Reporte de casos Revista Chilena de Neurocirugía 36 : 2011

Complications of Post-operative Seizure Prophylaxis

in Patients Submitted to Cranial Irradiation
Tobias Alécio Mattei*,Carlos R. Goulart*.,Charles Kondageski*,Murilo S. Meneses*,Maurício Coelho Neto*,Ricardo Ramina**
*Neurosurgery Department ‘’Instituto de Neurologia de Curitiba’’-Brazil.
**Chief of the Neurosurgery Department ‘’Instituto de Neurologia de Curitiba’’-Brazil

Rev. Chil. Neurocirugía 36: 61-65, 2011

Abstract
The clinical status of patients with malignant intracranial tumors, such as high-grade gliomas, is often aggravated by seizure
activity. Phenytoin is typically employed as prophylactic anticonvulsant in this setting. In such patients, severe systemic drug
reactions such as erythema multiforme (EM) may occur. However, in a subgroup of patients with brain radiation therapy, EM-like
lesions appear to develop in an increased ratio. The acronym ‘EMPACT’ (E: erythema; M: multiform; associated with P: phenyto-
in; A: and; C: cranial, radiation; T: therapy) has been suggested to best describes this syndrome. In this article, the authors pre-
sent 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. Because of these predictable complications we abandoned our routine institutional protocol which em-
ployed phenytoin for seizure prophylaxis for patients in the post-operative period following malignant tumor resection and which
expect to be irradiated in the near future. Once both carbamazepine and barbiturates show cross-sensitivity with phenytoin and
may interfere with serum levels of chemotherapy drugs, we now advocate, as other worldwide renown neuro-oncological cen-
ters, the use of valproate gabapentin, or alternatively, as recent literature guidelines suggests levetiracetam (keppra), for seizure
prophylaxis in this select subset of patients.

Key words: High grade glioma, seizure, phenytoin, seizure prophylaxis, brain radiation, erythema multiform.

Resumen
El estado clínico de los pacientes con tumores malignos intracraneales, como los gliomas de alto grado, es a menudo agravado
por la actividad convulsiva. La fenitoína es normalmente empleadaa como anticonvulsivante profiláctico en esto contexto. En
estos pacientes, graves reacciones sistémicas, como eritema multiforme (EM) puedem ocurrir. Sin embargo, en un subgrupo
de pacientes con terapia de radiación en el cerebro, lesiones de EM, parece que se desarrollan en una proporción mayor. ‘EM-
PACT’ La sigla (E: eritema, M: multiforme; asociados con P: fenitoína; A: y C: la radiación craneal, T: La terapia) Se ha sugerido
que mejor describe este síndrome. En esto artículo, los autores presentan un caso clínico de un paciente tratado con fenitoína
para la profilaxia de convulsiones, durante el período post-operatorio después de la resección de un glioma maligno, y que
presenta una erupción cutánea grave, que evoluciona con consecuencias graves debido al cambio brusco de medicamentos
anticonvulsivos. Debido a estas complicaciones predecibles, que abandonamos nuestro protocolo institucional de rutina que la
fenitoína empleadas para la profilaxia de convulsiones en los pacientes en el período post-operatorio después de la resección
del tumor maligno y que esperan ser irradiado en un futuro próximo. Una vez que ambos carbamazepina y los barbitúricos
mostran sensibilidad cruzada con fenitoína y puede interferir con los niveles séricos de drogas de la quimioterapia, ahora defen-
demos, como otros centros de renombre mundial neuro-oncológico, el uso de gabapentina valproato, o bien, como orientación
la literatura reciente sugiere levetiracetam (keppra), para la profilaxia de las convulsiones en este subgrupo seleccionado de
pacientes.

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 Revista Chilena de Neurocirugía 36 : 2011
Introduction
The clinical status of patients with malig-
nant intracranial tumors, such as high-
grade gliomas, is often aggravated by
seizure activity. Phenytoin is typically
employed as prophylactic anticonvul-
sant drug in this setting (2). Additionally,
many patients with metastatic intracra-
nial tumours receive anticonvulsants for
seizure prophylaxis despite their effica-
cy not having been clearly demonstra-
ted (1). In these patients, severe syste-
mic 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: phenyto-
in; A: and; C: cranial, radiation; T: the-
rapy) 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 seizu-
re 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 Mul-
tiform) with immediate post-operative
period without intercurrences. As the
patient presented seizure as initial ma-
nifestation of the tumor, he was dischar-
ged 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
62
with cranial irradiation and chemothera- hospital one month after the initial com-
py sessions. plication, with a significant lower Kar-
nofsky scale, with a major new neurolo-
After the 15th session of conformational gical deficit. He went on clinical oncolo-
radiotherapy, the patient was admitted gical treatment and follow-up, this time
at the emergence of our hospital with using valproate as a seizure prophylaxis
a subtle motor deficit at the left side indication.
(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 impro-
ved. At this time the patient presented
a progressive cutaneous rash most
prominent in the face, anterior surface
of thorax and perineal region. A simulta-
neous 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, unila-
teral non-photo-reagent midryasis and
other signs of uncal herniation. The pa-
tient was transferred immediately to ICU
where he was intubated. Emergency
CT scan demonstrated increase in bra-
in 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 hemiple-
gic on the left side. He spent eight more
days in ICU until he recovered cons-
ciousness. A traqueostomy was perfor-
med in order to substitute a prolonged
entubation and almost twenty days after
the operation the patient was still in hos-
pital in order to manage minor problems
with enteral feeding, tracheostomy can-
nula, gastric fluid aspirations and skin
complications in site of surgical incision.
The patient was discharged from the
Reporte de casos Revista Chilena de Neurocirugía 36 : 2011

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-epi-
leptic drugs (AEDs) prophylaxis. Milder
rashes, however, occurred in 18% of
Figure 1: Eritema-multiform cutaneous lesions and mucositis after 15 sessions of radiotherapy exposures to AEDs, including 22% ex-
during use of phenytoin as post-operative seizure prophylaxis. posure to phenytoin, compared with the
expected rate of 5-10% in non-irradiated
patients. Nevertheless, other small se-
ries 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 eye-
lids, facial swelling, and extension of the
rash over the trunk with blistering has
also been reported. (9).

Figure 2

Figure 4: Histopathological analysis of cuta-

neous lesion showing hydropic degeneration
Figure 3: Intra and post-operative images, demonstrating an extensive radionecrosis of the left of basal keratinocytes and intercellular edema
hemisphere with important midline shift, diffuse edema and compressive mass effect. (spongiosis). Hematoxylin Eosin (40X).

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 Revista Chilena de Neurocirugía 36 : 2011
Treatment
For erythema multiform reactions related
to phenytoin in irradiated patients, the
immediate cessation of phenytoin thera-
py is recommended, combined with ad-
ministration of systemic corticosteroids
(dexametasone 40mg/day) and, if avai-
lable, high doses of immunoglobulin’s.
Intensive local treatment and pain me-
dications 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 speci-
fic entity among the erythema multiform-
like drug reactions as it only appears af-
ter 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
64
phenytoin in patients submitted to cranial
irradiation, given that, at any sign of cu-
taneous reaction, the pharmacological
treatment could be withdrawn or substi-
tuted 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 with-
drawal of anti-convulsant therapy in these
patients may have hazardous consequen-
ces in terms of new seizures, leading, as
in the reported case, to great consequen-
ces in terms of morbidity of the primary
disease and reduction in life quality.
Phenytoin and other anti-convulsants,
such as phenobarbital and carbamaze-
pine, induce cytochrome P450 3A and
produce oxidative reactive intermediates
that may be implicated in hypersensitivity
reactions such as EM. Both carbamaze-
pine and barbiturates have shown cross-
sensitivity with phenytoin. Furthermore,
a case of EM in a patient receiving car-
bamazepine and whole brain radiation
therapy has been reported. Additionally,
these drugs may interfere with serum
levels of chemotherapy agents, compro-
mising adjuvant therapy.
Because of these predictable compli-
cations we have changed our routine
institutional protocol and now advoca-
te, as other worldwide renown neuro-
oncological centers (13)(4), the use of
valproate, gabapentin or, as preferred in
the neurosurgical oncology literature Le-
vetiracetam, 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
Reporte de casos Revista Chilena de Neurocirugía 36 : 2011

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