Acute Transient Encephalopathy Following Paclitaxel Treatment in anAdolescent with a Recurrent Suprasellar Germinoma

James Rook, DO, MPH,1 Tena Rosser, MD,2* Jason Fangusaro, MD,3 and Jonathan Finlay, MD3

INTRODUCTION

Although discovered in the 1960s from the needles and bark of

the Pacific Yew (Taxus brevifolia), Paclitaxel (PTX) did not gain

FDA approval as an antineoplastic agent for breast and ovarian

tumors until 1993 [1]. It is now used to treat a wide variety of solid

tumors. PTX interacts with microtubule proteins by stabilizing

tubulin polymerization, forming nonfunctional microtubules, and

arresting mitosis [2]. Myelosuppression and peripheral neuropathy

are well-documented primary toxicities [3]. PTX has minimal

penetration of the blood-brain barrier so central nervous system side

effects are rare [4,5]. However, transient mental status changes

following PTX infusion have been described in adults but not in

children [6–9]. In this report, we describe a 14-year-old femalewith

a recurrent suprasellar germinoma who developed an acute

encephalopathy following administration of PTX during a routine

hospital admission for chemotherapy.

CASE REPORT

A 14-year-old female with a recurrent suprasellar germinoma,

diabetes insipidus and panhypopituitarism was admitted to the

hospital for routine chemotherapy. She was originally diagnosed at

10 years of agewith a pure germinoma by biopsy. She had a negative

serum alpha-fetoprotein (AFP) and beta-human gonadotropin

(hCG) at the time. Approximately 1 month following her initial

diagnosis, she underwent partial resection of the tumor. She then

achieved a complete radiographic response with two cycles of

carboplatin and etoposide followed by focal irradiation. She

relapsed into her ventricular system beyond the field of irradiation

within 2 years. High dose cyclophosphamide followed by

myeloablative thiotepa, carboplatin and temozolomide with autol-

ogous hematopoietic cell rescue again achieved complete radio-

graphic (MRI) response.

One-year post-transplant, she recurred in the ventricular system

with a biopsy-proven pure germinoma. Her biopsy was complicated

by intratumoral hemorrhage that resulted in blindness. Her serum

and cerebrospinal fluid beta-hCG were elevated at the time.

Treatments including systemic temozolomide, intra-Ommaya top-

otecan and liposomal cytosine arabinoside proved ineffective, with

9 months of unremitting tumor progression. She then received two

cycles of paclitaxel (170 mg/m2), gemcitabine (800 mg/m2), and

oxaliplatin (100 mg/m2). Approximately 6 hr after her first cycle of

these combination chemotherapeutic agents, she developed tran-

sient decreased responsiveness and agitation. At the time, it was

assumed that her mental status changes were secondary to

intratumoral hemorrhage, although neuroimaging remained stable.

Approximately 4–6 hr after her second cycle, she again

developed confusion and decreased responsiveness. During this

time shewas also noted to have an episode of shaking of the right leg

lasting less than 1 min that was thought to be a seizure. Intravenous

lorezapam was given and she was loaded with fosphenytoin. No

further seizure-like events occurred. Concurrent medications

included cortef, bacrim, synthroid, desmopressin, and nystatin.

There was no history of fever or illness at the time.

A neurology consult was requested and subsequent examination

revealed an adolescent female minimally responsive to both verbal

and painful stimuli. She did not follow commands or answer

questions. The left pupil was dilated and sluggishly reactive at

baseline and the right pupil was more briskly reactive. Her face was

symmetric and she had an intact gag reflex. She had diffusely

increased tone and withdrew to painful stimuli purposefully in all

four extremities. Her deep tendon reflexes were brisk throughout

and she had bilateral plantar flexor responses.

There was no evidence of tumor progression, worsening

hydrocephalus or intracranial hemorrhage on neuroimaging. A

head CT scan with contrast showed decreased size of the suprasellar

mass and decreased ventricular size as well as decreased size of the

disseminated tumor located in the third, fourth, and lateral

ventricles. A subsequent brain MRI with contrast was consistent

with the head CT findings. An electroencephalogram performed on

the same day revealed diffuse slowing consistent with a generalized

encephalopathy but no epileptiform activity.

A thorough work-up to rule out infectious, metabolic, and endo-

crinologic causes was performed. She was pancytopenic. Her

Paclitaxel is an antineoplastic agent that is used in the treatmentof a variety of solid tumors. Dose-limiting side effects of myelosup-pression and peripheral neuropathy are well known. Paclitaxel hasminimal penetration of the blood-brain barrier and central nervoussystem side effects are rare. However, transient encephalopathy

following paclitaxel infusion has been described in adults but not inchildren. We present the case of a 14-year-old female with arecurrent suprasellar germinoma who developed an acute encepha-lopathy 4–6 hr following paclitaxel infusion. Pediatr Blood Cancer2008;50:699–700. � 2006 Wiley-Liss, Inc.

Key words: brain tumor; encephalopathy; neurotoxicity; paclitaxel; transient

——————1Department of Pediatrics, Loma Linda University Children’s

Hospital, Loma Linda University School of Medicine, Loma Linda,

California; 2Department of Neurology, Children’s Hospital Los

Angeles, Keck School of Medicine, Los Angeles, California; 3Neural

Tumors Program, Children’s Center for Cancer and Blood Diseases,

Children’s Hospital Los Angeles, Keck School of Medicine, Los

Angeles, California

*Correspondence to: Tena Rosser, Children’s Hospital Los Angeles,

Department of Neurology, M.S. 82, 4650 Sunset Blvd., Los Angeles,

CA 90027. E-mail: trosser@chla.usc.edu

Received 11 July 2006; Accepted 25 July 2006

� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.21040

Brief Reports 699

sodium, potassium, glucose, blood urea nitrogen, and creatinine

were normal, although there was a mild acidosis (CO2¼ 16 mEqu/

L) and amildly elevated chloridewhich were not felt to be clinically

significant. The free T4 and thyroid stimulating hormone levels

were low at 0.66 ng/dL and <0.03 ulU/ml, respectively, but were

unchanged from her labs from 1 month prior. The patient’s

symptoms gradually improved over approximately 72 hr and she

returned to her neurologic baseline. As other potential causes were

ruled out, her transient encephalopathy was ultimately felt to be

secondary to PTX toxicity.

DISCUSSION

Toxicity of the peripheral nervous system is a well-appreciated

side effect of PTX, but central nervous system side effects are rare.

Animal and human studies have demonstrated that intravenous PTX

typically does not cross the blood-brain barrier [4,5]. However,

several case reports have documented acute encephalopathy

following PTX infusion with normal doses in adults with whole

brain irradiation and prior brain surgery [6]. Ziske et al. reported

acute PTX-induced encephalopathy in two females with metastatic

breast cancer who received whole brain irradiation as well as in one

male with metastatic adenocarcinoma of the lung who received

whole brain irradiation in addition to a metastatectomy. Encephal-

opathy occurred within 6 hr of infusion and resolved spontaneously

in 4–6 hr in all three cases. Symptoms included disorientation, word

finding difficulties, attention problems, and confusion. It was

proposed that a disrupted blood-brain barrier from irradiation and

surgery predisposed to small and medium blood vessel damage,

facilitating acute mental status changes [6].

Delayed encephalopathy has also been reported in two women

with breast cancer 1 week after infusion of PTX. Symptoms of

confusion, behavioral changes and word finding difficulties

resolved without intervention [7]. In addition, high-dose PTX used

with hematopoietic cell support has been associated with severe

encephalopathy 7–23 days after infusion. Six of 114 individuals

developed a variety of mental status changes after receiving

>600mg/m2 of PTX. Five patients became obtunded and comatose,

and one patient developed paranoid ideations with confusion. Two

of these patients had previously receivedwhole brain irradiation [8].

As in prior cases of PTX encephalopathy, it is difficult to exclude

the diluent, Cremophor EL/ethanol, as a contributing factor. PTX is

formulated in 50% Cremophor EL and 50% ethanol [10].

Cremophor EL is known to be neurotoxic. Animals treated with

Cremophor EL have demonstrated decreased cerebral blood flow as

well as electroencephalographic changes [11,12]. It has also been

shown to affect coagulation factors, predisposing to thrombo-

embolic events [13,14]. The plasma alcohol level is proportional to

the infusion rate and the dose of paclitaxel given [6,15].

Similar to the adult patients described in previous case reports,

our adolescent had numerous reasons to have a disrupted blood-

brain barrier, including prior tumor resection and brain irradiation.

Therefore, we conclude that as in adults, acute transient encephal-

opathy can be a primary neurologic consequence of PTX therapy in

pediatric patients with diminished blood-brain barrier integrity.

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