Lamotrigine-induced hypersensitivity syndrome in a Han Chinese patient with the HLA-B*5801 genotype

Abstract

Antiepileptic drug (AED) therapy is the mainstay for treating epilepsy. Most of the adverse effects in AED therapy are mild, predictable, and dose-dependent. Cutaneous eruptions, which lead to drug withdrawal and hospitalization, are the most frequent idiosyncratic adverse reactions. Severe cutaneous adverse reactions (SCARs) with high morbidity and mortality, including Stevens– Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome, are not uncommon in AED therapy. A strong association between the allele of human leukocyte antigen HLA-B*1502 and carbamazepine-induced SJS has been found in Han Chinese [1]. The lower incidence of carbamazepine-induced SJS in Caucasians, in contrast to its higher incidence in Han Chinese, suggests that there is an ethnic difference in susceptibility. Lamotrigine, one of the newer AEDs, has been reported as a risk factor for skin rashes. We previously [2] identified the risk factors of skin rashes in the patients treated with an initially high dose and rapid escalation of the dose of lamotrigine, and co-medicated with valproic acid. The role of HLA B*1502 in lamotrigine-induced SJS has been investigated and no definite association was found in the studied Han Chinese population [3], which is the same as in Caucasians. In contrast, there seems to be a weak association between HLA B*5801 and lamotrigineinduced SCARs in Caucasians [4]. We report a female Han Chinese patient with epilepsy and lamotrigine-induced SCARs; a genetic study identified the HLA-B*5801 allele as a risk factor. A 32-year-old Han Chinese woman with epilepsy, treated in a special epilepsy clinic in National Cheng Kung University Hospital for years, had been given regular valproic acid therapy (400 mg/day) and had a seizure frequency of around once a month. As the frequency had increased to around once a week, lamotrigine (starting at 20 mg/day, with a 20 mg/week increase) was added. Four weeks later, with the lamotrigine dose at 100 mg/day, she was admitted because of a high fever, generalized erythema, and jaundice. The patient’s blood test revealed high levels of AST (413 U/L), GPT (496 U/L), total bilirubin (17.7 mg/dL), LDH (790 IU/L), alkaline phosphate (582 IU/L), and gamma-GT (821 U/L). Combined with the high fever and a generalized rash, the patient was diagnosed with drug hypersensitivity syndrome. A skin biopsy (Fig. 1) showed mild spongiosis and scattered necrotic keratinocytes in the spinous layer, and vacuolar interface alteration of the basal layers with an infiltration of small lymphocytes. She also showed a perivascular infiltrate of small lymphocytes with scattered neutrophils in the upper dermis. These findings are consistent with maculopapular drug eruption. Under the diagnosis of lamotrigine-induced SCARs, we performed genotyping for this patient and the results showed the J. C. Chow Y.-J. Wu J.-J. Tsai Department of Pediatrics, Chi-Mei Foundation Medical Center, Tainan, Taiwan