Original Paper

Pediatr Neurosurg 2002;37:203–205

L-Asparaginase-Induced Reversible PosteriorLeukoencephalopathy Syndrome in a Child withAcute Lymphoblastic Leukemia

Bharti Rathia Rajeev K. Azada N. Vasudhab Praveen Hissariab

Vijay Sawlania Rakesh K. Guptaa

Departments of aRadiology and bImmunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences,Lucknow, India

Received: April 23, 2002Accepted: June 6, 2002

Dr. Rakesh K. Gupta, MD, Additional Professor, MR SectionDepartment of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical SciencesLucknow, UP, 226014 (India)Tel. +91 522 440715 (ext. 2599/2600), Fax +91 522 440017/440973E-Mail rgupta@sgpgi.ac.in or rakeshree@hotmail.com

ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com

© 2002 S. Karger AG, Basel1016–2291/02/0374–0203$18.50/0

Accessible online at:www.karger.com/journals/pne

Key WordsL-Asparaginase W Acute lymphoblastic leukemia W

Reversible posterior leukoencephalopathy W MRI

AbstractReversible posterior leukoencephalopathy syndrome(RPLS) is being increasingly described with various etiol-ogies even in the absence of hypertension. We presentan 11-year-old patient with acute lymphoblastic leuke-mia who presented with seizures while on treatmentwith L-asparaginase. MRI showed bilaterally symmetri-cal nonenhancing occipital lesions characteristic ofRPLS. L-Asparaginase-induced RPLS is a rare cause ofneurological symptoms in patients on induction chemo-therapy.

Copyright © 2002 S. Karger AG, Basel

Introduction

Reversible posterior leukoencephalopathy syndrome(RPLS) is a rare neurological syndrome characterized byvisual disturbance, seizures, headache and altered senso-rium associated with white matter changes particularly inthe occipital lobes [1]. Although hypertensive encephalop-athy is the most common cause of RPLS, recently it has

been increasingly recognized in association with chemo-therapy, transplantation, transfusion and renal failure[1–4].

L-Asparaginase is the major component of regimensfor induction therapy of remission in acute lymphoblasticleukemia (ALL) [5]. Development of RPLS during thetreatment of ALL has been reported [6]. However, it is notyet clear which drug or drug interaction is responsible forRPLS changes in ALL. although both cerebral venousthrombosis and hemorrhage have been reported in L-asparaginase-treated patients with ALL, and partial orcomplete recovery has been documented in a few patients[7, 8], it was not described as RPLS. Pegaspargase, a syn-thetic congener of L-asparaginase, has been reported tocause reversible MRI changes during the treatment ofnon-Hodgkin’s lymphoma [9]. We report a patient withALL who developed RPLS following treatment with L-asparaginase and highlight the importance of its early rec-ognition with characteristic MRI features.

Case Report

An 11-year-old girl presented to us with a history of swelling ofthe neck for 15 days and epistaxis for 2 days. On examination, shehad anemia, generalized lymphadenopathy and hepatosplenomega-ly. Blood examination revealed hyperleukocytosis; bone marrowaspiration showed hypercellular marrow with 80–90% blasts. She

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204 Pediatr Neurosurg 2002;37:203–205 Rathi/Azad/Vasudha/Hissaria/Sawlani/Gupta

Fig. 1. a T2-weighted axial image at the lev-el of the midbrain shows hyperintensity inthe cortex and subcortical white matter inboth occipital lobes. b Follow-up MRI after1 month shows complete resolution.

was diagnosed as a high-risk case of ALL type I. Alkaline diuresis wasstarted to prevent tumor lysis syndrome. She developed fever on the2nd day of admission for which she received a 5-day course of aug-mentin (amoxicillin with clavulinic acid) and amikacin. Phase Iinduction chemotherapy was started on day 4 after admissionaccording to the high-risk Berlin Frankfurt and Münster protocol.She received vincristine and daunorubicin on days 4, 11 and 18, withL-asparaginase daily from the 4th to the 17th day and prednisolonedaily, from the 4th to the 31st day. On the 17th day, nearly an hourafter subcutaneous injection of L-asparaginase, the patient com-plained of giddiness and fell down, after which she went into alteredsensorium and had three episodes of generalized tonic clonic seizureseach lasting for about 2 min with loss of consciousness. She wasdilantanised and received diazepam. No visual complaints werenoted. She recovered rapidly from this neurological illness. Com-puted tomography done on the same day showed hypodensity inbilateral parietooccipital regions without any contrast enhancement.There was no evidence of any intracranial bleed. The MRI scan per-formed a day later revealed hyperintensity involving bilateral occipi-tal regions on T2-weighted images (fig. 1a). Postcontrast T1-weightedimages did not show any abnormal enhancement. She also developedleft lower limb weakness, which was probably a vincristine-inducedneuropathy. She was kept on anticonvulsant drugs for 1 month. Afterthe initial episode of seizure, she remained seizure free, so anticon-vulsant therapy was withdrawn.

On the 22nd day of induction, the patient’s blood examinationrevealed profound neutropenia with a total leukocyte count of 600,platelet count of 6,000/mm3 and absolute neutrophil count of 24. Hernext cycle of chemotherapy, which was due on the 25th day, wasdeferred for 1 week. On the 33rd day, she received the final dose offirst-phase induction chemotherapy, and vinblastine was given inplace of vincristine along with daunorubicin in view of the vincris-tine-induced neuropathy. Repeat MRI performed 1 month after thefirst MRI showed complete resolution of the occipital lesions(fig. 1b). Blood pressure was within normal limits during the entirecourse of phase I induction chemotherapy. After this, she completed

phase II induction chemotherapy, which included cyclophospha-mide, cytarabine, 6-mercaptopurine and intrathecal methotrexatealong with brain irradiation without complications.

Discussion

RPLS, elaborated by Hinchey et al. [2], is an acute pro-gressive neurologic syndrome associated predominantlywith white matter edema in the posterior part of the cere-brum. The cardinal features of RPLS are both clinical andradiological. The prominent symptoms include alteredmental status, headaches, seizures and visual distur-bances. The clinical findings in RPLS are not sufficientlyspecific to readily establish the diagnosis and may be seenin various neurologic conditions including stroke, cere-bral venous thrombosis, demyelinating disorder or en-cephalopathy.

On neuroimaging, parietooccipital regions in particu-lar are generally involved [2]. T2-weighted MR imagesshow diffuse hyperintensity selectively in bilateral pari-etooccipital white matter; however, involvement of graymatter is not uncommon [4, 10], as was noted in our case.In addition, there can be involvement of the basal ganglia,brain stem, cerebellum and anterior region of the cere-brum, e.g. frontal lobe [11, 12]. Contrast enhancement isnot a typical feature of RPLS [13], which is consistentwith the findings in the case under discussion.

The pathophysiology of RPLS has been a source ofextensive debate. It is believed that the transient radio-

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L-Asparaginase-Induced RPLS Pediatr Neurosurg 2002;37:203–205 205

logic lesions in RPLS represent a failure of the autoregula-tory capabilities of the cerebral vessels. This leads tohyperperfusion breakdown of the blood brain barrier andconsequent vasogenic edema [10, 13]. The preferentialinvolvement of the parietal and occipital lobes is hypothe-sized to be related to the observed relative reduction inthe sympathetic innervation of the posterior circulation[2, 10, 13]. Presumably, hypertension, seizures or bothmay trigger this hyperperfusion. Drugs have been postu-lated to contribute to this physiologic effect by direct cyto-toxic effects, by inducing or exacerbating hypertension orby lowering the seizure threshold. Some patients mayshow areas of transient enhancement of the overlying cor-tex and leptomeninges related to transient breakdown ofthe blood brain barrier [2].

Seizures were the main clinical presentation of RPLSin the present case. Seizures as the major clinical manifes-tation of RPLS have not been described in patientsundergoing chemotherapy, although they have been re-ported in association with acute hypertension, especiallyin patients with renal failure [3]. However, blood pressurein our patient remained normal before, after and at thetime of seizure activity.

Many therapeutic agents like cisplatin, cytarabine, cy-closporine, interferon-· and erythropoietin have beenknown to cause RPLS [2, 12, 14, 15]. In all of these pre-viously reported cases, there was a concomitant increasein blood pressure. The precise mechanism is still notknown, i.e. whether it is due to autoregulatory failure of

cerebral vessels or the result of direct cytotoxic effects ofthe drug on the cerebrovascular endothelium. A fewauthors have blamed combination treatment with chemo-therapeutic agents [1, 6]. Our patient received L-aspara-ginase, vincristine, daunorubicin and prednisolone. Allother drugs except L-asparaginase were continued with-out any recurrence of symptoms. In addition, the childdeveloped seizures and reversible MRI changes just afterthe completion of L-asparaginase treatment. Therefore,we think L-asparaginase to be the likely causative agentresponsible for these manifestations. L-Asparaginase isknown to cause vasculitis, thrombotic occlusion and hem-orrhage as its CNS manifestations. RPLS changes may berelated to transient thrombosis, reversible cerebral con-gestion and edema. Another possible mechanism could bedirect cytotoxicity, either immune mediated or by induc-ing hypertension-related failure of autoregulation. Autor-egulatory failure is highly unlikely in our case, as the childremained normotensive during the entire course of treat-ment.

Leukemic deposits and infarcts are usually thought tobe the cause of CNS manifestations in patients with ALL.Based on this case study, we conclude that RPLS shouldbe considered in the differential diagnosis in patients withALL presenting with neurological symptoms while un-dergoing chemotherapy. The typical topographic locationof the lesions on MRI could help in arriving at a definitivediagnosis of RPLS as the cause of the patient’s neurologi-cal problem.

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