Case Reports

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

THE CASE

A 16-year-old boy presented to the emergency room (ER) with pain, redness, and swelling of his right upper arm that had been bothering him for 2 days. He was the quarterback of his high school football team, a sport that he’d been playing since he was 8 years old. He indicated that his football training—which involved repetitive throwing with his right arm—had intensified over the previous 2 months.

Prior to the ER visit, the patient was healthy and active with no significant medical history. He’d had no shoulder trauma and there was no family history of any coagulopathies, venous thrombosis, or pulmonary embolism. He denied chest pain, shortness of breath, palpitations, and fever, and said that he did not smoke cigarettes or drink alcohol.

On physical examination, his blood pressure was 118/70 mm Hg and his heart rate was 74 beats per minute. He had nonpitting edema and erythema of his right upper arm. His radial and brachial pulses were strong and equal in both arms. Assessment of neurologic and vascular integrity produced positive Wright’s and Adson’s tests, but a negative Halstead’s test. (For more on these tests, see: Wright’s test, Adson’s test, and Halstead’s test.) The circumference of the patient’s right upper arm was 2.5 cm greater than the left upper arm. The remainder of the physical exam was normal.

THE DIAGNOSIS

A duplex ultrasound of the right upper arm revealed an acute occlusive thrombus in the axillary vein. We started the patient on intravenous heparin. A venogram confirmed thrombosis of the axillary-subclavian vein (FIGURE 1A). Based on the patient’s clinical presentation and the results of the venogram, we diagnosed Paget-Schroetter syndrome. The venogram was followed by thrombolysis with alteplase (FIGURE 1B) and a balloon angioplasty (FIGURE 1C). One week later, a repeat venogram demonstrated partial removal of the thrombus and an area of compression on the inferior aspect of the subclavian vein due to a cervical band (FIGURE 1D).

DISCUSSION

Paget-Schroetter syndrome (PSS), or effort thrombosis of the upper extremities, is defined as spontaneous thrombus in the axillary and subclavian veins that occurs as a consequence of strenuous upper-extremity activity. It is a rare condition with an incidence of one to 2 cases per 100,000 people per year, and represents 1% to 4% of all cases of deep vein thrombosis (DVT).¹

Spontaneous thrombosis of the upper extremities typically presents in young, otherwise healthy individuals. It has been described in athletes who are involved in ball games, games with rackets or clubs, aquatic sports, combatant sports, and in violin players.² The repetitive movements used in these activities can lead to compression of the axillary and subclavian veins by hypertrophied muscles. Repetitive trauma causes intimal damage and thrombogenesis.³

PSS is characterized by the abrupt, spontaneous swelling of the entire arm, cyanosis, and pain that occurs with use or overhead positioning. Enlarged subcutaneous veins are present in the upper arm, around the shoulder, or in the upper anterior chest wall (Urschel’s sign). The classic presentation is acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity.⁴ A low-grade fever, superficial thrombophlebitis, or neurologic symptoms may coexist. Certain provocative maneuvers can help reproduce the symptoms (TABLE 1^5,6). Complications of PSS include pulmonary embolism, postthrombotic syndrome (pain, heaviness, and swelling), and recurrent thrombosis.⁷

Contrast venography best shows the extent of thrombosis

Duplex ultrasound, with its high sensitivity and specificity, is the initial, noninvasive test of choice (TABLE 2^4,8-11). However, duplex ultrasound has a false-negative rate of 30% because it is highly technician-dependent and can be complicated by acoustic shadows from the clavicle or sternum.⁸

The most direct and definitive means to confirm the diagnosis of PSS is catheter-directed contrast venography.⁹ This method provides complete anatomic information regarding the site and extent of thrombosis, allows definitive evaluation of the collateral venous pathways, and is a necessary step toward the use of thrombolytic therapy. Contrast load, however, contraindicates the procedure in patients with renal failure and in those who are pregnant.

Contrast-enhanced computed tomography (CT) and magnetic resonance angiography (MRA) are also highly sensitive for detecting focal stenosis at the level of the first rib, the presence or absence of enlarged collateral veins, and the chronicity of any thrombus present. However, the usefulness of CT and magnetic resonance venography in initial screening is unclear, due to a lack of randomized controlled trials.

Treatment involves anticoagulants, thrombolytics, and possibly surgery

Prompt use of anticoagulation is indicated in PSS. Initial anticoagulation with low molecular weight unfractionated heparin or a direct thrombin inhibitor followed by warfarin for a minimum of 3 to 6 months is recommended.¹²

Patients treated with anticoagulation alone have a higher incidence of long-term residual symptoms, disability, and recurrent thrombosis.⁷ As a result, a more aggressive approach with the use of thrombolytic therapy is indicated, especially in young, active patients, to minimize long-term consequences. Alteplase or reteplase are used for this purpose. Thrombolysis is less likely to be beneficial if the thrombus is more than 2 weeks old or if there are inflammatory changes in the vein. The use of catheter-directed thrombolysis minimizes the risk of systemic adverse effects and achieves higher clot resolution rates.¹³

Because PSS is caused by compression of the vein, rather than a disorder of blood clotting, there is still a 50% to 70% risk of recurrent thrombosis despite thrombolysis and anticoagulation.¹⁴ Therefore, the most definitive management approach remains surgical treatment. Patients with recent thrombosis who are within the first several weeks of undergoing successful thrombolytic therapy are excellent candidates for surgery. Operative treatment for PSS includes first rib resection, scalene muscle removal, or subclavius muscle removal, along with removal of constricting scar tissue from around the vein.⁷

THE TAKEAWAY

PSS is characterized by upper-extremity DVT resulting from repetitive trauma to the subclavian-axillary vein. Early diagnosis of PSS with contrast venography and prompt use of anticoagulation can effectively restore venous patency, reduce the risk of rethrombosis, and return the patient to normal function. Primary care physicians should be aware of this condition, because delayed recognition in a high-functioning person can be potentially disabling.

Our patient had a first rib resection, partial division of the scalenus anterior and medius muscles, and lysis of the cervical band. Follow-up venography confirmed resolution of thrombosis without any complications. The patient was continued on anticoagulation with warfarin for 3 months.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.

Case Reports

A platoon of 24 US Marines participated in a 1-week outdoor training exercise (February 4–8) at the Marine Corps Training Area Bellows in Oahu, Hawaii. During the last 3 days of training, 15 (62.5%) marines presented to the same primary care provider with what appeared to be diffuse scattered lesions on the face, neck, and dorsal aspect of the hands. All 15 patients reported that they noticed the lesions upon waking up the morning after their second night at the training area. The patients were unable to recollect specific direct arthropod interactions, but they reported the presence of “bugs” in the training area and denied use of any insect repellents, insect nets, or sunscreen. Sleeping arrangements varied from covered vehicles and cots to sleeping bags on the ground, which were laundered independently by each marine and thereby were ruled out as a commonality. The patients denied working with any chemicals or cleansers while in the field. Further questioning of all 15 patients revealed a history of extended contact with live foliage as branches were broken off to build camouflaged sites.

The following week, a second platoon of 20 marines occupied a separate undisturbed portion of the same training area for a similar 1-week training evolution. Manifestation of similar symptoms among members of the second group, who had no contact with the initial 15 patients, supported the likely environmental etiology of the eruptions.

Figure 1. Numerous well-circumscribed, discrete, pink-red papules diffusely scattered across the face.

Figure 2. Papules with classic anemic halos.

Referral

Two patients from the first group were evaluated at the dermatology clinic at Tripler Army Medical Center (Honolulu, Hawaii) on day 10 of the initial outbreak. Cutaneous examination revealed numerous discrete, pink-red, well-circumscribed, 2- to 4-mm, dome-shaped papules exclusive to exposed areas on the face, neck, and dorsal aspect of the hands (Figures 1 and 2). Anemic halos surrounding the hand papules were noted (Figure 2). A punch biopsy in both patients revealed spongiotic dermatitis with superficial perivascular and interstitial lymphohistiocytic inflammation with eosinophils, suggestive of an arthropod bite (Figure 3). No retained arthropod parts wereidentified. Both patients were treated with triamcinolone ointment twice daily for 7 days with total resolution of the lesions.

Site Survey Results

Five days following the initial presentation of the first outbreak, a daytime site survey of the training area was conducted by a medical entomologist, an environmental health scientist, and a wildlife biologist. Records indicated that prior to the current utilization, the training area had not been used for 9 months. Approximately half of the training area was covered with mixed scrub vegetation and the remainder was clear pavement or sand (clear of vegetation). Feral hogs (Sus scrofa), cats (Felis domesticus), and mongooses (Herpestes javanicus) were observed at the site. Patient interviews and site survey ruled out a number of potential environmental irritants, including contact with fresh or salt water and chemical contaminants in the air or soil.

Because biting insects were suspected as the cause of the eruptions, an overnight entomological survey was conducted 3 weeks after the first outbreak under similar weather conditions and was centered in the area of an Australian pine (Casuarina equisetifolia) forest where most of the marines had slept during training. Mosquitoes (Aedes albopictus and Culex quinquefasciatus) were observed in the area, with an estimated biting rate of 1 to 2 bites per hour. Centipedes (Scolopendra subspinipes) were commonly observed after dark. There was no sign of heavy bird roosting or nesting, which would be a possible source of biting ectoparasites. Other than the Australian pine, notable vegetation present included Christmasberry (Schinus terebinthifolius), koa haole (Leucaena leucocephala), and Chinese banyan (Ficus microcarpa). A survey of the vegetation uncovered no notable insects, and no damage to the leaves of the Chinese banyans, which is typical of thrip infestation, was noted.

Figure 3. Superficial and deep perivascular and interstitial dermatitis (A)(H&E, original magnification ×10) with lymphocytic predominance (B)(H&E, original magnification ×40).

After completion of a resource-intensive investigation that included site survey, literature review, detailed patient history including thrips-associated skin manifestations, and thorough consultation with local dermatologists and entomologists, the findings seemingly pointed to thrips as the most likely etiology of the eruption seen in our patients and a diagnosis of Thysanoptera dermatitis was made.

Comment

Thrips are small winged insects in the order Thysanoptera, which comprises more than 5000 identified species ranging in size from 0.5 to 15 mm, though most are approximately 1 mm.¹ The insects typically are phytophagous (feeding on plants) and are attracted to humidity and seemingly the sweat of animals and humans.² Although largely a phytophagous organism, a few published cases of thrips exposure reported papular skin eruptions known as Thysanoptera dermatitis.^3-8 Several species of thrips across the globe have been associated with incidental attacks on humans to include “Heliothrips indicus Bagnall, a cotton pest of the Sudan; Thrips imagines Bagnall, reported in Australia; Limothrips cerealium (Haliday), in Germany; Gynaitkothrips uzeli Zimmerman, in Algeria; and other species.”⁷ In Hawaii, Gynaikothrips ficorum (Cuban laurel thrips) is a common pest of the Chinese banyan tree (F microcarpa) tree.⁹

A case series reported by Goldstein and Skipworth⁵ in the late 1960s of military personnel stationed in Oahu described exposure to similar environmental conditions with resultant lesions that were nearly identical to those seen in our patients. The final conclusion of the investigation was that Cuban laurel thrips were the likely etiology, though mites also were considered.⁵ In a subsequent commentary in 1968, Waisman¹⁰ reported similar eruptions in hospitalized patients with further comment regarding the nocturnal occurrence of the bites. Additionally, the eruptions were reported to be short lasting and devoid of discomfort, similar to our patient population.¹⁰

Following suit, Aeling⁶ published a case series in 1974 depicting several service members who presented with symptoms that were nearly identical to the symptoms experienced by our patients as well as those of Goldstein and Skipworth.⁵ The investigator coined the term hypoanesthetic halos in Hawaii to describe the findings and further reported that Hawaiian dermatologists were familiar with the symptoms and clinical presentation of the disease. Patients in this outbreak had observed small flying insects, similar to the reports from our patients, and postulated that the symptoms occurred secondary to insect bites.⁶

Since the report by Goldstein and Skipworth⁵ in 1968, the majority of the literature regarding Thysanoptera dermatitis has largely been in case reports. In 1987, Fishman⁷ reported the case of a 43-year-old woman who presented with a palm-sized area of grouped red puncta on the lateral neck with the subsequent entrapment and identification of a flower thrips from the patient’s clothing. In 2005, Leigheb et al² reported the case of a 30-year-old man with an erythematous papular cutaneous eruption on the anterior chest. In this case, the causative etiology was unequivocally confirmed upon identification of the presence of thrips on biopsy.² In 2006, Guarneri et al¹ reported the case of a 59-year-old farmer who had tentatively been diagnosed with delusional parasitosis until persistent presentation to a dermatologist for evaluation enabled the capture and identification of grain thrips. More recently, another case of likely Thysanoptera dermatitis was published in 2012 after a man presented with a slide-mounted thrip from his skin for evaluation as to a potential cause of a recurrent rash he had been experiencing.¹¹ In all of these cases, it was fortunate that a specific organism could be identified for 2 reasons: (1) members of the order Thysanoptera have a biological cycle of only 11 to 36 days, and (2) thrips may go virtually unnoticed by humans, as they are often difficult to see due to their small size.^2,12 Perhaps the most extensive report, however, comes from Childers et al⁸ in a descriptive case series published in 2005. In this report, the investigators provided a thorough detailing of multiple encounters dating back to 1883 through which patients were inadvertently exposed to various species of thrips and subsequently presented with arthropod bites.

Conclusion

The rapid and clustered manner of patient presentation in this case series makes it unique and highlights the need for further consideration of Thysanoptera dermatitis as a potential etiology for an outbreak of a papular eruption. Further reporting may help to better contextualize the true epidemiology of the condition and subsequently may trigger its greater inclusion in the differential diagnosis for a pruritic papular eruption.

Acknowledgments

We would like to extend our appreciation to Amy Spizuoco, DO (New York, New York), for her assistance with the initial diagnosis; Steve Montgomery, PhD (Honolulu, Hawaii), for his assistance with further entomological discussion of potential etiologies; and John R. Gilstad, MD (Honolulu, Hawaii), for contributing his thoughts on the differential diagnosis of the presenting symptoms.

Systemic cobalt toxicity has been reported in the literature after hip arthroplasty revisions for failed ceramic components secondary to third-body abrasive wear of cobalt-chrome (CoCr) components, as well as with metal-on-metal (MOM) hip arthroplasty designs. There have been several cases of systemic cobalt toxicity after revision for fractured ceramic components.^1,2 Of these 7 reported cases, all patients had neurologic complaints and 4 patients developed cardiomyopathy secondary to toxic cobalt levels, with 1 case being fatal.¹ MOM hip prostheses have also been associated with local and systemic problems secondary to metal debris. Adverse local tissue reactions have been reported to occur in up to 59% of patients, and, in some registries, the failure rate of MOM arthroplasty caused by these soft-tissue reactions is 2 to 3 times that of conventional metal-on-polyethylene design failures.^3,4 The occurrence of systemic complications from MOM total hip arthroplasty (THA) wear debris is much less common. There have been 6 cases of systemic cobalt toxicity reported in the literature resulting from MOM total hip prosthesis design.^1,2

We present a case of biopsy-confirmed cardiomyopathy secondary to cobalt toxicity from a MOM THA design with subsequent requirement for left ventricular assist device (LVAD) implantation despite prosthesis removal. To our knowledge, this is the first report in the literature of this specific implant design causing systemic cobalt toxicity. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a healthy nondiabetic man age 54 years who presented to our clinic 6 years after undergoing left THA and 5 years after undergoing right THA with the Biomet M2a-Magnum MOM prosthesis at an outside facility. The left-side components placed at the index procedure were a size 50 cup, 44 magnum head, 10 Taperloc stem (Biomet), and +9 neck. The right-side components were a size 52 cup, 46 magnum head, 10 Taperloc stem, and +3 neck. The patient emphasized that he was very happy with his hip prostheses and denied groin or thigh pain. His medical history was significant for exogenous obesity, and he denied any history of alcohol, tobacco, steroid, or recreational drug use.

The patient’s review of systems suggested that, approximately 11 months prior to presentation at our facility, he began having difficulty with his activities of daily living secondary to chest pressure with exertion, fatigue, and associated diaphoresis. He complained of decreased sensation in his feet bilaterally but denied any hearing loss, tinnitus, or vision changes. He underwent evaluation of the new-onset chest discomfort with a cardiac stress test that suggested no active cardiac ischemia. An echocardiogram revealed mitral regurgitation, stage II diastolic dysfunction with a left ventricular ejection fraction of 55%. Additionally, during this time period, the patient was being followed by his local orthopedic surgeon for an elevated cobalt level of 120 ppb and a chromium level of 109 ppb. The patient was referred to our clinic for recommendations regarding the elevated metal-ion levels. Upon initial evaluation, the patient denied any hip or groin pain. His physical examination revealed a nonantalgic gait with full range of motion and no signs of instability, tenderness, or masses. The patient was also noted to have no vibratory sensation in his feet bilaterally. The plain radiographs indicated bilateral MOM THA with acetabular inclination levels of 55º on the right and left sides. No cystic changes or other worrisome signs that would suggest implant loosening or failure were present (Figure 1). The serum metal levels were repeated and showed a cobalt level of 189 ppb and a chromium level of 71 ppb. Whole venous blood samples were drawn at our request using trace element tubes and were sent to Medtox Laboratories Inc. for analysis. Other pertinent laboratory values, including hematocrit and thyroid levels, were within normal limits. Because of concerns of systemic toxicity from significantly elevated cobalt and chromium levels, the patient elected to proceed with revision of the MOM components.

During the preoperative medical evaluation, the patient’s cardiac status was a concern, and the etiology of the cardiac dysfunction was unclear. Cardiac magnetic resonance imaging (MRI), which was performed to evaluate the extent and etiology of cardiac dysfunction, showed biventricular dysfunction. To evaluate the underlying myocardial tissue characteristics, delayed contrast imaging was performed and showed diffuse myocardial hyperenhancement of the anterior, lateral, and apical walls, with sparing of the base and midseptum. This type of extensive hyperenhancement is commonly seen with cardiac amyloidosis; however, the blood-pool kinetics during contrast administration is unusual for amyloidosis, as well as the diffuse edema noted on T2-weighted MRI. Importantly, cardiac MRI is very specific in excluding alternative diagnoses, such as postinfarct, infiltrative, acquired, viral, or alcoholic/drugs of abuse etiologies. In the absence of amyloidosis, the only other pattern that would be consistent with symptoms was diffuse, fulminant myocarditis of toxic origin lacking clinical evidence for an infectious origin. The patient’s prior exposure to cobalt was noted. Thus, the hyperenhancement and edema could be strong supportive evidence of cobalt infiltration, despite no reported cases in the literature of cobalt cardiomyopathy found on cardiac MRI.

Additional workup was initiated, and cardiac catheterization showed that the patient continued to decompensate, with worsening global left ventricular dysfunction with an ejection fraction of 30% without evidence of coronary artery disease. Also, he was noted to have mild renal impairment with a blood urea nitrogen level of 31 mg/dL and a creatinine level of 1.7 mg/dL. The etiology of the renal impairment was unknown and had not been established, according to the patient and his wife. The renal impairment was not thought to be caused by the elevated metal ions levels but likely resulted from prerenal azotemia secondary to decreased cardiac output. During catheterization, an endomyocardial biopsy was performed and the tissue sent to the Mayo Clinic pathology department for analysis. The sample showed myocyte hypertrophy and interstitial fibrosis with scattered myofibers containing large cytoplasmic vacuoles. Also present was karyomegaly consistent with myocyte hypertrophy (Figures 2A, 2B). Trichrome stain confirmed replacement of myofibers by collagen (Figure 2C). Electron microscopy performed on a paraffin block showed reduced contractile elements, vacuolar spaces, and increased lipofuscin. The findings were very consistent with, but not specific for, cardiomyopathy from cobalt toxicity. No evidence of an inflammatory infiltrate was identified. The diagnosis was cobalt cardiomyopathy based on biopsy, presentation, cobalt levels, and intraoperative findings.

The patient was admitted to the cardiac intensive care unit preoperatively and optimized with inotropic agents. A multidisciplinary consultation with the cardiology and anesthesia departments was obtained. Both recommended cardiac anesthesia with intraoperative Swan-Ganz catheter and transesophageal echo monitoring. Assuming that the patient remained hemodynamically stable with limited blood loss and the first hip was timely performed, the cardiology department recommended a single surgery, because fewer risks and complications could be expected than from a staged procedure. Subsequently, surgery was performed on the left hip via a conservative anterior approach on the fracture table. The patient remained stable with limited blood loss. During the same operating room time, revision of the right hip was performed using an anterior approach. The intraoperative findings showed evidence of pseudotumors in the adjacent soft tissues and abundant brown, creamy fluid upon entering the joint capsule, consistent with a metallic appearance. Both hips showed similar prosthetic findings. There was no significant visible wear of the large diameter metal heads or gross abnormality of the acetabular components. The trunnion area on both femoral implants was abnormal, revealing a black coating suggestive of marked corrosion. The components were all well fixed, without visible damage, and, because of his fragile cardiac status, the patient’s acetabular components were not revised. The trunnions were cleaned and the femoral heads were revised to active articulation dual-mobility metal-on-polyethylene constructs using 28-mm Biolox Option ceramic (CeramTec). The tissue specimens from the operation showed chronic inflammation with areas of fibroconnective tissue and bland fibrinoid necrosis with extensive brown pigment-laden macrophage reaction. The intraoperative cultures were negative.

The patient tolerated the surgery without complication, and his postoperative period was without incident. Nine months after surgery, the patient’s cobalt and chromium levels had declined to 16 ppb and 32 ppb, respectively (normal, <1 ppb). However, his cardiac status continued to worsen with significant shortness of breath and bilateral lower extremity edema despite diuresis. Follow-up cardiac MRI indicated progressive left and right dysfunction with ejection fractions of 23% and 25%, respectively. After progressive heart-failure symptoms, the patient was admitted to the hospital for severe congestive heart failure and underwent implantation of a HeartWare LVAD with tricuspid valve repair using an Edwards annuloplasty ring. He has since had a cardiac transplant and is doing well.

Discussion

To our knowledge, this is the first reported case of cardiomyopathy in a patient with elevated cobalt ion levels and a Biomet M2a-Magnum hip prosthesis. This is also the first reported case of cardiac MRI–defined cobalt cardiomyopathy. The cobalt levels seen in this patient were similar to those of other cases with systemic cobalt toxicity from a MOM hip construct. Mao and colleagues⁵ reported 2 cases of systemic cobalt toxicity in 2 patients with articular surface replacement hip prostheses.One patient presented with mild groin pain, neurologic symptoms, and a cobalt level of 410 ppb 5 years after her index procedure. The other patient presented with cardiac and neurologic symptoms but no hip complaints. The patient’s cobalt levels ranged from 185 ppb to 210 ppb. Both patients improved after their revision surgery, and their cobalt levels decreased. The 2 patients in Tower’s report⁶ were 49-year-old men who had articular surface replacement implants (DePuy). One patient who presented with progressive hip pain 11 months postoperatively developed neurologic symptoms and cardiomyopathy, with cobalt levels of 83 ppb before revision surgery 43 months after his index procedure. The other patient presented with hip pain and vertigo, headaches, fatigue, and dyspnea. He underwent hip revision 40 months postoperatively and required closed reduction under sedation for dislocation. Finally, and most recently, Allen and colleagues² reported a 59-year-old woman with a cobalt level of 287 ppb whose symptoms did not resolve after implantation of an LVAD or cardiac transplantation but only after removal of her bilateral hip prosthesis. Our case is most similar to this report but significantly adds to the literature in 2 distinct manners: (1) Biomet M2a-Magnum has not been implicated in cobalt toxicity; and (2) this is the first reported use of dedicated cardiac MRI to noninvasively define underlying cardiac pathology.

The cardiac manifestations secondary to systemic cobalt toxicity in this patient represent a frightening consequence of MOM prosthetic wear. The effects of cobalt toxicity on cardiac tissues were first described in a series of alcoholic patients from Manchester in 1900;⁷ however, it was not until 1967, in a series of patients in Quebec, that cobalt was found to be the inciting factor. In the modern era, hip arthroplasty techniques resulting in excessive cobalt and chromium wear have demonstrated the same findings of myocyte hypertrophy, interstitial fibrosis, and scattered myofibers containing large cytoplasmic inclusions.^8,9 The patient presented here has pathologic findings consistent with previous cases of cobalt cardiomyopathy; however, in the other cases of cardiomyopathy due to MOM total hip components, the patients’ cardiac conditions improved after the prostheses were revised and the cobalt levels began to diminish.^5,6In our case, the patient has sustained permanent damage to his myocardium and a progressive decline in his cardiac status, which is a deviation from reported cases as of 2014.

While there is no guideline to unequivocally diagnose cobalt cardiomyopathy, the constellation of findings, including pathologic, biologic, blood levels, imaging, and surgical, all uniformly indicate a unifying diagnosis. The lack of improvement after prosthetic device removal supports a diagnosis of permanent myocardial damage, which is consistent with cardiomyopathy of advanced toxic etiology.

Conclusion

This case presents a patient with bilateral MOM THAs, acetabular cup inclinations of greater than 55º, renal impairment, and cobalt levels greater than 60 ppb, with occult cardiac failure leading to LVAD implantation as a prelude to cardiac transplantation in order to avoid certain death. These factors have been shown, in prior case reports, to be associated with cardiac damage that may be reversible.⁶ However; it is important for orthopedic surgeons to recognize that certain hip prostheses can be associated or lead to irreversible cardiac damage.

Systemic cobalt toxicity has been reported in the literature after hip arthroplasty revisions for failed ceramic components secondary to third-body abrasive wear of cobalt-chrome (CoCr) components, as well as with metal-on-metal (MOM) hip arthroplasty designs. There have been several cases of systemic cobalt toxicity after revision for fractured ceramic components.^1,2 Of these 7 reported cases, all patients had neurologic complaints and 4 patients developed cardiomyopathy secondary to toxic cobalt levels, with 1 case being fatal.¹ MOM hip prostheses have also been associated with local and systemic problems secondary to metal debris. Adverse local tissue reactions have been reported to occur in up to 59% of patients, and, in some registries, the failure rate of MOM arthroplasty caused by these soft-tissue reactions is 2 to 3 times that of conventional metal-on-polyethylene design failures.^3,4 The occurrence of systemic complications from MOM total hip arthroplasty (THA) wear debris is much less common. There have been 6 cases of systemic cobalt toxicity reported in the literature resulting from MOM total hip prosthesis design.^1,2

We present a case of biopsy-confirmed cardiomyopathy secondary to cobalt toxicity from a MOM THA design with subsequent requirement for left ventricular assist device (LVAD) implantation despite prosthesis removal. To our knowledge, this is the first report in the literature of this specific implant design causing systemic cobalt toxicity. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a healthy nondiabetic man age 54 years who presented to our clinic 6 years after undergoing left THA and 5 years after undergoing right THA with the Biomet M2a-Magnum MOM prosthesis at an outside facility. The left-side components placed at the index procedure were a size 50 cup, 44 magnum head, 10 Taperloc stem (Biomet), and +9 neck. The right-side components were a size 52 cup, 46 magnum head, 10 Taperloc stem, and +3 neck. The patient emphasized that he was very happy with his hip prostheses and denied groin or thigh pain. His medical history was significant for exogenous obesity, and he denied any history of alcohol, tobacco, steroid, or recreational drug use.

The patient’s review of systems suggested that, approximately 11 months prior to presentation at our facility, he began having difficulty with his activities of daily living secondary to chest pressure with exertion, fatigue, and associated diaphoresis. He complained of decreased sensation in his feet bilaterally but denied any hearing loss, tinnitus, or vision changes. He underwent evaluation of the new-onset chest discomfort with a cardiac stress test that suggested no active cardiac ischemia. An echocardiogram revealed mitral regurgitation, stage II diastolic dysfunction with a left ventricular ejection fraction of 55%. Additionally, during this time period, the patient was being followed by his local orthopedic surgeon for an elevated cobalt level of 120 ppb and a chromium level of 109 ppb. The patient was referred to our clinic for recommendations regarding the elevated metal-ion levels. Upon initial evaluation, the patient denied any hip or groin pain. His physical examination revealed a nonantalgic gait with full range of motion and no signs of instability, tenderness, or masses. The patient was also noted to have no vibratory sensation in his feet bilaterally. The plain radiographs indicated bilateral MOM THA with acetabular inclination levels of 55º on the right and left sides. No cystic changes or other worrisome signs that would suggest implant loosening or failure were present (Figure 1). The serum metal levels were repeated and showed a cobalt level of 189 ppb and a chromium level of 71 ppb. Whole venous blood samples were drawn at our request using trace element tubes and were sent to Medtox Laboratories Inc. for analysis. Other pertinent laboratory values, including hematocrit and thyroid levels, were within normal limits. Because of concerns of systemic toxicity from significantly elevated cobalt and chromium levels, the patient elected to proceed with revision of the MOM components.

During the preoperative medical evaluation, the patient’s cardiac status was a concern, and the etiology of the cardiac dysfunction was unclear. Cardiac magnetic resonance imaging (MRI), which was performed to evaluate the extent and etiology of cardiac dysfunction, showed biventricular dysfunction. To evaluate the underlying myocardial tissue characteristics, delayed contrast imaging was performed and showed diffuse myocardial hyperenhancement of the anterior, lateral, and apical walls, with sparing of the base and midseptum. This type of extensive hyperenhancement is commonly seen with cardiac amyloidosis; however, the blood-pool kinetics during contrast administration is unusual for amyloidosis, as well as the diffuse edema noted on T2-weighted MRI. Importantly, cardiac MRI is very specific in excluding alternative diagnoses, such as postinfarct, infiltrative, acquired, viral, or alcoholic/drugs of abuse etiologies. In the absence of amyloidosis, the only other pattern that would be consistent with symptoms was diffuse, fulminant myocarditis of toxic origin lacking clinical evidence for an infectious origin. The patient’s prior exposure to cobalt was noted. Thus, the hyperenhancement and edema could be strong supportive evidence of cobalt infiltration, despite no reported cases in the literature of cobalt cardiomyopathy found on cardiac MRI.

Additional workup was initiated, and cardiac catheterization showed that the patient continued to decompensate, with worsening global left ventricular dysfunction with an ejection fraction of 30% without evidence of coronary artery disease. Also, he was noted to have mild renal impairment with a blood urea nitrogen level of 31 mg/dL and a creatinine level of 1.7 mg/dL. The etiology of the renal impairment was unknown and had not been established, according to the patient and his wife. The renal impairment was not thought to be caused by the elevated metal ions levels but likely resulted from prerenal azotemia secondary to decreased cardiac output. During catheterization, an endomyocardial biopsy was performed and the tissue sent to the Mayo Clinic pathology department for analysis. The sample showed myocyte hypertrophy and interstitial fibrosis with scattered myofibers containing large cytoplasmic vacuoles. Also present was karyomegaly consistent with myocyte hypertrophy (Figures 2A, 2B). Trichrome stain confirmed replacement of myofibers by collagen (Figure 2C). Electron microscopy performed on a paraffin block showed reduced contractile elements, vacuolar spaces, and increased lipofuscin. The findings were very consistent with, but not specific for, cardiomyopathy from cobalt toxicity. No evidence of an inflammatory infiltrate was identified. The diagnosis was cobalt cardiomyopathy based on biopsy, presentation, cobalt levels, and intraoperative findings.

The patient was admitted to the cardiac intensive care unit preoperatively and optimized with inotropic agents. A multidisciplinary consultation with the cardiology and anesthesia departments was obtained. Both recommended cardiac anesthesia with intraoperative Swan-Ganz catheter and transesophageal echo monitoring. Assuming that the patient remained hemodynamically stable with limited blood loss and the first hip was timely performed, the cardiology department recommended a single surgery, because fewer risks and complications could be expected than from a staged procedure. Subsequently, surgery was performed on the left hip via a conservative anterior approach on the fracture table. The patient remained stable with limited blood loss. During the same operating room time, revision of the right hip was performed using an anterior approach. The intraoperative findings showed evidence of pseudotumors in the adjacent soft tissues and abundant brown, creamy fluid upon entering the joint capsule, consistent with a metallic appearance. Both hips showed similar prosthetic findings. There was no significant visible wear of the large diameter metal heads or gross abnormality of the acetabular components. The trunnion area on both femoral implants was abnormal, revealing a black coating suggestive of marked corrosion. The components were all well fixed, without visible damage, and, because of his fragile cardiac status, the patient’s acetabular components were not revised. The trunnions were cleaned and the femoral heads were revised to active articulation dual-mobility metal-on-polyethylene constructs using 28-mm Biolox Option ceramic (CeramTec). The tissue specimens from the operation showed chronic inflammation with areas of fibroconnective tissue and bland fibrinoid necrosis with extensive brown pigment-laden macrophage reaction. The intraoperative cultures were negative.

The patient tolerated the surgery without complication, and his postoperative period was without incident. Nine months after surgery, the patient’s cobalt and chromium levels had declined to 16 ppb and 32 ppb, respectively (normal, <1 ppb). However, his cardiac status continued to worsen with significant shortness of breath and bilateral lower extremity edema despite diuresis. Follow-up cardiac MRI indicated progressive left and right dysfunction with ejection fractions of 23% and 25%, respectively. After progressive heart-failure symptoms, the patient was admitted to the hospital for severe congestive heart failure and underwent implantation of a HeartWare LVAD with tricuspid valve repair using an Edwards annuloplasty ring. He has since had a cardiac transplant and is doing well.

Discussion

To our knowledge, this is the first reported case of cardiomyopathy in a patient with elevated cobalt ion levels and a Biomet M2a-Magnum hip prosthesis. This is also the first reported case of cardiac MRI–defined cobalt cardiomyopathy. The cobalt levels seen in this patient were similar to those of other cases with systemic cobalt toxicity from a MOM hip construct. Mao and colleagues⁵ reported 2 cases of systemic cobalt toxicity in 2 patients with articular surface replacement hip prostheses.One patient presented with mild groin pain, neurologic symptoms, and a cobalt level of 410 ppb 5 years after her index procedure. The other patient presented with cardiac and neurologic symptoms but no hip complaints. The patient’s cobalt levels ranged from 185 ppb to 210 ppb. Both patients improved after their revision surgery, and their cobalt levels decreased. The 2 patients in Tower’s report⁶ were 49-year-old men who had articular surface replacement implants (DePuy). One patient who presented with progressive hip pain 11 months postoperatively developed neurologic symptoms and cardiomyopathy, with cobalt levels of 83 ppb before revision surgery 43 months after his index procedure. The other patient presented with hip pain and vertigo, headaches, fatigue, and dyspnea. He underwent hip revision 40 months postoperatively and required closed reduction under sedation for dislocation. Finally, and most recently, Allen and colleagues² reported a 59-year-old woman with a cobalt level of 287 ppb whose symptoms did not resolve after implantation of an LVAD or cardiac transplantation but only after removal of her bilateral hip prosthesis. Our case is most similar to this report but significantly adds to the literature in 2 distinct manners: (1) Biomet M2a-Magnum has not been implicated in cobalt toxicity; and (2) this is the first reported use of dedicated cardiac MRI to noninvasively define underlying cardiac pathology.

The cardiac manifestations secondary to systemic cobalt toxicity in this patient represent a frightening consequence of MOM prosthetic wear. The effects of cobalt toxicity on cardiac tissues were first described in a series of alcoholic patients from Manchester in 1900;⁷ however, it was not until 1967, in a series of patients in Quebec, that cobalt was found to be the inciting factor. In the modern era, hip arthroplasty techniques resulting in excessive cobalt and chromium wear have demonstrated the same findings of myocyte hypertrophy, interstitial fibrosis, and scattered myofibers containing large cytoplasmic inclusions.^8,9 The patient presented here has pathologic findings consistent with previous cases of cobalt cardiomyopathy; however, in the other cases of cardiomyopathy due to MOM total hip components, the patients’ cardiac conditions improved after the prostheses were revised and the cobalt levels began to diminish.^5,6In our case, the patient has sustained permanent damage to his myocardium and a progressive decline in his cardiac status, which is a deviation from reported cases as of 2014.

While there is no guideline to unequivocally diagnose cobalt cardiomyopathy, the constellation of findings, including pathologic, biologic, blood levels, imaging, and surgical, all uniformly indicate a unifying diagnosis. The lack of improvement after prosthetic device removal supports a diagnosis of permanent myocardial damage, which is consistent with cardiomyopathy of advanced toxic etiology.

Conclusion

This case presents a patient with bilateral MOM THAs, acetabular cup inclinations of greater than 55º, renal impairment, and cobalt levels greater than 60 ppb, with occult cardiac failure leading to LVAD implantation as a prelude to cardiac transplantation in order to avoid certain death. These factors have been shown, in prior case reports, to be associated with cardiac damage that may be reversible.⁶ However; it is important for orthopedic surgeons to recognize that certain hip prostheses can be associated or lead to irreversible cardiac damage.

Systemic cobalt toxicity has been reported in the literature after hip arthroplasty revisions for failed ceramic components secondary to third-body abrasive wear of cobalt-chrome (CoCr) components, as well as with metal-on-metal (MOM) hip arthroplasty designs. There have been several cases of systemic cobalt toxicity after revision for fractured ceramic components.^1,2 Of these 7 reported cases, all patients had neurologic complaints and 4 patients developed cardiomyopathy secondary to toxic cobalt levels, with 1 case being fatal.¹ MOM hip prostheses have also been associated with local and systemic problems secondary to metal debris. Adverse local tissue reactions have been reported to occur in up to 59% of patients, and, in some registries, the failure rate of MOM arthroplasty caused by these soft-tissue reactions is 2 to 3 times that of conventional metal-on-polyethylene design failures.^3,4 The occurrence of systemic complications from MOM total hip arthroplasty (THA) wear debris is much less common. There have been 6 cases of systemic cobalt toxicity reported in the literature resulting from MOM total hip prosthesis design.^1,2

We present a case of biopsy-confirmed cardiomyopathy secondary to cobalt toxicity from a MOM THA design with subsequent requirement for left ventricular assist device (LVAD) implantation despite prosthesis removal. To our knowledge, this is the first report in the literature of this specific implant design causing systemic cobalt toxicity. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

The patient was a healthy nondiabetic man age 54 years who presented to our clinic 6 years after undergoing left THA and 5 years after undergoing right THA with the Biomet M2a-Magnum MOM prosthesis at an outside facility. The left-side components placed at the index procedure were a size 50 cup, 44 magnum head, 10 Taperloc stem (Biomet), and +9 neck. The right-side components were a size 52 cup, 46 magnum head, 10 Taperloc stem, and +3 neck. The patient emphasized that he was very happy with his hip prostheses and denied groin or thigh pain. His medical history was significant for exogenous obesity, and he denied any history of alcohol, tobacco, steroid, or recreational drug use.

The patient’s review of systems suggested that, approximately 11 months prior to presentation at our facility, he began having difficulty with his activities of daily living secondary to chest pressure with exertion, fatigue, and associated diaphoresis. He complained of decreased sensation in his feet bilaterally but denied any hearing loss, tinnitus, or vision changes. He underwent evaluation of the new-onset chest discomfort with a cardiac stress test that suggested no active cardiac ischemia. An echocardiogram revealed mitral regurgitation, stage II diastolic dysfunction with a left ventricular ejection fraction of 55%. Additionally, during this time period, the patient was being followed by his local orthopedic surgeon for an elevated cobalt level of 120 ppb and a chromium level of 109 ppb. The patient was referred to our clinic for recommendations regarding the elevated metal-ion levels. Upon initial evaluation, the patient denied any hip or groin pain. His physical examination revealed a nonantalgic gait with full range of motion and no signs of instability, tenderness, or masses. The patient was also noted to have no vibratory sensation in his feet bilaterally. The plain radiographs indicated bilateral MOM THA with acetabular inclination levels of 55º on the right and left sides. No cystic changes or other worrisome signs that would suggest implant loosening or failure were present (Figure 1). The serum metal levels were repeated and showed a cobalt level of 189 ppb and a chromium level of 71 ppb. Whole venous blood samples were drawn at our request using trace element tubes and were sent to Medtox Laboratories Inc. for analysis. Other pertinent laboratory values, including hematocrit and thyroid levels, were within normal limits. Because of concerns of systemic toxicity from significantly elevated cobalt and chromium levels, the patient elected to proceed with revision of the MOM components.

During the preoperative medical evaluation, the patient’s cardiac status was a concern, and the etiology of the cardiac dysfunction was unclear. Cardiac magnetic resonance imaging (MRI), which was performed to evaluate the extent and etiology of cardiac dysfunction, showed biventricular dysfunction. To evaluate the underlying myocardial tissue characteristics, delayed contrast imaging was performed and showed diffuse myocardial hyperenhancement of the anterior, lateral, and apical walls, with sparing of the base and midseptum. This type of extensive hyperenhancement is commonly seen with cardiac amyloidosis; however, the blood-pool kinetics during contrast administration is unusual for amyloidosis, as well as the diffuse edema noted on T2-weighted MRI. Importantly, cardiac MRI is very specific in excluding alternative diagnoses, such as postinfarct, infiltrative, acquired, viral, or alcoholic/drugs of abuse etiologies. In the absence of amyloidosis, the only other pattern that would be consistent with symptoms was diffuse, fulminant myocarditis of toxic origin lacking clinical evidence for an infectious origin. The patient’s prior exposure to cobalt was noted. Thus, the hyperenhancement and edema could be strong supportive evidence of cobalt infiltration, despite no reported cases in the literature of cobalt cardiomyopathy found on cardiac MRI.

Additional workup was initiated, and cardiac catheterization showed that the patient continued to decompensate, with worsening global left ventricular dysfunction with an ejection fraction of 30% without evidence of coronary artery disease. Also, he was noted to have mild renal impairment with a blood urea nitrogen level of 31 mg/dL and a creatinine level of 1.7 mg/dL. The etiology of the renal impairment was unknown and had not been established, according to the patient and his wife. The renal impairment was not thought to be caused by the elevated metal ions levels but likely resulted from prerenal azotemia secondary to decreased cardiac output. During catheterization, an endomyocardial biopsy was performed and the tissue sent to the Mayo Clinic pathology department for analysis. The sample showed myocyte hypertrophy and interstitial fibrosis with scattered myofibers containing large cytoplasmic vacuoles. Also present was karyomegaly consistent with myocyte hypertrophy (Figures 2A, 2B). Trichrome stain confirmed replacement of myofibers by collagen (Figure 2C). Electron microscopy performed on a paraffin block showed reduced contractile elements, vacuolar spaces, and increased lipofuscin. The findings were very consistent with, but not specific for, cardiomyopathy from cobalt toxicity. No evidence of an inflammatory infiltrate was identified. The diagnosis was cobalt cardiomyopathy based on biopsy, presentation, cobalt levels, and intraoperative findings.

The patient was admitted to the cardiac intensive care unit preoperatively and optimized with inotropic agents. A multidisciplinary consultation with the cardiology and anesthesia departments was obtained. Both recommended cardiac anesthesia with intraoperative Swan-Ganz catheter and transesophageal echo monitoring. Assuming that the patient remained hemodynamically stable with limited blood loss and the first hip was timely performed, the cardiology department recommended a single surgery, because fewer risks and complications could be expected than from a staged procedure. Subsequently, surgery was performed on the left hip via a conservative anterior approach on the fracture table. The patient remained stable with limited blood loss. During the same operating room time, revision of the right hip was performed using an anterior approach. The intraoperative findings showed evidence of pseudotumors in the adjacent soft tissues and abundant brown, creamy fluid upon entering the joint capsule, consistent with a metallic appearance. Both hips showed similar prosthetic findings. There was no significant visible wear of the large diameter metal heads or gross abnormality of the acetabular components. The trunnion area on both femoral implants was abnormal, revealing a black coating suggestive of marked corrosion. The components were all well fixed, without visible damage, and, because of his fragile cardiac status, the patient’s acetabular components were not revised. The trunnions were cleaned and the femoral heads were revised to active articulation dual-mobility metal-on-polyethylene constructs using 28-mm Biolox Option ceramic (CeramTec). The tissue specimens from the operation showed chronic inflammation with areas of fibroconnective tissue and bland fibrinoid necrosis with extensive brown pigment-laden macrophage reaction. The intraoperative cultures were negative.

The patient tolerated the surgery without complication, and his postoperative period was without incident. Nine months after surgery, the patient’s cobalt and chromium levels had declined to 16 ppb and 32 ppb, respectively (normal, <1 ppb). However, his cardiac status continued to worsen with significant shortness of breath and bilateral lower extremity edema despite diuresis. Follow-up cardiac MRI indicated progressive left and right dysfunction with ejection fractions of 23% and 25%, respectively. After progressive heart-failure symptoms, the patient was admitted to the hospital for severe congestive heart failure and underwent implantation of a HeartWare LVAD with tricuspid valve repair using an Edwards annuloplasty ring. He has since had a cardiac transplant and is doing well.

Discussion

To our knowledge, this is the first reported case of cardiomyopathy in a patient with elevated cobalt ion levels and a Biomet M2a-Magnum hip prosthesis. This is also the first reported case of cardiac MRI–defined cobalt cardiomyopathy. The cobalt levels seen in this patient were similar to those of other cases with systemic cobalt toxicity from a MOM hip construct. Mao and colleagues⁵ reported 2 cases of systemic cobalt toxicity in 2 patients with articular surface replacement hip prostheses.One patient presented with mild groin pain, neurologic symptoms, and a cobalt level of 410 ppb 5 years after her index procedure. The other patient presented with cardiac and neurologic symptoms but no hip complaints. The patient’s cobalt levels ranged from 185 ppb to 210 ppb. Both patients improved after their revision surgery, and their cobalt levels decreased. The 2 patients in Tower’s report⁶ were 49-year-old men who had articular surface replacement implants (DePuy). One patient who presented with progressive hip pain 11 months postoperatively developed neurologic symptoms and cardiomyopathy, with cobalt levels of 83 ppb before revision surgery 43 months after his index procedure. The other patient presented with hip pain and vertigo, headaches, fatigue, and dyspnea. He underwent hip revision 40 months postoperatively and required closed reduction under sedation for dislocation. Finally, and most recently, Allen and colleagues² reported a 59-year-old woman with a cobalt level of 287 ppb whose symptoms did not resolve after implantation of an LVAD or cardiac transplantation but only after removal of her bilateral hip prosthesis. Our case is most similar to this report but significantly adds to the literature in 2 distinct manners: (1) Biomet M2a-Magnum has not been implicated in cobalt toxicity; and (2) this is the first reported use of dedicated cardiac MRI to noninvasively define underlying cardiac pathology.

The cardiac manifestations secondary to systemic cobalt toxicity in this patient represent a frightening consequence of MOM prosthetic wear. The effects of cobalt toxicity on cardiac tissues were first described in a series of alcoholic patients from Manchester in 1900;⁷ however, it was not until 1967, in a series of patients in Quebec, that cobalt was found to be the inciting factor. In the modern era, hip arthroplasty techniques resulting in excessive cobalt and chromium wear have demonstrated the same findings of myocyte hypertrophy, interstitial fibrosis, and scattered myofibers containing large cytoplasmic inclusions.^8,9 The patient presented here has pathologic findings consistent with previous cases of cobalt cardiomyopathy; however, in the other cases of cardiomyopathy due to MOM total hip components, the patients’ cardiac conditions improved after the prostheses were revised and the cobalt levels began to diminish.^5,6In our case, the patient has sustained permanent damage to his myocardium and a progressive decline in his cardiac status, which is a deviation from reported cases as of 2014.

While there is no guideline to unequivocally diagnose cobalt cardiomyopathy, the constellation of findings, including pathologic, biologic, blood levels, imaging, and surgical, all uniformly indicate a unifying diagnosis. The lack of improvement after prosthetic device removal supports a diagnosis of permanent myocardial damage, which is consistent with cardiomyopathy of advanced toxic etiology.

Conclusion

This case presents a patient with bilateral MOM THAs, acetabular cup inclinations of greater than 55º, renal impairment, and cobalt levels greater than 60 ppb, with occult cardiac failure leading to LVAD implantation as a prelude to cardiac transplantation in order to avoid certain death. These factors have been shown, in prior case reports, to be associated with cardiac damage that may be reversible.⁶ However; it is important for orthopedic surgeons to recognize that certain hip prostheses can be associated or lead to irreversible cardiac damage.

Benign fibrous histiocytoma (BFH) is a rare, well-recognized, primary skeletal tumor accounting for approximately 1% of all benign bone tumors. Spinal involvement is exceedingly rare with only 11 cases reported in the literature.^1,2 We present a case of BFH located in the cervical spine of a pediatric patient that was successfully treated with curretage through an anterior surgical approach, along with a review of the literature and appropriate management concerning BFH of the spine.

Case Report

A 14-year-old boy was tackled while playing football and noticed immediate neck pain and subjective paresthesia in the upper extremities. Examination revealed a nontender spine (cervical, thoracic, lumbar) and normal strength and range of motion in all extremities. Sensation was diffusely intact, long tract signs were absent, and gait was normal. On questioning, the patient endorsed mild antecedent neck pain but denied prior history of any trauma. Neck pain did not radiate and was slightly worsened by activity but was mostly intermittent and random. As the neck pain was very mild and was not interfering with daily activities, the patient had not sought care before presenting to the emergency department. He had no pertinent past medical or surgical history.

The patient presented with a computed tomography (CT) scan of his head and cervical spine and a magnetic resonance imaging (MRI) scan of the cervical spine. A magnetic resonance angiography (MRA) scan of the neck was ordered after his arrival.

Axial and sagittal CT (Figures 1A, 1B) showed a 1×1.2-cm discrete, expansile, lytic, radiolucent mass extending anterior from the left C2 vertebral body. The mass appeared to abut the left vertebral artery foramen. The cortical bone surrounding the lesion was thin but uniform. Sagittal and axial T1-weighted MRI (Figures 2A, 2B) showed the discrete, expansile, homogenous lesion with the same intensity as normal bone marrow. Sagittal and axial T2-weighted MRI (Figures 2C, 2D) showed a discrete, expansile, homogenous lesion with primarily high signal intensity. Sagittal short tau inversion recovery (STIR) MRI (Figure 2E) again showed the lesion with primarily low intensity. Given the close proximity of the lesion to the vertebral foramen, MRA was ordered; it showed the lesion was not interfering with the vertebral artery (Figure 2F).

The tumor’s location, in the left anterior aspect of the C2 vertebral body, was not conducive to percutaneous biopsy for establishing tissue diagnosis, so the decision was made to surgically excise the lesion. A left-sided anterior incision was made 2 fingerbreadths inferior to the jaw line in a neck crease. A head and neck surgeon assisted with dissection. Dissection was carried down through the skin, subcutaneous tissue, and platysma on to the anterior part of the spine medial to the carotid sheath. Superior thyroid nerve and vessels and superior laryngeal nerve were identified and preserved. Fluoroscopy confirmed correct location at C2. The tumor was easily visualized, and the outer shell broke easily with palpation. Gentle curettage was necessary when removing the tumor off the vertebral artery. A portion of the specimen was sent during surgery for frozen section, which showed infrequent mitotic figures and no other findings concerning for malignancy. No instability was created after curettage and excision of the tumor, so no grafting or instrumentation was necessary.

Grossly, the tumor was pale tan and firm. Histologic examination with hematoxylin-eosin staining revealed a bland spindle-cell neoplasm that focally involved bone. A storiform pattern was present. The cells had scant cytoplasm and oval to elongate nuclei with tapered ends. Significant nuclear pleomorphism was not seen. The stroma was loose, with focal myxoid change. Benign multinucleated giant cells were present. Mitotic activity was infrequent (Figures 3A–3D). Two attending pathologists reviewed the case material and the frozen and formalin-fixed specimens independently and concurred with the diagnosis of BFH. In addition, the case was reviewed at the surgical pathology consensus conference; the reviewers agreed on BFH, and additional studies were deemed unnecessary.

Given the patient’s complete clinical picture, the differential diagnosis included nonossifying fibroma (NOF), eosinophilic granuloma (EG), BFH, fibrous dysplasia, giant cell tumor (GCT), aneurysmal bone cyst (ABC), and osteoblastoma (OB).

Discussion

BFH is an extremely rare bone lesion, accounting for only 1% of all surgically managed bone tumors; not counting the present case, only 11 spine cases have been reported in the literature.^1,2 BFH of the spine traditionally causes nonspecific, poorly localized pain. The Table lists the reported cases of spinal BFH and their presenting symptoms, location, and treatment. BFH usually occurs in young adults, but the age range is 5 to 75 years.^2-4 Mean age of the 12 patients with spinal BFH in the literature (including ours) is 25 years.¹ In addition, spinal BFH appears to have no predilection for sex.

Skeletal BFH presents as a discrete, well-defined, osteolytic lesion with sharp borders and potentially a sclerotic rim.^4-6 Cortical expansion and even cortical disruption with invasion into adjacent tissue have occurred in flat bones.⁷ Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in storiform pattern.⁶

BFH shares many of its radiologic and histologic characteristics and clinical symptoms with other benign bone lesions (the tumors listed above). Therefore, accurate diagnosis of BFH requires appropriate correlation of clinical, radiographic, and histologic data.^2,3,8 Below is a comparison of BFH with related bone lesions.

Spinal BFH causes a nonspecific, poorly localized pain similar to that of EG, ABC, GCT, and OB.^3,9 NOF and fibrous dysplasia generally do not cause pain, unless these lesions are discovered secondary to a pathologic fracture.^8,10,11 Our patient had minor antecedent neck pain, which was brought to light by his football accident. ABC and OB are more locally aggressive than BFH and can cause neurologic symptoms by mass effect and spinal cord or nerve root compression.^1,8 In this case and in the 6 other cases of BFH of the cervical spine, there were no neurologic changes.^4,10

Of the tumors mentioned, NOF and EG almost always occur in children. However, NOF usually occurs in the metaphyseal region of long bones, and EG is usually accompanied by systemic symptoms, such as lymphadenopathy, hepatomegaly, and increased inflammatory markers.^1,8 Fibrous dysplasia usually presents in childhood but does not become symptomatic until adulthood. GCTs and OB predominantly occur in adulthood.^12,13 Our patient’s age and lack of other systemic symptoms supported the diagnosis of BFH.

Appearance on MRI is reported less with BFH than with other tumors, but heterogenous signal intensity similar to that of skeletal muscle on T1-weighted images and high signal intensity on T2-weighted images is typically reported.^8,14 NOF and fibrous dysplasia do not disrupt the bony cortex unless a pathologic fracture has occurred.⁴ GCTs are more aggressive lytic lesions with more aggressive radiologic features. GCTs generally cause cortical expansion/attenuation, and lack a sclerotic rim. GCTs also have a heterogenous appearance on MRI and give a low to intermediate signal on both T1- and T2-weighted images.^12,15 The appearance of EG is similar to that of BFH as an osteolytic lesion with a sclerotic rim, though EGs typically break through the cortex and acquire a “punched-out” look.^1,8 ABC typically is described as an expansile osteolytic lesion with a “soap-bubble” appearance on radiographs; periosteal elevation and cortical attenuation can also be visualized. MRI shows the typical multilobular appearance of the lesion with fluid levels.¹³

OB appears as a radiolucent lesion, with or without calcifications, surrounded by a thin margin of reactive bone.^14,16 A distinguishing characteristic of OB was thought to be intense radioisotope uptake on bone scintigraphy, but recently a bony BFH demonstrated intense uptake.¹⁷ OBs typically demonstrate nonspecific MRI results similar to those of BFH: low to intermediate signal on T1-weighted images and intermediate to high signal on T2-weighted images.¹³ In our patient’s case, the radiographic appearance and lack of specific radiographic findings consistent with the other tumors supported the diagnosis of BFH.

Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in a storiform pattern⁶ which was demonstrated in our patient’s case. In addition, significant nuclear pleomorphism, mitotic activity, and necrosis were absent—a difference between BFH and malignant fibrous histiocytoma.^4,15 The microscopic characteristics of BFH readily differentiate it from OB, ABC, EG, and GCT, but not from NOF on microscopic appearance alone. Clinical and radiographic findings must be consistent, as mentioned.^7,18

Complete surgical excision is the reported treatment for BFH. Prognosis after resection or curettage is usually good, and recurrences have been rare.^1,2 Depending on the intraspinous location of BFH, stabilization after resection or curettage may be necessary to prevent residual instability. Three of the 11 reported cases of spinal BFH required stabilization by anterior fusion or posterior pedicle screw fixation after resection.^1,2 The other 8 cases underwent excision alone or excision and grafting. All 11 patients were disease-free at a mean follow-up of 3.5 years.¹ In nonspinal BFH, however, both local recurrence and lung metastasis have been reported.^2,5,9,19 Clarke and colleagues⁹ reported local recurrences in 3 of 8 cases. These recurrences involved BFH in long bones of the leg, which had been treated with curettage and grafting. There has been no reliable report of a malignant change in BFH.^2,9 The only case of lung metastasis, reported by Unni and Dahlin⁶ in their study of 10 cases, occurred 2 years after local recurrence in the distal femur.Our patient was doing well at most recent follow-up, 6 months after surgery. He had no pain and had returned to normal activities. Although there are no reported cases of spinal BFH recurrence, we will follow this patient with imaging on an annual basis. His case is of particular interest to orthopedic surgeons because they encounter benign bone lesions every day, and many of these lesions are in difficult anatomical locations. Knowing the characteristics, differential diagnoses, and appropriate diagnostic workups for benign bone lesions is important for optimal and timely patient care.

Benign fibrous histiocytoma (BFH) is a rare, well-recognized, primary skeletal tumor accounting for approximately 1% of all benign bone tumors. Spinal involvement is exceedingly rare with only 11 cases reported in the literature.^1,2 We present a case of BFH located in the cervical spine of a pediatric patient that was successfully treated with curretage through an anterior surgical approach, along with a review of the literature and appropriate management concerning BFH of the spine.

Case Report

A 14-year-old boy was tackled while playing football and noticed immediate neck pain and subjective paresthesia in the upper extremities. Examination revealed a nontender spine (cervical, thoracic, lumbar) and normal strength and range of motion in all extremities. Sensation was diffusely intact, long tract signs were absent, and gait was normal. On questioning, the patient endorsed mild antecedent neck pain but denied prior history of any trauma. Neck pain did not radiate and was slightly worsened by activity but was mostly intermittent and random. As the neck pain was very mild and was not interfering with daily activities, the patient had not sought care before presenting to the emergency department. He had no pertinent past medical or surgical history.

The patient presented with a computed tomography (CT) scan of his head and cervical spine and a magnetic resonance imaging (MRI) scan of the cervical spine. A magnetic resonance angiography (MRA) scan of the neck was ordered after his arrival.

Axial and sagittal CT (Figures 1A, 1B) showed a 1×1.2-cm discrete, expansile, lytic, radiolucent mass extending anterior from the left C2 vertebral body. The mass appeared to abut the left vertebral artery foramen. The cortical bone surrounding the lesion was thin but uniform. Sagittal and axial T1-weighted MRI (Figures 2A, 2B) showed the discrete, expansile, homogenous lesion with the same intensity as normal bone marrow. Sagittal and axial T2-weighted MRI (Figures 2C, 2D) showed a discrete, expansile, homogenous lesion with primarily high signal intensity. Sagittal short tau inversion recovery (STIR) MRI (Figure 2E) again showed the lesion with primarily low intensity. Given the close proximity of the lesion to the vertebral foramen, MRA was ordered; it showed the lesion was not interfering with the vertebral artery (Figure 2F).

The tumor’s location, in the left anterior aspect of the C2 vertebral body, was not conducive to percutaneous biopsy for establishing tissue diagnosis, so the decision was made to surgically excise the lesion. A left-sided anterior incision was made 2 fingerbreadths inferior to the jaw line in a neck crease. A head and neck surgeon assisted with dissection. Dissection was carried down through the skin, subcutaneous tissue, and platysma on to the anterior part of the spine medial to the carotid sheath. Superior thyroid nerve and vessels and superior laryngeal nerve were identified and preserved. Fluoroscopy confirmed correct location at C2. The tumor was easily visualized, and the outer shell broke easily with palpation. Gentle curettage was necessary when removing the tumor off the vertebral artery. A portion of the specimen was sent during surgery for frozen section, which showed infrequent mitotic figures and no other findings concerning for malignancy. No instability was created after curettage and excision of the tumor, so no grafting or instrumentation was necessary.

Grossly, the tumor was pale tan and firm. Histologic examination with hematoxylin-eosin staining revealed a bland spindle-cell neoplasm that focally involved bone. A storiform pattern was present. The cells had scant cytoplasm and oval to elongate nuclei with tapered ends. Significant nuclear pleomorphism was not seen. The stroma was loose, with focal myxoid change. Benign multinucleated giant cells were present. Mitotic activity was infrequent (Figures 3A–3D). Two attending pathologists reviewed the case material and the frozen and formalin-fixed specimens independently and concurred with the diagnosis of BFH. In addition, the case was reviewed at the surgical pathology consensus conference; the reviewers agreed on BFH, and additional studies were deemed unnecessary.

Given the patient’s complete clinical picture, the differential diagnosis included nonossifying fibroma (NOF), eosinophilic granuloma (EG), BFH, fibrous dysplasia, giant cell tumor (GCT), aneurysmal bone cyst (ABC), and osteoblastoma (OB).

Discussion

BFH is an extremely rare bone lesion, accounting for only 1% of all surgically managed bone tumors; not counting the present case, only 11 spine cases have been reported in the literature.^1,2 BFH of the spine traditionally causes nonspecific, poorly localized pain. The Table lists the reported cases of spinal BFH and their presenting symptoms, location, and treatment. BFH usually occurs in young adults, but the age range is 5 to 75 years.^2-4 Mean age of the 12 patients with spinal BFH in the literature (including ours) is 25 years.¹ In addition, spinal BFH appears to have no predilection for sex.

Skeletal BFH presents as a discrete, well-defined, osteolytic lesion with sharp borders and potentially a sclerotic rim.^4-6 Cortical expansion and even cortical disruption with invasion into adjacent tissue have occurred in flat bones.⁷ Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in storiform pattern.⁶

BFH shares many of its radiologic and histologic characteristics and clinical symptoms with other benign bone lesions (the tumors listed above). Therefore, accurate diagnosis of BFH requires appropriate correlation of clinical, radiographic, and histologic data.^2,3,8 Below is a comparison of BFH with related bone lesions.

Spinal BFH causes a nonspecific, poorly localized pain similar to that of EG, ABC, GCT, and OB.^3,9 NOF and fibrous dysplasia generally do not cause pain, unless these lesions are discovered secondary to a pathologic fracture.^8,10,11 Our patient had minor antecedent neck pain, which was brought to light by his football accident. ABC and OB are more locally aggressive than BFH and can cause neurologic symptoms by mass effect and spinal cord or nerve root compression.^1,8 In this case and in the 6 other cases of BFH of the cervical spine, there were no neurologic changes.^4,10

Of the tumors mentioned, NOF and EG almost always occur in children. However, NOF usually occurs in the metaphyseal region of long bones, and EG is usually accompanied by systemic symptoms, such as lymphadenopathy, hepatomegaly, and increased inflammatory markers.^1,8 Fibrous dysplasia usually presents in childhood but does not become symptomatic until adulthood. GCTs and OB predominantly occur in adulthood.^12,13 Our patient’s age and lack of other systemic symptoms supported the diagnosis of BFH.

Appearance on MRI is reported less with BFH than with other tumors, but heterogenous signal intensity similar to that of skeletal muscle on T1-weighted images and high signal intensity on T2-weighted images is typically reported.^8,14 NOF and fibrous dysplasia do not disrupt the bony cortex unless a pathologic fracture has occurred.⁴ GCTs are more aggressive lytic lesions with more aggressive radiologic features. GCTs generally cause cortical expansion/attenuation, and lack a sclerotic rim. GCTs also have a heterogenous appearance on MRI and give a low to intermediate signal on both T1- and T2-weighted images.^12,15 The appearance of EG is similar to that of BFH as an osteolytic lesion with a sclerotic rim, though EGs typically break through the cortex and acquire a “punched-out” look.^1,8 ABC typically is described as an expansile osteolytic lesion with a “soap-bubble” appearance on radiographs; periosteal elevation and cortical attenuation can also be visualized. MRI shows the typical multilobular appearance of the lesion with fluid levels.¹³

OB appears as a radiolucent lesion, with or without calcifications, surrounded by a thin margin of reactive bone.^14,16 A distinguishing characteristic of OB was thought to be intense radioisotope uptake on bone scintigraphy, but recently a bony BFH demonstrated intense uptake.¹⁷ OBs typically demonstrate nonspecific MRI results similar to those of BFH: low to intermediate signal on T1-weighted images and intermediate to high signal on T2-weighted images.¹³ In our patient’s case, the radiographic appearance and lack of specific radiographic findings consistent with the other tumors supported the diagnosis of BFH.

Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in a storiform pattern⁶ which was demonstrated in our patient’s case. In addition, significant nuclear pleomorphism, mitotic activity, and necrosis were absent—a difference between BFH and malignant fibrous histiocytoma.^4,15 The microscopic characteristics of BFH readily differentiate it from OB, ABC, EG, and GCT, but not from NOF on microscopic appearance alone. Clinical and radiographic findings must be consistent, as mentioned.^7,18

Complete surgical excision is the reported treatment for BFH. Prognosis after resection or curettage is usually good, and recurrences have been rare.^1,2 Depending on the intraspinous location of BFH, stabilization after resection or curettage may be necessary to prevent residual instability. Three of the 11 reported cases of spinal BFH required stabilization by anterior fusion or posterior pedicle screw fixation after resection.^1,2 The other 8 cases underwent excision alone or excision and grafting. All 11 patients were disease-free at a mean follow-up of 3.5 years.¹ In nonspinal BFH, however, both local recurrence and lung metastasis have been reported.^2,5,9,19 Clarke and colleagues⁹ reported local recurrences in 3 of 8 cases. These recurrences involved BFH in long bones of the leg, which had been treated with curettage and grafting. There has been no reliable report of a malignant change in BFH.^2,9 The only case of lung metastasis, reported by Unni and Dahlin⁶ in their study of 10 cases, occurred 2 years after local recurrence in the distal femur.Our patient was doing well at most recent follow-up, 6 months after surgery. He had no pain and had returned to normal activities. Although there are no reported cases of spinal BFH recurrence, we will follow this patient with imaging on an annual basis. His case is of particular interest to orthopedic surgeons because they encounter benign bone lesions every day, and many of these lesions are in difficult anatomical locations. Knowing the characteristics, differential diagnoses, and appropriate diagnostic workups for benign bone lesions is important for optimal and timely patient care.

Benign fibrous histiocytoma (BFH) is a rare, well-recognized, primary skeletal tumor accounting for approximately 1% of all benign bone tumors. Spinal involvement is exceedingly rare with only 11 cases reported in the literature.^1,2 We present a case of BFH located in the cervical spine of a pediatric patient that was successfully treated with curretage through an anterior surgical approach, along with a review of the literature and appropriate management concerning BFH of the spine.

Case Report

A 14-year-old boy was tackled while playing football and noticed immediate neck pain and subjective paresthesia in the upper extremities. Examination revealed a nontender spine (cervical, thoracic, lumbar) and normal strength and range of motion in all extremities. Sensation was diffusely intact, long tract signs were absent, and gait was normal. On questioning, the patient endorsed mild antecedent neck pain but denied prior history of any trauma. Neck pain did not radiate and was slightly worsened by activity but was mostly intermittent and random. As the neck pain was very mild and was not interfering with daily activities, the patient had not sought care before presenting to the emergency department. He had no pertinent past medical or surgical history.

The patient presented with a computed tomography (CT) scan of his head and cervical spine and a magnetic resonance imaging (MRI) scan of the cervical spine. A magnetic resonance angiography (MRA) scan of the neck was ordered after his arrival.

Axial and sagittal CT (Figures 1A, 1B) showed a 1×1.2-cm discrete, expansile, lytic, radiolucent mass extending anterior from the left C2 vertebral body. The mass appeared to abut the left vertebral artery foramen. The cortical bone surrounding the lesion was thin but uniform. Sagittal and axial T1-weighted MRI (Figures 2A, 2B) showed the discrete, expansile, homogenous lesion with the same intensity as normal bone marrow. Sagittal and axial T2-weighted MRI (Figures 2C, 2D) showed a discrete, expansile, homogenous lesion with primarily high signal intensity. Sagittal short tau inversion recovery (STIR) MRI (Figure 2E) again showed the lesion with primarily low intensity. Given the close proximity of the lesion to the vertebral foramen, MRA was ordered; it showed the lesion was not interfering with the vertebral artery (Figure 2F).

The tumor’s location, in the left anterior aspect of the C2 vertebral body, was not conducive to percutaneous biopsy for establishing tissue diagnosis, so the decision was made to surgically excise the lesion. A left-sided anterior incision was made 2 fingerbreadths inferior to the jaw line in a neck crease. A head and neck surgeon assisted with dissection. Dissection was carried down through the skin, subcutaneous tissue, and platysma on to the anterior part of the spine medial to the carotid sheath. Superior thyroid nerve and vessels and superior laryngeal nerve were identified and preserved. Fluoroscopy confirmed correct location at C2. The tumor was easily visualized, and the outer shell broke easily with palpation. Gentle curettage was necessary when removing the tumor off the vertebral artery. A portion of the specimen was sent during surgery for frozen section, which showed infrequent mitotic figures and no other findings concerning for malignancy. No instability was created after curettage and excision of the tumor, so no grafting or instrumentation was necessary.

Grossly, the tumor was pale tan and firm. Histologic examination with hematoxylin-eosin staining revealed a bland spindle-cell neoplasm that focally involved bone. A storiform pattern was present. The cells had scant cytoplasm and oval to elongate nuclei with tapered ends. Significant nuclear pleomorphism was not seen. The stroma was loose, with focal myxoid change. Benign multinucleated giant cells were present. Mitotic activity was infrequent (Figures 3A–3D). Two attending pathologists reviewed the case material and the frozen and formalin-fixed specimens independently and concurred with the diagnosis of BFH. In addition, the case was reviewed at the surgical pathology consensus conference; the reviewers agreed on BFH, and additional studies were deemed unnecessary.

Given the patient’s complete clinical picture, the differential diagnosis included nonossifying fibroma (NOF), eosinophilic granuloma (EG), BFH, fibrous dysplasia, giant cell tumor (GCT), aneurysmal bone cyst (ABC), and osteoblastoma (OB).

Discussion

BFH is an extremely rare bone lesion, accounting for only 1% of all surgically managed bone tumors; not counting the present case, only 11 spine cases have been reported in the literature.^1,2 BFH of the spine traditionally causes nonspecific, poorly localized pain. The Table lists the reported cases of spinal BFH and their presenting symptoms, location, and treatment. BFH usually occurs in young adults, but the age range is 5 to 75 years.^2-4 Mean age of the 12 patients with spinal BFH in the literature (including ours) is 25 years.¹ In addition, spinal BFH appears to have no predilection for sex.

Skeletal BFH presents as a discrete, well-defined, osteolytic lesion with sharp borders and potentially a sclerotic rim.^4-6 Cortical expansion and even cortical disruption with invasion into adjacent tissue have occurred in flat bones.⁷ Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in storiform pattern.⁶

BFH shares many of its radiologic and histologic characteristics and clinical symptoms with other benign bone lesions (the tumors listed above). Therefore, accurate diagnosis of BFH requires appropriate correlation of clinical, radiographic, and histologic data.^2,3,8 Below is a comparison of BFH with related bone lesions.

Spinal BFH causes a nonspecific, poorly localized pain similar to that of EG, ABC, GCT, and OB.^3,9 NOF and fibrous dysplasia generally do not cause pain, unless these lesions are discovered secondary to a pathologic fracture.^8,10,11 Our patient had minor antecedent neck pain, which was brought to light by his football accident. ABC and OB are more locally aggressive than BFH and can cause neurologic symptoms by mass effect and spinal cord or nerve root compression.^1,8 In this case and in the 6 other cases of BFH of the cervical spine, there were no neurologic changes.^4,10

Of the tumors mentioned, NOF and EG almost always occur in children. However, NOF usually occurs in the metaphyseal region of long bones, and EG is usually accompanied by systemic symptoms, such as lymphadenopathy, hepatomegaly, and increased inflammatory markers.^1,8 Fibrous dysplasia usually presents in childhood but does not become symptomatic until adulthood. GCTs and OB predominantly occur in adulthood.^12,13 Our patient’s age and lack of other systemic symptoms supported the diagnosis of BFH.

Appearance on MRI is reported less with BFH than with other tumors, but heterogenous signal intensity similar to that of skeletal muscle on T1-weighted images and high signal intensity on T2-weighted images is typically reported.^8,14 NOF and fibrous dysplasia do not disrupt the bony cortex unless a pathologic fracture has occurred.⁴ GCTs are more aggressive lytic lesions with more aggressive radiologic features. GCTs generally cause cortical expansion/attenuation, and lack a sclerotic rim. GCTs also have a heterogenous appearance on MRI and give a low to intermediate signal on both T1- and T2-weighted images.^12,15 The appearance of EG is similar to that of BFH as an osteolytic lesion with a sclerotic rim, though EGs typically break through the cortex and acquire a “punched-out” look.^1,8 ABC typically is described as an expansile osteolytic lesion with a “soap-bubble” appearance on radiographs; periosteal elevation and cortical attenuation can also be visualized. MRI shows the typical multilobular appearance of the lesion with fluid levels.¹³

OB appears as a radiolucent lesion, with or without calcifications, surrounded by a thin margin of reactive bone.^14,16 A distinguishing characteristic of OB was thought to be intense radioisotope uptake on bone scintigraphy, but recently a bony BFH demonstrated intense uptake.¹⁷ OBs typically demonstrate nonspecific MRI results similar to those of BFH: low to intermediate signal on T1-weighted images and intermediate to high signal on T2-weighted images.¹³ In our patient’s case, the radiographic appearance and lack of specific radiographic findings consistent with the other tumors supported the diagnosis of BFH.

Histologically, BFHs contain spindle cells, multinucleated giant cells, and foam cells in a storiform pattern⁶ which was demonstrated in our patient’s case. In addition, significant nuclear pleomorphism, mitotic activity, and necrosis were absent—a difference between BFH and malignant fibrous histiocytoma.^4,15 The microscopic characteristics of BFH readily differentiate it from OB, ABC, EG, and GCT, but not from NOF on microscopic appearance alone. Clinical and radiographic findings must be consistent, as mentioned.^7,18

Complete surgical excision is the reported treatment for BFH. Prognosis after resection or curettage is usually good, and recurrences have been rare.^1,2 Depending on the intraspinous location of BFH, stabilization after resection or curettage may be necessary to prevent residual instability. Three of the 11 reported cases of spinal BFH required stabilization by anterior fusion or posterior pedicle screw fixation after resection.^1,2 The other 8 cases underwent excision alone or excision and grafting. All 11 patients were disease-free at a mean follow-up of 3.5 years.¹ In nonspinal BFH, however, both local recurrence and lung metastasis have been reported.^2,5,9,19 Clarke and colleagues⁹ reported local recurrences in 3 of 8 cases. These recurrences involved BFH in long bones of the leg, which had been treated with curettage and grafting. There has been no reliable report of a malignant change in BFH.^2,9 The only case of lung metastasis, reported by Unni and Dahlin⁶ in their study of 10 cases, occurred 2 years after local recurrence in the distal femur.Our patient was doing well at most recent follow-up, 6 months after surgery. He had no pain and had returned to normal activities. Although there are no reported cases of spinal BFH recurrence, we will follow this patient with imaging on an annual basis. His case is of particular interest to orthopedic surgeons because they encounter benign bone lesions every day, and many of these lesions are in difficult anatomical locations. Knowing the characteristics, differential diagnoses, and appropriate diagnostic workups for benign bone lesions is important for optimal and timely patient care.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon cutaneous eruption characterized by acute, extensive, nonfollicular, sterile pustules accompanied by widespread erythema, fever, and leukocytosis. The clinical hallmark is superficial, sterile, subcorneal pustular dermatosis, which typically starts on the face, axilla, and groin and then progresses to most of the body. Approximately 90% of AGEP cases are due to drug hypersensitivity to a newly initiated medication, while the other 10% are thought to be viral in origin.¹ Discontinuation of the offending agent may allow for complete resolution within 15 days. Agents commonly implicated in causing AGEP are antibiotics such as aminopenicillins, macrolides, and cephalosporins.² Hydroxychloroquine (HCQ) also has been reported to cause AGEP,^3-7 with resolution shortly after discontinuation of the drug,^4,6 close to the characteristic 15 days of AGEP due to alternate medications.We report an unusual case of HCQ-induced AGEP that lasted far beyond the typical 15 days. We also review other cases of HCQ-induced AGEP and possible mechanisms to explain our patient’s symptoms.

Figure 1. Acute generalized exanthematous pustulosis extending to the chest and upper extremities (A) as well as the shoulders and back (B).

Case Report

A 50-year-old woman who was previously diagnosed with rheumatoid factor seronegative, nonerosive rheumatoid arthritis, which was only moderately controlled with low-dose prednisone (5 mg once daily) after 2 months of treatment, was started on oral HCQ 200 mg twice daily by her rheumatologist. Two weeks after starting HCQ treatment, she developed a pustular exanthem that gradually spread on the back over the next 24 to 48 hours. She described the eruption initially as pruritic, but she then developed painful stinging sensations as the eruption spread. She visited her primary care physician the next day and stopped the HCQ after 14 days following a discussion with the physician. Her prednisone dosage was increased to 50 mg daily for 5 days, but by the fifth day the lesions had spread to the face, full back, shoulders, and upper chest (Figure 1). Morphologically, she presented to the dermatology clinic with innumerable 1- to 2-mm pustules with confluent erythema on the back, extending to the forearms (Figure 2). She also had scattered erythematous macules and papules on the buttocks, legs, and plantar surfaces of the feet. A biopsy taken from the right forearm demonstrated subcorneal pustular dermatosis consistent with AGEP. Prednisone 50 mg once daily was continued. She was scheduled for a follow-up in 3 days but instead went to the emergency department 1 day later due to worsening of the eruption, fever, and malaise. On examination there were multiple discrete and confluent erythematous plaques on the face that extended to the lower extremities. Pustules and scales were noted on the back. New pustules had developed on the hands and feet with intense pruritus.

On admission, her vitals were stable with mild tachycardia. Aggressive intravenous hydration was administered. Her white blood cell count was elevated at 28.3×10⁹/L (reference range, 4.5–10×10⁹/L). She was started on intravenous methylprednisolone 100 mg once daily; topical steroid wet wraps with triamcinolone 0.1% were applied to the trunk, arms, legs, and abdomen twice daily; and hydrocortisone cream 2.5% was applied to the face and intertriginous areas 3 times daily. Over the next 2 days, eruptions continued to persist and the patient reported worsening of pain despite treatment. On day 3, intravenous methylprednisolone 100 mg was switched to oral prednisone 80 mg once daily.

Over the ensuing 5 days, recurrent episodes of erythema on the back had spread to the extremities. After 1 week in the hospital, the diffuse erythema had improved and she had widespread desquamation. She was discharged and prescribed oral prednisone 80 mg once daily and topical therapy twice daily. The patient followed up in the dermatology clinic 4 days after discharge with a mildly pruritic eruption on the trunk and proximal lower extremities but otherwise was doing well. She was instructed to taper the prednisone by 10 mg every 4 days.

At a follow-up 3 weeks later, she had persistent stinging and tingling sensations, widespread xerosis, and diffuse patchy erythema primarily on the back and proximal extremities, which flared over the last week. The patient reported waxing and waning of the erythema and pruritus since being discharged from the hospital. Despite the recent flare, which was her fourth flare of cutaneous eruption, she showed marked improvement since her initial examination and 40 days after discontinuation of HCQ. She was taking prednisone 40 mg once daily and was advised to continue tapering the dose by 2 mg every 6 to 8 days as tolerated. At 81 days after AGEP onset, the eruption had resolved and the patient was back to her baseline prednisone dosage of 5 mg once daily.

Comment

Acute generalized exanthematous pustulosis is characterized by the sudden appearance of erythema and hundreds of sterile nonfollicular pustules, fever, and leukocytosis. Histologically, AGEP is composed of subcorneal and intraepidermal pustules, edema of the papillary dermis, and perivascular infiltrates of neutrophils and possible eosinophils. The pathogenesis of AGEP is thought to be due to the release of increased amounts of IL-8 by T cells, which attract and activate polymorphonuclear neutrophils.¹ Psoriasiform changes are uncommon. Clinically, AGEP is similar to pustular psoriasis but has shown to be its own distinct entity. Unlike patients with pustular psoriasis, patients with AGEP lack a personal or family history of psoriasis or arthritis, have a shorter duration of pustules and fever, and have a history of new medication administration. Other conditions to consider in the differential diagnosis include pustular psoriasis, subcorneal pustulosis, IgA pemphigus, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, and acute febrile neutrophilic dermatosis.

In AGEP, the average duration of medication exposure prior to onset varies depending on the causative agent. Antibiotics consistently have been shown to trigger symptoms after 1 day, whereas other medications, including HCQ, averaged closer to 11 days. Hydroxychloroquine is widely used to treat rheumatic and dermatologic diseases and has previously been reported to be a less common cause of AGEP³; however, a EuroSCAR study found that patients treated with HCQ were at a greater risk for AGEP.² Acute generalized exanthematous pustulosis usually follows a benign self-limiting course. Within days the eruption gradually evolves into superficial desquamation. Characteristically, removal of the offending agent typically leads to spontaneous resolution in less than 15 days. Resolution is generally without complications and, therefore, treatment is not always necessary. Death has been reported in up to 2% of cases.⁸ There are no known therapies that prevent the spread of lesions or further decline of the patient’s condition. Systemic corticosteroids often are used to treat AGEP with variable results.^1,5

Unique to our patient were recurring exacerbations of the cutaneous lesions beyond the typical 15 days for complete resolution. Even up to 40 days after discontinuation of medication, our patient continued to experience cutaneous symptoms. Other reported cases have not described patients with symptoms flaring or continuing for this extended period of time. A review of 7 external AGEP cases caused by HCQ (identified through a PubMed search of articles indexed for MEDLINE using the search terms acute generalized exanthematous pustulosis or eruption with hydroxychloroquine or plaquenil) showed resolution within 8 days to 3 weeks (Table).^3-6,8 One case report documented disease exacerbation on day 18 after tapering the methylprednisolone dose. This patient was then treated with cyclosporine and had a prompt recovery.⁵ One case of AGEP due to terbinafine reported continual symptoms for approximately 4 weeks after terbinafine discontinuation.⁹ Our patient’s continual symptoms beyond the typical 15 days may be due to the long half-life of HCQ, which is approximately 40 to 50 days. Systemic corticosteroids often are used to control severe eruptions in AGEP and were administered to our patient; however, their utility in shortening the duration or reducing the severity of the eruption has not been proven.

Conclusion

Hydroxychloroquine is a commonly used agent for dermatologic and rheumatologic conditions. The rare but severe acute adverse event of AGEP warrants caution in HCQ use. Correct diagnosis of AGEP with HCQ cessation generally is effective as therapy. Our patient demonstrated that not all cases of AGEP show rapid resolution of cutaneous symptoms after cessation of the drug. Hydroxychloroquine’s extended half-life of 40 to 50 days surpasses that of other medications known to cause AGEP and may explain our patient’s symptoms beyond the usual course.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon cutaneous eruption characterized by acute, extensive, nonfollicular, sterile pustules accompanied by widespread erythema, fever, and leukocytosis. The clinical hallmark is superficial, sterile, subcorneal pustular dermatosis, which typically starts on the face, axilla, and groin and then progresses to most of the body. Approximately 90% of AGEP cases are due to drug hypersensitivity to a newly initiated medication, while the other 10% are thought to be viral in origin.¹ Discontinuation of the offending agent may allow for complete resolution within 15 days. Agents commonly implicated in causing AGEP are antibiotics such as aminopenicillins, macrolides, and cephalosporins.² Hydroxychloroquine (HCQ) also has been reported to cause AGEP,^3-7 with resolution shortly after discontinuation of the drug,^4,6 close to the characteristic 15 days of AGEP due to alternate medications.We report an unusual case of HCQ-induced AGEP that lasted far beyond the typical 15 days. We also review other cases of HCQ-induced AGEP and possible mechanisms to explain our patient’s symptoms.

Figure 1. Acute generalized exanthematous pustulosis extending to the chest and upper extremities (A) as well as the shoulders and back (B).

Case Report

A 50-year-old woman who was previously diagnosed with rheumatoid factor seronegative, nonerosive rheumatoid arthritis, which was only moderately controlled with low-dose prednisone (5 mg once daily) after 2 months of treatment, was started on oral HCQ 200 mg twice daily by her rheumatologist. Two weeks after starting HCQ treatment, she developed a pustular exanthem that gradually spread on the back over the next 24 to 48 hours. She described the eruption initially as pruritic, but she then developed painful stinging sensations as the eruption spread. She visited her primary care physician the next day and stopped the HCQ after 14 days following a discussion with the physician. Her prednisone dosage was increased to 50 mg daily for 5 days, but by the fifth day the lesions had spread to the face, full back, shoulders, and upper chest (Figure 1). Morphologically, she presented to the dermatology clinic with innumerable 1- to 2-mm pustules with confluent erythema on the back, extending to the forearms (Figure 2). She also had scattered erythematous macules and papules on the buttocks, legs, and plantar surfaces of the feet. A biopsy taken from the right forearm demonstrated subcorneal pustular dermatosis consistent with AGEP. Prednisone 50 mg once daily was continued. She was scheduled for a follow-up in 3 days but instead went to the emergency department 1 day later due to worsening of the eruption, fever, and malaise. On examination there were multiple discrete and confluent erythematous plaques on the face that extended to the lower extremities. Pustules and scales were noted on the back. New pustules had developed on the hands and feet with intense pruritus.

On admission, her vitals were stable with mild tachycardia. Aggressive intravenous hydration was administered. Her white blood cell count was elevated at 28.3×10⁹/L (reference range, 4.5–10×10⁹/L). She was started on intravenous methylprednisolone 100 mg once daily; topical steroid wet wraps with triamcinolone 0.1% were applied to the trunk, arms, legs, and abdomen twice daily; and hydrocortisone cream 2.5% was applied to the face and intertriginous areas 3 times daily. Over the next 2 days, eruptions continued to persist and the patient reported worsening of pain despite treatment. On day 3, intravenous methylprednisolone 100 mg was switched to oral prednisone 80 mg once daily.

Over the ensuing 5 days, recurrent episodes of erythema on the back had spread to the extremities. After 1 week in the hospital, the diffuse erythema had improved and she had widespread desquamation. She was discharged and prescribed oral prednisone 80 mg once daily and topical therapy twice daily. The patient followed up in the dermatology clinic 4 days after discharge with a mildly pruritic eruption on the trunk and proximal lower extremities but otherwise was doing well. She was instructed to taper the prednisone by 10 mg every 4 days.

At a follow-up 3 weeks later, she had persistent stinging and tingling sensations, widespread xerosis, and diffuse patchy erythema primarily on the back and proximal extremities, which flared over the last week. The patient reported waxing and waning of the erythema and pruritus since being discharged from the hospital. Despite the recent flare, which was her fourth flare of cutaneous eruption, she showed marked improvement since her initial examination and 40 days after discontinuation of HCQ. She was taking prednisone 40 mg once daily and was advised to continue tapering the dose by 2 mg every 6 to 8 days as tolerated. At 81 days after AGEP onset, the eruption had resolved and the patient was back to her baseline prednisone dosage of 5 mg once daily.

Comment

Acute generalized exanthematous pustulosis is characterized by the sudden appearance of erythema and hundreds of sterile nonfollicular pustules, fever, and leukocytosis. Histologically, AGEP is composed of subcorneal and intraepidermal pustules, edema of the papillary dermis, and perivascular infiltrates of neutrophils and possible eosinophils. The pathogenesis of AGEP is thought to be due to the release of increased amounts of IL-8 by T cells, which attract and activate polymorphonuclear neutrophils.¹ Psoriasiform changes are uncommon. Clinically, AGEP is similar to pustular psoriasis but has shown to be its own distinct entity. Unlike patients with pustular psoriasis, patients with AGEP lack a personal or family history of psoriasis or arthritis, have a shorter duration of pustules and fever, and have a history of new medication administration. Other conditions to consider in the differential diagnosis include pustular psoriasis, subcorneal pustulosis, IgA pemphigus, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, and acute febrile neutrophilic dermatosis.

In AGEP, the average duration of medication exposure prior to onset varies depending on the causative agent. Antibiotics consistently have been shown to trigger symptoms after 1 day, whereas other medications, including HCQ, averaged closer to 11 days. Hydroxychloroquine is widely used to treat rheumatic and dermatologic diseases and has previously been reported to be a less common cause of AGEP³; however, a EuroSCAR study found that patients treated with HCQ were at a greater risk for AGEP.² Acute generalized exanthematous pustulosis usually follows a benign self-limiting course. Within days the eruption gradually evolves into superficial desquamation. Characteristically, removal of the offending agent typically leads to spontaneous resolution in less than 15 days. Resolution is generally without complications and, therefore, treatment is not always necessary. Death has been reported in up to 2% of cases.⁸ There are no known therapies that prevent the spread of lesions or further decline of the patient’s condition. Systemic corticosteroids often are used to treat AGEP with variable results.^1,5

Unique to our patient were recurring exacerbations of the cutaneous lesions beyond the typical 15 days for complete resolution. Even up to 40 days after discontinuation of medication, our patient continued to experience cutaneous symptoms. Other reported cases have not described patients with symptoms flaring or continuing for this extended period of time. A review of 7 external AGEP cases caused by HCQ (identified through a PubMed search of articles indexed for MEDLINE using the search terms acute generalized exanthematous pustulosis or eruption with hydroxychloroquine or plaquenil) showed resolution within 8 days to 3 weeks (Table).^3-6,8 One case report documented disease exacerbation on day 18 after tapering the methylprednisolone dose. This patient was then treated with cyclosporine and had a prompt recovery.⁵ One case of AGEP due to terbinafine reported continual symptoms for approximately 4 weeks after terbinafine discontinuation.⁹ Our patient’s continual symptoms beyond the typical 15 days may be due to the long half-life of HCQ, which is approximately 40 to 50 days. Systemic corticosteroids often are used to control severe eruptions in AGEP and were administered to our patient; however, their utility in shortening the duration or reducing the severity of the eruption has not been proven.

Conclusion

Hydroxychloroquine is a commonly used agent for dermatologic and rheumatologic conditions. The rare but severe acute adverse event of AGEP warrants caution in HCQ use. Correct diagnosis of AGEP with HCQ cessation generally is effective as therapy. Our patient demonstrated that not all cases of AGEP show rapid resolution of cutaneous symptoms after cessation of the drug. Hydroxychloroquine’s extended half-life of 40 to 50 days surpasses that of other medications known to cause AGEP and may explain our patient’s symptoms beyond the usual course.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon cutaneous eruption characterized by acute, extensive, nonfollicular, sterile pustules accompanied by widespread erythema, fever, and leukocytosis. The clinical hallmark is superficial, sterile, subcorneal pustular dermatosis, which typically starts on the face, axilla, and groin and then progresses to most of the body. Approximately 90% of AGEP cases are due to drug hypersensitivity to a newly initiated medication, while the other 10% are thought to be viral in origin.¹ Discontinuation of the offending agent may allow for complete resolution within 15 days. Agents commonly implicated in causing AGEP are antibiotics such as aminopenicillins, macrolides, and cephalosporins.² Hydroxychloroquine (HCQ) also has been reported to cause AGEP,^3-7 with resolution shortly after discontinuation of the drug,^4,6 close to the characteristic 15 days of AGEP due to alternate medications.We report an unusual case of HCQ-induced AGEP that lasted far beyond the typical 15 days. We also review other cases of HCQ-induced AGEP and possible mechanisms to explain our patient’s symptoms.

Figure 1. Acute generalized exanthematous pustulosis extending to the chest and upper extremities (A) as well as the shoulders and back (B).

Case Report

A 50-year-old woman who was previously diagnosed with rheumatoid factor seronegative, nonerosive rheumatoid arthritis, which was only moderately controlled with low-dose prednisone (5 mg once daily) after 2 months of treatment, was started on oral HCQ 200 mg twice daily by her rheumatologist. Two weeks after starting HCQ treatment, she developed a pustular exanthem that gradually spread on the back over the next 24 to 48 hours. She described the eruption initially as pruritic, but she then developed painful stinging sensations as the eruption spread. She visited her primary care physician the next day and stopped the HCQ after 14 days following a discussion with the physician. Her prednisone dosage was increased to 50 mg daily for 5 days, but by the fifth day the lesions had spread to the face, full back, shoulders, and upper chest (Figure 1). Morphologically, she presented to the dermatology clinic with innumerable 1- to 2-mm pustules with confluent erythema on the back, extending to the forearms (Figure 2). She also had scattered erythematous macules and papules on the buttocks, legs, and plantar surfaces of the feet. A biopsy taken from the right forearm demonstrated subcorneal pustular dermatosis consistent with AGEP. Prednisone 50 mg once daily was continued. She was scheduled for a follow-up in 3 days but instead went to the emergency department 1 day later due to worsening of the eruption, fever, and malaise. On examination there were multiple discrete and confluent erythematous plaques on the face that extended to the lower extremities. Pustules and scales were noted on the back. New pustules had developed on the hands and feet with intense pruritus.

On admission, her vitals were stable with mild tachycardia. Aggressive intravenous hydration was administered. Her white blood cell count was elevated at 28.3×10⁹/L (reference range, 4.5–10×10⁹/L). She was started on intravenous methylprednisolone 100 mg once daily; topical steroid wet wraps with triamcinolone 0.1% were applied to the trunk, arms, legs, and abdomen twice daily; and hydrocortisone cream 2.5% was applied to the face and intertriginous areas 3 times daily. Over the next 2 days, eruptions continued to persist and the patient reported worsening of pain despite treatment. On day 3, intravenous methylprednisolone 100 mg was switched to oral prednisone 80 mg once daily.

Over the ensuing 5 days, recurrent episodes of erythema on the back had spread to the extremities. After 1 week in the hospital, the diffuse erythema had improved and she had widespread desquamation. She was discharged and prescribed oral prednisone 80 mg once daily and topical therapy twice daily. The patient followed up in the dermatology clinic 4 days after discharge with a mildly pruritic eruption on the trunk and proximal lower extremities but otherwise was doing well. She was instructed to taper the prednisone by 10 mg every 4 days.

At a follow-up 3 weeks later, she had persistent stinging and tingling sensations, widespread xerosis, and diffuse patchy erythema primarily on the back and proximal extremities, which flared over the last week. The patient reported waxing and waning of the erythema and pruritus since being discharged from the hospital. Despite the recent flare, which was her fourth flare of cutaneous eruption, she showed marked improvement since her initial examination and 40 days after discontinuation of HCQ. She was taking prednisone 40 mg once daily and was advised to continue tapering the dose by 2 mg every 6 to 8 days as tolerated. At 81 days after AGEP onset, the eruption had resolved and the patient was back to her baseline prednisone dosage of 5 mg once daily.

Comment

Acute generalized exanthematous pustulosis is characterized by the sudden appearance of erythema and hundreds of sterile nonfollicular pustules, fever, and leukocytosis. Histologically, AGEP is composed of subcorneal and intraepidermal pustules, edema of the papillary dermis, and perivascular infiltrates of neutrophils and possible eosinophils. The pathogenesis of AGEP is thought to be due to the release of increased amounts of IL-8 by T cells, which attract and activate polymorphonuclear neutrophils.¹ Psoriasiform changes are uncommon. Clinically, AGEP is similar to pustular psoriasis but has shown to be its own distinct entity. Unlike patients with pustular psoriasis, patients with AGEP lack a personal or family history of psoriasis or arthritis, have a shorter duration of pustules and fever, and have a history of new medication administration. Other conditions to consider in the differential diagnosis include pustular psoriasis, subcorneal pustulosis, IgA pemphigus, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, and acute febrile neutrophilic dermatosis.

In AGEP, the average duration of medication exposure prior to onset varies depending on the causative agent. Antibiotics consistently have been shown to trigger symptoms after 1 day, whereas other medications, including HCQ, averaged closer to 11 days. Hydroxychloroquine is widely used to treat rheumatic and dermatologic diseases and has previously been reported to be a less common cause of AGEP³; however, a EuroSCAR study found that patients treated with HCQ were at a greater risk for AGEP.² Acute generalized exanthematous pustulosis usually follows a benign self-limiting course. Within days the eruption gradually evolves into superficial desquamation. Characteristically, removal of the offending agent typically leads to spontaneous resolution in less than 15 days. Resolution is generally without complications and, therefore, treatment is not always necessary. Death has been reported in up to 2% of cases.⁸ There are no known therapies that prevent the spread of lesions or further decline of the patient’s condition. Systemic corticosteroids often are used to treat AGEP with variable results.^1,5

Unique to our patient were recurring exacerbations of the cutaneous lesions beyond the typical 15 days for complete resolution. Even up to 40 days after discontinuation of medication, our patient continued to experience cutaneous symptoms. Other reported cases have not described patients with symptoms flaring or continuing for this extended period of time. A review of 7 external AGEP cases caused by HCQ (identified through a PubMed search of articles indexed for MEDLINE using the search terms acute generalized exanthematous pustulosis or eruption with hydroxychloroquine or plaquenil) showed resolution within 8 days to 3 weeks (Table).^3-6,8 One case report documented disease exacerbation on day 18 after tapering the methylprednisolone dose. This patient was then treated with cyclosporine and had a prompt recovery.⁵ One case of AGEP due to terbinafine reported continual symptoms for approximately 4 weeks after terbinafine discontinuation.⁹ Our patient’s continual symptoms beyond the typical 15 days may be due to the long half-life of HCQ, which is approximately 40 to 50 days. Systemic corticosteroids often are used to control severe eruptions in AGEP and were administered to our patient; however, their utility in shortening the duration or reducing the severity of the eruption has not been proven.

Conclusion

Hydroxychloroquine is a commonly used agent for dermatologic and rheumatologic conditions. The rare but severe acute adverse event of AGEP warrants caution in HCQ use. Correct diagnosis of AGEP with HCQ cessation generally is effective as therapy. Our patient demonstrated that not all cases of AGEP show rapid resolution of cutaneous symptoms after cessation of the drug. Hydroxychloroquine’s extended half-life of 40 to 50 days surpasses that of other medications known to cause AGEP and may explain our patient’s symptoms beyond the usual course.