Methotrexate-Induced Status Epilepticus

Aung Naing,* Don Luong, and Martine ExtermannH. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, Florida

We present a 46-year-old Caucasian male who wasreferred to our facility for evaluation and treatmentof acute myelogenous leukemia (AML-FAB M5b).Prior to coming to our facility, he failed 7+3 induc-tion twice and high-dose Ara-C induction once. Hepresented to our institution with 87% blasts in hisbone marrow, left orbital involvement, and amediastinal chloroma. He was given 2,500 cGy ofradiation to the left orbital region and enrolled inan experimental protocol using daunorubicin, Ara-C, topotecan, and etoposide. He subsequently failedthis protocol and was then put on MEC (mitoxan-trone, etoposide, and Ara-C). Because of CNS invol-vement of his leukemia, intraventricular methotrexatevia an Ommaya reservoir was planned.The Ommaya reservoir was placed and cleared by

neurosurgery prior to its use. The first dose of intra-ventricular MTX (MTX, 12 mg, with hydrocortisone,25 mg, intrathecally) via the Ommaya was adminis-tered according to standard precautions and pro-ceeded without any complications. Four days later,a second dose of intraventricular methotrexate wasadministered. Within 4 min of this dose, the patientwent into generalized tonic clonic status epilepticus.The patient was given lorazepam, propofol, loadedwith phenytoin, and intubated for airway protection.A CT scan and EEG were obtained. The CT scan

showed a minute amount of postoperative pneu-mocephalus. Otherwise, the CT showed no grossabnormalities. The EEG was done about 3 hr afterintubation and was markedly abnormal. It showedpoorly developed background activities and diffuseslow-wave activities associated with voltage suppres-sion, thereby indicating a postictal state. Thepatient’s condition improved overnight, and he wasextubated the next day.Four days later, a third dose intraventricular meth-

otrexate was administered in an ICU setting. Priorto administration of the methotrexate, the patient’sphenytoin level was checked and documented to betherapeutic. Again within 5 min, patient went intocomplex partial status epilepticus.Our team addressed the possibility that his seizures

might have been secondary to physical irritation of

the brain from manipulation of the Ommaya reser-voir. However, injection of normal saline into thereservoir did not induce any seizure activity. Wealso investigated the methotrexate that was given tothe patient. Correct concentrations of methotrexatewere administered. We also did not believe that themethotrexate was contaminated. Therefore, we con-cluded that the status epilepticus was induced by theintraventricular methotrexate.In adult AML, patients with CNS involvement can

be treated with high-dose cytarabine, intrathecalmethotrexate, cranial irradiation, or combinations ofthese modalities [1]. For active meningeal leukemia,the standard of therapy is intrathecal or intraven-tricular methotrexate [2]. In childhood acute lym-phoblastic leukemia, CNS therapy is highlyrecommended [3]. CNS therapy with irradiation andmethotrexate is associated with a wide variety neuro-toxicities, which have been categorized into threegroups. Acute reactions, occurring within hours todays of treatment, include nausea, vomiting, drowsi-ness, increased intracranial pressure, and arachnoidi-tis. Subacute reactions, occurring in days to weeks oftreatment, include a somnolence syndrome, seizures,cranial nerve palsies, cerebellar dysfunction, andhemiparesis/plegia. Delayed reactions, which are notseen for several months to years, include leukoence-phalopathy involving brain necrosis [4]. In our reviewof the literature, we rarely encounter seizures or sta-tus epilepticus as an acute reaction secondary to

Am. J. Hematol. 80:35–37, 2005. � 2005 Wiley-Liss, Inc.

Key words: seizure; status epilepticus; methotrexate; toxicity;leukemia; central nervous system

*Correspondence to: Aung Naing, H. Lee Moffitt Cancer Center& Research Institute, 12902, Magnolia Drive, Tampa, FL 33612.E-mail: nainga@moffitt.usf.edu

Received for publication 4 November 2004; Accepted 30 December2004

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.20365

American Journal of Hematology 80:35–37 (2005)

ª 2005 Wiley-Liss, Inc.

intrathecal or intraventricular methotrexate in adultpopulation.Several pathologic mechanisms have been postulated

thatmay be responsible formethotrexate-induced neuro-toxicity [5]. The exact nature of howmethotrexate affectsthe CNS is not clear. Methotrexate has cytotoxic effectson cells during the active cell cycle [6]. As a result, restingcells inG0 are resistant tomethotrexate. Because neuronsdo not replicate and stay in G0, methotrexate should nothave an effect on them. However, astrocytes showincreased degeneration and decreased viability whenthey are exposed to methotrexate [7].Methotrexate also decreases glucose metabolism in

the CNS and increases blood–brain permeability,allowing influx of possibly toxic low molecular weighthydrophilic molecules [8]. It is also known that cranialirradiation may cause direct damage to the blood–brain barrier, thereby increasing methotrexate perme-ability [9]. Moreover, concurrent radiation put cellsinto a resting phase (G0), thus decreasing the S-phaseeffect of methotrexate [10]. As a result, cranial irradia-tion can enhance neurotoxicity caused by intrathecalmethotrexate with no additional therapeutic effect [2].In one study, five patients with severe methotrexate-induced neurotoxicity had CSF methotrexate concen-trations averaging 13.8 times higher than the meanantifolate values. The investigators suggested that theneurotoxicity may be secondary to prolonged exposureto excessive drug concentration in the central nervoussystem [11]. In our patient, we did not check the post-seizure CSF methotrexate level.Methotrexate also elevates phenylalanine and

depletes tetrahydrobiopterin, resulting in decreasedproduction of catecholamines and biogenic amineneurotransmitters, thereby predisposing patients toseizures [5,12]. Biogenic amine neurotransmitterssuch as 5-hydroxyindoleacetic acid (5-HIAA) havebeen shown to have an effect in treating refractorymethotrexate induced neurotoxicity [13]. It has alsobeen demonstrated that nucleotide synthesis can beinhibited by methotrexate, resulting in elevated levelsof adenosine. This explains why aminophylline, areversible inhibitor of adenosine, can be used in treat-ing methotrexate-induced neurotoxicity [5,14,15]. Ithas also been reported that plasma homocysteinelevels are increased acutely following methotrexateadministration, possibly contributing to its neurotoxi-city [17]. In our patient, we did not obtain plasma orCSF homocysteine levels.Our patient unfortunately did not respond with

MEC induction. He was then induced with high-dose Ara-C that cleared his CSF. The patient wassubsequently referred to our blood and marrow trans-plant service where he received cyclophosphamideand TBI followed by allogenic stem-cell rescue.

There are some reported cases in the literaturedescribing acute seizures in patients who accidentallyreceived a life-threatening intrathecal dose of metho-trexate [18] or a combination of intrathecal metho-trexate and systemic methotrexate [19]. Seizures havebeen reported in children with acute lymphoblasticleukemia who received methotrexate for central ner-vous system prophylaxis [20].In conclusion, methotrexate induced neurotoxicity

ranges widely in effects and time course. It is a directeffect of methotrexate on the central nervous systemand enhanced by cranial irradiation. While seizureshave been documented as an acute or subacute ordelayed neurotoxicity, we submit this case as a rareexample of status epilepticus presenting as an acutereaction to intraventricular methotrexate in an adultpatient.

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Case Report: Methotrexate-Induced Status Epilepticus 37