Rashes are the most frequent idiosyncratic reactions to the drugs used to treat epilepsy. The aromatic compounds (phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine) are the ones most often responsible. Furthermore, there is a high degree of cross-reactivity within this group, particularly between phenytoin, carbamazepine, and phenobarbital, and possibly, lamotrigine. The problem arises most often in the first month of use. The typical eruption is maculopapular, mainly on the trunk; it usually resolves within days of discontinuing the medication. More severe rashes may develop, sometimes taking the form of erythema multiforme and Stevens-Johnson syndrome, or even toxic epidermal necrolysis, especially with lamotrigine.
Certain polymorphisms in HLA genes (HLA-B*1502) have been associated with an increased risk of these types of severe skin reactions, particularly those of Asian ancestry but probably also in Caucasians, in whom this genotype is rare. Another allele HLA-A*3101 may be associated with skin eruptions in Caucasians (McCormack et al), but it (HLA-B*1502) does not seem reasonable at this time to screen non-Asian patients for such an infrequent complication. Another rare systemic hypersensitivity syndrome associated with the use of antiepileptic medications is one of high fever, rash, lymphadenopathy, and pharyngitis. Eosinophilia and hepatitis (or nephritis) may follow.
If any of these reactions require that one of the aromatic drugs be replaced, valproate, gabapentin, topiramate, or levetiracetam are reasonable substitutes, depending, of course, on the nature of the seizures.
Discontinuation of Antiepileptic Drugs
Withdrawal of medications may be undertaken in patients who have been free of seizures for a prolonged period. There are few firm rules to guide the physician in this decision. One plan, applicable to most forms of epilepsy, is to obtain an EEG whenever withdrawal of medication is contemplated. We have taken the approach that if the tracing is abnormal by way of showing paroxysmal activity, it is generally better to continue treatment. However, a normal EEG may not be helpful in making the decision to discontinue medications. A prospective study by Callaghan and colleagues showed that in patients who had been seizure-free during 2 years of treatment with a single drug, one-third relapsed after discontinuation of the drug, and this relapse rate was much the same in adults and children and whether the drug was reduced over a period of weeks or months. The relapse rate was lower in patients with absence and generalized-onset seizures than in patients with focal seizures. Another study by Specchio and colleagues gave results similar to those of the large Medical Research Council Antiepileptic Drug Withdrawal Study—namely, that after 2 years on a single anticonvulsant during which no seizures had occurred, the rate of relapse was 40 percent 2.5 years later and 50 percent at 5 years after discontinuation; this compared to a seizure recurrence rate of 20 percent for patients remaining on medication. Some have suggested that a longer seizure-free period is associated with a lesser rate of relapse.
Often in practice, the suggestion to stop medications after a lengthy seizure free period comes from the patient, for example if pregnancy is planned or there are untoward side effects but otherwise, the change is never risk free and therefore is infrequently impelled by the physician. Decisions regarding the cessation of medication are also tempered by patient’s desire to continue driving and their concern that another seizure may prevent a return to driving.