Pediatr Blood Cancer 2015;62:539–541

BRIEF REPORT Severe Neurotoxicity Following Intrathecal Methotrexate With Nitrous Oxide Sedation in a Child With Acute Lymphoblastic Leukemia U. Lo¨bel,

MD,

1

J. Trah, MD,2 and G. Escherich,

Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include

MD

2

*

neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months. Pediatr Blood Cancer 2015;62:539–541. # 2014 Wiley Periodicals, Inc.

Key words: leukemia; methotrexate; neurotoxicity; nitrous oxide

INTRODUCTION Methotrexate (MTX) is widely used in chemotherapy protocols for treatment of acute lymphoblastic leukemia (ALL). Systemic treatment approaches differ, varying from low-dose [100 mg/m2] to high-dose MTX [5 g/m2] [1,2]. Intensified intrathecal MTX is a sufficient approach for treatment of central nervous system (CNS) leukemia and prophylaxis of CNS relapse [3]. MTX interacts with the folate pathway by replacing folate, a coenzyme for dihydrofolate reductase (DHFR), resulting in a cellular depletion of tetrahydrofolates (THF), which are essential for the conversion of homocysteine to methionine by the enzyme methioninesynthase [4]. Thus, the inhibition of the DHFR by MTX leads to an accumulation of homocysteine and depletion of S-adenosylmethionine. Both mechanisms are discussed as causes of neurotoxic side effects [5]. Neurotoxicity following MTX treatment is well described, depending on several factors, such as dose, route of administration and age [6–8]. Acute symptoms, occurring within minutes or hours after intrathecal application are headache, nausea, vomiting and dizziness, while intravenous application causes somnolence, confusion, fatigue, and seizures. Subacute symptoms (days to weeks) are characterized by hemiparesis, ataxia, confusion and seizures after intravenous application, whereas intrathecal MTX may be associated with a severe myelopathy, sensory changes, and paraplegia [7,8]. Severe neurotoxicity with quadriplegia, coma or even death has been described. These occur most frequently after a combination of high-dose MTX and intrathecal MTX, and on rare occasions after high-dose MTX and/or intrathecal MTX alone [7,8]. Nitrous oxide (N2O) is a volatile sedative, frequently used as an anesthetic agent for minor surgical procedures in pediatric patients. It is excreted essentially unchanged via the lungs and has a very short half-life of approximately 5 min [9]. N2O interacts within the folate pathway by oxidation of the cobalt-I (Coþ) cation leading to an inactivation of the cobalamin-dependant enzyme methionine synthase, resulting in accumulation of 5-THF together with homocysteine [10,11]. As a consequence, a reduction of THF after prolonged use of N2O was observed [12]. The reduction of methionine is thought to be responsible for impairment of hematopoiesis and for neurodegeneration and myelopathy in patients receiving N2O for prolonged anesthesia or with longterm use of N2O [13].  C

2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25270 Published online 31 October 2014 in Wiley Online Library (wileyonlinelibrary.com).

We present a patient with severe neurotoxicity after simultaneous administration of N2O and intrathecal MTX during the induction therapy of ALL.

CASE REPORT A 7-year-old female with no history of preexisting co-morbidities was diagnosed with B Precursor ALL. Induction therapy according to the CoALL 08-09 protocol was initiated. The first lumbar puncture was traumatic with an absolute cell count below 5 cells/ml, but with evidence of blasts (CNS4 status) [14], indicating two additional weekly doses of intrathecal MTX. While the first intrathecal MTX administration was applied under general anesthesia the following two MTX administrations were performed under N2O/oxygen gas mix (50%/50%) sedation via mask insufflation for less than 5 min before intrathecal application. Four days after the third intrathecal MTX application the patient was admitted to our hospital because of dysarthria and carpopedal spasms. The patient was neutropenic at the time of admission without infectious symptoms. The cerebrospinal fluid (CSF) revealed no signs of infection (Table I), but the c-reactive protein was slightly elevated, hence empiric antimicrobial therapy was started with ceftazidime. One day after admission, clinical symptoms worsened dramatically with somnolence, loss of muscle control and decreasing Glasgow coma scale to a score of four, which made intensive care treatment necessary. Anti-infective treatment was intensified the same day by adding antiviral and antifungal drugs. They were stopped after 7 days, because all microbiological laboratory results were negative. Additional Supporting Information may be found in the online version of this article at the publisher’s web-site. 1

Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Conflict of interest: The authors stated no conflict of interest.  Correspondence to: Gabriele Escherich, University Medical Center Hamburg-Eppendorf Clinic of Pediatric Hematology and Oncology, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: [email protected]

Received 24 June 2014; Accepted 18 August 2014

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TABLE I. Laboratory Parameters of the Patient on Admission

Laboratory parameters WBC RBC Hemoglobin Platelets Protein Albumin Bilirubin ASAT (GOT) ALAT (GPT) CrP Cyanocobalamin Folatic acid CSF Glucose Lactate Protein

Unit

Reference

Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.

Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in chara...
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