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The patient’s atrophic plaques with a violaceous rim, indurated borders, and ulceration on the anterior pretibial surface were consistent with ulcerated necrobiosis lipoidica (NL).

NL typically manifests on the bilateral pretibial region as small papules or nodules that expand into yellow-brown atrophic, telangiectatic plaques with an elevated violaceous rim.^1,2 Most lesions are asymptomatic due to nerve damage, but up to 35% of patients may experience pruritus and tenderness.² Close monitoring of lesions is recommended due to risk of ulceration and potential for malignancy.² Rare reports show development of squamous cell carcinoma within NL lesions.¹

Women are 3 times more likely than men to have NL, with an average age of onset between 30 and 40 years.¹ The exact pathogenesis of NL is unknown.² Theories include vascular abnormalities (immunoglobulin deposition or microangiopathic changes leading to collagen degradation), abnormalities of collagen synthesis, neutrophil migration, and elevated tumor necrosis factor-alpha levels.^1,3

While NL can be diagnosed clinically, a skin biopsy may be necessary in atypical lesions. The biopsy will reveal palisading granulomatous inflammation in the dermis, with multinucleated histiocytes palisading around degenerated collagen bundles.²

No treatment has proven to be effective for NL. Glucose control in patients with diabetes does not have a significant effect on the NL lesions.^1-3 Corticosteroids (topical, intralesional, and systemic—depending on the severity) are considered first-line therapy.^1-3 Lifestyle modifications, such as smoking cessation and trauma avoidance, are recommended to promote healing; proper wound care is important when there is ulceration.^1,3 Other treatment options include oral pentoxifylline, topical retinoids or calcineurin inhibitors, and systemic immune system modulators (eg, tumor necrosis factor inhibitors and cyclosporine).

Since this patient did not respond to the topical betamethasone, she was started on oral pentoxifylline 400 mg tid. Unfortunately, she had to discontinue the medication because of gastrointestinal upset and was then started on doxycycline 100 mg orally bid. She was lost to follow-up.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Harika Echuri, MD, Tulane University School of Medicine, New Orleans, LA, Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The patient’s atrophic plaques with a violaceous rim, indurated borders, and ulceration on the anterior pretibial surface were consistent with ulcerated necrobiosis lipoidica (NL).

NL typically manifests on the bilateral pretibial region as small papules or nodules that expand into yellow-brown atrophic, telangiectatic plaques with an elevated violaceous rim.^1,2 Most lesions are asymptomatic due to nerve damage, but up to 35% of patients may experience pruritus and tenderness.² Close monitoring of lesions is recommended due to risk of ulceration and potential for malignancy.² Rare reports show development of squamous cell carcinoma within NL lesions.¹

Women are 3 times more likely than men to have NL, with an average age of onset between 30 and 40 years.¹ The exact pathogenesis of NL is unknown.² Theories include vascular abnormalities (immunoglobulin deposition or microangiopathic changes leading to collagen degradation), abnormalities of collagen synthesis, neutrophil migration, and elevated tumor necrosis factor-alpha levels.^1,3

While NL can be diagnosed clinically, a skin biopsy may be necessary in atypical lesions. The biopsy will reveal palisading granulomatous inflammation in the dermis, with multinucleated histiocytes palisading around degenerated collagen bundles.²

No treatment has proven to be effective for NL. Glucose control in patients with diabetes does not have a significant effect on the NL lesions.^1-3 Corticosteroids (topical, intralesional, and systemic—depending on the severity) are considered first-line therapy.^1-3 Lifestyle modifications, such as smoking cessation and trauma avoidance, are recommended to promote healing; proper wound care is important when there is ulceration.^1,3 Other treatment options include oral pentoxifylline, topical retinoids or calcineurin inhibitors, and systemic immune system modulators (eg, tumor necrosis factor inhibitors and cyclosporine).

Since this patient did not respond to the topical betamethasone, she was started on oral pentoxifylline 400 mg tid. Unfortunately, she had to discontinue the medication because of gastrointestinal upset and was then started on doxycycline 100 mg orally bid. She was lost to follow-up.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Harika Echuri, MD, Tulane University School of Medicine, New Orleans, LA, Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The patient’s atrophic plaques with a violaceous rim, indurated borders, and ulceration on the anterior pretibial surface were consistent with ulcerated necrobiosis lipoidica (NL).

NL typically manifests on the bilateral pretibial region as small papules or nodules that expand into yellow-brown atrophic, telangiectatic plaques with an elevated violaceous rim.^1,2 Most lesions are asymptomatic due to nerve damage, but up to 35% of patients may experience pruritus and tenderness.² Close monitoring of lesions is recommended due to risk of ulceration and potential for malignancy.² Rare reports show development of squamous cell carcinoma within NL lesions.¹

Women are 3 times more likely than men to have NL, with an average age of onset between 30 and 40 years.¹ The exact pathogenesis of NL is unknown.² Theories include vascular abnormalities (immunoglobulin deposition or microangiopathic changes leading to collagen degradation), abnormalities of collagen synthesis, neutrophil migration, and elevated tumor necrosis factor-alpha levels.^1,3

While NL can be diagnosed clinically, a skin biopsy may be necessary in atypical lesions. The biopsy will reveal palisading granulomatous inflammation in the dermis, with multinucleated histiocytes palisading around degenerated collagen bundles.²

No treatment has proven to be effective for NL. Glucose control in patients with diabetes does not have a significant effect on the NL lesions.^1-3 Corticosteroids (topical, intralesional, and systemic—depending on the severity) are considered first-line therapy.^1-3 Lifestyle modifications, such as smoking cessation and trauma avoidance, are recommended to promote healing; proper wound care is important when there is ulceration.^1,3 Other treatment options include oral pentoxifylline, topical retinoids or calcineurin inhibitors, and systemic immune system modulators (eg, tumor necrosis factor inhibitors and cyclosporine).

Since this patient did not respond to the topical betamethasone, she was started on oral pentoxifylline 400 mg tid. Unfortunately, she had to discontinue the medication because of gastrointestinal upset and was then started on doxycycline 100 mg orally bid. She was lost to follow-up.

‌

Photo courtesy of Cyrelle F. Finan, MD. Text courtesy of Harika Echuri, MD, Tulane University School of Medicine, New Orleans, LA, Cyrelle F. Finan, MD, Department of Dermatology, and Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

On April 12, 2022, the US Preventive Services Task Force (USPSTF) published a draft recommendation on screening for anxiety in children and adolescents. The recommendation states that clinicians should screen for anxiety in those ages 8 to 18 years. This is a “B” recommendation, which means there is moderate certainty that screening for anxiety in these individuals has a moderate net benefit. The USPSTF felt that the evidence was insufficient to recommend for or against screening at ages 7 years and younger.¹

Anxiety is common among young people in America. A survey conducted in 2018-2019 found that 7.8% of children and adolescents (ages 3 to 17 years) had a current anxiety disorder.² The isolation created by the COVID-19 pandemic has been associated with increased rates of clinically significant psychiatric symptoms; one study suggested that in the first year of the pandemic, 20% of young people experienced elevated anxiety symptoms.^3,4 Anxiety disorders in childhood and adolescence also are associated with an increased likelihood of a future anxiety disorder, or depression, in adulthood.

Therapy may improve outcomes. There is evidence that treatment of anxiety disorders can result in improved clinical outcomes. Treatment options include psychotherapy, pharmacotherapy, or a combination of both.⁵

However, studies showing benefit were conducted in young people whose anxiety was identified via signs or symptoms. The USPSTF could find no direct evidence that identifying anxiety in asymptomatic youth leads to better outcomes. The current draft recommendation is based on indirect evidence on the accuracy of the screening tools and the results of therapy in those who are symptomatic.

Speaking of screening tools ... There were 3 listed in the USPSTF evidence review: the Screen for Child Anxiety Related Disorders (SCARED), which assesses for generalized anxiety disorder (GAD) and any anxiety disorder⁶; the Patient Health Questionnaire-Adolescent, which screens for GAD and panic disorder⁷; and the Social Phobia Inventory.⁸ The SCARED and Social Phobia Inventory are the most widely used clinically.

The accuracy of the screening tests differed. For detection of GAD, sensitivity ranged from 50% to 88% and specificity from 63% to 98%; for social anxiety disorder, sensitivity ranged from 67% to 93% and specificity from 69% to 94%. False-positive results ranged from 17 to 361 per 1000 for GAD and from 104 to 254 per 1000 for social anxiety disorder.¹

The USPSTF emphasized that anxiety should not be diagnosed based on a screening test alone. A positive screen should prompt further assessment and confirmation.

An unexpected rating. Given the opportunity costs to administer a screening tool, the high false-positive rates, and the lack of evidence that screening results in improved outcomes among asymptomatic youth, it is curious that this topic did not result in an “I” recommendation. Many screening interventions for children and adolescents with similar evidence profiles—including screening for suicide risk, drug abuse, eating disorders, and alcohol abuse—have previously received an “I.”⁹

Keep in mind that this is currently a draft recommendation that is open for public comment. The final recommendation will be published in 4 to 12 months.

Since the papules were worrisome for vasculitis, 2 punch biopsies were performed on smaller, younger lesions on the hand and 1 was submitted for direct immunofluorescence. Findings revealed a leukocytoclastic vasculitis (LCV) with prominent immunoglobulin A (IgA) deposits around the vessel wall. The clinical and pathologic findings were consistent with a rare fibrosing LCV called erythema elevatum diutinum (EED). The practice of sampling nonblanching purpura or papules for both standard pathology (hematoxylin and eosin) and direct immunofluorescence can facilitate the diagnosis of unusual conditions that may occur only a few times in one’s career.

EED is rare, chronic, and may be associated with IgA gammopathy, IgA antineutrophil cytoplasmic antibodies, recent streptococcal or HIV infections, or myelodysplastic syndrome. A robust work-up to identify whether any of these factors are at work is critical.¹ Distinct from other vasculitides, EED forms granulation tissue that becomes reinjured.

This patient was found to have an IgA monoclonal gammopathy that was monitored by Hematology. After checking her glucose-6-phosphate dehydrogenase activity, she was treated with oral dapsone 25 mg/d. Dapsone was titrated up to 100 mg/d, which improved her symptoms considerably and the ulcerated papule was surgically revised and closed. EED can last for years and ultimately clear or can persist indefinitely.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Since the papules were worrisome for vasculitis, 2 punch biopsies were performed on smaller, younger lesions on the hand and 1 was submitted for direct immunofluorescence. Findings revealed a leukocytoclastic vasculitis (LCV) with prominent immunoglobulin A (IgA) deposits around the vessel wall. The clinical and pathologic findings were consistent with a rare fibrosing LCV called erythema elevatum diutinum (EED). The practice of sampling nonblanching purpura or papules for both standard pathology (hematoxylin and eosin) and direct immunofluorescence can facilitate the diagnosis of unusual conditions that may occur only a few times in one’s career.

EED is rare, chronic, and may be associated with IgA gammopathy, IgA antineutrophil cytoplasmic antibodies, recent streptococcal or HIV infections, or myelodysplastic syndrome. A robust work-up to identify whether any of these factors are at work is critical.¹ Distinct from other vasculitides, EED forms granulation tissue that becomes reinjured.

This patient was found to have an IgA monoclonal gammopathy that was monitored by Hematology. After checking her glucose-6-phosphate dehydrogenase activity, she was treated with oral dapsone 25 mg/d. Dapsone was titrated up to 100 mg/d, which improved her symptoms considerably and the ulcerated papule was surgically revised and closed. EED can last for years and ultimately clear or can persist indefinitely.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Since the papules were worrisome for vasculitis, 2 punch biopsies were performed on smaller, younger lesions on the hand and 1 was submitted for direct immunofluorescence. Findings revealed a leukocytoclastic vasculitis (LCV) with prominent immunoglobulin A (IgA) deposits around the vessel wall. The clinical and pathologic findings were consistent with a rare fibrosing LCV called erythema elevatum diutinum (EED). The practice of sampling nonblanching purpura or papules for both standard pathology (hematoxylin and eosin) and direct immunofluorescence can facilitate the diagnosis of unusual conditions that may occur only a few times in one’s career.

EED is rare, chronic, and may be associated with IgA gammopathy, IgA antineutrophil cytoplasmic antibodies, recent streptococcal or HIV infections, or myelodysplastic syndrome. A robust work-up to identify whether any of these factors are at work is critical.¹ Distinct from other vasculitides, EED forms granulation tissue that becomes reinjured.

This patient was found to have an IgA monoclonal gammopathy that was monitored by Hematology. After checking her glucose-6-phosphate dehydrogenase activity, she was treated with oral dapsone 25 mg/d. Dapsone was titrated up to 100 mg/d, which improved her symptoms considerably and the ulcerated papule was surgically revised and closed. EED can last for years and ultimately clear or can persist indefinitely.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Microscopic evaluation of a dermoscopy-guided skin scraping revealed that this was a case of scabies.

Classically, patients with scabies have many excoriated papules or plaques on their hands, genitals, and trunk with itching so intense that their sleep is interrupted. However, scabies can also be diagnosed in patients who complain of itching but also have very subtle skin findings, such as a small dry patch or fissure (as in this case). Such subtle findings can be easily mistaken for mild hand dermatitis.

In the elderly, itching without a significant rash can arise from many causes. A short list includes dry skin, medications, kidney disease, liver disease, and of course, various dermatologic conditions. Dermoscopy is a sensitive and specific tool for investigating itching and areas of suspected infestation with mites.¹ A mite appears as an oval on dermoscopy, but the most recognizable part is the head and front legs, which appear as a single gray triangle. The photo shows that the most erythematous area around a burrow (black arrows) is an excellent place to start when looking through the dermatoscope. In this case, an area of broken skin was connected to a haphazard tunnel that ultimately led to the mite (white arrows).

Scabies may be effectively treated with topical permethrin 5% applied over every inch of the body from the top of the neck to the tips of the toes.

This topical treatment is left on for at least 8 hours and reapplied a week later. Also, remember to take a careful history of close contacts so that others who are affected may receive treatment.

This patient was treated with permethrin, as was her adult son who lived at home with her and had similar itching. Permethrin comes in 60 g tubes, which is enough to treat 1 adult twice. After 6 weeks, all itching symptoms in the patient had cleared.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Microscopic evaluation of a dermoscopy-guided skin scraping revealed that this was a case of scabies.

Classically, patients with scabies have many excoriated papules or plaques on their hands, genitals, and trunk with itching so intense that their sleep is interrupted. However, scabies can also be diagnosed in patients who complain of itching but also have very subtle skin findings, such as a small dry patch or fissure (as in this case). Such subtle findings can be easily mistaken for mild hand dermatitis.

In the elderly, itching without a significant rash can arise from many causes. A short list includes dry skin, medications, kidney disease, liver disease, and of course, various dermatologic conditions. Dermoscopy is a sensitive and specific tool for investigating itching and areas of suspected infestation with mites.¹ A mite appears as an oval on dermoscopy, but the most recognizable part is the head and front legs, which appear as a single gray triangle. The photo shows that the most erythematous area around a burrow (black arrows) is an excellent place to start when looking through the dermatoscope. In this case, an area of broken skin was connected to a haphazard tunnel that ultimately led to the mite (white arrows).

Scabies may be effectively treated with topical permethrin 5% applied over every inch of the body from the top of the neck to the tips of the toes.

This topical treatment is left on for at least 8 hours and reapplied a week later. Also, remember to take a careful history of close contacts so that others who are affected may receive treatment.

This patient was treated with permethrin, as was her adult son who lived at home with her and had similar itching. Permethrin comes in 60 g tubes, which is enough to treat 1 adult twice. After 6 weeks, all itching symptoms in the patient had cleared.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Microscopic evaluation of a dermoscopy-guided skin scraping revealed that this was a case of scabies.

Classically, patients with scabies have many excoriated papules or plaques on their hands, genitals, and trunk with itching so intense that their sleep is interrupted. However, scabies can also be diagnosed in patients who complain of itching but also have very subtle skin findings, such as a small dry patch or fissure (as in this case). Such subtle findings can be easily mistaken for mild hand dermatitis.

In the elderly, itching without a significant rash can arise from many causes. A short list includes dry skin, medications, kidney disease, liver disease, and of course, various dermatologic conditions. Dermoscopy is a sensitive and specific tool for investigating itching and areas of suspected infestation with mites.¹ A mite appears as an oval on dermoscopy, but the most recognizable part is the head and front legs, which appear as a single gray triangle. The photo shows that the most erythematous area around a burrow (black arrows) is an excellent place to start when looking through the dermatoscope. In this case, an area of broken skin was connected to a haphazard tunnel that ultimately led to the mite (white arrows).

Scabies may be effectively treated with topical permethrin 5% applied over every inch of the body from the top of the neck to the tips of the toes.

This topical treatment is left on for at least 8 hours and reapplied a week later. Also, remember to take a careful history of close contacts so that others who are affected may receive treatment.

This patient was treated with permethrin, as was her adult son who lived at home with her and had similar itching. Permethrin comes in 60 g tubes, which is enough to treat 1 adult twice. After 6 weeks, all itching symptoms in the patient had cleared.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A 4-mm punch biopsy of the annular border confirmed a diagnosis of localized granuloma annulare (GA).

There is a long list of differential diagnoses for annular patches and plaques; it includes tinea corporis and important systemic diseases such as sarcoidosis and Lyme disease. Clinical features of GA include annular, minimally scaly patches to plaques with central clearing on extensor surfaces in children and adults. Sometimes GA is much more widespread. Often, the diagnosis can be made clinically, but a punch biopsy of the deep dermis will confirm the diagnosis by showing palisading or interstitial granulomatous inflammation, necrobiotic collagen, and often mucin.

GA is a common inflammatory disorder with an uncertain etiology. Localized GA affects children and adults and is often self limiting. It may, however, last for months or years before resolving. Disseminated disease is much more recalcitrant with few good treatment options if topical steroids or phototherapy fails. Treatment for localized disease is much more successful with topical or intralesional steroids.

Trauma can cause a localized plaque to resolve; a lesion may resolve soon after a biopsy is performed. Possible related conditions include diabetes, thyroid disease, hepatitis C, and hyperlipidemia; but there is no consensus on focused screening. Similarly, associations or nonassociations with malignancy in adults have been cited, but evidence is lacking.¹

In this case, the patient and his family were reassured that the diagnosis wasn’t serious. In a single visit, he received a series of 6 to 7 injections of 10 mg/mL triamcinolone which led to resolution of the lesion in 4 weeks.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A 4-mm punch biopsy of the annular border confirmed a diagnosis of localized granuloma annulare (GA).

There is a long list of differential diagnoses for annular patches and plaques; it includes tinea corporis and important systemic diseases such as sarcoidosis and Lyme disease. Clinical features of GA include annular, minimally scaly patches to plaques with central clearing on extensor surfaces in children and adults. Sometimes GA is much more widespread. Often, the diagnosis can be made clinically, but a punch biopsy of the deep dermis will confirm the diagnosis by showing palisading or interstitial granulomatous inflammation, necrobiotic collagen, and often mucin.

GA is a common inflammatory disorder with an uncertain etiology. Localized GA affects children and adults and is often self limiting. It may, however, last for months or years before resolving. Disseminated disease is much more recalcitrant with few good treatment options if topical steroids or phototherapy fails. Treatment for localized disease is much more successful with topical or intralesional steroids.

Trauma can cause a localized plaque to resolve; a lesion may resolve soon after a biopsy is performed. Possible related conditions include diabetes, thyroid disease, hepatitis C, and hyperlipidemia; but there is no consensus on focused screening. Similarly, associations or nonassociations with malignancy in adults have been cited, but evidence is lacking.¹

In this case, the patient and his family were reassured that the diagnosis wasn’t serious. In a single visit, he received a series of 6 to 7 injections of 10 mg/mL triamcinolone which led to resolution of the lesion in 4 weeks.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A 4-mm punch biopsy of the annular border confirmed a diagnosis of localized granuloma annulare (GA).

There is a long list of differential diagnoses for annular patches and plaques; it includes tinea corporis and important systemic diseases such as sarcoidosis and Lyme disease. Clinical features of GA include annular, minimally scaly patches to plaques with central clearing on extensor surfaces in children and adults. Sometimes GA is much more widespread. Often, the diagnosis can be made clinically, but a punch biopsy of the deep dermis will confirm the diagnosis by showing palisading or interstitial granulomatous inflammation, necrobiotic collagen, and often mucin.

GA is a common inflammatory disorder with an uncertain etiology. Localized GA affects children and adults and is often self limiting. It may, however, last for months or years before resolving. Disseminated disease is much more recalcitrant with few good treatment options if topical steroids or phototherapy fails. Treatment for localized disease is much more successful with topical or intralesional steroids.

Trauma can cause a localized plaque to resolve; a lesion may resolve soon after a biopsy is performed. Possible related conditions include diabetes, thyroid disease, hepatitis C, and hyperlipidemia; but there is no consensus on focused screening. Similarly, associations or nonassociations with malignancy in adults have been cited, but evidence is lacking.¹

In this case, the patient and his family were reassured that the diagnosis wasn’t serious. In a single visit, he received a series of 6 to 7 injections of 10 mg/mL triamcinolone which led to resolution of the lesion in 4 weeks.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

A 63-YEAR-OLD SOUTHEAST ASIAN WOMAN presented with early satiety, mild swelling of her lower extremities, and several months of progressive shortness of breath that had become severe (provoked by activities of daily living). She had a history of longstanding, rate-controlled atrial fibrillation on oral anticoagulation. She also had a history of mitral valve stenosis that was treated 30 years earlier with mechanical valve replacement. The patient had previously been treated out of state and prior records were not available.

Chest radiography (CXR) was performed as part of the initial work-up (FIGURE 1) and demonstrated a substantially enlarged cardiac silhouette spanning the entire width of the chest without significant pleural effusion or evidence of airspace disease. Suspecting a primary cardiac pathology in this patient, we explored clinical findings of heart failure with transthoracic echocardiography.

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

A transthoracic echocardiogram (FIGURE 2A) revealed cardiomegaly with massive right atrial enlargement; a color-flow Doppler (FIGURE 2B) revealed severe tricuspid regurgitation, reduced right ventricular systolic function, and preserved left ventricular systolic function. All of these findings pointed to the diagnosis of rheumatic heart disease (RHD), especially in the context of prior mitral valve stenosis.

RHD affects more than 33 million people annually and remains a significant problem globally.¹ It’s associated with a relatively poor prognosis, especially if heart failure is present (as it was in this case).^2,3 Although the mitral and aortic valves are most commonly affected, approximately 34% of patients will develop tricuspid regurgitation.⁴ Right-side cardiac manifestations of RHD may lead to clinical heart failure with chronic venous congestion and, ultimately, cirrhosis.

Suspect RHD when encountering a new murmur in a patient with prior history of acute rheumatic fever, especially if they are living in or are from a country where rheumatic disease is endemic (most of the developing world).

The diagnosis is confirmed when echocardiographic findings demonstrate characteristic pathologic valve changes (eg, thickening of the anterior mitral valve leaflet, especially the leaflet tips and subvalvular apparatus).

The differential for an enlarged cardiac silhouette

The differential diagnosis for an enlarged cardiac silhouette on CXR includes cardiomegaly (as in this case), pericardial effusion, or a thoracic mass (either mediastinal or pericardial). Imaging artifact from patient orientation may also yield the appearance of an enlarged cardiac silhouette. Distinguishing between these entities may be accomplished by incorporating the history with selection of more definitive imaging (eg, echocardiogram or computed tomography).

Continue to: Management depends on the severity and symptoms

Percutaneous or surgical intervention may be required with RHD, depending on the clinical scenario. If the patient also has atrial fibrillation, medical management includes oral anticoagulation (with a vitamin K antagonist). Additionally, secondary prophylaxis with long-term antibiotics (directed against recurrent group A Streptococcus infection) is recommended for RHD patients with mitral stenosis.⁵ If the patient in this case had engaged in more regular cardiology follow-up, the progression of her tricuspid regurgitation may have been mitigated by surgical intervention and aggressive medical management (although the progression of RHD can eclipse standard treatments).⁵

In this case, a liver biopsy was pursued for prognostication. Unfortunately, the biopsy demonstrated cirrhosis with perisinusoidal fibrosis suggesting an advanced, end-stage clinical state. This diagnosis precluded the patient’s eligibility for advanced therapies such as right ventricular assist device implantation or cardiac transplantation. Surgical intervention (repair or replacement) was also deemed likely to be futile due to right ventricular dilatation and systolic dysfunction in the context of antecedent left-side valve intervention.

The patient elected to pursue palliative care and died at home several months later. In the years since this case occurred, less invasive tricuspid valve interventions have been explored, offering promise of amelioration of such cases in the future.⁶

A 63-YEAR-OLD SOUTHEAST ASIAN WOMAN presented with early satiety, mild swelling of her lower extremities, and several months of progressive shortness of breath that had become severe (provoked by activities of daily living). She had a history of longstanding, rate-controlled atrial fibrillation on oral anticoagulation. She also had a history of mitral valve stenosis that was treated 30 years earlier with mechanical valve replacement. The patient had previously been treated out of state and prior records were not available.

Chest radiography (CXR) was performed as part of the initial work-up (FIGURE 1) and demonstrated a substantially enlarged cardiac silhouette spanning the entire width of the chest without significant pleural effusion or evidence of airspace disease. Suspecting a primary cardiac pathology in this patient, we explored clinical findings of heart failure with transthoracic echocardiography.

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

A transthoracic echocardiogram (FIGURE 2A) revealed cardiomegaly with massive right atrial enlargement; a color-flow Doppler (FIGURE 2B) revealed severe tricuspid regurgitation, reduced right ventricular systolic function, and preserved left ventricular systolic function. All of these findings pointed to the diagnosis of rheumatic heart disease (RHD), especially in the context of prior mitral valve stenosis.

RHD affects more than 33 million people annually and remains a significant problem globally.¹ It’s associated with a relatively poor prognosis, especially if heart failure is present (as it was in this case).^2,3 Although the mitral and aortic valves are most commonly affected, approximately 34% of patients will develop tricuspid regurgitation.⁴ Right-side cardiac manifestations of RHD may lead to clinical heart failure with chronic venous congestion and, ultimately, cirrhosis.

Suspect RHD when encountering a new murmur in a patient with prior history of acute rheumatic fever, especially if they are living in or are from a country where rheumatic disease is endemic (most of the developing world).

The diagnosis is confirmed when echocardiographic findings demonstrate characteristic pathologic valve changes (eg, thickening of the anterior mitral valve leaflet, especially the leaflet tips and subvalvular apparatus).

The differential for an enlarged cardiac silhouette

The differential diagnosis for an enlarged cardiac silhouette on CXR includes cardiomegaly (as in this case), pericardial effusion, or a thoracic mass (either mediastinal or pericardial). Imaging artifact from patient orientation may also yield the appearance of an enlarged cardiac silhouette. Distinguishing between these entities may be accomplished by incorporating the history with selection of more definitive imaging (eg, echocardiogram or computed tomography).

Continue to: Management depends on the severity and symptoms

Percutaneous or surgical intervention may be required with RHD, depending on the clinical scenario. If the patient also has atrial fibrillation, medical management includes oral anticoagulation (with a vitamin K antagonist). Additionally, secondary prophylaxis with long-term antibiotics (directed against recurrent group A Streptococcus infection) is recommended for RHD patients with mitral stenosis.⁵ If the patient in this case had engaged in more regular cardiology follow-up, the progression of her tricuspid regurgitation may have been mitigated by surgical intervention and aggressive medical management (although the progression of RHD can eclipse standard treatments).⁵

In this case, a liver biopsy was pursued for prognostication. Unfortunately, the biopsy demonstrated cirrhosis with perisinusoidal fibrosis suggesting an advanced, end-stage clinical state. This diagnosis precluded the patient’s eligibility for advanced therapies such as right ventricular assist device implantation or cardiac transplantation. Surgical intervention (repair or replacement) was also deemed likely to be futile due to right ventricular dilatation and systolic dysfunction in the context of antecedent left-side valve intervention.

The patient elected to pursue palliative care and died at home several months later. In the years since this case occurred, less invasive tricuspid valve interventions have been explored, offering promise of amelioration of such cases in the future.⁶

A 63-YEAR-OLD SOUTHEAST ASIAN WOMAN presented with early satiety, mild swelling of her lower extremities, and several months of progressive shortness of breath that had become severe (provoked by activities of daily living). She had a history of longstanding, rate-controlled atrial fibrillation on oral anticoagulation. She also had a history of mitral valve stenosis that was treated 30 years earlier with mechanical valve replacement. The patient had previously been treated out of state and prior records were not available.

Chest radiography (CXR) was performed as part of the initial work-up (FIGURE 1) and demonstrated a substantially enlarged cardiac silhouette spanning the entire width of the chest without significant pleural effusion or evidence of airspace disease. Suspecting a primary cardiac pathology in this patient, we explored clinical findings of heart failure with transthoracic echocardiography.

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

A transthoracic echocardiogram (FIGURE 2A) revealed cardiomegaly with massive right atrial enlargement; a color-flow Doppler (FIGURE 2B) revealed severe tricuspid regurgitation, reduced right ventricular systolic function, and preserved left ventricular systolic function. All of these findings pointed to the diagnosis of rheumatic heart disease (RHD), especially in the context of prior mitral valve stenosis.

RHD affects more than 33 million people annually and remains a significant problem globally.¹ It’s associated with a relatively poor prognosis, especially if heart failure is present (as it was in this case).^2,3 Although the mitral and aortic valves are most commonly affected, approximately 34% of patients will develop tricuspid regurgitation.⁴ Right-side cardiac manifestations of RHD may lead to clinical heart failure with chronic venous congestion and, ultimately, cirrhosis.

Suspect RHD when encountering a new murmur in a patient with prior history of acute rheumatic fever, especially if they are living in or are from a country where rheumatic disease is endemic (most of the developing world).

The diagnosis is confirmed when echocardiographic findings demonstrate characteristic pathologic valve changes (eg, thickening of the anterior mitral valve leaflet, especially the leaflet tips and subvalvular apparatus).

The differential for an enlarged cardiac silhouette

The differential diagnosis for an enlarged cardiac silhouette on CXR includes cardiomegaly (as in this case), pericardial effusion, or a thoracic mass (either mediastinal or pericardial). Imaging artifact from patient orientation may also yield the appearance of an enlarged cardiac silhouette. Distinguishing between these entities may be accomplished by incorporating the history with selection of more definitive imaging (eg, echocardiogram or computed tomography).

Continue to: Management depends on the severity and symptoms

Percutaneous or surgical intervention may be required with RHD, depending on the clinical scenario. If the patient also has atrial fibrillation, medical management includes oral anticoagulation (with a vitamin K antagonist). Additionally, secondary prophylaxis with long-term antibiotics (directed against recurrent group A Streptococcus infection) is recommended for RHD patients with mitral stenosis.⁵ If the patient in this case had engaged in more regular cardiology follow-up, the progression of her tricuspid regurgitation may have been mitigated by surgical intervention and aggressive medical management (although the progression of RHD can eclipse standard treatments).⁵

In this case, a liver biopsy was pursued for prognostication. Unfortunately, the biopsy demonstrated cirrhosis with perisinusoidal fibrosis suggesting an advanced, end-stage clinical state. This diagnosis precluded the patient’s eligibility for advanced therapies such as right ventricular assist device implantation or cardiac transplantation. Surgical intervention (repair or replacement) was also deemed likely to be futile due to right ventricular dilatation and systolic dysfunction in the context of antecedent left-side valve intervention.

The patient elected to pursue palliative care and died at home several months later. In the years since this case occurred, less invasive tricuspid valve interventions have been explored, offering promise of amelioration of such cases in the future.⁶