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Gastrointestinal involvement complicating Stevens-Johnson syndrome
GASTROENTEROLOGY
1986:91:469-74
Gastrointestinal Involvement Complicating Stevens-Johnson Syndrome BRUCE ZWEIBAN, HARTLEY COHEN, and PARAKRAMA CHANDRASOMA Gastroenterology and Surgical Pathology Sections, Los Angeles County-University of Southern California Medical Center; and University of Southern California School of Medicine, Los Angeles, California
Three cases of Stevens-Johnson syndrome with intestinal involvement are described. Two patients had esophageal involvement, the severity of which paralleled skin lesions and, in 1 case, probably contributed to death. Dysphagia and bleeding were manifestations. The third patient was unique and had gastric, small and large bowel involvement with sparing of other mucosae. Cramps, severe exudative diarrhea, and bleeding were major clinical features. Unusual histologic features included sloughing of cells into the gland lumina of intestinal mucosa.
Erythema multiforme is an acute self-limited eruption of the skin and mucous membranes. The term “erythema multiforme” refers primarily to the cutaneous lesions as was originally described by Hebra (1) in 1866. When the disease primarily afflicts the mucosal surfaces, the condition often is called Stevens-Johnson syndrome. The mucous membranes most frequently involved are those of the eye and of the oral cavity. Involvement of the remainder of the gastrointestinal tract has been infrequently documented in the literature (2%lo), and there has been no description of the intestinal histology. We report 3 cases of Stevens-Johnson syndrome, 2 with esophageal involvement and 1 unique patient with diffuse intestinal involvement, and give a detailed histologic description of this condition as it affects the intestinal tract.
Received November 4, 1985. Accepted February 17, 1986. Address requests for reprints to: Hartley Cohen, M.D., Gastroenterology Section, Department of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. The authors thank Alice Madrid for help in preparing the manuscript. 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
Case Reports Case 1 A 36-yr-old black man was admitted with grand ma1 seizures. Two years previously he had been diagnosed as having systemic lupus erythematosus and was currently on hemodialysis for lupus nephropathy. He was started on phenytoin sodium. Seven days after admission he developed on his face and trunk a papular rash which was thought to be due to either an exacerbation of lupus skin lesions or phenytoin allergy. Phenytoin was discontinued and the patient was started on intravenous corticosteroids. The patient’s general condition, rash, and oropharyngeal lesions improved, and he was discharged 21 days after admission. Three weeks later the patient was readmitted for recurrence of seizure activity occurring during hemodialysis. His medications at that time included methylprednisolone, cimetidine, hydroxychloroquine sulfate, clonidine, and hydroxyzine hydrochloride. Physical examination revealed diffuse alopecia of the scalp and a healing rash. Scaly erythematous plaques were noted over the face and chest along with hypopigmentation of the abdomen and neck region. The patient’s oronasal mucosa was erythematous and friable but no discrete lesions were seen. Phenytoin was administered intravenously for the acute seizure activity and continued by mouth for the next 3 days. Thirty-six hours after the initial phenytoin dose the patient became febrile (100.6”F) with increased prominence of the erythematous papular rash on his back and neck with relative sparing of his extremities. He was begun on high dose corticosteroids. Three days after admission the patient complained of increasing malaise, joint pain, sore throat, and dysphagia localized to the substernal and xyphoid areas. Fivemillimeter white plaques were noted at this time on his lips, palate, pharynx, epiglottis, and nasal mucosa. Newly formed erythematous papules were present over his face, arms, chest, and back. Biopsy of a skin lesion showed changes consistent with erythema multiforme, dermalepidermal type. There was an upper dermal lymphocytic infiltrate around small blood vessels and along the dermoepidermal junction. Hydropic degeneration of the
470 ZWEIBAN ET AL.
GASTROENTEROLOGY Vol. 91, No. 2
rigure 1 Mucosal biopsy specimen of the esophagus, case 1, showing a strip of epithelium in which separation (probably not artefactual) of the mucosal-submucosal junction is seen in the lower left-hand corner. The mucosalsubmucosal junction is shown extending from this separation along the bottom of the photograph to the right-hand side. Intraepithelial inflammatory cells, vacuolation, and individual cell necrosis of epithelial cells are shown. The necrotic cells appear as hyalinized cells with pyknotic nuclei. This represents the viable epithelium in a biopsy specimen that was dominated by necrosis and ulceration. H & E, X100.
basal layer, and subepidermal separation with early vesicle formation was present. Scattered necrotic keratinocytes were present in the epidermis. Upper gastrointestinal endoscopy was performed 7 days after admission because of increasing dysphagia localized to the subxyphoid area. At endoscopy the mid and distal esophagus from 30 to 40 cm from the incisors was diffusely covered with 2.5-5-mm whitish plaques with friable erythematous bases and surrounding mucosa. Endoscopitally, these lesions appeared consistent with candidiasis. Biopsy of these lesions showed evidence of ulceration with acutely inflamed granulation tissue. Less involved strips of squamous epithelium showed scattered necrotic keratinocytes with homogeneous, deep pink cytoplasm and pyknotic nuclei (Figure 1). Fungi or viral inclusions were not seen. These findings are similar to epidermal changes in skin lesions of erythema multiforme. In the interim, cotton-wool exudates were observed on fundoscopic examination. These were initially interpreted as being consistent with disseminated candidiasis, and amphotericin treatment was begun. The patient continued to be febrile (maximum 105.O”F), and bullous lesions appeared on the trunk, genital area, and the lower extremities. On the 11th hospital day the patient had gross hematemesis along with gross melanotic stools and was given 3 U of packed red blood cells. On day 15, gross deepithelization of three-quarters of his back, his face, and extremities occurred. The following day the patient died. Postmortem findings revealed thick necrotic plaque formation with marked sloughing of the mid and distal esophagus. Microscopic examination revealed almost complete necrolysis of the mucosa with extensive ulceration and inflammation. Small residual islands of squamous epithelium showed changes similar to those in the biopsy specimen. There were similar lesions in the trachea
and bronchi. noted.
No other gastrointestinal
involvement
was
Case 2 A 19-yr-old Mexican man presented with a 6-day history of productive cough and sore throat. He complained of pain on swallowing, lesions on his lips, fever and chills for 3 days, and dysuria and swelling of the glans penis for 2 days. There was no history of prior drug ingestion, illness, or recent sexual contacts. Two days before admission he was given penicillin and nystatin. At the time of admission his temperature was 101.8”F. Scattered over the upper trunk and lower extremities were 6.5-mm purplish papular lesions; nonhemorrhagic vesicles were also present. Yellowish exudate of the conjunctiva was present bilaterally. Anterior cervical and submandibular lymph nodes were grossly enlarged. The mucous membrane of the lips was denuded with characteristic hemorrhagic crusting. Marked erythema with white membranous exudate was noted on the buccal mucosa, soft and hard palate, tonsils, and posterior pharynx. The glans penis and meatus also had denuded mucosa and whitish membranes. Target lesions were not present. The stool tested positive for occult blood. Throat and urethral cultures did not grow pathogens. The presumptive diagnosis of Stevens-Johnson syndrome was made and the patient was started on oral corticosteroids. One day after admission an upper fiberoptic endoscopy was performed to evaluate increasing dysphagia. The entire esophagus was erythematous, and multiple, z-mm, whitish plaques overlying inflamed denuded mucosa were visualized from the upper esophageal sphincter to the gastroesophageal junction. The stomach and duodenum were normal. A sigmoidoscopic examination to 56 cm was normal. Biopsy specimens from the
August 1986
THE GUT IN STEVENS-JOHNSON SYNDROME
471
esophagus showed extensive necrosis of the squamous mucosa with ulceration. The adjacent squamous epithelium showed marked intraepithelial inflammation and individual cell necrosis. Fungi or viral inclusions were not seen. The patient became afebrile after 48 h of corticosteroid administration. He was given antacids, the dysphagia improved, and the patient tolerated a soft diet by the fourth day of hospitalization. The patient was discharged on day 7, by which time the cutaneous lesions of the penis and trunk had shown remarkable improvement. The patient was lost to follow-up. Case 3 A 41-yr-old El Salvadoran woman was admitted with a Z-day history of wheezing and a generalized pruritic rash, which first appeared on the trunk and extremities, and then spread to the neck, face, buttocks, and lower extremities. Other than mild diabetes mellitus for which she was taking chlorpropamide, she was well until 2 wk before admission, when she noted increasing shortness of breath and a sore throat for which she was given a P-day course of erythromycin followed by a IO-day course of ampicillin. On admission her temperature was 100°F. She had erythematous macules and papules varying in size from 5 to 15 mm and becoming confluent on the neck, chest, abdomen, back, and extremities. Her tonsils were enlarged but the remainder of the oral mucosa was normal. There was marked end-expiratory wheezing bilaterally. The rest of the examination was normal. Abnormal serum test results were as follows: serum glucose, 209 mg/lOO ml; alkaline phosphatase, 207 U/L (normal
Figure 2. Endoscopic view of colonic mucosa that was edematous, erythematous, and friable with a pale yellow exudate. Dark or black areas, particularly on the left periphery, are hemorrhagic, superficially eroded lesions. (Bright, white ovoid areas at 3,6,and 10 o’clock positions
are light
reflections.)
glands. The glands showed extensive necrosis of epithelial cells. The necrotic cells showed pyknotic nuclei and homogenous pink cytoplasm, and in more extensively involved glands appeared to be sloughed out into the gland lumen [Figure 3). Superficial ulceration was present. There was no increase in the number of neutrophils, and crypt abscesses were not seen. Sections from the duodenal specimens showed complete absence of villi with surface ulceration. The glandular crypts showed changes that were identical with those described in the colonic mucosa, with extensive epithelial necrosis and marked lymphoplasmacytic infiltrate in the lamina propria (Figure 4). The Brunner’s glands showed no changes. Viral and bacterial cultures were negative. On hospital day 12 the patient’s condition abruptly deteriorated. She developed circulatory shock and renal, respiratory, and congestive heart failure. She was intubated and placed on a respirator. Vancomycin, metronidazole, gentamycin, dopamine, dobutamine, digoxin, and furosemide were administered intravenously. Because of the lack of improvement, high-dose intravenous corticosteroids were added and the patient’s clinical status rapidly improved. Four blood cultures grew out Haemophilus influenza group B. The patient continued to improve until hospital day 24 when she abruptly developed gross hemoptysis and bloody diarrhea. Emergency bronchoscopy revealed a grossly edematous trachea with Z-s-mm whitish plaques that, on biopsy, showed extensive epithelial necrosis with ulceration. Fungi were not present. Blood and sputum cultures grew Pseudomonas aeruginosa. The patient continued to deteriorate with hematemesis, melena, and hemoptysis and died on hospital day 25. The family refused an autopsy.
472
ZWEIBAN ET AL.
GASTROENTEROLOGY Vol. 91, No. z
Figure
Discussion Erythema multiforme has a wide spectrum of presentation (11-13) from minimal skin lesions progressing to the severe form known as toxic epidermal necrolysis, which was seen in our first patient. A prodrome of malaise, nausea, vomiting, and sore throat may occur 5-14 days before the skin lesions appear. Our second patient had such a prodrome.
3. Mucosal biopsy specimen of colon, case 3, showing necrotic epithelial cells with pyknotic nuclei that fill the gland lumina. Note the paucity of neutrophils in the lamina propria inflamtnatory cell infiltrate. H & E, x280.
The lips, buccal mucosa, tongue, conjunctivae, urethral meatus, vagina, and anus (listed in the order of their usual frequency of involvement) are the sites of most frequent mucosal involvement (14). Gastrointestinal involvement first was described by Hebra and Kaposi (8) in 1874 and later by Osler (9) in 1895 in his description of the visceral manifestations of erythema multiforme. The method of documentation
Figure
4. Mucosal biopsy specimen of duodenum, case 3, showing marked lymphoplasmacytic cell infiltration of the lamina propria and extensive epithelial cell necrosis in the glands. The luminal surface is at the top righthand side. H & E, x40.
THE GUT IN STEVENS-JOHNSON
August 1986
was by gross inspection of autopsy material. No pathological description of lesions was given and many of Osler’s cases were later revised as being examples of Henoch-Schonlein purpura (15). Although esophageal involvement in erythema multiforme is cited in dermatology textbooks, it is rarely well documented. Our first 2 cases show that involvement ranges from mild to very severe. Extensive necrolysis of the esophagus as in our first case, to our knowledge, has not been described in an adult in the English-language literature. Koblenzer (16), however, has reported a 2-mo-old child with acute epidermal necrolysis (which did not begin as erythema multiforme) in whom there also was severe esophageal ulceration, and others (17,18)have reported that at autopsy their patients with toxic epidermal necrolysis had “ulcerative enteritis.” There are two prior endoscopic descriptions of esophageal involvement with erythema multiforme. In 1 case (2) the appearance was indistinguishable from peptic esophagitis, but esophageal mucosal biopsy specimens were not obtained to exclude this or other etiologies. The second case, only recently reported (3), had a single small isolated plaque in the distal esophagus. With esophageal involvement, the major symptom is dysphagia as in both our first 2 cases, but severe bleeding also may occur as in our first case. Esophageal stricture also has been reported (L?),but most patients probably have complete healing as presumably occurred in our second case. The severity of the esophageal lesions in our cases correlated very well with the severity of their skin lesions, and the microscopic changes in the squamous mucosa of the esophagus were similar to those in the skin. Recognition of esophageal involvement is of potential importance, insofar as the endoscopic appearance may mimic that of candidiasis. Indeed, our first patient was begun on amphotericin treatment because of the report of the endoscopist and the finding of cotton-wool exudates on fundoscopic examination, which suggested disseminated candidiasis. Despite having pulmonary lesions in common, our second and third cases enigmatically had marked disparity in the extent and site of intestinal involvement. Moreover, our third case is unique in that the patient had extensive lesions of the intestinal mucosa with sparing of the ocular, oropharyngeal, and esophageal mucosa. Interestingly, the recently described case of esophageal involvement also had sparing of the palms, eyes, and oral cavity (3). Perhaps this unusual geographical distribution of lesions occurs more commonly, but has not been recognized because endoscopy with biopsy has not been performed or skin lesions have not been iden-
SYNDROME
473
tified or sampled to establish a diagnosis of erythema multiforme. The clinical features of intestinal involvement are nonspecific, being similar to those of any inflammatory bowel disease that has exudative diarrhea as a prominent characteristic. Endoscopically, the large and small bowel mucosa of our third case had an appearance similar to that of the more familiar involvement of buccal mucosa as seen in our second case. It was beefy red with overlying yellow exudative material that in the colon, although not typical of, may be confused with the appearance of antibiotic-associated pseudomembranous colitis or other colitides. The interpretation of the intestinal biopsy specimens from this patient with severe cutaneous erythema multiforme also presents problems. The biopsy appearance of acute severe cellular necrosis and absence of neutrophil leukocyte infiltration is extremely unusual and is unlike the more commonly seen inflammatory bowel diseases, but it does resemble features of graft-versus-host disease (19). Although intestinal mucosal involvement has been reported to occur in erythema multiforme, its histologic features have not been described. We believe the histologic features seen in case 3 are those of erythema multiforme affecting colonic and duodenal mucosa.
References 1. Hebra
F. On diseases of the skin including xanthamata. Translated by Farga CH. London: New Sydenham Society, 1866.
Stein M, Thomson CK, Sawicki JE, Martel AJ. Esophageal stricture complicating Stevens-Johnson syndrome. Am J Gastroenterol 1974:62:435-a. 3. Heer M, Altorfer J, Burger HR, Walti M. Bullous esophageal lesions due to co-trimoxazole: an immune-mediated process? Gastroenterology 1985;88:1954-7. 4. Womack CR, Randall CC. Erythema exudativum multiforme. Its association with viral infections. Am J Med 1953; 15:633-44. 5. Costello MJ. Erythema multiforme exudativum. J Invest Dermatol 1947;8:127-44. 6. Alexander MK, Cope S. Erythema multiforme exudativum major (Stevens-Johnson syndrome]. J Path01 Bacterial 1954;68:373-9. 7. Crawford G, Luikart RH II. Severe erythema multiforme: intestinal involvement. JAMA 1949;140:780-1. 8. Hebra F, Kaposi M. Erythema exudativum multiforme. In: Lehrbuch der Hautkrankheiten. Vol. 1. 2nd ed. Erlangen: Enke, 1874:249-52. 9. Osler W. On the visceral complications of erythema exudative multiforme. Am J Sci 1895;110:629-46, 10. Beck MH, Portnoy B. Severe erythema multiforme complicated by fatal gastrointestinal involvement following cotrimoxalone therapy. Clin Exp Dermatol 1979;4:201-4. 11. Ackerman AB, Penneys NS, Clark WH. Erythema multiforme exudativum: distinctive pathological process. Br J Dermatol 1971;84:554-65. 12. Orfanos CE, Schaumberg-Lever G, Lever WF. Dermal and 2.
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epidermal types of erythema multiforme. Arch Dermatol 1974;109:682-8. 13. Levitt L, Pearson RW. Sulindac-induced Stevens-Johnson toxic epidermal necrolysis syndrome. JAMA 1980;'243: 1262-3. 14. Elias PM, Fritsch PO. Erythema multiforme. In: Fitzpatrick TB, Eisen AZ, Wolff K, Fredberg IM, Austin KF, eds. Dermatology in general medicine. 2nd ed. New York: McGraw-Hill, 1979295-303. 15. Osler W. The visceral lesions of purpura and allied conditions. Br Med J 1914;1:517-25.
GASTROENTEROLOGY Vol. 91, No. 2
16. Koblenzer PJ. Acute epidermal necrolysis (Ritter von Rittershain-Lyell), A clinicopathological study. Arch Dermato1 1967;95:608-17. 17. Ellman MH, Fretzin DF, Olson W. Toxic epidermal necrolysis associated with allopurinol administration. Arch Dermatol 1975;111:986-90. 18. Chan HL. Observations on drug induced toxic epidermal necrolysis in Singapore. J Am Acad Dermatol 1984;10:973-8. 19. McDonald GB, Shulman HM, Sullivan KM, Spencer GD. Intestinal and hepatic complications of human bone marrow transplantation. Part 1. Gastroenterology 1986;90:466-77.
1986:91:469-74
Gastrointestinal Involvement Complicating Stevens-Johnson Syndrome BRUCE ZWEIBAN, HARTLEY COHEN, and PARAKRAMA CHANDRASOMA Gastroenterology and Surgical Pathology Sections, Los Angeles County-University of Southern California Medical Center; and University of Southern California School of Medicine, Los Angeles, California
Three cases of Stevens-Johnson syndrome with intestinal involvement are described. Two patients had esophageal involvement, the severity of which paralleled skin lesions and, in 1 case, probably contributed to death. Dysphagia and bleeding were manifestations. The third patient was unique and had gastric, small and large bowel involvement with sparing of other mucosae. Cramps, severe exudative diarrhea, and bleeding were major clinical features. Unusual histologic features included sloughing of cells into the gland lumina of intestinal mucosa.
Erythema multiforme is an acute self-limited eruption of the skin and mucous membranes. The term “erythema multiforme” refers primarily to the cutaneous lesions as was originally described by Hebra (1) in 1866. When the disease primarily afflicts the mucosal surfaces, the condition often is called Stevens-Johnson syndrome. The mucous membranes most frequently involved are those of the eye and of the oral cavity. Involvement of the remainder of the gastrointestinal tract has been infrequently documented in the literature (2%lo), and there has been no description of the intestinal histology. We report 3 cases of Stevens-Johnson syndrome, 2 with esophageal involvement and 1 unique patient with diffuse intestinal involvement, and give a detailed histologic description of this condition as it affects the intestinal tract.
Received November 4, 1985. Accepted February 17, 1986. Address requests for reprints to: Hartley Cohen, M.D., Gastroenterology Section, Department of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. The authors thank Alice Madrid for help in preparing the manuscript. 0 1986 by the American Gastroenterological Association 0016-5085/86/$3.50
Case Reports Case 1 A 36-yr-old black man was admitted with grand ma1 seizures. Two years previously he had been diagnosed as having systemic lupus erythematosus and was currently on hemodialysis for lupus nephropathy. He was started on phenytoin sodium. Seven days after admission he developed on his face and trunk a papular rash which was thought to be due to either an exacerbation of lupus skin lesions or phenytoin allergy. Phenytoin was discontinued and the patient was started on intravenous corticosteroids. The patient’s general condition, rash, and oropharyngeal lesions improved, and he was discharged 21 days after admission. Three weeks later the patient was readmitted for recurrence of seizure activity occurring during hemodialysis. His medications at that time included methylprednisolone, cimetidine, hydroxychloroquine sulfate, clonidine, and hydroxyzine hydrochloride. Physical examination revealed diffuse alopecia of the scalp and a healing rash. Scaly erythematous plaques were noted over the face and chest along with hypopigmentation of the abdomen and neck region. The patient’s oronasal mucosa was erythematous and friable but no discrete lesions were seen. Phenytoin was administered intravenously for the acute seizure activity and continued by mouth for the next 3 days. Thirty-six hours after the initial phenytoin dose the patient became febrile (100.6”F) with increased prominence of the erythematous papular rash on his back and neck with relative sparing of his extremities. He was begun on high dose corticosteroids. Three days after admission the patient complained of increasing malaise, joint pain, sore throat, and dysphagia localized to the substernal and xyphoid areas. Fivemillimeter white plaques were noted at this time on his lips, palate, pharynx, epiglottis, and nasal mucosa. Newly formed erythematous papules were present over his face, arms, chest, and back. Biopsy of a skin lesion showed changes consistent with erythema multiforme, dermalepidermal type. There was an upper dermal lymphocytic infiltrate around small blood vessels and along the dermoepidermal junction. Hydropic degeneration of the
470 ZWEIBAN ET AL.
GASTROENTEROLOGY Vol. 91, No. 2
rigure 1 Mucosal biopsy specimen of the esophagus, case 1, showing a strip of epithelium in which separation (probably not artefactual) of the mucosal-submucosal junction is seen in the lower left-hand corner. The mucosalsubmucosal junction is shown extending from this separation along the bottom of the photograph to the right-hand side. Intraepithelial inflammatory cells, vacuolation, and individual cell necrosis of epithelial cells are shown. The necrotic cells appear as hyalinized cells with pyknotic nuclei. This represents the viable epithelium in a biopsy specimen that was dominated by necrosis and ulceration. H & E, X100.
basal layer, and subepidermal separation with early vesicle formation was present. Scattered necrotic keratinocytes were present in the epidermis. Upper gastrointestinal endoscopy was performed 7 days after admission because of increasing dysphagia localized to the subxyphoid area. At endoscopy the mid and distal esophagus from 30 to 40 cm from the incisors was diffusely covered with 2.5-5-mm whitish plaques with friable erythematous bases and surrounding mucosa. Endoscopitally, these lesions appeared consistent with candidiasis. Biopsy of these lesions showed evidence of ulceration with acutely inflamed granulation tissue. Less involved strips of squamous epithelium showed scattered necrotic keratinocytes with homogeneous, deep pink cytoplasm and pyknotic nuclei (Figure 1). Fungi or viral inclusions were not seen. These findings are similar to epidermal changes in skin lesions of erythema multiforme. In the interim, cotton-wool exudates were observed on fundoscopic examination. These were initially interpreted as being consistent with disseminated candidiasis, and amphotericin treatment was begun. The patient continued to be febrile (maximum 105.O”F), and bullous lesions appeared on the trunk, genital area, and the lower extremities. On the 11th hospital day the patient had gross hematemesis along with gross melanotic stools and was given 3 U of packed red blood cells. On day 15, gross deepithelization of three-quarters of his back, his face, and extremities occurred. The following day the patient died. Postmortem findings revealed thick necrotic plaque formation with marked sloughing of the mid and distal esophagus. Microscopic examination revealed almost complete necrolysis of the mucosa with extensive ulceration and inflammation. Small residual islands of squamous epithelium showed changes similar to those in the biopsy specimen. There were similar lesions in the trachea
and bronchi. noted.
No other gastrointestinal
involvement
was
Case 2 A 19-yr-old Mexican man presented with a 6-day history of productive cough and sore throat. He complained of pain on swallowing, lesions on his lips, fever and chills for 3 days, and dysuria and swelling of the glans penis for 2 days. There was no history of prior drug ingestion, illness, or recent sexual contacts. Two days before admission he was given penicillin and nystatin. At the time of admission his temperature was 101.8”F. Scattered over the upper trunk and lower extremities were 6.5-mm purplish papular lesions; nonhemorrhagic vesicles were also present. Yellowish exudate of the conjunctiva was present bilaterally. Anterior cervical and submandibular lymph nodes were grossly enlarged. The mucous membrane of the lips was denuded with characteristic hemorrhagic crusting. Marked erythema with white membranous exudate was noted on the buccal mucosa, soft and hard palate, tonsils, and posterior pharynx. The glans penis and meatus also had denuded mucosa and whitish membranes. Target lesions were not present. The stool tested positive for occult blood. Throat and urethral cultures did not grow pathogens. The presumptive diagnosis of Stevens-Johnson syndrome was made and the patient was started on oral corticosteroids. One day after admission an upper fiberoptic endoscopy was performed to evaluate increasing dysphagia. The entire esophagus was erythematous, and multiple, z-mm, whitish plaques overlying inflamed denuded mucosa were visualized from the upper esophageal sphincter to the gastroesophageal junction. The stomach and duodenum were normal. A sigmoidoscopic examination to 56 cm was normal. Biopsy specimens from the
August 1986
THE GUT IN STEVENS-JOHNSON SYNDROME
471
esophagus showed extensive necrosis of the squamous mucosa with ulceration. The adjacent squamous epithelium showed marked intraepithelial inflammation and individual cell necrosis. Fungi or viral inclusions were not seen. The patient became afebrile after 48 h of corticosteroid administration. He was given antacids, the dysphagia improved, and the patient tolerated a soft diet by the fourth day of hospitalization. The patient was discharged on day 7, by which time the cutaneous lesions of the penis and trunk had shown remarkable improvement. The patient was lost to follow-up. Case 3 A 41-yr-old El Salvadoran woman was admitted with a Z-day history of wheezing and a generalized pruritic rash, which first appeared on the trunk and extremities, and then spread to the neck, face, buttocks, and lower extremities. Other than mild diabetes mellitus for which she was taking chlorpropamide, she was well until 2 wk before admission, when she noted increasing shortness of breath and a sore throat for which she was given a P-day course of erythromycin followed by a IO-day course of ampicillin. On admission her temperature was 100°F. She had erythematous macules and papules varying in size from 5 to 15 mm and becoming confluent on the neck, chest, abdomen, back, and extremities. Her tonsils were enlarged but the remainder of the oral mucosa was normal. There was marked end-expiratory wheezing bilaterally. The rest of the examination was normal. Abnormal serum test results were as follows: serum glucose, 209 mg/lOO ml; alkaline phosphatase, 207 U/L (normal
Figure 2. Endoscopic view of colonic mucosa that was edematous, erythematous, and friable with a pale yellow exudate. Dark or black areas, particularly on the left periphery, are hemorrhagic, superficially eroded lesions. (Bright, white ovoid areas at 3,6,and 10 o’clock positions
are light
reflections.)
glands. The glands showed extensive necrosis of epithelial cells. The necrotic cells showed pyknotic nuclei and homogenous pink cytoplasm, and in more extensively involved glands appeared to be sloughed out into the gland lumen [Figure 3). Superficial ulceration was present. There was no increase in the number of neutrophils, and crypt abscesses were not seen. Sections from the duodenal specimens showed complete absence of villi with surface ulceration. The glandular crypts showed changes that were identical with those described in the colonic mucosa, with extensive epithelial necrosis and marked lymphoplasmacytic infiltrate in the lamina propria (Figure 4). The Brunner’s glands showed no changes. Viral and bacterial cultures were negative. On hospital day 12 the patient’s condition abruptly deteriorated. She developed circulatory shock and renal, respiratory, and congestive heart failure. She was intubated and placed on a respirator. Vancomycin, metronidazole, gentamycin, dopamine, dobutamine, digoxin, and furosemide were administered intravenously. Because of the lack of improvement, high-dose intravenous corticosteroids were added and the patient’s clinical status rapidly improved. Four blood cultures grew out Haemophilus influenza group B. The patient continued to improve until hospital day 24 when she abruptly developed gross hemoptysis and bloody diarrhea. Emergency bronchoscopy revealed a grossly edematous trachea with Z-s-mm whitish plaques that, on biopsy, showed extensive epithelial necrosis with ulceration. Fungi were not present. Blood and sputum cultures grew Pseudomonas aeruginosa. The patient continued to deteriorate with hematemesis, melena, and hemoptysis and died on hospital day 25. The family refused an autopsy.
472
ZWEIBAN ET AL.
GASTROENTEROLOGY Vol. 91, No. z
Figure
Discussion Erythema multiforme has a wide spectrum of presentation (11-13) from minimal skin lesions progressing to the severe form known as toxic epidermal necrolysis, which was seen in our first patient. A prodrome of malaise, nausea, vomiting, and sore throat may occur 5-14 days before the skin lesions appear. Our second patient had such a prodrome.
3. Mucosal biopsy specimen of colon, case 3, showing necrotic epithelial cells with pyknotic nuclei that fill the gland lumina. Note the paucity of neutrophils in the lamina propria inflamtnatory cell infiltrate. H & E, x280.
The lips, buccal mucosa, tongue, conjunctivae, urethral meatus, vagina, and anus (listed in the order of their usual frequency of involvement) are the sites of most frequent mucosal involvement (14). Gastrointestinal involvement first was described by Hebra and Kaposi (8) in 1874 and later by Osler (9) in 1895 in his description of the visceral manifestations of erythema multiforme. The method of documentation
Figure
4. Mucosal biopsy specimen of duodenum, case 3, showing marked lymphoplasmacytic cell infiltration of the lamina propria and extensive epithelial cell necrosis in the glands. The luminal surface is at the top righthand side. H & E, x40.
THE GUT IN STEVENS-JOHNSON
August 1986
was by gross inspection of autopsy material. No pathological description of lesions was given and many of Osler’s cases were later revised as being examples of Henoch-Schonlein purpura (15). Although esophageal involvement in erythema multiforme is cited in dermatology textbooks, it is rarely well documented. Our first 2 cases show that involvement ranges from mild to very severe. Extensive necrolysis of the esophagus as in our first case, to our knowledge, has not been described in an adult in the English-language literature. Koblenzer (16), however, has reported a 2-mo-old child with acute epidermal necrolysis (which did not begin as erythema multiforme) in whom there also was severe esophageal ulceration, and others (17,18)have reported that at autopsy their patients with toxic epidermal necrolysis had “ulcerative enteritis.” There are two prior endoscopic descriptions of esophageal involvement with erythema multiforme. In 1 case (2) the appearance was indistinguishable from peptic esophagitis, but esophageal mucosal biopsy specimens were not obtained to exclude this or other etiologies. The second case, only recently reported (3), had a single small isolated plaque in the distal esophagus. With esophageal involvement, the major symptom is dysphagia as in both our first 2 cases, but severe bleeding also may occur as in our first case. Esophageal stricture also has been reported (L?),but most patients probably have complete healing as presumably occurred in our second case. The severity of the esophageal lesions in our cases correlated very well with the severity of their skin lesions, and the microscopic changes in the squamous mucosa of the esophagus were similar to those in the skin. Recognition of esophageal involvement is of potential importance, insofar as the endoscopic appearance may mimic that of candidiasis. Indeed, our first patient was begun on amphotericin treatment because of the report of the endoscopist and the finding of cotton-wool exudates on fundoscopic examination, which suggested disseminated candidiasis. Despite having pulmonary lesions in common, our second and third cases enigmatically had marked disparity in the extent and site of intestinal involvement. Moreover, our third case is unique in that the patient had extensive lesions of the intestinal mucosa with sparing of the ocular, oropharyngeal, and esophageal mucosa. Interestingly, the recently described case of esophageal involvement also had sparing of the palms, eyes, and oral cavity (3). Perhaps this unusual geographical distribution of lesions occurs more commonly, but has not been recognized because endoscopy with biopsy has not been performed or skin lesions have not been iden-
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tified or sampled to establish a diagnosis of erythema multiforme. The clinical features of intestinal involvement are nonspecific, being similar to those of any inflammatory bowel disease that has exudative diarrhea as a prominent characteristic. Endoscopically, the large and small bowel mucosa of our third case had an appearance similar to that of the more familiar involvement of buccal mucosa as seen in our second case. It was beefy red with overlying yellow exudative material that in the colon, although not typical of, may be confused with the appearance of antibiotic-associated pseudomembranous colitis or other colitides. The interpretation of the intestinal biopsy specimens from this patient with severe cutaneous erythema multiforme also presents problems. The biopsy appearance of acute severe cellular necrosis and absence of neutrophil leukocyte infiltration is extremely unusual and is unlike the more commonly seen inflammatory bowel diseases, but it does resemble features of graft-versus-host disease (19). Although intestinal mucosal involvement has been reported to occur in erythema multiforme, its histologic features have not been described. We believe the histologic features seen in case 3 are those of erythema multiforme affecting colonic and duodenal mucosa.
References 1. Hebra
F. On diseases of the skin including xanthamata. Translated by Farga CH. London: New Sydenham Society, 1866.
Stein M, Thomson CK, Sawicki JE, Martel AJ. Esophageal stricture complicating Stevens-Johnson syndrome. Am J Gastroenterol 1974:62:435-a. 3. Heer M, Altorfer J, Burger HR, Walti M. Bullous esophageal lesions due to co-trimoxazole: an immune-mediated process? Gastroenterology 1985;88:1954-7. 4. Womack CR, Randall CC. Erythema exudativum multiforme. Its association with viral infections. Am J Med 1953; 15:633-44. 5. Costello MJ. Erythema multiforme exudativum. J Invest Dermatol 1947;8:127-44. 6. Alexander MK, Cope S. Erythema multiforme exudativum major (Stevens-Johnson syndrome]. J Path01 Bacterial 1954;68:373-9. 7. Crawford G, Luikart RH II. Severe erythema multiforme: intestinal involvement. JAMA 1949;140:780-1. 8. Hebra F, Kaposi M. Erythema exudativum multiforme. In: Lehrbuch der Hautkrankheiten. Vol. 1. 2nd ed. Erlangen: Enke, 1874:249-52. 9. Osler W. On the visceral complications of erythema exudative multiforme. Am J Sci 1895;110:629-46, 10. Beck MH, Portnoy B. Severe erythema multiforme complicated by fatal gastrointestinal involvement following cotrimoxalone therapy. Clin Exp Dermatol 1979;4:201-4. 11. Ackerman AB, Penneys NS, Clark WH. Erythema multiforme exudativum: distinctive pathological process. Br J Dermatol 1971;84:554-65. 12. Orfanos CE, Schaumberg-Lever G, Lever WF. Dermal and 2.
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epidermal types of erythema multiforme. Arch Dermatol 1974;109:682-8. 13. Levitt L, Pearson RW. Sulindac-induced Stevens-Johnson toxic epidermal necrolysis syndrome. JAMA 1980;'243: 1262-3. 14. Elias PM, Fritsch PO. Erythema multiforme. In: Fitzpatrick TB, Eisen AZ, Wolff K, Fredberg IM, Austin KF, eds. Dermatology in general medicine. 2nd ed. New York: McGraw-Hill, 1979295-303. 15. Osler W. The visceral lesions of purpura and allied conditions. Br Med J 1914;1:517-25.
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16. Koblenzer PJ. Acute epidermal necrolysis (Ritter von Rittershain-Lyell), A clinicopathological study. Arch Dermato1 1967;95:608-17. 17. Ellman MH, Fretzin DF, Olson W. Toxic epidermal necrolysis associated with allopurinol administration. Arch Dermatol 1975;111:986-90. 18. Chan HL. Observations on drug induced toxic epidermal necrolysis in Singapore. J Am Acad Dermatol 1984;10:973-8. 19. McDonald GB, Shulman HM, Sullivan KM, Spencer GD. Intestinal and hepatic complications of human bone marrow transplantation. Part 1. Gastroenterology 1986;90:466-77.