IMAGES IN DERMATOLOGY Uma Paniker, MD, Section Editor
Mixed Signals: Toxic Epidermal Necrolysis Janna H. Villano, MD,a Elise O. Lovell, MDb a
Division of Medical Toxicology, Department of Emergency Medicine, University of California San Diego School of Medicine, San Diego and the bDepartment of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, Ill.
PRESENTATION An initial diagnosis underestimated the patient’s precarious situation. A 60-year-old woman presented to the emergency department after 2 days of redness and discharge in both eyes and 1 day of fever, chills, generalized myalgias, a rash on her back, and sore throat. Otherwise, a review of systems was negative. She had a history of hypertension, and for several months, she had been treated with metoprolol and diltiazem. An allopurinol regimen for gout had been initiated 3 days prior to presentation.
ASSESSMENT On triage evaluation, the patient had a fever of 102.2 F (39.0 C), blood pressure of 151/68 mmHg, a pulse of 69 beats per minute, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 98% on room air. She was uncomfortable but in no marked distress. Bilateral conjunctival erythema, chemosis, and copious purulent discharge from both eyes were evident. Her pupils were appropriately reactive. She had dry mucous membranes, bilateral tonsillar exudates in the oropharynx, normal breath sounds, and a small blistering eruption on her neck and upper back. Cardiovascular and abdominal examinations were unremarkable. A rapid test for group A streptococcal infection was negative. The initial emergency department diagnosis was viral pharyngitis with conjunctivitis. A culture of the ocular discharge was ordered to rule out gonococcal disease. A complete blood count revealed mild anemia with hemoglobin of 9.5 g/dL and a white blood cell count of 11.4 103 cells/mL. In addition, a basic metabolic profile demonstrated hypomagnesemia, hypokalemia, and renal insufficiency. Laboratory results were as follows: potassium, 2.6 mmol/L; Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Janna H. Villano, MD, UCSD Department of Emergency Medicine, Division of Medical Toxicology, 200 West Arbor Drive, San Diego, CA 92103. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.004
magnesium, 1.5 mg/dL; glucose, 123 mg/dL; bicarbonate, 28 mmol/L; blood urea nitrogen, 23 mg/dL; creatinine, 1.86 mg/dL; and a calculated glomerular filtration rate of 36 mL/min/1.73 m2. She was treated with intravenous fluids, acetaminophen, electrolyte repletion, opioid analgesics, topical ocular antibiotics, and intravenous clindamycin. After 4 hours, she was discharged home from the emergency department with prescriptions for clindamycin, moxifloxacin ophthalmic solution, and hydrocodone/acetaminophen elixir. The patient returned to the emergency department 2 days later complaining of worsening visual acuity, persistent ocular discharge, and photophobia. At this point, her oral temperature was 102.7 F (39.3 C), blood pressure was 182/73 mmHg, pulse was 66 beats per minute, respiratory rate was 18 breaths per minute, and oxygen saturation was 99% on room air. Alert but uncomfortable, she had bilateral copious discharge with conjunctival and scleral injection. Visual acuity was 20/200 bilaterally without a history of corrective lens use. Fluorescein examination disclosed bilateral corneal ulcerations. An intraoral examination was significant for mucosal lesions to the palate and ulceration of the lips. The patient’s neck was supple and nontender without meningeal signs or adenopathy. She had clear breath sounds and unremarkable cardiovascular and abdominal examinations. Flaccid bullous lesions were superimposed on purpuric papules and plaques, and she had skin sloughing with a positive Nikolsky sign (Figures 1 and 2). The exanthem was now diffuse, affecting her neck, face, abdomen, back, neck, and both upper and lower extremities, including her palms and soles. She had no urogenital lesions.
DIAGNOSIS The patient’s worsening diffuse bullous rash, which covered more than 30% of her body surface and involved her eyes, mucous membranes, and palms and soles, combined with fever and the temporal relationship between initiation of allopurinol and symptom onset, led to a working diagnosis of toxic epidermal necrolysis.1 Whereas Stevens-Johnson syndrome is defined by lesions involving less than 10% of
Villano and Lovell
Toxic Epidermal Necrolysis
Figure 1 The patient was photographed during her return visit to the hospital. These images demonstrated the extent of skin involvement.
the body surface area, the blistering and peeling of toxic epidermal necrolysis encompasses more than 30% of the body surface area. Patients with epidermolytic skin lesions covering 10-30% of the body surface area are diagnosed as having Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome.1,2 The differential diagnosis includes erythema multiforme, toxic shock syndrome, staphylococcal scalded skin syndrome, phototoxic reactions, erythematous or pustular drug eruptions, and paraneoplastic pemphigus. Women and the elderly are at greater risk for Stevens-Johnson syndrome and toxic epidermal necrolysis, as are those with certain genetic traits (for example, particular human leukocyte antigen types, interleukin-4 receptor polymorphisms, or diminished N-acetylation capacity), human immunodeficiency virus, malignancy, and systemic lupus erythematosus.3-9 Clinical presentation generally follows the first few days or weeks of
255 a drug exposure. A nonspecific influenza-like prodrome, marked by fever with ocular and/or oropharyngeal discomfort, often precedes cutaneous lesions by 24-72 hours.10 Commonly implicated medications include antibiotics, nonsteroidal anti-inflammatory drugs of the oxicam class, allopurinol, and anti-convulsants.11-13 While no specific laboratory abnormalities are diagnostic of toxic epidermal necrolysis, hematologic abnormalities, including anemia and lymphopenia, occur frequently. Neutropenia has been associated with a poor prognosis. Patients may also have mild elevations in transaminases levels.9,14,15 Repeat testing performed after our patient was readmitted identified several pertinent values: white blood cells, 4.7 103 cells/mL; hemoglobin, 10.7 g/dL; bicarbonate, 30 mmol/L; blood urea nitrogen, 27 mg/dL; creatinine, 1.62 mg/dL; and a calculated glomerular filtration rate of 42 mL/min/1.73 m2. While diagnosis of toxic epidermal necrolysis is primarily clinical, skin biopsy remains useful in differentiating toxic epidermal necrolysis from other dermatologic disorders. Frozen section biopsy expedites diagnosis.16
MANAGEMENT Discontinuation of the offending medication and supportive care, with an emphasis on fluid and electrolyte repletion, wound care, and eye care, are essential.17 Our patient received aggressive intravenous fluid resuscitation, analgesics, antipyretics, antiemetics, and ophthalmic antibiotic ointment for corneal ulcerations. She was also transferred to an area burn center, a tactic that improves prognosis independently of the percentage of body surface area involved.18,19 Her tetanus immunization was up to date. Steroid therapy was deferred after a discussion with physicians at the receiving facility. In general, glucocorticoids are not thought to be beneficial, and the use of intravenous immunoglobulin is also controversial.20,21 The Score of Toxic Epidermal Necrolysis (SCORTEN) scale has been developed as a measure for predicting mortality in patients with toxic epidermal necrolysis. Prognostic factors associated with the risk for mortality are detailed in
Table 1
The SCORTEN Scale22
Prognostic Risk Factor* Age greater than 40 years Heart rate > 120 beats per minute Involved body surface area > 10% Malignancy Serum glucose > 252 mg/dL (14 mmol/L) Serum bicarbonate < 20 mmol/L BUN > 28 mg/dL (10 mmol/L)
Figure 2 Note the sloughing of bullous lesions superimposed on purpuric papules and plaques. Photographs were taken with the patient’s permission for publication.
Mortality risk relates to total score: 0 to 1 correlates with a mortality risk of 3.2%, 2 correlates with a risk of 12.1%, 3 correlates with a risk of 35.3%, 4 correlates with a risk of 58.3%, and 5 correlates with a risk of 90%. BUN ¼ blood urea nitrogen. *Each prognostic risk factor is assigned 1 point.
256 Table 1.22 When the patient returned to the hospital, she had 3 SCORTEN risk factors, predicting a 35.3% risk for mortality. Ultimately, she was hospitalized for 29 days. During that time a skin biopsy showed full thickness epidermal necrosis consistent with toxic epidermal necrolysis. After an ophthalmology consultation, the patient was treated with topical antibiotic and anti-inflammatory medications, surgical removal of pseudomembranes, and insertion of bilateral sutureless amniotic membrane lenses. She required tracheostomy and a gastrostomy tube. At the time of hospital discharge, her wounds were significantly improved, and she was able to tolerate oral nutrition. While her visual acuity had not returned to baseline, it was significantly improved with the use of corrective lenses. Her tracheostomy was subsequently reversed.
References 1. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, StevensJohnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96. 2. Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94:419-436. 3. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell’s disease). Burns. 2010;36:152-163. 4. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428:486. 5. Struck MF, Hilbert P, Mockenhaupt M, Reichelt B, Steen M. Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes. Intensive Care Med. 2010;36:22-32. 6. Dietrich A, Kawakubo Y, Rzany B, Mockenhaupt M, Simon JC, Schöpf E. Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol. 1995;4:313-316. 7. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S. Association of IL4R polymorphisms with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2007;120:1457-1459. 8. Horne NS, Narayan AR, Young RM, Frieri M. Toxic epidermal necrolysis in systemic lupus erythematosus. Autoimmun Rev. 2006;5:160-164. 9. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol. 1990;23(6 Pt 1): 1039-1058.
The American Journal of Medicine, Vol 128, No 3, March 2015 10. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35-44. 11. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600-1607. 12. Sanmarkan AD, Sori T, Thappa DM, Jaisankar TJ. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis over a period of 10 years. Indian J Dermatol. 2011;56:25-29. 13. Halevy S, Ghislain PD, Mockenhaupt M, et al; EuroSCAR Study Group. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58:25-32. 14. Westly ED, Wechsler HL. Toxic epidermal necrolysis. Granulocytic leukopenia as a prognostic indicator. Arch Dermatol. 1984;120: 721-726. 15. Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol. 1987;123:1160-1165. 16. Fromowitz JS, Ramos-Caro FA, Flowers FP; University of Florida. Practical guidelines for the management of toxic epidermal necrolysis and StevenseJohnson syndrome. Int J Dermatol. 2007;46: 1092-1094. 17. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136:323-327. 18. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23:87-96. 19. McGee T, Munster A. Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center. Plast Reconstr Surg. 1998;102:1018-1022. 20. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of StevensJohnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008;58:33-40. 21. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33-36. 22. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115:149-153.
Mixed Signals: Toxic Epidermal Necrolysis Janna H. Villano, MD,a Elise O. Lovell, MDb a
Division of Medical Toxicology, Department of Emergency Medicine, University of California San Diego School of Medicine, San Diego and the bDepartment of Emergency Medicine, Advocate Christ Medical Center, Oak Lawn, Ill.
PRESENTATION An initial diagnosis underestimated the patient’s precarious situation. A 60-year-old woman presented to the emergency department after 2 days of redness and discharge in both eyes and 1 day of fever, chills, generalized myalgias, a rash on her back, and sore throat. Otherwise, a review of systems was negative. She had a history of hypertension, and for several months, she had been treated with metoprolol and diltiazem. An allopurinol regimen for gout had been initiated 3 days prior to presentation.
ASSESSMENT On triage evaluation, the patient had a fever of 102.2 F (39.0 C), blood pressure of 151/68 mmHg, a pulse of 69 beats per minute, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 98% on room air. She was uncomfortable but in no marked distress. Bilateral conjunctival erythema, chemosis, and copious purulent discharge from both eyes were evident. Her pupils were appropriately reactive. She had dry mucous membranes, bilateral tonsillar exudates in the oropharynx, normal breath sounds, and a small blistering eruption on her neck and upper back. Cardiovascular and abdominal examinations were unremarkable. A rapid test for group A streptococcal infection was negative. The initial emergency department diagnosis was viral pharyngitis with conjunctivitis. A culture of the ocular discharge was ordered to rule out gonococcal disease. A complete blood count revealed mild anemia with hemoglobin of 9.5 g/dL and a white blood cell count of 11.4 103 cells/mL. In addition, a basic metabolic profile demonstrated hypomagnesemia, hypokalemia, and renal insufficiency. Laboratory results were as follows: potassium, 2.6 mmol/L; Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Janna H. Villano, MD, UCSD Department of Emergency Medicine, Division of Medical Toxicology, 200 West Arbor Drive, San Diego, CA 92103. E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.004
magnesium, 1.5 mg/dL; glucose, 123 mg/dL; bicarbonate, 28 mmol/L; blood urea nitrogen, 23 mg/dL; creatinine, 1.86 mg/dL; and a calculated glomerular filtration rate of 36 mL/min/1.73 m2. She was treated with intravenous fluids, acetaminophen, electrolyte repletion, opioid analgesics, topical ocular antibiotics, and intravenous clindamycin. After 4 hours, she was discharged home from the emergency department with prescriptions for clindamycin, moxifloxacin ophthalmic solution, and hydrocodone/acetaminophen elixir. The patient returned to the emergency department 2 days later complaining of worsening visual acuity, persistent ocular discharge, and photophobia. At this point, her oral temperature was 102.7 F (39.3 C), blood pressure was 182/73 mmHg, pulse was 66 beats per minute, respiratory rate was 18 breaths per minute, and oxygen saturation was 99% on room air. Alert but uncomfortable, she had bilateral copious discharge with conjunctival and scleral injection. Visual acuity was 20/200 bilaterally without a history of corrective lens use. Fluorescein examination disclosed bilateral corneal ulcerations. An intraoral examination was significant for mucosal lesions to the palate and ulceration of the lips. The patient’s neck was supple and nontender without meningeal signs or adenopathy. She had clear breath sounds and unremarkable cardiovascular and abdominal examinations. Flaccid bullous lesions were superimposed on purpuric papules and plaques, and she had skin sloughing with a positive Nikolsky sign (Figures 1 and 2). The exanthem was now diffuse, affecting her neck, face, abdomen, back, neck, and both upper and lower extremities, including her palms and soles. She had no urogenital lesions.
DIAGNOSIS The patient’s worsening diffuse bullous rash, which covered more than 30% of her body surface and involved her eyes, mucous membranes, and palms and soles, combined with fever and the temporal relationship between initiation of allopurinol and symptom onset, led to a working diagnosis of toxic epidermal necrolysis.1 Whereas Stevens-Johnson syndrome is defined by lesions involving less than 10% of
Villano and Lovell
Toxic Epidermal Necrolysis
Figure 1 The patient was photographed during her return visit to the hospital. These images demonstrated the extent of skin involvement.
the body surface area, the blistering and peeling of toxic epidermal necrolysis encompasses more than 30% of the body surface area. Patients with epidermolytic skin lesions covering 10-30% of the body surface area are diagnosed as having Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome.1,2 The differential diagnosis includes erythema multiforme, toxic shock syndrome, staphylococcal scalded skin syndrome, phototoxic reactions, erythematous or pustular drug eruptions, and paraneoplastic pemphigus. Women and the elderly are at greater risk for Stevens-Johnson syndrome and toxic epidermal necrolysis, as are those with certain genetic traits (for example, particular human leukocyte antigen types, interleukin-4 receptor polymorphisms, or diminished N-acetylation capacity), human immunodeficiency virus, malignancy, and systemic lupus erythematosus.3-9 Clinical presentation generally follows the first few days or weeks of
255 a drug exposure. A nonspecific influenza-like prodrome, marked by fever with ocular and/or oropharyngeal discomfort, often precedes cutaneous lesions by 24-72 hours.10 Commonly implicated medications include antibiotics, nonsteroidal anti-inflammatory drugs of the oxicam class, allopurinol, and anti-convulsants.11-13 While no specific laboratory abnormalities are diagnostic of toxic epidermal necrolysis, hematologic abnormalities, including anemia and lymphopenia, occur frequently. Neutropenia has been associated with a poor prognosis. Patients may also have mild elevations in transaminases levels.9,14,15 Repeat testing performed after our patient was readmitted identified several pertinent values: white blood cells, 4.7 103 cells/mL; hemoglobin, 10.7 g/dL; bicarbonate, 30 mmol/L; blood urea nitrogen, 27 mg/dL; creatinine, 1.62 mg/dL; and a calculated glomerular filtration rate of 42 mL/min/1.73 m2. While diagnosis of toxic epidermal necrolysis is primarily clinical, skin biopsy remains useful in differentiating toxic epidermal necrolysis from other dermatologic disorders. Frozen section biopsy expedites diagnosis.16
MANAGEMENT Discontinuation of the offending medication and supportive care, with an emphasis on fluid and electrolyte repletion, wound care, and eye care, are essential.17 Our patient received aggressive intravenous fluid resuscitation, analgesics, antipyretics, antiemetics, and ophthalmic antibiotic ointment for corneal ulcerations. She was also transferred to an area burn center, a tactic that improves prognosis independently of the percentage of body surface area involved.18,19 Her tetanus immunization was up to date. Steroid therapy was deferred after a discussion with physicians at the receiving facility. In general, glucocorticoids are not thought to be beneficial, and the use of intravenous immunoglobulin is also controversial.20,21 The Score of Toxic Epidermal Necrolysis (SCORTEN) scale has been developed as a measure for predicting mortality in patients with toxic epidermal necrolysis. Prognostic factors associated with the risk for mortality are detailed in
Table 1
The SCORTEN Scale22
Prognostic Risk Factor* Age greater than 40 years Heart rate > 120 beats per minute Involved body surface area > 10% Malignancy Serum glucose > 252 mg/dL (14 mmol/L) Serum bicarbonate < 20 mmol/L BUN > 28 mg/dL (10 mmol/L)
Figure 2 Note the sloughing of bullous lesions superimposed on purpuric papules and plaques. Photographs were taken with the patient’s permission for publication.
Mortality risk relates to total score: 0 to 1 correlates with a mortality risk of 3.2%, 2 correlates with a risk of 12.1%, 3 correlates with a risk of 35.3%, 4 correlates with a risk of 58.3%, and 5 correlates with a risk of 90%. BUN ¼ blood urea nitrogen. *Each prognostic risk factor is assigned 1 point.
256 Table 1.22 When the patient returned to the hospital, she had 3 SCORTEN risk factors, predicting a 35.3% risk for mortality. Ultimately, she was hospitalized for 29 days. During that time a skin biopsy showed full thickness epidermal necrosis consistent with toxic epidermal necrolysis. After an ophthalmology consultation, the patient was treated with topical antibiotic and anti-inflammatory medications, surgical removal of pseudomembranes, and insertion of bilateral sutureless amniotic membrane lenses. She required tracheostomy and a gastrostomy tube. At the time of hospital discharge, her wounds were significantly improved, and she was able to tolerate oral nutrition. While her visual acuity had not returned to baseline, it was significantly improved with the use of corrective lenses. Her tracheostomy was subsequently reversed.
References 1. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, StevensJohnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92-96. 2. Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005;94:419-436. 3. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell’s disease). Burns. 2010;36:152-163. 4. Chung WH, Hung SI, Hong HS, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428:486. 5. Struck MF, Hilbert P, Mockenhaupt M, Reichelt B, Steen M. Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes. Intensive Care Med. 2010;36:22-32. 6. Dietrich A, Kawakubo Y, Rzany B, Mockenhaupt M, Simon JC, Schöpf E. Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol. 1995;4:313-316. 7. Ueta M, Sotozono C, Inatomi T, Kojima K, Hamuro J, Kinoshita S. Association of IL4R polymorphisms with Stevens-Johnson syndrome. J Allergy Clin Immunol. 2007;120:1457-1459. 8. Horne NS, Narayan AR, Young RM, Frieri M. Toxic epidermal necrolysis in systemic lupus erythematosus. Autoimmun Rev. 2006;5:160-164. 9. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol. 1990;23(6 Pt 1): 1039-1058.
The American Journal of Medicine, Vol 128, No 3, March 2015 10. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35-44. 11. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995;333:1600-1607. 12. Sanmarkan AD, Sori T, Thappa DM, Jaisankar TJ. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis over a period of 10 years. Indian J Dermatol. 2011;56:25-29. 13. Halevy S, Ghislain PD, Mockenhaupt M, et al; EuroSCAR Study Group. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58:25-32. 14. Westly ED, Wechsler HL. Toxic epidermal necrolysis. Granulocytic leukopenia as a prognostic indicator. Arch Dermatol. 1984;120: 721-726. 15. Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol. 1987;123:1160-1165. 16. Fromowitz JS, Ramos-Caro FA, Flowers FP; University of Florida. Practical guidelines for the management of toxic epidermal necrolysis and StevenseJohnson syndrome. Int J Dermatol. 2007;46: 1092-1094. 17. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136:323-327. 18. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002;23:87-96. 19. McGee T, Munster A. Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center. Plast Reconstr Surg. 1998;102:1018-1022. 20. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of StevensJohnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008;58:33-40. 21. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33-36. 22. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115:149-153.
