Toxic Epidermal Necrolysis Following Phenytoin and Cranial Irradiation.

Sir,

Toxic epidermal necrolysis (TEN) and Stevens–Johnson Syndrome (SJS) are considered as two ends of the spectrum of a severe drug reaction, differing only by their extent of skin detachment. The common offenders are nonsteroidal anti-inflammatory drugs, antimicrobials, aromatic anticonvulsants and allopurinol.[1] Higher risk for severe adverse drug reactions has been reported in those receiving combined whole brain radiotherapy (WBRT) and phenytoin.[23] Ahmed et al., proposed the acronym “EMPACT” syndrome (erythema multiforme, phenytoin and cranial irradiation therapy) to denote this.[4] Here we report a patient who developed fatal TEN while on WBRT and phenytoin.

A 33-year-old female patient was put on phenytoin 100 mg three times daily for late onset seizures and WBRT was initiated 4 weeks later as she was diagnosed to have leptomeningeal secondaries. After the third day of radiotherapy (300 centigrey daily), she manifested conjunctival congestion, periorbital edema and oral erosions that progressed with tenderness and detachment of skin of the head and neck [Figure 1a]. Four years earlier she had been treated with surgery and radiotherapy (3000 centigrey in 10 divided doses) for carcinoma breast without any untoward events.

Figure 1

(a) Hyperpigmented detached epidermis in a patient with toxic epidermal necrolysis. (b) Confluent purpuric macules on the trunk of the same patient. (c) Discreet and confluent purpuric macules on the upper limb of the same patient

Though phenytoin and WBRT were withheld, over the next 24 hours discrete and confluent purpuric macules appeared on the trunk [Figure 1b] and limbs [Figure 1c] with epidermal detachment involving more than 30% of body surface area, hence was diagnosed as TEN. Investigations revealed leukocytosis, elevated erythrocyte sedimentation rate and two times elevation of liver transaminases. Blood culture isolated methicillin-resistant staphylococci sensitive to vancomycin. In spite of supportive care and treatment with intravenous immunoglobulin G, systemic steroids, parenteral metronidazole and vancomycin she expired on the 5th day of the onset of the adverse event.

Toxic epidermal necrolysis in patients receiving WBRT and phenytoin indicates that this adverse reaction pattern shows a wide range of manifestations than those described by “EMPACT” syndrome.[5] Kandil et al. described SJS that started on the scalp, chest and back and then extended to other body parts in a patient with metastatic prostate cancer while on phenytoin and radiotherapy.[6] Initial sites of reaction corresponded to the ports of radiation therapy.

5-fluoroucil, carbamazepine and phenobarbitone are also known to increase the risk of EM/SJS when administered concomitantly with radiotherapy.[78]

Subsequently it is indicated that radiotherapy to any body part can place a patient at a high risk for adverse reactions to drugs inducing cytochrome P450 (CYP450) enzyme.[67] Proposed mechanism include radiotherapy-induced deficit of epoxide hydroxylase (enzyme responsible for eliminating toxic metabolites of aromatic anticonvulsants) and inhibitory effect of radiotherapy on suppressor T lymphocytes.[8]

A higher incidence of SJS-TEN in those receiving combined treatment with phenytoin and cranial irradiation compared to those on other aromatic anticonvulsants and radiotherapy to other body parts could be attributed to the widespread use of phenytoin as a prophylactic anticonvulsant and also to a higher risk for seizures in those with intracranial malignancies which in turn necessitate the concomitant use of anticonvulsants and radiotherapy.

The findings pointing to a combined effect of WBRT and phenytoin in our patient were the absence of any untoward reaction to radiotherapy 4 years earlier, initial TEN lesions appearing over the irradiated site and the more severe nature of the lesions at the site of radiotherapy. We report this case to highlight the need for close monitoring in patients receiving radiotherapy and drugs inducing cytochrome P 450. Levetiracetam or gabapentine are recommended as the preferred anticonvulsants in such cases.