CASE REPORT
The First Reported Case of Ureteral Perforation in a Patient With Severe Toxic Epidermal Necrolysis Syndrome Leopoldo M. Baccaro, MD,* Aniket Sakharpe, MD, MPH,* April Miller, DO,† Hamed Amani, MD‡
The aim of this study was to briefly review toxic epidermal necrolysis syndrome (TENS) and Steven Johnson Syndrome (SJS), as well as describe the unique complication of ureteral perforation. A case of ureteral perforation in an 18-year old woman with TENS was documented and reviewed. In addition to studying this unusual presentation the authors have also provided a brief review of TENS and SJS along with several common complications of this disease process. The patient in question suffered a severe case of TENS with extensive mucocutaneous involvement. After 2 weeks of intensive therapy, she suddenly became anuric. She developed obstructive uropathy and bilateral hydronephrosis from mucosal debris and sludge. A left forniceal rupture was visualized on pyelography. SJS and TENS are two different presentations in the spectrum of the same disease process. There have been descriptions of gastrointestinal, respiratory, vaginal, and ocular mucosal involvement, including cases of corneal and colonic perforation. However, acute renal failure secondary to ureteral obstruction and perforation has never been described. Although rare, one must entertain every possibility when attempting to diagnose complications of the disease. (J Burn Care Res 2014;35:e265–e268)
CASE PRESENTATION We present the case of an 18-year-old woman with no significant medical history except for a recent diagnosis of bipolar disorder. For this reason she had begun therapy with lamotrigine. She had also suffered an upper respiratory tract infection for which she had been treated with azithromycin 2 weeks earlier. After a prodrome of several days of fever, fatigue, and generalized malaise, she presented to an outside institution with a generalized rash. The initial diagnosis of Steven Johnson Syndrome (SJS) was made and she was subsequently transferred to our burn unit. However, by the time of her arrival to our facility it was evident that the patient had in fact developed Toxic Epidermal Necrolysis Syndrome From the *Department of General Surgery, Easton Hospital, Pennsylvania; †Department of Emergency Medicine, York Hospital, York, Pennsylvania; and ‡Burn Recovery Center, Lehigh Valley Hospital - Cedar Crest, Allentown, Pennsylvania. Address correspondence to Leopoldo M. Baccaro, MD, Department of General Surgery, Easton Hospital, 250 S. 21st Str, Easton, PA, 18042. Copyright © 2013 by the American Burn Association 1559-047X/2014 DOI: 10.1097/BCR.0b013e31829a4374
(TENS). With extensive mucocutaneous involvement from her scalp to the plantar aspect of both her feet, she developed a generalized maculopapular rash with widespread areas of blistering and desquamation. It was estimated that the area of desquamation had reached 46% TBSA. Mucosal involvement was also quite severe, affecting her eyes, mouth, and vaginal mucosa. She was intubated and sedated in order to protect her airway and provided with painfree wound care. Her corneal lesions were treated promptly using amniotic membrane contact lenses (Prokera®, BioTissue, Doral, FL), leading to an almost complete recovery of her vision without residual scarring. Her buccal and vaginal mucosal lesions were treated locally and were allowed to heal over a period of 2 weeks. Tampons wrapped in petrolatum gauze were replaced in the vaginal canal daily to prevent scarring between its walls. After 2 weeks of intensive wound care, her lesions, both cutaneous and of the mucous membranes, were completely healed. She was extubated and slowly began her rehabilitation. A urinary catheter was kept in place during this time to ensure adequate fluid balance and urine output. e265
Journal of Burn Care & Research July/August 2014
e266 Baccaro et al
Figure 1. Renal hydronephrosis.
ultrasound
revealing
bilateral
On the second day postextubation, the patient’s urine output dropped precipitously until the patient became anuric. Her creatinine level rose from 0.6 to 3.3 mg/dl over a period of 4 hours. A renal and pelvic ultrasound revealed bilateral hydronephrosis and free fluid in the pouch of Douglas (Figure 1). A cystogram with retrograde pyelography revealed obstruction of both ureters. The left pyelography (Figure 2) initially revealed a filling defect consistent with a calculus. However, upon fluoroscopic visualization of the renal pelvis, extravasation of contrast was noticed at the lower pole calyx, demonstrating a forniceal rupture. Once the ureteral catheter was removed a large amount of mucosal debris and sludge was drained. A 7-French double-J Kwart stent was placed. The right pyelography revealed a stenosis of distal ureter. A 6-French double-J Kwart stent was placed.
DISCUSSION SJS and TENS are two entities of a similar immunemodulated disorder affecting mucocutaneous
Figure 2. Left retrograde pyelogram demonstrating hydronephrosis with a filling defect consistent with a presumed calculus and a forniceal rupture at the lower pole calyx.
membranes, differentiated principally by surface area and severity of the disease. The precise demarcation between the two has been the subject of much debate, however, consensus reports have simplified the clinical criteria. SJS represents cases with less than 10% TBSA involvement, whereas TENS have more than 30% TBSA involvement. Those that fall in between are considered the SJS-TENS “overlap”.1 Another significant difference between the two is the rate of mortality, ranging from 1 to 5% in SJS and up to 50% in TENS.2,3 The incidence of both SJS and TENS is quite low, affecting women slightly more often than men. The incidence is also increased in the HIV-positive population.4 Severity of disease and subsequent outcomes can be quite variable. Several scoring systems have been proposed, however, a specific TENS severity score has been developed considering various factors,
Journal of Burn Care & Research Volume 35, Number 4
Figure 3. Right retrograde pyelogram demonstrating hydronephrosis.
including age, TBSA, serum urea level, glucose level, bicarbonate level, heart rate, and presence of malignancy.5 The etiology of SJS and TENS is vast, yet the majority of causes are related to adverse drug reactions. Hundreds of medications have been described as causative agents, particularly antibiotics and anticonvulsivants. Among the antibiotics most cases have been described with the use of sulfonamides, β-lactams, tetracyclines, and quinolones. The anticonvulsivants involved include phenytoin, phenobarbitol, carbamazepine, and lamotrigine. Other common agents include nevirapine, abacavir, nonsteroidal anti-inflammatories, and allopurinol. Additional etiologies have also been described, such as herpes virus infection, graft versus host disease in allogenic bone marrow transplant patients, exposure to industrial chemicals, certain vaccines, and Mycoplasma pneumoniae infections.1,6
Baccaro et al e267
Clinically, SJS and TENS present in a similar fashion. The initial prodromal phase is similar to that of a straightforward viral upper respiratory tract infection. Lasting 48 to 72 hours, this period is characterized by fever, malaise, headaches, myalgia, coughing, vomiting, diarrhea, and sore throat. The acute phase follows with systemic symptoms and mucocutaneous involvement. The classic dermatologic lesions are described as an acute maculopapular erthythematous rash with bullae formation. It appears as target lesions, with concentric zones of color change, with a dark red center with a surrounding lighter red halo. They exhibit Nikolsky’s sign, which is the formation of blisters with a slight rubbing motion over the lesions.1,7 This occurs when the epidermis separates from the dermis secondary to the necrosis of keratinocytes. Subsequent desquamation occurs, usually within the first 24 hours. Mucosal involvement can involve the entirety of the gastrointestinal (GI) and respiratory tracts, as well as the vaginal mucosa, and the ocular regions. Inflammation, ulceration, infectio,n and pseudomembrane formation of the conjunctiva and lid margins are common in SJS and TENS. Corneal ulceration and even perforation have also been described. Amniotic membrane transplantation can help suppress inflammation and scarring in the acute stage of the disease and help prevent sight-threatening complications.8,9 GI involvement is common; usually presenting symptoms are abdominal pain, diarrhea, and GI bleed. However, there have been reported cases of small bowel necrosis, and even colonic perforations.3,10,11 Respiratory tract involvement presents as dyspnea, bronchial hypersecretion, and marked hypoxemia during the early stages of TENS. Bronchial injury appears to be a poor prognostic factor.12 Throughout our literature search, nevertheless, we have not been able to find any cases of involvement of the urinary tract except for cases of urinary tract infections. Urinary tract mucosal sloughing, ureteral obstruction, and particularly perforation have not been described and we present the first case thus far. The patient in question presented with acute renal failure, manifested by a precipitous drop in urine output, becoming anuric almost 3 weeks after initial presentation. Her creatinine level rose from 0.6 to 3.3 mg/dl over a 24-hour period. An ultrasound of the kidney and pelvis revealed bilateral hydronephrosis and free fluid in the pouch of Douglas. A retrograde cystourethrogram revealed obstruction of both ureters with a left-sided forniceal perforation
e268 Baccaro et al
because of extensive ureteral mucosal sloughing. Both ureters were stented. The patient eventually continued to evolve favorably and recovered from this devastating case of SJS.
CONCLUSIONS SJS and TENS are two different presentations in the spectrum of the same disease process, differing in severity and surface area involved. Morbidity and mortality can reach staggering numbers, and care must be taken to treat the organ systems affected and prevent complications. There have been descriptions of GI, respiratory, vaginal, and ocular mucosal involvement, including cases of corneal and colonic perforation. However, acute renal failure secondary to ureteral obstruction and perforation has never been described. Although likely to be extremely rare, in patients in such critical conditions as those with TENS, one must entertain every possibility when attempting to diagnose complications of the disease. REFERENCES 1. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell’s disease). Burns 2010;36:152–63. 2. Khalili B, Bahna SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2006;97:272–80; quiz 281–3, 320.
Journal of Burn Care & Research July/August 2014
3. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 2005;153:241–53. 4. Trent J, Halem M, French LE, Kerdel F. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin Cutan Med Surg 2006;25:91–3. 5. 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;115:149–53. 6. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC; SCAR Study Group. Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138:1019–24. 7. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51:889–902. 8. Di Pascuale MA, Espana EM, Liu DT, et al. Correlation of corneal complications with eyelid cicatricial pathologies in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis syndrome. Ophthalmology 2005;112:904–12. 9. John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology 2002;109:351–60. 10. Sugimoto Y, Mizutani H, Sato T, Kawamura N, Ohkouchi K, Shimizu M. Toxic epidermal necrolysis with severe gastrointestinal mucosal cell death: a patient who excreted long tubes of dead intestinal epithelium. J Dermatol 1998;25:533–8. 11. Carter FM, Mitchell CK. Toxic epidermal necrolysis–an unusual cause of colonic perforation. Report of a case. Dis Colon Rectum 1993;36:773–7. 12. Lebargy F, Wolkenstein P, Gisselbrecht M, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med 1997;23:1237–44.
The First Reported Case of Ureteral Perforation in a Patient With Severe Toxic Epidermal Necrolysis Syndrome Leopoldo M. Baccaro, MD,* Aniket Sakharpe, MD, MPH,* April Miller, DO,† Hamed Amani, MD‡
The aim of this study was to briefly review toxic epidermal necrolysis syndrome (TENS) and Steven Johnson Syndrome (SJS), as well as describe the unique complication of ureteral perforation. A case of ureteral perforation in an 18-year old woman with TENS was documented and reviewed. In addition to studying this unusual presentation the authors have also provided a brief review of TENS and SJS along with several common complications of this disease process. The patient in question suffered a severe case of TENS with extensive mucocutaneous involvement. After 2 weeks of intensive therapy, she suddenly became anuric. She developed obstructive uropathy and bilateral hydronephrosis from mucosal debris and sludge. A left forniceal rupture was visualized on pyelography. SJS and TENS are two different presentations in the spectrum of the same disease process. There have been descriptions of gastrointestinal, respiratory, vaginal, and ocular mucosal involvement, including cases of corneal and colonic perforation. However, acute renal failure secondary to ureteral obstruction and perforation has never been described. Although rare, one must entertain every possibility when attempting to diagnose complications of the disease. (J Burn Care Res 2014;35:e265–e268)
CASE PRESENTATION We present the case of an 18-year-old woman with no significant medical history except for a recent diagnosis of bipolar disorder. For this reason she had begun therapy with lamotrigine. She had also suffered an upper respiratory tract infection for which she had been treated with azithromycin 2 weeks earlier. After a prodrome of several days of fever, fatigue, and generalized malaise, she presented to an outside institution with a generalized rash. The initial diagnosis of Steven Johnson Syndrome (SJS) was made and she was subsequently transferred to our burn unit. However, by the time of her arrival to our facility it was evident that the patient had in fact developed Toxic Epidermal Necrolysis Syndrome From the *Department of General Surgery, Easton Hospital, Pennsylvania; †Department of Emergency Medicine, York Hospital, York, Pennsylvania; and ‡Burn Recovery Center, Lehigh Valley Hospital - Cedar Crest, Allentown, Pennsylvania. Address correspondence to Leopoldo M. Baccaro, MD, Department of General Surgery, Easton Hospital, 250 S. 21st Str, Easton, PA, 18042. Copyright © 2013 by the American Burn Association 1559-047X/2014 DOI: 10.1097/BCR.0b013e31829a4374
(TENS). With extensive mucocutaneous involvement from her scalp to the plantar aspect of both her feet, she developed a generalized maculopapular rash with widespread areas of blistering and desquamation. It was estimated that the area of desquamation had reached 46% TBSA. Mucosal involvement was also quite severe, affecting her eyes, mouth, and vaginal mucosa. She was intubated and sedated in order to protect her airway and provided with painfree wound care. Her corneal lesions were treated promptly using amniotic membrane contact lenses (Prokera®, BioTissue, Doral, FL), leading to an almost complete recovery of her vision without residual scarring. Her buccal and vaginal mucosal lesions were treated locally and were allowed to heal over a period of 2 weeks. Tampons wrapped in petrolatum gauze were replaced in the vaginal canal daily to prevent scarring between its walls. After 2 weeks of intensive wound care, her lesions, both cutaneous and of the mucous membranes, were completely healed. She was extubated and slowly began her rehabilitation. A urinary catheter was kept in place during this time to ensure adequate fluid balance and urine output. e265
Journal of Burn Care & Research July/August 2014
e266 Baccaro et al
Figure 1. Renal hydronephrosis.
ultrasound
revealing
bilateral
On the second day postextubation, the patient’s urine output dropped precipitously until the patient became anuric. Her creatinine level rose from 0.6 to 3.3 mg/dl over a period of 4 hours. A renal and pelvic ultrasound revealed bilateral hydronephrosis and free fluid in the pouch of Douglas (Figure 1). A cystogram with retrograde pyelography revealed obstruction of both ureters. The left pyelography (Figure 2) initially revealed a filling defect consistent with a calculus. However, upon fluoroscopic visualization of the renal pelvis, extravasation of contrast was noticed at the lower pole calyx, demonstrating a forniceal rupture. Once the ureteral catheter was removed a large amount of mucosal debris and sludge was drained. A 7-French double-J Kwart stent was placed. The right pyelography revealed a stenosis of distal ureter. A 6-French double-J Kwart stent was placed.
DISCUSSION SJS and TENS are two entities of a similar immunemodulated disorder affecting mucocutaneous
Figure 2. Left retrograde pyelogram demonstrating hydronephrosis with a filling defect consistent with a presumed calculus and a forniceal rupture at the lower pole calyx.
membranes, differentiated principally by surface area and severity of the disease. The precise demarcation between the two has been the subject of much debate, however, consensus reports have simplified the clinical criteria. SJS represents cases with less than 10% TBSA involvement, whereas TENS have more than 30% TBSA involvement. Those that fall in between are considered the SJS-TENS “overlap”.1 Another significant difference between the two is the rate of mortality, ranging from 1 to 5% in SJS and up to 50% in TENS.2,3 The incidence of both SJS and TENS is quite low, affecting women slightly more often than men. The incidence is also increased in the HIV-positive population.4 Severity of disease and subsequent outcomes can be quite variable. Several scoring systems have been proposed, however, a specific TENS severity score has been developed considering various factors,
Journal of Burn Care & Research Volume 35, Number 4
Figure 3. Right retrograde pyelogram demonstrating hydronephrosis.
including age, TBSA, serum urea level, glucose level, bicarbonate level, heart rate, and presence of malignancy.5 The etiology of SJS and TENS is vast, yet the majority of causes are related to adverse drug reactions. Hundreds of medications have been described as causative agents, particularly antibiotics and anticonvulsivants. Among the antibiotics most cases have been described with the use of sulfonamides, β-lactams, tetracyclines, and quinolones. The anticonvulsivants involved include phenytoin, phenobarbitol, carbamazepine, and lamotrigine. Other common agents include nevirapine, abacavir, nonsteroidal anti-inflammatories, and allopurinol. Additional etiologies have also been described, such as herpes virus infection, graft versus host disease in allogenic bone marrow transplant patients, exposure to industrial chemicals, certain vaccines, and Mycoplasma pneumoniae infections.1,6
Baccaro et al e267
Clinically, SJS and TENS present in a similar fashion. The initial prodromal phase is similar to that of a straightforward viral upper respiratory tract infection. Lasting 48 to 72 hours, this period is characterized by fever, malaise, headaches, myalgia, coughing, vomiting, diarrhea, and sore throat. The acute phase follows with systemic symptoms and mucocutaneous involvement. The classic dermatologic lesions are described as an acute maculopapular erthythematous rash with bullae formation. It appears as target lesions, with concentric zones of color change, with a dark red center with a surrounding lighter red halo. They exhibit Nikolsky’s sign, which is the formation of blisters with a slight rubbing motion over the lesions.1,7 This occurs when the epidermis separates from the dermis secondary to the necrosis of keratinocytes. Subsequent desquamation occurs, usually within the first 24 hours. Mucosal involvement can involve the entirety of the gastrointestinal (GI) and respiratory tracts, as well as the vaginal mucosa, and the ocular regions. Inflammation, ulceration, infectio,n and pseudomembrane formation of the conjunctiva and lid margins are common in SJS and TENS. Corneal ulceration and even perforation have also been described. Amniotic membrane transplantation can help suppress inflammation and scarring in the acute stage of the disease and help prevent sight-threatening complications.8,9 GI involvement is common; usually presenting symptoms are abdominal pain, diarrhea, and GI bleed. However, there have been reported cases of small bowel necrosis, and even colonic perforations.3,10,11 Respiratory tract involvement presents as dyspnea, bronchial hypersecretion, and marked hypoxemia during the early stages of TENS. Bronchial injury appears to be a poor prognostic factor.12 Throughout our literature search, nevertheless, we have not been able to find any cases of involvement of the urinary tract except for cases of urinary tract infections. Urinary tract mucosal sloughing, ureteral obstruction, and particularly perforation have not been described and we present the first case thus far. The patient in question presented with acute renal failure, manifested by a precipitous drop in urine output, becoming anuric almost 3 weeks after initial presentation. Her creatinine level rose from 0.6 to 3.3 mg/dl over a 24-hour period. An ultrasound of the kidney and pelvis revealed bilateral hydronephrosis and free fluid in the pouch of Douglas. A retrograde cystourethrogram revealed obstruction of both ureters with a left-sided forniceal perforation
e268 Baccaro et al
because of extensive ureteral mucosal sloughing. Both ureters were stented. The patient eventually continued to evolve favorably and recovered from this devastating case of SJS.
CONCLUSIONS SJS and TENS are two different presentations in the spectrum of the same disease process, differing in severity and surface area involved. Morbidity and mortality can reach staggering numbers, and care must be taken to treat the organ systems affected and prevent complications. There have been descriptions of GI, respiratory, vaginal, and ocular mucosal involvement, including cases of corneal and colonic perforation. However, acute renal failure secondary to ureteral obstruction and perforation has never been described. Although likely to be extremely rare, in patients in such critical conditions as those with TENS, one must entertain every possibility when attempting to diagnose complications of the disease. REFERENCES 1. Lissia M, Mulas P, Bulla A, Rubino C. Toxic epidermal necrolysis (Lyell’s disease). Burns 2010;36:152–63. 2. Khalili B, Bahna SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2006;97:272–80; quiz 281–3, 320.
Journal of Burn Care & Research July/August 2014
3. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 2005;153:241–53. 4. Trent J, Halem M, French LE, Kerdel F. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin Cutan Med Surg 2006;25:91–3. 5. 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;115:149–53. 6. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schröder W, Roujeau JC; SCAR Study Group. Severe Cutaneous Adverse Reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138:1019–24. 7. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51:889–902. 8. Di Pascuale MA, Espana EM, Liu DT, et al. Correlation of corneal complications with eyelid cicatricial pathologies in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis syndrome. Ophthalmology 2005;112:904–12. 9. John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology 2002;109:351–60. 10. Sugimoto Y, Mizutani H, Sato T, Kawamura N, Ohkouchi K, Shimizu M. Toxic epidermal necrolysis with severe gastrointestinal mucosal cell death: a patient who excreted long tubes of dead intestinal epithelium. J Dermatol 1998;25:533–8. 11. Carter FM, Mitchell CK. Toxic epidermal necrolysis–an unusual cause of colonic perforation. Report of a case. Dis Colon Rectum 1993;36:773–7. 12. Lebargy F, Wolkenstein P, Gisselbrecht M, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med 1997;23:1237–44.
