The Journal of Family Practice

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].

A 25-year-old college student with no medical history sought care at our hospital for a nonproductive cough, subjective fevers, myalgia, and malaise that he’d developed 10 days earlier. The day before his visit, he’d also developed scratchy red eyes and a sore throat. He said he’d taken an over-the-counter cough suppressant to help with the cough, but his eyes and lips developed further redness and irritation.

On examination, the patient demonstra­ted conjunctival suffusion, periorbital edema, diffuse oral stomatitis with pseudomembranous crusting, and nasal crusting (FIGURE 1). His vital signs were within normal limits, and he had no epithelial skin eruptions or erosions in any other mucosal regions.

The patient was not currently sexually active and had one lifetime female sexual partner. He had no history of sexually transmitted infections or cold sores, and was not taking any medications, herbs, or supplements. During the initial 24 hours of admission, he developed 4 to 5 red targetoid papules on each hand (FIGURE 2).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: M pneumoniae-associated mucositis

The patient was admitted for observation to rule out Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). We felt that the degree of mucositis (extensive) compared to the number of targetoid papules on the hands (minimal) suggested a diagnosis of Mycoplasma pneumoniae-associated mucositis (MPAM), a subtype of erythema multiforme (EM) major. The patient’s prodrome of fever, cough, and malaise also supported a “walking pneumonia” diagnosis, such as MPAM.

Further testing. The patient had a normal chest x-ray and a negative respiratory virus polymerase chain reaction (PCR), but IgM serologies for Mycoplasma were elevated. Although the patient developed targetoid lesions on his hands during his first 24 hours in the hospital, he felt his constitutional symptoms had improved.

Exposure to Mycoplasma leads to an immune response

MPAM (also known as Fuchs’ syndrome and mycoplasma-associated mucositis with minimal skin manifestations) appears at some point during infection with M pneumoniae and causes severe ocular, oral, and sometimes genital symptoms with minimal skin manifestations.

The degree of mucositis (extensive) compared to the number of targetoid papules on the patient’s hands (minimal) suggested Mycoplasma pneumoniae-associated mucositis.

MPAM is primarily seen in young males. In one systemic review of 202 cases, the average age of the patients was 11.9 years and 66% were male.¹ Exposure to M pneumoniae is theorized to result in the production of autoantibodies to mycoplasma p1-adhesion molecules and to molecular mimicry of keratinocyte antigens located in the mucosa.^1-3

Mycoplasma organisms have not been isolated from the cutaneous lesions of patients with MPAM; they have only been isolated from the respiratory tract, supporting the theory that MPAM is the body’s immune response to Mycoplasma, rather than a direct pathologic effect.⁴ This pathogenesis is distinct from that of SJS/TEN, which is thought to involve CD8+ T-cell-mediated keratinocyte apoptosis (programed cell death). In addition, SJS/TEN is almost always drug induced.

First up in the differential: Rule out SJS/TEN

When evaluating a patient like ours with a blistering eruption, the most important diagnosis to exclude is SJS/TEN. This condition is usually triggered by a medication, which was absent in this case. SJS/TEN begins with a host of constitutional symptoms and an erythematous blistering eruption, which may be preceded by atypical targetoid (2-zoned) flat papules along with erosions on 2 or more mucosal surfaces.

Patients with SJS/TEN are usually critically ill and may have a guarded prognosis. Patients with MPAM have a more favorable prognosis and are unlikely to be critically ill—as was the case with our patient.

EM major is often associated with Mycoplasma infections. Patients with EM major may have fever and arthralgias, as well as extensive mucous membrane involvement including that of the lips/mouth, eyes, and genitals.

Experts agree that EM is separate from the SJS/TEN continuum, and that patients with EM major, including those with MPAM, are not at risk of developing SJS/TEN.⁵ EM is characterized by the presence of the more characteristic ‘target’ or ‘iris’ 3-zoned lesion—a central dusky purpura, surrounded by an elevated edematous pale ring, rimmed by a red macular outer ring. EM major is defined as EM along with involvement of one or more mucosal regions.

In this case, the patient had acral target lesions and oral and ocular mucosal involvement characteristic of EM major, without widespread skin erosions or sloughing commonly seen with SJS/TEN.

Kawasaki’s disease occurs in young children and presents with conjunctivitis and oral changes. However, patients with Kawasaki’s disease generally have a fever for >5 days, a strawberry tongue (not a part of the morphology of EM major or MPAM), and palmoplantar erythema and desquamation that are not common with EM major or MPAM.¹

Pemphigus vulgaris is uncommon in children and young adults. The disease does not present with diffuse mucositis nor diffuse blistering of the skin, but rather with discrete shallow erosions on the mucosa and the trunk along with flaccid bullae and erosions on the skin.

The morphologies of a fixed drug eruption (round purpuric patch) and toxic shock syndrome (diffuse macular erythema and widespread skin sloughing) are inconsistent with this patient’s diffuse mucositis, conjunctivitis, and targetoid lesions.

Confirm exposure to M pneumoniae

Testing with the purpose of ruling in MPAM is directed toward proving that the patient has been exposed to M pneumoniae. (Of note: M pneumoniae cannot be detected via routine commercial blood cultures.)

Serologic testing for elevated IgM antibodies to Mycoplasma is the most specific method. Various studies have found it to be positive in 100% of cases, but detection may be delayed for a couple of weeks while the body develops the requisite antibodies.⁴

Respiratory PCR for Mycoplasma is rapid and usu­ally appropriately positive, but may be negative in cases where the patient has spontaneously cleared the infection or has been exposed to antibiotics before development of the eruption.⁴ An infiltrate on chest imaging is supportive of the diagnosis.

Skin biopsy will demonstrate either mucositis and necrosis of keratinocytes or EM-like necrosis, but does not suggest an etiology.

Strikingly different paths of care

Distinguishing between SJS/TEN and EM major (including MPAM) is crucial to guiding management. Patients with SJS/TEN need critical care, particularly of their eyes and genitourinary and respiratory systems. Specialist consultation is often required.

Patients with erythema multiforme, including those with Mycoplasma pneumoniae-associated mucositis, are not at risk of developing Stevens-Johnson syndrome/toxic epidermal necrolysis.

For EM major, patients require supportive care along with ongoing assurances that the eruption has a benign prognosis. Hospital admission is not mandatory as long as adequate supportive care and symptom control can be provided on an outpatient basis. Early consultation with Ophthalmology, Oral Medicine, and Urology may also be key.

Keep in mind that patients may have severe stomatitis and pain that alter their ability to eat and perform normal activities. Thus, managing pain and ensuring adequate nutrition are crucial for successful support. While antibiotics treat active Mycoplasma infection, there is no clear evidence that antibiotics alter the course of the eruption, which is also consistent with the hypothesized pathogenesis.^3,4

While there is no clear statistical evidence that systemic immune suppression alters the disease course, a large proportion (31%) of patients in a recent systematic review of MPAM were treated with corticosteroids, and a smaller, but noteworthy, percentage (9%) were treated with intravenous immunoglobulins (IVIG).⁴ There are reports of severe stomatitis that didn’t improve with supportive care, but that showed dramatic improvement with IVIG treatment.^6,7

Our patient had difficulty controlling secretions and managing the painful mucositis of his mouth; he was initially unable to tolerate solid foods. Topical lidocaine solution for his mucositis caused burning and more discomfort, but acetaminophen-hydrocodone 300 mg-5 mg every 6 hours did relieve his pain. Wound care with a bland emollient and the application of non-stick dressings to his lips at night also helped to relieve some of the pain.

Because the patient’s oropharyngeal swelling made it hard for him to swallow, he received oral prednisone 0.5 mg/kg/d, which provided him with relief within 24 hours. The acute inflammation and eruption also subsided within 48 hours and the patient was discharged after 5 days of being hospitalized. He continued to recover as an outpatient, seeing his primary care physician within 2 weeks for final nutrition and wound care support. Two weeks after that, he had a dermatology appointment, and all of his lesions had re-epithelialized.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, MS, University of Texas Health Science Center at San Antonio, 7323 Snowden Road, Apt. 1205, San Antonio, TX 78240; [email protected].

A 21-year-old man presented to the dermatology clinic with a 2-month history of painless genital and perianal lesions. The patient reported having unprotected sex in recent months, but had no prior history of oral, penile, or anal mucosal lesions or ulcers. He was not on any medications or immunosuppressive agents and noted that the lesions did not represent a recurrence. He also reported a nonspecific, asymptomatic rash on his trunk and extremities that had been present for an unknown period of time.

The patient indicated that his primary care physician had looked at the genital/perianal lesions and told him they were genital warts. Previous treatments included an over-the-counter wart medication, cryotherapy, and a course of imiquimod, but none had helped.

The physical examination revealed multiple soft, moist, beefy papules and plaques around the genital area (FIGURE 1) and perianal region. In addition, there were multiple hyper-pigmented macules on the patient’s palms and soles (FIGURE 2), and reticulated, patchy eruptions on his arms, chest (FIGURE 3), and back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Secondary syphilis

The appearance of the genital and perianal lesions was consistent with condylomata lata—a cutaneous sign of secondary syphilis—rather than genital warts. The presence of a rash on the patient’s trunk and extremities further supported this diagnosis. We did a rapid plasma reagin (RPR) test and a Treponema pallidum particle agglutination test; we also tested for human immunodeficiency virus (HIV). The patient’s RPR titer was 1:128, and the T pallidum antibody test came back positive. HIV-1 and HIV-2 serology were negative.

Appearance of the lesions was a giveaway. Condylomata lata are flat-topped, broad papules that are usually located on folds of moist skin (particularly the genitals and anus), and have a smooth, gray, moist surface. Although they can be lobulated, they do not have the classic digitate projections that are characteristic of genital warts. A nonpruritic, symmetric, “raw ham”-colored papular eruption on a patient’s trunk, palms, and soles is also characteristic of secondary syphilis.¹ In this case, the reticular pattern on the patient’s chest represented the commonly seen lenticular rash of secondary syphilis.

Cutaneous lesions of secondary syphilis contain numerous spirochetes (T pallidum) and are highly infectious. Systemic symptoms of secondary syphilis may include fatigue, generalized lymphadenopathy, arthralgia, myalgia, pharyngitis, and headache.

Although condylomata lata can be lobulated, they do not have the classic digitate projections characteristic of genital warts.

Some patients may report having a recent chancre—a painless, self-limiting ulcer in the genital area—which is characteristic of primary syphilis (see “Single nontender ulcer on the glans,” J Fam Pract. 2017;66:253-255). For more on the stages of syphilis, see the TABLE². Our patient did not remember ever having a chancre.

Increase in cases. Rates of primary and secondary syphilis have increased in the past decade. In 2014, approximately 20,000 syphilis cases were reported—a record high since 1994.³ Men who have sex with men are particularly affected; however, increases in infection rates have also been noted in women and across people of all ages and ethnicities.³

Rule out other causes of genital lesions

Condyloma acuminata, commonly called genital warts, are localized human papilloma virus (HPV) infections that appear as discrete, gray to pale pink, lobulated papules that may coalesce to form a large, cauliflower-like mass. They are sexually transmitted and commonly involve the genital and anal areas. While physicians may confuse condylomata lata with genital warts, diffuse skin rashes and constitutional symptoms are not usually seen with genital warts.⁴

Fordyce spots are small, whitish, raised papules on the glans or the shaft of the penis or the vulva of the vagina. They may also appear on the lips and oral mucosa. They are a result of prominent sebaceous glands and are harmless. They are not infectious or sexually transmitted.^5,6

Lymphogranuloma venereum is an uncommon sexually transmitted disease caused by Chlamydia trachomatis. It is characterized by genital papules or ulcers, followed by bilateral, suppurative, inguinal adenitis known as buboes. The buboes may breakdown, form multiple fistulous openings, and discharge purulent material.⁶

Acute HIV may present with flu-like symptoms and well-circumscribed maculopapular rashes on the face, neck, and upper trunk. The palms and soles may also be affected. Patients with HIV may also develop genital plaque-like lesions from herpes simplex virus-2, genital warts from HPV, molluscum contagiosum, and, not uncommonly, anogenital malignancies.^7,8

Confluent and reticulated papillomatosis (CARP) is a disorder that occurs predominantly in young adults and teenagers, with cosmetically displeasing brown scaling macules that may coalesce to form patches or plaques affecting the neck, chest, back, and axillae. It is often mistaken for tinea versicolor.⁹ In this case, the eruption on the chest closely resembled CARP, but a diagnosis of CARP would not have explained the genital lesions.

Confirm diagnosis with treponemal tests

Syphilis is often a clinical diagnosis with pathologic confirmation. Patients suspected of having syphilis should be screened with nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) test or the RPR test, which become positive within 3 weeks of developing primary syphilis.

Diagnosis is confirmed with specific treponemal testing, such as with a fluorescent treponemal antibody absorption assay or the T pallidum particle agglutination test. HIV testing is recommended for all patients with syphilis.

Penicillin G is the mainstay of treatment

Proper selection of penicillin is paramount in the treatment of syphilis. Primary, secondary, and early latent syphilis are treated with an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. Patients with late latent or latent syphilis of unknown duration are treated with 3 doses of the same injection at weekly intervals, totaling 7.2 million units of benzathine penicillin G.¹⁰ Certain penicillin preparations (eg, combinations of benzathine penicillin and procaine penicillin) are not appropriate treatments because they do not provide adequate amounts of the antibiotic.

Watch for this reaction. Approximately 30% of patients following penicillin treatment for spirochete infection develop a Jarisch-Herxheimer reaction (JHR).¹¹ JHR is characterized by an abrupt onset of fever, chills, myalgia, tachycardia, vasodilatation with flushing, exacerbated maculopapular skin rash, or mild hypotension. Care for JHR is generally supportive.

Our patient received an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. His skin eruption and condylomata lata lesions were completely resolved at follow-up 6 months later.

As recommended by the Centers for Disease Control and Prevention,¹⁰ our patient’s RPR titers were repeated at 6 months and again at 12 months to verify a four-fold decline, indicating successful treatment.

CORRESPONDENCE
Anne Bartels, MD, General Medicine, Naval Hospital Camp Lejeune, 100 Brewster Blvd., Camp Lejeune, NC 28547; [email protected].

A 21-year-old man presented to the dermatology clinic with a 2-month history of painless genital and perianal lesions. The patient reported having unprotected sex in recent months, but had no prior history of oral, penile, or anal mucosal lesions or ulcers. He was not on any medications or immunosuppressive agents and noted that the lesions did not represent a recurrence. He also reported a nonspecific, asymptomatic rash on his trunk and extremities that had been present for an unknown period of time.

The patient indicated that his primary care physician had looked at the genital/perianal lesions and told him they were genital warts. Previous treatments included an over-the-counter wart medication, cryotherapy, and a course of imiquimod, but none had helped.

The physical examination revealed multiple soft, moist, beefy papules and plaques around the genital area (FIGURE 1) and perianal region. In addition, there were multiple hyper-pigmented macules on the patient’s palms and soles (FIGURE 2), and reticulated, patchy eruptions on his arms, chest (FIGURE 3), and back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Secondary syphilis

The appearance of the genital and perianal lesions was consistent with condylomata lata—a cutaneous sign of secondary syphilis—rather than genital warts. The presence of a rash on the patient’s trunk and extremities further supported this diagnosis. We did a rapid plasma reagin (RPR) test and a Treponema pallidum particle agglutination test; we also tested for human immunodeficiency virus (HIV). The patient’s RPR titer was 1:128, and the T pallidum antibody test came back positive. HIV-1 and HIV-2 serology were negative.

Appearance of the lesions was a giveaway. Condylomata lata are flat-topped, broad papules that are usually located on folds of moist skin (particularly the genitals and anus), and have a smooth, gray, moist surface. Although they can be lobulated, they do not have the classic digitate projections that are characteristic of genital warts. A nonpruritic, symmetric, “raw ham”-colored papular eruption on a patient’s trunk, palms, and soles is also characteristic of secondary syphilis.¹ In this case, the reticular pattern on the patient’s chest represented the commonly seen lenticular rash of secondary syphilis.

Cutaneous lesions of secondary syphilis contain numerous spirochetes (T pallidum) and are highly infectious. Systemic symptoms of secondary syphilis may include fatigue, generalized lymphadenopathy, arthralgia, myalgia, pharyngitis, and headache.

Although condylomata lata can be lobulated, they do not have the classic digitate projections characteristic of genital warts.

Some patients may report having a recent chancre—a painless, self-limiting ulcer in the genital area—which is characteristic of primary syphilis (see “Single nontender ulcer on the glans,” J Fam Pract. 2017;66:253-255). For more on the stages of syphilis, see the TABLE². Our patient did not remember ever having a chancre.

Increase in cases. Rates of primary and secondary syphilis have increased in the past decade. In 2014, approximately 20,000 syphilis cases were reported—a record high since 1994.³ Men who have sex with men are particularly affected; however, increases in infection rates have also been noted in women and across people of all ages and ethnicities.³

Rule out other causes of genital lesions

Condyloma acuminata, commonly called genital warts, are localized human papilloma virus (HPV) infections that appear as discrete, gray to pale pink, lobulated papules that may coalesce to form a large, cauliflower-like mass. They are sexually transmitted and commonly involve the genital and anal areas. While physicians may confuse condylomata lata with genital warts, diffuse skin rashes and constitutional symptoms are not usually seen with genital warts.⁴

Fordyce spots are small, whitish, raised papules on the glans or the shaft of the penis or the vulva of the vagina. They may also appear on the lips and oral mucosa. They are a result of prominent sebaceous glands and are harmless. They are not infectious or sexually transmitted.^5,6

Lymphogranuloma venereum is an uncommon sexually transmitted disease caused by Chlamydia trachomatis. It is characterized by genital papules or ulcers, followed by bilateral, suppurative, inguinal adenitis known as buboes. The buboes may breakdown, form multiple fistulous openings, and discharge purulent material.⁶

Acute HIV may present with flu-like symptoms and well-circumscribed maculopapular rashes on the face, neck, and upper trunk. The palms and soles may also be affected. Patients with HIV may also develop genital plaque-like lesions from herpes simplex virus-2, genital warts from HPV, molluscum contagiosum, and, not uncommonly, anogenital malignancies.^7,8

Confluent and reticulated papillomatosis (CARP) is a disorder that occurs predominantly in young adults and teenagers, with cosmetically displeasing brown scaling macules that may coalesce to form patches or plaques affecting the neck, chest, back, and axillae. It is often mistaken for tinea versicolor.⁹ In this case, the eruption on the chest closely resembled CARP, but a diagnosis of CARP would not have explained the genital lesions.

Confirm diagnosis with treponemal tests

Syphilis is often a clinical diagnosis with pathologic confirmation. Patients suspected of having syphilis should be screened with nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) test or the RPR test, which become positive within 3 weeks of developing primary syphilis.

Diagnosis is confirmed with specific treponemal testing, such as with a fluorescent treponemal antibody absorption assay or the T pallidum particle agglutination test. HIV testing is recommended for all patients with syphilis.

Penicillin G is the mainstay of treatment

Proper selection of penicillin is paramount in the treatment of syphilis. Primary, secondary, and early latent syphilis are treated with an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. Patients with late latent or latent syphilis of unknown duration are treated with 3 doses of the same injection at weekly intervals, totaling 7.2 million units of benzathine penicillin G.¹⁰ Certain penicillin preparations (eg, combinations of benzathine penicillin and procaine penicillin) are not appropriate treatments because they do not provide adequate amounts of the antibiotic.

Watch for this reaction. Approximately 30% of patients following penicillin treatment for spirochete infection develop a Jarisch-Herxheimer reaction (JHR).¹¹ JHR is characterized by an abrupt onset of fever, chills, myalgia, tachycardia, vasodilatation with flushing, exacerbated maculopapular skin rash, or mild hypotension. Care for JHR is generally supportive.

Our patient received an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. His skin eruption and condylomata lata lesions were completely resolved at follow-up 6 months later.

As recommended by the Centers for Disease Control and Prevention,¹⁰ our patient’s RPR titers were repeated at 6 months and again at 12 months to verify a four-fold decline, indicating successful treatment.

CORRESPONDENCE
Anne Bartels, MD, General Medicine, Naval Hospital Camp Lejeune, 100 Brewster Blvd., Camp Lejeune, NC 28547; [email protected].

A 21-year-old man presented to the dermatology clinic with a 2-month history of painless genital and perianal lesions. The patient reported having unprotected sex in recent months, but had no prior history of oral, penile, or anal mucosal lesions or ulcers. He was not on any medications or immunosuppressive agents and noted that the lesions did not represent a recurrence. He also reported a nonspecific, asymptomatic rash on his trunk and extremities that had been present for an unknown period of time.

The patient indicated that his primary care physician had looked at the genital/perianal lesions and told him they were genital warts. Previous treatments included an over-the-counter wart medication, cryotherapy, and a course of imiquimod, but none had helped.

The physical examination revealed multiple soft, moist, beefy papules and plaques around the genital area (FIGURE 1) and perianal region. In addition, there were multiple hyper-pigmented macules on the patient’s palms and soles (FIGURE 2), and reticulated, patchy eruptions on his arms, chest (FIGURE 3), and back.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Secondary syphilis

The appearance of the genital and perianal lesions was consistent with condylomata lata—a cutaneous sign of secondary syphilis—rather than genital warts. The presence of a rash on the patient’s trunk and extremities further supported this diagnosis. We did a rapid plasma reagin (RPR) test and a Treponema pallidum particle agglutination test; we also tested for human immunodeficiency virus (HIV). The patient’s RPR titer was 1:128, and the T pallidum antibody test came back positive. HIV-1 and HIV-2 serology were negative.

Appearance of the lesions was a giveaway. Condylomata lata are flat-topped, broad papules that are usually located on folds of moist skin (particularly the genitals and anus), and have a smooth, gray, moist surface. Although they can be lobulated, they do not have the classic digitate projections that are characteristic of genital warts. A nonpruritic, symmetric, “raw ham”-colored papular eruption on a patient’s trunk, palms, and soles is also characteristic of secondary syphilis.¹ In this case, the reticular pattern on the patient’s chest represented the commonly seen lenticular rash of secondary syphilis.

Cutaneous lesions of secondary syphilis contain numerous spirochetes (T pallidum) and are highly infectious. Systemic symptoms of secondary syphilis may include fatigue, generalized lymphadenopathy, arthralgia, myalgia, pharyngitis, and headache.

Although condylomata lata can be lobulated, they do not have the classic digitate projections characteristic of genital warts.

Some patients may report having a recent chancre—a painless, self-limiting ulcer in the genital area—which is characteristic of primary syphilis (see “Single nontender ulcer on the glans,” J Fam Pract. 2017;66:253-255). For more on the stages of syphilis, see the TABLE². Our patient did not remember ever having a chancre.

Increase in cases. Rates of primary and secondary syphilis have increased in the past decade. In 2014, approximately 20,000 syphilis cases were reported—a record high since 1994.³ Men who have sex with men are particularly affected; however, increases in infection rates have also been noted in women and across people of all ages and ethnicities.³

Rule out other causes of genital lesions

Condyloma acuminata, commonly called genital warts, are localized human papilloma virus (HPV) infections that appear as discrete, gray to pale pink, lobulated papules that may coalesce to form a large, cauliflower-like mass. They are sexually transmitted and commonly involve the genital and anal areas. While physicians may confuse condylomata lata with genital warts, diffuse skin rashes and constitutional symptoms are not usually seen with genital warts.⁴

Fordyce spots are small, whitish, raised papules on the glans or the shaft of the penis or the vulva of the vagina. They may also appear on the lips and oral mucosa. They are a result of prominent sebaceous glands and are harmless. They are not infectious or sexually transmitted.^5,6

Lymphogranuloma venereum is an uncommon sexually transmitted disease caused by Chlamydia trachomatis. It is characterized by genital papules or ulcers, followed by bilateral, suppurative, inguinal adenitis known as buboes. The buboes may breakdown, form multiple fistulous openings, and discharge purulent material.⁶

Acute HIV may present with flu-like symptoms and well-circumscribed maculopapular rashes on the face, neck, and upper trunk. The palms and soles may also be affected. Patients with HIV may also develop genital plaque-like lesions from herpes simplex virus-2, genital warts from HPV, molluscum contagiosum, and, not uncommonly, anogenital malignancies.^7,8

Confluent and reticulated papillomatosis (CARP) is a disorder that occurs predominantly in young adults and teenagers, with cosmetically displeasing brown scaling macules that may coalesce to form patches or plaques affecting the neck, chest, back, and axillae. It is often mistaken for tinea versicolor.⁹ In this case, the eruption on the chest closely resembled CARP, but a diagnosis of CARP would not have explained the genital lesions.

Confirm diagnosis with treponemal tests

Syphilis is often a clinical diagnosis with pathologic confirmation. Patients suspected of having syphilis should be screened with nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) test or the RPR test, which become positive within 3 weeks of developing primary syphilis.

Diagnosis is confirmed with specific treponemal testing, such as with a fluorescent treponemal antibody absorption assay or the T pallidum particle agglutination test. HIV testing is recommended for all patients with syphilis.

Penicillin G is the mainstay of treatment

Proper selection of penicillin is paramount in the treatment of syphilis. Primary, secondary, and early latent syphilis are treated with an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. Patients with late latent or latent syphilis of unknown duration are treated with 3 doses of the same injection at weekly intervals, totaling 7.2 million units of benzathine penicillin G.¹⁰ Certain penicillin preparations (eg, combinations of benzathine penicillin and procaine penicillin) are not appropriate treatments because they do not provide adequate amounts of the antibiotic.

Watch for this reaction. Approximately 30% of patients following penicillin treatment for spirochete infection develop a Jarisch-Herxheimer reaction (JHR).¹¹ JHR is characterized by an abrupt onset of fever, chills, myalgia, tachycardia, vasodilatation with flushing, exacerbated maculopapular skin rash, or mild hypotension. Care for JHR is generally supportive.

Our patient received an intramuscular injection of 2.4 million units of long-acting benzathine penicillin G. His skin eruption and condylomata lata lesions were completely resolved at follow-up 6 months later.

As recommended by the Centers for Disease Control and Prevention,¹⁰ our patient’s RPR titers were repeated at 6 months and again at 12 months to verify a four-fold decline, indicating successful treatment.

CORRESPONDENCE
Anne Bartels, MD, General Medicine, Naval Hospital Camp Lejeune, 100 Brewster Blvd., Camp Lejeune, NC 28547; [email protected].

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 28-year-old woman presents to your office for a routine health maintenance examination. She is currently using an oral contraceptive containing desogestrel and ethinyl estradiol for contraception and is inquiring about a refill for the coming year. What would you recommend?

When choosing a combined oral contraceptive (COC) for a patient, physicians often have “go-to” favorites—tried and true agents that are easy to prescribe on a busy clinic day. However, some of these may be placing patients at increased risk for venous thromboembolic events.

In general, when compared with nonusers, women who use COCs have a 2- to 4-fold increase in risk of venous thromboembolism (VTE) and an increased risk of myocardial infarction (MI) and stroke.^2,3 More specifically, higher doses of estrogen combined with the progesterones gestodene, desogestrel, and levonorgestrel, are associated with a higher risk of VTE.^2-6

In 2012, the European Medicines Agency warned that COCs containing drospirenone were associated with a higher risk of VTE than other preparations, despite similar estrogen content.⁷ The US Food and Drug Administration (FDA) produced a similar statement that same year, recommending that physicians carefully consider the risks and benefits before prescribing contraceptives containing drospirenone.⁸

The risks of ischemic stroke and MI have not been clearly established for varying doses of estrogen and different progesterones. This large observational study fills that informational gap by providing risk estimates for the various COC options.

STUDY SUMMARY

One combined oral contraceptive comes out ahead

The authors used an observational cohort model to determine the effects of different doses of estrogen combined with different progesterones in COCs on the risks of pulmonary embolism (PE), ischemic stroke, and MI.¹ Data were collected from the French national health insurance database and the French national hospital discharge database.^9,10 The study included just under 5 million women 15 to 49 years of age, living in France, with at least one prescription filled for COCs between July 2010 and September 2012.

The investigators calculated the absolute and relative risks of first PE, ischemic stroke, and MI in women using COC formulations containing either low-dose estrogen (20 mcg) or high-dose estrogen (30-40 mcg) combined with one of 5 progesterones (norethisterone, norgestrel, levonorgestrel, desogestrel, gestodene). The relative risk (RR) was adjusted for confounding factors, including age, complimentary universal health insurance, socioeconomic status, hypertension, diabetes, and consultation with a gynecologist in the previous year.

The absolute risk per 100,000 woman-years for all COC use was 33 for PE, 19 for ischemic stroke, and 7 for MI with a composite risk of 60. The RRs for low-dose estrogen vs high-dose estrogen were 0.75 (95% confidence interval [CI], 0.67-0.85) for PE, 0.82 (95% CI, 0.7-0.96) for ischemic stroke, and 0.56 (95% CI, 0.39-0.79) for MI. The absolute risk reduction (ARR) with low-dose estrogen vs high-dose estrogen was 14/100,000 person-years of use; the number needed to harm (NNH) was 7143.

Oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

Compared with levonorgestrel, desogestrel and gestodene were associated with higher RRs of PE but not arterial events (2.16; 95% CI, 1.93-2.41 for desogestrel and 1.63; 95% CI, 1.34-1.97 for gestodene). The ARR with levonorgestrel use as opposed to desogestrel for PE was 19/100,000 person-years of use (NNH=5263); the ARR with levonorgestrel use as opposed to gestodene was 12/100,000 person-years of use (NNH=8333). The authors concluded that for the same progesterone, using a lower dose of estrogen decreases risk of PE, ischemic stroke, and MI, and that oral contraceptives containing levonorgestrel and low-dose estrogen resulted in the lowest overall risks of PE and arterial thromboembolism.

WHAT’S NEW?

Low-dose estrogen and levonorgestrel confer lowest risk of 3 CV conditions

Prior studies have shown that COCs increase the risk of PE and may also increase the risks of ischemic stroke and MI.^3,11 Studies have also suggested that a higher dose of estrogen in COCs is associated with an increased risk of VTE.^11,12 This study shows that 20 mcg of estrogen combined with levonorgestrel is associated with the lowest risks of PE, MI, and ischemic stroke.

CAVEATS

A cohort study, no contraceptive start date, and incomplete tobacco use data

This is an observational cohort study, so it is subject to confounding factors and biases. It does, however, include a very large population, which improves validity. The study did not account for COC start date, which may be confounding because the risk of VTE is highest in the first 3 months to one year of COC use.¹² Data on tobacco use, a significant independent risk factor for arterial but not VTE, was incomplete, but in other studies has only marginally affected outcomes.^3,13

CHALLENGES TO IMPLEMENTATION

Low-dose estrogen is associated with increased vaginal spotting

One potential challenge to implementing this practice changer may be the increased rate of vaginal spotting associated with low-dose estrogen. COCs containing 20 mcg of estrogen are associated with spotting in approximately two-thirds of menstrual cycles over the course of a year.¹⁴ That said, women may prefer to endure the spotting in light of the improved safety profile of a lower-dose estrogen pill.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

In April of this year, 3 counties in Minnesota reported a measles outbreak, illustrating the danger of vaccine hesitancy that exists in some communities, resulting in low rates of childhood immunization. Fifty people—mostly children under the age of 5 and almost all unimmunized—have been diagnosed with measles since this outbreak began. As of early May, 11 had been hospitalized. Most of those infected have been American-born children of Somali immigrants.^1,2

At the time of the outbreak, only 42% of the Somali children had been immunized against measles, compared with 88.5% of non-Somalis in Minnesota.² Because of concern about the number of Somali children being diagnosed with autism, a condition apparently not recognized in Somalia, Somali parents living in Minnesota began questioning why this was occurring.

If measles is suspected, care for patients in an isolation room or one that can be kept unused afterwards.

High profile anti-vaccine advocates reportedly visited the community and advised these parents that the measles-mumps-rubella (MMR) vaccine was the cause of this rise in autism incidence and encouraged them to avoid the vaccine.² This series of events led to low vaccination rates in what was once a well-vaccinated community. The outbreak appears to have started with a Somali child who visited Africa and then returned to his community while incubating measles.

The clinical course of measles. Measles is an acute viral respiratory illness, which, after an incubation period of 10 to 12 days, starts with a fever (as high as 105° F), malaise, and at least one of the 3 “C”s—cough, coryza, and conjunctivitis.^3,4 A maculopapular rash then starts on the face and spreads to the trunk and the extremities (FIGURE 1). Koplik spots (FIGURE 2) can be seen on the oral mucosa. Children with measles look very ill. Patients are contagious for approximately 8 days, starting 4 days before the rash appears. Complications can include otitis media, bronchopneumonia, encephalitis, and diarrhea.

Measles is not a benign childhood illness. Before the licensure of live measles vaccine in 1963, an average of 549,000 measles cases were reported in the United States each year.³ That number is likely an underestimate due to inconsistent reporting, with a more plausible number of infections annually being 3 to 4 million.³ These regular epidemics led each year to about 48,000 people being hospitalized from complications, 1000 developing chronic disability from acute measles encephalitis, and about 500 dying from measles-related complications. Today, worldwide, an estimated 134,200 individuals die from measles each year.³

Where the risk is greatest. In the year 2000, measles was declared eliminated from the United States, meaning that endemic transmission was no longer occurring. Since then, the annual number of cases has ranged from a low of 37 in 2004 to a high of 667 in 2014.³ Most measles cases have occurred in unvaccinated individuals and primarily through importation by people infected in other countries who then transmit the infection upon entry or reentry to this country. In the United States, measles is more likely to spread and cause outbreaks in communities where large groups of people are unvaccinated.

Laboratory confirmation of measles is important to establish a correct clinical diagnosis, as well as to verify the infection for public health purposes. Confirmation is achieved by detecting in a patient’s blood sample the measles-specific IgM antibody or measles RNA by real-time polymerase chain reaction (RT-PCR). Obtain both a serum sample and a throat swab (or nasopharyngeal swab) from patients you suspect may have measles. Urine samples may also contain virus, and can be useful. The local health department can offer advice on how to collect and process these laboratory specimens.

Measles is a preventable infection

The Centers for Disease Control and Prevention (CDC) recommends routine childhood immunization with MMR vaccine, with the first dose given at age 12 through 15 months, and the second dose at 4 through 6 years of age (or at least 28 days following the first dose).^3,5 Others for whom the vaccine is recommended are included in the TABLE.³

Because the MMR vaccine is a modified live-virus vaccine, it is contraindicated for pregnant women and those with severe immune deficiencies. It is also contraindicated for individuals who have ever had a life-threatening allergic reaction to the antibiotic neomycin or to any other MMR vaccine component.⁴ That these high-risk groups cannot receive protection from the vaccine underscores the importance of maintaining community herd immunity at a high level to prevent the spread of infection.

In response to this latest outbreak, the Minnesota Department of Health (MDH) has augmented its routine recommendations regarding measles vaccine,¹ including advising that:

• All children 12 months and older who have not received the MMR vaccine and all adults born in 1957 (or later) who have not received the vaccine or ever had the measles should get the first dose as soon as possible.
• Children who live in counties where measles cases have occurred and who have received their first dose of the MMR vaccine at least 28 days ago should get their second dose as soon as possible.
• All Somali Minnesotan children statewide who received their first dose of the vaccine at least 28 days ago should get their second as soon as possible.
• Health care providers statewide may recommend an early (before age 4 years) second dose of the vaccine during routine appointments for children.

Preventing measles outbreaks and minimizing community impact

Measures family physicians can take to protect their staff, patients, and community from measles (and other infectious diseases) include ensuring that all staff are fully immunized as recommended by the CDC,⁶ vaccinating all patients according to the recommended immunization schedules, implementing and enforcing good infection control practices in the clinical setting, and taking appropriate measures to diagnose and manage individuals with suspected measles. These measures are described on the CDC Web site.⁷

Measles virus, commonly believed to be the most infectious agent known, is often transmitted in medical facilities. An individual can become infected simply by entering a closed space that had been occupied by someone with measles several hours earlier. In your facility, physically separate those with fever and rash from other patients as soon as possible and, if measles is suspected, care for them in an isolation room or one that can be kept unused afterwards.

Any time you suspect that a patient has measles, immediately inform the local public health department. The health department should conduct an investigation to find susceptible individuals, provide immunizations for case contacts (and immune globulin for unvaccinated pregnant women and those who are severely immunosuppressed), and implement isolation and quarantine measures as indica­ted by the situation.

There is no antiviral medication for measles. Aim treatment at controlling symptoms and addressing any complicating bacterial infections. Children who have severe illness should receive vitamin A at recommended doses.³

Outbreaks such as the one in Minnesota demonstrate the importance of family physicians working in collaboration with public health officials to minimize the effect of infectious illnesses on the community.

In April of this year, 3 counties in Minnesota reported a measles outbreak, illustrating the danger of vaccine hesitancy that exists in some communities, resulting in low rates of childhood immunization. Fifty people—mostly children under the age of 5 and almost all unimmunized—have been diagnosed with measles since this outbreak began. As of early May, 11 had been hospitalized. Most of those infected have been American-born children of Somali immigrants.^1,2

At the time of the outbreak, only 42% of the Somali children had been immunized against measles, compared with 88.5% of non-Somalis in Minnesota.² Because of concern about the number of Somali children being diagnosed with autism, a condition apparently not recognized in Somalia, Somali parents living in Minnesota began questioning why this was occurring.

If measles is suspected, care for patients in an isolation room or one that can be kept unused afterwards.

High profile anti-vaccine advocates reportedly visited the community and advised these parents that the measles-mumps-rubella (MMR) vaccine was the cause of this rise in autism incidence and encouraged them to avoid the vaccine.² This series of events led to low vaccination rates in what was once a well-vaccinated community. The outbreak appears to have started with a Somali child who visited Africa and then returned to his community while incubating measles.

The clinical course of measles. Measles is an acute viral respiratory illness, which, after an incubation period of 10 to 12 days, starts with a fever (as high as 105° F), malaise, and at least one of the 3 “C”s—cough, coryza, and conjunctivitis.^3,4 A maculopapular rash then starts on the face and spreads to the trunk and the extremities (FIGURE 1). Koplik spots (FIGURE 2) can be seen on the oral mucosa. Children with measles look very ill. Patients are contagious for approximately 8 days, starting 4 days before the rash appears. Complications can include otitis media, bronchopneumonia, encephalitis, and diarrhea.

Measles is not a benign childhood illness. Before the licensure of live measles vaccine in 1963, an average of 549,000 measles cases were reported in the United States each year.³ That number is likely an underestimate due to inconsistent reporting, with a more plausible number of infections annually being 3 to 4 million.³ These regular epidemics led each year to about 48,000 people being hospitalized from complications, 1000 developing chronic disability from acute measles encephalitis, and about 500 dying from measles-related complications. Today, worldwide, an estimated 134,200 individuals die from measles each year.³

Where the risk is greatest. In the year 2000, measles was declared eliminated from the United States, meaning that endemic transmission was no longer occurring. Since then, the annual number of cases has ranged from a low of 37 in 2004 to a high of 667 in 2014.³ Most measles cases have occurred in unvaccinated individuals and primarily through importation by people infected in other countries who then transmit the infection upon entry or reentry to this country. In the United States, measles is more likely to spread and cause outbreaks in communities where large groups of people are unvaccinated.

Laboratory confirmation of measles is important to establish a correct clinical diagnosis, as well as to verify the infection for public health purposes. Confirmation is achieved by detecting in a patient’s blood sample the measles-specific IgM antibody or measles RNA by real-time polymerase chain reaction (RT-PCR). Obtain both a serum sample and a throat swab (or nasopharyngeal swab) from patients you suspect may have measles. Urine samples may also contain virus, and can be useful. The local health department can offer advice on how to collect and process these laboratory specimens.

Measles is a preventable infection

The Centers for Disease Control and Prevention (CDC) recommends routine childhood immunization with MMR vaccine, with the first dose given at age 12 through 15 months, and the second dose at 4 through 6 years of age (or at least 28 days following the first dose).^3,5 Others for whom the vaccine is recommended are included in the TABLE.³

Because the MMR vaccine is a modified live-virus vaccine, it is contraindicated for pregnant women and those with severe immune deficiencies. It is also contraindicated for individuals who have ever had a life-threatening allergic reaction to the antibiotic neomycin or to any other MMR vaccine component.⁴ That these high-risk groups cannot receive protection from the vaccine underscores the importance of maintaining community herd immunity at a high level to prevent the spread of infection.

In response to this latest outbreak, the Minnesota Department of Health (MDH) has augmented its routine recommendations regarding measles vaccine,¹ including advising that:

• All children 12 months and older who have not received the MMR vaccine and all adults born in 1957 (or later) who have not received the vaccine or ever had the measles should get the first dose as soon as possible.
• Children who live in counties where measles cases have occurred and who have received their first dose of the MMR vaccine at least 28 days ago should get their second dose as soon as possible.
• All Somali Minnesotan children statewide who received their first dose of the vaccine at least 28 days ago should get their second as soon as possible.
• Health care providers statewide may recommend an early (before age 4 years) second dose of the vaccine during routine appointments for children.

Preventing measles outbreaks and minimizing community impact

Measures family physicians can take to protect their staff, patients, and community from measles (and other infectious diseases) include ensuring that all staff are fully immunized as recommended by the CDC,⁶ vaccinating all patients according to the recommended immunization schedules, implementing and enforcing good infection control practices in the clinical setting, and taking appropriate measures to diagnose and manage individuals with suspected measles. These measures are described on the CDC Web site.⁷

Measles virus, commonly believed to be the most infectious agent known, is often transmitted in medical facilities. An individual can become infected simply by entering a closed space that had been occupied by someone with measles several hours earlier. In your facility, physically separate those with fever and rash from other patients as soon as possible and, if measles is suspected, care for them in an isolation room or one that can be kept unused afterwards.

Any time you suspect that a patient has measles, immediately inform the local public health department. The health department should conduct an investigation to find susceptible individuals, provide immunizations for case contacts (and immune globulin for unvaccinated pregnant women and those who are severely immunosuppressed), and implement isolation and quarantine measures as indica­ted by the situation.

There is no antiviral medication for measles. Aim treatment at controlling symptoms and addressing any complicating bacterial infections. Children who have severe illness should receive vitamin A at recommended doses.³

Outbreaks such as the one in Minnesota demonstrate the importance of family physicians working in collaboration with public health officials to minimize the effect of infectious illnesses on the community.

In April of this year, 3 counties in Minnesota reported a measles outbreak, illustrating the danger of vaccine hesitancy that exists in some communities, resulting in low rates of childhood immunization. Fifty people—mostly children under the age of 5 and almost all unimmunized—have been diagnosed with measles since this outbreak began. As of early May, 11 had been hospitalized. Most of those infected have been American-born children of Somali immigrants.^1,2

At the time of the outbreak, only 42% of the Somali children had been immunized against measles, compared with 88.5% of non-Somalis in Minnesota.² Because of concern about the number of Somali children being diagnosed with autism, a condition apparently not recognized in Somalia, Somali parents living in Minnesota began questioning why this was occurring.

If measles is suspected, care for patients in an isolation room or one that can be kept unused afterwards.

High profile anti-vaccine advocates reportedly visited the community and advised these parents that the measles-mumps-rubella (MMR) vaccine was the cause of this rise in autism incidence and encouraged them to avoid the vaccine.² This series of events led to low vaccination rates in what was once a well-vaccinated community. The outbreak appears to have started with a Somali child who visited Africa and then returned to his community while incubating measles.

The clinical course of measles. Measles is an acute viral respiratory illness, which, after an incubation period of 10 to 12 days, starts with a fever (as high as 105° F), malaise, and at least one of the 3 “C”s—cough, coryza, and conjunctivitis.^3,4 A maculopapular rash then starts on the face and spreads to the trunk and the extremities (FIGURE 1). Koplik spots (FIGURE 2) can be seen on the oral mucosa. Children with measles look very ill. Patients are contagious for approximately 8 days, starting 4 days before the rash appears. Complications can include otitis media, bronchopneumonia, encephalitis, and diarrhea.

Measles is not a benign childhood illness. Before the licensure of live measles vaccine in 1963, an average of 549,000 measles cases were reported in the United States each year.³ That number is likely an underestimate due to inconsistent reporting, with a more plausible number of infections annually being 3 to 4 million.³ These regular epidemics led each year to about 48,000 people being hospitalized from complications, 1000 developing chronic disability from acute measles encephalitis, and about 500 dying from measles-related complications. Today, worldwide, an estimated 134,200 individuals die from measles each year.³

Where the risk is greatest. In the year 2000, measles was declared eliminated from the United States, meaning that endemic transmission was no longer occurring. Since then, the annual number of cases has ranged from a low of 37 in 2004 to a high of 667 in 2014.³ Most measles cases have occurred in unvaccinated individuals and primarily through importation by people infected in other countries who then transmit the infection upon entry or reentry to this country. In the United States, measles is more likely to spread and cause outbreaks in communities where large groups of people are unvaccinated.

Laboratory confirmation of measles is important to establish a correct clinical diagnosis, as well as to verify the infection for public health purposes. Confirmation is achieved by detecting in a patient’s blood sample the measles-specific IgM antibody or measles RNA by real-time polymerase chain reaction (RT-PCR). Obtain both a serum sample and a throat swab (or nasopharyngeal swab) from patients you suspect may have measles. Urine samples may also contain virus, and can be useful. The local health department can offer advice on how to collect and process these laboratory specimens.

Measles is a preventable infection

The Centers for Disease Control and Prevention (CDC) recommends routine childhood immunization with MMR vaccine, with the first dose given at age 12 through 15 months, and the second dose at 4 through 6 years of age (or at least 28 days following the first dose).^3,5 Others for whom the vaccine is recommended are included in the TABLE.³

Because the MMR vaccine is a modified live-virus vaccine, it is contraindicated for pregnant women and those with severe immune deficiencies. It is also contraindicated for individuals who have ever had a life-threatening allergic reaction to the antibiotic neomycin or to any other MMR vaccine component.⁴ That these high-risk groups cannot receive protection from the vaccine underscores the importance of maintaining community herd immunity at a high level to prevent the spread of infection.

In response to this latest outbreak, the Minnesota Department of Health (MDH) has augmented its routine recommendations regarding measles vaccine,¹ including advising that:

• All children 12 months and older who have not received the MMR vaccine and all adults born in 1957 (or later) who have not received the vaccine or ever had the measles should get the first dose as soon as possible.
• Children who live in counties where measles cases have occurred and who have received their first dose of the MMR vaccine at least 28 days ago should get their second dose as soon as possible.
• All Somali Minnesotan children statewide who received their first dose of the vaccine at least 28 days ago should get their second as soon as possible.
• Health care providers statewide may recommend an early (before age 4 years) second dose of the vaccine during routine appointments for children.

Preventing measles outbreaks and minimizing community impact

Measures family physicians can take to protect their staff, patients, and community from measles (and other infectious diseases) include ensuring that all staff are fully immunized as recommended by the CDC,⁶ vaccinating all patients according to the recommended immunization schedules, implementing and enforcing good infection control practices in the clinical setting, and taking appropriate measures to diagnose and manage individuals with suspected measles. These measures are described on the CDC Web site.⁷

Measles virus, commonly believed to be the most infectious agent known, is often transmitted in medical facilities. An individual can become infected simply by entering a closed space that had been occupied by someone with measles several hours earlier. In your facility, physically separate those with fever and rash from other patients as soon as possible and, if measles is suspected, care for them in an isolation room or one that can be kept unused afterwards.

Any time you suspect that a patient has measles, immediately inform the local public health department. The health department should conduct an investigation to find susceptible individuals, provide immunizations for case contacts (and immune globulin for unvaccinated pregnant women and those who are severely immunosuppressed), and implement isolation and quarantine measures as indica­ted by the situation.

There is no antiviral medication for measles. Aim treatment at controlling symptoms and addressing any complicating bacterial infections. Children who have severe illness should receive vitamin A at recommended doses.³

Outbreaks such as the one in Minnesota demonstrate the importance of family physicians working in collaboration with public health officials to minimize the effect of infectious illnesses on the community.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

Patients who suffer a stroke rarely have just one vascular risk factor. Therefore, the approach to secondary stroke prevention must be multifactorial. In fact, it has been estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes lifestyle modification and optimal medical management.¹ Such an achievement would save millions of people from disability and functional decline, as well as millions of dollars in related medical costs.

The initial approach to patients with stroke is focused on stabilization and a rapid work-up to identify the most likely etiology. Common causes of stroke include large artery atherosclerosis, cardiac emboli, and small vessel disease; less common causes include dissection, aortic emboli, and non-atherosclerotic vascular disease. If a complete diagnostic work-up is unrevealing, the stroke is said to be cryptogenic. Determining the correct etiology of a stroke is paramount to preventing secondary stroke (FIGURE^2-13).

Effective secondary prevention strategies designed to prevent a stroke or transient ischemic attack (TIA) in a patient with a known history of either event include lifestyle modifications, medications, and when appropriate, mechanical interventions. As a primary care physician (PCP), you are uniquely positioned to spearhead the prevention of secondary strokes: Not only are you at the forefront of prevention and the use of techniques such as motivational interviewing, but you also have longstanding relationships with many of your patients. In fact, the success of many interventions is improved by the informed, enduring, and trusting nature of relationships between patients and their PCPs.

In the first part of this 2-part series, we focused on subacute stroke management and outlined the recommended work-up for subacute stroke/TIA (see “Stroke: A road map to subacute management,” 2017;66:366-374). In this part, we focus on secondary prevention. The more common modifiable conditions encountered in primary care are discussed here, while many of the more rare etiologies (hypercoagulable states, sickle cell disease, and vasculitis) are outside the scope of this article.

Lifestyle interventions: Target tobacco use, obesity, alcohol intake

Lifestyle modifications can have a positive impact on many of America’s most prevalent diseases, and stroke is no exception.¹⁴ Many of the disease states identified as risk factors for stroke (type 2 diabetes, hypertension, dyslipidemia) are exacerbated by tobacco use, obesity, and excessive alcohol intake.

Does your patient smoke? Up to 25% of all strokes are directly attributable to cigarette smoking.¹⁵ Smoking raises an individual’s risk for stroke in a dose-dependent fashion.^15,16 One study demonstrated that, compared to never-smokers, women ages 15 to 49 years who smoked a half-pack per day had an odds ratio for ischemic stroke of 2.2; those who smoked 2 packs per day had an odds ratio of 9.1.¹⁷ After cessation, stroke risk generally returns to baseline within 5 years.¹⁶ Thus, smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

Is your patient overweight? While obesity in and of itself is a risk factor for stroke, a focus on nutrition and physical activity as mechanisms for weight loss is far superior to focusing on either element alone. Physical activity—consisting of at least 40 minutes of moderate intensity aerobic exercise 3 to 4 times per week—and a diet that emphasizes fruits and vegetables, whole grains, and healthy fats, have both independently demonstrated benefits in secondary stroke prevention and are important parts of American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.^2,3

It’s estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes optimal medical management.

The Mediterranean Diet, which emphasizes consumption of fruits and vegetables, legumes, tree nuts, olive oil, and lean protein, has long been associated with cardiovascular benefit.¹⁸ One prospective, randomized, single-blinded trial involving approximately 600 patients that looked at secondary prevention of coronary heart disease found that following the diet significantly reduced mortality compared with a usual prudent post-infarct diet (number needed to treat [NNT]=30 over 4 years).¹⁹

Is alcohol consumption an issue? Chronic heavy alcohol intake contributes to the development of hemorrhagic and ischemic stroke through multiple mechanisms, including alcohol-induced hypertension, alcoholic cardiomyopathy, and atrial fibrillation (AF). Light or moderate alcohol consumption has a paradoxical mild protective effect on ischemic stroke, thought to possibly be mediated by an increase in high-density lipoprotein (HDL) level and mild antiplatelet effect.³

AHA/American Stroke Association (ASA) guidelines indicate that no more than one standard drink per day for women and 2 drinks per day for men is reasonable.³ Counsel patients who drink in excess of this about the benefits of decreasing alcohol intake or abstaining altogether.

Choosing medications to manage BP, cholesterol, and clotting

Optimize blood pressure control. Blood pressure (BP) plays a critical role in both the management and prevention of stroke and is considered to be the most important modifiable risk factor in both primary and secondary stroke prevention.²⁰ In the first 24 to 48 hours following a cerebral ischemic event that is not eligible for thrombolysis, permissive hypertension (treating BP only if it exceeds 220/120 mm Hg unless there is a concurrent medical illness that requires you do so) is appropriate, as hypotension or rapid fluctuations in BP can be harmful.²¹

This flexibility does not continue into the subacute phase of management (at a minimum, after the initial 48 hours) or into secondary prevention. Initiation and titration of oral agents to gradually achieve a BP <140/90 mm Hg or a reduction of 10/5 mm Hg for patients already within optimal range are the most widely recognized goals.^3,20 Patients with stroke secondary to small vessel disease may benefit from an even lower goal of <130/<80 mm Hg.¹¹ Encourage patients to monitor their BP at home for added accuracy and consistency.²²

Pharmacologic BP management is appropriate for patients who are consistently above optimal range despite attempting recommended lifestyle modifications. The data are relatively consistent with respect to the effects of different drug classes after a stroke: beta-blockers have no effect on any outcome; thiazide diuretics significantly reduce stroke and total vascular events; angiotensin-converting enzyme (ACE) inhibitors significantly reduce myocardial infarction (MI); and the combination of an ACE inhibitor and thiazide diuretic reduces stroke, MI, and combined vascular events.⁴

This has led many stroke specialists to recommend the combination of an ACE inhibitor or angiotensin II receptor blocker (ARB) and a thiazide diuretic as a first-line approach to secondary stroke prevention rather than a beta-blocker (assuming there is no additional indication for a beta-blocker). Similarly, there is ample evidence to show that the magnitude of BP reduction is proportional to the reduction in recurrent vascular events.³

Make use of statin therapy—regardless of LDL. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial⁵ explored the potential role of statin medication for secondary stroke prevention. Researchers randomly assigned almost 5000 participants who’d had a stroke or TIA one to 6 months before study entry (but had no known history of coronary artery disease) to placebo or a high-intensity statin (80 mg/d atorvastatin). The statin group demonstrated a 4.9-year absolute risk reduction in fatal or nonfatal recurrent stroke of 1.9% (NNT=53).

Given these findings and those from other studies, the AHA and ASA recommend treating patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein (LDL) level.³ Of note, statins are not indicated for the secondary prevention of hemorrhagic stroke.

Select antiplatelet therapy based on ischemic stroke subtype. Investigators are still trying to determine the optimal antiplatelet for secondary stroke prevention; it is likely that the ideal choice depends largely on the etiology of the stroke. Trials that did not select patients based on subtype of ischemic stroke have not shown a long-term benefit from dual antiplatelet therapy (clopidogrel and aspirin),^23,24 and one double-blind, multicenter trial involving more than 3000 patients with recent stroke secondary to small vessel disease demonstrated harm from such therapy in terms of a significantly increased risk of bleeding and death.⁶

Smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

However, a 2011 study compared aggressive medical management (aspirin 325 mg/d plus clopidogrel 75 mg/d for 90 days) alone to aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The study involved almost 500 patients who'd had a recent TIA or stroke attributed to intracranial atherosclerotic stenosis. The authors found that the 30-day rate of stroke or death was 14.7% in the PTAS group vs 5.8% in the medical management group.²⁵

Similarly, a randomized double-blind, placebo-controlled trial published in 2013 involving over 5000 patients in China found that short-term use of dual antiplatelets (clopidogrel and aspirin for the first 21 days after an ischemic event, followed by aspirin monotherapy for 90 days) had an absolute risk reduction of 3.5% without increasing the risk of major bleeding in patients with high-risk TIA or minor stroke.²⁶

All stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin (75-325 mg); research has shown that lower doses are as effective as higher doses but with a lower risk of adverse gastrointestinal effects, including bleeding.^3,20 Aspirin 81 mg/d is a common effective dose.

For patients who cannot tolerate aspirin due to allergy, clopidogrel 75 mg/d is a reasonable alternative. Long-term studies of aspirin vs clopidogrel⁷ and clopidogrel vs extended-release dipyridamole⁸ showed no difference in secondary stroke prevention. The International Stroke Trial²⁷ and Chinese Acute Stroke Trial²⁸ both indicate that aspirin should be started as soon as possible after the onset of an acute stroke.

This special population should probably get antiplatelets, too. One recent study explored the use of an antiplatelet vs anticoagulation therapy for stroke patients with carotid artery dissection. The CADISS (Cervical Artery Dissection in Stroke Study) trial²⁹ randomized 250 patients with extracranial carotid and vertebral artery dissection with onset of symptoms within the previous 7 days to either antiplatelet or anticoagulation therapy and found no difference in the primary outcomes of recurrent stroke or death. The study also demonstrated a low risk of recurrent stroke in this population, which was 2% at 3-month follow-up.

Most patients with cervical artery dissection, therefore, are now treated with antiplatelet therapy. That said, situations may still arise in which anticoagulation can be considered, and consultation with a neurologist for guidance on choice of therapy is recommended.

Is an anticoagulant in order? Which agent, when

The most common cause of cardioembolic stroke is AF, which accounts for at least 15% of ischemic strokes, a number that rises in those over the age of 80.^20,30,31 A meta-analysis of more than 28,000 patients with non-valvular AF demonstrated that warfarin reduced the risk of stroke by 64%.³²

All ischemic stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin.

The rate of intracerebral hemorrhages during oral anticoagulation ranges from 0.3% to 0.6% per year.³³ The risk of bleeding complications can be mitigated by keeping international normalized ratios ≤3.0, maintaining good BP control, and avoiding concurrent use of antiplatelets in the absence of a clear indication for them.³³

Several risk assessment scores, such as the HAS-BLED,³⁴ can help with estimating the risk of hemorrhagic complications, although these scores have their limitations.^35,36 Even in an older population (mean age 83 years) with a high risk for falls, warfarin provided a net benefit in a composite endpoint of out-of-hospital death or hospitalization for stroke, MI, or hemorrhage in a retrospective study of over 1200 Medicare beneficiaries.³⁷

AF is not the only cause of cardioembolic stroke to consider. Additional high-risk factors warranting anticoagulation include rheumatic mitral valve disease, the presence of mechanical aortic or mitral valves, known mural thrombus, and acute anterior ST segment elevation myocardial infarctions (STEMIs) with resulting anterior apical dyskinesis/akinesis and concurrent ischemic stroke/TIA.³ (The specific management of each of these situations is beyond the scope of this paper.)

The choice of anticoagulation agent is based on multiple factors, including cost, risk of non-reversible bleeding, drug interactions, renal function, and patient preference. Approved options currently include warfarin/­vitamin K antagonist therapy, apixaban, rivaroxaban, dabigatran and edoxaban.³ Choice of therapy will continue to evolve as reversal agents, such as idarucizumab, are developed. Idarucizumab, a reversal agent for dabigatran, received approval from the US Food and Drug Administration in October 2015.³⁸

When to start anticoagulation. There are limited data regarding the optimal timing of initiation of anticoagulation following a stroke; however, a recent multicenter prospective study supported the common practice of initiating anticoagulation therapy within 4 to 14 days of the event.³⁹ Individual patient factors must be taken into consideration, including the size of the stroke (the larger the stroke, the higher the risk for hemorrhagic transformation), BP control, any additional risk factors for bleeding, and the estimated risk of early recurrent stroke.

Bridging patients onto anticoagulation with unfractionated or low-molecular-weight heparin in the setting of acute stroke is not recommended.⁴⁰ Results from randomized controlled trials involving unfractionated heparin, heparinoids, and low-molecular-weight heparin have not reported any benefit to these agents over aspirin at preventing early stroke recurrence.^27,41,42

For immobile or hospitalized patients. Subcutaneous heparin for the prevention of deep vein thrombosis (DVT) during immobility and hospitalization is recommended.⁴³ Patients who cannot tolerate anticoagulation should be maintained on low-dose antiplatelet therapy. Experts do not recommend dual treatment with aspirin and anticoagulation in most cases. However, recent coronary artery stent placement does require temporary dual treatment, with duration dependent on the type of stent placed.

A role for glycemic control? Still to be determined

The specific role of diabetic management in secondary stroke prevention remains unclear. The 2008 ACCORD trial,⁴⁴ a randomized study involving over 10,000 patients with a median glycated hemoglobin level of 8.1%, investigated intensive hyperglycemic control (targeting a glycated hemoglobin level <6.0% vs <7.9%) as a means of decreasing cardiovascular risk. However, the trial ended 17 months early because of an increase in all-cause mortality in the intensive treatment arm compared with the standard management group. The same trial was also unable to demonstrate a decrease in stroke risk with a decrease in A1c.⁴⁴

More recently, the IRIS (Insulin Resistance Intervention after Stroke) trial⁴⁵ (2016) found a 2.8% absolute risk reduction in stroke or MI among participants who had a stroke or TIA in the previous 6 months who were treated with pioglitazone vs placebo over 4.8 years (NNT=36). Participants were required to have insulin resistance, but were excluded if they had diabetes. The authors did, however, report a notable increase in the risk of bone fractures requiring surgery or hospitalization in the pioglitazone arm (5.1% vs 3.2%; number needed to harm [NNH]=53).

Treat patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein level.

The impact this single study should have on standard secondary prevention is not yet clear. The authors concluded, “It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy.”⁴⁵

Determining whether mechanical interventions are needed

Almost all conditions leading to stroke warrant active medical management, but a few benefit from procedural intervention, as well.