Letter to the Editor

Visual loss following high-dose cytosinearabinoside (ARA-C)

To the Editor:Cytosine arabinoside (ARA-C) is a pyrimidineanalog of proven bene®t in the treatment of acutemyelogenous leukemia (AML) including centralnervous system involvement. Since the introductionof high-dose regimens, neurologic toxicity ofintravenous ARA-C has become noticeable (1, 2).Important predisposing risk factors include cumu-lative doses, age >60 yr, renal impairment andhepatic dysfunction (3). The neurotoxicity is pre-dominantly cerebellar and manifested as dysarthria,ataxia and lack of coordination (1, 2). Lesscommonly cerebral toxicity manifests as somno-lence and confusion or psychosis; seizures have beendescribed and, rarely, peripheral neuropathy (4).Spontaneous recovery occurs in most patients afterstopping the drug. We describe a case of persistentoptic neuropathy leading to severe visual lossfollowing administration of high-dose ARA-C.

A 33-yr-old woman was diagnosed with AML(M4 subtype). She received induction therapy witha combination of low-dose ARA-C (continuousinfusion at 100 mg/m2 for 7 d), idarubicin andetoposide. Post-induction she developed sepsisand transient renal failure attributed to the useof aminoglycosides (creatinine up to 265 mmol/L).After recovery, her bone marrow aspiration(BMA) revealed a complete remission, and high-dose ARA-C (3 g/m2 every 12 h for 3 alternatedays) was given as a consolidation therapy. Oneweek later the patient developed fever 39uC andneurological symptoms: ataxia, dysarthria and alack of coordination compatible with a diagnosisof acute cerebellitis. Computerized tomography(CT) of the brain and lumbar puncture (LP) werenormal. EEG was not contributory. The patientreceived antibiotics, with improvement of thefever and neurologic symptoms. However, aweek later she developed a gradual loss ofvision in both eyes which progressed to severevisual loss (®nger counting and 1/18 in the rightand left eyes, respectively). Fundus examination

showed blurring and swelling of the disc marginswith scattered retinal hemorrhages. Repeat brainCT and MRI showed no signs of leukemicin®ltration. LP was normal and BMA showedno evidence of leukemia. During the next 4months her visual acuity gradually improved to 1/6 and 20/130 in the right and left eyes,respectively. A right relative afferent pupillarydefect (+1) was observed. Optic disc swellingresolved and temporal optic pallor was observed.Most retinal hemorrhages have resolved. She isstill in complete remission of the leukemia.

The mechanism of ARA-C neurotoxicity isunknown. High CSF levels of ARA-C and itsactive metabolites are achieved after systemic high-dose therapy. In the absence of cytidine deaminasefrom the CNS, ARA-C is not catabolized to theinactive metabolite uracil arabinoside. Thus,supratherapeutic levels of the drug can be main-tained in the CSF for the duration of high-doseARA-C therapy, although no study had shownsigni®cant association between neurotoxicity andplasma or CSF drug levels (4). Neurotoxicity ofARA-C, especially cerebellar dysfunction, havebeen extensively reported with an incidence of10±15% (1, 2, 5). Optic neuropathy has beendescribed once before (5). In our case there was astrong temporal relationship between the adminis-tration of high-dose ARA-C and the occurrence ofvisual loss. Leukemic involvement and infection ofCNS were excluded.

Neurotoxicity from high-dose ARA-C has beenusually noted 3±8 d after initiation of the treatment(4). In our case cerebellar dysfunction appeared1 wk after treatment with ARA-C, and visual lossappeared a week later. The dosage of ARA-Cprecipitating neurotoxicity is usually in the range of36 g/m2, but the syndrome has been reported withcumulative dose as low as 15 g/m2 (1, 5). Our patientreceived 18 g/m2. The transient impairment of renalfunction in our patient could have contributed tothe development of neurotoxicity.

Eur J Haematol 2000: 64: 208±209Printed in UK. All rights reserved

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EUROPEANJOURNAL OF HAEMATOLOGY

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In conclusion, optic neuropathy with severevisual loss should be added to the list of symptomsof neurologic toxicity of ARA-C, and can appear atrelatively moderate dose of the drug.

References

1. HERZIG RH, HERZIG GP, WOLFF SN, et al. Central nervoussystem effects of high dose cytosine arabinoside. Sem Oncol1987;14 (suppl):21±24.

2. HWANG T-I, YUNG WKA, ESTEY EH, FIELDS WS. Centralnervous system toxicity with high dose ARA-C. Neurology1985;35:1475±1479.

3. RUBIN EH, ANDERSON JW, GERG DT, et al. Risk factors forhigh-dose ARA-C neurotoxicity: an analysis of cancer andleukemia group B trial in patients with acute myeloidleukemia. J Clin Oncol 1992;10:948±953.

4. BAKER WJ, ROYER GL, WEISS RB. Cytarabine and neurologictoxicity. J Clin Oncol 1991;9:679±693.

5. HOFFMAN DL, HOWARD JR, SARMA R, RIGGS JE.Encephalopathy, myelopathy, optic neuropathy, and anos-

mia associated with intravenous ARA-C. Clin Neuro-pharmacol 1993;16:258±262.

Joseph Schwartz1, Yair Alster2, O®ra Ben-Tal1,Anat Lowenstein2

Departments of1Hematology and

2Opthalmology,

Tel-Aviv Sourasky Medical Center, Tel-AvivUniversity, Sackler Medical School, Israel

Correspondence: Joseph Schwartz, MD,Department of Hematology, Tel-Aviv SouraskyMedical Center, 6 Weizman St., Tel-Aviv, 64239,IsraelTel: +972-3-6973576Fax: +972-3-6974452e-mail: eljosch@actcom.co.il

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