Approach Considerations
Management of patients with Stevens-Johnson syndrome usually is provided in intensive care units or burn centers. No specific treatment of Stevens-Johnson syndrome is noted; therefore, most patients are treated symptomatically. In principle, the symptomatic treatment of patients with Stevens-Johnson syndrome does not differ from the treatment of patients with extensive burns.
Prehospital and emergency department care
Paramedics should recognize the presence of severe fluid loss and should treat patients with Stevens-Johnson syndrome as they would patients with thermal burns.
Most patients present early and prior to obvious signs of hemodynamic compromise. The single most important role for the ED physician is to detect Stevens-Johnson syndrome/toxic epidermal necrolysis early and initiate the appropriate ED and inpatient management.
Withdrawal of the suspected offending agent is critically important. Timing of withdrawal has been linked to outcome. Underlying diseases and secondary infections must be identified and treated.
Patients should be treated with special attention to airway and hemodynamic stability, fluid status, wound/burn care, and pain control. Care in the ED must be directed to fluid replacement and electrolyte correction. Treatment is primarily supportive and symptomatic. Some have advocated corticosteroids, cyclophosphamide, plasmapheresis, hemodialysis, and immunoglobulin.
Manage oral lesions with mouthwashes. Topical anesthetics are useful in reducing pain and allowing the patient to take in fluids.
Skin lesions are treated as burns. Areas of denuded skin must be covered with compresses of saline or Burow solution.
Address tetanus prophylaxis.
Supportive Systemic Therapy
Fluid management is provided by macromolecules and saline solutions during the first 24 hours. Phosphate salts are necessary in the presence of hypophosphatemia. The amount of fluids required in patients with Stevens-Johnson syndrome is usually less than in those patients with burns covering the same body surface area.
After the second day of hospitalization, oral intake of fluids provided by nasogastric tube often is begun, so that intravenous fluids can be tapered progressively and discontinued, usually in 2 weeks.
Massive parenteral nutrition is necessary as soon as possible to replace the protein loss and to promote healing of cutaneous lesions. Intravenous insulin therapy may be required because of impaired glycoregulation.
Environmental temperature raised to 30-32°C reduces caloric loss through the skin. Fluidized air beds are recommended if a large portion of the skin on the patient's backside is involved. Heat shields and infrared lamps are used to help reduce heat loss.
Anticoagulation with heparin for the duration of hospitalization is recommended. Antacids reduce the incidence of gastric bleeding.
Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Tranquilizers are used to the extent limited by respiratory status.
Infection Control
Patients with Stevens-Johnson syndrome are at a high risk for infection. Sterile handling and/or reverse-isolation nursing techniques are essential to decrease the risk for nosocomial infection. Cultures of blood, catheters, gastric tubes, and urinary tubes must be performed regularly.
Because of the association between Stevens-Johnson syndrome and sulfonamides, avoid the use of silver sulfadiazine, which is commonly used in burn units. Instead, use another antiseptic, such as 0.5% silver nitrate or 0.05% chlorhexidine, to paint and bathe the affected skin areas.
Prophylactic systemic antibiotics are not recommended. Antimicrobials are indicated in cases of urinary tract or cutaneous infections, either of which may lead to bacteremia.
The diagnosis of sepsis is difficult. Carefully consider the decision to administer systemic antibiotics. The first signs of infection are an increase in the number of bacteria cultured from the skin, a sudden drop in fever, and deterioration of the patient's condition, indicating the need for antibiotic therapy.
The choice of antibiotic is usually based on the bacteria present on the skin. Because of impaired pharmacokinetics, similar to that present in burn patients, the administration of high doses may be required to reach therapeutic levels. Monitoring the serum levels is necessary to adjust the dosage.
Skin Care
Several skin care approaches have been described. Extensive debridement of nonviable epidermis, followed by immediate cover with biologic dressings, are among the recommended treatments. Biologic dressings may include the following:
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Porcine cutaneous xenografts
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Cryopreserved cutaneous allografts
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Amnion-based skin substitutes
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Collagen-based skin substitutes
The ophthalmology literature supports concurrent coverage of the involved eye(s) with amniotic membrane. [35]
Leaving the involved epidermis that has not yet peeled off in place and using biologic dressings only on raw dermis also has been recommended. Skin allotransplantation reduces pain, minimizes fluid loss, improves heat control, and prevents bacterial infection. Hyperbaric oxygen can also improve healing.
Immunomodulatory Therapy
Stevens-Johnson syndrome is a rare disorder with relatively high mortality and morbidity rates. To date, because of a lack of consensus on the proposed therapeutic modalities, intensive supportive management and withdrawal of the offending drug remain the criterion standard.
For any intervention, a prospective randomized controlled trial would be the most appropriate step to validate its use. However, a large number of patients are required to reach statistical significance. Furthermore, for ethical reasons, withdrawal of a potentially life-saving therapy for the sake of randomization with a placebo control is not possible.
Several therapeutic modalities have been advocated for the treatment of Stevens-Johnson syndrome based on the current, yet incomplete, understanding of its pathogenetic mechanisms. Plasmapheresis, immunosuppressive therapy, and intravenous immunoglobulin (IVIG) have been used with variably successful results.
The use of systemic steroids remains controversial. Some authors believe that they are contraindicated, especially because there may be some question about the diagnosis. Patients with infection-induced erythema multiforme do worse when steroids are given. (Note that the differentiation between Stevens-Johnson syndrome and erythema multiforme should be possible even in the acute stage.) [36] Prolonged treatment with systemic steroids has been associated with an increased prevalence of complications.
However, concerns about the safety of systemic corticosteroids in the treatment of Stevens-Johnson syndrome are based on a few case series; in those reports, systemic corticosteroids were administered too late in the course of the disease, in inappropriately low doses, and for a very long duration that actually impaired the healing process and increased the risk for sepsis. The currently advocated approach for corticosteroid use suggests the early use of short-term (4-7 days), high-dose intravenous corticosteroids. [37, 38]
The ophthalmology literature contains several papers that advocate systemic and topical steroids to minimize ocular morbidity. [39, 40] Authors have cited salvage of vision when pulse steroid therapy has been given. [36, 40] Others have concluded that IV steroids and immunoglobulins do not improve outcome. [41]
The role of other immunosuppressive therapy, that is, cyclosporine, azathioprine, or cyclophosphamide, in the acute phase is less popular, particularly since such medication typically takes weeks to begin to influence immunologic reactions. Cyclophosphamide has been reported to be the culprit drug that induced Stevens-Johnson syndrome in one instance. [42]
Nevertheless, the role of cyclosporine in the treatment of the acute phase of Stevens-Johnson syndrome has been revisited, and, indeed, it showed encouraging results. [10] Also, immunosuppressive therapy may play a pivotal role in the management of the chronic ocular surface inflammation that can occur later on in selected cases.
The rationale for the use of IVIG is the most appealing. Based on in vitro and clinical data, IVIG can block the Fas receptors on the surface of the keratinocytes, thus interfering with the Fas-Fas ligand mediated apoptosis. [43] Encouraging results were reported when IVIG was used in high doses very early in the course of the disease and for a short period. Unfortunately, there is no consensus regarding either the dose or the duration of treatment with IVIG. [6]
Prophylactic use of IVIG has been reported. One group used IVIG in a patient who underwent cardiac catheterization but who had 4 previous Stevens-Johnson syndrome episodes after intravenous contrast injection. [44]
However, a large European study designed to evaluate the efficacy of various treatments, the EuroSCAR Study, "found no sufficient evidence of a benefit for any specific treatment." [45] The group looked at mortality in patients treated with IVIG and corticosteroids. However, in a letter to the editor, Pehr disagreed with the findings in the EuroSCAR study citing inadequate doses of IVIG and corticosteroids in that study. [46]
Interestingly, few studies have addressed the effect of systemic steroids or IVIG on either the development or the outcome of ocular manifestations in Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Neither treatment appeared to influence the ocular outcome in patients in 2 reports. [47, 2]
Treatment of Acute Ocular Manifestations
Treatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface. As inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and mechanical symblepharon lysis.
In case of exposure keratopathy, tarsorrhaphy may be required.
Maintenance of ocular integrity can be achieved through the use of amniotic membrane grafting, adhesive glues, lamellar grafts, and penetrating keratoplasty, either in the acute phase or in subsequent follow-up care.
Visual rehabilitation in patients with visual impairment can be considered once the eye has been quiet for at least 3 months.
Treatment of Chronic Ocular Manifestations
In the case of mild chronic superficial keratopathy, long-term lubrication may be sufficient. In addition to lubrication, some patients may require a cosmetically acceptable long-term lateral tarsorrhaphy.
The visual rehabilitation in patients with severe ocular involvement, resulting in profound dry eye syndrome with posterior lid margin keratinization, limbal stem cell deficiency, persistent epithelial defects with subsequent corneal neovascularization, and frank corneal opacity with surface conjunctivalization and keratinization, is difficult and often frustrating for both the patient and the physician. A close, usually long-term, relationship between the patient and the ophthalmologist needs to be established to achieve the best possible result.
The removal of keratinized plaques from the posterior lid margins, along with mucous membrane grafting and/or amniotic membrane grafting, is usually the first step and one of the most important determining factors in the future success of corneal surgeries. Preferably, a skilled oculoplastic surgeon with specific experience on patients with Stevens-Johnson syndrome should perform this procedure.
Subsequently, limbal stem cell transplantation and amniotic membrane grafting with superficial keratectomy removing conjunctivalized or keratinized ocular surface can follow. Patients with persistent corneal opacity require lamellar or penetrating keratoplasty in the next step, but each exposure to alloantigenic material increases the odds of tissue rejection. Therefore, the author’s advice is to strive for major, if not perfect, resurrection of the useful vision, rather than perform allografts of both eyes and keratoplasties.
To preserve corneal clarity after the visual reconstruction, the long-term use of gas-permeable scleral contact lenses may be necessary to protect the ocular surface. Large-diameter gas-permeable prosthetic lenses specifically designed to vault over the entire corneal surface and rest on the sclera have provided both comfort and better visual acuity in selected cases. A special liquid fills the space between the back surface of the lens and the front surface of the cornea. This liquid acts as a buffer and protects the compromised corneal tissue.
Long-term management frequently involves the treatment of trichitic lashes and/or eyelid margin repair for distichiasis or entropion. If the ocular surface repeatedly fails to heal after multiple surgical interventions, keratoprosthesis may be considered as a last resort
Consultations and Long-Term Monitoring
Consultants may help establish the diagnosis and direct inpatient care. A dermatologist is the most likely clinician to establish the diagnosis, with or without biopsy. Severe cases may require the involvement of a burn specialist or plastic surgeons, internal medicine, critical care, or pediatrics consultants to direct inpatient care. Ophthalmology consultation is mandatory for those with ocular involvement. Depending on organ system involvement, consultations with a gastroenterologist, pulmonologist, and nephrologist may be helpful.
Patients with SJS require regular monitoring of their medications and status. Although patients with erythema multiforme minor may be treated as outpatients with topical steroids, those with erythema multiforme major (ie, Stevens-Johnson syndrome) must be hospitalized. Cases of erythema multiforme minor must be followed closely. Some authors recommend daily follow-up.
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A patient with severe eye involvement associated with Stevens-Johnson syndrome. Note corneal neovascularization and conjunctivalization of the ocular surface.
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Epithelial defect of the cornea with neovascularization and surface conjunctivalization.
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Note extensive sloughing of epidermis from Stevens-Johnson syndrome. Courtesy of David F. Butler, MD.
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Sheetlike desquamation on the foot in a patient with toxic epidermal necrolysis. Courtesy of Robert Schwartz, MD.
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Hemorrhagic crusting of the mucous membranes in toxic epidermal necrolysis. Similar lesions are seen in Stevens-Johnson syndrome. Courtesy of Robert Schwartz, MD.
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Note early cutaneous slough with areas of violaceous erythema.
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Extensive sloughing on the face.
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Note the presence of both 2-zoned atypical targetoid lesions and bullae.
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Extensive blistering and sloughing on the back.
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Extensive sloughing on the back.
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Note extensive sloughing.
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Low-power view showing full-thickness epidermal necrosis.
