ Table 1 outlines the use of nucleic acid amplification in several clinical situations. Use and interpretation of this test in suspected tuberculosis often requires consultation with clinicians who are experienced in the diagnosis of this disease.

How should an interferon-gamma-release assay or a tuberculin skin test be used in evaluating suspected tuberculosis?

Patients who have never tested positive for tuberculosis on a skin test should be tested by tuberculin skin testing or with an interferon-gamma-release assay during an evaluation for suspected pulmonary tuberculosis. The interferon-gamma-release assays available in the United States are the QuantiFERON-TB Gold In-Tube test and the T-Spot TB test. Most larger hospitals have one of the two available.

Of note: up to 25% of patients with active tuberculosis can have a negative skin test or interferon-gamma-release assay at the time of initial diagnosis, the number being higher in those who are immunosuppressed.

An interferon-gamma-release assay, which is performed on the patient’s serum, is preferred in those who have previously received the BCG vaccine, as there is no cross-reactivity between the vaccine and the antigens in the assay. In patients with active tuberculosis, the interferon-gamma-release assay does not perform any better than the skin test, so the choice of test should be determined by availability. Table 2 compares the characteristics of tuberculin skin testing and the interferon- gamma-release assay.¹⁹

In evaluating for active tuberculosis, a positive skin test or interferon-gamma-release assay can be helpful in increasing the likelihood of tuberculosis, but a negative result does not exclude active tuberculosis.

Is computed tomography necessary in patients suspected of having active pulmonary tuberculosis?

Additional imaging is often performed in patients with suspected pulmonary tuberculosis, or before the diagnosis of tuberculosis is considered. Computed tomography provides more detailed images of pulmonary infiltrates and may reveal more extensive disease than plain radiography, but the images are not diagnostic. Ultimately, sputum and sometimes tissue are required. Far too often, a sputum smear for acid-fast bacilli is the last test to be performed, after both computed tomography and bronchoscopy have been done. In addition, in order to undergo computed tomography, the patient must be removed from airborne infection isolation.

The decision to perform computed tomography must be individualized to the patient and to the clinical situation. It is certainly not a necessary test for the diagnosis of pulmonary tuberculosis.

When should the diagnosis be reported?

Tuberculosis is a reportable illness in the United States. Although each state varies in its specific requirements, if tuberculosis treatment is being initiated or tuberculosis is strongly suspected, a report should be made to the local public health authority for tuberculosis within 24 hours.

This report allows for outreach services to be offered to the patient, often including directly observed therapy in which doses of antituberculosis treatment are provided and observed to ensure completion of treatment. In addition, public health authorities bear the responsibility for contact investigation to determine if transmission of tuberculosis has occurred in the community.

Tuberculosis rates in the United States are at an all-time low, which is good news for public health. However, as clinicians see fewer cases of tuberculosis, their skill at making this diagnosis rapidly diminishes.

In 2012, for the first time, fewer than 10,000 tuberculosis cases were reported in the United States to the Centers for Disease Control and Prevention (CDC),¹ for a case rate of 3.2 per 100,000. This is in sharp contrast to the worldwide burden of tuberculosis: the World Health Organization² estimated that there were 8.6 million new cases of tuberculosis in 2012. As a result of travel and immigration, clinicians in the United States will continue to see sporadic cases of active tuberculosis in their hospitals and clinics.

This review describes the clinical and radiographic clues to the diagnosis of pulmonary tuberculosis, discusses the use and discontinuation of respiratory isolation, and reviews the use of new diagnostic technologies.

CASE 1: A COLLEGE STUDENT WITH FATIGUE

A 23-year-old graduate student presents to the student health clinic with vague symptoms of fatigue and several pounds of weight loss over the past 3 months. When asked about coughing, he says he thinks he has had a mild, nonproductive cough for about a month. On examination he is thin, appears comfortable, and has faint rales in the right middle lung zone.

The clinician thinks that the symptoms are likely related to stress, lack of sleep, and difficulty adapting to graduate school life. However, in view of the pulmonary finding on examination, the physician obtains a complete blood cell count (CBC) and a chest radiograph. The CBC is normal. The radiograph (Figure 1) reveals a patchy, somewhat nodular infiltrate in the right upper lobe. The radiologist reviews the results, noting that tuberculosis is high on the list of possible diagnoses. The clinician calls the student and obtains the following additional history.

The patient was born in Thailand and arrived in the United States 3 months ago. Soon after his arrival, he had a tuberculin skin test with purified protein derivative in the student health department, which produced an induration 18 mm in diameter. The patient dismissed this finding as a false-positive result, attributing it to having received BCG vaccine in his native country, and he therefore did not follow up as recommended for a chest radiograph. He denies having fever, night sweats, or hemoptysis.

Since the patient lives in a college dormitory and has four roommates, the clinician admits him to the hospital for further evaluation and for airborne infection isolation. Sputum smears are positive for acid-fast bacilli, and samples ultimately grow Mycobacterium tuberculosis. He is started on standard antituberculosis treatment with isoniazid, rifampin, ethambutol, and pyrazinamide and discharged about 1 week later. He does well. Approximately 50 of his classmates are tested for possible exposure to tuberculosis.

CASE 2: A MAN WITH ACUTE-ONSET SYMPTOMS

A 35-year-old man presents to the emergency department for evaluation of cough with sputum production, fever, nausea, vomiting, and diarrhea. The symptoms began suddenly 1 week previously. He has no medical history, was born in the United States, and works in computer sales. On examination he looks uncomfortable, is slightly tachypneic, and has a temperature of 101°F (38.3°C).

Given his complaint of cough, chest radiography and a CBC are ordered. The white blood cell count is 18.0 × 10⁹/L (reference range 4.5–11.0), with 50% bands (reference range 3%–5%). The chest radiograph (Figure 2) shows a dense infiltrate in the right upper lobe, with air bronchograms and possible right hilar fullness.

The patient is diagnosed with community-acquired pneumonia, and because his oral intake is poor, he is admitted to the hospital and started on azithromycin and ceftriaxone. Blood cultures the next day grow Streptococcus pneumoniae. He fully recovers. A follow-up radiograph is performed 6 weeks later because of the right hilar fullness, and it is normal.

COMMENT

These two cases demonstrate the importance of clinical, demographic, laboratory, and radiographic clues to raise or lower our suspicion for pulmonary tuberculosis. Both patients had right-upper-lobe infiltrates on radiography, yet the diagnosis of tuberculosis was considered only in the first patient.

CLINICAL CLUES TO PULMONARY TUBERCULOSIS

Symptoms of tuberculosis are generally indolent in onset, often so much so that the patient does not realize that he or she is sick until after starting treatment and beginning to improve. In addition, the symptoms can be vague, including only mild fatigue and cough. The classic symptoms of prolonged nonproductive cough, hemoptysis, weight loss, and fever often do not appear until the disease is quite advanced in the lung and the patient has been sick for months.

Since the symptoms of tuberculosis can be nonspecific, the patient’s social and demographic characteristics are important in assessing the likelihood that his or her current illness is tuberculosis.

Foreign birth

Almost two-thirds of all reported tuberculosis cases in the United States are in people who were born outside of the United States.¹ The highest risk of reactivation appears to be within the first 5 years after immigration to the United States.³

Other risk factors

• Extensive travel to tuberculosis-endemic regions of the world
• Previous incarceration
• Intravenous drug use
• Work in health care
• Homelessness
• Known exposure to tuberculosis in the past.

Certain medical conditions predispose to reactivation of tuberculosis and should be considered when evaluating someone for active tuberculosis. These include human immunodeficiency virus infection and immunosuppression from tumor necrosis factor inhibitors, steroids, and medications used in organ transplantation. Other risk factors include diabetes requiring insulin, end-stage renal disease, and hematologic malignancies.⁴ Absence of these risk factors does not exclude tuberculosis, but it decreases the likelihood.

Findings on physical examination and laboratory testing are generally nonspecific in active tuberculosis. In particular, fever is present in 40% to 80% of patients. The white blood cell count is generally normal or only slightly elevated.

Radiographic signs

While the presenting symptoms and physical findings can be nonspecific, there are definite clues to the diagnosis of tuberculosis on chest radiography. In adults, most cases of tuberculosis are reactivation-type, which means the patient was exposed to tuberculosis many months to years in the past.

Reactivation-type tuberculosis usually occurs in the upper lobes, classically in the apical and posterior segments. The infiltrates tend to be patchy rather than densely consolidated. Cavitation, when present, increases the likelihood of tuberculosis. Intrathoracic lymphadenopathy, which occurs in primary tuberculosis, is generally not seen in adults with typical reactivation pulmonary tuberculosis.

However, adults who are highly immunosuppressed, such as those with advanced human immunodeficiency virus infection, organ transplant recipients, or those taking tumor necrosis factor inhibitors, may have radiographic features that are atypical for tuberculosis. For example, they may present with hilar adenopathy or lower-lobe infiltrates.⁵

Are there clinical prediction rules for tuberculosis?

Because tuberculosis rates have been declining and most hospitals have a limited number of rooms for airborne infection isolation, several studies have evaluated clinical prediction rules for diagnosing pulmonary tuberculosis.

Reactivation-type tuberculosis usually occurs in the upper lobes

In general, the signs and symptoms that predict tuberculosis are similar to those discussed above, including chronic symptoms, immunosuppression, birth in a region with a high incidence of the disease, a chest radiograph showing upper-zone findings, a positive tuberculin skin test, and fever.^6–8 The studies that identified these factors are limited in generalizability as they were performed and validated in single institutions, and the prediction rules have not been widely adopted. Yet they provide a straightforward way to determine which patients should be prioritized for isolation.

RETURN TO THE CASES

The student in case 1 had several features suggesting tuberculosis: indolent and nonspecific symptoms, normal CBC, patchy upper-lobe infiltrates, birth in a country that has a high incidence of tuberculosis, and a positive skin test.

In contrast, the man in case 2 had features that made tuberculosis much less likely: acute symptoms, markedly elevated white blood cell count, and densely consolidated infiltrate. He was also born in the United States and had no additional risk factors for tuberculosis exposure.

EVALUATION OF SUSPECTED TUBERCULOSIS

Who should be admitted to the hospital for evaluation?

In general, a patient with suspected tuberculosis can be evaluated as an outpatient. However, there are a number of reasons to consider hospital admission for the initial workup and for starting treatment:

• Clinical instability requiring inpatient care: eg, hypoxia, unstable vital signs, inability to tolerate oral intake
• Residence in a congregate setting such as a homeless shelter, nursing home, or college dormitory, where there is an ongoing risk of transmitting the infection to others
• Concern that the patient might be lost to follow-up if discharged from the emergency department or clinic
• Vulnerable contacts living in the home with the patient (eg, newborn infants, severely immunosuppressed people)
• Lack of resources in the community to provide prompt evaluation and initiation of treatment; most urban areas have tuberculosis clinics with outreach staff available to provide support for patients, but these resources are scarcer in rural regions.

When should a patient be placed in airborne infection isolation?

Patients with suspected active pulmonary tuberculosis should be placed in airborne infection isolation (also called respiratory or negative-pressure isolation). The purpose of this isolation method is to prevent transmission to other patients and to health care workers. Isolation and other environmental and personal controls such as ultraviolet light and N-95 masks are highly effective in preventing transmission.⁹

However, there are disadvantages to placing patients in isolation. Only 1 out of every 10 to 25 patients isolated actually has tuberculosis,¹⁰ and patients typically remain in isolation for 4 to 7 days. Therefore, unnecessary isolation can delay diagnostic testing for other illnesses and may waste already-limited health care resources. In addition, isolation carries the potential for decreased contact with providers.

When can a patient be released from isolation?

One of the problems with airborne infection isolation is determining when it is safe to discontinue it, especially when the diagnosis of tuberculosis appears less likely.

Traditionally, we have used the requirement of three negative sputum smears for acid-fast bacilli on 3 separate days, as well as low clinical suspicion for tuberculosis. The use of three sputum smears for acid-fast bacilli is based on studies^11,12 in populations that have a high prevalence of tuberculosis. These studies found that after three sputum smears were obtained, additional sputum smears were unlikely to improve the sensitivity of the test. The studies focused on maximizing the sensitivity of the test and detecting all potential cases.^11,12 However, in US hospitals today, the focus is on rapidly excluding the diagnosis of tuberculosis to minimize hospital length of stay and to allow evaluation for alternative diagnoses.

A problem with isolation is when to discontinue it

Several studies have called into question the need for three negative sputum smears to discontinue isolation.^13–16 Mathew et al¹³ found a negative predictive value of 97.8% with a single negative sputum smear for the diagnosis of culture-positive tuberculosis. Each additional sputum increased the negative predictive value by only 0.2%. The authors suggested that one or two negative sputum smears are sufficient to discontinue isolation in a region that has a low incidence of tuberculosis. These studies were all performed at single institutions in the United States and Canada, and their findings are relevant to regions that have a low incidence of tuberculosis.

The CDC continues to recommend that airborne infection isolation be discontinued only when either another diagnosis is made that explains the clinical syndrome or the patient has three negative acid-fast bacilli sputum smear results or two negative acid-fast bacilli smears and one negative nucleic amplification test (discussed below). These should be done at least 8 hours apart and should include at least one early-morning specimen.⁹

In a minority of cases, empiric treatment for tuberculosis is indicated despite negative sputum smears, based on clinical and radiographic manifestations. Patients receiving empiric treatment for pulmonary tuberculosis should remain in airborne infection isolation during the initiation of treatment (if a hospital stay is required) until cleared by a specialist in infectious disease or tuberculosis.

Can molecular techniques help in rapidly diagnosing tuberculosis?

Additional tests for tuberculosis that are performed on clinical specimens have been available for the past 10 years.

Nucleic acid amplification can detect tuberculosis directly in sputum, bronchoscopy specimens, or other clinical specimens. It is available at reference laboratories, large hospitals, and many state laboratories, often with 24-hour turnaround. Both commercial and in-house tests are performed. The CDC considers nucleic acid amplification to be very helpful and underutilized. An important limitation of the test is that it performs best in smear-positive specimens, with a sensitivity of 96.8%, whereas its sensitivity in smear-negative samples is only 73%.¹⁷ For this reason, nucleic acid amplification is still not widely used in US hospitals.

The CDC recommends nucleic acid amplification testing in all patients in whom the diagnosis of tuberculosis is being considered but is not yet confirmed.¹⁸ Table 1 outlines the use of nucleic acid amplification in several clinical situations. Use and interpretation of this test in suspected tuberculosis often requires consultation with clinicians who are experienced in the diagnosis of this disease.

How should an interferon-gamma-release assay or a tuberculin skin test be used in evaluating suspected tuberculosis?

Patients who have never tested positive for tuberculosis on a skin test should be tested by tuberculin skin testing or with an interferon-gamma-release assay during an evaluation for suspected pulmonary tuberculosis. The interferon-gamma-release assays available in the United States are the QuantiFERON-TB Gold In-Tube test and the T-Spot TB test. Most larger hospitals have one of the two available.

Of note: up to 25% of patients with active tuberculosis can have a negative skin test or interferon-gamma-release assay at the time of initial diagnosis, the number being higher in those who are immunosuppressed.

An interferon-gamma-release assay, which is performed on the patient’s serum, is preferred in those who have previously received the BCG vaccine, as there is no cross-reactivity between the vaccine and the antigens in the assay. In patients with active tuberculosis, the interferon-gamma-release assay does not perform any better than the skin test, so the choice of test should be determined by availability. Table 2 compares the characteristics of tuberculin skin testing and the interferon- gamma-release assay.¹⁹

In evaluating for active tuberculosis, a positive skin test or interferon-gamma-release assay can be helpful in increasing the likelihood of tuberculosis, but a negative result does not exclude active tuberculosis.

Is computed tomography necessary in patients suspected of having active pulmonary tuberculosis?

Additional imaging is often performed in patients with suspected pulmonary tuberculosis, or before the diagnosis of tuberculosis is considered. Computed tomography provides more detailed images of pulmonary infiltrates and may reveal more extensive disease than plain radiography, but the images are not diagnostic. Ultimately, sputum and sometimes tissue are required. Far too often, a sputum smear for acid-fast bacilli is the last test to be performed, after both computed tomography and bronchoscopy have been done. In addition, in order to undergo computed tomography, the patient must be removed from airborne infection isolation.

The decision to perform computed tomography must be individualized to the patient and to the clinical situation. It is certainly not a necessary test for the diagnosis of pulmonary tuberculosis.

When should the diagnosis be reported?

Tuberculosis is a reportable illness in the United States. Although each state varies in its specific requirements, if tuberculosis treatment is being initiated or tuberculosis is strongly suspected, a report should be made to the local public health authority for tuberculosis within 24 hours.

This report allows for outreach services to be offered to the patient, often including directly observed therapy in which doses of antituberculosis treatment are provided and observed to ensure completion of treatment. In addition, public health authorities bear the responsibility for contact investigation to determine if transmission of tuberculosis has occurred in the community.

Tuberculosis rates in the United States are at an all-time low, which is good news for public health. However, as clinicians see fewer cases of tuberculosis, their skill at making this diagnosis rapidly diminishes.

In 2012, for the first time, fewer than 10,000 tuberculosis cases were reported in the United States to the Centers for Disease Control and Prevention (CDC),¹ for a case rate of 3.2 per 100,000. This is in sharp contrast to the worldwide burden of tuberculosis: the World Health Organization² estimated that there were 8.6 million new cases of tuberculosis in 2012. As a result of travel and immigration, clinicians in the United States will continue to see sporadic cases of active tuberculosis in their hospitals and clinics.

This review describes the clinical and radiographic clues to the diagnosis of pulmonary tuberculosis, discusses the use and discontinuation of respiratory isolation, and reviews the use of new diagnostic technologies.

CASE 1: A COLLEGE STUDENT WITH FATIGUE

A 23-year-old graduate student presents to the student health clinic with vague symptoms of fatigue and several pounds of weight loss over the past 3 months. When asked about coughing, he says he thinks he has had a mild, nonproductive cough for about a month. On examination he is thin, appears comfortable, and has faint rales in the right middle lung zone.

The clinician thinks that the symptoms are likely related to stress, lack of sleep, and difficulty adapting to graduate school life. However, in view of the pulmonary finding on examination, the physician obtains a complete blood cell count (CBC) and a chest radiograph. The CBC is normal. The radiograph (Figure 1) reveals a patchy, somewhat nodular infiltrate in the right upper lobe. The radiologist reviews the results, noting that tuberculosis is high on the list of possible diagnoses. The clinician calls the student and obtains the following additional history.

The patient was born in Thailand and arrived in the United States 3 months ago. Soon after his arrival, he had a tuberculin skin test with purified protein derivative in the student health department, which produced an induration 18 mm in diameter. The patient dismissed this finding as a false-positive result, attributing it to having received BCG vaccine in his native country, and he therefore did not follow up as recommended for a chest radiograph. He denies having fever, night sweats, or hemoptysis.

Since the patient lives in a college dormitory and has four roommates, the clinician admits him to the hospital for further evaluation and for airborne infection isolation. Sputum smears are positive for acid-fast bacilli, and samples ultimately grow Mycobacterium tuberculosis. He is started on standard antituberculosis treatment with isoniazid, rifampin, ethambutol, and pyrazinamide and discharged about 1 week later. He does well. Approximately 50 of his classmates are tested for possible exposure to tuberculosis.

CASE 2: A MAN WITH ACUTE-ONSET SYMPTOMS

A 35-year-old man presents to the emergency department for evaluation of cough with sputum production, fever, nausea, vomiting, and diarrhea. The symptoms began suddenly 1 week previously. He has no medical history, was born in the United States, and works in computer sales. On examination he looks uncomfortable, is slightly tachypneic, and has a temperature of 101°F (38.3°C).

Given his complaint of cough, chest radiography and a CBC are ordered. The white blood cell count is 18.0 × 10⁹/L (reference range 4.5–11.0), with 50% bands (reference range 3%–5%). The chest radiograph (Figure 2) shows a dense infiltrate in the right upper lobe, with air bronchograms and possible right hilar fullness.

The patient is diagnosed with community-acquired pneumonia, and because his oral intake is poor, he is admitted to the hospital and started on azithromycin and ceftriaxone. Blood cultures the next day grow Streptococcus pneumoniae. He fully recovers. A follow-up radiograph is performed 6 weeks later because of the right hilar fullness, and it is normal.

COMMENT

These two cases demonstrate the importance of clinical, demographic, laboratory, and radiographic clues to raise or lower our suspicion for pulmonary tuberculosis. Both patients had right-upper-lobe infiltrates on radiography, yet the diagnosis of tuberculosis was considered only in the first patient.

CLINICAL CLUES TO PULMONARY TUBERCULOSIS

Symptoms of tuberculosis are generally indolent in onset, often so much so that the patient does not realize that he or she is sick until after starting treatment and beginning to improve. In addition, the symptoms can be vague, including only mild fatigue and cough. The classic symptoms of prolonged nonproductive cough, hemoptysis, weight loss, and fever often do not appear until the disease is quite advanced in the lung and the patient has been sick for months.

Since the symptoms of tuberculosis can be nonspecific, the patient’s social and demographic characteristics are important in assessing the likelihood that his or her current illness is tuberculosis.

Foreign birth

Almost two-thirds of all reported tuberculosis cases in the United States are in people who were born outside of the United States.¹ The highest risk of reactivation appears to be within the first 5 years after immigration to the United States.³

Other risk factors

• Extensive travel to tuberculosis-endemic regions of the world
• Previous incarceration
• Intravenous drug use
• Work in health care
• Homelessness
• Known exposure to tuberculosis in the past.

Certain medical conditions predispose to reactivation of tuberculosis and should be considered when evaluating someone for active tuberculosis. These include human immunodeficiency virus infection and immunosuppression from tumor necrosis factor inhibitors, steroids, and medications used in organ transplantation. Other risk factors include diabetes requiring insulin, end-stage renal disease, and hematologic malignancies.⁴ Absence of these risk factors does not exclude tuberculosis, but it decreases the likelihood.

Findings on physical examination and laboratory testing are generally nonspecific in active tuberculosis. In particular, fever is present in 40% to 80% of patients. The white blood cell count is generally normal or only slightly elevated.

Radiographic signs

While the presenting symptoms and physical findings can be nonspecific, there are definite clues to the diagnosis of tuberculosis on chest radiography. In adults, most cases of tuberculosis are reactivation-type, which means the patient was exposed to tuberculosis many months to years in the past.

Reactivation-type tuberculosis usually occurs in the upper lobes, classically in the apical and posterior segments. The infiltrates tend to be patchy rather than densely consolidated. Cavitation, when present, increases the likelihood of tuberculosis. Intrathoracic lymphadenopathy, which occurs in primary tuberculosis, is generally not seen in adults with typical reactivation pulmonary tuberculosis.

However, adults who are highly immunosuppressed, such as those with advanced human immunodeficiency virus infection, organ transplant recipients, or those taking tumor necrosis factor inhibitors, may have radiographic features that are atypical for tuberculosis. For example, they may present with hilar adenopathy or lower-lobe infiltrates.⁵

Are there clinical prediction rules for tuberculosis?

Because tuberculosis rates have been declining and most hospitals have a limited number of rooms for airborne infection isolation, several studies have evaluated clinical prediction rules for diagnosing pulmonary tuberculosis.

Reactivation-type tuberculosis usually occurs in the upper lobes

In general, the signs and symptoms that predict tuberculosis are similar to those discussed above, including chronic symptoms, immunosuppression, birth in a region with a high incidence of the disease, a chest radiograph showing upper-zone findings, a positive tuberculin skin test, and fever.^6–8 The studies that identified these factors are limited in generalizability as they were performed and validated in single institutions, and the prediction rules have not been widely adopted. Yet they provide a straightforward way to determine which patients should be prioritized for isolation.

RETURN TO THE CASES

The student in case 1 had several features suggesting tuberculosis: indolent and nonspecific symptoms, normal CBC, patchy upper-lobe infiltrates, birth in a country that has a high incidence of tuberculosis, and a positive skin test.

In contrast, the man in case 2 had features that made tuberculosis much less likely: acute symptoms, markedly elevated white blood cell count, and densely consolidated infiltrate. He was also born in the United States and had no additional risk factors for tuberculosis exposure.

EVALUATION OF SUSPECTED TUBERCULOSIS

Who should be admitted to the hospital for evaluation?

In general, a patient with suspected tuberculosis can be evaluated as an outpatient. However, there are a number of reasons to consider hospital admission for the initial workup and for starting treatment:

• Clinical instability requiring inpatient care: eg, hypoxia, unstable vital signs, inability to tolerate oral intake
• Residence in a congregate setting such as a homeless shelter, nursing home, or college dormitory, where there is an ongoing risk of transmitting the infection to others
• Concern that the patient might be lost to follow-up if discharged from the emergency department or clinic
• Vulnerable contacts living in the home with the patient (eg, newborn infants, severely immunosuppressed people)
• Lack of resources in the community to provide prompt evaluation and initiation of treatment; most urban areas have tuberculosis clinics with outreach staff available to provide support for patients, but these resources are scarcer in rural regions.

When should a patient be placed in airborne infection isolation?

Patients with suspected active pulmonary tuberculosis should be placed in airborne infection isolation (also called respiratory or negative-pressure isolation). The purpose of this isolation method is to prevent transmission to other patients and to health care workers. Isolation and other environmental and personal controls such as ultraviolet light and N-95 masks are highly effective in preventing transmission.⁹

However, there are disadvantages to placing patients in isolation. Only 1 out of every 10 to 25 patients isolated actually has tuberculosis,¹⁰ and patients typically remain in isolation for 4 to 7 days. Therefore, unnecessary isolation can delay diagnostic testing for other illnesses and may waste already-limited health care resources. In addition, isolation carries the potential for decreased contact with providers.

When can a patient be released from isolation?

One of the problems with airborne infection isolation is determining when it is safe to discontinue it, especially when the diagnosis of tuberculosis appears less likely.

Traditionally, we have used the requirement of three negative sputum smears for acid-fast bacilli on 3 separate days, as well as low clinical suspicion for tuberculosis. The use of three sputum smears for acid-fast bacilli is based on studies^11,12 in populations that have a high prevalence of tuberculosis. These studies found that after three sputum smears were obtained, additional sputum smears were unlikely to improve the sensitivity of the test. The studies focused on maximizing the sensitivity of the test and detecting all potential cases.^11,12 However, in US hospitals today, the focus is on rapidly excluding the diagnosis of tuberculosis to minimize hospital length of stay and to allow evaluation for alternative diagnoses.

A problem with isolation is when to discontinue it

Several studies have called into question the need for three negative sputum smears to discontinue isolation.^13–16 Mathew et al¹³ found a negative predictive value of 97.8% with a single negative sputum smear for the diagnosis of culture-positive tuberculosis. Each additional sputum increased the negative predictive value by only 0.2%. The authors suggested that one or two negative sputum smears are sufficient to discontinue isolation in a region that has a low incidence of tuberculosis. These studies were all performed at single institutions in the United States and Canada, and their findings are relevant to regions that have a low incidence of tuberculosis.

The CDC continues to recommend that airborne infection isolation be discontinued only when either another diagnosis is made that explains the clinical syndrome or the patient has three negative acid-fast bacilli sputum smear results or two negative acid-fast bacilli smears and one negative nucleic amplification test (discussed below). These should be done at least 8 hours apart and should include at least one early-morning specimen.⁹

In a minority of cases, empiric treatment for tuberculosis is indicated despite negative sputum smears, based on clinical and radiographic manifestations. Patients receiving empiric treatment for pulmonary tuberculosis should remain in airborne infection isolation during the initiation of treatment (if a hospital stay is required) until cleared by a specialist in infectious disease or tuberculosis.

Can molecular techniques help in rapidly diagnosing tuberculosis?

Additional tests for tuberculosis that are performed on clinical specimens have been available for the past 10 years.

Nucleic acid amplification can detect tuberculosis directly in sputum, bronchoscopy specimens, or other clinical specimens. It is available at reference laboratories, large hospitals, and many state laboratories, often with 24-hour turnaround. Both commercial and in-house tests are performed. The CDC considers nucleic acid amplification to be very helpful and underutilized. An important limitation of the test is that it performs best in smear-positive specimens, with a sensitivity of 96.8%, whereas its sensitivity in smear-negative samples is only 73%.¹⁷ For this reason, nucleic acid amplification is still not widely used in US hospitals.

The CDC recommends nucleic acid amplification testing in all patients in whom the diagnosis of tuberculosis is being considered but is not yet confirmed.¹⁸ Table 1 outlines the use of nucleic acid amplification in several clinical situations. Use and interpretation of this test in suspected tuberculosis often requires consultation with clinicians who are experienced in the diagnosis of this disease.

How should an interferon-gamma-release assay or a tuberculin skin test be used in evaluating suspected tuberculosis?

Patients who have never tested positive for tuberculosis on a skin test should be tested by tuberculin skin testing or with an interferon-gamma-release assay during an evaluation for suspected pulmonary tuberculosis. The interferon-gamma-release assays available in the United States are the QuantiFERON-TB Gold In-Tube test and the T-Spot TB test. Most larger hospitals have one of the two available.

Of note: up to 25% of patients with active tuberculosis can have a negative skin test or interferon-gamma-release assay at the time of initial diagnosis, the number being higher in those who are immunosuppressed.

An interferon-gamma-release assay, which is performed on the patient’s serum, is preferred in those who have previously received the BCG vaccine, as there is no cross-reactivity between the vaccine and the antigens in the assay. In patients with active tuberculosis, the interferon-gamma-release assay does not perform any better than the skin test, so the choice of test should be determined by availability. Table 2 compares the characteristics of tuberculin skin testing and the interferon- gamma-release assay.¹⁹

In evaluating for active tuberculosis, a positive skin test or interferon-gamma-release assay can be helpful in increasing the likelihood of tuberculosis, but a negative result does not exclude active tuberculosis.

Is computed tomography necessary in patients suspected of having active pulmonary tuberculosis?

Additional imaging is often performed in patients with suspected pulmonary tuberculosis, or before the diagnosis of tuberculosis is considered. Computed tomography provides more detailed images of pulmonary infiltrates and may reveal more extensive disease than plain radiography, but the images are not diagnostic. Ultimately, sputum and sometimes tissue are required. Far too often, a sputum smear for acid-fast bacilli is the last test to be performed, after both computed tomography and bronchoscopy have been done. In addition, in order to undergo computed tomography, the patient must be removed from airborne infection isolation.

The decision to perform computed tomography must be individualized to the patient and to the clinical situation. It is certainly not a necessary test for the diagnosis of pulmonary tuberculosis.

When should the diagnosis be reported?

Tuberculosis is a reportable illness in the United States. Although each state varies in its specific requirements, if tuberculosis treatment is being initiated or tuberculosis is strongly suspected, a report should be made to the local public health authority for tuberculosis within 24 hours.

This report allows for outreach services to be offered to the patient, often including directly observed therapy in which doses of antituberculosis treatment are provided and observed to ensure completion of treatment. In addition, public health authorities bear the responsibility for contact investigation to determine if transmission of tuberculosis has occurred in the community.

In the fall of 2014, the United States experienced an outbreak of severe respiratory illness due to a virus of emerging importance, enterovirus D68 (EV-D68). Here, we review the features of this virus and related viruses, the clinical syndromes this virus causes, the epidemiology of the recent outbreak, and its diagnosis and treatment.

THE ENTEROVIRUSES: AN OVERVIEW

Originally identified in 1962 from the throat swab of a child with pneumonia, human EV-D68 has unique genetic and clinical features that blur the typical division between human enteroviruses and rhinoviruses.1–4 Enteroviruses and rhinoviruses are closely related species within the Picornaviridae family that are now classified together within the genus Enterovirus.⁵ Picornaviruses are small, nonenveloped, positive-stranded RNA viruses of medical significance.

Poliovirus: The first enterovirus discovered

The first human enterovirus to be discovered was poliovirus.⁶ Although sporadic cases of “infantile paralysis” occurred before the late 19th century, epidemic poliomyelitis abruptly appeared in Europe and the United States beginning around 1880. Before the introduction in 1955 of the inactivated poliovirus vaccine and then the oral poliovirus vaccine, polio was one of the most feared illnesses in the developed world. Outbreaks occurred primarily in cities during summer months. At its peak, epidemic polio killed or paralyzed more than  half a million people a year.

One hypothesis to explain the sudden emergence of epidemic polio is that improved personal hygiene and public sanitation delayed the age at which children acquired this enteric infection.⁷ Infections acquired after infancy occurred in the absence of maternal antibodies that may have protected against the virus’s propensity to invade the nervous system.

Nonpolio human enteroviruses

In the decades since poliovirus was discovered, more than 100 nonpolio human enteroviruses have been recognized.⁸ This group includes the coxsackieviruses, echoviruses, and the newer numbered nonpolio human enteroviruses classified into four species, designated Human enterovirus A, B, C, and D. The last of these, Human enterovirus D, includes three serotypes known to cause disease in humans: EV-D68, EV-D70, and EV-D94.⁹

The genus Enterovirus includes the polioviruses; nonpolio enteroviruses A, B, C, and D; and rhinoviruses

As with poliovirus infection, most people infected with a nonpolio human enterovirus have a mild illness without distinctive features.⁵ In temperate climates, enteroviral infections are most common during the summer and fall and are an important cause of the “summer cold.” In tropical climates, the seasonal pattern is absent, and infections may occur throughout the year.

The clinical syndromes associated with a nonpolio human enterovirus can include nonspecific febrile illness; upper respiratory tract infection; pharyngitis; herpangina; hand, foot, and mouth syndrome; various skin exanthems; bronchiolitis; asthma exacerbation; gastrointestinal manifestations such as diarrhea and vomiting (which are especially common); more serious clinical syndromes such as hepatitis, pancreatitis, and cardiomyopathy; and neurologic illness, including aseptic meningitis, encephalitis, and polio-like paralytic disease.

Outbreaks caused by nonpolio human enteroviruses occur on a regular basis, may vary by strain from year to year, and often occur within a geographic region; multiple strains may circulate simultaneously. Occasionally, as with EV-D68 in August 2014 in the United States, epidemics can emerge suddenly and spread rapidly across the world, causing disease in hundreds or thousands of people, demonstrating the breadth of illness associated with particular strains.¹⁰

ENTEROVIRUS D68: AN EMERGING PATHOGEN

EV-D68 was first isolated in the United States from four children in Berkeley, California, who had lower respiratory tract symptoms (bronchiolitis and pneumonia) in 1962. The finding was published in the medical literature in 1967.¹ Since its initial identification, EV-D68 was infrequently reported as a cause of human disease, with the US Centers for Disease Control and Prevention (CDC) listing only 26 cases in the 36 years from 1970 through 2005.¹¹

However, the past decade has seen EV-D68 emerge as a significant respiratory pathogen, with more reports of acute respiratory illness associated with it in North America, Europe, and Asia, especially in children.^12–17 A seasonal pattern may exist; a longitudinal survey of samples collected from New York City detected a focal outbreak in the fall of 2009.¹⁸

The observation that recent EV-D68 outbreaks have primarily been in children suggests that most adults have immunity to it. In this regard, seroepidemiologic studies from Finland demonstrated that most adults have neutralizing antibodies from previous infection.⁹

The blurred line between enteroviruses and rhinoviruses

Enteroviruses and rhinoviruses are typically distinguished on the basis of the temperature at which they grow best (rhinoviruses grow better at lower temperatures, allowing them to replicate in the nose) and their sensitivity to acidity (enteroviruses are more resistant, enabling them to survive in the stomach).

The original (“Fermon”) strain of EV-D68 isolated in 1962 was first classified as an enterovirus because it was resistant to low pH.¹ However, when molecular sequencing became available, EV-D68 was found to be identical to human rhinovirus 87 (HRV87), a phylogenetic outlier among the rhinoviruses that binds to cells at a receptor site distinct from that of other human rhinoviruses.¹⁹

Thereafter, further testing showed that both EV-D68 and HRV87 isolates were sensitive to acid treatment by two different methods.⁴ Moreover, unlike most enteroviruses, EV-D68 behaves like a rhinovirus and grows preferentially at 33°C, the temperature of the nose.²

How enterovirus D68 enters cells

Viral surface proteins, including hemagglutinin, from certain respiratory viruses have the ability to bind sugars on cells in the nose and lungs, which facilitates viral entry and replication. EV-D68 binds specifically to alpha 2-6 sialic acid, the predominant sialic acid found in the human upper respiratory tract.^19,20 The absence of EV-D68 binding affinity for alpha 2-3 sialic acid, present in ciliated epithelial cells of the lower tract, suggests that alternative mechanisms may be responsible for the severe lower respiratory disease associated with this virus.

During the last decade, EV-D68 has emerged as a significant respiratory pathogen

Entry of EV-D68 into cells requires additional mediators. EV-D70 belongs to the same genetic cluster as EV-D68 and enters HeLa cells using decay-accelerating factor (DAF).²¹ Evidence that EV-D68 also uses DAF for cell entry comes from experiments showing that monoclonal antibodies against DAF inhibit the cytopathic effects of this virus.⁴ Virus-receptor interactions have been more thoroughly characterized for other enteroviruses.²² In this regard, coxsackieviruses of group B use DAF as a coreceptor. Since DAF is expressed at high levels in both epithelial and endothelial cells, it may play an important role in the induction of the viremia that precedes the infection of specific tissues such as the heart or pancreas.

Different strains exist

EV-D68 strains can be divided into three genetic groups based on the sequence of the capsid-coding VP1 region, the most variable genome region of enteroviruses.²³

Investigators have explored whether emergent EV-D68 strains differ in their anti-
genicity and receptor-binding properties in comparison to the Fermon strain isolated in 1962.²⁰ Using antisera generated from various strains of EV-D68, significant differences were observed in terms of hemagglutination inhibition and neutralization titers both between emergent strains and the original Fermon strain and among the emergent strains.

Viremia in systemic disease

Like other enteroviruses, EV-D68 has the ability to infect lymphocytes.⁹ This may provide a mechanism by which the virus is transported during the viremic phase to secondary target organs. Indeed, EV-D68 was detected in the serum of 12 (43%) of 28 pediatric patients with pneumonia and positive nasopharyngeal swabs.²⁴

Interestingly, whether EV-D68 was detected in the serum varied with age. Viremia was not detected in the serum of children younger than 1 year, an observation suggesting that maternal antibodies protect against viremia.

The role of viremia in systemic disease associated with EV-D68 is intriguing, especially since delayed acquisition of polio infection beyond infancy is hypothesized to have contributed to disease severity.⁷

ENTEROVIRUS D68 CAUSES SEVERE LOWER RESPIRATORY DISEASE

While identification of large numbers of patients with respiratory illnesses due to EV-D68 in a single season is unique to 2014, clusters of EV-D68-related respiratory illnesses have previously been recognized.^25,26

As with EV-D68 outbreaks in other parts of the world, the outbreak in the US Midwest in August 2014 primarily involved children, many of whom needed to be admitted to the hospital because of severe lower respiratory symptoms.¹⁰ In the 30 children admitted to two children’s hospitals described in the initial report, difficulty breathing, hypoxemia, and wheezing were common. A minority of patients (23%) presented with fever. Of hospitalized children, 67% required admission to the intensive care unit. Two patients required intubation, including one who required extracorporeal membrane oxygenation. Six required bilevel positive airway pressure therapy.

Cleveland Clinic experience

At Cleveland Clinic during the same time, nearly 45% of patients identified with a respiratory enterovirus infection required intensive care.

For patients previously diagnosed with asthma, chronic lung disease, or wheezing, essential supportive care measures included continuing the inhaled steroids the patients were already taking, early use of short-acting beta agonists, and, in those with previously diagnosed asthma, consideration of a systemic steroid. Many of our patients with previously diagnosed asthma had an unusually long prodrome of an increase in mild symptoms, followed by a rapid and severe decline in respiratory status.

At the later phase, supportive care measures that were needed included maintenance of hydration and monitoring of oxyhemoglobin saturation with use of supplemental oxygen as necessary, as well as close observation of clinical indicators of respiratory distress, such as development of crackles, asymmetric air exchange, and progression in wheezing or in use of accessory muscles. In an attempt to avoid invasive ventilatory support in patients with asthma or other comorbid conditions, some patients were treated with aerosolized epinephrine, ipratropium, heliox, and noninvasive positive pressure ventilatory support.

NEUROLOGIC DISEASE: ACUTE FLACCID PARALYSIS

Although EV-D68 causes primarily respiratory illness, systemic disease occurs, especially neurologic involvement.

Before the recent outbreak of EV-D68, two cases of neurologic involvement from EV-D68 were reported. The first of these, mentioned in a 2006 enterovirus surveillance report issued by the CDC, was in a young adult with acute flaccid paralysis and EV-D68 isolated from the cerebral spinal fluid.¹¹ In the second case, from 2010, a 5-year-old boy developed fatal meningomyeloencephalitis. The child had presented with pneumonia and acute flaccid paralysis. EV-D68 was identified in his cerebral spinal fluid by polymerase chain reaction (PCR), and histopathologic study of the meninges, cerebellum, midbrain, pons, medulla, and cervical cord demonstrated extensive T-cell lymphocytic meningomyelitis and encephalitis, characterized by prominent neuronophagia in motor nuclei.²⁷

At the same time as the recent outbreak of EV-D68 respiratory disease, neurologists throughout the United States observed an increase in the number of children with polio-like acute flaccid paralysis. On September 26, 2014, the CDC issued an alert describing acute neurologic illness with focal limb weakness of unknown etiology in children, possibly associated with EV-D68.²⁸ The report described nine cases of an acute neurologic illness in children ages 1 through 18 years (median age, 10) hospitalized in Colorado between August 9 and September 17, 2014. Common clinical features included acute focal limb weakness and paralysis and acute cranial nerve dysfunction, with no altered mental status or seizures. Pain before the onset of weakness was also identified as a common complaint.

Specific findings on magnetic resonance imaging of the spinal cord consisted of nonenhancing lesions largely restricted to the gray matter and in most cases spanning more than one level of the spinal cord. In patients with cranial nerve dysfunction, correlating nonenhancing brainstem lesions were observed.

Neurologists observed an increase in the number of children with polio-like acute flaccid paralysis

Most children experienced a febrile respiratory illness in the 2 weeks preceding the onset of neurologic symptoms. In most cases, cerebrospinal fluid analyses demonstrated mild or moderate pleocytosis consistent with an inflammatory or infectious process, with normal to mildly elevated protein and normal glucose levels. In six of the eight patients tested, nasopharyngeal specimens were positive for rhinovirus-enterovirus. Of the six positive specimens, at least four were typed as EV-D68.

The CDC also reported a second cluster of cases of acute flaccid paralysis with anterior myelitis on magnetic resonance imaging, in 23 children (mean age 10 years) in California from June 2012 to June 2014.²⁹ No common cause was identified, although clinical and laboratory findings supported a viral etiology. Two patients tested positive for EV-D68 from upper respiratory tract specimens. Common features among the clinical presentations included an upper respiratory or gastrointestinal prodrome less than 10 days before the onset of the paralysis (83%), cerebrospinal fluid pleocytosis (83%), and absence of sensory deficits (78%). Ten patients (43%) also had concomitant mental status changes, and eight (34%) had cranial nerve abnormalities.

Details regarding outcomes from these paralytic illnesses remain unclear, although it would appear that time to recovery has been prolonged in many cases, and the degree of recovery remains uncertain.

TREATMENT IS SUPPORTIVE

The treatment of EV-D68 infection is mainly supportive, as no specific antiviral therapy is currently available for any of the enteroviruses. Critically ill patients require organ-specific supportive care.

Potential targets for novel antienteroviral therapies exist; some of the experimental compounds were initially evaluated for their activity against polioviruses or rhinoviruses.³⁰

TESTING MAY HAVE A ROLE

In general, testing does not play a role in the management of patients with mild disease, but it may be indicated for epidemiologic purposes or for specific diagnosis in critically ill patients. Molecular techniques are commonly used to detect respiratory viruses from clinical samples, either as discrete tests or as a multiplex viral panel.

Since patients with EV-D68 infection typically have respiratory symptoms, the virus is generally tested for in nasal wash samples. However, depending on the clinical presentation, it may be appropriate to attempt to detect the virus from other sites using either PCR or culture.

Many clinical laboratories use real-time PCR assays designed to detect both rhinoviruses and enteroviruses, but these tests do not distinguish between the species. While more specific real-time PCR assays are available that generally distinguish rhinoviruses from enteroviruses,³¹ during the recent outbreak our laboratory observed that confirmed EV-D68 samples cross-reacted with rhinovirus. Most clinical laboratories do not routinely perform viral sequence analysis to specifically identify EV-D68, but this test may be obtained through state health departments and the CDC on a case-by-case basis.

Recently, the CDC’s enterovirus laboratory announced the development of a real-time PCR assay specifically for EV-D68, which may make specific detection more readily available.

INFECTION PREVENTION

The routes by which EV-D68 is transmitted are not fully understood. In contrast to most enteroviruses, which are spread in a fecal-oral manner, it is possible that EV-D68 is also spread through close respiratory or mucous contact.

For this reason, interim infection prevention guidelines issued by the CDC recommend that hospitals use droplet precautions along with contact or standard precautions, depending on the scenario.³² In our children’s hospital, we use droplet and contact precautions for hospitalized patients.

In the fall of 2014, the United States experienced an outbreak of severe respiratory illness due to a virus of emerging importance, enterovirus D68 (EV-D68). Here, we review the features of this virus and related viruses, the clinical syndromes this virus causes, the epidemiology of the recent outbreak, and its diagnosis and treatment.

THE ENTEROVIRUSES: AN OVERVIEW

Originally identified in 1962 from the throat swab of a child with pneumonia, human EV-D68 has unique genetic and clinical features that blur the typical division between human enteroviruses and rhinoviruses.1–4 Enteroviruses and rhinoviruses are closely related species within the Picornaviridae family that are now classified together within the genus Enterovirus.⁵ Picornaviruses are small, nonenveloped, positive-stranded RNA viruses of medical significance.

Poliovirus: The first enterovirus discovered

The first human enterovirus to be discovered was poliovirus.⁶ Although sporadic cases of “infantile paralysis” occurred before the late 19th century, epidemic poliomyelitis abruptly appeared in Europe and the United States beginning around 1880. Before the introduction in 1955 of the inactivated poliovirus vaccine and then the oral poliovirus vaccine, polio was one of the most feared illnesses in the developed world. Outbreaks occurred primarily in cities during summer months. At its peak, epidemic polio killed or paralyzed more than  half a million people a year.

One hypothesis to explain the sudden emergence of epidemic polio is that improved personal hygiene and public sanitation delayed the age at which children acquired this enteric infection.⁷ Infections acquired after infancy occurred in the absence of maternal antibodies that may have protected against the virus’s propensity to invade the nervous system.

Nonpolio human enteroviruses

In the decades since poliovirus was discovered, more than 100 nonpolio human enteroviruses have been recognized.⁸ This group includes the coxsackieviruses, echoviruses, and the newer numbered nonpolio human enteroviruses classified into four species, designated Human enterovirus A, B, C, and D. The last of these, Human enterovirus D, includes three serotypes known to cause disease in humans: EV-D68, EV-D70, and EV-D94.⁹

The genus Enterovirus includes the polioviruses; nonpolio enteroviruses A, B, C, and D; and rhinoviruses

As with poliovirus infection, most people infected with a nonpolio human enterovirus have a mild illness without distinctive features.⁵ In temperate climates, enteroviral infections are most common during the summer and fall and are an important cause of the “summer cold.” In tropical climates, the seasonal pattern is absent, and infections may occur throughout the year.

The clinical syndromes associated with a nonpolio human enterovirus can include nonspecific febrile illness; upper respiratory tract infection; pharyngitis; herpangina; hand, foot, and mouth syndrome; various skin exanthems; bronchiolitis; asthma exacerbation; gastrointestinal manifestations such as diarrhea and vomiting (which are especially common); more serious clinical syndromes such as hepatitis, pancreatitis, and cardiomyopathy; and neurologic illness, including aseptic meningitis, encephalitis, and polio-like paralytic disease.

Outbreaks caused by nonpolio human enteroviruses occur on a regular basis, may vary by strain from year to year, and often occur within a geographic region; multiple strains may circulate simultaneously. Occasionally, as with EV-D68 in August 2014 in the United States, epidemics can emerge suddenly and spread rapidly across the world, causing disease in hundreds or thousands of people, demonstrating the breadth of illness associated with particular strains.¹⁰

ENTEROVIRUS D68: AN EMERGING PATHOGEN

EV-D68 was first isolated in the United States from four children in Berkeley, California, who had lower respiratory tract symptoms (bronchiolitis and pneumonia) in 1962. The finding was published in the medical literature in 1967.¹ Since its initial identification, EV-D68 was infrequently reported as a cause of human disease, with the US Centers for Disease Control and Prevention (CDC) listing only 26 cases in the 36 years from 1970 through 2005.¹¹

However, the past decade has seen EV-D68 emerge as a significant respiratory pathogen, with more reports of acute respiratory illness associated with it in North America, Europe, and Asia, especially in children.^12–17 A seasonal pattern may exist; a longitudinal survey of samples collected from New York City detected a focal outbreak in the fall of 2009.¹⁸

The observation that recent EV-D68 outbreaks have primarily been in children suggests that most adults have immunity to it. In this regard, seroepidemiologic studies from Finland demonstrated that most adults have neutralizing antibodies from previous infection.⁹

The blurred line between enteroviruses and rhinoviruses

Enteroviruses and rhinoviruses are typically distinguished on the basis of the temperature at which they grow best (rhinoviruses grow better at lower temperatures, allowing them to replicate in the nose) and their sensitivity to acidity (enteroviruses are more resistant, enabling them to survive in the stomach).

The original (“Fermon”) strain of EV-D68 isolated in 1962 was first classified as an enterovirus because it was resistant to low pH.¹ However, when molecular sequencing became available, EV-D68 was found to be identical to human rhinovirus 87 (HRV87), a phylogenetic outlier among the rhinoviruses that binds to cells at a receptor site distinct from that of other human rhinoviruses.¹⁹

Thereafter, further testing showed that both EV-D68 and HRV87 isolates were sensitive to acid treatment by two different methods.⁴ Moreover, unlike most enteroviruses, EV-D68 behaves like a rhinovirus and grows preferentially at 33°C, the temperature of the nose.²

How enterovirus D68 enters cells

Viral surface proteins, including hemagglutinin, from certain respiratory viruses have the ability to bind sugars on cells in the nose and lungs, which facilitates viral entry and replication. EV-D68 binds specifically to alpha 2-6 sialic acid, the predominant sialic acid found in the human upper respiratory tract.^19,20 The absence of EV-D68 binding affinity for alpha 2-3 sialic acid, present in ciliated epithelial cells of the lower tract, suggests that alternative mechanisms may be responsible for the severe lower respiratory disease associated with this virus.

During the last decade, EV-D68 has emerged as a significant respiratory pathogen

Entry of EV-D68 into cells requires additional mediators. EV-D70 belongs to the same genetic cluster as EV-D68 and enters HeLa cells using decay-accelerating factor (DAF).²¹ Evidence that EV-D68 also uses DAF for cell entry comes from experiments showing that monoclonal antibodies against DAF inhibit the cytopathic effects of this virus.⁴ Virus-receptor interactions have been more thoroughly characterized for other enteroviruses.²² In this regard, coxsackieviruses of group B use DAF as a coreceptor. Since DAF is expressed at high levels in both epithelial and endothelial cells, it may play an important role in the induction of the viremia that precedes the infection of specific tissues such as the heart or pancreas.

Different strains exist

EV-D68 strains can be divided into three genetic groups based on the sequence of the capsid-coding VP1 region, the most variable genome region of enteroviruses.²³

Investigators have explored whether emergent EV-D68 strains differ in their anti-
genicity and receptor-binding properties in comparison to the Fermon strain isolated in 1962.²⁰ Using antisera generated from various strains of EV-D68, significant differences were observed in terms of hemagglutination inhibition and neutralization titers both between emergent strains and the original Fermon strain and among the emergent strains.

Viremia in systemic disease

Like other enteroviruses, EV-D68 has the ability to infect lymphocytes.⁹ This may provide a mechanism by which the virus is transported during the viremic phase to secondary target organs. Indeed, EV-D68 was detected in the serum of 12 (43%) of 28 pediatric patients with pneumonia and positive nasopharyngeal swabs.²⁴

Interestingly, whether EV-D68 was detected in the serum varied with age. Viremia was not detected in the serum of children younger than 1 year, an observation suggesting that maternal antibodies protect against viremia.

The role of viremia in systemic disease associated with EV-D68 is intriguing, especially since delayed acquisition of polio infection beyond infancy is hypothesized to have contributed to disease severity.⁷

ENTEROVIRUS D68 CAUSES SEVERE LOWER RESPIRATORY DISEASE

While identification of large numbers of patients with respiratory illnesses due to EV-D68 in a single season is unique to 2014, clusters of EV-D68-related respiratory illnesses have previously been recognized.^25,26

As with EV-D68 outbreaks in other parts of the world, the outbreak in the US Midwest in August 2014 primarily involved children, many of whom needed to be admitted to the hospital because of severe lower respiratory symptoms.¹⁰ In the 30 children admitted to two children’s hospitals described in the initial report, difficulty breathing, hypoxemia, and wheezing were common. A minority of patients (23%) presented with fever. Of hospitalized children, 67% required admission to the intensive care unit. Two patients required intubation, including one who required extracorporeal membrane oxygenation. Six required bilevel positive airway pressure therapy.

Cleveland Clinic experience

At Cleveland Clinic during the same time, nearly 45% of patients identified with a respiratory enterovirus infection required intensive care.

For patients previously diagnosed with asthma, chronic lung disease, or wheezing, essential supportive care measures included continuing the inhaled steroids the patients were already taking, early use of short-acting beta agonists, and, in those with previously diagnosed asthma, consideration of a systemic steroid. Many of our patients with previously diagnosed asthma had an unusually long prodrome of an increase in mild symptoms, followed by a rapid and severe decline in respiratory status.

At the later phase, supportive care measures that were needed included maintenance of hydration and monitoring of oxyhemoglobin saturation with use of supplemental oxygen as necessary, as well as close observation of clinical indicators of respiratory distress, such as development of crackles, asymmetric air exchange, and progression in wheezing or in use of accessory muscles. In an attempt to avoid invasive ventilatory support in patients with asthma or other comorbid conditions, some patients were treated with aerosolized epinephrine, ipratropium, heliox, and noninvasive positive pressure ventilatory support.

NEUROLOGIC DISEASE: ACUTE FLACCID PARALYSIS

Although EV-D68 causes primarily respiratory illness, systemic disease occurs, especially neurologic involvement.

Before the recent outbreak of EV-D68, two cases of neurologic involvement from EV-D68 were reported. The first of these, mentioned in a 2006 enterovirus surveillance report issued by the CDC, was in a young adult with acute flaccid paralysis and EV-D68 isolated from the cerebral spinal fluid.¹¹ In the second case, from 2010, a 5-year-old boy developed fatal meningomyeloencephalitis. The child had presented with pneumonia and acute flaccid paralysis. EV-D68 was identified in his cerebral spinal fluid by polymerase chain reaction (PCR), and histopathologic study of the meninges, cerebellum, midbrain, pons, medulla, and cervical cord demonstrated extensive T-cell lymphocytic meningomyelitis and encephalitis, characterized by prominent neuronophagia in motor nuclei.²⁷

At the same time as the recent outbreak of EV-D68 respiratory disease, neurologists throughout the United States observed an increase in the number of children with polio-like acute flaccid paralysis. On September 26, 2014, the CDC issued an alert describing acute neurologic illness with focal limb weakness of unknown etiology in children, possibly associated with EV-D68.²⁸ The report described nine cases of an acute neurologic illness in children ages 1 through 18 years (median age, 10) hospitalized in Colorado between August 9 and September 17, 2014. Common clinical features included acute focal limb weakness and paralysis and acute cranial nerve dysfunction, with no altered mental status or seizures. Pain before the onset of weakness was also identified as a common complaint.

Specific findings on magnetic resonance imaging of the spinal cord consisted of nonenhancing lesions largely restricted to the gray matter and in most cases spanning more than one level of the spinal cord. In patients with cranial nerve dysfunction, correlating nonenhancing brainstem lesions were observed.

Neurologists observed an increase in the number of children with polio-like acute flaccid paralysis

Most children experienced a febrile respiratory illness in the 2 weeks preceding the onset of neurologic symptoms. In most cases, cerebrospinal fluid analyses demonstrated mild or moderate pleocytosis consistent with an inflammatory or infectious process, with normal to mildly elevated protein and normal glucose levels. In six of the eight patients tested, nasopharyngeal specimens were positive for rhinovirus-enterovirus. Of the six positive specimens, at least four were typed as EV-D68.

The CDC also reported a second cluster of cases of acute flaccid paralysis with anterior myelitis on magnetic resonance imaging, in 23 children (mean age 10 years) in California from June 2012 to June 2014.²⁹ No common cause was identified, although clinical and laboratory findings supported a viral etiology. Two patients tested positive for EV-D68 from upper respiratory tract specimens. Common features among the clinical presentations included an upper respiratory or gastrointestinal prodrome less than 10 days before the onset of the paralysis (83%), cerebrospinal fluid pleocytosis (83%), and absence of sensory deficits (78%). Ten patients (43%) also had concomitant mental status changes, and eight (34%) had cranial nerve abnormalities.

Details regarding outcomes from these paralytic illnesses remain unclear, although it would appear that time to recovery has been prolonged in many cases, and the degree of recovery remains uncertain.

TREATMENT IS SUPPORTIVE

The treatment of EV-D68 infection is mainly supportive, as no specific antiviral therapy is currently available for any of the enteroviruses. Critically ill patients require organ-specific supportive care.

Potential targets for novel antienteroviral therapies exist; some of the experimental compounds were initially evaluated for their activity against polioviruses or rhinoviruses.³⁰

TESTING MAY HAVE A ROLE

In general, testing does not play a role in the management of patients with mild disease, but it may be indicated for epidemiologic purposes or for specific diagnosis in critically ill patients. Molecular techniques are commonly used to detect respiratory viruses from clinical samples, either as discrete tests or as a multiplex viral panel.

Since patients with EV-D68 infection typically have respiratory symptoms, the virus is generally tested for in nasal wash samples. However, depending on the clinical presentation, it may be appropriate to attempt to detect the virus from other sites using either PCR or culture.

Many clinical laboratories use real-time PCR assays designed to detect both rhinoviruses and enteroviruses, but these tests do not distinguish between the species. While more specific real-time PCR assays are available that generally distinguish rhinoviruses from enteroviruses,³¹ during the recent outbreak our laboratory observed that confirmed EV-D68 samples cross-reacted with rhinovirus. Most clinical laboratories do not routinely perform viral sequence analysis to specifically identify EV-D68, but this test may be obtained through state health departments and the CDC on a case-by-case basis.

Recently, the CDC’s enterovirus laboratory announced the development of a real-time PCR assay specifically for EV-D68, which may make specific detection more readily available.

INFECTION PREVENTION

The routes by which EV-D68 is transmitted are not fully understood. In contrast to most enteroviruses, which are spread in a fecal-oral manner, it is possible that EV-D68 is also spread through close respiratory or mucous contact.

For this reason, interim infection prevention guidelines issued by the CDC recommend that hospitals use droplet precautions along with contact or standard precautions, depending on the scenario.³² In our children’s hospital, we use droplet and contact precautions for hospitalized patients.

In the fall of 2014, the United States experienced an outbreak of severe respiratory illness due to a virus of emerging importance, enterovirus D68 (EV-D68). Here, we review the features of this virus and related viruses, the clinical syndromes this virus causes, the epidemiology of the recent outbreak, and its diagnosis and treatment.

THE ENTEROVIRUSES: AN OVERVIEW

Originally identified in 1962 from the throat swab of a child with pneumonia, human EV-D68 has unique genetic and clinical features that blur the typical division between human enteroviruses and rhinoviruses.1–4 Enteroviruses and rhinoviruses are closely related species within the Picornaviridae family that are now classified together within the genus Enterovirus.⁵ Picornaviruses are small, nonenveloped, positive-stranded RNA viruses of medical significance.

Poliovirus: The first enterovirus discovered

The first human enterovirus to be discovered was poliovirus.⁶ Although sporadic cases of “infantile paralysis” occurred before the late 19th century, epidemic poliomyelitis abruptly appeared in Europe and the United States beginning around 1880. Before the introduction in 1955 of the inactivated poliovirus vaccine and then the oral poliovirus vaccine, polio was one of the most feared illnesses in the developed world. Outbreaks occurred primarily in cities during summer months. At its peak, epidemic polio killed or paralyzed more than  half a million people a year.

One hypothesis to explain the sudden emergence of epidemic polio is that improved personal hygiene and public sanitation delayed the age at which children acquired this enteric infection.⁷ Infections acquired after infancy occurred in the absence of maternal antibodies that may have protected against the virus’s propensity to invade the nervous system.

Nonpolio human enteroviruses

In the decades since poliovirus was discovered, more than 100 nonpolio human enteroviruses have been recognized.⁸ This group includes the coxsackieviruses, echoviruses, and the newer numbered nonpolio human enteroviruses classified into four species, designated Human enterovirus A, B, C, and D. The last of these, Human enterovirus D, includes three serotypes known to cause disease in humans: EV-D68, EV-D70, and EV-D94.⁹

The genus Enterovirus includes the polioviruses; nonpolio enteroviruses A, B, C, and D; and rhinoviruses

As with poliovirus infection, most people infected with a nonpolio human enterovirus have a mild illness without distinctive features.⁵ In temperate climates, enteroviral infections are most common during the summer and fall and are an important cause of the “summer cold.” In tropical climates, the seasonal pattern is absent, and infections may occur throughout the year.

The clinical syndromes associated with a nonpolio human enterovirus can include nonspecific febrile illness; upper respiratory tract infection; pharyngitis; herpangina; hand, foot, and mouth syndrome; various skin exanthems; bronchiolitis; asthma exacerbation; gastrointestinal manifestations such as diarrhea and vomiting (which are especially common); more serious clinical syndromes such as hepatitis, pancreatitis, and cardiomyopathy; and neurologic illness, including aseptic meningitis, encephalitis, and polio-like paralytic disease.

Outbreaks caused by nonpolio human enteroviruses occur on a regular basis, may vary by strain from year to year, and often occur within a geographic region; multiple strains may circulate simultaneously. Occasionally, as with EV-D68 in August 2014 in the United States, epidemics can emerge suddenly and spread rapidly across the world, causing disease in hundreds or thousands of people, demonstrating the breadth of illness associated with particular strains.¹⁰

ENTEROVIRUS D68: AN EMERGING PATHOGEN

EV-D68 was first isolated in the United States from four children in Berkeley, California, who had lower respiratory tract symptoms (bronchiolitis and pneumonia) in 1962. The finding was published in the medical literature in 1967.¹ Since its initial identification, EV-D68 was infrequently reported as a cause of human disease, with the US Centers for Disease Control and Prevention (CDC) listing only 26 cases in the 36 years from 1970 through 2005.¹¹

However, the past decade has seen EV-D68 emerge as a significant respiratory pathogen, with more reports of acute respiratory illness associated with it in North America, Europe, and Asia, especially in children.^12–17 A seasonal pattern may exist; a longitudinal survey of samples collected from New York City detected a focal outbreak in the fall of 2009.¹⁸

The observation that recent EV-D68 outbreaks have primarily been in children suggests that most adults have immunity to it. In this regard, seroepidemiologic studies from Finland demonstrated that most adults have neutralizing antibodies from previous infection.⁹

The blurred line between enteroviruses and rhinoviruses

Enteroviruses and rhinoviruses are typically distinguished on the basis of the temperature at which they grow best (rhinoviruses grow better at lower temperatures, allowing them to replicate in the nose) and their sensitivity to acidity (enteroviruses are more resistant, enabling them to survive in the stomach).

The original (“Fermon”) strain of EV-D68 isolated in 1962 was first classified as an enterovirus because it was resistant to low pH.¹ However, when molecular sequencing became available, EV-D68 was found to be identical to human rhinovirus 87 (HRV87), a phylogenetic outlier among the rhinoviruses that binds to cells at a receptor site distinct from that of other human rhinoviruses.¹⁹

Thereafter, further testing showed that both EV-D68 and HRV87 isolates were sensitive to acid treatment by two different methods.⁴ Moreover, unlike most enteroviruses, EV-D68 behaves like a rhinovirus and grows preferentially at 33°C, the temperature of the nose.²

How enterovirus D68 enters cells

Viral surface proteins, including hemagglutinin, from certain respiratory viruses have the ability to bind sugars on cells in the nose and lungs, which facilitates viral entry and replication. EV-D68 binds specifically to alpha 2-6 sialic acid, the predominant sialic acid found in the human upper respiratory tract.^19,20 The absence of EV-D68 binding affinity for alpha 2-3 sialic acid, present in ciliated epithelial cells of the lower tract, suggests that alternative mechanisms may be responsible for the severe lower respiratory disease associated with this virus.

During the last decade, EV-D68 has emerged as a significant respiratory pathogen

Entry of EV-D68 into cells requires additional mediators. EV-D70 belongs to the same genetic cluster as EV-D68 and enters HeLa cells using decay-accelerating factor (DAF).²¹ Evidence that EV-D68 also uses DAF for cell entry comes from experiments showing that monoclonal antibodies against DAF inhibit the cytopathic effects of this virus.⁴ Virus-receptor interactions have been more thoroughly characterized for other enteroviruses.²² In this regard, coxsackieviruses of group B use DAF as a coreceptor. Since DAF is expressed at high levels in both epithelial and endothelial cells, it may play an important role in the induction of the viremia that precedes the infection of specific tissues such as the heart or pancreas.

Different strains exist

EV-D68 strains can be divided into three genetic groups based on the sequence of the capsid-coding VP1 region, the most variable genome region of enteroviruses.²³

Investigators have explored whether emergent EV-D68 strains differ in their anti-
genicity and receptor-binding properties in comparison to the Fermon strain isolated in 1962.²⁰ Using antisera generated from various strains of EV-D68, significant differences were observed in terms of hemagglutination inhibition and neutralization titers both between emergent strains and the original Fermon strain and among the emergent strains.

Viremia in systemic disease

Like other enteroviruses, EV-D68 has the ability to infect lymphocytes.⁹ This may provide a mechanism by which the virus is transported during the viremic phase to secondary target organs. Indeed, EV-D68 was detected in the serum of 12 (43%) of 28 pediatric patients with pneumonia and positive nasopharyngeal swabs.²⁴

Interestingly, whether EV-D68 was detected in the serum varied with age. Viremia was not detected in the serum of children younger than 1 year, an observation suggesting that maternal antibodies protect against viremia.

The role of viremia in systemic disease associated with EV-D68 is intriguing, especially since delayed acquisition of polio infection beyond infancy is hypothesized to have contributed to disease severity.⁷

ENTEROVIRUS D68 CAUSES SEVERE LOWER RESPIRATORY DISEASE

While identification of large numbers of patients with respiratory illnesses due to EV-D68 in a single season is unique to 2014, clusters of EV-D68-related respiratory illnesses have previously been recognized.^25,26

As with EV-D68 outbreaks in other parts of the world, the outbreak in the US Midwest in August 2014 primarily involved children, many of whom needed to be admitted to the hospital because of severe lower respiratory symptoms.¹⁰ In the 30 children admitted to two children’s hospitals described in the initial report, difficulty breathing, hypoxemia, and wheezing were common. A minority of patients (23%) presented with fever. Of hospitalized children, 67% required admission to the intensive care unit. Two patients required intubation, including one who required extracorporeal membrane oxygenation. Six required bilevel positive airway pressure therapy.

Cleveland Clinic experience

At Cleveland Clinic during the same time, nearly 45% of patients identified with a respiratory enterovirus infection required intensive care.

For patients previously diagnosed with asthma, chronic lung disease, or wheezing, essential supportive care measures included continuing the inhaled steroids the patients were already taking, early use of short-acting beta agonists, and, in those with previously diagnosed asthma, consideration of a systemic steroid. Many of our patients with previously diagnosed asthma had an unusually long prodrome of an increase in mild symptoms, followed by a rapid and severe decline in respiratory status.

At the later phase, supportive care measures that were needed included maintenance of hydration and monitoring of oxyhemoglobin saturation with use of supplemental oxygen as necessary, as well as close observation of clinical indicators of respiratory distress, such as development of crackles, asymmetric air exchange, and progression in wheezing or in use of accessory muscles. In an attempt to avoid invasive ventilatory support in patients with asthma or other comorbid conditions, some patients were treated with aerosolized epinephrine, ipratropium, heliox, and noninvasive positive pressure ventilatory support.

NEUROLOGIC DISEASE: ACUTE FLACCID PARALYSIS

Although EV-D68 causes primarily respiratory illness, systemic disease occurs, especially neurologic involvement.

Before the recent outbreak of EV-D68, two cases of neurologic involvement from EV-D68 were reported. The first of these, mentioned in a 2006 enterovirus surveillance report issued by the CDC, was in a young adult with acute flaccid paralysis and EV-D68 isolated from the cerebral spinal fluid.¹¹ In the second case, from 2010, a 5-year-old boy developed fatal meningomyeloencephalitis. The child had presented with pneumonia and acute flaccid paralysis. EV-D68 was identified in his cerebral spinal fluid by polymerase chain reaction (PCR), and histopathologic study of the meninges, cerebellum, midbrain, pons, medulla, and cervical cord demonstrated extensive T-cell lymphocytic meningomyelitis and encephalitis, characterized by prominent neuronophagia in motor nuclei.²⁷

At the same time as the recent outbreak of EV-D68 respiratory disease, neurologists throughout the United States observed an increase in the number of children with polio-like acute flaccid paralysis. On September 26, 2014, the CDC issued an alert describing acute neurologic illness with focal limb weakness of unknown etiology in children, possibly associated with EV-D68.²⁸ The report described nine cases of an acute neurologic illness in children ages 1 through 18 years (median age, 10) hospitalized in Colorado between August 9 and September 17, 2014. Common clinical features included acute focal limb weakness and paralysis and acute cranial nerve dysfunction, with no altered mental status or seizures. Pain before the onset of weakness was also identified as a common complaint.

Specific findings on magnetic resonance imaging of the spinal cord consisted of nonenhancing lesions largely restricted to the gray matter and in most cases spanning more than one level of the spinal cord. In patients with cranial nerve dysfunction, correlating nonenhancing brainstem lesions were observed.

Neurologists observed an increase in the number of children with polio-like acute flaccid paralysis

Most children experienced a febrile respiratory illness in the 2 weeks preceding the onset of neurologic symptoms. In most cases, cerebrospinal fluid analyses demonstrated mild or moderate pleocytosis consistent with an inflammatory or infectious process, with normal to mildly elevated protein and normal glucose levels. In six of the eight patients tested, nasopharyngeal specimens were positive for rhinovirus-enterovirus. Of the six positive specimens, at least four were typed as EV-D68.

The CDC also reported a second cluster of cases of acute flaccid paralysis with anterior myelitis on magnetic resonance imaging, in 23 children (mean age 10 years) in California from June 2012 to June 2014.²⁹ No common cause was identified, although clinical and laboratory findings supported a viral etiology. Two patients tested positive for EV-D68 from upper respiratory tract specimens. Common features among the clinical presentations included an upper respiratory or gastrointestinal prodrome less than 10 days before the onset of the paralysis (83%), cerebrospinal fluid pleocytosis (83%), and absence of sensory deficits (78%). Ten patients (43%) also had concomitant mental status changes, and eight (34%) had cranial nerve abnormalities.

Details regarding outcomes from these paralytic illnesses remain unclear, although it would appear that time to recovery has been prolonged in many cases, and the degree of recovery remains uncertain.

TREATMENT IS SUPPORTIVE

The treatment of EV-D68 infection is mainly supportive, as no specific antiviral therapy is currently available for any of the enteroviruses. Critically ill patients require organ-specific supportive care.

Potential targets for novel antienteroviral therapies exist; some of the experimental compounds were initially evaluated for their activity against polioviruses or rhinoviruses.³⁰

TESTING MAY HAVE A ROLE

In general, testing does not play a role in the management of patients with mild disease, but it may be indicated for epidemiologic purposes or for specific diagnosis in critically ill patients. Molecular techniques are commonly used to detect respiratory viruses from clinical samples, either as discrete tests or as a multiplex viral panel.

Since patients with EV-D68 infection typically have respiratory symptoms, the virus is generally tested for in nasal wash samples. However, depending on the clinical presentation, it may be appropriate to attempt to detect the virus from other sites using either PCR or culture.

Many clinical laboratories use real-time PCR assays designed to detect both rhinoviruses and enteroviruses, but these tests do not distinguish between the species. While more specific real-time PCR assays are available that generally distinguish rhinoviruses from enteroviruses,³¹ during the recent outbreak our laboratory observed that confirmed EV-D68 samples cross-reacted with rhinovirus. Most clinical laboratories do not routinely perform viral sequence analysis to specifically identify EV-D68, but this test may be obtained through state health departments and the CDC on a case-by-case basis.

Recently, the CDC’s enterovirus laboratory announced the development of a real-time PCR assay specifically for EV-D68, which may make specific detection more readily available.

INFECTION PREVENTION

The routes by which EV-D68 is transmitted are not fully understood. In contrast to most enteroviruses, which are spread in a fecal-oral manner, it is possible that EV-D68 is also spread through close respiratory or mucous contact.

For this reason, interim infection prevention guidelines issued by the CDC recommend that hospitals use droplet precautions along with contact or standard precautions, depending on the scenario.³² In our children’s hospital, we use droplet and contact precautions for hospitalized patients.

Snoring, snorting, gasping, and obstruc­tive sleep apnea are caused by col­lapse of the pharyngeal airway during sleep.¹ Pathophysiology includes a combi­nation of anatomical and physiological vari­ables.¹ Common anatomical predisposing conditions include abnormalities of pharyn­geal, lingual, and dental arches; physiologi­cal concerns are advancing age, male sex, obesity, use of sedatives, body positioning, and reduced muscle tone during rapid eye movement sleep. Coexistence of anatomic and physiological elements can produce significant narrowing of the upper airway.

Comorbidities include vascular, meta­bolic, and psychiatric conditions. As many as one-third of people with symptoms of sleep apnea report depressed mood; approx­imately 10% of these patients meet criteria for moderate or severe depression.²

In short, sleep-disordered breathing has a globally negative effect on mental health.

When should you consider obtaining a sleep apnea study?
Refer patients for a sleep study when snor­ing, snorting, gasping, or pauses in breathing occur during sleep, or in the case of daytime sleepiness, fatigue, or unrefreshing sleep that cannot be explained by another medical or psychiatric illness.² A sleep specialist can determine the most appropriate intervention for sleep-disordered breathing.

An apneic event is characterized by complete cessation of airflow; hypopnea is a partially compromised airway. In either event, at least a 3% decrease in oxygen saturation occurs for at least 10 seconds.³ A diagnosis of obstructive sleep apnea or hypopnea is required when polysomnography reveals either of:
   • ≥5 episodes of apnea or hypopnea, or both, per hour of sleep, with symptoms of a rhythmic breathing disturbance or daytime sleepiness or fatigue
   • ≥15 episodes of apnea or hypopnea, or both, per hour of sleep, regardless of accom­panying symptoms.²

What are the treatment options? 
   • Continuous positive airway pressure (CPAP) machines.
   • Surgical procedures include adeno-tonsillectomy in children and surgical maxilla-mandibular advancement or pala­tal implants for adults.
   • A novel implantable electrical stimu­lation device stimulates the hypoglossal nerve, which activates the genioglossus muscle, thus moving the tongue forward to open the airway.
   • An anterior mandibular positioning (AMP) device increases the diameter of the retroglossal space by preventing posterior movement of the mandible and tongue, thereby limiting encroachment on the air­way diameter and reducing the potential for collapse.^1-4

When should you recommend an AMP device?
Consider recommending an AMP device to treat sleep-disordered breathing when (1) lifestyle changes, such as sleep hygiene, weight loss, and stopping sedatives, do not work and (2) a CPAP machine or a surgical procedure is contraindicated or has been ineffective.¹ An AMP device can minimize snoring and relieve airway obstruction, especially in patients with supine position-related apnea.⁴ To keep the airway open in non-supine position-related cases, an AMP device might be indicated in addition to CPAP delivered nasally.¹

This plastic oral appliance is either a 1- or 2-piece design, and looks and is sized simi­larly to an athletic mouth-protection guard or an oral anti-bruxism tooth-protection appliance. It is affixed to the mandible and maxillary arches by clasps (Figure).

An AMP device is contraindicated when the device cannot be affixed to the dental arches and in some patients with an anatom­ical or pain-related temporomandibular joint disorder.⁵ The device is easy to use, nonin­vasive, readily accessible, and less expensive than alternatives.³

How can you help maintain treatment adherence?
AMP devices can induce adverse effects, including dental pain or discomfort through orthodontic alterations; patient reports and follow-up can yield detection and device adjustments can alleviate such problems. Adherence generally is good, with complaints usually limited to minor tooth discomfort, occlusive changes, and increased or decreased salivation.⁵ In our clinical experience, many patients find these devices comfortable and easy to use, but might complain of feeling awkward when wearing them.

Changes in occlusion can occur during long-term treatment with an AMP device. Proper fitting is essential to facilitate a more open airway and the ability to speak and drink fluids, and to maintain safety, even if vomiting occurs while the device is in place.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Snoring, snorting, gasping, and obstruc­tive sleep apnea are caused by col­lapse of the pharyngeal airway during sleep.¹ Pathophysiology includes a combi­nation of anatomical and physiological vari­ables.¹ Common anatomical predisposing conditions include abnormalities of pharyn­geal, lingual, and dental arches; physiologi­cal concerns are advancing age, male sex, obesity, use of sedatives, body positioning, and reduced muscle tone during rapid eye movement sleep. Coexistence of anatomic and physiological elements can produce significant narrowing of the upper airway.

Comorbidities include vascular, meta­bolic, and psychiatric conditions. As many as one-third of people with symptoms of sleep apnea report depressed mood; approx­imately 10% of these patients meet criteria for moderate or severe depression.²

In short, sleep-disordered breathing has a globally negative effect on mental health.

When should you consider obtaining a sleep apnea study?
Refer patients for a sleep study when snor­ing, snorting, gasping, or pauses in breathing occur during sleep, or in the case of daytime sleepiness, fatigue, or unrefreshing sleep that cannot be explained by another medical or psychiatric illness.² A sleep specialist can determine the most appropriate intervention for sleep-disordered breathing.

An apneic event is characterized by complete cessation of airflow; hypopnea is a partially compromised airway. In either event, at least a 3% decrease in oxygen saturation occurs for at least 10 seconds.³ A diagnosis of obstructive sleep apnea or hypopnea is required when polysomnography reveals either of:
   • ≥5 episodes of apnea or hypopnea, or both, per hour of sleep, with symptoms of a rhythmic breathing disturbance or daytime sleepiness or fatigue
   • ≥15 episodes of apnea or hypopnea, or both, per hour of sleep, regardless of accom­panying symptoms.²

What are the treatment options? 
   • Continuous positive airway pressure (CPAP) machines.
   • Surgical procedures include adeno-tonsillectomy in children and surgical maxilla-mandibular advancement or pala­tal implants for adults.
   • A novel implantable electrical stimu­lation device stimulates the hypoglossal nerve, which activates the genioglossus muscle, thus moving the tongue forward to open the airway.
   • An anterior mandibular positioning (AMP) device increases the diameter of the retroglossal space by preventing posterior movement of the mandible and tongue, thereby limiting encroachment on the air­way diameter and reducing the potential for collapse.^1-4

When should you recommend an AMP device?
Consider recommending an AMP device to treat sleep-disordered breathing when (1) lifestyle changes, such as sleep hygiene, weight loss, and stopping sedatives, do not work and (2) a CPAP machine or a surgical procedure is contraindicated or has been ineffective.¹ An AMP device can minimize snoring and relieve airway obstruction, especially in patients with supine position-related apnea.⁴ To keep the airway open in non-supine position-related cases, an AMP device might be indicated in addition to CPAP delivered nasally.¹

This plastic oral appliance is either a 1- or 2-piece design, and looks and is sized simi­larly to an athletic mouth-protection guard or an oral anti-bruxism tooth-protection appliance. It is affixed to the mandible and maxillary arches by clasps (Figure).

An AMP device is contraindicated when the device cannot be affixed to the dental arches and in some patients with an anatom­ical or pain-related temporomandibular joint disorder.⁵ The device is easy to use, nonin­vasive, readily accessible, and less expensive than alternatives.³

How can you help maintain treatment adherence?
AMP devices can induce adverse effects, including dental pain or discomfort through orthodontic alterations; patient reports and follow-up can yield detection and device adjustments can alleviate such problems. Adherence generally is good, with complaints usually limited to minor tooth discomfort, occlusive changes, and increased or decreased salivation.⁵ In our clinical experience, many patients find these devices comfortable and easy to use, but might complain of feeling awkward when wearing them.

Changes in occlusion can occur during long-term treatment with an AMP device. Proper fitting is essential to facilitate a more open airway and the ability to speak and drink fluids, and to maintain safety, even if vomiting occurs while the device is in place.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Snoring, snorting, gasping, and obstruc­tive sleep apnea are caused by col­lapse of the pharyngeal airway during sleep.¹ Pathophysiology includes a combi­nation of anatomical and physiological vari­ables.¹ Common anatomical predisposing conditions include abnormalities of pharyn­geal, lingual, and dental arches; physiologi­cal concerns are advancing age, male sex, obesity, use of sedatives, body positioning, and reduced muscle tone during rapid eye movement sleep. Coexistence of anatomic and physiological elements can produce significant narrowing of the upper airway.

Comorbidities include vascular, meta­bolic, and psychiatric conditions. As many as one-third of people with symptoms of sleep apnea report depressed mood; approx­imately 10% of these patients meet criteria for moderate or severe depression.²

In short, sleep-disordered breathing has a globally negative effect on mental health.

When should you consider obtaining a sleep apnea study?
Refer patients for a sleep study when snor­ing, snorting, gasping, or pauses in breathing occur during sleep, or in the case of daytime sleepiness, fatigue, or unrefreshing sleep that cannot be explained by another medical or psychiatric illness.² A sleep specialist can determine the most appropriate intervention for sleep-disordered breathing.

An apneic event is characterized by complete cessation of airflow; hypopnea is a partially compromised airway. In either event, at least a 3% decrease in oxygen saturation occurs for at least 10 seconds.³ A diagnosis of obstructive sleep apnea or hypopnea is required when polysomnography reveals either of:
   • ≥5 episodes of apnea or hypopnea, or both, per hour of sleep, with symptoms of a rhythmic breathing disturbance or daytime sleepiness or fatigue
   • ≥15 episodes of apnea or hypopnea, or both, per hour of sleep, regardless of accom­panying symptoms.²

What are the treatment options? 
   • Continuous positive airway pressure (CPAP) machines.
   • Surgical procedures include adeno-tonsillectomy in children and surgical maxilla-mandibular advancement or pala­tal implants for adults.
   • A novel implantable electrical stimu­lation device stimulates the hypoglossal nerve, which activates the genioglossus muscle, thus moving the tongue forward to open the airway.
   • An anterior mandibular positioning (AMP) device increases the diameter of the retroglossal space by preventing posterior movement of the mandible and tongue, thereby limiting encroachment on the air­way diameter and reducing the potential for collapse.^1-4

When should you recommend an AMP device?
Consider recommending an AMP device to treat sleep-disordered breathing when (1) lifestyle changes, such as sleep hygiene, weight loss, and stopping sedatives, do not work and (2) a CPAP machine or a surgical procedure is contraindicated or has been ineffective.¹ An AMP device can minimize snoring and relieve airway obstruction, especially in patients with supine position-related apnea.⁴ To keep the airway open in non-supine position-related cases, an AMP device might be indicated in addition to CPAP delivered nasally.¹

This plastic oral appliance is either a 1- or 2-piece design, and looks and is sized simi­larly to an athletic mouth-protection guard or an oral anti-bruxism tooth-protection appliance. It is affixed to the mandible and maxillary arches by clasps (Figure).

An AMP device is contraindicated when the device cannot be affixed to the dental arches and in some patients with an anatom­ical or pain-related temporomandibular joint disorder.⁵ The device is easy to use, nonin­vasive, readily accessible, and less expensive than alternatives.³

How can you help maintain treatment adherence?
AMP devices can induce adverse effects, including dental pain or discomfort through orthodontic alterations; patient reports and follow-up can yield detection and device adjustments can alleviate such problems. Adherence generally is good, with complaints usually limited to minor tooth discomfort, occlusive changes, and increased or decreased salivation.⁵ In our clinical experience, many patients find these devices comfortable and easy to use, but might complain of feeling awkward when wearing them.

Changes in occlusion can occur during long-term treatment with an AMP device. Proper fitting is essential to facilitate a more open airway and the ability to speak and drink fluids, and to maintain safety, even if vomiting occurs while the device is in place.

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

To recap what I discussed in Part 1 of this article (December 2014): As part of a trend across all medical specialty boards, the American Board of Psychiatry and Neurology (ABPN) instituted a recertification pro­cess for all new general psychiatry certifications, starting October 1, 1994.¹ In 2000, the specialties that comprise the American Board of Medical Specialties (ABMS) agreed to develop a comprehensive maintenance of certification (MOC) process to demonstrate ongoing learning and com­petency beyond what can be captured by a recertification examination. All ABMS member boards now use a 4-part process for recertification.

A great deal of professional and personal importance has been attached to maintaining one’s general and sub­specialty certifications. To that end, the 2 parts of this article highlight current ABPN MOC requirements and provide resources for understanding, tracking, and completing the self-assessment (SA) and performance-in-practice (PIP) components.

In this installment, I examine 3 components of MOC:
   • continuing medical education (CME), including SA requirements
   • improvement in medical practice (PIP)
   • continuous maintenance of certification (C-MOC)

In addition to this review, all physicians who are subject to MOC should download and read the 20-page revised MOC Program booklet v. 2.1 (May 2014).²

Continuing medical education
The CME requirement is clear: All diplo­mate physicians must accrue, on average, 30 Category-1 CME credits a year; the CME must be relevant to the specialty or subspecialty in which the diplomate prac­tices.³ For physicians who hold >1 ABPN certificates, the total CME requirement is the same; CME credits can be applied across each specialty and subspecialty.

The May 2014 MOC revision states that, for physicians who certified or recertified between 2005 and 2011 and who applied for the 2015 examination in 2014, the required CME credit total is 270.2 For all subsequent years of certification or recertification, including 2012, diplomates are enrolled in C-MOC, which is described below.²

To even out the accrual of CME credits across the prior 10 years, ABPN mandates that, for diplomates who certified or recer­tified between 2005 and 2011, one hundred fifty of the CME credits be accrued in the 5 years before they apply for the examina­tion. Diplomates in C-MOC should accrue, on average, 30 CME credits a year in each of the 3-year blocks (ie, 90 units in each block).²

Self-assessment
SA is a specific form of CME that is designed to provide comprehensive test-based feedback on knowledge acquired, to enhance the learning process.⁴ SA CME feedback must include:
   • the correct answer to each test question
   • recommended literature resources for each question
   • performance compared to peers on each question.

Given the structured nature of SA activi­ties, beginning January 1, 2014, one must use only ABPN-approved SA products (see Related Resources for a list of APBN-approved SA products).⁵

Table 1 and Table 2 outline SA require­ments for, respectively, physicians who certified or recertified from 2005 through 2011, and those who certified or recertified in 2012 (and later). The SA requirement increases after 2011 to 24 credits in each 3-year block (8 credits a year, on average).² Multiple SA activities can be used to fulfill the credit requirement of each 3-year block.

Improvement in medical practice, or PIP
Physicians who are active clinically must complete PIP modules. Each module comprises peer or patient feedback plus a clinical aspect. The May 2014 MOC revi­sion simplified the feedback process to mandate peer or patient feedback—but not both, as required previously.² For the feedback PIP module, the physician selects 5 peers or patients to complete review forms, examines the results, and creates a plan of improvement. An exception to this “rule of 5” applies to diplomates who have a supervisor capable of evaluating all gen­eral competencies, defined below.

Related Resources provides a link to ABPN-created forms.

Within 24 months, but not sooner than 1 month, 5 peers or patients (or 1 appli­cable supervisor) are selected to complete review forms; changes in practice are noted. The same peers or patients might be selected for a second review. As noted in Table 1 and Table 2, the number of PIP modules is fewer for physicians who certi­fied or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²

There are 6 ABPN-approved feedback module options, of which the diplomate must choose 1 in any given block²:
   • 5 patient surveys
   • 5 peer evaluations of general competencies^a
   • 5 resident evaluations of general competencies^a  
   • 360° evaluation of general competencies,a with 5 respondents
   • institutional peer review of general competencies,^a with 5 respondents
   • 1 supervisor evaluation of general competencies.^a

^aGeneral competencies include patient care; practice-based learning and improvement; professionalism; medical knowledge; interpersonal and communication skills; and system-based practices.

Although many institutions have a quality improvement (QI) program, that program must be approved by the Multi-Specialty MOC Portfolio Approval Program sponsored by ABMS for a clinician to receive credit for 1 PIP clinical module. If the approved QI program includes patient or peer feedback (eg, a survey), the diplo­ mate can receive credit for 1 PIP feedback module.²

For the clinical PIP module, the physician selects 5 charts for review and examines them based on criteria found in an ABPN-approved (starting in 2014) PIP product. (Related Resources provides a link to this list.) After reviewing the initial 5 charts, a plan for improvement is created. Within 24 months, but no sooner than 1 month, 5 charts are again selected and reviewed, and changes in practice are noted. The same charts can be selected for the second review.

As noted in Table 1 and Table 2, the number of PIP modules is fewer for those who initially certified or recertified between 2005 and 2011; from 2012 onward, 1 PIP clinical module is required in each 3-year block.²


The C-MOC process
Physicians who certified or recertified in 2012, or who will certify or recertify after that year, are enrolled automatically in C-MOC.^6,7 The purpose of C-MOC is to keep diplomates on track to fulfill the higher level of SA requirements that began with this group; this is done by mandating use of the ABPN Physician Folios system. As shown in Table 2, there is no longer a 10-year cycle; instead, there are continuous 3-year stages, within which each diplomate must accrue 90 CME cred­its (on average, 30 credits a year), 24 SA credits (on average, 8 a year), 1 PIP clinical module, and 1 PIP feedback module.^6,7

The first 3-year block of C-MOC require­ments will be waived for physicians who complete Accreditation Council on Graduate Medical Education–accredited or ABPN-approved subspecialty training in 2012 or later—if they pass the corre­sponding ABPN subspecialty examination during the first 3-year block of enrollment in C-MOC.2 For diplomates enrolled in C-MOC, failure to track progress of each 3-year block, via the ABPN Physician Folios system, has significant consequences: Those who do not complete the first stage of the program by the end of 3 years will be listed on the ABPN Web site as “certified— not meeting MOC requirements.” Those who do not complete 2 stages by the end of 6 years will be listed as “not certified.”²

Cognitive exam still in place. The only remnant of the old 10-year cycle is the requirement to pass the cognitive examina­tion every 10 years, although the exam can be taken earlier if the diplomate wishes. If all requirements are met and one does not sit for, or fails, the exam, the ABPN Web site will report the diplomate as “not meet­ing MOC requirements.” One can retake the exam within 1 year of the failed or missed exam, but a subsequent failure or missed exam will result in being listed as “not certified.”²

Fee structure. Instead of a single fee paid at the time of the exam(s), physicians in the C-MOC program pay an annual fee that covers participation in ABPN Physician Folios and 1 exam in a 10-year period. Fewer than 10 years of participation, or applying for a combined examination (for diplomates who hold multiple certifica­tions), requires an additional fee.⁷ 

Bottom Line
Maintenance of certification (MOC) is manageable, although it requires you to be familiar with its various elements. Those elements include continuing medical education (CME requirements); the additional self-assessment component of CME; performance-in-practice modules; and continuous maintenance of certification. The MOC program booklet of the American Board of Psychiatry and Neurology provides all necessary details.

Disclosure
Dr. Meyer reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Chronic  disruptive and impulsive behaviors are significant concerns for psychiatric clinicians because of their persistence and potential legal ramifications. To date, few studies have assessed treatment options for pyromania, oppositional defiant disorder (ODD), intermittent explosive disorder (IED), kleptomania, and conduct disorder (CD).

This article reviews the literature on the treatment of these disorders, focusing primarily on randomized, controlled studies. Because of the lack of clinical studies for these disorders, however, case studies and open tri­als are mentioned for reference. Summaries of supported medication and psychological interventions are provided for each disorder.

Categorizing impulse-control disorders
The DSM-5 created a new chapter on disruptive, impulse control, and conduct disorders that brought together disorders previously classified as disorders usually first diagnosed in infancy, childhood, or adolescence (ODD, CD) and impulse-control disorders not elsewhere classified. These disorders are unified by the presence of difficult, disruptive, aggressive, or antisocial behavior. Disruptive, aggressive, or antisocial behavior usu­ally is a multifaceted behavior, often associated with physical or verbal injury to self, others, or objects or with violating the rights of others. These behaviors can appear in several forms and can be defensive, premedi­tated, or impulsive.

Despite a high prevalence in the general population¹ and in psychi­atric cohorts,² disruptive and impulse-control disorders have been rela­tively understudied. Controlled trials of treatments do not exist for many impulse-control disorders, and there are no FDA-approved medications for any of these disorders.
 

Oppositional defiant disorder
Irritability, anger, defiance, and temper are specific descriptors of ODD. ODD seems to be a developmental antecedent for some youth with CD, suggesting that these dis­orders could reflect different stages of a spectrum of disruptive behavior. Transient oppositional behavior is common among children and adolescents, but ODD occurs in 1% to 11% of youth.³ The disorder is more prevalent among boys before puberty and has an equal sex prevalence in young people after puberty.

Regrettably, most ODD research has included patients with comorbidities, most commonly attention-deficit/hyperactivity disorder (ADHD). Because of this limita­tion, the drugs and programs discussed below are drawn from meta-analyses and review articles.

Pharmacotherapy. No medications have been FDA-approved for ODD. Studies assess­ing ODD have employed a variety of meth­odologies, not all of which are double-blind. The meta-analyses and reviews cited in this section include both randomized and open trials, and should be interpreted as such.

Stimulants are commonly used to treat ODD because of a high comorbidity rate with ADHD, and these drugs have improved ODD symptoms in randomized trials.⁴ Methylphenidate and d-amphetamine have shown some efficacy in trials of ODD and CD.^5-7 These medications are most commonly used when ODD is complicated by ADHD symptoms.

Antipsychotics also have been used to treat ODD, with the largest body of research suggesting that risperidone has some effi­cacy. Risperidone usually is considered a second- or third-line option because it has been associated with adverse effects in chil­dren and adolescents and requires caution in younger populations, despite its potential efficacy.^4,8-10

Alpha-2 agonists—clonidine and guanfa­cine—have shown some efficacy in treating ODD but have not been studied extensively. Studies of clonidine, however, often have grouped ODD, CD, and ADHD, which lim­its our understanding of this medication for ODD alone.^4,5,11

Atomoxetine has been studied for ODD, but its efficacy is limited, with different meta-analyses finding distinct results regarding efficacy. One explanation for these dispa­rate findings is that improvements in oppo­sitional symptoms may be secondary to improvement in ADHD symptoms.^7,12-14

Psychological treatments. As noted for pharmacotherapy, this section provides gen­eral information on empirically studied ther­apies. A series of meta-analyses have been included for further review, but are not iso­lated to randomized, controlled studies.

Individual therapy has shown consistent improvements in ODD. Examples include behavior modification therapy and parent-child interaction therapy. These sessions emphasize skills to manage outbursts and erratic emotionality. Emotion regulation and behavior and social skills training have shown significant reductions in target mea­sures. Some of these programs incorporate both patient and parent components.^15-17

Family/teacher training programs such as “Helping the Noncompliant Child” and the “Triple P” have yielded significant improve­ments. These programs focus on ways to manage the child’s oppositional behavior at home and in the classroom, as well as strate­gies to limit positive reinforcement for prob­lem behaviors.^17-20

Group programs have shown some effi­cacy with ODD. These programs cover a wide number of needs and intents. Examples include the “Incredible Years” program and the Community Parent Education Program. Research has found that these programs show some efficacy as preemptive measures to reduce the rate of ODD among adolescents.

Conclusions. A number of treatment options for ODD have shown some efficacy. However, many of these options have only been studied in patients with comorbid ADHD, which limits current knowledge about ODD as a distinct disorder.

Intermittent explosive disorder
IED is defined by recurrent, significant out­bursts of aggression, often leading to assaul­tive acts against people or property, which are disproportionate to outside stressors and are not better explained by another psy­chiatric diagnosis. Research suggests IED is common, with 6.3% of a community sample meeting criteria for lifetime IED.²¹

IED symptoms tend to start in adolescence and appear to be chronic.^21,22 People with IED regard their behavior as distressing and prob­lematic.²² Outbursts generally are short-lived (usually <30 minutes) and frequent (multiple times a month²²). Legal and occupational dif­ficulties are common.²²

Pharmacotherapy. Data on drug treatment for IED comes for a small set of double-blind studies (Table). Although pharmacotherapies have been studied for treating aggression, impulsivity, and vio­lent behavior, only 5 controlled studies are specific to IED.

A double-blind, randomized, placebo-controlled trial of fluoxetine in 100 par­ticipants with IED found that fluoxetine produced a sustained reduction in aggression and irritability as early as the second week of treatment. Full or partial remission of impul­sive aggressive behaviors occurred in 46% of fluoxetine-treated subjects. These findings have been supported by studies assessing other samples of aggressive patients, but not specifically IED.^23,24 Another treatment study found that oxcarbazepine produced signifi­cant improvements in IED symptom severity, specifically on impulsive aggression.²⁵

In a randomized, double-blind, placebo-controlled study, 96 participants with Cluster B personality disorders, 116 with IED, and 34 with posttraumatic stress disorder were assigned to divalproex sodium or placebo for 12 weeks. Using an intent-to-treat analysis, divalproex had no significant influence on aggression in patients with IED.²⁶ Similarly, a study assessing levetiracetam for IED did not show any improvements to measures of impulsive aggression.²⁷

Psychological treatments. The only available study on psychological treatments for IED found that patients receiving active cognitive-behavioral therapy (CBT) or group therapy showed significant improvements compared with waitlist controls. These improvements spanned several target symptoms of IED.²⁸

Conclusions. Although there is a paucity of treatment studies for IED, fluoxetine may be an effective treatment based on available studies, and oxcarbazepine has shown some preliminary efficacy. CBT also has shown some initial efficacy in reducing symptom severity in IED.

Conduct disorder
The essential feature of CD is a repetitive and persistent pattern of behavior in which the basic rights of others or social norms are vio­lated.³ These behaviors can entail:
   • aggressive conduct that causes or threatens harm to others or to animals
   • nonaggressive behavior resulting in property damage
   • deceitfulness or theft
   • serious violation of rules.

Prevalence among the general population is 2% to 10%. The disorder is more common among boys than girls.³

Pharmacotherapy. No medication is FDA-approved to treat CD. Fifteen con­trolled studies have examined medica­tions in patients with CD (Table), although a number of these included a high rate of comorbid ADHD.

To date, 7 studies have shown efficacy with lithium for patients with CD.^29-35 A number of trials assessing lithium also included a treatment condition with halo­peridol, which showed significant improve­ment.^29,30,33,34 Both lithium and haloperidol were associated with select deficits on cog­nitive tests, suggesting that there may be risks associated with these medications.

Preliminary double-blind results have indicated that methylphenidate, risperi­done, quetiapine, molindone, thioridazine, and carbamazepine might be effective options for treating CD.^36-43 The evidence for these medications is limited and addi­tional studies are needed to replicate initial findings.

Three studies of divalproex sodium have shown some efficacy in randomized stud­ies comparing high and low dosages of the drug.^40-42 Because these studies did not include a placebo, additional studies are necessary to corroborate these findings.

Psychological treatments. Several forms of behavioral, family-based, and school-based therapies have been found effective in randomized trials. Specifically, behavioral therapy and parental skills training have shown consistent benefits for patients and their families. As with ODD, parental train­ing programs for CD focus on parents’ skill acquisition to help manage outbursts and aggressive behavior. These treatments often follow a similar course to those used for other externalizing and disruptive disorders.^44-46

Conclusions. Based on evidence, psychother­apy and some pharmacotherapies (eg, lith­ium) could be considered first-line treatment options for CD. Psychotherapy programs have shown efficacy in reducing aggression in high-risk groups.⁴⁴ Lithium or antipsychot­ics could be useful for patients who do not respond sufficiently to psychotherapy. The risk of cognitive deficits with lithium and antipsychotics should be weighed against potential benefits of these medications.^33,34

Kleptomania
Kleptomania is characterized by repetitive, poorly controlled stealing of items that are not needed for personal use. Kleptomania often begins in late adolescence or early adulthood.⁴⁷ The course of the illness gen­erally is chronic, with waxing and waning symptoms. Women are twice as likely as men to suffer from kleptomania.⁴⁸ People with kleptomania frequently hoard, discard, or return stolen items.⁴⁷

Most people with kleptomania try unsuc­cessfully to stop stealing, which often leads to feelings of shame and guilt.⁴⁸ Many (64% to 87%) have been arrested because of their stealing behavior⁴⁷; a smaller percentage (15% to 23%) have been incarcerated.⁴⁸ Suicide attempts are common among these patients.⁴⁹

Pharmacotherapy. There has been only 1 randomized, placebo-controlled study of pharmacotherapy for kleptomania (Table). An 8-week, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of oral naltrexone, 50 to 150 mg/d, in 25 patients with kleptomania. Those taking naltrexone had a significantly greater reduc­tion in total score than those taking placebo on the Yale-Brown Obsessive Compulsive Scale Modified for Kleptomania; in stealing urges; and in stealing behavior. The mean effective dosage of naltrexone was 116.7 (± 44.4) mg/d.⁵⁰

Naltrexone was well tolerated, with mini­mal nausea, and did not cause elevation of liver enzymes.

There is one available open-label study with a double-blind discontinuation phase assessing the efficacy of escitalopram for kleptomania. Continuation of escitalopram during the blinded discontinuation phase did produce lower relapse rates.⁵¹

Psychological treatments. There are no con­trolled studies of psychological treatments for kleptomania. Case reports suggest that cognitive and behavioral therapies might be effective:
   • A young man who underwent 7 ses­sions of covert sensitization, combined with exposure and response prevention, over a 4-month period was able to reduce his steal­ing frequency.⁵²
   • In another case, a young woman underwent 5 weekly sessions when she was instructed to practice covert sensitiza­tion whenever she had an urge to steal. She remained in remission for 14 months with only a single lapse in behavior and with no reported urges to steal.⁵³
   • In 2 patients, imaginal desensitization in fourteen 15-minutes sessions over 5 days resulted in complete remission of symptoms for a 2-year period.⁵⁴

Conclusions. The single controlled study of naltrexone for kleptomania suggests that naltrexone might be a beneficial treatment for this disorder. No controlled trials of psy­chosocial interventions have been reported. The current psychological research is based primarily on case reports.

This state of affairs likely is because of (1) the low prevalence of kleptomania and (2) clinical difficulties in treating patients involved in illegal activities. Nevertheless, there is a need for systematic studies of treat­ing this disorder; such studies could involve collaboration across multiple treatment cen­ters because of the disorder’s low prevalence.

Pyromania
Pyromania is characterized by (1) deliberate and purposeful fire setting on >1 occasion; (2) tension or affective arousal before the act; (3) fascination with, interest in, curiosity about, or attraction to fire and its situational con­texts; and (4) pleasure, gratification, or relief when setting fires or when witnessing or par­ticipating in their aftermath.³

Although pyromania is thought to be a disorder primarily affecting men, recent research suggests that the sex ratio is equal among adults and may be slightly higher among adolescent females. Mean age of onset usually is late adoles­cence. Pyromania appears to be chronic if untreated.⁵⁵

Urges to set fires are common and the fire setting is almost always pleasurable. Severe distress follows the fire setting, and persons with pyromania report significant functional impairment. High rates of co-occurring psy­chiatric disorders (depression, substance use disorders, other impulse-control dis­orders) are common among persons with pyromania.⁵⁵

Pharmacotherapy. There are no random­ized, controlled clinical trials examining pharmacotherapy for treating pyromania. There are no FDA-approved medications for pyromania.

In case reports, medications that have shown benefit in treating pyromania include topiramate, escitalopram, sertraline, fluox­etine, lithium, and a combination of olan­zapine and sodium valproate. An equal number of medications have shown no ben­efit: fluoxetine, valproic acid, lithium, sertra­line, olanzapine, escitalopram, citalopram, and clonazepam. A case report of an 18-year-old man with pyromania described success­fully using a combination of topiramate with 3 weeks of daily CBT to achieve significant symptom improvement.^56,57

Pyromania is a largely unrecognized dis­order that causes significant psychological, social, and legal repercussions. Because few persons with pyromania volunteer informa­tion regarding fire-setting, it is important that clinicians recognize the disorder and screen patients appropriately. Various treatments have been helpful in case studies, but more research on the etiology and treatment of the disorder is needed.^56,57

Conclusions based on the literature
In disruptive, impulse-control, and conduct disorders, the systematic study of treatment efficacy and tolerability is in its infancy. With few controlled studies published, it is not possible to make treatment recommendations with confidence. There are no FDA-approved drugs for treating any of these disorders.

Nonetheless, specific psychotherapies and drug therapies offer promising options, but often are based on small studies, often in patient populations with prominent comor­bidities, and have not been replicated by independent investigators. For all of these disorders, issues such as which psycho­therapy or medication to use and the ideal duration of treatment cannot be sufficiently addressed with the available data.

In conjunction with emerging epidemio­logical data supporting a relatively high prevalence of disruptive, impulse-control, and conduct disorders, the small amount of data regarding effective treatments highlights the clinical need for additional research.

Bottom Line
Empirically supported treatment options for impulse-control disorders currently are limited, because only select disorders have been studied across multiple trials. New research is needed to confirm possible treatment options and identify effective psychotherapeutic and pharmacological treatment alternatives.
 

Related Resources
• Grant JE. Impulse control disorders: a clinician’s guide to un­derstanding and treating behavioral addictions. New York, NY: W. W. Norton & Company; 2008.
• Grant JE, Kim SW. Stop me because I can’t stop myself: tak­ing control of impulsive behavior. New York, NY: McGraw- Hill; 2003.
• American Academy of Child and Adolescent Psychiatry. Conduct disorder resource center. http://www.aacap.org/AACAP/FamiliesandYouth/ResourceCenters/ConductDisorderResourceCenter/Home.aspx.

Drug Brand Names
Atomoxetine • Strattera                      Methylphenidate • Ritalin
Carbamazepine • Tegretol                  Molindone • Moban
Citalopram • Celexa                            Naltrexone • ReVia
Clonazepam • Klonopin                      Olanzapine • Zyprexa
Clonidine • Catapres                           Oxcarbazepine • Trileptal
D-amphetamine • Dexedrine               Quetiapine • Seroquel
Divalproex sodium • Depakote            Risperidone • Risperdal
Escitalopram • Lexapro                       Sertraline • Zoloft
Fluoxetine • Prozac                             Sodium valproate • Depacon
Guanfacine • Intuniv                           Thioridazine • Mellaril
Haloperidol • Haldol                             Topiramate • Topamax
Levetiracetam • Keppra                       Valproic acid • Depakote
Lithium • Eskalith, Lithobid  

Disclosures
Dr. Grant receives grant or research support from Brainsway, Forest Pharmaceuticals, and Roche Pharmaceuticals. Mr. Leppink reports no financial relationship with any company whose products are mentioned in this article or with competing products.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.

Suvorexant, FDA-approved to treat insomnia, has demonstrated efficacy in helping patients with insomnia improve their ability to fall asleep and remain asleep (Table 1).¹ This first-in-class compound represents a novel mechanism of action to promoting sleep that may avoid some prob­lems associated with other hypnotics.²

Because orexin antagonists have not been used outside of clinical trials, it is too soon to tell whether suvorexant will have the ideal real-world efficacy and safety profile to make it a first-line treatment for insomnia patients, or if it will be reserved for those who have failed a trial of several other treatments.⁴

In theory, the orexin antagonist approach to treating insomnia could represent a major advance that modulates the fundamental pathology of the disorder.⁵ The syndrome of chronic insomnia encompasses not just the nighttime sleep disturbance but also an assort­ment of daytime symptoms that can include fatigue, poor concentration, irritability, and decreased school or work performance but usually not sleepiness. This constellation of nighttime and daytime symptoms could be conceptualized as a manifestation of persis­tent CNS hyperarousal. Because the orexin system promotes and reinforces arousal, per­haps an orexin antagonist that dampens the level of orexin activity will ameliorate the full spectrum of insomnia symptoms—not sim­ply sedate patients.⁶

How suvorexant works
Suvorexant is a potent and reversible dual orexin-receptor antagonist. The orexin system, first described in 1998, has a key role in promoting and stabilizing wake­fulness.⁷ Evidence suggests that people with chronic insomnia exhibit a central hyperarousal that perpetuates their sleep difficulty. Accordingly, a targeted phar­maceutical approach that reduces orexin activity should facilitate sleep onset and sleep maintenance for these patients. It is well known that the regulation of sleep and wakefulness depends on the interaction of multiple nuclei within the hypothalamus. Orexinergic neurons in the perifornical-lateral hypothalamic region project widely in the CNS and have especially dense con­nections with wake-promoting cholinergic, serotonergic, noradrenergic, and histamin­ergic neurons.⁶

A precursor prepro-orexin peptide is split into 2 orexin neurotransmitters (orexin A and orexin B). These 2 orexins bind with 2 G-protein-coupled receptors (OX1R and OX2R) that have both overlapping and distinct distributions.⁷ Suvorexant is highly selective and has similar affinity for OX1R and OX2R, functioning as an antag­onist for both.⁸ Fundamentally, suvorexant enhances sleep by dampening the arous­ing wake drive.

Pharmacokinetics
Suvorexant is available as an immediate-release tablet with pharmacokinetic prop­erties that offer benefits for sleep onset and maintenance.⁹ Ingestion under fasting conditions results in a median time to maxi­mum concentration (T_max) of approximately 2 hours, although the T_max values vary widely from patient to patient (range 30 minutes to 6 hours). Although suvorexant can be taken with food, there is a modest absorption delay after a high-fat meal, resulting in a further T_max delay of approximately 1.5 hours.

Suvorexant is primarily metabolized through the cytochrome P450 (CYP) 3A path­way, with limited contribution by CYP2C19. There are no active metabolites. The suvorex­ant blood level and risk of side effects will be higher with concomitant use of CYP3A inhibitors. The drug should not be adminis­tered with strong CYP3A inhibitors; the ini­tial dosage should be reduced with moderate CYP3A inhibitors. Concomitant use of strong CYP3A inducers can result in a low suvorex­ant level and reduced efficacy.

Suvorexant has little effect on other med­ications, although a person taking digoxin might experience intestinal P-glycoprotein inhibition with a slight rise in the digoxin level. In a patient taking both medica­tions, monitoring of the digoxin level is recommended.

The elimination half-life of suvorexant is approximately 12 hours, with a steady state in approximately 3 days. Because the half-life of suvorexant is moderately long for a sleep-promoting medication, use of the drug might be associated with residual sleepiness the morning after bedtime dosing. The risk for next-morning sleepiness or impairment should be minimized, however, when using the recommended dosages. Elimination is approximately two-thirds through feces and one-third in the urine.

Suvorexant metabolism can be affected by sex and body mass index. Females and obese people have a modestly elevated expo­sure to suvorexant, as reflected by the area under the curve and maximum concentra­tion (C_max). These patients might not require dosage adjustments unless they are obese and female, in which case they should take a lower dosage.

Age and race have not been shown to influence suvorexant metabolism to a signifi­cant degree. Patients with renal impairment and those with mild or moderate hepatic impairment do not need dosage adjust­ment. Suvorexant has not been evaluated in patients with severe hepatic impairment.

Efficacy
Suvorexant showed significant evidence of improved sleep onset and sleep maintenance in patients with insomnia in clinical trials. The key efficacy clinical trials with insomnia patients included a phase-IIb dose-finding study,¹⁰ 2 similar 3-month phase-III studies,¹¹ and one 12-month phase-III safety study that incorporated efficacy outcomes.¹² All these trials included subjective sleep measures and all except for the long-term safety study also incorporated polysomnographic assess­ment. The specific sleep laboratory outcomes were latency to persistent sleep (LPS), wake after the onset of persistent sleep (WASO), total sleep time (TST), and sleep efficiency (SE). Subjective sleep outcomes were time to sleep onset (sTSO), wake after sleep onset (sWASO), and total sleep time (sTST). Other exploratory endpoints also were assessed. These efficacy and safety studies mostly were performed at dosages considerably higher than those approved by the FDA.

The dose-finding (phase-IIb) trial was conducted with non-geriatric (age 18 to 64) patients with insomnia in a random­ized, double-blind, crossover design of two 4-week periods with subjects given a nightly placebo or suvorexant (10 mg, 20 mg, 40 mg, or 80 mg).¹⁰ Each of the 4 groups included approximately 60 subjects. The 2 co-primary endpoints were SE at Night 1 and the end of Week 4; secondary endpoints were LPS and WASO. Suvorexant was associated with dos­age-related improvements in SE and WASO compared with placebo at both time points. Carryover effects from the period-1 active drug group complicated the analysis of LPS.

The phase-III efficacy and safety trials were performed with 40 mg high dosage (HD) and 20 mg low dosage (LD) groups for adults and with 30 mg HD and 15 mg LD groups for geriatric (age ≥65) patients.¹¹ Two similarly designed 3-month randomized, double-blind, placebo-controlled pivotal efficacy studies assessed objective and sub­jective sleep measures in 4 groups with non-geriatric (HD and LD) and geriatric (HD and LD) insomnia patients.

After baseline assessment, patients took nightly bedtime doses of placebo; suvorexant, 40 mg or 20 mg (non-geriatric individuals); or suvorexant, 30 mg or 15 mg (geriatric indi­viduals). All subjects kept a daily electronic diary and had polysomnographic recordings performed on Night 1, at the end of Month 1, and at the end of Month 3. Both the indi­vidual studies and combined analyses (2,030 subjects) showed that, in non-geriatric and geriatric patients, HD suvorexant resulted in significantly greater improvement in key subjective and objective measures through­out the study (Table 2,⁹ and Table 3,⁹), with the exception of a single LPS outcome in 1 study, compared with placebo. The LD dosages also demonstrated efficacy, but to a reduced extent.

Subjective sleep outcomes were assessed in a 1-year randomized, placebo-controlled trial with nightly placebo, suvorexant, 40 mg, for non-geriatric, or suvorexant, 30 mg, for geriatric insomnia patients.12 The 1-year phase was completed with 484 subjects. Key efficacy outcomes were sTST and sTSO changes from baseline during the first month of treatment. Compared with placebo, suvorexant dosages demonstrated significantly greater efficacy, improvements that were sustained throughout the year.

Clinical trials found suvorexant to be gen­erally safe and well tolerated.¹³ However, specific safety concerns led the FDA to approve the medication at dosages lower than those assessed in the phase-III studies.¹

Somnolence was the most common adverse event in clinical trials. In the phase- IIb dose-finding study, somnolence was reported in <1% in the placebo group, but was associated with suvorexant in 2% of the 10 mg group, 5% with 20 mg, 12% with 40 mg, and 11% with 80 mg.⁹ In the phase-III combined analysis of the 3-month studies, somnolence was reported by 3% in the placebo group and 7% of non-geriatric patients taking 20 mg or geriatric patients taking 15 mg. Somnolence was reported in 8% of women and 3% of men taking the 15 mg or 20 mg dosage in these stud­ies. The 1-year study was performed only with higher suvorexant dosages (30 mg and 40 mg), in comparison with placebo. In this long-term trial, somnolence was reported by 13% of subjects taking suvorexant and 3% taking placebo.

Additional safety issues in trials included excessive daytime sleepiness, impaired driv­ing, suicidal ideation, sleep paralysis, hyp­nagogic/hypnopompic hallucinations, and cataplexy-like symptoms.⁹ Occurrences of these events are rare but have been reported more often among patients taking suvorex­ant than among those taking placebo.

Unique clinical issues
The U.S. Drug Enforcement Agency has categorized suvorexant as a Schedule IV controlled substance. Although there is no evidence of physiological dependence or withdrawal symptoms with suvorexant, studies with recreational substance abusers have shown that the likeability rating is simi­lar to that of zolpidem.¹³

Contraindication
Suvorexant is contraindicated in patients with narcolepsy.⁹ The underlying pathol­ogy of narcolepsy involves a marked reduction in orexin functioning with corre­sponding excessive sleepiness and related symptoms, such as cataplexy, hypnago­gic hallucinations, and sleep paralysis. Although suvorexant has not been evalu­ated in patients with narcolepsy, the drug might, hypothetically, put patients at higher risk of the full spectrum of narco­lepsy symptoms.

There are no other contraindications for suvorexant.


Dosing
Suvorexant should be taken no more than once a night within 30 minutes of bedtime and with at least 7 hours before the planned wake time.⁹ The recommended starting dosage is 10 mg. If this dosage is well toler­ated but insufficiently effective, the dosage can be increased to a maximum of 20 mg. The 5-mg dosage is recommended for indi­viduals taking a moderate CYP3A inhibitor. Generally, patients should take the lowest effective dosage.

There are no specified limitations on the duration of suvorexant use. There is no evidence of withdrawal effects when discontinuing the medication. Patients tak­ing suvorexant should be educated about possible next-day effects that might impair driving or other activities that require full mental alertness, especially if they are tak­ing the 20-mg dosage.

Bottom Line
Suvorexant is FDA-approved for treating sleep onset and sleep maintenance insomnia. The drug is a dual orexin-receptor antagonist, which targets persistent CNS hyperarousal. In clinical trials, suvorexant improved the ability to fall asleep and remain asleep in patients with insomnia. It is generally safe and well tolerated. However, these studies evaluated dosages higher than those approved by the FDA.

Related Resources
• Jacobson LH, Callander GE, Hoyer D. Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol. 2014; 7(6):711-730.
• Neubauer DN. New and emerging pharmacotherapeutic approaches for insomnia. Int Rev Psychiatry. 2014;26(2): 214-224.

Drug Brand Names
Doxepin • Silenor             Suvorexant • Belsomra
Digoxin • Lanoxin             Zaleplon • Sonata
Eszopiclone • Lunesta       Zolpidem • Ambien,
Ramelteon • Rozerem            Edluar, Intermezzo

Disclosure
Dr. Neubauer is a consultant to Ferring Pharmaceuticals and Vanda Pharmaceuticals.