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BRIEF COMMUNICATION Year : 2011 | Volume : 59 | Issue : 3 | Page : 231-233

Mucous membrane grafting for the post-Steven-Johnson syndrome symblepharon: A case report Jayanta Kumar Das, Jnanankar Medhi, Ranjay Chakravarty, Ronel Soibam, Jayanta Kumar Das, Jnanankar Medhi, Ranjay Chakravarty, Ronel Soibam Sri Sankaradeva Nethralaya, Beltola, Guwahati - 781 028, Assam, India Date of Submission Date of Acceptance Date of Web Publication 20-Dec-2008 22-Mar-2010 13-May2011

Correspondence Address: Jayanta Kumar Das Senior Consultant, Sri Sankaradeva Nethralaya, Beltola, Guwahati - 781 028, Assam India Jayanta Kumar Das Senior Consultant, Sri Sankaradeva Nethralaya, Beltola, Guwahati - 781 028, Assam India

DOI: 10.4103/0301-4738.81039 PMID: 21586847

Abstract An 18-year-old woman was referred with late sequelae of chloroquine-induced Steven-Johnson syndrome. At the time of presentation, the symblepharon was involving the upper lids to almost the whole of the cornea, and part of the lower bulbar conjunctiva with the lower lid bilaterally. Other ocular examinations were not possible due to the symblepharon. B-scan ultrasonography revealed acoustically clear vitreous, normal chorioretinal thickness, and normal optic nerve head, with an attached retina. Conjunctivo-corneal adhesion released by superficial lamellar dissection of the cornea. Ocular surface reconstruction was carried out with a buccal mucous membrane. A bandage contact lens was placed over the cornea followed by the symblepharon ring to prevent further adhesion. The mucosal graft was well taken up along with corneal re-epithelization. Best

corrected visual acuity of 20/120 in both sides after 1 month and 20/80 after 3 months was achieved and maintained till the 2.5-year follow-up.

Keywords: Ocular surface reconstruction, Steven-Johnson syndrome, superficial keratectomy

How to cite this article: Das JK, Medhi J, Chakravarty R, Soibam R, Das JK, Medhi J, Chakravarty R, Soibam R. Mucous membrane grafting for the post-Steven-Johnson syndrome symblepharon: A case report. Indian J Ophthalmol 2011;59:231-3 How to cite this URL: Das JK, Medhi J, Chakravarty R, Soibam R, Das JK, Medhi J, Chakravarty R, Soibam R. Mucous membrane grafting for the post-Steven-Johnson syndrome symblepharon: A case report. Indian J Ophthalmol [serial online] 2011 [cited 2011 Oct 26];59:231-3. Available from: http://www.ijo.in/text.asp?2011/59/3/231/81039

Steven-Johnson syndrome (SJS) is known to be caused by sensitivity to drugs, variety of infection, certain vaccines, toxins, deep X-ray therapy, malignancy, food, and pregnancy. [1] The role of drugs is said to be the most important. The commonest causative drug has been reported to be long-acting sulfonamides [1] and among the antimalarial drugs, chloroquine is said to be the most notorious causative agent. [2] The treatment aims at the restoration of the anatomical structures and physiologic properties of the ocular surface. [3] In chronic phase, autologous or allogenic limboconjunctival graft are best used for transplantation. However, due to unavailability of the conjunctival tissue for transplantation in cases of bilateral involvement, another autologous graft, i.e., mucosal or amniotic membrane is used. Case Report

An 18-year-old female patient presented with inability to open both eyes for 6 weeks. She had a history of fever from malaria 2 months back for which she was treated with oral chloroquin phosphate 500 mg. She developed erythematous papular eruptions on the trunk, mouth, and limbs along with pain, redness, and watering from both eyes 5 days after taking the medication followed by gross diminution of vision and inability to open her eyes. She was diagnosed to be a case of SJS and was treated conservatively elsewhere. The erythematous lesions resolved completely at 4 weeks with medications, but she was unable to open her eyes and she was referred to us for further evaluation and management. At the time of presentation, her visual acuity was positive perception of light in both eyes, with both the upper lids adhered to almost the whole of the cornea, and part of the lower bulbar conjunctiva with the lower lid [Figure 1].

Other ocular examination was not possible due to adhesion. Intraocular pressure was found digitally normal. B-scan ultrasonography (USG) revealed acoustically clear vitreous, normal chorioretinal thickness, and normal optic nerve head with an attached retina. Figure 1: Preoperative view: gross appearance (a). Close-up view shows the cornea and upper tarsal conjunctiva being totally adhered in both eyes (b) Click here to view

Routine blood examination, blood glucose, and serum urea and creatinine levels were within normal limits. Physician evaluation was done by meticulous history taking, clinical examinations, and key laboratory examinations to exclude other blistering skin diseases such as pemphigus vulgaris, bullous pemphigoid, mucocutaneous diseases like Behet's syndrome and Reiter's syndrome, and vasculitis like systemic lupus erythematosus. The patient was taken up for surgery and superficial lamellar dissection of the cornea was done to separate the conjunctivocorneal adhesion, followed by release of symblepharon between palpebral and bulbar conjunctiva. The inspection of the limbus revealed areas of scattered peripheral corneal neovascularization affecting less than 3 clock hours in both eyes, which implied the areas of limbal stem cell deficiency (LSCD) of the corresponding areas. Rest of the limbus appeared clinically healthy. The buccal mucous membrane was harvested after injecting 2% xylocaine with adrenaline (1 in 200,000) into the proposed site and the graft was removed from below moving upward. After harvesting, the extra fat was removed from the graft. A mucous membrane graft (MMG) of size 27 8 mm (right eye) and 26 8 mm (left eye) was placed over the raw area of superior bulbar conjunctiva and secured with interrupted stitches using 8-0 vicryl. The lower bulbar conjunctiva was covered by a MMG of size 15 7 mm (right eye) and 14 7 mm (left eye) and sutured in a similar fashion. A bandage contact lens (BCL) was placed over the cornea. This was followed by the placement of a symblepharon ring to prevent the recurrence of symblepharon and a temporary tarsorrhaphy was placed in both eyes to achieve some pressure effect on the MMG by the symblepharon ring [Figure 2]. The patient was given a systemic antibiotic (cephalexin 500 mg three times a day for 5 days) and a nonsteroidal anti-inflammatory (Ibugesic 100 mg, -paracetamol 500 mg, combination twice daily after meal for 4 days) along with a topical antibiotic steroid (Gatiflxaciin with dexamethasone, one drop six times a day for 1 month) combination, and a tear substitute (Carboymethylcellulose) was prescribed for six times a day for 6 months. Figure 2: Early post-operative view (seventh day): - gross appearance (a). Close-up view of both eyes with the bandage contact lens and symblepharon ring seen in situ (b) Click here to view

The re-epithelialization of the corneal epithelium was completed by in 10 days. Temporary tarsorrhaphy was removed after 2 weeks and both the BCL and the symblepharon ring was removed at 4 weeks. Except few sectors of peripheral corneal vascularization, no other sequelae were observed postoperatively. The patient showed remarkable recovery. Best corrected visual acuity of 20/120 in both sides after 1 month and 20/80 after 3 months [Figure 3] was achieved and maintained till the 2.5-year follow-up without any other sequelae.

Figure 3: Postoperative view (3 months): gross appearance (a). Close-up view showing well reconstruction in the inferior fornix in both eyes (b) Click here to view

Discussion

The exact etiology of SJS is not known and the understanding of the etiopathogenesis and management protocol of ocular adnexal complication of SJS has been limited so far. Often, patients of SJS are treated by a physician or dermatologist in early phases and later referred to an eye care center. Patients often consult an ophthalmologist with severe ocular sequelae only after the resolution of skin lesions, as in our case. The acute stage of the SJS is characaterized by bilateral catarrhal and membranous conjunctivitis. During the chronic stage of the disease, most patients have various alterations of the ocular surface, such as symblepaharon, entropion, trichiasis, dry eye, limbal cell deficiency, conjunctival inflammation and corneal neovascularization. [4],[5] The major aim of treatment in late phases of SJS is ocular surface reconstruction to correct cicatricial sequalae and chronic inflammation. [3] Management option in late cases is a challenge and is often frustrating, because of the combination of various alterations in surface milieu causing severe dryness and surface inflammation leading to treatment failure. Several surgical approaches for the reconstruction of the ocular surface in cicatricial disorders with or without significant LSCD have been tried with encouraging results. [6] To reconstruct and maintain the ocular surface, a healthy conjunctiva when available, is the ideal material for grafting. [7] A full-thickness oral MMG is the simplest graft [7] to use if a conjunctiva is not available. It is preferred over split-thickness mucosal grafts as it contracts less in comparison, though a split-thickness graft is more preferable from the cosmesis point of view because of its lesser bulk and pinky appearance [7] However, amniotic membrane transplantation (AMT) is an accepted approach to the surgical management of chronic symblephera because of the unique properties of the membrane, [8] especially in cases with significant LSCD. [9] It can be combined with limbal transplantation and with an adjunctive antimetabolite. However, in cases with an

adequate reserve of limbal stem cells, mucosal tissue transplantation achieves equally good results [10] as seen in our case. Mucosal tissue transplantation can be considered in situations where cost and inadequate infrastructure are concerned. Our case had a partial LSCD which was scattered and amounting to 3-4 clock hours in each eye. As such the corneal re-epitheliazation was satisfactory after the procedure. In cases of severe bilateral LSCD, an additional procedure of stem cell harvesting and ex vivo culture would have been required. The ultimate aim of treatment of the chronic phase of ocular surface disorders like SJS is restoration of the anatomical structures and physiologic properties of the ocular surface.

References 1. Bianchine JR, Macareg PV, Lasang LI, Azarnoff DL, Brunk SF, Hvidberg EF, et al. Drugs as Histological factors in SJ Syndrome. Am J Med 1968;44:390-405. Beedimoni RS, Rambhimaiah S. Oral chloroquine-induced Stevens-Johnson Syndrome. Indian J Pharmacol 2004;36:101. Shimazaki J, Yang H-Y, Tsubota K. Amniotic membrane transplantation for ocular surface reconstruction in patients with chemical and thermal burns. Ophthalmology. 1997;104:2068-76. Stewart MG, Duncan NO 3rd, Franklin DJ, Friedman EM, Sulek M. Head and neck manifestations of erythema multiforme in children. Otolaryngol Head Neck Surg 1994;111:236-42. [PUBMED] Tsubota K, Satake Y, Kaido M, Shinozaki N, Shimmura S, Bissen-Miyajima H, et al. Treatment of severe ocular surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med 1999;340:1697-703. [PUBMED] [FULLTEXT] Gomes JA, Santos MS, Ventura S, Donato WB, Cunha MC, Hfling-Lima AL. Amniotic membrane with living related corneal Limbal/Conjunctival Allograft for Ocular Surface Reconstruction in Stevens-Johnson Syndrome. Arch Ophthalmol 2003;121:1369-74. Henderson H, Collin J. Mucous Membrane Grafting. In: Geerling G, Brewitt H, editors. Surgery for the Dry Eye. Vol. 41. Basel, Karger: Dev Ophthalmol; 2008. p. 230-42.

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Shimazaki J, Shinozaki N, Tsubota K. Transplantation of amniotic membrane and limbal autograft for patients with recurrent pterygium associated with symblepharon. Br J Ophthalmol 1998;82:235-40. [PUBMED] [FULLTEXT] 9. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol 1999;83:399-402. [PUBMED] [FULLTEXT] 10. Manner GE, Mathers WD, Wofley DE, Martinez JA. Hard palate mucosa graft in Stevens-Johnson syndrome. Am J Ophthalmol 1994;118:786-91.

Case Report

Stevens-Johnson Syndrome in a Boy With Macrolide-Resistant Mycoplasma pneumoniae Pneumonia

1. 2. 3. 4. 5. 6. T. Prescott Atkinson, MD, PhDa, Suresh Boppana, MDa, Amy Theos, MDb, L. Scott Clements, MD, PhDc, Li Xiao, PhDd, Ken Waites, MDd

+ Author Affiliations 1. Departments of aPediatrics, 2. bDermatology, and 3. dPathology, University of Alabama at Birmingham, Birmingham, Alabama; and 4. cDepartment of Pediatrics, University of South Alabama, Mobile, Alabama Next Section

Abstract
Mycoplasma pneumoniae is a highly specialized parasitic bacterium that is a significant cause of community-acquired pneumonia in children. Although most such respiratory infections are mild, a minor percentage of patients require hospitalization and, occasionally, intensive treatment for respiratory failure. A variety of extrapulmonary sequelae of M pneumoniae infections have been described, including Stevens-Johnson syndrome. Macrolide resistance in M pneumoniae has developed rapidly in Asia, particularly in China, over the past decade and is now appearing in the United States. Emerging resistance to macrolides creates a therapeutic conundrum, particularly for pediatricians caring for young children in whom absolute or relative contraindications exist for the use of tetracyclines or fluoroquinolones, the 2 other main classes of drugs shown to be efficacious for M pneumoniae. We describe here the case of a child with a prolonged febrile illness associated with Stevens-Johnsonlike mucocutaneous involvement who was found to have a respiratory infection with macrolide-resistant M pneumoniae. Key Words:

Mycoplasma pneumoniae Stevens-Johnson syndrome drug resistance

pneumonia

A marked increase in resistance to macrolides has occurred with Mycoplasma pneumoniae in Asia over the past decade, particularly in China. Recent reports have documented that up to 90% of M pneumoniae isolates in China are now highly resistant to macrolides; resistance was recently documented in the United States and may be found in up to 27% of cases.1,,3 Macrolide resistance in this common respiratory pathogen should be of interest to pediatricians because of the lack of alternative antibiotics available to treat infections in young children. Extrapulmonary manifestations of M pneumoniae infection have been described, including arthritis, encephalitis, and Stevens-Johnson syndrome (SJS).4,,6 Here we present a case of SJS in a child after a respiratory infection with macrolide-resistant M pneumoniae. Previous SectionNext Section

CASE REPORT
A previously healthy 10-year-old boy developed 2 to 3 weeks of malaise and upper respiratory infection symptoms, then worsening cough and fever to 39C, followed 2 days later by worsening sore throat, mouth ulcers, and anorexia. He then developed a progressive bullous rash that began on his hands and feet and became generalized. He was admitted briefly to a local hospital and then transferred to the University of South Alabama in Mobile, where he was diagnosed with SJS and pneumonia on the basis of his mucocutaneous findings and an ill-defined left lower-lobe infiltrate on his admission chest radiograph. He continued to have cough without respiratory distress or supplementary oxygen requirement. M pneumoniae infection was strongly considered in view of the clinical history and presentation, and he was treated with intravenous azithromycin and ceftriaxone along with 3 doses of intravenous immunoglobulin (Ig) (1 g/kg) and morphine for severe pain. When the patient's skin and mucus membrane disease continued to worsen, he was transferred on the third hospital day to Children's Hospital in Birmingham, Alabama, 10 days after the onset of fever.

Past Medical/Family/Social History

The patient had been generally healthy. There was no family history of frequent infections. Two weeks earlier, the patient's younger brother had had bronchitis with fever to 39C.

Physical Examination
After transfer to Children's Hospital in Birmingham, his examination revealed a florid mucocutaneous dermatosis (Fig 1). There were multiple erosions over his tongue and hard palate and a large bulla covering the mucosal surface of his lower lip. The conjunctival membranes were injected, and there were small erosions on the pinna of the right ear. Numerous tender, tense bullae on an erythematous base were noted on his arms, legs, palms and soles. Over the buttocks they coalesced to form annular, targetoid, and polycyclic lesions. There were a few typical target lesions on his palms. In addition, bullae were

present on the shaft of his penis (Fig 2), and mild erythema and desquamation were noted around his urethral meatus.

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FIGURE 1 Mucocutaneous lesions caused by M pneumoniae infection. A, Mucus membrane involvement; B, extensive deep bullae on the palms, showing some healing and scattered fresh lesions; C, larger bullae scattered across the buttocks, occasionally becoming confluent; D, close-up of tense bullae on an extremity.

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FIGURE 2 Cutaneous ulcerations on the shaft of the patient's penis.

Continued Hospital Course

Members of the ophthalmology department and the burn unit surgical nursing team were

consulted. Skin biopsies were performed in the dermatology department on hospital days 3 and 6 and revealed a subepidermal blister with acute inflammation suggestive of linear IgA bullous disease. However, there was no deposition of IgA, IgG, or IgM at the basement membrane zone. Fever and new evolving skin lesions continued for 1 week after admission. By hospital day 7 the ophthalmology consultant believed that there was some evidence for mild anterior uveitis bilaterally, possibly related to blisters of the bulbar conjunctivae, and recommended topical tobramycin/corticosteroid drops. The patient required a nasogastric tube for nutrition and a morphine patient-controlled anesthesia pump for pain control.

Laboratory Studies
The patient's initial chest radiograph after transfer to Children's Hospital in Birmingham revealed a tiny left effusion, whereas a second chest radiograph 6 days later revealed only some peribronchial cuffing. A complete blood count and differential revealed only a mild left shift. Serum IgG and IgM levels were moderately elevated; the former was likely attributable to his 3 intravenous Ig infusions in Mobile; follow-up measurements 18 months after discharge revealed serum IgM and IgG levels below normal for the patient's age (Table 1) (all Ig levels were measured in the Children's Hospital clinical laboratory by using a Vitros Fusion 5.1 analyzer [Randox Laboratories, Kearneysville, WV]). Results of tests for serum IgM, IgA, and IgG antibodies to M pneumoniae were all positive (IgG: 3.69 ISR [positive: >1.1 ISR]; IgA: 63 BU/mL [positive: >21 BU/mL]; IgM: 4715 U/mL [positive: >950 U/mL]), and although a throat culture tested negative for M pneumoniae, results of a real-time polymerase chain reaction (PCR) assay targeting the repMp gene were positive.7 A real-time PCR assay designed to detect macrolide resistance in M pneumoniae8 revealed that the organism was positive for the A2063G mutation in the 16S ribosomal RNA gene, which has been associated with resistance. View this table:

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TABLE 1 Serum Ig Levels

Continued Hospital Course and Discharge

On the seventh hospital day in Children's Hospital in Birmingham, he was started on oral prednisolone (2 mg/kg per day), dapsone (25 mg/day), and levofloxacin (400 mg daily); he subsequently improved and was discharged on the 12th day. Permission for publication of this case report was obtained from the University of Alabama at Birmingham institutional review board, the patient, and his parents. Previous SectionNext Section

DISCUSSION
Review of M pneumoniae Infections
M pneumoniae is a cell-wallless highly specialized parasitic bacterium that infects the ciliated epithelium of the human respiratory tract. Infection spreads primarily by airborne droplets, whereby the organisms adhere to the respiratory epithelium via a specialized adhesive tip and then spread slowly through the respiratory tract; the incubation period is often as long as 3 weeks. Symptoms may last for several weeks but usually ameliorate with antibiotic treatment.9 M pneumoniaeinduced SJS with bullous skin lesions and mucocutaneous ulcerations has been known for decades and is the most common infection-associated cause of this condition.10,,20 Some reports have documented isolation of the organism from skin lesions, which suggests that SJS represents true extrapulmonary spread of the active infection, at least in some instances.21,22 As with the respiratory infections, M pneumoniaeinduced SJS can be recurrent in some people.23 Because extrapulmonary spread of M pneumoniae has been reported in hypogammaglobulinemic patients,24,25 it is interesting that the patient's follow-up serum IgG and IgM levels were low (Table 1).

Macrolide Resistance in M pneumoniae

Historically, macrolides have been the treatment of choice for pediatric M pneumoniae infections because of the potential toxicities of fluoroquinolones and tetracyclines in young children. Macrolide resistance has been detected with increasing frequency in Japan and China as a result of selective pressure attributable to widespread use of macrolide antibiotics for treatment of respiratory infections.26,,28 The appearance of resistance in France and Germany has also been documented within the past 3 years.29,30 According to recent studies, >80% of M pneumoniae infections in Shanghai and 90% in Beijing are currently caused by macrolide-resistant strains.2,26 Although the current prevalence of resistance in the United States is unknown, a Centers for Disease Control and Preventionbased investigation of a 20062007 outbreak of M pneumoniae respiratory illness associated with 3 cases of encephalitis found that 3 of 11 isolates (27%) were macrolide-resistant, and we have documented the occurrence of macrolide-resistant M pneumoniae in hospitalized children in Alabama.3,8

Diagnosis
Clinically useful diagnostic tools for the detection of M pneumoniae infection are presently limited to serologic assays and nucleic acidbased amplification systems, which generally use PCR technology.4 Culture is relatively insensitive and can take up to 6 weeks. Positive serologic test results at least 1 week into the course of a significant illness provide supportive evidence, but because of the prevalence of IgG titers in the population, antibodies obtained at a single time point may not be indicative of acute infection.

Furthermore, early in the course of infection, patients may not have made sufficient antibody to yield a positive result, older adults may not produce an IgM response, and IgM may persist in some people for years.6,31,32 Immunodeficient people may not be capable of mounting an antibody response at all. PCR, particularly real-time PCR, has been the most important innovation in the rapid, accurate diagnosis of M pneumoniae infections and in the determination of antibiotic resistance.3,8 The high levels of sensitivity and specificity are offset by the well-known propensity for false-positive results caused by contamination, issues that are under intense scrutiny as the development of DNA-based point-of-care diagnostic tests continues.4

Therapy
Treatment with antibiotics from the penicillin or cephalosporin families, the drugs most commonly used by physicians for the treatment of respiratory infections, has no effect on mycoplasmas because of the absence of a cell wall.33 Antibiotic therapy with the bacteriostatic antibiotics from the macrolide or tetracycline classes improves respiratory symptoms, but the organisms may still be cultured from the respiratory tract even after treatment, sometimes for months.34,,37 It is important to note that tetracyclines are contraindicated in children younger than 8 years because of permanent staining of the developing teeth. Ketolide antibiotics have some efficacy against M pneumoniae,38 but no ketolides are currently available for use in children in the United States. Fluoroquinolones are effective clinically, but none of them are currently approved for pediatric use, and these drugs must be used with caution because of the possibility of toxicity or adverse effects. Clinical efficacy of other antibiotic classes has not been demonstrated. Corticosteroids have been advocated for adjunctive use in severe M pneumoniae infections,39,,42 their potential efficacy perhaps related to suppression of immunologic hypersensitivity6,43,44 and/or a direct inhibitory effect on the growth of the organism.45 There is also supportive experimental evidence from animal models.42 However, the use of corticosteroids in M pneumoniaeassociated SJS has not been well studied because the complication is infrequent. There have been scattered case reports suggesting that doses such as those that may be used for respiratory infection with M pneumoniae may be efficacious.20 Current recommendations suggest that, if used in severe cases, intravenous solumedrol at 2 to 2.5 mg/kg per day should be started early in the course of the disease.10 Previous SectionNext Section

CONCLUSIONS
M pneumoniae should be considered in patients with SJS, particularly those with an associated respiratory infection. As has been documented in patients with M pneumoniae arthritis, mild humoral deficiencies may be a risk factor for M pneumoniaeassociated SJS, a subject that deserves further study. Emerging macrolide resistance in M pneumoniae is likely to present an increasingly significant therapeutic problem for clinicians in the treatment of complicated illness caused by M pneumoniae in young children for whom the

use of tetracyclines and fluoroquinolones is not normally considered. Previous SectionNext Section

Footnotes
o Accepted February 8, 2011. Address correspondence to T. Prescott Atkinson, MD, PhD, Division of Pediatric Allergy, Asthma and Immunology, Children's Hospital, Park Place 220, 1600 7th Ave South, Birmingham, AL 35233. E-mail: patkinson@peds.uab.edu FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. SJS = Stevens-Johnson syndrome Ig = immunoglobulin PCR = polymerase chain reaction Previous Section

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