A DIFFICULT DIAGNOSIS
Oral ulcers and an unusual skin rash in a teenager Tamara Brining, MMSc, PA-C
CASE A 17-year-old girl presented to the ED with a complaint of mouth ulcers and a rash on her hands and feet. She said that symptoms started 7 days ago when her lips and oral mucosa first showed painful enlarging ulcerations. Shortly thereafter she developed a fine mobilliform type of rash on the palms of her hands and dorsal and plantar surfaces of her feet. She denied concurrent fever, upper respiratory infection symptoms, new environmental exposures, or recent international travel. She confirmed that at the time of symptom onset she was not menstruating or using tampons. The patient has a history of bipolar disease and mononucleosis but otherwise is healthy and up-to-date on routine vaccinations. Her medications include lithium, clonazepam, ibuprofen, acetaminophen, and an oral contraceptive pill (brand unknown). She does not take herbal or natural remedies. A review of systems elicited only a recent change in bipolar medication from fluoxetine to lithium in the last 2 weeks. After 1 week of symptoms, the patient sought care at a local urgent care and was diagnosed with hand-foot-mouth disease. She was advised to use supportive therapy such as ibuprofen and acetaminophen for pain and to see the dermatologist for a follow-up evaluation. At her 48-hour follow-up with dermatology (2 days ago), her rash had begun to spread proximally up her extremities and trunk, with the oral ulcerations beginning to crust and spread to the perioral area. The dermatologist concurred with the original diagnosis made at urgent care. By the time the patient arrived at the ED, her rash had evolved to blistering of the skin and mouth. Her vital signs were BP, 137/90 mm Hg; heart rate, 119; respirations, 16; temperature, 98.4° F (36.9° C); and Spo2, 99% on room air. Tamara Brining practices emergency medicine and is assistant medical director for advanced practice providers at Valley Hospital in Spokane Valley, Wash. She also is an orthopedic first assistant at Northwest Orthopaedic Specialists in Spokane Valley, Wash. The author has disclosed no potential conflicts of interest, financial or otherwise. Adrian Banning, MMS, PA-C, department editor DOI: 10.1097/01.JAA.0000476224.39882.38 Copyright © 2016 American Academy of Physician Assistants
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FIGURE 1. Crusted oral ulcerations
PHYSICAL EXAMINATION The patient was a young woman in no apparent distress. She was normocephalic and atraumatic; her eyes were nonicteric and her conjunctiva and sclera clear. Her nares were patent with a nose ring in place. The periorbital area showed large 1- to 2-cm raised macules on the face and mucosa with some areas of confluence that developed a yellow, crusted, sloughing film and friable tissue beneath (Figure 1). Similar lesions were present throughout the buccal mucosa, vermillion border, gingivae, and posterior oropharynx. Her tongue showed some geographic ulcerations, but minimal. The skin examination revealed diffuse, raised, erythematous macules with vesicle and bullae formation in many areas of the extremities. Confluence of macules was noted with irregular borders. The patient’s entire body was affected, including the palms and soles of the feet. Two areas on the left and right proximal lateral thighs had sloughed away, revealing friable, dark pink, moist dermal tissue. The patient had a positive Nikolsky sign on more than two lesions (Figures 2 and 3). DIFFERENTIAL DIAGNOSIS • hand-foot-mouth disease • erythema multiforme • Stevens-Johnson syndrome/toxic epidermal necrolysis • staphylococcal toxic shock syndrome DISCUSSION The patient has Stevens-Johnson syndrome with developing toxic epidermal necrolysis, a reaction characterized by a prodrome of flu-like symptoms, with pharyngitis or Volume 29 • Number 2 • February 2016
Copyright © 2016 American Academy of Physician Assistants
Oral ulcers and an unusual skin rash in a teenager
mucositis, followed by mucocutaneous epidermal vesicles and bullae, which coalesce and slough. Early in the course of the disease, Stevens-Johnson syndrome can be difficult to distinguish from hand-foot-mouth disease, erythema multiforme, and toxic epidermal necrolysis. A thorough history and physical examination are key to an early accurate diagnosis. In this patient, the recent change in medications should be considered as a possible cause of her skin lesions. Hand-foot-mouth disease, which is typically caused by enterovirus or coxsackie virus, may have a similar prodrome as Stevens-Johnson syndrome; however, the location of the rash in the two syndromes is different. In hand-footmouth disease, oral lesions typically are anterior to the faucial pillars on the tongue and buccal mucosa; in StevensJohnson syndrome, they are on the hard palate or gingivolabial/vermillion border. Hand-foot-mouth lesions rarely occur on the face, as they do in 90% of patients with Stevens-Johnson syndrome.1 Also, skin lesions caused by hand-foot-mouth disease typically are not as painful as those in Stevens-Johnson syndrome, and will diminish over 3 to 4 days.2 Although oral lesions on the gingivolabial and vermillion border regions are common in Stevens-Johnson syndrome and erythema multiforme, the latter condition can be ruled out because the patient’s lesions are not target lesions. These lesions, a hallmark of erythema multiforme, have three concentric zones of color change: a central dusky or blistered area, a dark red inflammatory zone surrounded by a pale ring of edema, and a peripheral erythematous halo.3 Ninety percent of cases of erythema multiforme are associated with infection (viral, bacterial, or fungal), with herpes simplex virus being the most commonly isolated viral cause. Toxic shock syndrome can present as menstrual or nonmenstrual with a very rapid onset of malaise and a diffuse, red, macular rash resembling sunburn that involves the palms and soles. Patients with toxic shock syndrome have a fever greater than 102° F (38.9 °C), hypotension, diffuse erythroderma, desquamation, and involvement of at least three organ systems.4 Stevens-Johnson syndrome is classified as skin detachment of less than 10% of body surface area (BSA). Toxic epidermal necrolysis is classified as more than 30% of BSA involvement. BSA involvement between 10% and 30% may be referred to as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.5 The pathogenesis is incompletely understood, but thought to be a cell-mediated cytotoxic reaction against keratinocytes in the epidermis leading to cell apoptosis. Cytotoxic T cells and natural killer cells secrete granulysin protein, which is thought to cause apoptosis. In some cases, the offending drug may bind to the major histocompatibility complex and the T-cell receptors, leading to the release of granulysin. Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with carbamazepine
FIGURE 2. Friable dermal tissue on the patient’s proximal
lateral thigh
FIGURE 3. Large bullae on the right volar forearm
and other aromatic anticonvulsants in some patients of Asian and South Asian ancestry who have human leukocyte antigen and cytochrome P450 variations.6 The incidence of Stevens-Johnson syndrome, toxic epidermal necrolysis, and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap ranges from 2 to 7 cases per million people per year, with Stevens-Johnson syndrome being most common. The age range is varied and the condition is more common in women than men. Mortality for Stevens-Johnson syndrome is 10%, increasing to 30% in patients who also have toxic epidermal necrolysis.7 The scorten criteria can be used for risk assessment and appropriate management of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.8 Medications are the leading cause of Stevens-Johnson syndrome, and most cases develop within the first 8 weeks of starting the medication. Some of the most common medications are anticonvulsants, sulfonamide antibiotics, and nonsteroidal anti-inflammatory drugs.9 During the acute phase of the disease, patients are at high risk for electrolyte derangements and loss of fluid secondary to the denuded skin. Mucocutaneous sloughing is the hallmark of the disease, but epithelial necrosis can occur within the esophagus and intestines. Patients
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2016 American Academy of Physician Assistants
www.JAAPA.com
55
A DIFFICULT DIAGNOSIS
are at risk for pulmonary manifestations including pneumonitis and acute respiratory distress syndrome.10 Early deep shave or punch biopsy can confirm the cause of the rash and help distinguish it from other causes. The hallmark of Stevens-Johnson syndrome with toxic epidermal necrolysis is epidermal keratinocyte necrosis. In early lesions, apoptotic keratinocytes are scattered in the basal layer of the epidermis. In established lesions, full-thickness epidermal necrosis and subepidermal bullae containing eosinophils may be seen along with perivascular inflammation.11 OUTCOME The patient’s urinalysis was negative for pregnancy, leukocyte esterase, nitrites, and blood. She had findings of 3+ bacteria so her urine sample was sent for culture. A complete blood cell count showed a hemoglobin level of 14.8 g/dL (normal range, 13.5 to 17.5 g/dL), hematocrit of 43.6% (normal range, 41% to 53%), and white blood cell count of 9,300 cells/mm3 without bands (normal range, 4,500 to 11,000 cells/mm3). A complete metabolic panel showed a sodium level of 133 mEq/L (normal range, 136 to 145 mEq/L), potassium of 4.6 mEq/L (normal range, 3.5 to 5.1 mEq/L), creatinine of 1.2 mg/dL (normal range, 0.8 to 1.3 mg/dL), and nonfasting glucose of 85 mg/dL (normal range, 74 to 106 mg/dL). Her liver function tests were within normal range as well. While the healthcare team awaited the patient’s lithium level, she was started on fluid hydration with IV 0.9% sodium chloride solution. Her open wounds were dressed with nonadhering bandages. The patient and her family were counseled on discontinuation of lithium and ibuprofen, as both may have contributed to her disease. The patient’s scorten was 2 (indicating a 12% mortality risk) and nearly 10% of her BSA was affected by sloughing; however, her overall lesion burden was diffuse, affecting more than 75% of her body. She was transferred from the initial community hospital ED to a local pediatric ICU. There she received fluid resuscitation, wound care, antibiotic therapy, and pain control. Shortly thereafter, she was transferred to a Level 1 trauma center with a full burn unit facility for further care and treatment. The patient
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remained at the burn unit for 14 days until stable for discharge and has remained on close watch with weekly visits by dermatology for 3 months. She is still recovering physically, but also emotionally due to intense scarring from a secondary iatrogenic superinfection with methicillin-resistant S. aureus. JAAPA REFERENCES 1. Letko E, Papaliodis DN, Papaliodis GN, et al. StevensJohnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4): 419-436. 2. Alsop J, Flewett TH, Foster JR. “Hand-foot-and-mouth disease” in Birmingham in 1959. Br Med J. 1960;2(5214): 1708-1711. 3. Roujeau JC. Erythema multiforme. In: Wolff K, Goldsmith LA, Katz SI, et al., eds. Fitzpatrick’s Dermatology in General Medicine. New York, NY: McGraw-Hill Cos., Inc.; 2008:343. 4. Andrews MM, Parent EM, Barry M, Parsonnet J. Recurrent nonmenstrual toxic shock syndrome: clinical manifestations, diagnosis, and treatment. Clin Infect Dis. 2001;32(10):1470-1479. 5. Bastuji-Garin S. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Investigative Dermatol. 2000;149. 6. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993; 129(1):92-96. 7. Correia O, Delgado L, Ramos JP, et al. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement. Arch Dermatol. 1993;129(4): 466-468. 8. de Prost N, Ingen-Housz-Oro S, Duong Ta, et al. Bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore). 2010;28-36. 9. Mockenhaupt M, Viboud C, Dunant A, et al. StevensJohnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128(1):35-44. 10. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133(5):1197-1204. 11. Rzany B, Hering O, Mockenhaupt M, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 1996;135(1):6-11.
Volume 29 • Number 2 • February 2016
Copyright © 2016 American Academy of Physician Assistants
Oral ulcers and an unusual skin rash in a teenager Tamara Brining, MMSc, PA-C
CASE A 17-year-old girl presented to the ED with a complaint of mouth ulcers and a rash on her hands and feet. She said that symptoms started 7 days ago when her lips and oral mucosa first showed painful enlarging ulcerations. Shortly thereafter she developed a fine mobilliform type of rash on the palms of her hands and dorsal and plantar surfaces of her feet. She denied concurrent fever, upper respiratory infection symptoms, new environmental exposures, or recent international travel. She confirmed that at the time of symptom onset she was not menstruating or using tampons. The patient has a history of bipolar disease and mononucleosis but otherwise is healthy and up-to-date on routine vaccinations. Her medications include lithium, clonazepam, ibuprofen, acetaminophen, and an oral contraceptive pill (brand unknown). She does not take herbal or natural remedies. A review of systems elicited only a recent change in bipolar medication from fluoxetine to lithium in the last 2 weeks. After 1 week of symptoms, the patient sought care at a local urgent care and was diagnosed with hand-foot-mouth disease. She was advised to use supportive therapy such as ibuprofen and acetaminophen for pain and to see the dermatologist for a follow-up evaluation. At her 48-hour follow-up with dermatology (2 days ago), her rash had begun to spread proximally up her extremities and trunk, with the oral ulcerations beginning to crust and spread to the perioral area. The dermatologist concurred with the original diagnosis made at urgent care. By the time the patient arrived at the ED, her rash had evolved to blistering of the skin and mouth. Her vital signs were BP, 137/90 mm Hg; heart rate, 119; respirations, 16; temperature, 98.4° F (36.9° C); and Spo2, 99% on room air. Tamara Brining practices emergency medicine and is assistant medical director for advanced practice providers at Valley Hospital in Spokane Valley, Wash. She also is an orthopedic first assistant at Northwest Orthopaedic Specialists in Spokane Valley, Wash. The author has disclosed no potential conflicts of interest, financial or otherwise. Adrian Banning, MMS, PA-C, department editor DOI: 10.1097/01.JAA.0000476224.39882.38 Copyright © 2016 American Academy of Physician Assistants
54
www.JAAPA.com
FIGURE 1. Crusted oral ulcerations
PHYSICAL EXAMINATION The patient was a young woman in no apparent distress. She was normocephalic and atraumatic; her eyes were nonicteric and her conjunctiva and sclera clear. Her nares were patent with a nose ring in place. The periorbital area showed large 1- to 2-cm raised macules on the face and mucosa with some areas of confluence that developed a yellow, crusted, sloughing film and friable tissue beneath (Figure 1). Similar lesions were present throughout the buccal mucosa, vermillion border, gingivae, and posterior oropharynx. Her tongue showed some geographic ulcerations, but minimal. The skin examination revealed diffuse, raised, erythematous macules with vesicle and bullae formation in many areas of the extremities. Confluence of macules was noted with irregular borders. The patient’s entire body was affected, including the palms and soles of the feet. Two areas on the left and right proximal lateral thighs had sloughed away, revealing friable, dark pink, moist dermal tissue. The patient had a positive Nikolsky sign on more than two lesions (Figures 2 and 3). DIFFERENTIAL DIAGNOSIS • hand-foot-mouth disease • erythema multiforme • Stevens-Johnson syndrome/toxic epidermal necrolysis • staphylococcal toxic shock syndrome DISCUSSION The patient has Stevens-Johnson syndrome with developing toxic epidermal necrolysis, a reaction characterized by a prodrome of flu-like symptoms, with pharyngitis or Volume 29 • Number 2 • February 2016
Copyright © 2016 American Academy of Physician Assistants
Oral ulcers and an unusual skin rash in a teenager
mucositis, followed by mucocutaneous epidermal vesicles and bullae, which coalesce and slough. Early in the course of the disease, Stevens-Johnson syndrome can be difficult to distinguish from hand-foot-mouth disease, erythema multiforme, and toxic epidermal necrolysis. A thorough history and physical examination are key to an early accurate diagnosis. In this patient, the recent change in medications should be considered as a possible cause of her skin lesions. Hand-foot-mouth disease, which is typically caused by enterovirus or coxsackie virus, may have a similar prodrome as Stevens-Johnson syndrome; however, the location of the rash in the two syndromes is different. In hand-footmouth disease, oral lesions typically are anterior to the faucial pillars on the tongue and buccal mucosa; in StevensJohnson syndrome, they are on the hard palate or gingivolabial/vermillion border. Hand-foot-mouth lesions rarely occur on the face, as they do in 90% of patients with Stevens-Johnson syndrome.1 Also, skin lesions caused by hand-foot-mouth disease typically are not as painful as those in Stevens-Johnson syndrome, and will diminish over 3 to 4 days.2 Although oral lesions on the gingivolabial and vermillion border regions are common in Stevens-Johnson syndrome and erythema multiforme, the latter condition can be ruled out because the patient’s lesions are not target lesions. These lesions, a hallmark of erythema multiforme, have three concentric zones of color change: a central dusky or blistered area, a dark red inflammatory zone surrounded by a pale ring of edema, and a peripheral erythematous halo.3 Ninety percent of cases of erythema multiforme are associated with infection (viral, bacterial, or fungal), with herpes simplex virus being the most commonly isolated viral cause. Toxic shock syndrome can present as menstrual or nonmenstrual with a very rapid onset of malaise and a diffuse, red, macular rash resembling sunburn that involves the palms and soles. Patients with toxic shock syndrome have a fever greater than 102° F (38.9 °C), hypotension, diffuse erythroderma, desquamation, and involvement of at least three organ systems.4 Stevens-Johnson syndrome is classified as skin detachment of less than 10% of body surface area (BSA). Toxic epidermal necrolysis is classified as more than 30% of BSA involvement. BSA involvement between 10% and 30% may be referred to as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.5 The pathogenesis is incompletely understood, but thought to be a cell-mediated cytotoxic reaction against keratinocytes in the epidermis leading to cell apoptosis. Cytotoxic T cells and natural killer cells secrete granulysin protein, which is thought to cause apoptosis. In some cases, the offending drug may bind to the major histocompatibility complex and the T-cell receptors, leading to the release of granulysin. Stevens-Johnson syndrome and toxic epidermal necrolysis have been associated with carbamazepine
FIGURE 2. Friable dermal tissue on the patient’s proximal
lateral thigh
FIGURE 3. Large bullae on the right volar forearm
and other aromatic anticonvulsants in some patients of Asian and South Asian ancestry who have human leukocyte antigen and cytochrome P450 variations.6 The incidence of Stevens-Johnson syndrome, toxic epidermal necrolysis, and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap ranges from 2 to 7 cases per million people per year, with Stevens-Johnson syndrome being most common. The age range is varied and the condition is more common in women than men. Mortality for Stevens-Johnson syndrome is 10%, increasing to 30% in patients who also have toxic epidermal necrolysis.7 The scorten criteria can be used for risk assessment and appropriate management of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.8 Medications are the leading cause of Stevens-Johnson syndrome, and most cases develop within the first 8 weeks of starting the medication. Some of the most common medications are anticonvulsants, sulfonamide antibiotics, and nonsteroidal anti-inflammatory drugs.9 During the acute phase of the disease, patients are at high risk for electrolyte derangements and loss of fluid secondary to the denuded skin. Mucocutaneous sloughing is the hallmark of the disease, but epithelial necrosis can occur within the esophagus and intestines. Patients
JAAPA Journal of the American Academy of Physician Assistants
Copyright © 2016 American Academy of Physician Assistants
www.JAAPA.com
55
A DIFFICULT DIAGNOSIS
are at risk for pulmonary manifestations including pneumonitis and acute respiratory distress syndrome.10 Early deep shave or punch biopsy can confirm the cause of the rash and help distinguish it from other causes. The hallmark of Stevens-Johnson syndrome with toxic epidermal necrolysis is epidermal keratinocyte necrosis. In early lesions, apoptotic keratinocytes are scattered in the basal layer of the epidermis. In established lesions, full-thickness epidermal necrosis and subepidermal bullae containing eosinophils may be seen along with perivascular inflammation.11 OUTCOME The patient’s urinalysis was negative for pregnancy, leukocyte esterase, nitrites, and blood. She had findings of 3+ bacteria so her urine sample was sent for culture. A complete blood cell count showed a hemoglobin level of 14.8 g/dL (normal range, 13.5 to 17.5 g/dL), hematocrit of 43.6% (normal range, 41% to 53%), and white blood cell count of 9,300 cells/mm3 without bands (normal range, 4,500 to 11,000 cells/mm3). A complete metabolic panel showed a sodium level of 133 mEq/L (normal range, 136 to 145 mEq/L), potassium of 4.6 mEq/L (normal range, 3.5 to 5.1 mEq/L), creatinine of 1.2 mg/dL (normal range, 0.8 to 1.3 mg/dL), and nonfasting glucose of 85 mg/dL (normal range, 74 to 106 mg/dL). Her liver function tests were within normal range as well. While the healthcare team awaited the patient’s lithium level, she was started on fluid hydration with IV 0.9% sodium chloride solution. Her open wounds were dressed with nonadhering bandages. The patient and her family were counseled on discontinuation of lithium and ibuprofen, as both may have contributed to her disease. The patient’s scorten was 2 (indicating a 12% mortality risk) and nearly 10% of her BSA was affected by sloughing; however, her overall lesion burden was diffuse, affecting more than 75% of her body. She was transferred from the initial community hospital ED to a local pediatric ICU. There she received fluid resuscitation, wound care, antibiotic therapy, and pain control. Shortly thereafter, she was transferred to a Level 1 trauma center with a full burn unit facility for further care and treatment. The patient
56
www.JAAPA.com
remained at the burn unit for 14 days until stable for discharge and has remained on close watch with weekly visits by dermatology for 3 months. She is still recovering physically, but also emotionally due to intense scarring from a secondary iatrogenic superinfection with methicillin-resistant S. aureus. JAAPA REFERENCES 1. Letko E, Papaliodis DN, Papaliodis GN, et al. StevensJohnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94(4): 419-436. 2. Alsop J, Flewett TH, Foster JR. “Hand-foot-and-mouth disease” in Birmingham in 1959. Br Med J. 1960;2(5214): 1708-1711. 3. Roujeau JC. Erythema multiforme. In: Wolff K, Goldsmith LA, Katz SI, et al., eds. Fitzpatrick’s Dermatology in General Medicine. New York, NY: McGraw-Hill Cos., Inc.; 2008:343. 4. Andrews MM, Parent EM, Barry M, Parsonnet J. Recurrent nonmenstrual toxic shock syndrome: clinical manifestations, diagnosis, and treatment. Clin Infect Dis. 2001;32(10):1470-1479. 5. Bastuji-Garin S. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Investigative Dermatol. 2000;149. 6. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993; 129(1):92-96. 7. Correia O, Delgado L, Ramos JP, et al. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement. Arch Dermatol. 1993;129(4): 466-468. 8. de Prost N, Ingen-Housz-Oro S, Duong Ta, et al. Bacteremia in Stevens-Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore). 2010;28-36. 9. Mockenhaupt M, Viboud C, Dunant A, et al. StevensJohnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128(1):35-44. 10. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013;133(5):1197-1204. 11. Rzany B, Hering O, Mockenhaupt M, et al. Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 1996;135(1):6-11.
Volume 29 • Number 2 • February 2016
Copyright © 2016 American Academy of Physician Assistants
