Drug-induced liver injury. In vitro demonstration of hypersensitivity to both phenytoin and phenobarbital

Abstract

Fever, lymphadenopathy, exfoliative dermatitis, and evidence of drug-induced liver injury developed in a 16-year-old girl three weeks after beginning therapy with phenytoin and phenobarbital. This clinical syndrome can be caused by either of these structurally related drugs but has been more frequently attributed to phenytoin. In vitro studies disclosed marked reactivity of this patient's lymphocytes to concentrations of both drugs, which encompassed their measured serum levels. The demonstration of dual reactivity raises concerns about continuing administration of phenobarbital during an apparent phenytoin-induced reaction. Whether this potential risk is greater than the risk of stopping all anticonvulsant medications in a patient with a seizure disorder is not known and remains to be established.

Hypersensitivity to Aromatic Anticonvulsants: In Vivo and In Vitro Cross-Reactivity Studies

“…Several studies regarding patients with hypersensitivity reactions to aromatic anticonvulsants assessed immunologic cross-reactivity among the latter by patch tests and/or LTTs and found positive responses to more than one drug [13,[38][39][40][41][42][43][44][45][46][47][48][49]. However, most of such studies are reports of single patients [38-40, 42, 43, 45, 46, 48].…”

“…However, most of such studies are reports of single patients [38-40, 42, 43, 45, 46, 48]. Moreover, some of the patients found positive to more than one aromatic anticonvulsant in allergologic tests had actually suffered hypersensitivity reactions either in response to sequential exposure to more than one drug [39,42,43] or during a treatment that included more than one aromatic anticonvulsant [38,40]. Therefore, coexisting sensitizations could not be excluded in most of these studies.…”

Cross-sensitivity of skin rashes with antiepileptic drug use

“…DISCUSSION Cross-sensitivity among aromatic AEDs (CBZ, LTG, OXC, PHT, PB) is said to occur in 40 -58% of patients 4,5,8,10,12,13,15 and has been reported as high as 80% in an in vitro assay. 10 Our results are generally consistent with these findings, but expand upon them in a larger population (n ϭ 1,875, with 72 patients having rash to more than one AED) than prior reports and involving more AEDs, including the newer ones.…”

“…[1][2][3] Cross-sensitivity of rash has been reported between various AEDs, but is most commonly encountered in patients treated with aromatic AEDs such as phenytoin, phenobarbital, carbamazepine, oxcarbazepine, and lamotrigine. [4][5][6][7][8][9][10][11][12][13][14] Few studies have determined the frequency of cross-sensitivity of rash among a large number of patients taking multiple AEDs. [4][5][6][7][8][9][10][11][12][13][14] A recent study from our database investigated predictors of AED-related rash in 1,890 outpatients: for most AEDs, the risk of developing a rash increased three-to fourfold if the patient had a rash to one or more other AEDs, or an allergy (with or without rash) to a non-AED medication.…”

Immunological Adverse Effects of Anticonvulsants

“…Phenytoin and carbamazepine are the two drugs most frequently involved, but there have been occasional reports with other drugs (Anthony 1970;Bercel et al 1950;Black & Fivenson 1989). In some cases, patients may be reactive to more than one agent (Black & Fivenson 1989;Kahn et al 1984;Maguire et al 1987;Reents et al 1989). The diagnosis of AILD should be seriously considered in any patient on anticonvulsant therapy with a lymphadenopathy of unknown origin.…”