Stevens-Johnson syndrome is a rare (1-2 cases per million population per year) but life-threatening mucocutaneous reaction characterized by detachment of epidermis, acute skin blisters, and mucous membrane erosions. Desipite many etiological factors, certain drugs such as antibiotics, antiepileptics, and analgesics are usually considered to be responsible for the disease
1. Among antiepileptics the mostly accused ones are phenytoin, carbamazepine, phenobarbital, and recently lamotrigine. The risk arises most frequently within the first 2-8 weeks of antiepileptic treatment
2-5, 6. Liver damage, heamatologic and central nervous system findings are the common side effects of valproic acid. Cutaneous side effects are quite rare and result twisting and thinning of hair and alopecia, rarely
7.
Although the exact mechanism(s) of LTG-related SJS remain to be elucidated yet, there are two hypotheses about this issue. In immunological hypothesis, drug metabolites have been claimed to assume the role of hapten and lead to particularly T-cell originated immunological reactions and cell-associated cytotoxicity. This hypothesis has been proved by demonstrating the infiltrations of CD8+ T cells into epidermis and CD4+ T cells into dermis with lymphocyte transformation test and immunohistological investgations 1,8. Other hypothesis claims that, VA probably interferes with metabolizing of LTG by glucuronide inhibition, thus leads to increased serum LTG levels, or alteration of LTG metabolism. This interference causes accumulation of toxic intermediate metabolites and severe skin reactions 9. Weintraub et al 10 reported that valproic acid decreases lamotrigine clearance by approximately 60% in a study with 570 patients.
Our patient had used only VA for three years, previously. Therefore, this drug was not considered as etiologic factor. However, we believe that the increment of LTG dose from 25 mg/day to 50 mg/day which metabolizes through glucuronidation, might have increased LTG blood level and caused skin reaction. Severe cutaneous reactions following LTG treatment may ocur even in case of low initial and gradually increasing doses 8, 11. According to Guberman et al 12, children have an approximately three-fold risk of developing serious rash with lamotrigine, moreover the risk may increase when one exceeds the advised initial doses for titration or when combined with valproate. Drugs are the most common factors for development of SJS whereas mycoplasma and herpes virus infections comprise less common causes 1. There was no bacterial growth in cultures of our patient. Additionally, the bacterial and viral serology were all negative. Therefore, no infection was considered as a cause in this case.
In conclusion, the side effects of drugs should be followed carefully in the patients requiring combined antiepileptic drugs. Severe skin reactions may be prevented by avoiding of concomitant use of drugs that are metabolized in the liver, slow dose escalation, and routine measurement of LTG blood levels. Clinicians should be aware of the fact that combination of of antiepileptic drugs increases the risk of SJS especially in children. Patients who undergo therapy with AEDs should be informed about possible cutaneous adverse effects and the therapy should be discontinued if any rash appears.