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ARTICLES: Natacha Levi, Sylvie Bastuji-Garin, Maja Mockenhaupt, Jean-Claude Roujeau, Antoine Flahault, Judith P. Kelly, Elvira Martin, David W. Kaufman, and Patrick Maison Medications as Risk Factors of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Children: A Pooled Analysis Pediatrics 2009; 123: e297-e304 [Abstract] [Full text] [PDF]

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Stevens-Johnson syndrome with ocular sequelae

Mayumi Ueta, Chie Sotozono, Shigeru Kinoshita   (29 April 2009)

Stevens-Johnson syndrome with ocular sequelae 29 April 2009
Mayumi Ueta, ophthalmologist Kyoto Prefectural University of Medicine, Chie Sotozono, Shigeru Kinoshita Send letter to journal: Re: Stevens-Johnson syndrome with ocular sequelae mueta{at}koto.kpu-m.ac.jp Mayumi Ueta, et al.	Stevens-Johnson syndrome (SJS), an acute inflammatory vesiculobullous reaction of the skin and mucous membranes, was first described in 1922 by the American pediatricians Stevens and Johnson (Stevens AM, Johnson FC. 1922). They reported 2 boys aged 7 and 8 who presented with gan extraordinary, generalized eruption with continued fever, inflamed buccal mucosa and severe purulent conjunctivitish that progressed to severe visual disturbance. By careful inquiry that showed that no drugs had been administered to either patient, they ruled out that the skin eruption was due to drug ingestion. Other pediatricians subsequently claimed that SJS was associated with infectious agents such as Mycoplasma pneumoniae (Leaute-Labreze C, et.al. 2000) or a viral etiology involving herpes simplex-, Epstein-Barr-, cytomegalo-, and varicella zoster virus (Forman R, et.al. 2002). On the other hand, dermatologists reported that SJS and its severe variant, toxic epidermal necrolysis (TEN), are life-threatening severe adverse drug reactions characterized by high fever, rapidly developing blistering exanthema of macules, and target-like lesions accompanied by mucosal involvement and skin detachment (Roujeau JC, et.al. 1995). The number of causative drugs was estimated to exceed 100 (Wolf R, et.al. Clin Dermatol. 2005). Dermatologists tend to see patients with SJS/TEN in the acute stage while many patients encountered by ophthalmologists present in the chronic stage. Of our 110 SJS/TEN patients, more than 80% were in the chronic stage when they first reported to our hospital. It is difficult for ophthalmologists to render a differential diagnosis of SJS or TEN when patients present in the chronic stage because the vesiculobullous skin lesion expressed in the acute- have healed by the chronic stage. Thus, ophthalmologists tend to report both SJS and TEN as gSJSh in a broad sense. Our diagnosis of SJS/TEN (SJS in the broad sense) was based on a confirmed history of acute-onset high fever, serious mucocutaneous illness with skin eruptions, and involvement of at least 2 mucosal sites including the ocular surface (Sotozono C, et.al. 2007, Ueta M, et. al. 2007). In the acute stage, SJS/TEN patients manifest severe conjunctivitis, alolpecia, and corneal/conjunctival epithelial defects with vesiculobullous skin lesions. Without adequate treatment, persistent epithelial defects occur and often progress to corneal melting and perforation. In the chronic stage, ocular surface complications such as conjunctival invasion into the cornea due to corneal epithelial stem cell deficiency, symblepharon, ankyloblepharon, dry eye, trichiasis, and in some instances, keratinization of the ocular surface, persist despite the healing of the skin lesions (Sotozono C, et.al. 2007). The conjunctival invasion into the cornea results in severe visual disturbance. SJS/TEN is one of the most devastating ocular surface diseases leading to corneal damage and loss of vision. Moreover, we observed that more than 95% of patients with SJS/TEN with ocular complications had lost their fingernails in the acute- or subacute stage and that some continue to have transformed nails even after healing of the skin lesions (Ueta M, et. al. 2007). The reported incidence of ocular complications in SJS/TEN is 50-68% (Power WJ, et. al. 1995, Yetiv JZ, et. al. 1980). Drugs are probably the most widely accepted etiologic factor in SJS/TEN. It is worth noting that SJS/TEN patients often experienced the prodromata, including nonspecific fever, coryza, and sore throat, that closely mimic upper respiratory tract infections commonly treated with antibiotics (Ueta, et. al. 2007, Yetiv JZ, et. al. 1980). Yetiv et. al., (Yetiv JZ, et. al. 1980) who performed a retrospective analysis of the etiologic factors in 54 SJS patients diagnosed at Johns Hopkins between 1996 and 1976, concluded that drugs and infections were especially suspect as etiologic agents in SJS. They stated that although they were able to review information on the administered drugs, they could not conclude that these drugs were in fact the etiologic factors because the prodromata of SJS (nonspecific fever, coryza, sore throat, and malaise) involve symptoms that closely mimic upper respiratory tract infections commonly treated with antibiotics. They warned that although SJS is frequently attributed to antibiotics, it is impossible to state unequivocally that SJS developed as a result of the drug treatment because the possibility that the prodromata would have progressed to full-blown SJS in the absence of the drugs cannot be ruled out. In our series of general population including adults and children, about 80% presented with SJS after receiving antibiotics, cold remedies, and/or non-steroid anti-inflammatory drugs to treat the common cold. On the other hand, only several developed SJS after undergoing drug treatment for the prevention of convulsion. Furthoremore, of our 110 SJS/TEN patients, 39 (35%) presented with SJS when they were children < 15 years of age. 38 of 39 our children SJS/TEN patients experienced the prodromata, including nonspecific fever, coryza, and sore throat, that closely mimic upper respiratory tract infections commonly treated with antibiotics and 32 of 38 presented with SJS after receiving antibiotics, cold remedies, and/or non-steroid anti- inflammatory drugs to treat the common cold and 6 presented with SJS without medication. Only one developed SJS after undergoing drug treatment for the prevention of convulsion. According to a group of dermatologists, allopurinol, a uric acid-lowering drug (17.4%), anticonvulsants such as carbamazepine (8.2%), nevirapine (5.5%), phenobarbital (5.3%), phenytoin (5.0%), and lamotrigine (3.7%) were frequently associated with SJS or TEN, as was cotrimoxazole (6.3%), an antibiotic (Hung SI, et. al. 2005). Levi et. al. (Levi N, et. al. 2009) also reported that not only antiinfectives (40%), acetaminophen (37%) and NSAIDs (5%), but also antiepileptics (30%) were strongly associated with SJS/TEN in children < 15 years of age. We posit that the SJS/TEN patients seen by dermatologists are not always the same as SJS/TEN patients consulting opthalmologists. Conflict of Interest: None declared