Case Reports

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.

THE CASE

A 47-year-old African American woman was admitted to the hospital with pulmonary edema revealed on a computed tomography (CT) scan. She had a history of systemic lupus erythematosus (SLE), hypertension, and end-stage renal disease (ESRD). The patient had been hospitalized one month earlier for lupus nephritis with a hypertensive emergency that led to a seizure. During this earlier hospitalization, she was given a diagnosis of posterior reversible encephalopathy syndrome.

Two weeks into her more recent hospitalization, the patient developed a fever that was accompanied by cough and fatigue. By the third week, there was no identified cause of the fever, and the patient met the criteria for fever of unknown origin (FUO).

Her medications included cyclophosphamide, prednisone, nebivolol, clonidine, phenytoin, and epoetin alfa. The patient was also receiving dialysis every other day. Chest x-ray findings suggested pneumonia, and the patient was treated with vancomycin and piperacillin/tazobactam. However, her fever persisted after completing the antibiotics. Central line sepsis was high in the differential, as the patient was on dialysis, but blood and catheter tip cultures were negative. Chest and abdominal CT scans showed no new disease process. Urine and sputum cultures were collected and were negative for infection. Drug-induced fever was then suspected, but was ruled out when the fever persisted after the removal of potential offending agents (phenytoin, nebivolol, and cyclophosphamide).

THE DIAGNOSIS

We then followed the American Academy of Family Physicians’ diagnostic protocol for FUO.¹

Initial labs included a complete blood count (CBC), 2 blood cultures, a urine culture, erythrocyte sedimentation rate (ESR), a purified protein derivative skin test, chest and abdominal CT scans, and double-stranded DNA (dsDNA) levels (since this patient had known SLE). The patient’s hemoglobin level and mean corpuscular volume were consistent with normocytic anemia, which was attributed to the ESRD. The ESR was mildly elevated at 46 mm/hr, but dsDNA was not, ruling out a lupus flare. Thrombocytopenia (platelet count, 82 K/mcL) and lymphocytopenia (absolute lymphocyte count, 0.2 K/mcL) were assumed to be secondary to cyclophosphamide use.

Because the initial labs were non-diagnostic, we proceeded with a sputum stain and culture, human immunodeficiency virus testing, a hepatitis panel, and a peripheral blood smear.¹ All were negative except for the peripheral blood smear, which showed hemophagocytic cells. This was the first finding that brought hemophagocytic lymphohistiocytosis (HLH) into the differential.

We then performed a bone marrow biopsy (FIGURE), which also revealed hemophagocytic cells, so we ordered HLH-specific labs (more on those in a bit). Liver enzymes were elevated to 3 times their normal value. Triglycerides (414 mg/dL), ferritin (>15,000 ng/mL), and interleukin-2 (IL-2) receptor levels (>20,000 pg/m) were also elevated.

The patient was tested for herpes simplex virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV), since these viruses are associated with HLH. She had 3.1 million copies/mL of CMV, leading to the diagnosis of secondary HLH. This diagnosis might not have been made if not for a persistent fever investigation.

HLH is a life-threatening syndrome of excessive immune activation that results in tissue damage.² There are primary and secondary forms, but they share the same mechanism of impaired regulation of cytotoxic granules and cytokines. Primary HLH results from a congenital gene mutation,³ while secondary HLH is triggered by an autoimmune or inflammatory disease or an infection.⁴ EBV is the most common viral etiology, followed closely by CMV.⁵

The diagnosis may be established genetically (based on mutations of the genes loci PRF1, UNC13D, or STX11) or by fulfillment of 5 out of 8 criteria: fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell activity; and an elevated ferritin level (>500 ng/mL). Elevated soluble CD25 and IL-2 receptor markers are HLH-specific markers.³ This patient had fever, cytopenia, hypertriglyceridemia, hemophagocytosis, and elevated ferritin with elevated IL-2, meeting the criteria for secondary HLH.

First treat the underlying condition, then the HLH

Treatment for HLH includes treating the underlying condition (such as EBV or CMV) with antiretroviral medications, and using immunosuppressive agents such as chemotherapy drugs and steroids for the HLH.

Our patient was treated with valganciclovir 900 mg/d for 2 weeks for the CMV and an etoposide/prednisone taper for 3 months for HLH chemotherapy and suppression. Within one month, her CMV viral load decreased to <300 copies/mL and her fever resolved. Ferritin, triglycerides, and liver enzyme levels returned to normal within 3 months.

THE TAKEAWAY

FUO can be frustrating for both the physician and the patient. Not only is the differential large, but testing is extensive. It is important to get a thorough history and to consider medications as the cause. Testing should be patient-specific and systematic. Persistent investigation is critical to saving the patient’s life.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

The process of wound healing has been well characterized. Immediately following injury, neutrophils arrive at the site in response to chemotactic factors produced by the coagulation cascade. Monocytes follow 24 to 36 hours later; transform into macrophages; and begin to phagocytose tissue debris, organisms, and any remaining neutrophils. In turn, macrophages release chemotactic factors such as basic fibroblast growth factor to attract fibroblasts to the wound, which then begin the process of synthesizing collagen and ground substance. Fibroblasts then take over as the dominant cell type, with collagen synthesis continuing for approximately 6 weeks. Keratinocytes and endothelial cells also proliferate during this time. After approximately 6 weeks, collagen remodeling begins. Tensile strength of the wound may continue to increase up to one year after the injury.^1,2

Corticosteroids inhibit wound healing in several ways. Notably, they decrease the number of circulating monocytes, leading to fewer macrophages in the tissue at the site of injury, which then leads to impaired phagocytosis and reduced release of chemotactic factors that attract fibroblasts. Additionally, corticosteroids can inhibit collagen synthesis and remodeling, leading to delayed wound healing and decreased tensile strength of the wound as well as impacting capillary proliferation.³

The subtypes of EDS were reclassified in 1998 by Beighton et al,⁴ and the benign hypermobility type (EDS-BHT)(formerly type III) is considered the least severe. There is some controversy as to whether this subtype constitutes a separate diagnosis from the benign familial joint hypermobility syndrome. It is characterized by hypermobility of the joints (objectively measured with the Beighton scale) and mild hyperextensibility of the skin, and patients often have a history of joint subluxations and dislocations with resultant degenerative joint disease and chronic pain. Manifestations of fragile skin and soft tissue (eg, abnormal wound healing or scarring; spontaneous tearing of the skin, ligaments, tendons, or organs) are notably absent from the findings in this syndrome.⁵ The genetic basis for EDS is unknown in the majority of patients, although a deficiency in tenascin X (secondary to defects in the tenascin XB gene [TNXB]) has been identified in a small subset (<5%) of patients, leading to elastic fiber abnormalities, reduced collagen deposition, and impaired cross-linking of collagen.^6,7 Inheritance usually is autosomal dominant but also can be autosomal recessive. In contrast, the classic type of EDS (formerly types I and II) is associated with atrophic scarring and tissue fragility, in addition to joint hypermobility and skin hyperextensibility. Type V collagen mutations are found in more than half of patients with this disorder.⁸

We present the case of a patient with EDS-BHT who developed large nonhealing cutaneous ulcerations with initiation of high-dose systemic corticosteroids for treatment of dermatomyositis. This case provides a dramatic illustration of the effects of the use of chronic systemic corticosteroids on skin fragility and wound healing in patients with an underlying inherited defect in collagen or connective tissue.

Case Report

A 23-year-old man with an unremarkable medical history was admitted to our inpatient cardiology service with palpitations attributable to new-onset atrial fibrillation. Dermatology was consulted to evaluate a rash of approximately 4 months’ duration that started on the dorsal aspect of the hands, then progressed to involve the extensor elbows and knees. The rash also was associated with fatigue, arthralgia, and proximal muscle weakness. A taper of prednisone that was prescribed approximately 2 months prior to admission by a rheumatologist for presumed dermatomyositis improved his symptoms, but they recurred with discontinuation of the medication.

Physical examination revealed reddish, violaceous and hyperpigmented patches on the dorsal aspect of the hands and digits and the extensor aspect of the knees and elbows. A skin biopsy from the right elbow showed a mild interface reaction and nonspecific direct immunofluorescence, consistent with a diagnosis of dermatomyositis. Autoimmune serologies were negative, including antinuclear, anti–Jo-1, anti–Mi-2, anti–Sjögren syndrome antigen A, anti–Sjögren syndrome antigen B, anti-Smith, and antiribonucleoprotein antibodies. Creatine kinase and rheumatoid factor levels were within reference range. Electromyogram was supportive of the diagnosis of dermatomyositis, showing an irritable myopathy. Cardiac magnetic resonance imaging showed an acute inflammatory process of the myocardium, and a transthoracic echocardiogram revealed a depressed left ventricular ejection fraction of 35% to 40% (reference range, 55%–70%). His cardiac disease also was attributed to dermatomyositis, and he was managed by cardiology with anangiotensin-converting enzyme inhibitor and antiarrhythmic therapy. Rheumatology was consulted and prednisone 60 mg once daily was started, with the patient reporting improvement in his muscle weakness and the rash.

Interestingly, the patient also noted a history of joint hypermobility, and a genetics consultation was obtained during the current hospitalization. He denied a history of abnormal scarring or skin problems, but he did note dislocation of the patella on 2 occasions and an umbilical hernia repair at 3 years of age. A paternal uncle had a history of similar joint hypermobility. His Beighton score was noted to be 8/8 (bending at the waist was unable to be tested due to recent lumbar puncture obtained during this hospitalization). The patient was diagnosed with EDS-BHT, and no further workup was recommended.

Subsequent to his hospitalization for several days, the patient’s prednisone was slowly tapered down from 60 mg once daily to 12.5 mg once daily, and azathioprine was started and titrated up to 150 mg once daily. Approximately 6 months after his initial hospitalization, he was readmitted due to increased pain of the right knee with concern for osteomyelitis. Dermatology was again consulted, and at this time, the patient reported a 4-month history of nonhealing ulcers to the knees and elbows (Figure 1). He stated that the ulcers were initially about the size of a pencil eraser and had started approximately 2 months after the prednisone was started, with subsequent slow enlargement. He noted a stinging sensation with enlargement of the ulcers, but otherwise they were not painful. He denied major trauma to the areas. He noted that his prior rash from the dermatomyositis seemed to have resolved, along with his muscle weakness, and he reported weight gain and improvement in his energy levels. Physical examination at this time revealed several stigmata of chronic systemic corticosteroids, including fatty deposits in the face (moon facies) and between the shoulders (buffalo hump), facial acne, and numerous erythematous striae on the trunk and proximal extremities (Figure 2). Multiple noninflammatory ulcers with punched-out borders ranging in size from 0.5 to 6 cm were seen at sites overlying bony prominences, including the bilateral extensor elbows and knees and the right plantar foot. Similar ulcers were noted on the trunk within the striae. Some of the ulcers were covered with a thick hyperkeratotic crust. A biopsy from the edge of an ulcer on the right side of the flank showed only dermal fibrosis. Workup by orthopedic surgery was felt to be inconsistent with osteomyelitis, and plastic surgery was consulted to consider surgical options for repair. Consequently, the patient was taken to the operating room for primary closure of the ulcers to the bilateral knees and right elbow. He has been followed closely by plastic surgery, with the use of joint immobilization to promote wound healing.

Comment

This case represents a dramatic illustration of the effects of chronic systemic corticosteroids on skin fragility and wound healing in a patient with an underlying genetic defect in the connective tissue. The ulcers were all located within striae or overlying bony prominences where the skin was subjected to increased tension; however, the patient reported no problems with wound healing or scarring at these sites prior to the initiation of corticosteroids, suggesting that the addition of this medication was disruptive to the cutaneous wound healing mechanisms. This case is unique because abnormal wound healing in an EDS patient was so clearly linked to the initiation of systemic steroids.

The exact pathogenesis of the patient’s ulcers is unclear. The diagnosis of EDS was primarily clinical, and without genetic testing, we cannot state with certainty the underlying molecular problem in this patient. Although tenascin X deficiency has been found in a few patients, a genetic defect remains uncharacterized in most patients with EDS-BHT, and in most situations, EDS-BHT remains a clinical diagnosis. In 2001, Schalkwijk et al⁹ first described the association of tenascin X deficiency and EDS in 5 patients, and they noted delayed wound healing in 1 patient who had received systemic corticosteroids for congenital adrenal hyperplasia. The authors remarked that it was not clear whether the abnormality was linked to the patient’s EDS or to his treatment with systemic corticosteroids.⁹ Furthermore, it is possible that our patient in fact has a milder variant of classic type EDS and that the manifestations of tissue fragility remained subclinical until the addition of systemic corticosteroids. It also is interesting to note that muscle weakness can be a symptom of EDS, both classic and BHT of EDS, but our patient’s muscle weakness improved with immunosuppression, supporting an underlying autoimmune disease as the cause for it.¹⁰ Skin ulcerations have been reported as a rare manifestation of dermatomyositis, but it is remarkable that his ulcers progressed as his other dermatomyositis symptoms improved with therapy, suggesting that his autoimmune disease was not the underlying cause for the ulcers.^11-13 This case points to the need to thoughtfully consider the adverse effects of corticosteroids on wound healing in patients with an inherited disorder of collagen or connective tissue such as EDS.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

Mefloquine is a synthetic antimalarial drug structurally related to quinine. The drug was developed by the Walter Reed Army Institute of Research during a decades-long program that started during the Vietnam War in response to concerns of rising resistance to chloroquine.¹

The prelicensing clinical testing of mefloquine, originally known as WR 142,490, was conducted in part among U.S. military service members.^2,3 Soon after receiving FDA approval in 1989, under the brand name Lariam, it was recommended for use within the U.S. military.⁴ Over the following 2 decades, mefloquine was a common exposure during military deployments to malaria endemic areas.

Although the original U.S. mefloquine drug label noted that neuropsychiatric reactions could occur with use, changes to the drug label mandated by the FDA in July 2013, including a black box warning, described a potential for these to persist long after the drug has been discontinued.^5,6 These changes have served to reinforce earlier U.S. military policy changes beginning in 2009 that deprioritized use of the drug in favor of safer and better-tolerated antimalarials. Consequently, more than a quarter century after its introduction, mefloquine now is only rarely prescribed to members of the U.S. military.⁷

In addition to limiting current use of the drug, the recent boxed warning may have important implications for service-connected disability claims adjudication by the VA for veterans previously exposed to the drug. This report presents a case of a nondeployed veteran exposed to mefloquine during an early military postmarketing study who developed chronic neuropsychiatric symptoms linked to the drug that were recently deemed service-connected. This report concludes with some comments on the likely implications of this case for future similar disability claims.

Case Presentation

In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine.⁸ As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.

Discussion

Although the original 1989 FDA-approved mefloquine label had warned to discontinue the drug if specific prodromal symptoms of “anxiety, depression, restlessness or confusion” were noted,as illustrated by this case, this guidance was not always consistently communicated to service members.⁵ Indeed, few service members in the 1991 military postmarketing study discontinued the medication even after reporting such symptoms.⁸ Vivid dreams, often described as “terrifying nightmares with technicolor clarity” were reported by 7% of study participants. Similarly, concentration problems were reported in 5%; irritability in 4%; anger and moodiness each in 1%; and insomnia in 25%. Two study participants, after failing to discontinue mefloquine at the onset of severe insomnia, were later hospitalized for severe depression and suicidal thoughts, later deemed due to preexisting conditions. Despite these seemingly unfavorable results, mefloquine was nonetheless deemed well tolerated.⁸

Military Use of Mefloquine

Beginning in 1992, use of mefloquine for prophylaxis of malaria was then widely directed within the U.S. military during operations in Somalia. There, a majority of personnel received mefloquine under conditions of command-directed and directly observed administration of the drug.^9,10 Again, drug label guidance describing the prodromal psychiatric symptoms that should have prompted discontinuation of mefloquine were either not consistently adhered to or not communicated. In one Somalia-era study, only 1 in 344 service members, or 0.3%, discontinued the drug.¹¹

Throughout the remainder of the 1990s, mefloquine remained the antimalarial drug of choice for most U.S. military operations, and when combat began in Afghanistan in 2001, widespread use was also directed there.^12,13 The following year, after national attention was directed to concerns of severe behavioral toxicity from the drug among personnel returning from Afghanistan, the manufacturer issued subtle changes to the mefloquine label warnings.^5,14

These label changes adjusted the previously exclusive list of prodromal symptoms to an illustrative list, emphasizing that “if psychiatric symptoms such as [emphasis added] acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted.”⁵

In 2001 a randomized double-blinded trial demonstrated that symptoms of anxiety and depression occurred in at least 4% of mefloquine users, insomnia in 13%, and abnormal dreams in 14%. Nevertheless, an Army memorandum issued soon after the labeling change significantly understated the known risks of developing such psychiatric symptoms, erroneously claiming that these occurred from mefloquine only “at a rate of one per 2,000 to 13,000 persons.”^15,16

Updated FDA Guidelines

In 2003, with widespread use of the drug being again directed during operations in Iraq, the FDA required that all mefloquine prescriptions be accompanied by a patient medication guide with warnings echoing those of the drug label that users seek medical attention should “possible signs of more serious mental problems” develop.^5,17 However, surveys suggested that few U.S. service members received these warnings or even verbal instructions to that effect.^17-19 During later congressional testimony, a service member who had experienced 3 weeks of nightmares prior to self-discontinuing the drug testified “every soldier I know has problems with it.”²⁰

In response, a senior military medical leader—failing to recognize that the nightmares the soldier reported were in fact psychiatric symptoms and possible signs of more serious mental problems that required the drug’s discontinuation—may have undermined the FDA-directed warnings by dismissing the soldier’s testimony as “perception,” maintaining instead “that perceptions can become realities” should it become “held that this medication is widely problematic.”²⁰

Given that certain preexisting conditions, including anxiety and depression, were known to confound recognition of incident psychiatric symptoms that required discontinuation of the drug, the original 1989 mefloquine label had noted that the drug should be used with caution in such patients. In subsequent years, this language was strengthened, and such patients were formally contraindicated the drug.²¹

Citing formal policy, senior military medical leaders provided assurance during congressional testimony that service members with these conditions would not be prescribed mefloquine.^16,18,20 However, later analysis of a large group of deployed service members revealed that 1 in 7 with contraindications to mefloquine had been prescribed the drug contrary to drug label guidance.²¹

Black Box Warning

With growing recognition of the challenges in using mefloquine as directed by the drug label, a 2009 Army policy memorandum prioritized the use of safer and better-tolerated daily medications, such as doxycycline and atovaquone-proguanil, and stated that “[m]efloquine should only be used for personnel with contraindications to doxycycline.”²² This policy was extended throughout the other military services later that year.²³ After concerns were raised that service members were still being prescribed the drug contrary to policy, further restrictions were formalized in early 2013 prior to the boxed warning, with mefloquine reserved for those only “with intolerance or contraindications” to the first-line drugs.^24,25

In a later memorandum announcing the July 2013 boxed warning, the military revealed that the number of active-duty personnel prescribed mefloquine had steadily decreased in prior years from 17,361 in 2008 to only 2,040 in 2012.⁷ Although the military has not released precise figures on the number of U.S. military personnel exposed to mefloquine since the drug’s introduction, based on a variety of sources, the total is likely to far exceed 100,000.^7,26

The major changes to the mefloquine label in 2013, including the boxed warning, clarified that neurologic and psychiatric effects from mefloquine could “persist after mefloquine has been discontinued.” The accompanying FDA Drug Safety Communication noted neurologic AEs from the drug, which include but are not limited to “dizziness, loss of balance, or ringing in the ears,” could “occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent.”⁶ Other neurologic symptoms listed in the drug label include vertigo, hearing impairment, headache, visual disturbances, sensory and motor neuropathies, including paresthesia, tremor, ataxia, convulsions, and encephalopathy.⁶

The updated drug label also made clear that psychiatric AEs from mefloquine, such as anxiety, paranoia, and depression to hallucinations and psychotic behavior, “have been reported to continue for months or years after mefloquine has been stopped.” Other psychiatric symptoms listed in the drug label include memory impairment, confusion, somnolence, insomnia, abnormal dreams, aggression, agitation, restlessness, mood swings, panic attacks, psychosis, and suicidal ideation.⁶

The 2013 boxed warning also served to reemphasize guidance first articulated in 2002 that any psychiatric symptom—presumably including abnormal dreams and insomnia—occurring during mefloquine use should be considered prodromal, prompting the drug’s immediate discontinuation.⁵ Specifically, the boxed warning explicitly cautioned that given the risk for serious psychiatric disturbances or neurologic AEs when used for malaria prophylaxis, “if psychiatric or neurologic symptoms occur, the drug should be discontinued and an alternative medication should be substituted.”⁶

Drug of Last Resort

By late 2013, partially on the basis of the boxed warning, the U.S. military declared mefloquine a “drug of last resort.”^7,27 The U.S. Army Special Operations Command (USASOC) took the further step of prohibiting use of mefloquine altogether and, according to news reports, directed that medical and command staff assess whether certain personnel experiencing AEs from the drug may mistakenly have been thought to be malingering, have PTSD, or have other psychological problems.²⁸

As the boxed warning and the USASOC order suggest, veterans exposed to mefloquine may have incurred a broad range of neurologic or psychiatric disorders or had others aggravated during military service as a result of their use of the drug. The effects of mefloquine may have confounded the diagnosis of neurologic or psychiatric disorders related to military service.^26,29 As these AEs may be a direct result of mefloquine prescribed during military service, those with disabling diagnoses consistent with these effects may be entitled to claim disability compensation through the VA.

Of potential significant relevance to this adjudication process is a memorandum written in early 2012, in which the military conceded:

Some deploying Service members have been provided mefloquine for malaria prophylaxis without appropriate documentation in their medical records and without proper screening for contraindications. In addition, not all individuals have been provided the required mefloquine medication guide and wallet information card, as required by the Food and Drug Administration. ²⁴

Veterans claiming a service-connected disability as a result of their use of mefloquine should therefore not always be expected to have documentation of prescribing in their military medical records. Although the VA could consider denying such claims for absence of proof of a nexus to military service, in light of this memorandum, the VA may need to consider other evidence of plausible exposure, including veteran testimony and deployment history.

It is also conceivable that the VA could consider denying such claims by arguing that the veteran directly contributed to the disability through willful misconduct by not adhering to mefloquine label guidance. However, as this memorandum establishes that mefloquine use was frequently directed without communication of the drug label precautions and warnings, the VA should consider that veterans claiming a service-connected disability frequently will not have known or otherwise been unable to discontinue the medication at the onset of prodromal symptoms.

It is also possible that the VA might deny claims on the basis that the claimed disabilities reflect preexisting conditions. However, as the memorandum establishes, use of mefloquine also was occasionally inappropriately directed to those with documented contraindications to the medication, who would have increased risk of AEs. As a result, veterans with preexisting neurologic or psychiatric conditions or disorders who nonetheless were prescribed mefloquine may reasonably claim these were aggravated during military service.

Conclusion

As this case suggests, in the coming years, as awareness of the chronic AEs of mefloquine increases among the veteran population, claims related to prior use of the drug are likely to increase and become of significant interest to the VA. Veterans with plausible exposure to mefloquine with neuropsychiatric disabilities who have yet to file a claim may be able to do so, and those veterans whose claims for service-connection were unfavorably adjudicated may be able to reopen their claims on the basis of the new material evidence in the 2012 military memorandum and the 2013 boxed warning.

This case report also suggests that service-connected disability claims arising from chronic neuropsychiatric AEs from mefloquine may prove to be of significant financial consequence. Further research to better define both the extent of prior mefloquine use among U.S. military personnel and the nature and prevalence of those chronic neurologic and psychiatric disorders caused by the drug would be helpful in informing improvements in the efficient and fair adjudication of such service-connected disability claims.

Case

A 39-year-old woman, previously in good health, presented to the ED with a chief complaint of severe sore throat, which she said had begun approximately 4 hours prior and was rapidly worsening. She thought her voice sounded muffled, and said she was now having difficulty swallowing her saliva. The patient denied fever but did admit to chills. She experienced onset of shortness of breath 30 minutes prior to arrival to the ED.

The patient stated that she was a house painter and had been working in the home of someone who had several dogs. While not previously allergic to animals, the patient was concerned exposure to the dogs might have contributed to her symptoms. Regarding her social history, the patient admitted to daily consumption of beer, but denied smoking cigarettes. She had no known drug allergies.

On physical examination, the patient was afebrile. Her vital signs were: heart rate, 125 beats/min; blood pressure, 137/74 mm Hg; and respiratory rate, 18 breaths/min. Oxygen saturation was 99% on room air. Overall, the patient appeared anxious and exhibited mild inspiratory stridor. Examination of the eyes and ears were normal. There was no obvious inflammation or swelling of the posterior pharynx; the tongue was normal; there was no swelling of the floor of the mouth; and the uvula was midline and without swelling.

The patient was noted to having difficulty handling her secretions. She exhibited full range of motion of her neck. Her trachea was tender upon palpation but without jugular venous distension or lymphadenopathy. The cardiac examination was significant for tachycardia with a regular rhythm and without murmurs, rubs, or gallops; the pulmonary examination was normal except for transmitted upper airway sounds. The patient’s abdominal, dermatological, and neurological examinations were all normal.

Based on the examination findings, the differential diagnosis included allergic reaction, angioedema, epiglottitis, and retropharyngeal abscess. An intravenous (IV) line was placed and blood was drawn for laboratory evaluation, which included a complete blood count, basic metabolic panel (BMP), and a quantitative pregnancy test. Given the patient’s history, the emergency physician (EP) was most concerned for an allergic reaction, and administered epinephrine 0.5 mg (1:1,000) intramuscularly (IM) in the mid-anterolateral thigh, in addition to methylprednisolone, 125 mg; diphenhydramine, 25 mg; and famotidine, 20 mg IV.

A portable soft-tissue lateral radiograph of the neck was obtained. Radiology services interpreted the film as showing “prominent prevertebral soft tissues and epiglottis.

Discussion

While the incidence of pediatric epiglottitis has decreased since the introduction of the Haemophilus influenzae type b (Hib) vaccine in 1985, adult epiglottitis continues to represent a potentially life-threatening condition whose incidence has remained constant over the past several decades.^1,2 The incidence of supraglottitis in adults is now 2.5 times greater than the incidence in children.^3,4

Several important differences exist in the presentation and management of adults who present with inflammation of the epiglottis as compared to children. Children commonly present with an acute onset of symptoms, and due to their smaller and more pliant airway anatomy, they often experience stridor and respiratory distress.^3,5 The inflammation in children is typically confined to the epiglottis and aryepiglottic folds, while in adults the inflammation can affect not only the epiglottis, but also supraglottic structures such as the pharynx, uvula, and aryepiglottic folds. For this reason, in adults the condition is often referred to as “supraglottitis.”^2,6 Adults with supraglottitis most likely present in their 30s, 40s, and 50s, while children present between the ages of 2 and 5 years old.^1,3,7 In adults, men more commonly present with supraglottitis than women.^1,2 Cigarette smokers and patients with hypertension, diabetes mellitus (DM), chronic obstructive pulmonary disease, or human immunodeficiency virus/AIDS are at increased risk for supraglottitis.^3,4 The mortality rate for adults with supraglottitis ranges from 1.2% to 7.1%.³

Etiology

Prior to the use of the Hib vaccine, Hib was the most common cause of epiglottitis, and remains so for children.¹ Currently, the most common cause of supraglottitis in adults is Group A beta-hemolytic Streptococci.² Other etiologies include other bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas species, Klebsiella pneumoniae, Pasteurella multocida, Neisseria species), viruses (herpes simplex, varicella, parainfluenza), trauma, and thermal injuries.^1,4,5,8

Signs and Symptoms

Throat pain, dysphagia, odynophagia, and muffled voice are common complaints of adults presenting to the ED with supraglottitis.^2,7 Fever is usually, but not always, present; the complaint of cough, however, is rare.^2,3,4 Other less frequent complaints include hoarseness and drooling. Adults can also present with cervical lymphadenopathy, anterior neck tenderness, and cellulitis of the neck and chest.^2,4 In general, the more severe cases will progress rapidly over a few hours. Due to the larger anatomy in adults, they are more likely than children to experience a gradual progression of symptoms, and supraglottitis will be missed on the initial presentation in up to 50% of adults.^3,4 Stridor or respiratory compromise does occur in a minority of adult patients with supraglottitis. The need for artificial airway support (ie, endotracheal intubation, cricothyroidotomy) in adults ranges from 6.6% to 16%.^9,10

Making the Diagnosis

The gold standard for diagnosing supraglottitis is direct laryngoscopy.^3,4 This point is emphasized in our case report, since the CT scan was concerning for a retropharyngeal abscess, and not supraglottitis. The examination of the oropharynx is generally safer and better tolerated in adults compared to pediatric patients, since airway compromise is much less likely. On occasion, inflammation, erythema, and edema of the epiglottis, aryepiglottic folds, or arytenoid cartilages can be observed.⁵ More commonly, the supraglottic structures are not visualized, and the posterior oropharynx appears relatively normal. This should serve as a clue for possible supraglottitis.

In suspected cases of adult supraglottitis without emergent airway compromise, lateral soft-tissue radiographs can be obtained to look for the “thumb sign,” indicating a swollen epiglottis. In adult supraglottitis, the width of the epiglottis is usually greater than 8 mm.¹¹ Other abnormal radiographic findings include arytenoid and aryepiglottic fold enlargement, thinning of the airway, and an increase in size of the prevertebral space. Plain film sensitivity rates range from 38% to 98%.

Complete blood count and throat cultures are not particularly helpful in adult cases. Blood cultures, while only about 30% sensitive in adults, should be considered as supraglottitis can result in secondary infection in the central nervous system, lungs, and surrounding structures.^3,5

If available, otolaryngology services should be consulted to evaluate the airway, and IV antibiotics, such as a third-generation cephalosporin (eg, ceftriaxone, cefotaxime), should be initiated to include coverage of Hib.³ If methicillin-resistant S aureus is a concern, vancomycin should be added. Clindamycin or metronidazole should also be given if anaerobes are suspected.^4,7 The location for performing the nasopharyngeal laryngoscopy varies, depending on the patient’s age (ie, pediatric vs adult), severity of symptoms, presence of airway compromise, and local practice and custom.

Advanced imaging studies (CT scan or magnetic resonance imaging) can help identify the presence of an abscess and delineate the extent of the infection, but are not indicated in the early diagnosis and management of suspected adult supraglottitis.⁴ As our case demonstrates, CT is neither highly sensitive nor specific for the diagnosis of epiglottitis. The role of ultrasound in the evaluation of suspected epiglottitis is still being developed. One recent study compared 15 healthy volunteers with 15 patients diagnosed with epiglottitis by an otolaryngologist using laryngoscopy.¹² A statistically significant difference was observed in the anteroposterior diameter of the epiglottis at the midpoint and both lateral edges between the study subjects and healthy volunteers.¹² While there was overlap in the ranges for the midpoint, there was no overlap in both lateral edges between the two groups.¹²

Treatment

The vast majority of adult cases of supraglottitis are managed medically without airway intervention. Patients presenting with a rapid onset of symptoms and in respiratory distress or with stridor, drooling, or cyanosis, should be managed with early airway intervention. The use of corticosteroids is controversial, and has not been proven beneficial in any prospective trials.^1-4,6,7,13

Admission to a critical care unit is indicated initially, even in patients who are not intubated, as they can experience delayed airway compromise with progression of the infection and edema.¹³

Complications

Abscess formation is a serious complication of supraglottitis, is present in up to 30% of cases, and is more likely to be seen in adults than in children.¹³ Since the adult larynx and surrounding tissues are larger than in children, often the infection is present longer, which allows for an abscess to develop. The risk of abscess formation is increased in patients with DM or those in whom a foreign body is present.

Numerous organisms have been isolated from supraglottic abscesses in adults, and in addition to incision and drainage, antibiotics covering both gram-positive organisms and anaerobes should be initiated.⁵ The presence of a supraglottic abscess increases the need for emergent intubation.¹³ In addition, a supraglottic abscess increases the mortality rate to 30%.³ Other complications from supraglottitis include mediastinitis, cervical adenitis, meningitis, and pneumonia.^4,5

Conclusion

While the incidence of epiglottitis in the pediatric patient population has fallen, the incidence in adults remains relatively stable. Clinicians should consider supraglottitis in the differential diagnosis of adults presenting with severe sore throat, dysphagia, or stridor. While airway compromise in adults is uncommon, it does occur. Soft-tissue lateral neck radiographs can help make the diagnosis, but the gold standard remains laryngoscopy. All patients should be started on IV antibiotics and admitted to the ICU initially for airway watch.

Case

A 39-year-old woman, previously in good health, presented to the ED with a chief complaint of severe sore throat, which she said had begun approximately 4 hours prior and was rapidly worsening. She thought her voice sounded muffled, and said she was now having difficulty swallowing her saliva. The patient denied fever but did admit to chills. She experienced onset of shortness of breath 30 minutes prior to arrival to the ED.

The patient stated that she was a house painter and had been working in the home of someone who had several dogs. While not previously allergic to animals, the patient was concerned exposure to the dogs might have contributed to her symptoms. Regarding her social history, the patient admitted to daily consumption of beer, but denied smoking cigarettes. She had no known drug allergies.

On physical examination, the patient was afebrile. Her vital signs were: heart rate, 125 beats/min; blood pressure, 137/74 mm Hg; and respiratory rate, 18 breaths/min. Oxygen saturation was 99% on room air. Overall, the patient appeared anxious and exhibited mild inspiratory stridor. Examination of the eyes and ears were normal. There was no obvious inflammation or swelling of the posterior pharynx; the tongue was normal; there was no swelling of the floor of the mouth; and the uvula was midline and without swelling.

The patient was noted to having difficulty handling her secretions. She exhibited full range of motion of her neck. Her trachea was tender upon palpation but without jugular venous distension or lymphadenopathy. The cardiac examination was significant for tachycardia with a regular rhythm and without murmurs, rubs, or gallops; the pulmonary examination was normal except for transmitted upper airway sounds. The patient’s abdominal, dermatological, and neurological examinations were all normal.

Based on the examination findings, the differential diagnosis included allergic reaction, angioedema, epiglottitis, and retropharyngeal abscess. An intravenous (IV) line was placed and blood was drawn for laboratory evaluation, which included a complete blood count, basic metabolic panel (BMP), and a quantitative pregnancy test. Given the patient’s history, the emergency physician (EP) was most concerned for an allergic reaction, and administered epinephrine 0.5 mg (1:1,000) intramuscularly (IM) in the mid-anterolateral thigh, in addition to methylprednisolone, 125 mg; diphenhydramine, 25 mg; and famotidine, 20 mg IV.

A portable soft-tissue lateral radiograph of the neck was obtained. Radiology services interpreted the film as showing “prominent prevertebral soft tissues and epiglottis.

Discussion

While the incidence of pediatric epiglottitis has decreased since the introduction of the Haemophilus influenzae type b (Hib) vaccine in 1985, adult epiglottitis continues to represent a potentially life-threatening condition whose incidence has remained constant over the past several decades.^1,2 The incidence of supraglottitis in adults is now 2.5 times greater than the incidence in children.^3,4

Several important differences exist in the presentation and management of adults who present with inflammation of the epiglottis as compared to children. Children commonly present with an acute onset of symptoms, and due to their smaller and more pliant airway anatomy, they often experience stridor and respiratory distress.^3,5 The inflammation in children is typically confined to the epiglottis and aryepiglottic folds, while in adults the inflammation can affect not only the epiglottis, but also supraglottic structures such as the pharynx, uvula, and aryepiglottic folds. For this reason, in adults the condition is often referred to as “supraglottitis.”^2,6 Adults with supraglottitis most likely present in their 30s, 40s, and 50s, while children present between the ages of 2 and 5 years old.^1,3,7 In adults, men more commonly present with supraglottitis than women.^1,2 Cigarette smokers and patients with hypertension, diabetes mellitus (DM), chronic obstructive pulmonary disease, or human immunodeficiency virus/AIDS are at increased risk for supraglottitis.^3,4 The mortality rate for adults with supraglottitis ranges from 1.2% to 7.1%.³

Etiology

Prior to the use of the Hib vaccine, Hib was the most common cause of epiglottitis, and remains so for children.¹ Currently, the most common cause of supraglottitis in adults is Group A beta-hemolytic Streptococci.² Other etiologies include other bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas species, Klebsiella pneumoniae, Pasteurella multocida, Neisseria species), viruses (herpes simplex, varicella, parainfluenza), trauma, and thermal injuries.^1,4,5,8

Signs and Symptoms

Throat pain, dysphagia, odynophagia, and muffled voice are common complaints of adults presenting to the ED with supraglottitis.^2,7 Fever is usually, but not always, present; the complaint of cough, however, is rare.^2,3,4 Other less frequent complaints include hoarseness and drooling. Adults can also present with cervical lymphadenopathy, anterior neck tenderness, and cellulitis of the neck and chest.^2,4 In general, the more severe cases will progress rapidly over a few hours. Due to the larger anatomy in adults, they are more likely than children to experience a gradual progression of symptoms, and supraglottitis will be missed on the initial presentation in up to 50% of adults.^3,4 Stridor or respiratory compromise does occur in a minority of adult patients with supraglottitis. The need for artificial airway support (ie, endotracheal intubation, cricothyroidotomy) in adults ranges from 6.6% to 16%.^9,10

Making the Diagnosis

The gold standard for diagnosing supraglottitis is direct laryngoscopy.^3,4 This point is emphasized in our case report, since the CT scan was concerning for a retropharyngeal abscess, and not supraglottitis. The examination of the oropharynx is generally safer and better tolerated in adults compared to pediatric patients, since airway compromise is much less likely. On occasion, inflammation, erythema, and edema of the epiglottis, aryepiglottic folds, or arytenoid cartilages can be observed.⁵ More commonly, the supraglottic structures are not visualized, and the posterior oropharynx appears relatively normal. This should serve as a clue for possible supraglottitis.

In suspected cases of adult supraglottitis without emergent airway compromise, lateral soft-tissue radiographs can be obtained to look for the “thumb sign,” indicating a swollen epiglottis. In adult supraglottitis, the width of the epiglottis is usually greater than 8 mm.¹¹ Other abnormal radiographic findings include arytenoid and aryepiglottic fold enlargement, thinning of the airway, and an increase in size of the prevertebral space. Plain film sensitivity rates range from 38% to 98%.

Complete blood count and throat cultures are not particularly helpful in adult cases. Blood cultures, while only about 30% sensitive in adults, should be considered as supraglottitis can result in secondary infection in the central nervous system, lungs, and surrounding structures.^3,5

If available, otolaryngology services should be consulted to evaluate the airway, and IV antibiotics, such as a third-generation cephalosporin (eg, ceftriaxone, cefotaxime), should be initiated to include coverage of Hib.³ If methicillin-resistant S aureus is a concern, vancomycin should be added. Clindamycin or metronidazole should also be given if anaerobes are suspected.^4,7 The location for performing the nasopharyngeal laryngoscopy varies, depending on the patient’s age (ie, pediatric vs adult), severity of symptoms, presence of airway compromise, and local practice and custom.

Advanced imaging studies (CT scan or magnetic resonance imaging) can help identify the presence of an abscess and delineate the extent of the infection, but are not indicated in the early diagnosis and management of suspected adult supraglottitis.⁴ As our case demonstrates, CT is neither highly sensitive nor specific for the diagnosis of epiglottitis. The role of ultrasound in the evaluation of suspected epiglottitis is still being developed. One recent study compared 15 healthy volunteers with 15 patients diagnosed with epiglottitis by an otolaryngologist using laryngoscopy.¹² A statistically significant difference was observed in the anteroposterior diameter of the epiglottis at the midpoint and both lateral edges between the study subjects and healthy volunteers.¹² While there was overlap in the ranges for the midpoint, there was no overlap in both lateral edges between the two groups.¹²

Treatment

The vast majority of adult cases of supraglottitis are managed medically without airway intervention. Patients presenting with a rapid onset of symptoms and in respiratory distress or with stridor, drooling, or cyanosis, should be managed with early airway intervention. The use of corticosteroids is controversial, and has not been proven beneficial in any prospective trials.^1-4,6,7,13

Admission to a critical care unit is indicated initially, even in patients who are not intubated, as they can experience delayed airway compromise with progression of the infection and edema.¹³

Complications

Abscess formation is a serious complication of supraglottitis, is present in up to 30% of cases, and is more likely to be seen in adults than in children.¹³ Since the adult larynx and surrounding tissues are larger than in children, often the infection is present longer, which allows for an abscess to develop. The risk of abscess formation is increased in patients with DM or those in whom a foreign body is present.

Numerous organisms have been isolated from supraglottic abscesses in adults, and in addition to incision and drainage, antibiotics covering both gram-positive organisms and anaerobes should be initiated.⁵ The presence of a supraglottic abscess increases the need for emergent intubation.¹³ In addition, a supraglottic abscess increases the mortality rate to 30%.³ Other complications from supraglottitis include mediastinitis, cervical adenitis, meningitis, and pneumonia.^4,5

Conclusion

While the incidence of epiglottitis in the pediatric patient population has fallen, the incidence in adults remains relatively stable. Clinicians should consider supraglottitis in the differential diagnosis of adults presenting with severe sore throat, dysphagia, or stridor. While airway compromise in adults is uncommon, it does occur. Soft-tissue lateral neck radiographs can help make the diagnosis, but the gold standard remains laryngoscopy. All patients should be started on IV antibiotics and admitted to the ICU initially for airway watch.

Case

A 39-year-old woman, previously in good health, presented to the ED with a chief complaint of severe sore throat, which she said had begun approximately 4 hours prior and was rapidly worsening. She thought her voice sounded muffled, and said she was now having difficulty swallowing her saliva. The patient denied fever but did admit to chills. She experienced onset of shortness of breath 30 minutes prior to arrival to the ED.

The patient stated that she was a house painter and had been working in the home of someone who had several dogs. While not previously allergic to animals, the patient was concerned exposure to the dogs might have contributed to her symptoms. Regarding her social history, the patient admitted to daily consumption of beer, but denied smoking cigarettes. She had no known drug allergies.

On physical examination, the patient was afebrile. Her vital signs were: heart rate, 125 beats/min; blood pressure, 137/74 mm Hg; and respiratory rate, 18 breaths/min. Oxygen saturation was 99% on room air. Overall, the patient appeared anxious and exhibited mild inspiratory stridor. Examination of the eyes and ears were normal. There was no obvious inflammation or swelling of the posterior pharynx; the tongue was normal; there was no swelling of the floor of the mouth; and the uvula was midline and without swelling.

The patient was noted to having difficulty handling her secretions. She exhibited full range of motion of her neck. Her trachea was tender upon palpation but without jugular venous distension or lymphadenopathy. The cardiac examination was significant for tachycardia with a regular rhythm and without murmurs, rubs, or gallops; the pulmonary examination was normal except for transmitted upper airway sounds. The patient’s abdominal, dermatological, and neurological examinations were all normal.

Based on the examination findings, the differential diagnosis included allergic reaction, angioedema, epiglottitis, and retropharyngeal abscess. An intravenous (IV) line was placed and blood was drawn for laboratory evaluation, which included a complete blood count, basic metabolic panel (BMP), and a quantitative pregnancy test. Given the patient’s history, the emergency physician (EP) was most concerned for an allergic reaction, and administered epinephrine 0.5 mg (1:1,000) intramuscularly (IM) in the mid-anterolateral thigh, in addition to methylprednisolone, 125 mg; diphenhydramine, 25 mg; and famotidine, 20 mg IV.

A portable soft-tissue lateral radiograph of the neck was obtained. Radiology services interpreted the film as showing “prominent prevertebral soft tissues and epiglottis.

Discussion

While the incidence of pediatric epiglottitis has decreased since the introduction of the Haemophilus influenzae type b (Hib) vaccine in 1985, adult epiglottitis continues to represent a potentially life-threatening condition whose incidence has remained constant over the past several decades.^1,2 The incidence of supraglottitis in adults is now 2.5 times greater than the incidence in children.^3,4

Several important differences exist in the presentation and management of adults who present with inflammation of the epiglottis as compared to children. Children commonly present with an acute onset of symptoms, and due to their smaller and more pliant airway anatomy, they often experience stridor and respiratory distress.^3,5 The inflammation in children is typically confined to the epiglottis and aryepiglottic folds, while in adults the inflammation can affect not only the epiglottis, but also supraglottic structures such as the pharynx, uvula, and aryepiglottic folds. For this reason, in adults the condition is often referred to as “supraglottitis.”^2,6 Adults with supraglottitis most likely present in their 30s, 40s, and 50s, while children present between the ages of 2 and 5 years old.^1,3,7 In adults, men more commonly present with supraglottitis than women.^1,2 Cigarette smokers and patients with hypertension, diabetes mellitus (DM), chronic obstructive pulmonary disease, or human immunodeficiency virus/AIDS are at increased risk for supraglottitis.^3,4 The mortality rate for adults with supraglottitis ranges from 1.2% to 7.1%.³

Etiology

Prior to the use of the Hib vaccine, Hib was the most common cause of epiglottitis, and remains so for children.¹ Currently, the most common cause of supraglottitis in adults is Group A beta-hemolytic Streptococci.² Other etiologies include other bacteria (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas species, Klebsiella pneumoniae, Pasteurella multocida, Neisseria species), viruses (herpes simplex, varicella, parainfluenza), trauma, and thermal injuries.^1,4,5,8

Signs and Symptoms

Throat pain, dysphagia, odynophagia, and muffled voice are common complaints of adults presenting to the ED with supraglottitis.^2,7 Fever is usually, but not always, present; the complaint of cough, however, is rare.^2,3,4 Other less frequent complaints include hoarseness and drooling. Adults can also present with cervical lymphadenopathy, anterior neck tenderness, and cellulitis of the neck and chest.^2,4 In general, the more severe cases will progress rapidly over a few hours. Due to the larger anatomy in adults, they are more likely than children to experience a gradual progression of symptoms, and supraglottitis will be missed on the initial presentation in up to 50% of adults.^3,4 Stridor or respiratory compromise does occur in a minority of adult patients with supraglottitis. The need for artificial airway support (ie, endotracheal intubation, cricothyroidotomy) in adults ranges from 6.6% to 16%.^9,10

Making the Diagnosis

The gold standard for diagnosing supraglottitis is direct laryngoscopy.^3,4 This point is emphasized in our case report, since the CT scan was concerning for a retropharyngeal abscess, and not supraglottitis. The examination of the oropharynx is generally safer and better tolerated in adults compared to pediatric patients, since airway compromise is much less likely. On occasion, inflammation, erythema, and edema of the epiglottis, aryepiglottic folds, or arytenoid cartilages can be observed.⁵ More commonly, the supraglottic structures are not visualized, and the posterior oropharynx appears relatively normal. This should serve as a clue for possible supraglottitis.

In suspected cases of adult supraglottitis without emergent airway compromise, lateral soft-tissue radiographs can be obtained to look for the “thumb sign,” indicating a swollen epiglottis. In adult supraglottitis, the width of the epiglottis is usually greater than 8 mm.¹¹ Other abnormal radiographic findings include arytenoid and aryepiglottic fold enlargement, thinning of the airway, and an increase in size of the prevertebral space. Plain film sensitivity rates range from 38% to 98%.

Complete blood count and throat cultures are not particularly helpful in adult cases. Blood cultures, while only about 30% sensitive in adults, should be considered as supraglottitis can result in secondary infection in the central nervous system, lungs, and surrounding structures.^3,5

If available, otolaryngology services should be consulted to evaluate the airway, and IV antibiotics, such as a third-generation cephalosporin (eg, ceftriaxone, cefotaxime), should be initiated to include coverage of Hib.³ If methicillin-resistant S aureus is a concern, vancomycin should be added. Clindamycin or metronidazole should also be given if anaerobes are suspected.^4,7 The location for performing the nasopharyngeal laryngoscopy varies, depending on the patient’s age (ie, pediatric vs adult), severity of symptoms, presence of airway compromise, and local practice and custom.

Advanced imaging studies (CT scan or magnetic resonance imaging) can help identify the presence of an abscess and delineate the extent of the infection, but are not indicated in the early diagnosis and management of suspected adult supraglottitis.⁴ As our case demonstrates, CT is neither highly sensitive nor specific for the diagnosis of epiglottitis. The role of ultrasound in the evaluation of suspected epiglottitis is still being developed. One recent study compared 15 healthy volunteers with 15 patients diagnosed with epiglottitis by an otolaryngologist using laryngoscopy.¹² A statistically significant difference was observed in the anteroposterior diameter of the epiglottis at the midpoint and both lateral edges between the study subjects and healthy volunteers.¹² While there was overlap in the ranges for the midpoint, there was no overlap in both lateral edges between the two groups.¹²

Treatment

The vast majority of adult cases of supraglottitis are managed medically without airway intervention. Patients presenting with a rapid onset of symptoms and in respiratory distress or with stridor, drooling, or cyanosis, should be managed with early airway intervention. The use of corticosteroids is controversial, and has not been proven beneficial in any prospective trials.^1-4,6,7,13

Admission to a critical care unit is indicated initially, even in patients who are not intubated, as they can experience delayed airway compromise with progression of the infection and edema.¹³

Complications

Abscess formation is a serious complication of supraglottitis, is present in up to 30% of cases, and is more likely to be seen in adults than in children.¹³ Since the adult larynx and surrounding tissues are larger than in children, often the infection is present longer, which allows for an abscess to develop. The risk of abscess formation is increased in patients with DM or those in whom a foreign body is present.

Numerous organisms have been isolated from supraglottic abscesses in adults, and in addition to incision and drainage, antibiotics covering both gram-positive organisms and anaerobes should be initiated.⁵ The presence of a supraglottic abscess increases the need for emergent intubation.¹³ In addition, a supraglottic abscess increases the mortality rate to 30%.³ Other complications from supraglottitis include mediastinitis, cervical adenitis, meningitis, and pneumonia.^4,5

Conclusion

While the incidence of epiglottitis in the pediatric patient population has fallen, the incidence in adults remains relatively stable. Clinicians should consider supraglottitis in the differential diagnosis of adults presenting with severe sore throat, dysphagia, or stridor. While airway compromise in adults is uncommon, it does occur. Soft-tissue lateral neck radiographs can help make the diagnosis, but the gold standard remains laryngoscopy. All patients should be started on IV antibiotics and admitted to the ICU initially for airway watch.

Case

A 25-year-old college student presented to the ED following a near-syncopal episode. The patient stated he had felt lightheaded and had fallen to his knees immediately after taking a shower earlier that morning, but did not experience any loss of consciousness or injury. He denied a history of syncope or any recent trauma or fatigue. A review of the patient’s systems was negative. His medical history was remarkable for irritable bowel syndrome; he had no surgical history. Regarding his social history, he admitted to occasional alcohol use but denied any tobacco or illicit drug use. He was not on any current prescription or over-the-counter medications and denied any allergies.

The patient’s initial vital signs at presentation were: blood pressure, 112/58 mm Hg; heart rate, 86 beats/min; temperature, 97.9°F; and respiratory rate, 18 breaths/min. Oxygen saturation was 100% on room air. The patient reported pain in his left shoulder, epigastric region, and right flank. He rated his pain as a “4” on a 0-to-10 pain scale.

On physical examination, the patient was alert and oriented; he was thin and had mild pallor. His head, eyes, ears, nose, and throat; cardiac; pulmonary; and neurological examinations were normal. The abdominal examination revealed a soft, minimally tender epigastrium but with normal bowel sounds. Initial laboratory studies were remarkable for low hemoglobin (Hgb; 12.0 g/dL) and elevated aspartate transaminase (105 U/L), alanine aminotransferase (168 U/L), total bilirubin (1.6 mg/dL), and glucose (179 mg/dL) levels. The patient’s troponin I and lipase levels were within normal range. An electrocardiogram was unremarkable.

Given the patient’s elevated hepatic enzymes, right upper quadrant ultrasound was obtained, which demonstrated a normal gallbladder, a moderate amount of complicated free fluid (with hyper-echoic densities suggestive of coagulated blood) in all four quadrants, and splenomegaly measuring 13.7 cm (Figure 1a and 1b).

Positive:

• Epstein-Barr virus (EBV)

• Viral capsid antigen (VCA) immuno­globulin G

• VCA immunoglobulin M

Negative:

• Mononuclear spot test
• Human immunodeficiency virus
• Hepatitis B and C
• Antinuclear antibodies
• Venereal disease research laboratory test

The rest of the patient’s recovery was uneventful, and he was discharged home in stable condition on hospital day 3.

Discussion

Although the spleen is the most common intra-abdominal organ that can rupture with blunt abdominal trauma, splenic rupture in the absence of trauma is very rare. Nontraumatic splenic rupture (NSR) has been associated with pathological and nonpathological spleens.^1,2 A systemic review of NSRs showed that 7% of the 845 patients in the review had completely normal spleens; the remaining 93% had some form of splenic pathology.¹

Etiology

The top three causes of splenic enlargement associated with NSR include hematologic malignancies, viral infections, and inflammation.^1,2 Although viruses, such as EBV and cytomegalovirus, represent almost 15% of the pathological causes of NSR, it is not uncommon for a patient to have multiple pathological processes present.¹ Our patient’s enlarged spleen was due to acute infectious mononucleosis.

Signs and Symptoms

Diagnosing NSR can be challenging and it is often missed or discovered incidentally during evaluation (as was initially the case with our patient).³ Several signs and symptoms present in our patient were red herrings that warranted closer analysis. The patient’s complaint of left shoulder pain suggested left hemidiaphragm irritation from the NSR. Furthermore, our patient’s near-syncopal episode was possibly due to acute vagal simulation from the initial contact of blood with the peritoneal cavity.⁴ The maximal vagal stimulus was likely transient, as our patient returned to baseline after a brief near-syncopal episode.

As illustrated in our case, though tachycardia is common in splenic rupture, not all patients present with this sign. The absence of tachycardia in our patient can be explained by the elevation of his baseline enteric vagal tone due to the continued presence of blood in the peritoneum.⁵ There are also other factors associated with the absence of tachycardia. For example, a well-conditioned athlete presenting with states of shock due to splenic rupture may not show signs of tachycardia.⁶

San Francisco Syncope Rule

The San Francisco Syncope Rule (SFSR) is a clinical decision-making risk-stratification tool used to determine outcomes and disposition of ED patients presenting with syncope.⁷ It is important to note that if we had used a straightforward application of the SFSR upon our patient’s initial presentation, the results would have been negative, suggesting he was not at risk for short-term serious outcomes.⁷

Imaging Studies

As demonstrated in our patient, a quick point-of-care (POC) bedside ultrasound scan can reveal the presence of free fluid in the abdomen to help with the diagnosis. On ultrasound, the presence of free fluid in the right upper quadrant is more commonly found in the hepatorenal recess, whereas in the left upper quadrant free fluid is seen sub-diaphragmatic/suprasplenic first before fluid is seen in the splenorenal recess. Bedside ultrasound can accurately detect as little as 100 mL of free fluid in the abdominal cavity, with a 90% sensitivity and 99% specificity.⁸

An ultrasound is highly sensitive as a preliminary screening tool to identify the presence of free intraperitoneal fluid and has some limited utility in identifying any disruption in the splenic echotexture that may suggest a laceration or hematoma. Ultrasound, however, has poor specificity in identifying solid organ injuries.⁹

Computed tomography scanning is the imaging modality of choice for assessing splenic injuries, and should be obtained to confirm the presence of a solid organ injury, as well as to grade the degree of injury and thereby determine the need for surgical intervention.¹⁰ It is worth noting that in a hemodynamically unstable patient, exploratory laparotomy may be embarked upon without a CT scan and positive free fluid on ultrasound.

Splenic Injury Scale

Splenic injury is classified on a scale of 1 (mild injury) to 5 (severe injury) (Table).¹¹

Conclusion

This case illustrates an uncommon presentation of NSR and underscores the importance of considering NSR in the differential diagnoses of patients presenting with abdominal pain—a sign with such a broad differential that NSR could easily be missed during evaluation. Based on its high sensitivity and specificity in detecting the presence of free fluid in the abdominal cavity, POC ultrasound imaging should be used to evaluate patients presenting with abdominal pain and syncopal or near-syncopal symptoms. This case further demonstrates that the absence of tachycardia or signs of shock should not rule out NSR.

Case

A 25-year-old college student presented to the ED following a near-syncopal episode. The patient stated he had felt lightheaded and had fallen to his knees immediately after taking a shower earlier that morning, but did not experience any loss of consciousness or injury. He denied a history of syncope or any recent trauma or fatigue. A review of the patient’s systems was negative. His medical history was remarkable for irritable bowel syndrome; he had no surgical history. Regarding his social history, he admitted to occasional alcohol use but denied any tobacco or illicit drug use. He was not on any current prescription or over-the-counter medications and denied any allergies.

The patient’s initial vital signs at presentation were: blood pressure, 112/58 mm Hg; heart rate, 86 beats/min; temperature, 97.9°F; and respiratory rate, 18 breaths/min. Oxygen saturation was 100% on room air. The patient reported pain in his left shoulder, epigastric region, and right flank. He rated his pain as a “4” on a 0-to-10 pain scale.

On physical examination, the patient was alert and oriented; he was thin and had mild pallor. His head, eyes, ears, nose, and throat; cardiac; pulmonary; and neurological examinations were normal. The abdominal examination revealed a soft, minimally tender epigastrium but with normal bowel sounds. Initial laboratory studies were remarkable for low hemoglobin (Hgb; 12.0 g/dL) and elevated aspartate transaminase (105 U/L), alanine aminotransferase (168 U/L), total bilirubin (1.6 mg/dL), and glucose (179 mg/dL) levels. The patient’s troponin I and lipase levels were within normal range. An electrocardiogram was unremarkable.

Given the patient’s elevated hepatic enzymes, right upper quadrant ultrasound was obtained, which demonstrated a normal gallbladder, a moderate amount of complicated free fluid (with hyper-echoic densities suggestive of coagulated blood) in all four quadrants, and splenomegaly measuring 13.7 cm (Figure 1a and 1b).

Positive:

• Epstein-Barr virus (EBV)

• Viral capsid antigen (VCA) immuno­globulin G

• VCA immunoglobulin M

Negative:

• Mononuclear spot test
• Human immunodeficiency virus
• Hepatitis B and C
• Antinuclear antibodies
• Venereal disease research laboratory test

The rest of the patient’s recovery was uneventful, and he was discharged home in stable condition on hospital day 3.

Discussion

Although the spleen is the most common intra-abdominal organ that can rupture with blunt abdominal trauma, splenic rupture in the absence of trauma is very rare. Nontraumatic splenic rupture (NSR) has been associated with pathological and nonpathological spleens.^1,2 A systemic review of NSRs showed that 7% of the 845 patients in the review had completely normal spleens; the remaining 93% had some form of splenic pathology.¹

Etiology

The top three causes of splenic enlargement associated with NSR include hematologic malignancies, viral infections, and inflammation.^1,2 Although viruses, such as EBV and cytomegalovirus, represent almost 15% of the pathological causes of NSR, it is not uncommon for a patient to have multiple pathological processes present.¹ Our patient’s enlarged spleen was due to acute infectious mononucleosis.

Signs and Symptoms

Diagnosing NSR can be challenging and it is often missed or discovered incidentally during evaluation (as was initially the case with our patient).³ Several signs and symptoms present in our patient were red herrings that warranted closer analysis. The patient’s complaint of left shoulder pain suggested left hemidiaphragm irritation from the NSR. Furthermore, our patient’s near-syncopal episode was possibly due to acute vagal simulation from the initial contact of blood with the peritoneal cavity.⁴ The maximal vagal stimulus was likely transient, as our patient returned to baseline after a brief near-syncopal episode.

As illustrated in our case, though tachycardia is common in splenic rupture, not all patients present with this sign. The absence of tachycardia in our patient can be explained by the elevation of his baseline enteric vagal tone due to the continued presence of blood in the peritoneum.⁵ There are also other factors associated with the absence of tachycardia. For example, a well-conditioned athlete presenting with states of shock due to splenic rupture may not show signs of tachycardia.⁶

San Francisco Syncope Rule

The San Francisco Syncope Rule (SFSR) is a clinical decision-making risk-stratification tool used to determine outcomes and disposition of ED patients presenting with syncope.⁷ It is important to note that if we had used a straightforward application of the SFSR upon our patient’s initial presentation, the results would have been negative, suggesting he was not at risk for short-term serious outcomes.⁷

Imaging Studies

As demonstrated in our patient, a quick point-of-care (POC) bedside ultrasound scan can reveal the presence of free fluid in the abdomen to help with the diagnosis. On ultrasound, the presence of free fluid in the right upper quadrant is more commonly found in the hepatorenal recess, whereas in the left upper quadrant free fluid is seen sub-diaphragmatic/suprasplenic first before fluid is seen in the splenorenal recess. Bedside ultrasound can accurately detect as little as 100 mL of free fluid in the abdominal cavity, with a 90% sensitivity and 99% specificity.⁸

An ultrasound is highly sensitive as a preliminary screening tool to identify the presence of free intraperitoneal fluid and has some limited utility in identifying any disruption in the splenic echotexture that may suggest a laceration or hematoma. Ultrasound, however, has poor specificity in identifying solid organ injuries.⁹

Computed tomography scanning is the imaging modality of choice for assessing splenic injuries, and should be obtained to confirm the presence of a solid organ injury, as well as to grade the degree of injury and thereby determine the need for surgical intervention.¹⁰ It is worth noting that in a hemodynamically unstable patient, exploratory laparotomy may be embarked upon without a CT scan and positive free fluid on ultrasound.

Splenic Injury Scale

Splenic injury is classified on a scale of 1 (mild injury) to 5 (severe injury) (Table).¹¹

Conclusion

This case illustrates an uncommon presentation of NSR and underscores the importance of considering NSR in the differential diagnoses of patients presenting with abdominal pain—a sign with such a broad differential that NSR could easily be missed during evaluation. Based on its high sensitivity and specificity in detecting the presence of free fluid in the abdominal cavity, POC ultrasound imaging should be used to evaluate patients presenting with abdominal pain and syncopal or near-syncopal symptoms. This case further demonstrates that the absence of tachycardia or signs of shock should not rule out NSR.

Case

A 25-year-old college student presented to the ED following a near-syncopal episode. The patient stated he had felt lightheaded and had fallen to his knees immediately after taking a shower earlier that morning, but did not experience any loss of consciousness or injury. He denied a history of syncope or any recent trauma or fatigue. A review of the patient’s systems was negative. His medical history was remarkable for irritable bowel syndrome; he had no surgical history. Regarding his social history, he admitted to occasional alcohol use but denied any tobacco or illicit drug use. He was not on any current prescription or over-the-counter medications and denied any allergies.

The patient’s initial vital signs at presentation were: blood pressure, 112/58 mm Hg; heart rate, 86 beats/min; temperature, 97.9°F; and respiratory rate, 18 breaths/min. Oxygen saturation was 100% on room air. The patient reported pain in his left shoulder, epigastric region, and right flank. He rated his pain as a “4” on a 0-to-10 pain scale.

On physical examination, the patient was alert and oriented; he was thin and had mild pallor. His head, eyes, ears, nose, and throat; cardiac; pulmonary; and neurological examinations were normal. The abdominal examination revealed a soft, minimally tender epigastrium but with normal bowel sounds. Initial laboratory studies were remarkable for low hemoglobin (Hgb; 12.0 g/dL) and elevated aspartate transaminase (105 U/L), alanine aminotransferase (168 U/L), total bilirubin (1.6 mg/dL), and glucose (179 mg/dL) levels. The patient’s troponin I and lipase levels were within normal range. An electrocardiogram was unremarkable.

Given the patient’s elevated hepatic enzymes, right upper quadrant ultrasound was obtained, which demonstrated a normal gallbladder, a moderate amount of complicated free fluid (with hyper-echoic densities suggestive of coagulated blood) in all four quadrants, and splenomegaly measuring 13.7 cm (Figure 1a and 1b).

Positive:

• Epstein-Barr virus (EBV)

• Viral capsid antigen (VCA) immuno­globulin G

• VCA immunoglobulin M

Negative:

• Mononuclear spot test
• Human immunodeficiency virus
• Hepatitis B and C
• Antinuclear antibodies
• Venereal disease research laboratory test

The rest of the patient’s recovery was uneventful, and he was discharged home in stable condition on hospital day 3.

Discussion

Although the spleen is the most common intra-abdominal organ that can rupture with blunt abdominal trauma, splenic rupture in the absence of trauma is very rare. Nontraumatic splenic rupture (NSR) has been associated with pathological and nonpathological spleens.^1,2 A systemic review of NSRs showed that 7% of the 845 patients in the review had completely normal spleens; the remaining 93% had some form of splenic pathology.¹

Etiology

The top three causes of splenic enlargement associated with NSR include hematologic malignancies, viral infections, and inflammation.^1,2 Although viruses, such as EBV and cytomegalovirus, represent almost 15% of the pathological causes of NSR, it is not uncommon for a patient to have multiple pathological processes present.¹ Our patient’s enlarged spleen was due to acute infectious mononucleosis.

Signs and Symptoms

Diagnosing NSR can be challenging and it is often missed or discovered incidentally during evaluation (as was initially the case with our patient).³ Several signs and symptoms present in our patient were red herrings that warranted closer analysis. The patient’s complaint of left shoulder pain suggested left hemidiaphragm irritation from the NSR. Furthermore, our patient’s near-syncopal episode was possibly due to acute vagal simulation from the initial contact of blood with the peritoneal cavity.⁴ The maximal vagal stimulus was likely transient, as our patient returned to baseline after a brief near-syncopal episode.

As illustrated in our case, though tachycardia is common in splenic rupture, not all patients present with this sign. The absence of tachycardia in our patient can be explained by the elevation of his baseline enteric vagal tone due to the continued presence of blood in the peritoneum.⁵ There are also other factors associated with the absence of tachycardia. For example, a well-conditioned athlete presenting with states of shock due to splenic rupture may not show signs of tachycardia.⁶

San Francisco Syncope Rule

The San Francisco Syncope Rule (SFSR) is a clinical decision-making risk-stratification tool used to determine outcomes and disposition of ED patients presenting with syncope.⁷ It is important to note that if we had used a straightforward application of the SFSR upon our patient’s initial presentation, the results would have been negative, suggesting he was not at risk for short-term serious outcomes.⁷

Imaging Studies

As demonstrated in our patient, a quick point-of-care (POC) bedside ultrasound scan can reveal the presence of free fluid in the abdomen to help with the diagnosis. On ultrasound, the presence of free fluid in the right upper quadrant is more commonly found in the hepatorenal recess, whereas in the left upper quadrant free fluid is seen sub-diaphragmatic/suprasplenic first before fluid is seen in the splenorenal recess. Bedside ultrasound can accurately detect as little as 100 mL of free fluid in the abdominal cavity, with a 90% sensitivity and 99% specificity.⁸

An ultrasound is highly sensitive as a preliminary screening tool to identify the presence of free intraperitoneal fluid and has some limited utility in identifying any disruption in the splenic echotexture that may suggest a laceration or hematoma. Ultrasound, however, has poor specificity in identifying solid organ injuries.⁹

Computed tomography scanning is the imaging modality of choice for assessing splenic injuries, and should be obtained to confirm the presence of a solid organ injury, as well as to grade the degree of injury and thereby determine the need for surgical intervention.¹⁰ It is worth noting that in a hemodynamically unstable patient, exploratory laparotomy may be embarked upon without a CT scan and positive free fluid on ultrasound.

Splenic Injury Scale

Splenic injury is classified on a scale of 1 (mild injury) to 5 (severe injury) (Table).¹¹

Conclusion

This case illustrates an uncommon presentation of NSR and underscores the importance of considering NSR in the differential diagnoses of patients presenting with abdominal pain—a sign with such a broad differential that NSR could easily be missed during evaluation. Based on its high sensitivity and specificity in detecting the presence of free fluid in the abdominal cavity, POC ultrasound imaging should be used to evaluate patients presenting with abdominal pain and syncopal or near-syncopal symptoms. This case further demonstrates that the absence of tachycardia or signs of shock should not rule out NSR.

Aneurysmal bone cysts (ABC) are expansile, hemorrhagic, non-neoplastic lesions that can be locally destructive¹ and that can arise either de novo or secondary to another benign or malignant lesion.² Although primary and secondary ABCs typically are benign, there are cases of malignant degeneration of primary ABCs, though the transformation arises almost exclusively in the context of prior radiation exposure.^3-5 Malignant change without history of irradiation is rare; only 6 such cases have been reported.^5-10 In 4 of these cases, the transformation was to osteosarcoma.^5,8-10

Here we report on an ABC that degenerated into a fibroblastic osteosarcoma—the fifth such case in the medical literature. In addition to reviewing the earlier cases, we describe the radiologic and histologic underpinnings of this diagnosis and the insight that they provide into the pathogenesis of this rare process. Although the prevailing view is that ABCs are benign, it is important to know these lesions have the potential to undergo malignant transformation, even in the absence of prior radiation exposure. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy and previously asymptomatic 37-year-old man presented with thigh pain after a minor fall onto a couch. Radiographs showed a diaphyseal femoral pathologic fracture adjacent to a small but benign-appearing cystic lesion (Figures 1A, 1B).

Two years later, the patient had a bicycle accident and, after 2 weeks of significantly increased thigh swelling, presented to the emergency department at the referring institution. Radiographs showed a lytic lesion in the femoral diaphysis that was highly suspicious for malignancy (Figures 3A, 3B).

Discussion

Aneurysmal bone cysts are expansile, hemorrhagic, locally destructive lesions that generally develop within the first 3 decades of life. Ever since they were first described by Jaffe and Lichtenstein¹¹ in 1942, the most widely accepted theory of their pathogenesis has been that they begin as a benign reactive vascular process.¹² However, more recent molecular studies by Oliveira and colleagues¹³ and Panoutsakopoulos and colleagues¹⁴ have demonstrated a clonal neoplastic basis for primary ABCs related to cytogenetic upregulation of oncogenes USP6 and CDH11 after translocation of 17p13 and 16q22.

Given the clonal nature of these lesions, it is surprising that malignant transformation is so rare. Until now, there have been only 4 reports of an ABC undergoing malignant degeneration to osteosarcoma without prior radiation exposure.

Aneurysmal bone cysts (ABC) are expansile, hemorrhagic, non-neoplastic lesions that can be locally destructive¹ and that can arise either de novo or secondary to another benign or malignant lesion.² Although primary and secondary ABCs typically are benign, there are cases of malignant degeneration of primary ABCs, though the transformation arises almost exclusively in the context of prior radiation exposure.^3-5 Malignant change without history of irradiation is rare; only 6 such cases have been reported.^5-10 In 4 of these cases, the transformation was to osteosarcoma.^5,8-10

Here we report on an ABC that degenerated into a fibroblastic osteosarcoma—the fifth such case in the medical literature. In addition to reviewing the earlier cases, we describe the radiologic and histologic underpinnings of this diagnosis and the insight that they provide into the pathogenesis of this rare process. Although the prevailing view is that ABCs are benign, it is important to know these lesions have the potential to undergo malignant transformation, even in the absence of prior radiation exposure. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy and previously asymptomatic 37-year-old man presented with thigh pain after a minor fall onto a couch. Radiographs showed a diaphyseal femoral pathologic fracture adjacent to a small but benign-appearing cystic lesion (Figures 1A, 1B).

Two years later, the patient had a bicycle accident and, after 2 weeks of significantly increased thigh swelling, presented to the emergency department at the referring institution. Radiographs showed a lytic lesion in the femoral diaphysis that was highly suspicious for malignancy (Figures 3A, 3B).

Discussion

Aneurysmal bone cysts are expansile, hemorrhagic, locally destructive lesions that generally develop within the first 3 decades of life. Ever since they were first described by Jaffe and Lichtenstein¹¹ in 1942, the most widely accepted theory of their pathogenesis has been that they begin as a benign reactive vascular process.¹² However, more recent molecular studies by Oliveira and colleagues¹³ and Panoutsakopoulos and colleagues¹⁴ have demonstrated a clonal neoplastic basis for primary ABCs related to cytogenetic upregulation of oncogenes USP6 and CDH11 after translocation of 17p13 and 16q22.

Given the clonal nature of these lesions, it is surprising that malignant transformation is so rare. Until now, there have been only 4 reports of an ABC undergoing malignant degeneration to osteosarcoma without prior radiation exposure.

Aneurysmal bone cysts (ABC) are expansile, hemorrhagic, non-neoplastic lesions that can be locally destructive¹ and that can arise either de novo or secondary to another benign or malignant lesion.² Although primary and secondary ABCs typically are benign, there are cases of malignant degeneration of primary ABCs, though the transformation arises almost exclusively in the context of prior radiation exposure.^3-5 Malignant change without history of irradiation is rare; only 6 such cases have been reported.^5-10 In 4 of these cases, the transformation was to osteosarcoma.^5,8-10

Here we report on an ABC that degenerated into a fibroblastic osteosarcoma—the fifth such case in the medical literature. In addition to reviewing the earlier cases, we describe the radiologic and histologic underpinnings of this diagnosis and the insight that they provide into the pathogenesis of this rare process. Although the prevailing view is that ABCs are benign, it is important to know these lesions have the potential to undergo malignant transformation, even in the absence of prior radiation exposure. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A healthy and previously asymptomatic 37-year-old man presented with thigh pain after a minor fall onto a couch. Radiographs showed a diaphyseal femoral pathologic fracture adjacent to a small but benign-appearing cystic lesion (Figures 1A, 1B).

Two years later, the patient had a bicycle accident and, after 2 weeks of significantly increased thigh swelling, presented to the emergency department at the referring institution. Radiographs showed a lytic lesion in the femoral diaphysis that was highly suspicious for malignancy (Figures 3A, 3B).

Discussion

Aneurysmal bone cysts are expansile, hemorrhagic, locally destructive lesions that generally develop within the first 3 decades of life. Ever since they were first described by Jaffe and Lichtenstein¹¹ in 1942, the most widely accepted theory of their pathogenesis has been that they begin as a benign reactive vascular process.¹² However, more recent molecular studies by Oliveira and colleagues¹³ and Panoutsakopoulos and colleagues¹⁴ have demonstrated a clonal neoplastic basis for primary ABCs related to cytogenetic upregulation of oncogenes USP6 and CDH11 after translocation of 17p13 and 16q22.

Given the clonal nature of these lesions, it is surprising that malignant transformation is so rare. Until now, there have been only 4 reports of an ABC undergoing malignant degeneration to osteosarcoma without prior radiation exposure.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

CD30⁺ primary cutaneous lymphoproliferative disorders (pcLPDs) are the second most common cause of cutaneous T-cell lymphoma, accounting for approximately 25% to 30% of cases.¹ These disorders comprise a spectrum that includes primary cutaneous anaplastic large-cell lymphoma (pcALCL); lymphomatoid papulosis (LyP); and borderline lesions, which share clinicopathologic features of both pcALCL and LyP. Lymphomatoid papulosis is characterized as chronic, recurrent, papular or papulonodular skin lesions that typically are multifocal and regress spontaneously within weeks to months, only leaving small scars with atrophy and/or hyperpigmentation.² Cutaneous anaplastic large-cell lymphoma typically presents as solitary or grouped nodules or tumors that may undergo spontaneous partial or complete regression in approximately 25% of cases³ but often persist if not treated. Patients may have an array of lesions comprising the spectrum of CD30 pcLPDs.⁴

There is no curative therapy for CD30⁺ pcLPDs. Although active treatment is not necessary for LyP, low-dose methotrexate (MTX)(10–50 mg weekly) or phototherapy are the preferred initial suppressive therapies for symptomatic patients with scarring, facial lesions, or multiple symptomatic lesions.⁵ Observation with expectant follow-up is an option in pcALCL, though spontaneous regression is less likely than in LyP. For single or grouped pcALCL lesions, local radiation is the first-line therapy.⁶ Multifocal pcALCL lesions also can be treated with low-dose MTX,^2,5 as in LyP, or local radiation to selected areas. Although local radiotherapy is considered a first-line treatment in pcALCL, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. We report the complete response of refractory pcALCL lesions to low-dose radiation while remaining on MTX weekly without any adverse effects.

Case Report

A 51-year-old woman presented with a 3-year history of CD30⁺ pcLPD manifesting primarily as pcALCL involving the head and neck, as well as LyP involving the head, arms, and trunk (T3N0M0). For 2 years her treatment regimen included clobetasol propionate cream 0.05% as needed for new lesions and 2 courses of standard-dose localized external beam radiation for larger pcALCL tumors on the right cheek and right side of the chin (Figure 1)(total dose for each course of treatment was 20 Gy and 36 Gy, respectively, each administered over 2–3 weeks). Because new unsightly papulonodules continued to develop on the patient’s face, she subsequently required low-dose oral MTX 30 mg once weekly for suppression of new lesions and was stable on this regimen for a year. However, she experienced an increase in LyP/pcALCL activity on the face during a 2-week break from MTX when she developed a herpes zoster infection on the right side of the forehead.

On physical examination 1 month later, 5 tiny pink papules scattered on the left eyebrow, left cheek, and left side of the chin were noted. She was advised to continue applying the clobetasol cream as needed and was restarted on MTX 10 mg once weekly. However, she developed 2 additional 1-cm nodules on the left side of the chin, neck, and shoulder. Methotrexate was increased to 30 mg once weekly over 2 weeks, which was the original dose prior to interruption, but the nodules grew to 1.5-cm in diameter. Due to their clinical appearance, the nodules were believed to be early pcALCL lesions (Figure 2A). Given the cosmetically sensitive location of the nodules, palliative radiotherapy was recommended rather than observe for possible regression. Based on a prior report by Neelis et al⁷ demonstrating efficacy of low-dose radiotherapy for cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, we recommended starting with low radiation doses. Our patient was treated with 400 cGy twice to the left side of the chin and left side of the neck (800 cGy total at each site) while remaining on MTX 30 mg once weekly. This treatment was well tolerated without side effects and no evidence of radiation dermatitis. On follow-up examination 1 week later, the nodules had regressed and no new lesions were present (Figure 2B).

The patient has stayed on oral MTX and occasionally develops small lesions that quickly resolve with clobetasol cream. She has been followed for 3 years after radiotherapy and all 3 previously irradiated sites have remained recurrence free. Furthermore, she has not developed any new larger nodules or tumors and her MTX dose has been decreased to 15 mg once weekly.

Comment

Local radiotherapy is considered a first-line treatment of pcALCL; however, there is limited evidence on its clinical efficacy as well as the optimal dose and technique. Although no standard dose exists for pcALCL, the National Comprehensive Cancer Network guidelines⁸ recommend doses of 12 to 36 Gy in mycosis fungoides/Sézary syndrome subtypes of cutaneous T-cell lymphoma, which are consistent with guidelines published by the European Society for Medical Oncology.⁹ High complete response rates have been demonstrated in pcALCL at doses of 34 to 44 Gy⁶; however, lesions tend to recur elsewhere on the skin in 36% to 41% of patients despite treatment.^2,10 Lower doses of radiation therapy would provide several advantages over higher-dose therapy if a complete response could be achieved without greatly increasing the local recurrence rate. In cases of local recurrence, low-dose radiation would more easily permit retreatment of lesions compared to higher doses of radiation. Similarly, in patients with multifocal pcALCL, lower doses of radiotherapy may allow for treatment of larger skin areas while limiting potential treatment risks. Furthermore, low-dose therapy would allow for treatments to be delivered more quickly and with less inconvenience to the patient who is likely to need multiple future treatments to other areas. Low-dose radiation has been described with a favorable efficacy profile for mycosis fungoides^7,11 but has not been studied in patients with CD30⁺ pcLPDs.

Our case is notable because the patient remained on MTX during radiation therapy. Because MTX can act as a radiosensitizer, current standard practice is to stop MTX while administering radiation therapy. High oncologic doses of MTX can occasionally produce severe skin reactions at the irradiated site^12-14; however, reports of the use of lower weekly doses in combination with radiation are sparse. Our patient had refractory disfiguring facial lesions that would immediately recur once MTX was stopped. Low-dose radiation therapy was administered while she remained on her weekly MTX doses. With this treatment, she achieved a complete response, developed no radiation dermatitis, and had no further new skin lesions appear.

Conclusion

We reported the use of low-dose radiation therapy for the treatment of localized pcALCL in a patient who remained on low-dose oral MTX. Additional studies will be necessary to more fully evaluate the efficacy of using low-dose radiation both as monotherapy and in combination with MTX for pcALCL.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

Bullous pemphigoid (BP) is an acquired, autoimmune, subepidermal blistering disease that is more common in elderly patients.¹ An association with internal neoplasms and BP has been established; however, there is debate regarding the precise nature of the relationship.² Several gastrointestinal tract tumors have been associated with BP, including adenocarcinoma of the colon, adenosquamous cell carcinoma and adenocarcinoma of the stomach, adenocarcinoma of the rectum, and liver and bile duct malignancies.^3-5 Association with pancreatic neoplasms (eg, carcinoma of the pancreas) rarely has been reported.^5-7 We present an unusual case of a lymphoepithelial cyst of the pancreas in a patient with BP.

Case Report

A 67-year-old man presented with erythematous crusted plaques and pink scars over the chest, back, arms, and legs (Figure 1). A 1.5-cm tense bullous lesion was observed on the right knee. The patient’s medical history was notable for biopsy-proven BP of 8 months’ duration as well as diabetes mellitus and hypothyroidism. The patient was being followed by his surgeon for a 1.9-cm soft-tissue lesion in the pancreatic tail and was awaiting surgical excision at the time of the current presentation. The pancreatic lesion was discovered incidentally on magnetic resonance imaging performed following urologic concerns. At the current presentation, the patient’s medications included nifedipine, hydralazine, metoprolol, torsemide, aspirin, levothyroxine, atorvastatin, insulin lispro, and insulin glargine. He had previously been treated for BP with prednisone at a maximum dosage of 60 mg daily, clobetasol propionate cream 0.05%, and mupirocin ointment 2% without improvement. Because of substantial weight gain and poorly controlled diabetes, prednisone was discontinued.

Bullous pemphigoid had been diagnosed histopathologically by a prior dermatologist. Hematoxylin and eosin staining demonstrated a subepidermal separation with eosinophils within the perivascular infiltrate (Figure 2). Direct immunofluorescence was noted in a linear pattern at the dermoepidermal junction with IgG and C3. Bullous pemphigoid antigen antibodies 1 and 2 were obtained via enzyme-linked immunosorbent assay with a positive BP-1 antigen antibody of 19 U/mL (positive, >15 U/mL) and a normal BP-2 antigen antibody of less than 9 U/mL (reference range, <9 U/mL). The glucagon level was elevated at 245 pg/mL (reference range, ≤134 pg/mL).

The patient was prescribed minocycline 100 mg twice daily and niacinamide 500 mg 3 times daily. Topical treatment with clobetasol and mupirocin was continued. One month later, the patient returned with an increase in disease activity. Changes to his therapeutic regimen were deferred until after excision of the pancreatic lesion based on the decision not to start immunosuppressive therapy until the precise nature of the pancreatic lesion was determined.

The patient underwent excision of the pancreatic lesion approximately 3 months later, which proved to be a benign lymphoepithelial cyst of the pancreas. Histology of the cyst consisted of dense fibrous tissue with a squamous epithelial lining focally infiltrated by lymphocytes (Figure 3A). Immunoperoxidase staining of the cyst revealed focal linear areas of C3d staining along the basement membrane of the stratified squamous epithelium (Figure 3B).

The patient stated that his skin started to improve virtually immediately following the excision without systemic treatment for BP. On follow-up examination 3 weeks postoperatively, no bullae were observed and there was a notable decrease in erythematous crusted plaques (Figure 4).

Comment

Paraneoplastic BP has been documented; however, lymphoepithelial cysts of the pancreas in association with BP are rare. We propose that the lymphoepithelial cyst of the pancreas provided the immunologic stimulus for the development of cutaneous BP based on the observation that our patient’s condition remarkably improved with resection of the tumor.

There are fewer than 100 cases of lymphoepithelial cysts of the pancreas reported in the literature.⁸ The histologic appearance is consistent with a true cyst exhibiting a well-differentiated stratified squamous epithelium, often with keratinization, surrounded by lymphoid tissue. These tumors are most commonly seen in middle-aged men and are frequently found incidentally,^8-10 as was the case with our patient. Although histologically similar, lymphoepithelial cysts of the pancreas are considered distinct from lymphoepithelial cysts of the parotid gland or head and neck region.¹⁰ Lymphoepithelial cysts of the pancreas are unrelated to elevated glucagon levels; it is likely that our patient’s glucagon levels were associated with his history of diabetes.¹¹

In theory, any process that involves deposition of C3 should be positive for C3d on immunoperoxidase staining. Other dermatologic inflammatory conditions stain positively with C3d, such as systemic lupus erythematosus, discoid lupus erythematosus, subacute cutaneous lupus erythematosus, and dermatomysositis.¹³ The staining for these diseases correlates with the site of the associated inflammatory component seen on hematoxylin and eosin staining. The staining of C3d along the basement membrane of stratified squamous epithelium in the lymphoepithelial cyst of the pancreas seen in our patient closely resembles the staining seen in cutaneous BP.

A proposed mechanism for BP in our patient would be exposure of BP-1 antigen in the pancreatic cyst leading to antibody recognition and C3 deposition along the basement membrane in the cyst, as evidenced by C3d immunoperoxidase staining. The IgG and C3 deposition along the cutaneous basement membrane would then represent a systemic response to the antigen exposure in the cyst. Thus, the lymphoepithelial cyst provided the immunologic stimulus for the development of the cutaneous BP. This theory is based on the observation of our patient’s rapid improvement without a change in his treatment regimen immediately after surgical excision of the cyst.

Despite the plausibility of our hypothesis, several questions remain regarding the validity of our assumptions. Although sensitive for C3 deposition, C3d immunoperoxidase staining is not specific for BP. If the proposed mechanism for causation is true, one might have expected that a subepithelial cleft along the basement membrane of the pancreatic cyst would be observed, which was not seen. A repeat BP antigen antibody was not obtained, which would have been helpful in determining if there was clearance of the antibody that would have correlated with the clinical resolution of the BP lesions.

Conclusion

Our case suggests that paraneoplastic BP is a genuine entity. Indeed, the primary tumor itself may be the immunologic stimulus in the development of BP. Recalcitrant BP should raise the question of a neoplastic process that is exposing the BP antigen. If a thorough review of systems accompanied by corroborating laboratory studies suggests a neoplastic process, the suspect lesion should be further evaluated and surgically excised if clinically indicated. Further evaluation of neoplasms with advanced staining methods may aid in establishing the causative nature of tumors in the development of BP.

Acknowledgments

We are grateful to John Stanley, MD, and Aimee Payne, MD (both from Philadelphia, Pennsylvania), for theirinsights into this case.

THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.

THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.

THE CASE

A 49-year-old woman visited our family medicine clinic because she’d had 3 episodes of epistaxis during the previous month. She’d already visited the emergency department, and the doctor there had treated her symptomatically and referred her to our clinic.

On physical examination, we noted a whitish mass in the patient’s right nostril that was attached to the nasal septum. The patient’s vital signs were within normal limits. She had a history of hypertension, depression, anxiety, gastroesophageal reflux disease, and post-traumatic stress disorder. Her medications included amlodipine-benazepril, atenolol-chlorthalidone, citalopram, clonazepam, prazosin, and omeprazole. The patient lived alone and denied using tobacco or illicit drugs, but she drank one to 2 glasses of brandy every day. She denied any past medical or family history of similar complaints, autoimmune disorders, or skin rashes.

A complete blood count, international normalized ratio, sedimentation rate, anti-nuclear antibody test, and an anti-neutrophil cytoplasmic antibody panel were normal.

THE DIAGNOSIS

We referred the patient to an ear, nose, and throat doctor for a nasal endoscopy and a biopsy, which showed granulation tissue. A maxillofacial computed tomography (CT) scan revealed a 1.44 cm x 0.8 cm polypoid soft tissue mass in the right nasal cavity adherent to the nasal septum with no posterior extension (FIGURE 1).

Pyogenic granuloma (PG) is a benign vascular tumor of the skin and mucous membranes that is not associated with an infection. Rather, it is a hyperplastic, neovascular, inflammatory response to an angiogenic stimulus. Several enhancers and inhibitors of angiogenesis have been shown to play a role in PG, including hormones, medications, and local injury. In fact, a local injury or hormonal factor is identified as a stimulus in more than half of PG patients.¹

The hormone connection. Estrogen promotes production of nerve growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor beta 1. Progesterone enhances inflammatory mediators as well. Although there are no direct receptors for estrogen and progesterone in the oral and nasal mucosa, some of these pro-inflammatory effects create an environment conducive to the development of PG. This is supported by several studies documenting an increased incidence of PGs with oral contraceptive use and regression of PGs after childbirth.^2-4

In more than half of patients with pyogenic granuloma, a local injury or hormonal factor is at work.

Medication may play a role. Drug-induced PG has also been described in several studies.^5,6 Offending medications include systemic and topical retinoids, capecitabine, etoposide, 5-fluorouracil, cyclosporine, docetaxel, and human immunodeficiency virus protease inhibitors.

Local injury may also be a culprit. Nasal PGs are commonly attached to the anterior septum and typically result from nasal packing, habitual picking, or nose boring.⁷ In this particular case, however, we were unable to identify the irritant.

The classic presentation

PG classically presents as a painless mass that spontaneously develops over days to weeks. The mass can be sessile or pedunculated, and is frequently hemorrhagic. Intranasal PG usually presents with epiphora.⁷ While the prevalence of intraoral PG was found to be one in 25,000 individuals³, data for nasal lesions is scarce. Most cases of PG are seen in the second and third decades of life.^1,3 In children, PG is slightly more predominant in males.^1,3 Mucosal lesions, however, have a higher incidence in females.^1,3 Granuloma gravidarum, the term used to describe mucosal PG in pregnant females, was found in 0.2% to 5% of pregnancies.^2,3,8

Differential Dx includes warts, squamous cell carcinoma

The differential diagnosis of PG includes Spitz nevus, glomus tumors, common warts, amelanotic melanoma, squamous cell carcinoma, basal cell carcinoma, Kaposi’s sarcoma, bacillary angiomatosis, infantile hemangioma, and angiolymphoid hyperplasia, among others.^3,5 Foreign bodies, nasal polyps, angiofibroma, meningocele, Wegener’s granulomatosis, and sarcoidosis should also be considered.

Radiologic evaluation may be beneficial—especially with nasal lesions—when looking for findings suggestive of malignancy. Both CT and magnetic resonance imaging with contrast identify PG as a soft tissue mass with lobulated contours,^9,10 but histopathologic analysis is required to confirm the diagnosis. The histopathologic appearance of PG is characterized by a polypoid lesion with circumscribed anastomosing networks of capillaries arranged in one or more lobules at the base in an edematous and fibroblastic stroma.

Alternatives to surgery include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents, but the recurrence rate with these is often higher.

Treatment is determined by the location and size of the lesion

The most suitable treatment is determined by considering the location of the lesion, the characteristics of the lesion (morphology/size), its amenability to surgery, risk of scar formation, and the presence or absence of a causative irritant. Excision is often preferred because it yields a specimen for pathologic analysis. Alternative treatments include electrocautery, cryotherapy, laser therapy, and intralesional and topical agents,^3,6,7 but the recurrence rate is higher (up to 15%) with some of these modalities, when compared with excision (3.6%).³

Our patient underwent excision of the mass and was seen for an annual follow-up appointment. All of her symptoms resolved and no recurrence was noted.

THE TAKEAWAY

Although PG is a common and benign condition, it is rarely seen in the nasal cavity without an obvious history of a possible irritant. PG should be considered as a diagnosis for rapidly growing cutaneous or mucosal hemorrhagic lesions. Appropriate tissue pathology is essential to rule out malignancy and other serious conditions, such as bacillary angiomatosis and Wegener’s granulomatosis.

Treatment is usually required to avoid the frequent complications of ulceration and bleeding. Surgical treatments are preferred. The location of the lesion largely determines whether referral to a specialist is necessary.