Special Report: Stevens-Johnson syndrome

Special to Ophthalmology Times

Acute Stevens-Johnson syndrome with severe lid margin inflammation and sloughing of the palpebral conjunctiva. (Image courtesy of Darren Gregory, MD)

Stevens-Johnson syndrome (SJS) and its more severe variant, toxic epidermal necrolysis (TEN), are among the worst diseases of the ocular surface. However, they rarely present in daily practice, so ophthalmologists are unlikely to make the diagnosis. Despite their rarity, it is crucial for ophthalmologists to recognize the early ophthalmic signs of SJS/TEN so if either are suspected and ocular involvement is severe, timely referral can be made to a facility equipped to provide appropriate treatment.

SJS/TEN are immune-mediated diseases that are most commonly the result of an adverse drug reaction.¹ Antibiotics and anticonvulsants are among the most commonly implicated triggers. Early signs of SJS/TEN are sore throat, fever, and rash. If a patient has these symptoms and has recently started taking commonly implicated medications, including lamotrigine, allopurinol, sulfa antibiotics, or phenytoin, the suspicion for SJS/TEN should be high. Patients are often misdiagnosed with more common conditions and sent home from the emergency department or urgent care because SJS/TEN is usually not suspected until a blistering rash emerges.

Ocular involvement

The eyes are affected in most patients with SJS/TEN.^2,3 Epithelial sloughing and inflammation are characteristics of the disease, and these can involve the eyelid margins and eyelashes, the palpebral and bulbar conjunctiva, and the corneas. Damage to the ocular surface begins with widespread necrosis in the epidermal layers and is followed by intense inflammation. Even in cases where skin sloughing on other parts of the body is limited, ocular surface epithelial sloughing can be significant.^4,5

Therefore, regardless of the severity of overall skin involvement, it is important that all patients with acute SJS/TEN be evaluated by an ophthalmologist. The acute phase of the illness can vary in length but is typically equivalent to the duration of active blistering and epithelial sloughing.⁶ Sloughing and inflammation of the ocular mucosal epithelium during the acute phase of SJS/TEN can lead to scarring of the eyelids and ocular surface, resulting in pain and vision loss.⁷ The extent of epithelial sloughing of the conjunctiva and cornea determine the severity of the acute eye involvement and can guide management.⁸ Inflammation control is the top priority of treatment, and application of cryopreserved amniotic membrane (AM) during the acute phase of the disease controls inflammation and greatly decreases the occurrence of severe cicatricial sequelae and associated vision loss.^7,9,10

Cryopreserved amniotic membrane

Because ophthalmologists outside of large academic institutions rarely see patients with SJS/TEN, some may not be familiar with AM’s role in treatment. Increasing awareness about AM as an effective SJS/TEN treatment option is a priority for ophthalmologists like myself, who regularly care for patients with acute SJS/TEN. Two types of AMs are used for ophthalmic purposes: cryopreserved and dehydrated.

The cryopreservation process allows AM to retain heavy chain (HC) peptide, covalently conjugated with high-molecular-weight hyaluronic acid (HA), which is noncovalently complexed with pentraxin 3 (PTX3), forming HC-HA/PTX3. This biologic matrix is responsible for the anti-inflammatory and regenerative healing properties of cryopreserved amniotic membrane (CAM).¹¹ Although dehydrated AM is effective only for wound coverage, CAM suppresses inflammation by facilitating neutrophil apoptosis, polarizing M1 to M2 macrophages, and suppressing Th1 and Th17 lymphocyte activation.¹²

The use of CAM transplantation for the surgical treatment of SJS was first described by Thomas John et al, in 2002,¹³ and in 2004, Tseng reported that anti-inflammatory and antiscarring action resulted when CAM was used in the acute phase to treat these highly inflamed eyes.¹⁴ Since 2004, multiple reports in the literature and my own anecdotal experience illustrate that application of CAM to the eyes and eyelids early in the acute phase of SJS/TEN can limit the severity of ocular damage.⁸ Furthermore, an ophthalmology consult early in the acute phase, followed by aggressive use of CAM, can substantially reduce the visual morbidity of SJS/TEN in the chronic phase.^9,10

The consensus is that, in cases with severe eye involvement, AM should be applied within 1 week of the onset of eye inflammation.⁶ Because there is little risk with the CAM procedure but significant risk in forgoing the application of CAM in a patient who might need it, erring on the side of treatment is recommended in cases of borderline severity.

At our facility, we prefer to perform CAM transplantation under an operating microscope in an operating room whenever possible.

We use half of a 3.5-cm2 sheet of CAM (AmnioGraft; BioTissue, Inc) on each eyelid and a full 3.5-cm2 AM sheet, or a Prokera (BioTissue, Inc), on the ocular surface. A Prokera is a thin, 16-mm–diameter plastic ring with a sheet of AM stretched across the lumen of the ring. Prokera is placed over the cornea like a contact lens. With Prokera, the AM portion only covers the cornea and perilimbal conjunctiva, so it should only be used in cases that have limited bulbar conjunctival sloughing. AmnioGraft (or larger custom-ordered CAM sheets) should be used when more extensive coverage of the bulbar conjunctiva is necessary. However, regardless of the exact technique, the AM should cover the lid margins, palpebral conjunctiva, and ocular surface, including the cornea.

Transporting these critically ill patients to an operating room may be challenging or even impossible, so having bedside options is beneficial. Additionally, increasing the simplicity and ease of CAM transplantation may foster more widespread adoption of the procedure. The bedside methods use a single large sheet of CAM that is initially positioned over the eyelids and eye. It is then sutured or glued to the skin of the lower eyelid, then folded up and over the lid margin into the fornix, where it is held in place by a ring-shaped conformer constructed from pliable, small-bore intravenous tubing.^15,16

Postoperative care

Postoperatively, tobramycin/dexamethasone ointment should be applied to the eyelid margins and eyelashes 4 times per day to minimize inflammation and to prevent desiccation of the lid margin AM. Educating the nursing staff on the proper application of the ointment and its importance is essential.

An ophthalmologic exam must be performed daily that includes rinsing the eyes with sterile saline to remove the buildup of ointment and serosanguinous debris. The corneas should be evaluated for the presence of infiltrates under the AM. The AM can be moved with a cotton-tipped swab. If a whitish area does not move along with the membrane. It may be a corneal infiltrate and should be examined.

Topical quinolone drops and corticosteroid drops are also applied 4 times per day. In most cases, the AMs degrade after approximately a week, so the drops should be reapplied if there are areas of persistent severe inflammation.

Patient access to SJS/TEN eye care

There is still a lot of room for improvement in the eye care of patients with acute SJS. A recent survey noted that only 66% of burn intensive care units in the United States routinely seek an ophthalmologic consultation for patients with acute SJS/TEN.¹⁷ This must improve, and efforts are underway to accomplish this.

First, through conferences and publications, education at burn centers and in the ophthalmology community regarding the current eye care recommendations for acute SJS is being improved. Secondly, a list of regional referral centers that are equipped to perform CAM transplantation on an urgent basis must be compiled and distributed so ophthalmologists across the country will know where to refer patients with acute SJS with severe eye involvement. Finally, ophthalmologists must be able to recognize significant ocular involvement in SJS/TEN so they can advocate for these patients to be transferred to a center where they can get higher-level care when needed.

Darren Gregory, MD

E: darren.gregory@cuanschutz.edu

P: 720-848-2020

Darren G. Gregory, MD, is affiliated with UCHealth Sue Anschutz-Rodgers Eye Center and is an associate professor of ophthalmology at the University of Colorado School of Medicine in Aurora.

References

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2. Yip LW, Thong BY, Lim J, et al. Ocular manifestations and complications of Stevens-Johnson syndrome and toxic epidermal necrolysis: an Asian series. Allergy. 2007;62(5):527-531. doi:10.1111/j.1398-9995.2006.01295.x

3. López-García JS, Rivas Jara L, García-Lozano CI, Conesa E, de Juan IE, Murube del Castillo J. Ocular features and histopathologic changes during follow-up of toxic epidermal necrolysis. Ophthalmology. 2011;118(2):265-271. doi:10.1016/j.ophtha.2010.06.035

4. Gueudry J, Roujeau JC, 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. doi:10.1001/archdermatol.2009.540

5. Morales ME, Purdue GF, Verity SM, Arnoldo BD, Blomquist PH. Ophthalmic manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis and relation to SCORTEN. Am J Ophthalmol. 2010;150(4):505-510.e1. doi:10.1016/j.ajo.2010.04.026

6. Kohanim S, Palioura S, Saeed HN, et al. Acute and chronic ophthalmic involvement in Stevens-Johnson syndrome/toxic epidermal necrolysis - a comprehensive review and guide to therapy. II. ophthalmic disease. Ocul Surf. 2016;14(2):168-188. doi:10.1016/j.jtos.2016.02.001

7. Gregory DG. The ophthalmologic management of acute Stevens-Johnson syndrome. Ocul Surf. 2008;6(2):87-95. doi:10.1016/s1542-0124(12)70273-2

8. Gregory DG. New grading system and treatment guidelines for the acute ocular manifestations of Stevens-Johnson syndrome. Ophthalmology. 2016;123(8):1653-1658. doi:10.1016/j.ophtha.2016.04.041

9. Shanbhag SS, Hall L, Chodosh J, Saeed HN. Long-term outcomes of amniotic membrane treatment in acute Stevens-Johnson syndrome/toxic epidermal necrolysis. Ocul Surf. 2020;18(3):517-522. doi:10.1016/j.jtos.2020.03.004

10. Gregory DG. USA: ophthalmologic evaluation and management of acute Stevens-Johnson syndrome. Front Med (Lausanne). 2021;8:670643. doi:10.3389/fmed.2021.670643

11. Cooke M, Tan EK, Mandrycky C, He H, O’Connell J, Tseng SC. Comparison of cryopreserved amniotic membrane and umbilical cord tissue with dehydrated amniotic membrane/chorion tissue. J Wound Care. 2014;23(10):465-476. doi:10.12968/jowc.2014.23.10.465

12. Jirsova K, Jones GLA. Amniotic membrane in ophthalmology: properties, preparation, storage and indications for grafting-a review. Cell Tissue Bank. 2017;18(2):193-204. doi:10.1007/s10561-017-9618-5

13. John T, Foulks GN, John ME, Cheng K, Hu D. Amniotic membrane in the surgical management of acute toxic epidermal necrolysis. Ophthalmology. 2002;109(2):351-360. doi:10.1016/s0161-6420(01)00900-9

14. Tseng SC, Espana EM, Kawakita T, et al. How does amniotic membrane work?. Ocul Surf. 2004;2(3):177-187. doi:10.1016/s1542-0124(12)70059-9

15. Ma KN, Thanos A, Chodosh J, Shah AS, Mantagos IS. A novel technique for amniotic membrane transplantation in patients with acute Stevens-Johnson syndrome. Ocul Surf. 2016;14(1):31-36. doi:10.1016/j.jtos.2015.07.002

16. Shanbhag SS, Chodosh J, Saeed HN. Sutureless amniotic membrane transplantation with cyanoacrylate glue for acute Stevens-Johnson syndrome/toxic epidermal necrolysis. Ocul Surf. 2019;17(3):560-564. doi:10.1016/j.jtos.2019.03.001

17. Le HG, Saeed H, Mantagos IS, Mitchell CM, Goverman J, Chodosh J. Burn unit care of Stevens Johnson syndrome/toxic epidermal necrolysis: a survey. Burns. 2016;42(4):830-835. doi:10.1016/j.burns.2015.12.001