Is there pseudolymphoma cross reactivity between antiepileptics? Is it a class effect?

Fråga: Is there pseudolymphoma cross reactivity between antiepileptics? Is it a class effect? The question concerns a man in his 70s who had been treated with phenytoin for epilepsy for several years. Three month ago he developed itching plaques on his trunk. The eruptions were biopsised and the condition was diagnosed as psuedolymphoma, possibly due to the phenytoin treatment. Phenytoin was changed to valproate about five weeks ago, but there is still no improvement.

Sammanfattning: Pseudolymphoma is a potentially life-threatening drug-induced syndrome, which can be confused with true lymphoma. Cross-reactions among aromatic antiepileptic drugs (phenytoin, phenobarbital and carbamazepine) have been described in anticonvulsant hypersensitivity syndrome. There is at least one case report where cross-reactivity between valproate (non-aromatic) and carbamazepine occurred. The clinical symptoms normally resolve within two weeks to two month after withdrawal of the drug. Possibly, if there is no improvement within this time, the patient whom the question concerns might represent another case of cross-reactivity between an aromatic (phenytoin) and non-aromatic (valproate) anticonvulsant. In the event of progression before that, valproate should be discontinued.

Svar: Pseudolymphoma is a relatively rare drug-induced syndrome, which can be confused with cutaneous lymphoma. It is clinically characterized by findings such as erythematous patch, maculopapular eruption or nodules, fever, lymphadenopati, arthralgia, hepatosplenomegaly, abnormal liver profile and eosinophilia. The syndrome can lead to death if there are extensive skin lesions, severe hepatitis, agranulocytosis and neutropenia (1). The patogenetic mechanism is not fully understood. It has been suggested that pseudolymphoma might not reflect a true hypersensitivity reaction, but rather a non-specific dysregulated immune reaction, which may allow the proliferation of an identical T-cell clone (2).

Pseudolymphoma has been reported for several antiepileptics including phenytoin, fenobarbital, carbamazepine, valproate and lamotrigin (1,2,3,4). It is stated to occur after one week to two years of exposure to the drug, and normally resolve within two weeks to two months after drug discontinuation. Except drug withdrawal, systemic steroids are prevalently used, even though it is unclear whether steroids can affect the disease process significantly. Furthermore symptomatic and local therapy for fever, pruritus and skin lesions is often required (1).

Occasionally, pseudolymphoma has been used synonymously with anticonvulsant hypersensitivity syndrome, which is characterized by a triad of fever, rash and internal organ involvement. The two syndromes present similar symptoms, but pseudolymphoma applies only to patients with both clinical and histological features suggestive of lymphoma.

Regarding the anticonvulsant hypersensitivity syndrome, a high percentage of cross reactivity (up to 75%) has been reported among the aromatic antiepileptics (phenytoin, phenobarbital and carbamazepine). There is at least one case report about pseudolymphoma cross reactivity between valproate (non-aromatic) and carbamazepin (3). We have not found any reports about cross-reactions concerning other non-aromatic anticonvulsants.

We recommend this case to be reported to the regional adverse drug reaction monitoring centre.

1. Choi TS, Doh KS, Kim SH, Jang MS, Suh KS, Kim ST. Clinopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Br J Dermatol 2003;148:730-6.
2. Cogrel O, Beylot-Barry M, Vergier B, Dubus P, Doutre MS, Merlio JP, et al. Sodium valproate-induced cutaneous pseudolymphoma followed by recurrence with carbamazepine. Br J Dermatol 2001;144:1235-8.
3. Knowels SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome. Incidence, pervention and management. Drug Saf 1999;21(6):489-501.
4. Pathak P, McLachlan RS. Drug-induced psuedolymphoma secondary to lamotrigine. Neurology 1998;50(5):1509-10.