Stevens-Johnson Syndrome

Dangerous
Didn't play the corresponding interactive case or want to try it again? Click here to do so.

Diagnosis and reasoning

The spectrum of medical emergencies encompasses virtually every clinical specialty and subspecialty; of these, some are extremely common, while others are very rare; of necessity, the emergency physician must be prepared to handle all of them. The patient in this case is an excellent example in point. Even a cursory glance shows that her symptoms are primarily dermatological in nature; the question lies in determining which condition or conditions might be the likely culprit(s). Clinical dermatology is very often an exercise in pattern matching; thus a careful history and through examination are essential. This reveals several important findings: - Bilateral non-exudative conjunctivitis - Extensive involvement of the oral mucosa, with multiple hemorrhagic erosions - Multiple, tender macules on the trunk and limbs Considering the above, key possibilities include viral exanthems, fixed drug eruptions, erythema multiforme (EM), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and perhaps staphylococcal scalded skin syndrome (SSSS). Viral exanthems and fixed drug eruptions are clinically less likely, as the oral lesions encountered in these are rarely hemorrhagic or erosive. SSSS is very rare in this age group, with 98% of cases occurring in children 6 years or less; nevertheless, this should be kept in mind if the other possibilities are excluded. EM is a possibility; however typical or atypical raised 'target' lesions are present in most such patients, while such extensive involvement of the body surface area (BSA) would be distinctly unusual. In addition, note that the Nikolsky sign is negative in these patients. SJS/TEN are not only possible, but also highly probable; note that NSAIDs such as Ibuprofen are well known to cause the disease, while the time interval since initiation of therapy is also compatible. SJS/TEN is a dermatological emergency with a high mortality and morbidity; once this is clinically suspected, treatment should be commenced immediately. A skin biopsy will confirm the clinical diagnosis; however, treatment should never be delayed pending biopsy results. Note also that SJS and TEN can only be differentiated by determining the maximum extent of skin involvement during the entire course of the disease; as she has presented relatively early, the lesions may yet expand further. It should also be appreciated that these lesions will subsequently progress into bullae formation and outright desquamation; as the deleterious effects of skin loss are similar to those encountered in a burns patient, she should be referred to a burns unit early on, for expert care. Ocular complications are very common, and a cause of considerable long-term morbidity (including outright blindness); early referral to an ophthalmologist and subsequent coordination of care is associated with markedly better outcomes. Her mortality risk should be determined via the SCORTEN system; this requires measurement of serum glucose, urea and bicarbonate levels. Fortunately, her score amounts to only 1 point, which indicates a low risk of mortality. Last but not least, as Ibuprofen appears to be the causative drug, this should be stopped at once; it is probably prudent to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) as a whole, and use other agents for analgesia. The use of system corticosteroids in SJS/TEN is controversial, with studies showing little or no benefit; while topical antibiotics may be used to prevent secondary skin infections (if raw areas are present), systemic antibiotic therapy is rarely justifiable.


Discussion

Stevens-Johnson Syndrome (SJS) is an acute cutaneous reaction characterized by extensive blistering and shedding of the skin; it is closely related to toxic epidermal necrolysis (TEN), which is believed to be a more severe variant of the same condition. Overall, SJS is rare, with an incidence of 1 to 2 per 1,000,000 individuals per year in the United States; the disease can strike at any age, and affects all racial groups. In the vast majority of cases, SJS is a complication of medication use, with the disease typically developing within the first month of therapy; while most often associated with oral or parenteral dosage, the disease has been known to occur following topical use. The most common drugs implicated include allopurinol; sulfonamide antibiotics such as trimethoprim-sulfamethoxazole; beta-lactam antibiotics such as penicillins and cephalosporins; quinolones; anticonvulsants such as carbamazepine, phenytoin, phenobarbital, and valproic acid; and non steroidal anti-inflammatory drugs (NSAIDs) including naproxen, ibuprofen, and the oxicams. Less often, SJS may be triggered by viral, bacterial or fungal infections. Human Immunodeficiency Virus (HIV) infection is an independent risk factor for SJS; this is magnified by the fact that many of these patients are on a cocktail of drugs. There is also evidence that certain individuals may be genetically predisposed to develop the condition; known phenotypes include the human leukocyte antigens (HLA)-B12 and HLA-B*1502. The pathogenesis of SJS is not fully understood, although it is believed to be immune-mediated, as re-challenging an individual with the same drug can result in rapid recurrence of the disease. Affected individuals often experience a prodrome of a few days, resembling a mild upper respiratory tract infection. This is followed by the abrupt development of skin lesions, usually in the presternal region of the trunk and face, as well as the palms and soles. The skin lesions typically manifest as generalized erythematous macules which may have purpuric centers; these then progress to large confluating blisters with subsequent epidermal detachment. In the following 3 to 5 days, separation of the epidermis progresses, resulting in large denuded areas. A positive Nikolsky sign is often present; in this, tangential mechanical pressure is exerted in several erythematous zones, with subsequent epidermal detachment characterized by the development of blisters constituting a positive sign. Note however that the Nikolsky sign is not specific to SJS, as it may be positive in autoimmune bullous diseases. The buccal, genital and/or ocular mucosa are involved in more than 90% of patients, and in some cases the respiratory and gastrointestinal tracts are also affected. Ocular involvement can range from acute conjunctivitis, eyelid edema, erythema, crusts, and ocular discharge, to conjunctival membrane or pseudomembrane formation or corneal erosion, and, in severe cases, to cicatrizing lesions, symblepharon, fornix foreshortening, and corneal ulceration. SJS is diagnosed clinically, and confirmed histologically; the presence of widespread necrosis of the epidermis involving all layers confirms the diagnosis. Direct immunofluorescence staining should be performed to rule out autoimmune blistering diseases; there should be no immunoglobulin or complement deposition in the epidermis or dermoepidermal zone. Note that SJS is differentiated from TEN via the degree of skin detachment at the time of maximum extent; SJS is defined as skin detachment involving less than 10% of the body surface area (BSA), while TEN is defined as skin detachment involving more than 30% of the BSA. Detachment of between 10% to 30% of the BSA is defined as overlap SJS/TEN. It should be appreciated that that as skin detachment progresses over several days, it may be impossible to determine if the patient has SJS or TEN during the early stages. As soon as the diagnosis of SJS or TEN has been established, the severity and prognosis of the disease should be determined; this can be established via the SCORTEN disease severity scoring system: - Age >40 years - Malignancy - Tachycardia (>120 bpm) - Epidermal detachment >10% - Serum Urea >10 mmol/L - Serum Glucose >14 mmol/L - Bicarbonate < 20 mmol/L Each variable present counts as 1 point; individuals who score 3 points or more are at high risk of mortality and should be managed in an intensive care setting. The acute management of SJS includes withdrawal of the culprit drugs, rapid initiation of supportive care, and in some cases, adjuvant drug therapy. A detailed drug history should be obtained, and the likely causative drug(s) identified if possible; the earlier the causative agent is withdrawn, the better the eventual prognosis. Careful management of fluid and electrolyte requirements is crucial, given the loss of epidermal barrier function; hyponatremia, hypokalemia and hypophosphatemia are frequently present, and should be managed aggressively. The skin lesions should be treated conservatively, without skin debridement, as the blistered skin acts as a natural biological dressing which favors re-epithelialization. Non-adhesive wound dressings should used when required. Note that early transfer to a burn unit, where experienced personnel can provide aggressive skin care, has been shown to positively influence survival. Urgent referral to an ophthalmologist is mandatory, as visual outcomes are best in individuals who receive specific ophthalmological treatment during the first week of disease. Adequate pain relief and psychological support should not be forgotten. While secondary infection of the skin should be excluded via swab cultures, prophylactic antibiotics in the absence of infection are unnecessary, and may even be harmful, by promoting the growth of resistant bacteria. Unfortunately, no single adjuvant agent has demonstrated uniform efficacy in controlled clinical trials. However, case series and non-controlled studies have shown that intravenous immunoglobulins (IVIG), Cyclosporin A, and Cyclophosphamide may be efficacious in these patients. While plasmapheresis and treatment with tumor necrosis factor (TNF) antagonists have also been attempted, there is yet insufficient data to draw a conclusion on their efficacy. Note that controlled trials have not shown any benefit from systemic steroids; in addition, therapy with the immunomodulator thalidomide paradoxically resulted in increased mortality. SJS is a life-threatening disease, with a mortality rate ranging from 1% to 5%; there is also significant long-term morbidity, including symblepharon, conjunctival synechiae, entropion, ingrowth of eyelashes, cutaneous scarring, irregular pigmentation, eruptive nevi, persistent erosions of the mucous membranes, phimosis, vaginal synechiae, nail dystrophy, and diffuse hair loss.


Take home messages

  1. SJS is diagnosed clinically, and confirmed by biopsy.
  2. Ocular complications are common in these patients; early referral to an ophthalmologist is mandatory.
  3. Early transfer to a specialized burns unit is associated with better outcomes in these patients.

Insightful, fun cases to improve your diagnostic skills

Use your detective skills, strengthen fundamentals faster, and access a wealth of knowledge.

  1. Am Fam Physician. 2010 Oct 1;82(7):773-80. Dermatologic emergencies. Usatine RP, Sandy N.
  2. Ann Allergy Asthma Immunol. 2005 Apr;94(4):419-36; quiz 436-8, 456. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Letko E, Papaliodis DN, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS.
  3. Crit Care Med. 2011 Jun;39(6):1521-32. doi: 10.1097/CCM.0b013e31821201ed. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Gerull R, Nelle M, Schaible T.
  4. Dermatol Ther. 2011 Mar-Apr;24(2):207-18. doi: 10.1111/j.1529-8019.2011.01396.x. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options. Worswick S, Cotliar J.
  5. Int J Dermatol. 2012 Aug;51(8):889-902. doi: 10.1111/j.1365-4632.2011.05348.x. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Sokumbi O, Wetter DA.
  6. J Am Acad Dermatol. 2013 Aug;69(2):173.e1-13; quiz 185-6. doi: 10.1016/j.jaad.2013.05.003. Toxic epidermal necrolysis: Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. Schwartz RA, McDonough PH, Lee BW.
  7. J Am Acad Dermatol. 2013 Aug;69(2):187.e1-16; quiz 203-4. doi: 10.1016/j.jaad.2013.05.002. Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. Schwartz RA, McDonough PH, Lee BW.
  8. Orphanet J Rare Dis. 2010 Dec 16;5:39. doi: 10.1186/1750-1172-5-39. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Harr T, French LE.
  9. Pediatr Ann. 2010 Oct;39(10):667-9, 672-4. doi: 10.3928/00904481-20100922-11. Stevens-Johnson syndrome and toxic epidermal necrolysis. Treat J.