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Complications of post-operative seizure prophylaxis in patients submitted to cranial irradiation.

Introduction

The clinical status of patients with malignant intracranial tumors, such as highgrade gliomas, is often aggravated by seizure activity. Phenytoin is typically employed as prophylactic anticonvulsant drug in this setting (2). Additionally, many patients with metastatic intracranial tumours receive anticonvulsants for seizure prophylaxis despite their efficacy not having been clearly demonstrated (1). In these patients, severe systemic drug reactions such as erythema multiforme (EM) may occur. However, in a subgroup of patients submitted to brain radiation therapy, EM-like lesions appear to develop in an increased ratio. (3)(6)(5)(7).

The acronym EMPACT (E: erythema; M: multiforme; associated with P: phenytoin; A: and; C: cranial, radiation; T: therapy) was suggested to best describe this specific syndrome. It was proposed that a specific type IV-sensitization to phenytoin could be responsible for the clinical symptoms (16).

The authors present a case report of a patient treated with phenytoin for seizure prophylaxis, during the post-operative period following resection of a malignant glioma, and who presented a severe cutaneous rash, evolving with serious consequences due to abrupt change of seizure medications.

Case Report

E. J. P., male, 43 year-old, was operated on January 2007 of a right-side parietal lobe expansive lesion (histopathological analysis revealed a Glioblastoma Multiform) with immediate post-operative period without intercurrences. As the patient presented seizure as initial manifestation of the tumor, he was discharged from the hospital in the sixth day after surgery taking phenytoin in dose of 300mg/day as seizure prophylaxis. The patient was sent to the oncological team in order to plan adjuvant therapy with cranial irradiation and chemotherapy sessions.

After the 15th session of conformational radiotherapy, the patient was admitted at the emergence of our hospital with a subtle motor deficit at the left side (strenght grade four). The CT showed an extensive area of radionecrosis in the left hemisphere causing a significant brain edema, with midline shift. The patient was transferred to the Intensive Care Unit. After therapeutics for brain edema his consciousness level improved. At this time the patient presented a progressive cutaneous rash most prominent in the face, anterior surface of thorax and perineal region. A simultaneous severe mucositis also appeared, leading to necessity of a naso-enteral tube for feeding (Fig. 1).

The patient was discharged from the ICU three days latter in Glasgow Coma Scale (GCS) 15, and phenytoin was substituted by valproate. Twelve hours after this medication change the patient had a tonic-clonic seizure event, with rapid decrease in consciousness, unilateral non-photo-reagent midryasis and other signs of uncal herniation. The patient was transferred immediately to ICU where he was intubated. Emergency CT scan demonstrated increase in brain edema, most likely due to prolonged seizure activity (Fig. 2).

He was operated on straight away for descompressive craniectomy. (Fig. 3)

The patient, who had motor strength grade four in the superior left limb, woke up on the 1st day after surgery hemiplegic on the left side. He spent eight more days in ICU until he recovered consciousness. A traqueostomy was performed in order to substitute a prolonged entubation and almost twenty days after the operation the patient was still in hospital in order to manage minor problems with enteral feeding, tracheostomy cannula, gastric fluid aspirations and skin complications in site of surgical incision. The patient was discharged from the hospital one month after the initial complication, with a significant lower Karnofsky scale, with a major new neurological deficit. He went on clinical oncological treatment and follow-up, this time using valproate as a seizure prophylaxis indication.

[FIGURE 1 OMITTED]

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[FIGURE 3 OMITTED]

Discussion

Incidence

In the largest review of this issue in the medical literature (12) only one case of a severe form of erythema multiforme was found in a series of 289 patients treated with radiotherapy and using anti-epileptic drugs (AEDs) prophylaxis. Milder rashes, however, occurred in 18% of exposures to AEDs, including 22% exposure to phenytoin, compared with the expected rate of 5-10% in non-irradiated patients. Nevertheless, other small series showed a much higher incidence, with the clinical picture differing from the classic form of EM in that the erythema began on the scalp and spread quickly to the extremities, progressing in some cases to extensive blistering and even death (8)(10)(11) (Fig. 4).

The pervasive involvement of the oral mucosa, as in the reported case, with conjunctivitis and synechiae of the eyelids, facial swelling, and extension of the rash over the trunk with blistering has also been reported. (9).

[FIGURE 4 OMITTED]

Treatment

For erythema multiform reactions related to phenytoin in irradiated patients, the immediate cessation of phenytoin therapy is recommended, combined with administration of systemic corticosteroids (dexametasone 40mg/day) and, if available, high doses of immunoglobulin's. Intensive local treatment and pain medications are also recommended. Patch testing to phenytoin is usually positive after 72 hours of the beginning of the event. (14;15)

Conclusions

EMPACT should be classified as a specific entity among the erythema multiformlike drug reactions as it only appears after radiotherapy and seizure prophylaxis with the anticonvulsant phenytoin.

Some authors have emphasized that due to low incidence of severe cutaneous rash, there would be no problem in using phenytoin in patients submitted to cranial irradiation, given that, at any sign of cutaneous reaction, the pharmacological treatment could be withdrawn or substituted without any further problems.

Although we agree that severe skin rashes are not so common among patients with brain tumors receiving radiation therapy and phenytoin, the effect of acute withdrawal of anti-convulsant therapy in these patients may have hazardous consequences in terms of new seizures, leading, as in the reported case, to great consequences in terms of morbidity of the primary disease and reduction in life quality.

Phenytoin and other anti-convulsants, such as phenobarbital and carbamazepine, induce cytochrome P450 3A and produce oxidative reactive intermediates that may be implicated in hypersensitivity reactions such as EM. Both carbamazepine and barbiturates have shown cross-sensitivity with phenytoin. Furthermore, a case of EM in a patient receiving carbamazepine and whole brain radiation therapy has been reported. Additionally, these drugs may interfere with serum levels of chemotherapy agents, compromising adjuvant therapy.

Because of these predictable complications we have changed our routine institutional protocol and now advocate, as other worldwide renown neurooncological centers (13)(4), the use of valproate, gabapentin or, as preferred in the neurosurgical oncology literature Levetiracetam, for post-operative seizure prophylaxis in patients who may expect to receive brain radiation therapy in the near course of their care. (17)

Recibido: 04.11.10

Aceptado: 03.01.11

References

(1.) Aguiar D, Pazo R Duran I Terrasa J Arrivi A Manzano H Martin J Rifa J. Toxic epidermal necrolysis in patients receiving anticonvulsants and cranial irradiation: a risk to consider. J Neurooncol. 66[3], 345-350. 2004. Ref Type: Generic.

(2.) Ahmed I, Reichenberg J Lucas A Shehan JM. Erythema multiforme associated with phenytoin and cranial radiation therapy: a report of three patients and review of the literature. Int J Dermatol.43(1):67-73 43[1], 67-73. 2004. Ref Type: Generic.

(3.) Aydin F, Cokluk C Senturk N Aydin K Canturk MT Turanli AY. Stevens-Johnson syndrome in two patients treated with cranial irradiation and phenytoin. J Eur Acad Dermatol Venereol. 20[5], 588-590. 2006. Ref Type: Generic.

(4.) Beenen LF, Lindeboom J Kasteleijn-Nolst Trenite DG Heimans JJ Snoek FJ Touw DJ Ader HJ van Alphen HA. Comparative double blind clinical trial of phenytoin and sodium valproate as anticonvulsant prophylaxis after craniotomy: efficacy, tolerability, and cognitive effects. J Neurol Neurosurg Psychiatry. 67[4], 474-480. 1999. Ref Type: Generic.

(5.) Borg MF, Probert JC Zwi LJ. Is phenytoin contraindicated in patients receiving cranial irradiation? Australas Radiol. 39[1], 42-46. 1995. Ref Type: Generic.

(6.) Camartin C, Reinhart WH Kuhn M. Brain irradiation and phenytoin: a dangerous liaison? Schweiz Rundsch Med Prax. 92[9], 393-396. 2003. Ref Type: Generic.

(7.) Cockey GH, Amann ST Reents SB Lynch JW Jr. Stevens-Johnson syndrome resulting from whole-brain radiation and phenytoin. Am J Clin Oncol. 19[1], 32-34. 1996. Ref Type: Generic.

(8.) Delattre JY, Safai B Posner JB. Erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and phenytoin. Neurology 38[2], 194-198. 1998. Ref Type: Generic.

(9.) Eralp Y, Aydiner A Tas F Saip P Topuz E. Stevens-Johnson syndrome in a patient receiving anticonvulsant therapy during cranial irradiation. Am J Clin Oncol. 24[4], 347-350. 2001. Ref Type: Generic.

(10.) Giroud M, Oriol P Sgro M Lambert D Justrabo E Escousse A Thierry A Dumas R. Erythema multiforme induced by the combination of phenytoin and cerebral irradiation. Therapie 45[1], 23-25. 1990. Ref Type: Generic.

(11.) Khafaga YM, Jamshed A Allam AA Mourad WA Ezzat A Al Eisa A Gray AJ Schultz H. Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol. 38[1], 111-116. 1999. Ref Type: Generic.

(12.) Mamon HJ, Wen PY Burns AC Loeffler JS. Allergic skin reactions to anticonvulsant medications in patients receiving cranial radiation therapy. Epilepsia. 40[3], 341-344. 1999. Ref Type: Generic.

(13.) Micali G, Linthicum K Han N West DP. Increased risk of erythema multiforme major with combination anticonvulsant and radiation therapies. Pharmacotherapy 19[2], 223-227. 1999. Ref Type: Generic.

(14.) Oner Dincbas F, Yoruk S Demirkesen C Uzel O Koca S and x. Toxic epidermal necrolysis after cranial radiotherapy and phenytoin treatment. Onkologie 27[4], 389-392. 2004. Ref Type: Generic.

(15.) Weltman E, Salvajoli JV. Stevens-Johnson syndrome resulting from whole-brain irradiation and phenytoin. Am J Clin Oncol. 19[1], 32-34. 1996. Ref Type: Generic.

(16.) Wohrl S, Loewe R Pickl WF Stingl G Wagner SN. EMPACT syndrome. J Dtsch Dermatol Ges. 3, 39-43. 2005. Ref Type: Generic.

(17.) Vecht C, van Breemen M. Optimizing therapy of seizures in patients with brain tumors. Neurology 67(12 Supplement 4):S10. 2006. Ref Type: Generic.

Tobias Alecio Mattei *, Carlos R. Goulart *, Charles Kondageski *, Murilo S. Meneses *, Mauricio Coelho Neto *, Ricardo Ramina **

* Neurosurgery Department "Instituto de Neurologia de Curitiba"--Brazil.

** Chief of the Neurosurgery Department "Instituto de Neurologia de Curitiba"--Brazil
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Title Annotation:Reporte de casos
Author:Alecio Mattei, Tobias; Goulart, Carlos R.; Kondageski, Charles; Meneses, Murilo S.; Coelho Neto, Mau
Publication:Revista Chilena de Neurocirugia
Date:Jan 1, 2011
Words:1657
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