Annals of Indian Academy of Neurology
  Users Online: 913 Home | About the Journal | InstructionsCurrent Issue | Back IssuesLogin      Print this page Email this page  Small font size Default font size Increase font size

Table of Contents
Year : 2013  |  Volume : 16  |  Issue : 3  |  Page : 418-421

Methotrexate induced leucoencephalopathy: A stroke mimic

1 Department of Neurology, National Neuroscience Institute, Singapore
2 Department of Hematology, Singapore General Hospital, Singapore

Date of Submission08-Jun-2012
Date of Decision09-Jul-2012
Date of Acceptance20-Jul-2012
Date of Web Publication26-Aug-2013

Correspondence Address:
Tushar D Gosavi
Department of Neurology, National Neuroscience Institute, c/o Singapore General Hospital, Outram Road, Singapore-169608
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-2327.116922

Rights and Permissions



With increasing usage of thrombolysis in the treatment of acute ischemic strokes within 4.5- hour window, it is becoming more important to recognize stroke mimics. Though the incidence of stroke mimics being thrombolysed is less than 3%, it is essential to diagnose them so as to avoid wrong thrombolytic treatment which carries potential complications of bleeding. We describe the case of a 17 year old girl with acute lymphoblastic leukemia, who developed stroke like episodes on two consecutive challenges with a chemotherapeutic regime which included intravenous and intrathecal methotrexate. She had MRI changes consistent with acute ischemic stroke on both occasions. Her deficits recovered completely and spontaneously, as did the MRI changes. She did not have any further episodes when methotrexate was excluded from the chemotherapeutic regime.

Keywords: Leucoencephalopathy, methotrexate, stroke mimic

How to cite this article:
Gosavi TD, Ahmad MT, Lee LH, Lim SH. Methotrexate induced leucoencephalopathy: A stroke mimic. Ann Indian Acad Neurol 2013;16:418-21

How to cite this URL:
Gosavi TD, Ahmad MT, Lee LH, Lim SH. Methotrexate induced leucoencephalopathy: A stroke mimic. Ann Indian Acad Neurol [serial online] 2013 [cited 2021 Jan 23];16:418-21. Available from:

   Case Report Top

A 16-year-old girl diagnosed to have acute lymphocytic leukaemia (ALL) was admitted for consolidation phase of chemotherapy. Her previous chemotherapy cycles were uneventful. Nine days after the second cycle of consolidation chemotherapy which included IV-Methotrexate (IV-MTX) and Intrathecal-Methotrexate (IT-MTX) she developed sudden onset of parasthesias over left face and left side of body while watching television in her hospital bed. On trying to move her limbs immediately after these symptoms, she noticed clumsiness in using her left upper limb and weakness in her left lower limb. An urgent neurology referral was made for possible stroke. Her power was grade 4/5 in the left upper limb and 4+/5 in the left lower limb. There was no significant ataxia. The deep tendon reflexes were normal and symmetrical in all four limbs. Plantar reflexes were flexors. The abdominal reflexes were present and bilaterally symmetrical. There was approximately 20% reduction in pinprick sensations in left half of face. There was no objective sensory sign in the limbs. Due to sudden onset of the symptoms, a clinical impression of sensory motor neurological deficits due to a cerebrovascular event was made and an urgent MRI brain was requested.

MRI Brain was done 3.5 hours after onset of symptoms [Figure 1]. On FLAIR images, a 2 cm Χ 1.5 cm minimally hyper-intense oval-shape lesion was noted in the right fronto-parietal subcortical region. The lesion showed restricted diffusion on DWI images. MRA was normal [Figure 2]a,b. The lesion was reported as lacunar infarct. The patient was started on antiplatelet agents. Her neurological deficits subsided when she woke up next morning, about 16 hours after their onset.
Figure 1: MRI scan after the first onset of symptoms. (a) Diffusion weighted MRI image showing an area of restricted diffusion in the right fronto - parietal subcortical white matter. (b) The area of restricted diffusion is hypointense on ADC map. (c) FLAIR image showed minimal hyperintensity in the same region

Click here to view
Figure 2 (a - b): Normal MR angiogram

Click here to view

Carotid and transcranial Doppler study, 2DECHO, ECG were normal. Thrombophilia screens, ANA, dsDNA, lupus anticoagulant were negative. Lipid panel and homocysteine levels were normal. EEG was unremarkable. Antiplatelet agents were continued.

Five days after the above neurologic event, the patient received her third cycle of consolidation chemotherapy also consisting of IV-MTX and IT-MTX. She developed thrombocytopenia secondary to chemotherapy and her antiplatelet agents were stopped. On day 11 of this chemotherapy cycle and 3 days after stopping antiplatelet agents, she had another episode of acute onset of left upper and lower limb numbness and weakness along with numbness over left side of face. She woke up with these symptoms which she described to be exactly similar to the first episode. Clinical examination revealed mild weakness in the left upper and lower limb (grade 4+/5). There was no ataxia. The deep tendon reflexes were normal and symmetrical in all 4 limbs, plantars were flexors bilaterally and there was slight reduction in pin prick sensation over left half of her face.

Repeat MRI of the brain [Figure 3] again showed an area of restricted diffusion around the area of the initial lesion. Because of the temporal relation to methotrexate treatment, a clinical diagnosis of methotrexate neurotoxicity was made. This time her neurological deficits resolved within 6 hours. Five days later, MRI of brain was repeated and it showed near complete resolution of the lesions [Figure 4] [For timeline of events see [Figure 5].
Figure 3: Repeat MRI after recurrence of symptoms. (a) Diffusion weighted image showing restricted diffusion in the fronto-parietal subcortex surrounding the area of initial insult seen in Figure 1. (b) The area of restricted diffusion was hypointense on ADC map. (c) FLAIR image showed minimal hyperintensity

Click here to view
Figure 4: Repeat MRI after resolution of neurologic deficits and 5 days after MRI shown in Figure 2. DWI (a) ADC. (b) and FLAIR (c) images show near complete resolution of lesions

Click here to view
Figure 5: Summary of timeline of events

Click here to view

   Discussion Top

Our patient had 2 clinical events which were consistent with sensory-motor lacunar syndrome. She also had definite MRI lesions consistent with an acute infarct.

Stroke is the commonest but not the only cause of restricted diffusion on MRI. Restricted diffusion can occur in any setting of cytotoxic edema. Bacterial abscesses, certain epidermoid tumors, central portions of some primary and secondary brain tumors (as they outgrow their blood supply and become ischemic), an acute MS plaque may exhibit restriction diffusion. Differential diagnoses of cortical diffusion restriction include venous infarct, viral encephalitis, meningitis, CJD, mitochondrial cytopathies and postictal state. [1]

A transient or a delayed-reversible methotrexate leukoencephalopathy mimicking cerebrovascular accident has been described as a complication of chemotherapy, most commonly in recipients of intrathecal methotrexate for childhood leukaemia. [2],[3] Our patient presented with hemiparesis and sensory symptoms which were attributed to the involvement of corticospinal tract and the third order sensory fibres in the corona radiata. The temporal relation of symptoms to administration of MTX was reproduced on consecutive exposures and the lesion recurred at the same place.

In methotrexate-induced leucoencephalopathies, the exact histologic and pathophysiologic correlate of the lesion with diffusion restriction is unknown. In previous reports, a reversible metabolic encephalopathy leading to cytotoxic edema in cerebral white matter was postulated. [2] Other hypothesis included focal demyelination, microinfarctions and direct toxic effects to the CNS by damaging the neuronal tissue. [4] In animal studies, an intraventricular infusion of toxic metabolites of chemotherapeutic agents was shown to cause myelin swelling and vacuolation in an early, possibly reversible stage. These were followed by fragmentation, granularity and myelin loss in the later, possibly partially reversible or irreversible, stage. [5] Whether this could be extrapolated to methotrexate leucoencephalopathy needs further investigations. Polymorphisms in the enzyme 5, 10-methylene tetrahydrofolate reductase may predispose an individual to leucoencephalopathy following methotrexate exposure, [6] which might partly explain why only a few patients exposed to methotrexate develop leucoencephalopathy.

On the first occasion our patient developed symptoms 9 days after completion of her methotrexate dose, while the second episode occurred 11 days after the methotrexate. Previous studies have reported a variable time of onset of clinical features ranging from 6 hours to 11 days after administration of chemotherapy. [2] The mechanism as to why the clinical onset is delayed and variable after the initial exposure is still unknown. Interestingly, in our patient, the focal diffusion abnormality recurred at the same site on both occasions. Why particularly this area of the brain was predisposed remains an unanswered.

Our patient had spontaneous clinical and radiological resolution of the neurotoxicity. However, the standard treatment for methotrexate-induced encephalopathy remains supportive and includes removal of the offending chemotherapeutic agent, administration of steroid in an attempt to reduce white matter oedema, and use of antidote such as folinic acid. [7],[8]

   Conclusion Top

A clinical and radiological stroke like episode can be a presentation of MTX neurotoxicity. A high index of suspicion should be kept in an appropriate clinical setting to avoid unwarranted antiplatelet or thrombolytic therapy in this stroke mimic.

   References Top

1.Sheerin F, Pretorius PM, Briley D, Meagher T. Differential diagnosis of restricted diffusion confined to the cerebral cortex. Clin Radiol 2008;63:1245-53.  Back to cited text no. 1
2.Baehring JM, Fulbright RK. Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients. J Neurol Neurosurg Psychiatry 2008;79:535-9.  Back to cited text no. 2
3.Manousakis G, Hsu D, Diamond CA, Rowley H. Teaching NeuroImages: Methotrexate leukoencephalopathy mimicking a transient ischemic attack. Neurology 2010;75: e34.  Back to cited text no. 3
4.Vezmar S, Becker A, Bode U, Jaehde U. Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 2003;49:92-104.  Back to cited text no. 4
5.Akiba T, Okeda R, Tajima T. Metabolites of 5-fluorouracil, alpha-fluoro-beta-alanine and fluoroacetic acid, directly injure myelinated fibers in tissue culture. Acta Neuropathol 1996;92:8-13.  Back to cited text no. 5
6.Strunk T, Gottschalk S, Goepel W, Bucsky P, Schultz C. Subacute leukencephalopathy after low-dose intrathecal methotrexate in an adolescent heterozygous for the MTHFR C677T polymorphism. Med Pediatr Oncol 2003;40:48-50.  Back to cited text no. 6
7.Wilks MJ, Tie ML, Pozza CH. CT and MRI appearances of methotrexate leucoencephalopathy. Australas Radiol 2002;46:80-3.  Back to cited text no. 7
8.Ohmoto Y, Kajiwara K, Kato S, Nisizaki T, Ito H, Tamura S. Atypical MRI findings in treatment-related leukoencephalopathy: Case report. Neuroradiology 1996;38:128-33.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

This article has been cited by
1 MR screening of candidates for thrombolysis: How to identify stroke mimics?
F. Danière,M. Edjlali-Goujon,C. Mellerio,G. Turc,O. Naggara,L. Tselikas,W. Ben Hassen,M. Tisserand,C. Lamy,R. Souillard-Scemama,S. Flais,J.F. Meder,C. Oppenheim
Journal of Neuroradiology. 2014;
[Pubmed] | [DOI]
2 Methotrexate
Reactions Weekly. 2013; 1471(1): 32
[Pubmed] | [DOI]


Print this article  Email this article


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Article in PDF (1,599 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

   Case Report
    Article Figures

 Article Access Statistics
    PDF Downloaded44    
    Comments [Add]    
    Cited by others 2    

Recommend this journal