Figure 1: Erythematous papules on face /neck and hemorrhagic crust on lips of patient.

Figure 2: Purpuric lesions on the trunk, extremities, and genital region of patient.

Laboratory findings were as follows; WBC: 5250/µL, RBC: 4,940,000/µL, hemoglobin: 11.8 g/dl, platelet: 182,000/µL, sedimentation: 31/hr. The chest radiograph was normal. In biochemical studies, serum glucose level, renal function tests, electrolyte and bilirubin levels were in normal range, and liver function tests were; AST: 54 U/L and ALT: 24 U/L. There were no bacterial growth in nasal, throat, blood, urine, and fecal culturs. Mycoplasma, herpes simplex virus, Ebstein-Barr virus, Cytomegalovirus, hepatitis virus (A, B, C, and E), and HIV serologies were all negative. Lamotrigine level was 3.8 mcg/ml and VA level was 27,6 mcg/ml in blood of the patient. The patient was diagnosed with lamotrigine-related SJS on the basis of history and physical findings, and according to the current consensus guidelines. The lamotrigine was stopped immediately and anticonvulsant therapy of the patient was changed as valproic acid and diazepam for any seizure risk. Additional treatment including fluid replacement, methylprednisolone (1mg/kg/day), oral antibiotic, bicarbonate and clorhexidine mouth wash for oral mucosal lesions, wet dressing for epidermal surfaces were applied. Following the treatment, lesions progressively resolved and the dose of prednisolone was reduced gradually. The patient showed a sufficient recovery and he was discharged after 20 days.

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.