Editor’s Note: Ophthalmology Times is pleased to announce Sophia Y. Wang, MD, and co-author Shahzad Mian, MD, of the University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, as the winners of the 2016 Resident Writer’s Award Program, sponsored by Allergan. The winning entry is featured here.
The Ophthalmology Times Resident Writer’s Award Program is a unique recognition opportunity designed to promote excellence in ocular surface disease education. It was created to acknowledge outstanding case identification and written presentation skills in ophthalmology residents.
A 59-year-old otherwise healthy man presented with an acute-onset diffuse rash involving over 90% of his body surface area, including oral, genital, and ocular mucosal involvement, in the setting of treatment with trimethoprim-sulfamethoxazole for a minor infection. Initial ophthalmic examination was notable for development of extensive corneal epithelial defects in both eyes as well as conjunctival sloughing and pseudomembrane formation.
He was diagnosed with toxic epidermal necrolysis with ocular involvement. Initial ocular treatment included topical ocular antibiotic and steroid, which was rapidly escalated to placement of amniotic membrane rings followed by amniotic membrane grafts sutured to cover the entire ocular surface. By discharge 7 weeks later, his visual acuity was 20/20 in both eyes and remained excellent at last follow-up 7 months after presentation. He had minor non-sight-threatening sequelae including mild symblephara bilaterally and a residual inferior corneal scar on the right.
A 59-year-old otherwise healthy man presented with an acute-onset diffuse and worsening rash. He was on day 9 of a course of oral trimethoprim-sulfamethoxazole (Bactrim, Roche) prescribed by his primary care provider for a thumbnail infection when he developed a body ache and chills, followed by a red raised rash which spread across his body. He presented to the emergency department where he was treated with oral prednisone and admitted for worsening rash, which had spread to include his lips, oral and genital mucosa, trunk, and extremities. A day later, he developed red eyes and had difficulty opening them. He was transferred to the University of Michigan Burn Intensive Care Unit. He had no known previous allergies, including to sulfa drugs.
The ophthalmology service was consulted upon admission to the burn unit, three days after his initial presentation. An external exam showed diffuse erythematous and violaceous plaques on the face, trunk, extremities, and penis, involving over 90% total body surface area, with desquamation on the back, arms, and abdomen. There was crusting and erosion on the lips and hard palate. His near visual acuity was 20/30 in both eyes (OU). Pupils, motility, and IOP were unremarkable. He had copious mucoid discharge on the lashes, subconjunctival hemorrhages, and conjunctival injection with pseudomembrane formation bilaterally. He had an 8 mm by 7 mm corneal epithelial defect in the right eye (OD) with no stromal infiltration and no corneal epithelial defect in the left eye (OS). The remainder of the ophthalmic examination was unremarkable.
Discussion and diagnosis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a continuum of rare but life-threatening inflammatory reactions defined by percentage body surface area (BSA) involved. Less than 10% BSA involvement is SJS; over 30% BSA involvement is TEN; and between 10-30% BSA involvement is SJS/TEN overlap. This patient presented with a diffuse desquamating rash of over 90% BSA, with mucous membrane and ocular involvement, in the setting of exposure to a sulfa antibiotic, consistent with TEN.
Sulfa drugs such as trimethoprim-sulfamethoxazole are classically associated with SJS/TEN; others include allopurinol, lamotrigine, carbamazepine, phenytoin/fosphenytoin, and certain NSAIDs.1 Suspected culprit drugs should be discontinued. Overall mortality is 20-25%,2 and incidence of acute ocular involvement is up to 80%,1 with signs including eyelid skin and conjunctival sloughing, pseudomembrane formation, and corneal epithelial defects and ulceration. These acute inflammatory injuries lead to chronic ocular sequelae in over 60% of patients,2 including conjunctival and corneal scarring, symblepharon formation, dry eye from lacrimal gland system obstruction, limbal stem cell deficiency, and friction-induced chronic microtrauma from trichiasis and entropion, all resulting in severe ocular discomfort and blindness.1
Initial topical pharmacological therapies are supportive, consisting of lubrication with artificial tears and topical antibiotics to prevent superinfection. Topical steroid therapy is thought to reduce the intense local inflammation which leads to scarring.3 Systemic immunosuppression with oral or intravenous steroids has been controversial due to increased risk of infection, and intravenous immunoglobulin (IVIG) has not been shown to improve ocular outcomes.1 After initial ophthalmic examination, the patient began ocular treatment with ofloxacin four times daily, prednisolone acetate 1% hourly, and preservative-free artificial tears hourly OU.
The following day, his acuity worsened to 20/200 OD and 20/800 OS, with development of a new 4 mm by 6 mm corneal epithelial defect OS. Given the rapid worsening on topical therapies alone, treatment was escalated to include amniotic membrane transplantation (AMT).
Amniotic membrane consists of the innermost layer of the placental membrane and exerts anti- inflammatory and anti-scarring effects by secreting anti-inflammatory cytokines, inducing apoptosis of immune cells entrapped in the stromal matrix, and downregulating genes related to scar formation by suppressing TGF-beta signaling in ocular surface fibroblasts.4 Commercial amniotic membrane is available as cryopreserved tissue, either in sheets (AmnioGraft, Bio-Tissue) or mounted on a 16 mm diameter ring (PROKERA, Bio-Tissue) which rests on the ocular surface similar to a contact lens.
The rings were placed OU on hospital day 2. By hospital day 4, the patient was intubated and sedated for altered mental status. Sloughing of the conjunctiva beyond the diameter of the rings was observed, indicating areas that could not be treated with device alone. On hospital day 5, the patient underwent surgical placement of sutured amniotic membrane, symblepharon rings and suture tarsorrhaphy for both eyes. Surgical AMT completely covers the ocular surface by suturing the membrane from upper to lower lid margins, at the level of or external to the grey line. The graft was secured into the fornices with a symblepharon ring fashioned from IV tubing, sized appropriately for the patient.4,5
In several case series, treatment with AMT was associated with visual outcomes of 20/40 or better4-6 and reduced the incidence of long-term poor visual outcomes compared to treatment without AMT.7 A recent grading system indicates that the presence of fluorescein staining on greater than 1/3 of at least one lid margin, any corneal epithelial defects, or conjunctival staining larger than 1 cm constitutes severe ocular involvement and should be treated urgently with AMT.6
On hospital day 16, the patient’s tarsorrhaphies were removed. The amniotic membranes had started to dissolve. A complete epithelial defect OD and a central 1 mm epithelial defect OS remained. New diameter rings were placed in both eyes, which then dissolved and were removed on hospital day 20, by which time his corneal epithelial effects had healed. As he convalesced over the next several weeks, his left eye remained stable while small epithelial defects re-appeared and healed in his right eye. He was discharged home after 47 days in the hospital, by which time his visual acuity had recovered to 20/20 OU.
Ophthalmic monitoring continued in the outpatient setting. By 1 week after discharge, all remaining epithelial defects were healed; by 4 weeks after discharge, all topical antibiotic and steroid drops were discontinued. At his last follow-up examination 6 months after discharge, his distance visual acuity remained 20/20 OU. He had mild symblepharon OU and residual inferior corneal scarring OD.
Summary and conclusions
Ten key points in the management of TEN:
SJS/TEN is a severe life-threatening inflammatory reaction associated with common medications such as sulfa drugs, which should be discontinued.
The overall risk of mortality with SJS/TEN is 20-25%.
Up to 80% patients with SJS/TEN have ocular involvement.
Urgent ophthalmologic assessment is necessary.
Acute ocular involvement may be mild with only conjunctivitis, but can progress rapidly to include corneal and conjunctival defects.
Early use of topical corticosteroids and antibiotics is recommended.
Treatment with systemic corticosteroids and IVIG is controversial and has not been shown to improve ocular outcomes.
Corneal and conjunctival epithelial sloughing should be treated with amniotic membrane grafts, including use of rings or sutured placement.
Long-term complications include scarring, symblephara, dry eye, and trichiasis, which can lead to severe discomfort and ultimately blindness.
Close follow-up and treatment of acute ocular involvement can prevent long-term visual loss.
Fu Y, Gregory DG, Sippel KC, Bouchard CS, Tseng SCG. The Ophthalmologist’s Role in the Management of Acute Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Ocul Surf 2010;8(4):193–203.
Gueudry J, Roujeau J-C, Binaghi M, Soubrane G, Muraine M. Risk factors for the development of ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145(2):157–162.
Ciralsky JB, Sippel KC, Gregory DG. Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. Curr Opin Ophthalmol 2013;24(4):321–8.
Shay E, Kheirkhah A, Liang L, Sheha H, Gregory DG, Tseng SCG. Amniotic Membrane Transplantation as a New Therapy for the Acute Ocular Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Surv Ophthalmol 2009;54(6):686–96.
Shammas MC, Lai EC, Sarkar JS, Yang J, Starr CE, Sippel KC. Management of Acute Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Utilizing Amniotic Membrane and Topical Corticosteroids. Am J Ophthalmol 2010;149(2):203–213.e2.
Gregory DG. New Grading System and Treatment Guidelines for the Acute Ocular Manifestations of Stevens-Johnson Syndrome. Ophthalmology [Internet] 2016 [cited 2016 Jun 21];Available from: http://www.sciencedirect.com/science/article/pii/S0161642016302329
Hsu M, Jayaram A, Verner R, Lin A, Bouchard C. Indications and outcomes of amniotic membrane transplantation in the management of acute stevens-johnson syndrome and toxic epidermal necrolysis: a case-control study. Cornea 2012;31(12):1394–402.