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Year : 2012  |  Volume : 8  |  Issue : 2  |  Page : 292-296

Methotrexate-induced acute toxic leukoencephalopathy

Department of Diagnostic Radiology, Singapore General Hospital, Singapore

Date of Web Publication26-Jul-2012

Correspondence Address:
Parag R Salkade
Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore-169608
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.98993

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 > Abstract 

Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year period.

Keywords: Acute toxic leukoencephalopathy, diffusion weighted magnetic resonance imaging, methotrexate

How to cite this article:
Salkade PR, Lim TA. Methotrexate-induced acute toxic leukoencephalopathy. J Can Res Ther 2012;8:292-6

How to cite this URL:
Salkade PR, Lim TA. Methotrexate-induced acute toxic leukoencephalopathy. J Can Res Ther [serial online] 2012 [cited 2022 Oct 6];8:292-6. Available from: https://www.cancerjournal.net/text.asp?2012/8/2/292/98993

 > Introduction Top

The central nervous system is recognized as a sanctuary for tumor cells in patients with lymphoreticular malignant disease. Acute lymphoblastic leukemia (ALL) is one of the most common haematological malignancies of childhood treated with methotrexate (MTX), as it crosses the blood-brain barrier. [1]

Although multiple drugs are used in addition to MTX, the acute neurotoxicity reported in patients with ALL who are undergoing therapy is usually attributed to MTX. MTX-associated neurotoxicity is often termed as 'leukoencephalopathy' (LEP). Acute MTX induced leukoencephalopathy (MTX-LEP) may present as seizure or focal neurological deficit but fortunately the neurological deficits are often transient. Herein, we report a local Chinese girl who had this rare complication. DW-MRI should be used in routine clinical practice to document reversible changes and differentiate from ischemia. [2],[3]

 > Case Report Top

A previously healthy 16-year-old Chinese girl presented with fever, generalized malaise and bilateral lower limb pain since two weeks. Complete blood picture revealed marked leukocytosis. Bone marrow showed blast cells and immunophenotyping was consistent with B precursor acute lymphoid leukemia (Pre-B ALL). The examination of central nervous system was normal, and cerebrospinal fluid (CSF) was negative for blast cells. She was treated with the modified consolidation therapy protocol (ALL-BFM) that consisted of intravenous and intrathecal methotrexate amongst other chemotherapeutic drugs, along with folinic acid rescue until serum MTX levels were less than 0.02 and prophylactic treatment with granulocyte-colony stimulating factor (GCSF) with good clinical response.

Nine days after the second cycle of high dose intravenous and intrathecal methotrexate therapy (3 weeks from start of first cycle of high dose intravenous and intrathecal MTX therapy), she developed sudden onset of left sided hemiparesis and numbness with ipsilateral upper motor neuron facial nerve palsy. She was fully conscious with normal vital signs. The CSF study consistently revealed no blast cells. An urgent electroencephalogram, echocardiogram, ultrasonic Doppler of carotid arteries were all normal, as was all thrombophilic screening. She recovered fully within 3 days with no numbness or neurological deficit. Subsequently, a 3 rd cycle of intravenous and intrathecal methotrexate therapy was given. After 12 days, she developed recurrence of left hemiparesis and left upper motor neuron facial nerve palsy. Once again, she recovered fully within 3 days.

During both these discrete focal neurological events, DW-MRI along with usual conventional MRI sequences with post gadolinium contrast enhanced scans were procured within 24 h of symptom onset. The DW-MRI [Figure 1]a consistently showed a focal area of restricted diffusion with corresponding low signal on ADC map [Figure 1]b involving the right centrum semiovale that was correlated with the observed neurological impairment. The concurrent T2 weighted image [Figure 1]c and post contrast T1 weighted image [Figure 1]d revealed neither marked signal change nor abnormal post contrast enhancement respectively. The MR angiogram of Circle of Willis was unremarkable and no dural venous sinus thrombosis was seen.
Figure 1a: Axial DWI shows focal restricted diffusion in right centrum semiovale (arrow)
Figure 1b: Corresponding ADC map (arrow)
Figure 1c: The axial T2WI showed no signifi cant signal abnormality in right centrum semiovale
Figure 1d: Post gadolinium T1WI showed no pathological enhancement in corresponding region

Click here to view

After 15 days of the 3 rd cycle of MTX treatment, when the patient's neurological signs and symptoms had subsided, a repeat MRI with DW imaging [Figure 2]a and corresponding ADC map [Figure 2]b showed almost complete resolution of restricted diffusion in right centrum semiovale. There were no marked signal changes in the affected region of right centrum semiovale on T2WI [Figure 2]c and FLAIR sequence [Figure 2]d, and also no enhancement was seen on post contrast T1 weighted image. As the white matter changes were reversible in DW imaging, and were most likely related to the administration of high dose intravenous and intrathecal MTX, the drug was withheld for the next cycle. However, during subsequent chemotherapy cycles, the treatment was continued using high dose intravenous and intrathecal MTX, as neurological and radiological changes were transient.
Figure 2:

Click here to view

Clinical follow up for last two years revealed no residual neurological impairment.

 > Discussion Top

Leukoencephalopathy is a structural alteration of cerebral white matter in which myelin suffers the most damage. [4]

The term 'toxic leukoencephalopathy' may be due to toxins secondary to chemotherapy or immunosuppressive therapy, or environmental or infectious in origin or may be due to cranial irradiation. Acute toxic leukoencephalopathy should be considered in the differential diagnosis of a patient who presents with recent onset of neurologic deficit and known exposure to a toxin that has been described as injuring the white matter. Various medications can cause toxic leukoencephalopathy with variable clinical severity, and usually a mild reversible form occurs. [5]

Histological findings include demyelination, myelin pallor, myelin vacuolation, axonal spheroids or macrophage infiltration and necrosis considered as the severe end point of spectrum. [3],[5]

Methotrexate (MTX) with or without cranial irradiation is a crucial component of multimodality therapy to treat and prevent CNS disease in childhood B- precursor ALL, and also the most frequently implicated offending agent capable of inducing neurological complications. [2],[6]

The basic pathophysiologic mechanisms leading to MTX-LEP are unknown but are most likely multifactorial, which includes increased adenosine accumulation, homocysteine elevation and its excitatory effect on n-methyl-D aspartate (NMDA) receptor and alteration in biopterin metabolism. [2]

Methotrexate (MTX) is a cell cycle-specific agent that inhibits the enzyme dihydrofolate reductase, preventing the conversion of folic acid to tetrahydrofolic acid and inhibiting cell replication. MTX also causes a relative excess of homocysteine, a byproduct of the folate deficiency, which is thought to induce small-vessel vasculopathy. A diminished choline-to-creatine ratio has been reported in children with MTX-related neurotoxicity; this may be related to disturbances of myelin metabolism or inhibition of glucose metabolism, induced by MTX. [3]

The incidence of MTX-LEP ranges from 3 to 10%, and varies with the dose, route of administration and frequency of MTX given, [3] the risk factors being high dose treatment, intrathecal route, young age and association with cranial irradiation. [2]

Previously reported clinical manifestation of acute MTX neurotoxicity includes headache, confusion seizures, disorientation and focal neurological deficit. [1]

Moreover, the time of induction to onset of neurotoxicity varies from 2 to 127 weeks. [3] In our case, the time of onset of neurological deficit was about 3 weeks from induction of high dose MTX treatment.

Diffusion weighted MR imaging provides unique information on viability of the brain tissue, and its image contrast is dependent on motion of water molecules. It can be reliably used to distinguish vasogenic edema from cytotoxic edema. Diffusion weighted images and apparent diffusion coefficient (ADC) maps are read concurrently to diagnose cytotoxic edema. The cytotoxic edema appears hyperintense on DWI and almost always hypointense on ADC map for 1-2 weeks; while vasogenic edema is always hyperintense on both DWI and ADC maps. Therefore, this sequence helps in detection of acute brain infarction that results in diminished random water motion and also differentiates acute infarction from other non-stroke like disease processes. The DWI abnormalities are usually indicative of irreversible cytotoxic injury. [7]

However, the transient areas of restricted diffusion on DW-MRI as seen in our case have been reported in patients with sustained seizure activity, and also in those having acute neurotoxicity associated with MTX. In these conditions, the diffusion weighted MR abnormalities are not necessarily associated with irreversible cell death. [3]

Ours is not the initial report of acute MTX-induced leukoencephalopathy studied with DW imaging that mimics a cerebrovascular event. [1],[2],[3],[5],[8]

Rollins et al, [3] reported only 5 patients who had acute MTX neurotoxicity out of 194 children (age ranging from 12 to 15 years) diagnosed with pre-B cell ALL. They established temporal relationship between the acute neurotoxicity and intrathecal administration of MTX, and most often occurred 22-23 weeks into chemotherapy. Their stroke like symptoms resolved within 24-36 h. Sandoval et al, [8] also reported a 13-year-old female patient with acute MTX-induced neurotoxicity that occurred during consolidation phase for pre- B cell ALL, which showed restricted diffusion in bilateral centrum semiovale and splenium of corpus callosum. Clinically, she recovered completely within 2 h of onset. Three weeks after admission, her diffusion abnormalities normalized, with no post contrast enhancement.

Mckinney et al, [5] reviewed 32 patients (age range 11- 70 years) over an 8-year period diagnosed with medication-related toxic leukoencephalopathy with appearance of bilateral symmetric periventricular white matter reduced diffusion on initial MRI. Out of 32 patients of toxic leukoencephalopathy due to various medications, MTX was the causative factor in 3 patients.

Mahoney et al,[6] reported 95 patients out of 1218 (7.8%) with acute MTX-induced neurotoxicity and described majority of events being seizures. The increased incidence of MTX-LEP was due to increased cumulative exposure of intravenous MTX, increased MTX-leucoverin ratio and choice and timing of intrathecal therapy. Inaba H [1] reported 7 out of 8 patients were more than 10 years old, and 4 patients had delayed systemic MTX excretion requiring additional leucoverin. The tendency toward lower MTX clearance in adolescents may contribute to the age risk, there being no significant relation between MTX pharmacokinetic parameter and leukoencephalopathy.

However, our case is unique as we not only validated the reversible changes radiologically on diffusion weighted MR imaging on follow up scan, but also had a long-term clinical follow up for two years that showed no residual neurological deficit.

MR findings were not consistent with posterior reversible encephalopathy syndrome (PRES) as clinically patient did not have hypertension, and distribution of lesions in PRES is usually in cortex and subcortical white matter, most often in the parieto-occipital lobes. [6]

Therefore, diffusion abnormalities in acute MTX neurotoxicity appear to indicate cerebral dysfunction, but not necessarily overt structural injury to the cerebrum.

The initial presentation of acute MTX neurotoxicity may be explained on the basis of the metabolic derangement from folate deficiency and homocysteine elevation that was induced by cumulative effects of repeated administration of MTX, which might have resulted in small vessel vasculopathy or can have indirect excitotoxic effects. [2],[5],[8]

Despite 2-year follow up, a long-term neurological effect in terms of cognitive function or intellectual impairment remain unknown and an additional prospective study with neuropsychological assessment is needed to delineate the actual impact of this clinical phenomenon.

 > Conclusion Top

MTX-induced LEP presents as focal area of restricted diffusion in deep periventricular white matter which is reversible radiologically on Diffusion weighted MR imaging and corresponding ADC map, with parallel clinical outcome. Such changes in deep cerebral white matter not necessarily indicate an irreversible cytotoxic injury. Alerting clinician to this potential reversible condition can help facilitate appropriate management.

 > References Top

1.Inaba H, Khan RB, Laningham FH, Crews KR, Pui CH, Daw NC. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008;19:178-84.  Back to cited text no. 1
2.Fisher MJ, Khademian ZP, Simon EM, Zimmerman RA, Bilaniuk LT. Diffusion-weighted MR imaging of early Methotrexate-Related Neurotoxicity in Children. AJNR Am J Neuroradiol 2005;26:1686-9.   Back to cited text no. 2
3.Rollins N, Winick N, Bash R, Booth T. Acute Methotrexate Neurotoxicity: Findings on Diffusion-Weighted Imaging and Correlation with Clinical Outcome. AJNR Am J Neuroradiol 2004;25:1688-95.  Back to cited text no. 3
4.Filley CM, Kleinschmidt-DeMasters BK. Toxic encephalopathy. N Engl J Med 2001;345:425-32.   Back to cited text no. 4
5.McKinney AM, Kieffer SA, Paylor RT, SantaCruz KS, Kendi A, Lucato L. Acute Toxic Leukoencephalopathy: Potential for Reversibility Clinically and on MRI with Diffusion-Weighted and FLAIR Imaging. AJR Am J Roentgenol 2009;193:192-206.   Back to cited text no. 5
6.Mahoney DH Jr, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N, et al. Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy-a Pediatric Oncology Group study. J Clin Oncol 1998;16:1712-22.   Back to cited text no. 6
7.Schaefer PW, Grant PE, Gonzalez RG. Diffusion-weighted MR Imaging of Brain. Radiology 2000;217:331-45.  Back to cited text no. 7
8.Sandoval C, Kutscher M, Jayabose S, Tenner M. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003;24:1887-90.  Back to cited text no. 8


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