Current understanding of delayed anticonvulsant hypersensitivity reactions

Abstract

Hypersensitivity syndrome (HSS) reactions are one of the most feared idiosyncratic drug reactions and are most common with exposure to antiepileptic drugs (AEDs), sulfonamides, nonsteroidal antiinflammatory drugs, corticosteroids, and allopurinol. HSS is associated with chemotoxic and T-cell-mediated inflammatory injuries in barrier tissue systems that contain cytochrome oxidases (e.g., skin, mucosa, liver, and lungs) and can be seen as a derangement in the defense system against xenobiotics-bioactive foreign molecules. The mechanisms for anticonvulsant HSS are incompletely understood but involve genetic susceptibility, with accumulation of AEDs and oxidized metabolites causing major histocompatibility complex (MHC) and non-MHC-dependent clonal activation of T cells and subsequent cytokine/chemokine production in T cells, keratinocytes, and other target cells. This review discusses the classification and possible mechanisms for anticonvulsant HSS.

FIGURE 1

Possible stages in the development of keratinocyte injury with hypersensitivity syndrome. Cytochrome oxidation of aromatic AEDs to reactive arene oxides eventually leads to MHC-dependent presentation of AED antigen and binding with T-cell receptors. Keratinocyte toxicity may be caused directly by injury from reactive intermediates, by CD8+ T cell cytotoxicity, or by perforin and granzyme B release by T-helper (CD4+) cells. AED, antiepileptic drug; ICAM-1, intercellular adhesion molecule 1; LFA-1, leukocyte function-related antigen-1; MHC, major histocompatibility complex; TCR, T-cell receptor. Adapted from J of Invest Derm 2000;114(6):1164–1173 and Ann Intern Med 2003;139(8):683–693.