Med Pediatr Oncol 2003;41:101–102

CORRESPONDENCETransient Encephalopathy Following High-Dose Methotrexate

Sir: Methotrexate can cause acute neurotoxicity character-ized by confusion, disorientation, seizures, and focal neurologicdeficits [1]. We read with interest the brief report by Peyriereet al. [2] of transient encephalopathy associated with high-dosemethotrexate (HDMTX) in a child with leukemia. Our experi-ence, and what has been commonly known of the condition,differs from their description. We would like to report an addi-tional patient and comment on the management of similarcases.

A 14-year-old girl with acute lymphoblastic leukemia was toreceive four 2-weekly courses of HDMTX 5 g/m2 as 24-hrinfusion followed by triple intrathecal chemotherapy withmethotrexate, cytarabine, and hydrocortisone at the end of eachinfusion. She had not been irradiated cranially. The first infu-sion was completed uneventfully. Nine days after the com-mencement of the second 5 g/m2 infusion, the child presentedwith right hemiplegia and transient slurring of speech. Theneurologic signs resolved completely over the next 48 hr. Thethird HDMTX infusion was then given at a dose of 2 g/m2.Nine days later, she presented again with choreiform move-ments involving her right upper and lower limbs. The symp-toms resolved over 24 hr. The planned fourth HDMTX infusionwas replaced by weekly oral treatment at 20 mg/m2/dose whilethe intrathecal medications were continued. No neurologicproblems were reported thereafter. Her renal function remainednormal throughout this period and only a mild elevation ofalanine aminotransferase was observed. The serum methotrex-ate levels, measured at 48 hr after the commencement ofHDMTX infusion, were 0.71, 0.33, and 0.11 mmol/L for thethree courses of treatment, respectively. Magnetic resonanceimaging showed a focal area of hyperintensity only over the leftcentrum semiovale on diffusion-weighted images following thefirst episode of encephalopathy. Following the second episode,the centrum semiovale of each cerebral hemisphere was sym-metrically affected. In addition, there were small areas of hy-perintense signals in both thalamic nuclei on the T2-weightedimages. The patient was well and in first complete remission11 months after diagnosis.

Our case thus differs from that reported by Peyriere et al. [2]in two ways. (1) There was a delay in the onset of neurologicchanges following HDMTX infusion; and (2) the pharmacoki-netics of methotrexate did not appear to be related to theencephalopathy. These are similar to the observations in 8among 259 patients with leukemia reported by Rubnitz et al.[1]. In those patients, signs of neurologic deficits appeared 5–13 days after HDMTX, and methotrexate pharmacokineticparameters in symptomatic patients were similar to matchedcontrols. Thus, the case of encephalopathy described byPeyriere et al. appears to be directly related to an abnormallyhigh serum methotrexate level, whereas the pathogenesisremains unknown for most other patients [1].

The recurrent appearance of neurologic signs exactly 9 daysafter HDMTX infusions in our patient is peculiar, and was onlyobserved in one of the eight cases reported by Rubnitz et al [1].Lowering the total dose from 5 to 2 g/m2 was not useful, but theencephalopathy did not recur when the treatment was switchedto low-dose oral methotrexate. Intrathecal methotrexate, whichhad been given regularly with or without HDMTX, did notseem to be related directly to the encephalopathy.

The rapid, spontaneous, and complete recovery of thetransient encephalopathy associated with HDMTX within 1–3 days [1] would make the effect of any mitigating agentsuspect unless a randomized study confirms any alleged benefit.Bernini et al. originally reported the use of aminophylline inmethotrexate-induced neurotoxicity as defined by nausea,vomiting, lethargy, and headache [3]. Six children developed‘‘neurotoxicity’’ within 24 hr of systemic plus intrathecalmethotrexate treatment. Their symptoms did not respond tostandard analgesic and antiemetic therapy but were amelioratedby aminophylline infusion. The successful experience ofPeyriere et al. [2] was therefore unique and worth furtherstudy. However, we would caution the use of aminophyllineunder such circumstances especially in the presence of renalimpairment [4].

Anselm C.W. Lee, MRCP*and C.H. Li, MRCP

Department of Paediatrics, Tuen Mun Hospital,New Territories, Hong Kong, China

Y.C. Wong, FRCRDepartment of Diagnostic Radiology

Tuen Mum HospitalNew Territories, Hong Kong, China

REFERENCES

1. Rubnitz JE, Relling MV, Harrison PL, et al. Transient encephalopathy

following high-dosemethotrexate treatment in childhood acute lymphoblastic

leukemia. Leukemia 1998;12:1176–1181.

2. Peyriere H, Poiree M, Cociglio M, et al. Reversal of neurologic disturbances

related to high-dose methotrexate by aminophylline. Med Pediatr Oncol

2001;36:662–664.

3. Bernini JC, Fort DW, Griener JC, et al. Aminophylline for methotrexate-

induced neurotoxicity. Lancet 1995;345:544–547.

4. Leakey TE, Elias-Jones AC, Coates PE, et al. Pharmacokinetics of theophyl-

line and its metabolites during acute renal failure. A case report. Clin

Pharmacokinet 1991;21:400–408.

——————*Correspondence to: Dr. Anselm C.W. Lee, MRCP, Department of Paediatrics,

Tuen Mun Hospital, New Territories, Hong Kong, China.

E-mail: aclee@netvigator.com

Received 14 June 2001; Accepted 29 August 2001

� 2003 Wiley-Liss, Inc.DOI 10.1002/mpo.1339