Open AccessAnnals of Hematology & Oncology
Case Report

Subacute Encephalopathy with TranshemisphericTransition of a Focal Lesion Following Intrathecal
Methotrexate Injection in Pre-B-Cell Acute
Lymphoblastic Leukemia: A Case Report
Ando Y1, Sato Y1*, Kuwashima S2, Fukushima K1,Okuya M1, Imataka G1, Kurosawa H1 and Arisaka
O1
1
Department of Pediatrics, Dokkyo Medical University,Japan
2
Department of Radiology, Dokkyo Medical University,
Japan

Abstract
Intrathecal injection of methotrexate (MTX) is important in the treatment ofmeningeal leukemia to prevent relapse in the central nerve system in patientswith acute lymphoblastic leukemia (ALL). However, intrathecal injection of MTX
sometime induces subacute encephalopathy.

*Corresponding author: Yuya Sato, Department ofPediatrics, Dokkyo Medical University School of Medicine
880 Kita-Kobayashi, Mibu, Tochigi 321-0207, Japan
Received: August 27, 2016; Accepted: October 03,
2016; Published: October 04, 2016

A female patient with pre-B cell ALL developed relapsing-remitting
encephalopathy associated with the intrathecal injection of methotrexate. TheJapan Pediatric Leukemia Study Group ALL B-12 protocol had been followed.
Right-sided paralysis developed 2 days after the fourth intrathecal injection of
MTX. Diffusion-weighted images (DWI) during magnetic resonance imaging
revealed a high-signal area in the left centrum semiovale. The right-sided
paralysis resolved, only to be followed by left-sided paralysis and dysarthria.
Simultaneously with these symptoms, the left-sided DWI signal was decreased
and a new abnormal signal intensity lesion appeared on the right. The patient
recovered from the paralysis and dysarthria 4 days after the onset of theneurological symptoms. The phenomena with which our patient presented weresimilar to those of multiple sclerosis, but no myelin basic protein or oligoclonalband was detected in the cerebrospinal fluid.
The mechanism that causes subacute encephalopathy after intrathecal
injection of MTX is similar to that in the development of multiple sclerosis, butwith no induction of myelin basic protein or oligoclonal band.
Keywords: Subacute encephalopathy; Methotrexate; Acute lymphoblastic
leukemia; Intrathecal injection

Introduction

Case Presentation

Methotrexate (MTX) is key drug in patients with acutelymphoblastic leukemia (ALL) for the treatment of meningeal
leukemia or to prevent relapse in the central nervous system. MTX
is administered by intravenous or intrathecal injection. However,it has also neurotoxic effects [1]. Cases of subacute MTX-induced
encephalopathy reported previously showed strong signal changes on
diffusion-weighted images (DWIs) obtained with magnetic resonanceimaging (MRI) [1-11]. Although the intravenous or intrathecal
injection of MTX is assumed to be neurotoxic because it induces
metabolic changes in the central nervous system, the mechanism
underlying the development of subacute encephalopathy is unclear[1,7,10-12].

A 10-year-old female child was admitted to our hospital with
pre-B-cell ALL, which was positive forCD10, CD19, CD22, CD20,
CD24, and HLA-DR. The leukemic blasts had not infiltrated thecentral nervous system. There was not neurological symptom.
Induction therapy was administered for 5 weeks according to theJapan Pediatric Leukemia Study Group (JPLSG) ALL B-12 protocol,
with two intrathecal injections of three drugs: 12 mg of MTX, 30
mg of cytarabine, and 10 mg of prednisolone. Complete remission
was achieved with this induction therapy. Consolidation therapy,
which consisted of cytarabine, cyclophosphamide, mercaptopurine,
l-asparaginase, and two intrathecal injections of MTX, cytarabine, andprednisolone, was commenced on day 36 after the induction therapy
was completed. The fourth intrathecal injection of MTX, cytarabine,and prednisolone was given on day 45. Paralysis of the right sidedeveloped on day 57, and DWI revealed a high-signal lesion in theleft centrum semiovale (Figure 1A). Magnetic resonance angiography(MRA) revealed no obstructions or malformations of the cerebral
arteries (Figure 1B). The patient’s platelet count was 1.5×1010/L. The
prothrombin time international normalization ratio was 1.00. The

We report a patient in whom subacute encephalopathy wasinduced by the intrathecal injection of MTX. Subacute encephalopathy
was observed as chronological and spatial changes on DWI, withthe simultaneous development of central nervous system disorders,which was similar to pathogenesis of multiple sclerosis. We propose amechanism underlying subacute MTX-induced encephalopathy.
Ann Hematol Oncol - Volume 3 Issue 9 - 2016
ISSN : 2375-7965 | www.austinpublishinggroup.com
Sato et al. © All rights are reserved

Citation: Ando Y, Sato Y, Kuwashima S, Fukushima K, Okuya M, Imataka G, et al. Subacute Encephalopathy
with Transhemispheric Transition of a Focal Lesion Following Intrathecal Methotrexate Injection in Pre-B-Cell
Acute Lymphoblastic Leukemia: A Case Report. Ann Hematol Oncol. 2016; 3(9): 1112.

Sato Y

Austin Publishing GroupMTX have also been reported previously [3-5,8,10, 11,13]. However,our patient’s right-sided paralysis recovered 14 days after intrathecal
injection, but left-sided paralysis and dysarthria developed almost
immediately. The high-signal lesion on the left side decreased anda new area of high signal appeared on the right (Figure 1A and C).
Thus, our patient’s case was characterized by chronological andspatial changes in the lesions detected on DWI, and the synchronousdevelopment of central nervous system disorders after MTX
intrathecal injection. These phenomena are consistent with thepathogenesis of multiple sclerosis (MS).

Figure 1: Analysis of the brain with MRI and SPECT.
a. Diffusion-weighted image (DWI) showed restricted diffusion in the left
centrum semiovale during the period of right-sided paralysis.
b. Axial MR angiography (MRA) revealed no occlusion or malformation of thebrain vessels.
c. DWI obtained 2 days after the first episode. At this time, the right-sidedparalysis had resolved, but left-sided paralysis and dysarthria had developed.
DWI showed subtle decreased intensity in the left centrum semiovale, anddemonstrated a new lesion in the right centrum semiovale.
d. SPECT showed no defect area.

activated partial thromboplastin time was 31.3s. Fibrinogen was 448
mg/dL. No bacteria or viruses were cultured from the cerebrospinal
fluid (CSF). No myelin basic protein or oligoclonal band was detectedin the CSF. Anticoagulant and antiplatelet therapies were performed.
The physical symptoms resolved by day 58, but paralysis of the left
side and dysarthria developed suddenly on day 59. The signal of theleft-sided cerebral lesion was decreased, and a new lesion was detectedon the right side (Figure 1C). No defect was detected with singlephoton emission computed tomography (SPECT) (Figure1D). All thephenomena had disappeared by day 60. There were not abnormalitiesof laboratory analysis during paralysis developing. Remaining JPLSG
ALL-12 protocol which included that nine time of MTX intrathecal
injections and four rounds of high-dose MTX therapy were done forour patient, but paralysis was never developed again.

Discussion
There are previous reports of transient encephalopathy inducedby MTX that have shown high-signal brain lesions on DWI [1,36,8,10,13,14]. MTX-induced encephalopathy is categorized as acute,subacute, or chronic [1,3-6,8,10, 13, 14]. However, it is unclear how
this encephalopathy is induced by MTX.
In our patient, paralysis of the right side occurred 12 days after the
intrathecal administration of MTX (Figure 1A). Therefore, subacute
MTX-induced encephalopathy is consistent with the presentationof our patient [1], and was detected as a high-signal lesion on DWI,
as in previous reports [3-5,8,10,11,13]. Second episodes of subacute
MTX-induced encephalopathy after subsequent rounds of intrathecal
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MS has a high component of neuronal, axonal, and myelin loss
[15].These changes develop in three steps: the immune dysregulationof myelin; the infiltration of the blood-brain barrier by dendritic cells,
macrophages, and Th1 and Th17 lymphocytes; and the activation ofproinflammatory cytokines and the production of oxygen and nitricoxide by the infiltrating cells [15]. This progressive pathogenesis
produces myelin basic protein and an oligoclonal band in the CSF
of MS patients [15]. We consider that in our patient, MTX induced
the dysregulation of the immunological mechanism, as occurs in thedevelopment of MS, but without the induction of myelin basic protein
or the oligoclonal band. Therefore, the symptoms of our patient areinteresting in terms of the development of subacute MTX-induced
encephalopathy.
Transient ischemic attack (TIA) also produces reversible
neurological disorders. However, SPECT images obtained in ourpatient showed no defect induced by vascular insufficiency (Figure1D). This result indicates that there was no vascular insufficiency
at the time of the patient’s neurological dysfunction. Her bloodcoagulation capacity was normal and there was no suggestion ofhypercoagulation. These results confirmed that a TIA did not occur
in our patient.
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Ann Hematol Oncol - Volume 3 Issue 9 - 2016
ISSN : 2375-7965 | www.austinpublishinggroup.com
Sato et al. © All rights are reserved
Submit your Manuscript | www.austinpublishinggroup.com

Citation: Ando Y, Sato Y, Kuwashima S, Fukushima K, Okuya M, Imataka G, et al. Subacute Encephalopathy
with Transhemispheric Transition of a Focal Lesion Following Intrathecal Methotrexate Injection in Pre-B-Cell
Acute Lymphoblastic Leukemia: A Case Report. Ann Hematol Oncol. 2016; 3(9): 1112.

Ann Hematol Oncol 3(9): id1112 (2016) - Page - 03