Slowly But Surely, Seizure Therapy Gets Personalized

Andrew N. Wilner, MD


November 05, 2014

Phenytoin Cutaneous Adverse Reactions

I saw a woman many years ago in the hospital with fever, lymphadenopathy, and liver function abnormalities associated with phenytoin. Her case has stuck with me, probably because her EEG/video monitoring demonstrated nonepileptic seizures and not epilepsy. She suffered from a serious complication of phenytoin, a drug she didn't even need!

Of all the antiepileptic drugs (AEDs), phenytoin is associated with the highest rate of rashes (5.9%), followed by lamotrigine (4.8%) and carbamazepine (3.7%).[1] Although usually mild, drug rashes can be life-threatening if they take the form of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reactions with eosinophilia and systemic symptoms (DRESS).[2]

A recent study[3] revealed that phenytoin-related severe cutaneous adverse reactions are associated with CYP2C9*3 missense variants on chromosome 10 in an Asian population. This case-controlled study included 105 cases of phenytoin-related severe cutaneous adverse reactions (61 SJS or TEN, 44 DRESS); 78 cases of maculopapular exanthema; 130 phenytoin-tolerant control individuals; and 3655 population control individuals from Japan, Malaysia, and Taiwan. A genome-wide association study (GWAS) included 60 cases with severe phenytoin-related reactions and 412 Taiwanese controls. The results were validated in Taiwanese, Japanese, and Malaysian populations.

GWAS identified a cluster of 16 single nucleotide polymorphisms in CYP2C genes on chromosome 10 (10q23.33). Of these, the missense variant rs1057910 (CYP2C9*3) had the highest association (odds ratio, 12) with phenytoin-related severe cutaneous adverse reactions.


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