Enhancing Treatment of Acute Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis with Cryopreserved Amniotic Membrane

By Charles Bouchard, MD

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are systemic inflammatory conditions characterized by mucocutaneous tenderness, blistering, and sloughing of the skin and mucus membranes, including at the ocular surface.^1–3 Both conditions are rare, with an estimated incidence rate of 1 to 7 cases per million person-years.⁴ Stevens-Johnson syndrome and TEN are considered medical emergencies; the average mortality rate for SJS is 1% to 5% and, for TEN, as high as 25% to 35%.¹ Stevens-Johnson syndrome and TEN are considered 2 ends of a single disease spectrum, differing by the amount of body surface involved. Stevens-Johnson syndrome affects <10% of the total body surface area (TBSA), TEN involves more than 30% of the TBSA, and overlap SJS/TEN affects between 10% and 30% TBSA.⁵

Most SJS/TEN cases can be attributed to genetic predisposition and drug hypersensitivity, with about 5% to 20% of cases being idiopathic.^1,6,7 In previous genetics studies, a strong association has been identified between the HLA-B*1502 allele and carbamazepine-induced SJS/TEN in Han Chinese and Thai populations.^8,9 A second strong association has been reported between the HLA-B*5801 allele and allopurinol-induced SJS/TEN.¹ More than 100 medications have been linked to the development of SJS/TEN, including many antibiotics and sulfa-containing compounds.⁶

The pathogenesis of SJS/TEN has received considerable attention in the past decades, but its exact mechanism remains unclear.¹⁰ Onset is primarily driven by inflammatory processes, characterized by the aggregation of cytotoxic CD8+ T lymphocytes in blister fluids that coincide with lesions that exhibit keratinocyte apoptosis histopathologically.¹ While specific drugs are often responsible for triggering SJS/TEN, their exact role in the disease process is still under investigation.

Stevens-Johnson syndrome/TEN primarily affects the skin and mucous membranes, including the conjunctival mucosa. In the acute stage of these conditions (0‑3 months after symptom onset), bilateral conjunctivitis has been reported in 15% to 75% of patients, and ulcerations of the conjunctiva and/or cornea have been reported in 25% of patients.^2,11 Ocular manifestations in the subacute stage (3‑6 months) involve persistent ocular surface inflammation, corneal epithelial defects, dry eye, and eyelid margin keratinization.^12,13 In the chronic stage (>6 months), up to 35% of patients with SJS/TEN develop chronic ocular sequelae characterized by persistent inflammation and ulceration, leading to limbal stem cell deficiency, ocular surface failure, and severe vision loss.^3,14,15

Diagnosing and Managing SJS/TEN
Broadly, the diagnosis of SJS/TEN relies on a combination of clinical signs and histological examination. Suspected cases—typically based on mucocutaneous features—can be confirmed in a skin biopsy by the presence of necrotic epidermal tissue and inflammatory processes.³

On the ocular surface, SJS and TEN are complex, multifactorial disorders that may manifest in a variety of ways. To rate SJS/TEN severity, ocular grading systems for both the acute and chronic disease stages have been introduced, categorizing cases based on the degree of corneal, conjunctival, and eye margin involvement.^3,16-18 In addition to assessing a patient’s SJS/TEN signs and symptoms, these grading systems are also important for guiding treatment decisions.

Because they are fulminant and life-threatening diseases, SJS and TEN require immediate medical intervention. Unfortunately, ophthalmologists may not be engaged during early disease management due to the severity of these systemic conditions. Because of the critical window of opportunity in the first week of disease onset, however, early and aggressive ocular medical and surgical intervention is crucial to reduce long-term ocular complications and preserve vision.

The initial treatment of acute ocular surface disease in SJS/TEN typically involves an aggressive regimen of topical corticosteroids and broad-spectrum antibiotics to reduce local inflammation.^2,3 For example, prednisolone acetate eye drops should be administered every hour, along with fluoroquinolone antibiotic eye drops 4 to 6 times a day. A steroid ointment can also be applied as a slow-release agent to further reduce inflammation in the meibomian glands and eyelids.^18,19

During the subacute and chronic stages of SJS/TEN, treatment focuses on using medical and surgical approaches to reduce inflammation, correct lid margin abnormalities, and improve visual function.^{2,11,15,19,20} Treatment options in late-stage SJS/TEN include therapeutic contact lenses, stem cell transplantation, and mucus membrane grafting.^21,22 Managing late-stage SJS/TEN is typically more challenging, further emphasizing the importance of early treatment and prevention.^13,15,17

Managing SJS/TEN with CAM
In addition to topical drugs, amniotic membrane (AM) transplantation is an established therapy for acute SJS/TEN-associated ocular surface conditions.^16,23-26 AM has natural healing, anti-inflammatory, and anti-scarring properties, making it effective in treating a variety of ocular surface disorders.²⁷ To minimize disease progression in SJS/TEN, AM transplantation should be performed as early as possible, ideally within the first week after symptom onset.^16,19,19,26 Furthermore, AM should highly considered for SJS/TEN cases, as the SJS/TEN disease trajectory is highly variable with potentially irreversible ocular consequences.

Different types of AM are available, including dehydrated AM, cryopreserved AM (CAM), and CAM-incorporated corneal bandage (Prokera; BioTissue, Inc). Compared to dehydrated AM, the cryopreservation process used to manufacture CAM is better at maintaining the structural integrity of the tissue and preserving key therapeutic biomolecules. CAM is also the only membrane available in the size needed for the management of SJS/TEN (5×10 cm).

Unlike many other ocular surface disorders that can be effectively treated with Prokera, SJS/TEN involves inflammation in the eyelid margin, which plays an important role in SJS/TEN pathology and can lead to keratinization and ocular surface degeneration.¹⁵ While Prokera is easy to use, it has limited efficacy in addressing underlying lid inflammation in SJS/TEN. In the management of SJS/TEN, however, CAM is preferred overall due to its versatility in placement, but it requires sophisticated surgical procedures and experienced surgeons.

There are 2 common approaches to CAM transplantation surgery. In one approach, CAM is sutured to the upper and lower lids with the support of a symblepharon ring.²³ Positive results have been reported with this approach,²⁸ but it can be time consuming and requires an operating microscope.¹¹ The second approach is sutureless and relies on the use of an adhesive, such as fibrin glue²⁹ or cyanoacrylate glue,^15,26,30 to affix CAM to the eyelid margins. This procedure can be performed at the bedside without sedation, although anesthesia may still be necessary for young children.¹³

Patients with SJS/TEN and their family members should be consulted before undergoing any CAM transplant, as the procedure causes opaque eyes and temporary vision loss. In addition, multiple transplants may be necessary depending on tissue response and the severity of local inflammation.

When transplanted during the acute phase of the SJS/TEN, AM has demonstrated effectiveness in reducing ocular complications and improving postoperative visual outcomes.^26,31 Clinical studies further support the positive effects of AM, with patients who receive AM treatment typically having better visual outcomes.^25,32

Limited Resources Requires Increased Awareness
Despite significant advancements in our understanding of pathology and surgical techniques, treating SJS/TEN remains challenging.¹⁰ Due to the rarity of these disorders, the amount of surgical expertise and educational materials available for patients and families are limited. Efforts are underway to streamline the process of connecting patients with nearby SJS/TEN specialists.

Additionally, our center is working to share and distribute an educational brochure that supports the practitioners, patients, and family members who wish to enhance their understanding of SJS/TEN and its management.^33,34 With increased awareness and improved treatment approaches, I am hopeful that, in the near future, we will have a better understanding of SJS/TEN, wider availability of genetic screening for at-risk patients, and urgent referrals to institutions with well-equipped burn centers staffed with ophthalmologists trained on AM grafting.

References

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