Original Paper Pediatr Neurosurg 2002;37:203–205 Received: April 23, 2002 Accepted: June 6, 2002 L-Asparaginase-Induced Reversible Posterior Leukoencephalopathy Syndrome in a Child with Acute Lymphoblastic Leukemia Bharti Rathi a Rajeev K. Azad a N. Vasudha b Praveen Hissaria b Vijay Sawlani a Rakesh K. Gupta a Departments of a Radiology and b Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Key Words L-Asparaginase W Acute lymphoblastic leukemia W Reversible posterior leukoencephalopathy W MRI Abstract Reversible posterior leukoencephalopathy syndrome (RPLS) is being increasingly described with various etiologies even in the absence of hypertension. We present an 11-year-old patient with acute lymphoblastic leukemia who presented with seizures while on treatment with L-asparaginase. MRI showed bilaterally symmetrical nonenhancing occipital lesions characteristic of RPLS. L-Asparaginase-induced RPLS is a rare cause of neurological symptoms in patients on induction chemotherapy. Copyright © 2002 S. Karger AG, Basel been increasingly recognized in association with chemotherapy, transplantation, transfusion and renal failure [1–4]. L-Asparaginase is the major component of regimens for induction therapy of remission in acute lymphoblastic leukemia (ALL) [5]. Development of RPLS during the treatment of ALL has been reported [6]. However, it is not yet clear which drug or drug interaction is responsible for RPLS changes in ALL. although both cerebral venous thrombosis and hemorrhage have been reported in Lasparaginase-treated patients with ALL, and partial or complete recovery has been documented in a few patients [7, 8], it was not described as RPLS. Pegaspargase, a synthetic congener of L-asparaginase, has been reported to cause reversible MRI changes during the treatment of non-Hodgkin’s lymphoma [9]. We report a patient with ALL who developed RPLS following treatment with Lasparaginase and highlight the importance of its early recognition with characteristic MRI features. Introduction ABC © 2002 S. Karger AG, Basel 1016–2291/02/0374–0203$18.50/0 Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/journals/pne Case Report An 11-year-old girl presented to us with a history of swelling of the neck for 15 days and epistaxis for 2 days. On examination, she had anemia, generalized lymphadenopathy and hepatosplenomegaly. Blood examination revealed hyperleukocytosis; bone marrow aspiration showed hypercellular marrow with 80–90% blasts. She Dr. Rakesh K. Gupta, MD, Additional Professor, MR Section Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences Lucknow, UP, 226014 (India) Tel. +91 522 440715 (ext. 2599/2600), Fax +91 522 440017/440973 E-Mail rgupta@sgpgi.ac.in or rakeshree@hotmail.com Downloaded by: TOBB Ekonomi ve Teknoloji 193.140.109.10 - 4/28/2014 7:50:01 PM Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare neurological syndrome characterized by visual disturbance, seizures, headache and altered sensorium associated with white matter changes particularly in the occipital lobes [1]. Although hypertensive encephalopathy is the most common cause of RPLS, recently it has Fig. 1. a T2-weighted axial image at the level of the midbrain shows hyperintensity in the cortex and subcortical white matter in both occipital lobes. b Follow-up MRI after 1 month shows complete resolution. 204 Pediatr Neurosurg 2002;37:203–205 phase II induction chemotherapy, which included cyclophosphamide, cytarabine, 6-mercaptopurine and intrathecal methotrexate along with brain irradiation without complications. Discussion RPLS, elaborated by Hinchey et al. [2], is an acute progressive neurologic syndrome associated predominantly with white matter edema in the posterior part of the cerebrum. The cardinal features of RPLS are both clinical and radiological. The prominent symptoms include altered mental status, headaches, seizures and visual disturbances. The clinical findings in RPLS are not sufficiently specific to readily establish the diagnosis and may be seen in various neurologic conditions including stroke, cerebral venous thrombosis, demyelinating disorder or encephalopathy. On neuroimaging, parietooccipital regions in particular are generally involved [2]. T2-weighted MR images show diffuse hyperintensity selectively in bilateral parietooccipital white matter; however, involvement of gray matter 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 cerebrum, e.g. frontal lobe [11, 12]. Contrast enhancement is not a typical feature of RPLS [13], which is consistent with the findings in the case under discussion. The pathophysiology of RPLS has been a source of extensive debate. It is believed that the transient radio- Rathi/Azad/Vasudha/Hissaria/Sawlani/ Gupta Downloaded by: TOBB Ekonomi ve Teknoloji 193.140.109.10 - 4/28/2014 7:50:01 PM was diagnosed as a high-risk case of ALL type I. Alkaline diuresis was started to prevent tumor lysis syndrome. She developed fever on the 2nd day of admission for which she received a 5-day course of augmentin (amoxicillin with clavulinic acid) and amikacin. Phase I induction chemotherapy was started on day 4 after admission according to the high-risk Berlin Frankfurt and Münster protocol. She received vincristine and daunorubicin on days 4, 11 and 18, with L-asparaginase daily from the 4th to the 17th day and prednisolone daily, from the 4th to the 31st day. On the 17th day, nearly an hour after subcutaneous injection of L-asparaginase, the patient complained of giddiness and fell down, after which she went into altered sensorium and had three episodes of generalized tonic clonic seizures each lasting for about 2 min with loss of consciousness. She was dilantanised and received diazepam. No visual complaints were noted. She recovered rapidly from this neurological illness. Computed tomography done on the same day showed hypodensity in bilateral parietooccipital regions without any contrast enhancement. There was no evidence of any intracranial bleed. The MRI scan performed a day later revealed hyperintensity involving bilateral occipital regions on T2-weighted images (fig. 1a). Postcontrast T1-weighted images did not show any abnormal enhancement. She also developed left lower limb weakness, which was probably a vincristine-induced neuropathy. She was kept on anticonvulsant drugs for 1 month. After the initial episode of seizure, she remained seizure free, so anticonvulsant therapy was withdrawn. On the 22nd day of induction, the patient’s blood examination revealed profound neutropenia with a total leukocyte count of 600, platelet count of 6,000/mm3 and absolute neutrophil count of 24. Her next cycle of chemotherapy, which was due on the 25th day, was deferred for 1 week. On the 33rd day, she received the final dose of first-phase induction chemotherapy, and vinblastine was given in place of vincristine along with daunorubicin in view of the vincristine-induced neuropathy. Repeat MRI performed 1 month after the first MRI showed complete resolution of the occipital lesions (fig. 1b). Blood pressure was within normal limits during the entire course of phase I induction chemotherapy. After this, she completed logic lesions in RPLS represent a failure of the autoregulatory capabilities of the cerebral vessels. This leads to hyperperfusion breakdown of the blood brain barrier and consequent vasogenic edema [10, 13]. The preferential involvement of the parietal and occipital lobes is hypothesized to be related to the observed relative reduction in the sympathetic innervation of the posterior circulation [2, 10, 13]. Presumably, hypertension, seizures or both may trigger this hyperperfusion. Drugs have been postulated to contribute to this physiologic effect by direct cytotoxic effects, by inducing or exacerbating hypertension or by lowering the seizure threshold. Some patients may show areas of transient enhancement of the overlying cortex and leptomeninges related to transient breakdown of the blood brain barrier [2]. Seizures were the main clinical presentation of RPLS in the present case. Seizures as the major clinical manifestation of RPLS have not been described in patients undergoing chemotherapy, although they have been reported in association with acute hypertension, especially in patients with renal failure [3]. However, blood pressure in our patient remained normal before, after and at the time of seizure activity. Many therapeutic agents like cisplatin, cytarabine, cyclosporine, interferon-· and erythropoietin have been known to cause RPLS [2, 12, 14, 15]. In all of these previously reported cases, there was a concomitant increase in blood pressure. The precise mechanism is still not known, i.e. whether it is due to autoregulatory failure of cerebral vessels or the result of direct cytotoxic effects of the drug on the cerebrovascular endothelium. A few authors have blamed combination treatment with chemotherapeutic agents [1, 6]. Our patient received L-asparaginase, vincristine, daunorubicin and prednisolone. All other drugs except L-asparaginase were continued without any recurrence of symptoms. In addition, the child developed seizures and reversible MRI changes just after the completion of L-asparaginase treatment. Therefore, we think L-asparaginase to be the likely causative agent responsible for these manifestations. L-Asparaginase is known to cause vasculitis, thrombotic occlusion and hemorrhage as its CNS manifestations. RPLS changes may be related to transient thrombosis, reversible cerebral congestion and edema. Another possible mechanism could be direct cytotoxicity, either immune mediated or by inducing hypertension-related failure of autoregulation. Autoregulatory failure is highly unlikely in our case, as the child remained normotensive during the entire course of treatment. Leukemic deposits and infarcts are usually thought to be the cause of CNS manifestations in patients with ALL. 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