EMPACT Syndrome Associated with Phenobarbital

Abstract

Intracranial malignancies can be complicated by seizure activity, and anticonvulsants such as phenytoin are usually administered to prevent this neurological kind of complication. Cranial radiation therapy is instead the treatment of choice when the tumor is unresectable. Anyway, the combination of phenytoin and cranial radiation therapy can lead to a rare and severe mucocutaneous complication called EMPACT syndrome. It is composed of "erythema (E) multiforme (M) associated with phenytoin (P) and (A) cranial radiation (C) therapy (T)." Herein, we report 2 cases of EMPACT syndrome related to the use of phenobarbital instead of phenytoin as usually described in literature.

Is this a simple drug eruption to be discharged?

“…About thirty cases have been described so far 1, 2, 4. No correlation was found between size and severity of cutaneous eruptions and the dose of phenytoin or radiation therapy, or the origin or size of intracranial malignancy 3, 5. In previous case reports, associated cancers were glioblastoma multiforme, glioma, astrocytoma or tumors with brain metastases like lung cancer, breast cancer, germinoma, melanoma, angiosarcoma, chondrosarcoma or bronchial carcinoma.…”

“…Many mechanisms were asserted in the pathway of phenytoin metabolism. Animal studies showed that radiation to brain may cause a rise in cellular autoimmunity by upregulating mRNA expression of immunologic cytokines in rats 5 . Radiation may also induce a defect in epoxide hydrolase, an enzyme that breaks down the drug, causing accumulation of oxidative metabolites 2, 5.…”

“…Animal studies showed that radiation to brain may cause a rise in cellular autoimmunity by upregulating mRNA expression of immunologic cytokines in rats 5 . Radiation may also induce a defect in epoxide hydrolase, an enzyme that breaks down the drug, causing accumulation of oxidative metabolites 2, 5. Additionally, phenytoin and its metabolites can activate CD4, CD8 T-cells and diminish the functions of T-suppressor, NK and B cells 7, 8.…”

“…Especially levetiracetam is a better choice to avoid skin lesions as other anti-epileptic drugs like phenobarbital, valproic acid, and carbamazepine had been associated with EM. Additionally, both carbamazepine and barbiturates may cause cross-reactions in patients that are sensitive to phenytoin as they share same aromatic chain in their chemical structure 1, 2, 5…”

General Aspects of Adverse Cutaneous Drug Reactions

“…The development of EM confi ned to the radiation fi eld during or following cranial radiation in patients receiving prophylactic anticonvulsant therapy with phenytoin was recently defi ned as EMPACT (Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy) [ 21 , 22 ]. Phenobarbital has also been reported to cause EMPACT [ 23 ].…”