Case Reports

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare nodular unencapsulated mass that is characterized by benign anomalous vascular hyperplasia of epithelioidlike endothelial cells attached to dilated blood vessels. The mass is surrounded by lymphocytes and eosinophils that can present clinically as papules, plaques, or nodules.¹ The etiology of ALHE is unknown; it is hypothesized that it is a vascular neoplasm or a lymphoproliferative disorder.

Coccidioidomycosis (CM) is a prevalent deep fungal infection endemic to the southwestern United States caused by Coccidioides immitis and Coccidioides posadasii. Infection can occur from direct inoculation through abrasions or direct trauma but usually occurs through the inhalation of spores and can result in a reactive rash (eg, Sweet syndrome, erythema nodosum, interstitial granulomatous dermatitis).² Coccidioidomycosis also can result in respiratory pneumonia and dissemination from pulmonary infection of the skin. As such, it is important to distinguish CM and its immunologically mediated eruptions for accurate diagnosis and treatment.

We report a novel case of ALHE as a reactive dermatologic presentation in a patient with CM.

Case Report

A 72-year-old woman presented to the dermatology clinic with itchy papules and plaques on the arms and legs of 17 years’ duration. Her medical history included coronary artery disease and hypercholesterolemia as well as a remote history of cutaneous marginal zone B-cell lymphoma of the nose, which was confirmed by histology and treated more than 10 years prior and has remained in remission for 6 years. Her current medications included aspirin, atorvastatin, lisinopril, and metoprolol succinate.

Our patient first presented to our dermatology clinic for itchy nodules and papules on the legs and arms. The patient previously had been seen by another dermatologist 2 months prior for the same condition. At that time, biopsies of the lesions were reported as prurigo nodules. Physical examination at the current presentation revealed round, pink to flesh-colored, raised papules and plaques scattered on the arms and legs (Figure 1). The differential diagnosis included lymphomatoid papulosis, cutaneous B-cell lymphoma, pseudolymphoma, cutaneous CM, and papular mucinosis.

Four-mm punch biopsies of the right proximal pretibial region and left knee region were taken and sent for histologic analysis, direct immunofluorescence testing, and tissue culture. Testing for atypical mycobacteria and deep fungal infection was negative; bacterial cultures and sensitivity testing were negative. Direct immunofluorescence testing was negative. Microscopic examination of material from the right proximal pretibial region showed widely dilated, variously shaped, large blood vessels in a multinodular pattern; the vessels also were surrounded by an inflammatory cell infiltrate containing eosinophils. Histologic findings were consistent with ALHE.

Subsequent biopsies were completed 2 weeks and 1 month from the initial presentation. Both histology reports—from 2 different histopathology laboratories—were consistent with ALHE (Figure 2). Additional work-up during the patient’s initial visit to our clinic for the rash included CM serologic testing, which demonstrated IgM and IgG antibodies. Subsequently, chest radiography revealed a 2.2×2.3-cm mass in the right lower lobe of the lung. Follow-up computed tomography 1 month later confirmed the nodule in the same area to be 2.3×2.1×1.8 cm.

The patient was referred to pulmonology and was treated for pulmonary CM with oral fluconazole 200 mg twice daily for 4 months. Initial treatment also included clobetasol cream 0.05% applied twice daily, which did not produce marked improvement in pruritus. Narrowband UVB phototherapy was attempted, but the patient could not complete the course because of travel time to the office; however, the patient’s ALHE improved considerably with the fluconazole treatment for pulmonary CM.

Oral doxycycline 100 mg twice daily was added to the fluconazole 2 months after her initial visit to our office, which kept the ALHE at bay and helped with the pruritus (Figure 3). Pulmonology and primary care comanaged the pulmonary CM with oral fluconazole 200 mg twice daily. Repeat serologic testing for CM was negative for IgG and IgM after 14 months since the initial visit to the office.

Comment

Pulmonary CM infection has varying dermatologic manifestations. A PubMed search of articles indexed for MEDLINE using the terms ALHE and coccidioidomycosis yielded no case reports; in fact, there have been few reported cases of ALHE at all. Notable conditions associated with ALHE include membranous nephropathy and arteriovenous malformations treated with corticosteroids and surgery, respectively.^3,4 Our case is a rare presentation of CM infection manifesting with ALHE. Following treatment and remission for our patient’s CM infection, the ALHE lesion decreased in size.

Standard treatment of uncomplicated CM involves azole antifungals, typically oral fluconazole or itraconazole 400 to 600 mg/d. In more severe cases (eg, immunocompromised patients) amphotericin B can be used.⁵ Our patient was treated with oral fluconazole 200 mg twice daily for 4 months.

In the literature, treatment via surgical excision, steroid injection, pulsed-dye laser therapy, and radiotherapy also has been described.^6-8 Antibiotics including clindamycin, doxycycline, and amoxicillin-clavulanate also have been shown to be effective.⁹

In our patient, ALHE improved when oral doxycycline 100 mg twice daily was added to the oral fluconazole. In fact, after 4 months of treatment, the CM infection and ALHE lesions both improved to a point at which the lesions were not visible. When those lesions recurred 15 months later, they responded with another course of doxycycline and fluconazole.

Upon recurrence, the patient was asked to have her care transferred to her pulmonologist, who then managed the fluconazole regimen. During the pulmonologist’s workup, no peripheral eosinophilia was found. This is important because eosinophils can be a marker for CM infection; in this case, however, the ALHE lesion was a reactive process to the infection. Classically known to play a reactive role in fungal infection, these white blood cells demonstrate reactivity to the environmental fungus Alternaria alternata by contact-dependent killing, utilizing β2 integrins and CD11b to recognize and adhere to β-glucan. Eosinophils react through contact-dependent killing, releasing cytotoxic granule proteins and proinflammatory mediators, and have been documented to occur in CM and Paracoccidioides brasiliensis infection, in which they deposit major basic protein on the organism.¹⁰ Most pertinent to our case with ALHE and CM is the ability of eosinophils to communicate with other immune cells. Eosinophils play a role in the active inflammation of CM through cytokine signaling, which may propagate formation of ALHE.

The function of eosinophils in ALHE is poorly understood; it is unclear whether they act as a primary driver of pathogenesis or are simply indicators of secondary infiltration or infection. Our review of the current literature suggests that eosinophils are unnecessary for progression of ALHE but might be involved at its onset. As reported, even monoclonal antibody therapy (eg, mepolizumab and benralizumab) that effectively depletes eosinophil levels by negating IL-5 signaling do not slow progression of ALHE.¹¹ Symptomatic changes are modest at best (ie, simply softening the ALHE nodules).

Our patient had no peripheral eosinophilia, suggesting that the onset of ALHE might not be caused by eosinophilia but a different inflammatory process—in this patient, by CM. Because peripheral eosinophilia was not seen in our patient, the presence of eosinophils in the ALHE lesion likely is unnecessary for its onset or progression but is a secondary process that exacerbates the lesion. The pathogenesis is unknown but could be directed toward lymphocytes and plasma cells, with eosinophils as part of the dynamic process.¹¹

Conclusion

Because reports of an association between CM and ALHE are limited, our case is distinguished by a unique clinical presentation of ALHE. When a patient is given a diagnosis of ALHE, it therefore is important to consider exposure to CM as a cause, especially in patients who reside in or travel to a region where CM is endemic.

Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.¹ Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.

Case Presentation

A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.

Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).² A punch biopsy was confirmatory (Figure 2A).³ The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.

Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.

Discussion

DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.³ Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).⁴ Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.³ The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.⁵ Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.⁵ Overall mortality rate may be as high as 10% most commonly due to acute liver failure.⁵ Biopsy may be helpful in the diagnosis but is not always specific.⁵ Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).⁵ 

The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.² Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.⁶ Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.² Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.⁷ Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.⁸

Treatment

For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.¹⁰ Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.¹¹

A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.¹² However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.¹²

The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.¹³ Patients may not regain full adrenal function for 12 to 18 months.¹⁴ Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.¹⁰

Conclusions

DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.¹² Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.

Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.¹ Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.

Case Presentation

A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.

Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).² A punch biopsy was confirmatory (Figure 2A).³ The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.

Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.

Discussion

DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.³ Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).⁴ Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.³ The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.⁵ Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.⁵ Overall mortality rate may be as high as 10% most commonly due to acute liver failure.⁵ Biopsy may be helpful in the diagnosis but is not always specific.⁵ Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).⁵ 

The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.² Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.⁶ Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.² Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.⁷ Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.⁸

Treatment

For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.¹⁰ Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.¹¹

A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.¹² However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.¹²

The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.¹³ Patients may not regain full adrenal function for 12 to 18 months.¹⁴ Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.¹⁰

Conclusions

DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.¹² Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.

Drug-induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, is a potentially fatal drug-induced hypersensitivity reaction that is characterized by a cutaneous eruption, multiorgan involvement, viral reactivation, and hematologic abnormalities. As the nomenclature of this disease advances, consensus groups have adopted DIHS/DRESS to underscore that both names refer to the same clinical phenomenon.¹ Autoimmune sequelae have been reported after DIHS/DRESS that include vitiligo, thyroid disease, and type 1 diabetes mellitus (T1DM). We present a case of lamotrigine-associated DIHS/DRESS complicated by an unusually prolonged course requiring oral corticosteroids and narrow-band ultraviolet B (UVB) treatment and with development of extensive alopecia areata and autoimmune thyroiditis.

Case Presentation

A 35-year-old female Filipino patient was prescribed lamotrigine 25 mg daily for bipolar II disorder and titrated to 100 mg twice daily after 1 month. One week after the increase, the patient developed a diffuse morbilliform rash covering their entire body along with facial swelling and generalized pruritus. Lamotrigine was discontinued after lamotrigine allergy was diagnosed. The patient improved following a 9-day oral prednisone taper and was placed on oxcarbazepine 300 mg twice daily to manage their bipolar disorder. One day after completing the taper, the patient presented again with worsening rash, swelling, and cervical lymphadenopathy. Oxcarbazepine was discontinued, and oral prednisone 60 mg was reinstituted for an additional 11 days.

Dermatology evaluated the patient 10 days after completion of the second oral steroid taper (1 month after cessation of lamotrigine). The patient had erythroderma along with malaise, fevers, chills, and fatigue and a diffuse burning sensation (Figure 1). The patient was hypotensive and tachycardic with significant eosinophilia (42%; reference range, 0%-8%), transaminitis, and renal insufficiency. The patient was diagnosed with DIHS/DRESS based on their clinical presentation and calculated RegiSCAR score of 7 (score > 5 corresponds with definite DIHS/DRESS and points were given for fever, enlarged lymph nodes, eosinophilia ≥ 20%, skin rash extending > 50% of their body, edema and scaling, and 2 organs involved).² A punch biopsy was confirmatory (Figure 2A).³ The patient was started on prednisone 80 mg once daily along with topical fluocinonide 0.05% ointment. However, the patient’s clinical status deteriorated, requiring hospital admission for heart failure evaluation. The echocardiogram revealed hyperdynamic circulation but was otherwise unremarkable.

Four months after DIHS/DRESS resolution and cessation of steroids, the patient noted significant patches of smooth alopecia on their posterior scalp and was diagnosed with alopecia areata. Treatment with intralesional triamcinolone over 2 months resulted in regrowth of hair (Figure 3). A month later, the patient reported increasing fatigue and anorexia. The patient was evaluated once more for AI, this time with low morning cortisol and low adrenocorticotrophic hormone (ACTH) levels—consistent with AI secondary to prolonged glucocorticoid therapy. The patient also was concomitantly evaluated for hypothyroidism with significantly elevated thyroperoxidase antibodies—confirming the diagnosis of Hashimoto thyroiditis.

Discussion

DIHS/DRESS syndrome is a rare, but potentially life-threatening hypersensitivity to a medication, often beginning 2 to 6 weeks after exposure to the causative agent. The incidence of DIHS/DRESS in the general population is about 2 per 100,000.³ Our patient presented with DIHS/DRESS 33 days after starting lamotrigine, which corresponds with the published mean onset of anticonvulsant-induced DIHS/DRESS (29.7-33.3 days).⁴ Recent evidence shows that time from drug exposure to DIHS/DRESS symptoms may vary by drug class, with antibiotics implicated as precipitating DIHS/DRESS in < 15 days.³ The diagnosis of DIHS/DRESS may be complicated for many reasons. The accompanying rash may be morbilliform, erythroderma, or exfoliative dermatitis with multiple anatomic regions affected.⁵ Systemic involvement with various internal organs occurs in > 90% of cases, with the liver and kidney involved most frequently.⁵ Overall mortality rate may be as high as 10% most commonly due to acute liver failure.⁵ Biopsy may be helpful in the diagnosis but is not always specific.⁵ Diagnostic criteria include RegiSCAR and J-SCAR scores; our patient met criteria for both (Table).⁵ 

The pathogenesis of DIHS/DRESS remains unclear. Proposed mechanisms include genetic predisposition with human leukocyte antigen (HLA) haplotypes, autoimmune with a delayed cell-mediated immune response associated with herpesviruses, and abnormal enzymatic pathways that metabolize medications.² Although no HLA has been identified between lamotrigine and DIHS, HLA-A*02:07 and HLA-B*15:02 have been associated with lamotrigine-induced cutaneous drug reactions in patients of Thai ancestry.⁶ Immunosuppression also is a risk factor, especially when accompanied by a primary or reactivated HHV-6 infection, as seen in our patient.² Additionally, HHV-6 infection may be a common link between DIHS/DRESS and autoimmune thyroiditis but is believed to involve elevated levels of interferon-γ-induced protein-10 (IP-10) that may lead to excessive recruitment of cytotoxic T cells into target tissues.⁷ Elevated levels of IP-10 are seen in many autoimmune conditions, such as autoimmune thyroiditis, Sjögren syndrome, and Graves disease.⁸

Treatment

For management, early recognition and discontinuation of the offending agent is paramount. Systemic corticosteroids are the accepted treatment standard. Symptoms of DIHS/DRESS usually resolve between 3 and 18 weeks, with the mean resolution time at 7 weeks.¹⁰ Our patient developed a prolonged course with persistent eosinophilia for 20 weeks and cutaneous symptoms for 32 weeks—requiring 40 weeks of oral prednisone. The most significant clinical improvement occurred during the 8-week period low-dose nbUVB was used (Figure 4). There also are reports outlining the successful use of intravenous immunoglobulin, cyclosporine, cyclophosphamide, rituximab, or plasma exchange in cases refractory to oral corticosteroids.¹¹

A recent retrospective case control study showed that treatment of DIHS/DRESS with cyclosporine in patients who had a contraindication to steroids resulted in faster resolution of symptoms, shorter treatment durations, and shorter hospitalizations than did those treated with corticosteroids.¹² However, the data are limited by a significantly smaller number of patients treated with cyclosporine than steroids and the cyclosporine treatment group having milder cases of DIHS/DRESS.¹²

The risk of AI is increased for patients who have taken > 20 mg of prednisone daily ≥ 3 weeks, an evening dose ≥ 5 mg for a few weeks, or have a Cushingoid appearance.¹³ Patients may not regain full adrenal function for 12 to 18 months.¹⁴ Our patient had a normal basal serum cortisol level 2 weeks after prednisone cessation and then presented 5 months later with AI. While the reason for this period of normality is unclear, it may partly be due to the variable length of hypothalamic-pituitary-adrenal axis recovery time. Thus, ACTH stimulation tests in addition to serum cortisol may be done in patients with suspected AI for higher diagnostic certainty.¹⁰

Conclusions

DIHS/DRESS is a severe cutaneous adverse reaction that may require a prolonged treatment course until symptom resolution (40 weeks of oral prednisone in our patient). Oral corticosteroids are the mainstay of treatment, but long-term use is associated with significant adverse effects, such as AI in our patient. Alternative therapies, such as cyclosporine, look promising, but further studies are needed to determine safety profile and efficacy.¹² Additionally, patients with DIHS/DRESS should be educated and followed for potential autoimmune sequelae; in our patient alopecia areata and autoimmune thyroiditis were late sequelae, occurring 14 and 15 months, respectively, after onset of DIHS/DRESS.

Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

THE CASE

A 27-year-old man with no past medical history presented to his primary care physician (PCP) for a routine physical. He reported experiencing muscle weakness and fatigue for the previous 1 to 2 months. Two blood pressure measurements were recorded: 138/80 mm Hg and 142/95 mm Hg. The patient was given a diagnosis of hypertension and started on ­triamterene/hydrochlorothiazide. Labwork was ordered, including a complete metabolic panel, lipid panel, urinalysis, thyroid-stimulating hormone (TSH) plus thyroxine (T4), HIV antibodies, and a complete blood count.

The samples were drawn 1 week later, and the results were notable for low-normal TSH with a T4 of 0.8 ng/dL (normal range, 0.9-2.3 ng/dL); sodium, 151 mmol/L (normal range, 136-145 mmol/L); potassium, 3.4 mmol/L (normal range, 3.6-5.2 mmol/L); and white blood cell count, 13.8 x 10³/mcL. The electrolyte abnormalities were attributed to the triamterene/hydrochlorothiazide, which was stopped. One week later, repeat labs showed a persistent potassium level of 3.0 mmol/L; sodium, 141 mmol/L; and glucose, 310 mg/dL. Follow-up A1C was measured at 7.4%.

At the next appointment (2 weeks after initial evaluation), the patient received a diagnosis of type 2 diabetes in addition to new-onset essential hypertension. He expressed surprise at his diagnoses, as he said he primarily ate a balanced diet with plenty of vegetables and lots of healthy home-cooked meals. His body mass index (BMI) was in normal range, and he said he exercised regularly.

The patient was started on metformin 500 mg/d and referred to Endocrinology. After seeing the endocrinologist, who agreed with metformin for initial management, the patient contacted his PCP with concerns about worsening “muscle wasting.” Based on these ongoing symptoms, the patient was advised to go to the emergency department (ED).

In the ED, the patient reported muscle aches and weakness, weight gain, dyspnea on exertion, and polyuria. He also said that his face had widened with his weight gain, and his weakness was greatest in his thighs compared to his distal lower extremities. Labs drawn in the ED indicated hyperglycemia (glucose, 334 mg/dL) and severe hypokalemia (potassium, 2.2 mmol/L).

THE DIAGNOSIS

The patient was admitted in the afternoon for further evaluation, and a random serum cortisol measurement was ordered. The results showed an elevated cortisol level (55.2 mcg/dL; normal range, 3-20 mcg/dL). This was followed by a profoundly positive low-dose dexamethasone suppression test with a morning cortisol level of 75.9 mcg/dL (normal range, < 1.8 mcg/dL). With these findings, the diagnosis of Cushing syndrome was made and the focus of the evaluation shifted to localization.

An adrenocorticotropic hormone (ACTH) measurement was ordered, as well as magnetic resonance imaging (MRI) of the pituitary gland and of the abdomen to assess the adrenal glands. Both MRIs were negative, prompting a high-dose 8-mg dexamethasone suppression test to be performed. The patient’s morning cortisol level remained elevated (69.9 mcg/dL), confirming the diagnosis of Cushing syndrome.

Continue to: Based on the results...

Based on the results of the dexamethasone suppression test, a pituitary adenoma was unlikely (as they are often suppressed to < 5 mcg/dL with this test). The patient’s morning ACTH results came back as elevated (356.6 pg/mL; normal range, 10-60 pg/mL), suggesting inappropriate ACTH secretion, which most often has an ectopic source. However, a nuclear medicine octreotide scan and multiple computed tomography scans failed to locate such a source.

The patient eventually underwent bilateral petrosal venous sinus sampling to definitively rule out a pituitary source. Lastly, he underwent nuclear medicine positron emission tomography, which identified a nodular opacity in the anterior left lung apex, demonstrating moderate radiotracer activity (FIGURE 1).

THE DISCUSSION

Cushing syndrome is rarely encountered—it is estimated to affect 2% of patients with uncontrolled diabetes¹ and 1% of those with uncontrolled hypertension²—and requires a high level of clinical suspicion. This case highlights the importance of considering secondary causes of diabetes in patients who present atypically. This patient presented with symptoms consistent with Cushing syndrome that went unrecognized initially; these included high blood pressure, rounded face, weak muscles, hypokalemia, and intermittent hypernatremia in addition to new-onset hyperglycemia.^2-5 Despite the atypical findings, evaluation for diabetes and potential secondary causes was neglected until an ED evaluation 1 month after initial presentation. The work-up for possible Cushing syndrome was completed in the hospital but could easily have been conducted in the outpatient setting.

Making the diagnosis. When Cushing syndrome is suspected, consider consultation with Endocrinology. It is important to exclude exogenous glucocorticoid exposure through a thorough review of the patient’s medications.² The Endocrine Society² recommends that one of the following tests be performed:

• 24-hour urine free cortisol (≥ 2 tests)
• Overnight 1-mg dexamethasone suppression test
• Late-night salivary cortisol test.

Results within normal range make Cushing syndrome an unlikely diagnosis; however, for patients with suggestive clinical features, further work-up may be warranted.

Continue to: Any abnormal result...

Any abnormal result is an indication to exclude a physiologic cause of hypercortisolism by repeating at least 1 of the previous studies. As with the initial testing, normal results may rule out Cushing syndrome, while abnormal results would be confirmatory. (Conflicting results require additional evaluation.)

Morbidity and mortality. Finding the etiology of Cushing syndrome can present a challenge but is also rewarding due to the reversible nature of most of the abnormalities. That said, Cushing syndrome can have a significant impact on morbidity and mortality.

Morbidity. The case patient developed compression fractures throughout his thoracic and lumbar spine, with a loss of 4 inches in height, attributed to the delay in curative treatment (FIGURE 2); these were identified about 2 months after his initial presentation to a health care facility. In addition to bone mineral density, cognitive function and quality of life can be impacted by untreated hypercortisolism and Cushing syndrome.²

Mortality. In the earliest studies^6,7 (from the 1930s-1950s), the average survival rate was about 4.6 years and the 5-year survival was just 50%—and yet, outcomes data from modern treatment modalities are scant. While there is limited data on outcomes in untreated disease, the Endocrine Society states that treatment of moderate-to-severe cases “clearly reduces mortality and morbidity” while early identification and treatment of mild cases “would reduce the risk of residual morbidity.”²

Our patient underwent video-assisted thoracoscopic surgery, during which a nodule in the anterior lingula was removed. In addition, lymph node dissection was performed. Two lymph nodes were positive for atypical well-differentiated carcinoid tumor. After surgical removal, the patient’s cortisol levels normalized and his diabetes resolved.

THE TAKEAWAY

In primary care, the frequency at which we evaluate and diagnose type 2 diabetes without secondary cause can lead to cognitive biases, such as anchoring bias, that impact patient care. In this case, the atypical secondary nature of the diabetes was missed at 3 outpatient appointments prior to presentation at the hospital ED. In an active patient who has a normal BMI and a healthy diet—but systemic symptoms—it is critical to consider secondary causes of diabetes, such as Cushing syndrome.

CORRESPONDENCE
Anna Murley Squibb, MD, 2145 North Fairfield Road, Suite 100, Beavercreek, OH 45385; [email protected]

THE CASE

A 27-year-old man with no past medical history presented to his primary care physician (PCP) for a routine physical. He reported experiencing muscle weakness and fatigue for the previous 1 to 2 months. Two blood pressure measurements were recorded: 138/80 mm Hg and 142/95 mm Hg. The patient was given a diagnosis of hypertension and started on ­triamterene/hydrochlorothiazide. Labwork was ordered, including a complete metabolic panel, lipid panel, urinalysis, thyroid-stimulating hormone (TSH) plus thyroxine (T4), HIV antibodies, and a complete blood count.

The samples were drawn 1 week later, and the results were notable for low-normal TSH with a T4 of 0.8 ng/dL (normal range, 0.9-2.3 ng/dL); sodium, 151 mmol/L (normal range, 136-145 mmol/L); potassium, 3.4 mmol/L (normal range, 3.6-5.2 mmol/L); and white blood cell count, 13.8 x 10³/mcL. The electrolyte abnormalities were attributed to the triamterene/hydrochlorothiazide, which was stopped. One week later, repeat labs showed a persistent potassium level of 3.0 mmol/L; sodium, 141 mmol/L; and glucose, 310 mg/dL. Follow-up A1C was measured at 7.4%.

At the next appointment (2 weeks after initial evaluation), the patient received a diagnosis of type 2 diabetes in addition to new-onset essential hypertension. He expressed surprise at his diagnoses, as he said he primarily ate a balanced diet with plenty of vegetables and lots of healthy home-cooked meals. His body mass index (BMI) was in normal range, and he said he exercised regularly.

The patient was started on metformin 500 mg/d and referred to Endocrinology. After seeing the endocrinologist, who agreed with metformin for initial management, the patient contacted his PCP with concerns about worsening “muscle wasting.” Based on these ongoing symptoms, the patient was advised to go to the emergency department (ED).

In the ED, the patient reported muscle aches and weakness, weight gain, dyspnea on exertion, and polyuria. He also said that his face had widened with his weight gain, and his weakness was greatest in his thighs compared to his distal lower extremities. Labs drawn in the ED indicated hyperglycemia (glucose, 334 mg/dL) and severe hypokalemia (potassium, 2.2 mmol/L).

THE DIAGNOSIS

The patient was admitted in the afternoon for further evaluation, and a random serum cortisol measurement was ordered. The results showed an elevated cortisol level (55.2 mcg/dL; normal range, 3-20 mcg/dL). This was followed by a profoundly positive low-dose dexamethasone suppression test with a morning cortisol level of 75.9 mcg/dL (normal range, < 1.8 mcg/dL). With these findings, the diagnosis of Cushing syndrome was made and the focus of the evaluation shifted to localization.

An adrenocorticotropic hormone (ACTH) measurement was ordered, as well as magnetic resonance imaging (MRI) of the pituitary gland and of the abdomen to assess the adrenal glands. Both MRIs were negative, prompting a high-dose 8-mg dexamethasone suppression test to be performed. The patient’s morning cortisol level remained elevated (69.9 mcg/dL), confirming the diagnosis of Cushing syndrome.

Continue to: Based on the results...

Based on the results of the dexamethasone suppression test, a pituitary adenoma was unlikely (as they are often suppressed to < 5 mcg/dL with this test). The patient’s morning ACTH results came back as elevated (356.6 pg/mL; normal range, 10-60 pg/mL), suggesting inappropriate ACTH secretion, which most often has an ectopic source. However, a nuclear medicine octreotide scan and multiple computed tomography scans failed to locate such a source.

The patient eventually underwent bilateral petrosal venous sinus sampling to definitively rule out a pituitary source. Lastly, he underwent nuclear medicine positron emission tomography, which identified a nodular opacity in the anterior left lung apex, demonstrating moderate radiotracer activity (FIGURE 1).

THE DISCUSSION

Cushing syndrome is rarely encountered—it is estimated to affect 2% of patients with uncontrolled diabetes¹ and 1% of those with uncontrolled hypertension²—and requires a high level of clinical suspicion. This case highlights the importance of considering secondary causes of diabetes in patients who present atypically. This patient presented with symptoms consistent with Cushing syndrome that went unrecognized initially; these included high blood pressure, rounded face, weak muscles, hypokalemia, and intermittent hypernatremia in addition to new-onset hyperglycemia.^2-5 Despite the atypical findings, evaluation for diabetes and potential secondary causes was neglected until an ED evaluation 1 month after initial presentation. The work-up for possible Cushing syndrome was completed in the hospital but could easily have been conducted in the outpatient setting.

Making the diagnosis. When Cushing syndrome is suspected, consider consultation with Endocrinology. It is important to exclude exogenous glucocorticoid exposure through a thorough review of the patient’s medications.² The Endocrine Society² recommends that one of the following tests be performed:

• 24-hour urine free cortisol (≥ 2 tests)
• Overnight 1-mg dexamethasone suppression test
• Late-night salivary cortisol test.

Results within normal range make Cushing syndrome an unlikely diagnosis; however, for patients with suggestive clinical features, further work-up may be warranted.

Continue to: Any abnormal result...

Any abnormal result is an indication to exclude a physiologic cause of hypercortisolism by repeating at least 1 of the previous studies. As with the initial testing, normal results may rule out Cushing syndrome, while abnormal results would be confirmatory. (Conflicting results require additional evaluation.)

Morbidity and mortality. Finding the etiology of Cushing syndrome can present a challenge but is also rewarding due to the reversible nature of most of the abnormalities. That said, Cushing syndrome can have a significant impact on morbidity and mortality.

Morbidity. The case patient developed compression fractures throughout his thoracic and lumbar spine, with a loss of 4 inches in height, attributed to the delay in curative treatment (FIGURE 2); these were identified about 2 months after his initial presentation to a health care facility. In addition to bone mineral density, cognitive function and quality of life can be impacted by untreated hypercortisolism and Cushing syndrome.²

Mortality. In the earliest studies^6,7 (from the 1930s-1950s), the average survival rate was about 4.6 years and the 5-year survival was just 50%—and yet, outcomes data from modern treatment modalities are scant. While there is limited data on outcomes in untreated disease, the Endocrine Society states that treatment of moderate-to-severe cases “clearly reduces mortality and morbidity” while early identification and treatment of mild cases “would reduce the risk of residual morbidity.”²

Our patient underwent video-assisted thoracoscopic surgery, during which a nodule in the anterior lingula was removed. In addition, lymph node dissection was performed. Two lymph nodes were positive for atypical well-differentiated carcinoid tumor. After surgical removal, the patient’s cortisol levels normalized and his diabetes resolved.

THE TAKEAWAY

In primary care, the frequency at which we evaluate and diagnose type 2 diabetes without secondary cause can lead to cognitive biases, such as anchoring bias, that impact patient care. In this case, the atypical secondary nature of the diabetes was missed at 3 outpatient appointments prior to presentation at the hospital ED. In an active patient who has a normal BMI and a healthy diet—but systemic symptoms—it is critical to consider secondary causes of diabetes, such as Cushing syndrome.

CORRESPONDENCE
Anna Murley Squibb, MD, 2145 North Fairfield Road, Suite 100, Beavercreek, OH 45385; [email protected]

THE CASE

A 27-year-old man with no past medical history presented to his primary care physician (PCP) for a routine physical. He reported experiencing muscle weakness and fatigue for the previous 1 to 2 months. Two blood pressure measurements were recorded: 138/80 mm Hg and 142/95 mm Hg. The patient was given a diagnosis of hypertension and started on ­triamterene/hydrochlorothiazide. Labwork was ordered, including a complete metabolic panel, lipid panel, urinalysis, thyroid-stimulating hormone (TSH) plus thyroxine (T4), HIV antibodies, and a complete blood count.

The samples were drawn 1 week later, and the results were notable for low-normal TSH with a T4 of 0.8 ng/dL (normal range, 0.9-2.3 ng/dL); sodium, 151 mmol/L (normal range, 136-145 mmol/L); potassium, 3.4 mmol/L (normal range, 3.6-5.2 mmol/L); and white blood cell count, 13.8 x 10³/mcL. The electrolyte abnormalities were attributed to the triamterene/hydrochlorothiazide, which was stopped. One week later, repeat labs showed a persistent potassium level of 3.0 mmol/L; sodium, 141 mmol/L; and glucose, 310 mg/dL. Follow-up A1C was measured at 7.4%.

At the next appointment (2 weeks after initial evaluation), the patient received a diagnosis of type 2 diabetes in addition to new-onset essential hypertension. He expressed surprise at his diagnoses, as he said he primarily ate a balanced diet with plenty of vegetables and lots of healthy home-cooked meals. His body mass index (BMI) was in normal range, and he said he exercised regularly.

The patient was started on metformin 500 mg/d and referred to Endocrinology. After seeing the endocrinologist, who agreed with metformin for initial management, the patient contacted his PCP with concerns about worsening “muscle wasting.” Based on these ongoing symptoms, the patient was advised to go to the emergency department (ED).

In the ED, the patient reported muscle aches and weakness, weight gain, dyspnea on exertion, and polyuria. He also said that his face had widened with his weight gain, and his weakness was greatest in his thighs compared to his distal lower extremities. Labs drawn in the ED indicated hyperglycemia (glucose, 334 mg/dL) and severe hypokalemia (potassium, 2.2 mmol/L).

THE DIAGNOSIS

The patient was admitted in the afternoon for further evaluation, and a random serum cortisol measurement was ordered. The results showed an elevated cortisol level (55.2 mcg/dL; normal range, 3-20 mcg/dL). This was followed by a profoundly positive low-dose dexamethasone suppression test with a morning cortisol level of 75.9 mcg/dL (normal range, < 1.8 mcg/dL). With these findings, the diagnosis of Cushing syndrome was made and the focus of the evaluation shifted to localization.

An adrenocorticotropic hormone (ACTH) measurement was ordered, as well as magnetic resonance imaging (MRI) of the pituitary gland and of the abdomen to assess the adrenal glands. Both MRIs were negative, prompting a high-dose 8-mg dexamethasone suppression test to be performed. The patient’s morning cortisol level remained elevated (69.9 mcg/dL), confirming the diagnosis of Cushing syndrome.

Continue to: Based on the results...

Based on the results of the dexamethasone suppression test, a pituitary adenoma was unlikely (as they are often suppressed to < 5 mcg/dL with this test). The patient’s morning ACTH results came back as elevated (356.6 pg/mL; normal range, 10-60 pg/mL), suggesting inappropriate ACTH secretion, which most often has an ectopic source. However, a nuclear medicine octreotide scan and multiple computed tomography scans failed to locate such a source.

The patient eventually underwent bilateral petrosal venous sinus sampling to definitively rule out a pituitary source. Lastly, he underwent nuclear medicine positron emission tomography, which identified a nodular opacity in the anterior left lung apex, demonstrating moderate radiotracer activity (FIGURE 1).

THE DISCUSSION

Cushing syndrome is rarely encountered—it is estimated to affect 2% of patients with uncontrolled diabetes¹ and 1% of those with uncontrolled hypertension²—and requires a high level of clinical suspicion. This case highlights the importance of considering secondary causes of diabetes in patients who present atypically. This patient presented with symptoms consistent with Cushing syndrome that went unrecognized initially; these included high blood pressure, rounded face, weak muscles, hypokalemia, and intermittent hypernatremia in addition to new-onset hyperglycemia.^2-5 Despite the atypical findings, evaluation for diabetes and potential secondary causes was neglected until an ED evaluation 1 month after initial presentation. The work-up for possible Cushing syndrome was completed in the hospital but could easily have been conducted in the outpatient setting.

Making the diagnosis. When Cushing syndrome is suspected, consider consultation with Endocrinology. It is important to exclude exogenous glucocorticoid exposure through a thorough review of the patient’s medications.² The Endocrine Society² recommends that one of the following tests be performed:

• 24-hour urine free cortisol (≥ 2 tests)
• Overnight 1-mg dexamethasone suppression test
• Late-night salivary cortisol test.

Results within normal range make Cushing syndrome an unlikely diagnosis; however, for patients with suggestive clinical features, further work-up may be warranted.

Continue to: Any abnormal result...

Any abnormal result is an indication to exclude a physiologic cause of hypercortisolism by repeating at least 1 of the previous studies. As with the initial testing, normal results may rule out Cushing syndrome, while abnormal results would be confirmatory. (Conflicting results require additional evaluation.)

Morbidity and mortality. Finding the etiology of Cushing syndrome can present a challenge but is also rewarding due to the reversible nature of most of the abnormalities. That said, Cushing syndrome can have a significant impact on morbidity and mortality.

Morbidity. The case patient developed compression fractures throughout his thoracic and lumbar spine, with a loss of 4 inches in height, attributed to the delay in curative treatment (FIGURE 2); these were identified about 2 months after his initial presentation to a health care facility. In addition to bone mineral density, cognitive function and quality of life can be impacted by untreated hypercortisolism and Cushing syndrome.²

Mortality. In the earliest studies^6,7 (from the 1930s-1950s), the average survival rate was about 4.6 years and the 5-year survival was just 50%—and yet, outcomes data from modern treatment modalities are scant. While there is limited data on outcomes in untreated disease, the Endocrine Society states that treatment of moderate-to-severe cases “clearly reduces mortality and morbidity” while early identification and treatment of mild cases “would reduce the risk of residual morbidity.”²

Our patient underwent video-assisted thoracoscopic surgery, during which a nodule in the anterior lingula was removed. In addition, lymph node dissection was performed. Two lymph nodes were positive for atypical well-differentiated carcinoid tumor. After surgical removal, the patient’s cortisol levels normalized and his diabetes resolved.

THE TAKEAWAY

In primary care, the frequency at which we evaluate and diagnose type 2 diabetes without secondary cause can lead to cognitive biases, such as anchoring bias, that impact patient care. In this case, the atypical secondary nature of the diabetes was missed at 3 outpatient appointments prior to presentation at the hospital ED. In an active patient who has a normal BMI and a healthy diet—but systemic symptoms—it is critical to consider secondary causes of diabetes, such as Cushing syndrome.

CORRESPONDENCE
Anna Murley Squibb, MD, 2145 North Fairfield Road, Suite 100, Beavercreek, OH 45385; [email protected]

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

Priapism is a disorder that occurs when the penis maintains a prolonged erection in the absence of appropriate stimulation. The disorder is typically divided into subgroups based on arterial flow: low flow (ischemic) and high flow (nonischemic). Ischemic priapism is the most common form and results from venous congestion due to obstructed outflow and inability of cavernous smooth muscle to contract, resulting in compartment syndrome, tissue hypoxia, hypercapnia, and acidosis.¹ Conditions that result in hypercoagulable states and hyperviscosity are associated with ischemic priapism. COVID-19 is well known to cause an acute respiratory illness and systemic inflammatory response and has been increasingly associated with coagulopathy. Studies have shown that 20% to 55% of patients admitted to the hospital for COVID-19 show objective laboratory evidence of a hypercoagulable state.²

To date, there are 6 reported cases of priapism occurring in the setting of COVID-19 with all cases demonstrating the ischemic subtype. The onset of priapism from the beginning of infectious symptoms ranged from 2 days to more than a month. Five of the cases occurred in patients with critical COVID-19 and 1 in the setting of mild disease.^3-8 Two critically ill patients did not receive treatment for their ischemic priapism as they were transitioned to expectant management and/or comfort measures.Most were treated with cavernosal blood aspiration and intracavernosal injections of phenylephrine or ethylephrine. Some patients were managed with prophylactic doses of anticoagulation after the identification of priapism; others were transitioned to therapeutic doses. Two patients were followed postdischarge; one patient reported normal nighttime erections with sexual desire 2 weeks postdischarge, and another patient, who underwent a bilateral T-shunt procedure after unsuccessful phenylephrine injections, reported complete erectile dysfunction at 3 months postdischarge.^4,7 There was a potentially confounding variable in 2 cases in which propofol infusions were used for sedation management in the setting of mechanical ventilation.^6,8 Propofol has been linked to priapism through its blockade of sympathetic activation resulting in persistent relaxation of cavernosal smooth muscle.⁹ We present a unique case of COVID-19–associated ischemic priapism as our patient had moderate rather than critical COVID-19.

Case Presentation

A 67-year-old male patient presented to the emergency department for a painful erection of 34-hour duration. The patient had been exposed to COVID-19 roughly 2 months prior. Since the exposure, he had experienced headache, nonproductive cough, sore throat, and decreased appetite with weight loss. His medical history included hypertension, thoracic aortic aneurysm, B-cell type chronic lymphocytic leukemia (CLL), and obstructive sleep apnea. Daily outpatient medications included atenolol 100 mg, hydrochlorothiazide 25 mg, and omeprazole 20 mg. The patient stopped tobacco use about 30 years previously. He reported no alcohol consumption or illicit drug use and had no previous episodes of prolonged erection.

The patient was afebrile, hemodynamically stable, and had an oxygen saturation of 92% on room air. Physical examination revealed clear breath sounds and an erect circumcised penis without any lesions, discoloration, or skin necrosis. Laboratory data were remarkable for the following values: 125,660 cells/μL white blood cells (WBCs), 13.82 × 10³/ μL neutrophils, 110.58 × 10³/μL lymphocytes, 1.26 × 10³/μL monocytes, no blasts, 9.4 gm/dL hemoglobin, 100.3 fl mean corpuscular volume, 417,000 cells/μL platelets, 23,671 ng/mL D-dimer, 29.6 seconds activated partial thromboplastin time (aPTT), 16.3 seconds prothrombin time, 743 mg/dL fibrinogen, 474 U/L lactate dehydrogenase, and 202.1 mg/dL haptoglobin. A nasopharyngeal reverse transcription polymerase chain reaction test resulted positive for the SARS-CoV-2 virus, and subsequent chest X-ray revealed bilateral, hazy opacities predominantly in a peripheral distribution. Computed tomography (CT) angiogram of the chest did not reveal pulmonary emboli, pneumothorax, effusions, or lobar consolidation. However, it displayed bilateral ground-glass opacities with interstitial consolidation worst in the upper lobes. Corporal aspiration and blood gas analysis revealed a pH of 7.05, Pco₂ of 64 mm Hg, and Po₂ of 33 mm Hg.

Differential Diagnosis

The first consideration in the differential diagnosis of priapism is to differentiate between ischemic and nonischemic. Based on the abnormal blood gas results above, this case clearly falls within the ischemic spectrum. Ischemic priapism secondary to CLL-induced hyperleukocytosis was considered. It has been noted that up to 20% of priapism cases in adults are related to hematologic disorders.¹⁰ While it is not uncommon to see hyperleukocytosis (total WBC count > 100 × 10⁹/L) in CLL, leukostasis is rare with most reports demonstrating WBC counts > 1000 × 10⁹/L.¹¹ Hematology, vascular surgery, and urology services were consulted and agreed that ischemic priapism was due to microthrombi or pelvic vein thrombosis secondary to COVID-19–associated coagulopathy (CAC) was the most likely etiology.

Treatment

After corporal aspiration, intracorporal phenylephrine was administered. Diluted phenylephrine (100 ug/mL) was injected every 5 to 10 minutes while intermittently aspirating and irrigating multiple sites along the lateral length of the penile shaft. This initial procedure reduced the erection from 100% to 30% rigidity, with repeat blood gas analysis revealing minimal improvement. CT of the abdomen and pelvis with IV contrast revealed no evidence of pelvic thrombi. A second round of phenylephrine injections were administered, resulting in detumescence. The patient was treated with 2 to 3 L/min of oxygen supplementation via nasal cannula, a 5-day course of remdesivir and low-intensity heparin drip. Following the initial low-intensity heparin drip, the patient transitioned to therapeutic enoxaparin and subsequently was discharged on apixaban for a 3-month course. Since discharge, the patient followed up with hematology. He tolerated and completed the anticoagulation regimen without any recurrences of priapism or residual deficits.

Discussion

Recent studies have overwhelmingly analyzed the incidence and presentation of thrombotic complications in critically ill patients with COVID-19. CAC has been postulated to result from endotheliopathy along with immune cell activation and propagation of coagulation. While COVID-19 has been noted to create lung injury through binding angiotensin-converting enzyme 2 receptors expressed on alveolar pneumocytes, it increasingly has been found to affect endothelial cells throughout the body. Recent postmortem analyses have demonstrated direct viral infection of endothelial cells with consequent diffuse endothelial inflammation, as evidenced by viral inclusions, sequestered immune cells, and endothelial apoptosis.^12,13 Manifestations of this endotheliopathy have been delineated through various studies.

An early retrospective study in Wuhan, China, illustrated that 36% of the first 99 patients hospitalized with COVID-19 demonstrated an elevated D-dimer, 6% an elevated aPTT, and 5% an elevated prothrombin time.¹⁴ Another retrospective study conducted in Wuhan found a 25% incidence of venous thromboembolic complications in critically ill patients with severe COVID-19.¹⁵ In the Netherlands, a study reported the incidence of arterial and venous thrombotic complications to be 31% in 184 critically ill patients with COVID-19, with 81% of these cases involving pulmonary emboli.¹⁶

To our knowledge, our patient is the seventh reported case of ischemic priapism occurring in the setting of a COVID-19 infection, and the first to have occurred in its moderate form. Ischemic priapism is often a consequence of penile venous outflow obstruction and resultant stasis of hypoxic blood.⁷ The prothrombotic state induced by CAC has been proposed to cause the obstruction of small emissary veins in the subtunical space and in turn lead to venous stasis, which propagates the formation of ischemic priapism.⁸ Furthermore, 4 of the previously reported cases shared laboratory data on their patients, and all demonstrated elevated D-dimer and fibrinogen levels, which strengthens this hypothesis.^3,5,7,8 CLL presents a potential confounding variable in this case; however, as we have reviewed earlier, the risk of leukostasis at WBC counts < 1000 × 10⁹/L is very low.¹¹ It is also probable that the patient had some level of immune dysregulation secondary to CLL, leading to his prolonged course and slow clearance of the virus.

Conclusions

Although only a handful of CAC cases leading to ischemic priapism have been reported, the true incidence may be much higher. While our case highlights the importance of considering COVID-19 infection in the differential diagnosis of ischemic priapism, more research is needed to understand incidence and definitively establish a causative relationship.

Priapism is a disorder that occurs when the penis maintains a prolonged erection in the absence of appropriate stimulation. The disorder is typically divided into subgroups based on arterial flow: low flow (ischemic) and high flow (nonischemic). Ischemic priapism is the most common form and results from venous congestion due to obstructed outflow and inability of cavernous smooth muscle to contract, resulting in compartment syndrome, tissue hypoxia, hypercapnia, and acidosis.¹ Conditions that result in hypercoagulable states and hyperviscosity are associated with ischemic priapism. COVID-19 is well known to cause an acute respiratory illness and systemic inflammatory response and has been increasingly associated with coagulopathy. Studies have shown that 20% to 55% of patients admitted to the hospital for COVID-19 show objective laboratory evidence of a hypercoagulable state.²

To date, there are 6 reported cases of priapism occurring in the setting of COVID-19 with all cases demonstrating the ischemic subtype. The onset of priapism from the beginning of infectious symptoms ranged from 2 days to more than a month. Five of the cases occurred in patients with critical COVID-19 and 1 in the setting of mild disease.^3-8 Two critically ill patients did not receive treatment for their ischemic priapism as they were transitioned to expectant management and/or comfort measures.Most were treated with cavernosal blood aspiration and intracavernosal injections of phenylephrine or ethylephrine. Some patients were managed with prophylactic doses of anticoagulation after the identification of priapism; others were transitioned to therapeutic doses. Two patients were followed postdischarge; one patient reported normal nighttime erections with sexual desire 2 weeks postdischarge, and another patient, who underwent a bilateral T-shunt procedure after unsuccessful phenylephrine injections, reported complete erectile dysfunction at 3 months postdischarge.^4,7 There was a potentially confounding variable in 2 cases in which propofol infusions were used for sedation management in the setting of mechanical ventilation.^6,8 Propofol has been linked to priapism through its blockade of sympathetic activation resulting in persistent relaxation of cavernosal smooth muscle.⁹ We present a unique case of COVID-19–associated ischemic priapism as our patient had moderate rather than critical COVID-19.

Case Presentation

A 67-year-old male patient presented to the emergency department for a painful erection of 34-hour duration. The patient had been exposed to COVID-19 roughly 2 months prior. Since the exposure, he had experienced headache, nonproductive cough, sore throat, and decreased appetite with weight loss. His medical history included hypertension, thoracic aortic aneurysm, B-cell type chronic lymphocytic leukemia (CLL), and obstructive sleep apnea. Daily outpatient medications included atenolol 100 mg, hydrochlorothiazide 25 mg, and omeprazole 20 mg. The patient stopped tobacco use about 30 years previously. He reported no alcohol consumption or illicit drug use and had no previous episodes of prolonged erection.

The patient was afebrile, hemodynamically stable, and had an oxygen saturation of 92% on room air. Physical examination revealed clear breath sounds and an erect circumcised penis without any lesions, discoloration, or skin necrosis. Laboratory data were remarkable for the following values: 125,660 cells/μL white blood cells (WBCs), 13.82 × 10³/ μL neutrophils, 110.58 × 10³/μL lymphocytes, 1.26 × 10³/μL monocytes, no blasts, 9.4 gm/dL hemoglobin, 100.3 fl mean corpuscular volume, 417,000 cells/μL platelets, 23,671 ng/mL D-dimer, 29.6 seconds activated partial thromboplastin time (aPTT), 16.3 seconds prothrombin time, 743 mg/dL fibrinogen, 474 U/L lactate dehydrogenase, and 202.1 mg/dL haptoglobin. A nasopharyngeal reverse transcription polymerase chain reaction test resulted positive for the SARS-CoV-2 virus, and subsequent chest X-ray revealed bilateral, hazy opacities predominantly in a peripheral distribution. Computed tomography (CT) angiogram of the chest did not reveal pulmonary emboli, pneumothorax, effusions, or lobar consolidation. However, it displayed bilateral ground-glass opacities with interstitial consolidation worst in the upper lobes. Corporal aspiration and blood gas analysis revealed a pH of 7.05, Pco₂ of 64 mm Hg, and Po₂ of 33 mm Hg.

Differential Diagnosis

The first consideration in the differential diagnosis of priapism is to differentiate between ischemic and nonischemic. Based on the abnormal blood gas results above, this case clearly falls within the ischemic spectrum. Ischemic priapism secondary to CLL-induced hyperleukocytosis was considered. It has been noted that up to 20% of priapism cases in adults are related to hematologic disorders.¹⁰ While it is not uncommon to see hyperleukocytosis (total WBC count > 100 × 10⁹/L) in CLL, leukostasis is rare with most reports demonstrating WBC counts > 1000 × 10⁹/L.¹¹ Hematology, vascular surgery, and urology services were consulted and agreed that ischemic priapism was due to microthrombi or pelvic vein thrombosis secondary to COVID-19–associated coagulopathy (CAC) was the most likely etiology.

Treatment

After corporal aspiration, intracorporal phenylephrine was administered. Diluted phenylephrine (100 ug/mL) was injected every 5 to 10 minutes while intermittently aspirating and irrigating multiple sites along the lateral length of the penile shaft. This initial procedure reduced the erection from 100% to 30% rigidity, with repeat blood gas analysis revealing minimal improvement. CT of the abdomen and pelvis with IV contrast revealed no evidence of pelvic thrombi. A second round of phenylephrine injections were administered, resulting in detumescence. The patient was treated with 2 to 3 L/min of oxygen supplementation via nasal cannula, a 5-day course of remdesivir and low-intensity heparin drip. Following the initial low-intensity heparin drip, the patient transitioned to therapeutic enoxaparin and subsequently was discharged on apixaban for a 3-month course. Since discharge, the patient followed up with hematology. He tolerated and completed the anticoagulation regimen without any recurrences of priapism or residual deficits.

Discussion

Recent studies have overwhelmingly analyzed the incidence and presentation of thrombotic complications in critically ill patients with COVID-19. CAC has been postulated to result from endotheliopathy along with immune cell activation and propagation of coagulation. While COVID-19 has been noted to create lung injury through binding angiotensin-converting enzyme 2 receptors expressed on alveolar pneumocytes, it increasingly has been found to affect endothelial cells throughout the body. Recent postmortem analyses have demonstrated direct viral infection of endothelial cells with consequent diffuse endothelial inflammation, as evidenced by viral inclusions, sequestered immune cells, and endothelial apoptosis.^12,13 Manifestations of this endotheliopathy have been delineated through various studies.

An early retrospective study in Wuhan, China, illustrated that 36% of the first 99 patients hospitalized with COVID-19 demonstrated an elevated D-dimer, 6% an elevated aPTT, and 5% an elevated prothrombin time.¹⁴ Another retrospective study conducted in Wuhan found a 25% incidence of venous thromboembolic complications in critically ill patients with severe COVID-19.¹⁵ In the Netherlands, a study reported the incidence of arterial and venous thrombotic complications to be 31% in 184 critically ill patients with COVID-19, with 81% of these cases involving pulmonary emboli.¹⁶

To our knowledge, our patient is the seventh reported case of ischemic priapism occurring in the setting of a COVID-19 infection, and the first to have occurred in its moderate form. Ischemic priapism is often a consequence of penile venous outflow obstruction and resultant stasis of hypoxic blood.⁷ The prothrombotic state induced by CAC has been proposed to cause the obstruction of small emissary veins in the subtunical space and in turn lead to venous stasis, which propagates the formation of ischemic priapism.⁸ Furthermore, 4 of the previously reported cases shared laboratory data on their patients, and all demonstrated elevated D-dimer and fibrinogen levels, which strengthens this hypothesis.^3,5,7,8 CLL presents a potential confounding variable in this case; however, as we have reviewed earlier, the risk of leukostasis at WBC counts < 1000 × 10⁹/L is very low.¹¹ It is also probable that the patient had some level of immune dysregulation secondary to CLL, leading to his prolonged course and slow clearance of the virus.

Conclusions

Although only a handful of CAC cases leading to ischemic priapism have been reported, the true incidence may be much higher. While our case highlights the importance of considering COVID-19 infection in the differential diagnosis of ischemic priapism, more research is needed to understand incidence and definitively establish a causative relationship.

Priapism is a disorder that occurs when the penis maintains a prolonged erection in the absence of appropriate stimulation. The disorder is typically divided into subgroups based on arterial flow: low flow (ischemic) and high flow (nonischemic). Ischemic priapism is the most common form and results from venous congestion due to obstructed outflow and inability of cavernous smooth muscle to contract, resulting in compartment syndrome, tissue hypoxia, hypercapnia, and acidosis.¹ Conditions that result in hypercoagulable states and hyperviscosity are associated with ischemic priapism. COVID-19 is well known to cause an acute respiratory illness and systemic inflammatory response and has been increasingly associated with coagulopathy. Studies have shown that 20% to 55% of patients admitted to the hospital for COVID-19 show objective laboratory evidence of a hypercoagulable state.²

To date, there are 6 reported cases of priapism occurring in the setting of COVID-19 with all cases demonstrating the ischemic subtype. The onset of priapism from the beginning of infectious symptoms ranged from 2 days to more than a month. Five of the cases occurred in patients with critical COVID-19 and 1 in the setting of mild disease.^3-8 Two critically ill patients did not receive treatment for their ischemic priapism as they were transitioned to expectant management and/or comfort measures.Most were treated with cavernosal blood aspiration and intracavernosal injections of phenylephrine or ethylephrine. Some patients were managed with prophylactic doses of anticoagulation after the identification of priapism; others were transitioned to therapeutic doses. Two patients were followed postdischarge; one patient reported normal nighttime erections with sexual desire 2 weeks postdischarge, and another patient, who underwent a bilateral T-shunt procedure after unsuccessful phenylephrine injections, reported complete erectile dysfunction at 3 months postdischarge.^4,7 There was a potentially confounding variable in 2 cases in which propofol infusions were used for sedation management in the setting of mechanical ventilation.^6,8 Propofol has been linked to priapism through its blockade of sympathetic activation resulting in persistent relaxation of cavernosal smooth muscle.⁹ We present a unique case of COVID-19–associated ischemic priapism as our patient had moderate rather than critical COVID-19.

Case Presentation

A 67-year-old male patient presented to the emergency department for a painful erection of 34-hour duration. The patient had been exposed to COVID-19 roughly 2 months prior. Since the exposure, he had experienced headache, nonproductive cough, sore throat, and decreased appetite with weight loss. His medical history included hypertension, thoracic aortic aneurysm, B-cell type chronic lymphocytic leukemia (CLL), and obstructive sleep apnea. Daily outpatient medications included atenolol 100 mg, hydrochlorothiazide 25 mg, and omeprazole 20 mg. The patient stopped tobacco use about 30 years previously. He reported no alcohol consumption or illicit drug use and had no previous episodes of prolonged erection.

The patient was afebrile, hemodynamically stable, and had an oxygen saturation of 92% on room air. Physical examination revealed clear breath sounds and an erect circumcised penis without any lesions, discoloration, or skin necrosis. Laboratory data were remarkable for the following values: 125,660 cells/μL white blood cells (WBCs), 13.82 × 10³/ μL neutrophils, 110.58 × 10³/μL lymphocytes, 1.26 × 10³/μL monocytes, no blasts, 9.4 gm/dL hemoglobin, 100.3 fl mean corpuscular volume, 417,000 cells/μL platelets, 23,671 ng/mL D-dimer, 29.6 seconds activated partial thromboplastin time (aPTT), 16.3 seconds prothrombin time, 743 mg/dL fibrinogen, 474 U/L lactate dehydrogenase, and 202.1 mg/dL haptoglobin. A nasopharyngeal reverse transcription polymerase chain reaction test resulted positive for the SARS-CoV-2 virus, and subsequent chest X-ray revealed bilateral, hazy opacities predominantly in a peripheral distribution. Computed tomography (CT) angiogram of the chest did not reveal pulmonary emboli, pneumothorax, effusions, or lobar consolidation. However, it displayed bilateral ground-glass opacities with interstitial consolidation worst in the upper lobes. Corporal aspiration and blood gas analysis revealed a pH of 7.05, Pco₂ of 64 mm Hg, and Po₂ of 33 mm Hg.

Differential Diagnosis

The first consideration in the differential diagnosis of priapism is to differentiate between ischemic and nonischemic. Based on the abnormal blood gas results above, this case clearly falls within the ischemic spectrum. Ischemic priapism secondary to CLL-induced hyperleukocytosis was considered. It has been noted that up to 20% of priapism cases in adults are related to hematologic disorders.¹⁰ While it is not uncommon to see hyperleukocytosis (total WBC count > 100 × 10⁹/L) in CLL, leukostasis is rare with most reports demonstrating WBC counts > 1000 × 10⁹/L.¹¹ Hematology, vascular surgery, and urology services were consulted and agreed that ischemic priapism was due to microthrombi or pelvic vein thrombosis secondary to COVID-19–associated coagulopathy (CAC) was the most likely etiology.

Treatment

After corporal aspiration, intracorporal phenylephrine was administered. Diluted phenylephrine (100 ug/mL) was injected every 5 to 10 minutes while intermittently aspirating and irrigating multiple sites along the lateral length of the penile shaft. This initial procedure reduced the erection from 100% to 30% rigidity, with repeat blood gas analysis revealing minimal improvement. CT of the abdomen and pelvis with IV contrast revealed no evidence of pelvic thrombi. A second round of phenylephrine injections were administered, resulting in detumescence. The patient was treated with 2 to 3 L/min of oxygen supplementation via nasal cannula, a 5-day course of remdesivir and low-intensity heparin drip. Following the initial low-intensity heparin drip, the patient transitioned to therapeutic enoxaparin and subsequently was discharged on apixaban for a 3-month course. Since discharge, the patient followed up with hematology. He tolerated and completed the anticoagulation regimen without any recurrences of priapism or residual deficits.

Discussion

Recent studies have overwhelmingly analyzed the incidence and presentation of thrombotic complications in critically ill patients with COVID-19. CAC has been postulated to result from endotheliopathy along with immune cell activation and propagation of coagulation. While COVID-19 has been noted to create lung injury through binding angiotensin-converting enzyme 2 receptors expressed on alveolar pneumocytes, it increasingly has been found to affect endothelial cells throughout the body. Recent postmortem analyses have demonstrated direct viral infection of endothelial cells with consequent diffuse endothelial inflammation, as evidenced by viral inclusions, sequestered immune cells, and endothelial apoptosis.^12,13 Manifestations of this endotheliopathy have been delineated through various studies.

An early retrospective study in Wuhan, China, illustrated that 36% of the first 99 patients hospitalized with COVID-19 demonstrated an elevated D-dimer, 6% an elevated aPTT, and 5% an elevated prothrombin time.¹⁴ Another retrospective study conducted in Wuhan found a 25% incidence of venous thromboembolic complications in critically ill patients with severe COVID-19.¹⁵ In the Netherlands, a study reported the incidence of arterial and venous thrombotic complications to be 31% in 184 critically ill patients with COVID-19, with 81% of these cases involving pulmonary emboli.¹⁶

To our knowledge, our patient is the seventh reported case of ischemic priapism occurring in the setting of a COVID-19 infection, and the first to have occurred in its moderate form. Ischemic priapism is often a consequence of penile venous outflow obstruction and resultant stasis of hypoxic blood.⁷ The prothrombotic state induced by CAC has been proposed to cause the obstruction of small emissary veins in the subtunical space and in turn lead to venous stasis, which propagates the formation of ischemic priapism.⁸ Furthermore, 4 of the previously reported cases shared laboratory data on their patients, and all demonstrated elevated D-dimer and fibrinogen levels, which strengthens this hypothesis.^3,5,7,8 CLL presents a potential confounding variable in this case; however, as we have reviewed earlier, the risk of leukostasis at WBC counts < 1000 × 10⁹/L is very low.¹¹ It is also probable that the patient had some level of immune dysregulation secondary to CLL, leading to his prolonged course and slow clearance of the virus.

Conclusions

Although only a handful of CAC cases leading to ischemic priapism have been reported, the true incidence may be much higher. While our case highlights the importance of considering COVID-19 infection in the differential diagnosis of ischemic priapism, more research is needed to understand incidence and definitively establish a causative relationship.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Insulin injection therapy is one of the most widely used health care interventions to manage both type 1 and type 2 diabetes mellitus (T1DM/T2DM). Globally, more than 150 to 200 million people inject insulin into their upper posterior arms, buttocks, anterior and lateral thighs, or abdomen.^1,2 In an ideal world, every patient would be using the correct site and rotating their insulin injection sites in accordance with health care professional (HCP) recommendations—systematic injections in one general body location, at least 1 cm away from the previous injection.² Unfortunately, same-site insulin injection (repeatedly in the same region within 1 cm of previous injections) is a common mistake made by patients with DM—in one study, 63% of participants either did not rotate sites correctly or failed to do so at all.

Insulin-resistant cutaneous complications may occur as a result of same-site insulin injections. The most common is lipohypertrophy, reported in some studies in nearly 50% of patients with DM on insulin therapy.⁴ Other common cutaneous complications include lipoatrophy and amyloidosis. Injection-site acanthosis nigricans, although uncommon, has been reported in 18 cases in the literature.

Most articles suggest that same-site insulin injections decrease local insulin sensitivity and result in tissue hypertrophy because of the anabolic properties of insulin and increase in insulin binding to insulin-like growth factor-1 (IGF-1) receptor.^5-20 The hyperkeratotic growth and varying insulin absorption rates associated with these cutaneous complications increase chances of either hyper- or hypoglycemic episodes in patients.^10,11,13 It is the responsibility of the DM care professional to provide proper insulin-injection technique education and perform routine inspection of injection sites to reduce cutaneous complications of insulin therapy. The purpose of this article is to (1) describe a case of acanthosis nigricans resulting from insulin injection at the same site; (2) review case reports in the literature describing injection-site acanthosis nigricans resulting from same-site insulin injections; (3) describe localized cutaneous complications associated with the use of insulin; and (4) discuss clinical implications and lessons learned from the literature.

Case Presentation

A 75-year-old patient with an 8-year history of T2DM, as well as stable coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and stage 3 chronic kidney disease, presented with 2 discrete abdominal hyperpigmented plaques. At the time of the initial clinic visit, the patient was taking metformin 1000 mg twice daily and insulin glargine 40 units once daily. When insulin was initiated 7 years prior, the patient received neutral protamine Hagedorn (NPH) insulin for the first year and transitioned to insulin glargine. After 4 years of insulin therapy, insulin aspart was added and discontinued after 2 years. The patient’s hemoglobin A_1c (HbA_1c) was 6.8%, suggesting good glycemic control.

The patient reported 5 years of progressive, asymptomatic hyperpigmentation of the skin surrounding his insulin glargine injection sites and injecting in these same sites daily without rotation. He reported no additional skin changes or symptoms. He had noticed no skin changes while using NPH insulin during his first year of insulin therapy. On examination, the abdominal wall skin demonstrated 2 well-demarcated, nearly black, soft, velvety plaques, measuring 9 × 8 cm on the left side and 4 × 3.5 cm on the right, suggesting acanthosis nigricans (Figure 1A). The remainder of the skin examination, including the flexures, was normal. Of note, the patient received biweekly intramuscular testosterone injections in the gluteal region for secondary hypogonadism with no adverse dermatologic effects. A skin punch biopsy was performed and revealed epidermal papillomatosis and hyperkeratosis, confirming the clinical diagnosis of acanthosis nigricans (Figure 2).

After a review of insulin-injection technique at his clinic visit, the patient started rotating insulin injection sites over his entire abdomen, and the acanthosis nigricans partially improved. A few months later, the patient stopped rotating the insulin injection site, and the acanthosis nigricans worsened again. Because of worsening glycemic control, the patient was then started on insulin aspart. He did not develop any skin changes at the insulin aspart injection site, although he was not rotating its site of injection.

Subsequently, with reeducation and proper injection-site rotation, the patient had resolution of his acanthosis nigricans (Figure 1b).

Discussion

A review of the literature revealed 18 reported cases of acanthosis nigricans at sites of repeated insulin injection (Table).^5-20 Acanthosis nigricans at the site of insulin injection afflicts patients of any age, with cases observed in patients aged 14 to 75 years. Sixteen (84%) of 19 cases were male. Fourteen cases (73%) had T2DM; the rest of the patients had T1DM. The duration of insulin injection therapy prior to onset ranged from immediate to 13 years (median 4 years). Fourteen cases (73%) were reported on the abdomen; however, other sites, such as thighs and upper arm, also were reported. Lesions size varied from 12 to 360 cm². Two cases had associated amyloidosis. The average HbA_1c reported at presentation was 10%. Following insulin injection-site rotation, most of the cases reported improvement of both glycemic control and acanthosis nigricans appearance.

In the case described by Kudo and colleagues, a 59-year-old male patient with T2DM had been injecting insulin into the same spot on his abdomen for 10 years. He developed acanthosis nigricans and an amyloidoma so large and firm that it bent the needle when he injected insulin.¹¹

Most of the cases we found in the literature were after 2005 and associated with the use of human or analog insulin. These cases may be related to a bias, as cases may be easier to find in digital archives in the later years, when human or analog insulins have been in common use. Also noteworthy, in cases that reported dosage, most were not very high, and the highest daily dose was 240 IU/d. Ten reports of injection-site acanthosis nigricans were in dermatology journals; only 5 reports were in endocrinology journals and 3 in general medical journals, indicating possible less awareness of this phenomenon in other HCPs who care for patients with DM.

Complications of Same-Site Injections

Acanthosis nigricans. Commonly found in the armpits, neck folds, and groin, acanthosis nigricans is known as one of the calling cards for insulin resistance, obesity, and hyperinsulinemia.²¹ Acanthosis nigricans can be seen in people with or without DM and is not limited to those on insulin therapy. However, same-site insulin injections for 4 to 6 years also may result in injection-site acanthosis nigricans–like lesions because of factors such as insulin exposure at the local tissue level.¹⁶

Acanthosis nigricans development is characterized by hyperpigmented, hyperkeratotic, velvety, and sometimes verrucous plaques.⁶ Acanthosis nigricans surrounding repeated injection sites is hypothesized to develop as a result of localized hyperinsulinemia secondary to insulin resistance, which increases the stimulation of IGF, thereby causing epidermal hypertrophy.^5-20 If insulin injection therapy continues to be administered through the acanthosis nigricans lesion, it results in decreased insulin absorption, leading to poor glycemic control.¹³

Acanthosis nigricans associated with insulin injection is reversible. After rotation of injection sites, lesions either decrease in size or severity of appearance.^5-8,11 Also, by avoiding injection into the hyperkeratotic plaques and using normal subcutaneous tissue for injection, patients’ response to insulin improves, as measured by HbA_1c and by decreased daily insulin requirement.^{6-8,10,12,18-20}

Lipohypertrophy. This is characterized by an increase in localized adipose tissue and is the most common cutaneous complication of insulin therapy.² Lipohypertrophy presents as a firm, rubbery mass in the location of same-site insulin injections.²² Development of lipohypertrophy is suspected to be the result of either (1) anabolic effect of insulin on local adipocytes, promoting fat and protein synthesis; (2) an autoimmune response by immunoglobulin (Ig) G or IgE antibodies to insulin, immune response to insulin of different species, or to insulin injection techniques; or (3) repeated trauma to the injection site from repeated needle usage.^4,23

In a study assessing the prevalence of lipohypertrophy and its relation to insulin technique, 49.1% of participants with lipohypertrophy had glycemic variability compared with 6.5% of participants without lipohypertrophy.³ Johansson and colleagues described an impairment of insulin absorption in lipohypertrophic tissues, causing a 25% lower plasma insulin concentration compared with that of normal tissues.⁴ These findings suggest a significant effect of lipohypertrophy on insulin absorption—unnecessarily increasing insulin consumption and worsening glycemic control.

Primary prevention measures include injection site inspection and patient education about rotation and abstaining from needle reuse.²² If a patient already has signs of lipohypertrophy, data supports education and insulin injection technique practice as simple and effective means to reduce insulin action variability and increase glycemic control.²⁴

Lipoatrophy. Lipoatrophy is described as a local loss of subcutaneous adipose tissue often in the face, buttocks, legs and arm regions and can be rooted in genetic, immune, or drug-associated etiologies.²⁵ Insulin-induced lipoatrophy is suspected to be the result of tumor necrosis factor-α hyperproduction in reaction to insulin crystal presence at the injection site.^26,27 Overall, lipoatrophy development has decreased since the use of recombinant human insulin and analog insulin therapy.²⁸ The decrease is hypothesized to be due to increased subcutaneous tissue absorption rate of human insulin and its analog, decreasing overall adipocyte exposure to localized high insulin concentration.²⁷ Treatments for same-site insulin-derived lipoatrophy include changing injection sites and preparation of insulin.²⁶ When injection into the lipoatrophic site was avoided, glycemic control and lipoatrophy appearance improved.²⁶

Amyloidosis. Amyloidosis indicates the presence of an extracellular bundle of insoluble polymeric protein fibrils in tissues and organs.²⁹ Insulin-induced amyloidosis presents as a hard mass or ball near the injection site.²⁹ Insulin is one of many hormones that can form amyloid fibrils, and there have been several dozen cases reported of amyloid formation at the site of insulin injection.^29-31 Although insulin-derived amyloidosis is rare, it may be misdiagnosed as lipohypertrophy due to a lack of histopathologic testing or general awareness of the complication.²⁹

In a case series of 7 patients with amyloidosis, all patients had a mean HbA_1c of 9.3% (range, 8.5-10.2%) and averaged 1 IU/kg bodyweight before intervention.³⁰ After the discovery of the mass, participants were instructed to avoid injection into the amyloidoma, and average insulin requirements decreased to 0.48 IU/kg body weight (P = .40).³⁰ Patients with amyloidosis who rotated their injection sites experienced better glycemic control and decreased insulin requirements.³⁰

Pathophysiology of Localized Insulin Resistance

Insulin regulates glucose homeostasis in skeletal muscle and adipose tissue, increases hepatic and adipocyte lipid synthesis, and decreases adipocyte fatty acid release.³² Generalized insulin resistance occurs when target tissues have decreased glucose uptake in response to circulating insulin.³² Insulin resistance increases the amount of free insulin in surrounding tissues. At high concentrations, insulin fosters tissue growth by binding to IGF-1 receptors, stimulating hypertrophy and reproduction of keratinocytes and fibroblasts.³³ This pathophysiology helps explain the origin of localized acanthosis nigricans at same-site insulin injections.

Conclusions

Cutaneous complications are a local adverse effect of long-term failure to rotate insulin injection sites. Our case serves as a call to action for HCPs to improve education regarding insulin injection-site rotation, conduct routine injection-site inspection, and actively document cases as they occur to increase public awareness of these important complications.

If a patient with DM presents with unexplained poor glycemic control, consider questioning the patient about injection-site location and how often they are rotating the insulin injection site. Inspect the site for cutaneous complications. Of note, if a patient has a cutaneous complication due to insulin injection, adjust or decrease the insulin dosage when rotating sites to mitigate the risk of hypoglycemic episodes.

Improvement of glycemic control, cosmetic appearance of injection site, and insulin use all begin with skin inspection, injection technique education, and periodic review by a HCP.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.