Journal of the Neurological Sciences 353 (2015) 169–171
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
A unique radiological case of intrathecal methotrexate-induced toxic leukoencephalopathy Jiwon Yang, Gap Su Kim, Hyeon-Mi Park ⁎ Department of Neurology, Gachon University Gil Medical Center, South Korea
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 2 March 2015 Received in revised form 24 March 2015 Accepted 1 April 2015 Available online 11 April 2015 Keywords: Diffusion magnetic resonance imaging Methotrexate Leukoencephalopathy
© 2015 Elsevier B.V. All rights reserved.
1. Introduction Methotrexate (MTX) is a necessary antimetabolite for the treatment of oncological disorders in all age groups. It was first introduced in 1948 for treatment of childhood lymphocytic leukemia [1]. Intrathecal methotrexate is used for prophylaxis and treatment of meningeal leukemia. Neurological adverse effects of methotrexate are not uncommon. Chronic leukoencephalopathy is the most serious neurotoxicity, particularly when it is administered intrathecally in combination with cranial radiation therapy, and is characterized by insidious evolution of dementia, pseudobulbar palsy or ataxia with widespread white matter changes. On the other hand, acute neurological toxicity is rare and not well understood. The diagnosis of acute focal symptoms from MTX treatment is difficult and sometimes challenging in patients who show restriction on diffusion-weighted image. Herein, we report on a case of acute MTX leukoencephalopathy with a unique radiological finding. 2. Case report A 19-year old male was urgently consulted to the neurology department for sudden-onset dysarthria and weakness of left upper extremity. He had been diagnosed with acute biphenotypic leukemia five months ⁎ Corresponding author at: Department of Neurology, Gil Hospital Gil Medical Center 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, South Korea. Tel.: +82 32 460 3346; fax: +82 32 460 3344. E-mail address: [email protected] (H.-M. Park).
http://dx.doi.org/10.1016/j.jns.2015.04.001 0022-510X/© 2015 Elsevier B.V. All rights reserved.
previously. Soon afterward, he underwent induction chemotherapy using vincristine, prednisolone, daunorubicin, and L-asparaginase. However, induction treatment failed and subsequently he was treated with high-dose cytarabine and idarubicin, followed by consolidation chemotherapy using cyclophosphamide, vincristine, adriamycin, and dexamethasone. He had received intrathecal administration of MTX (15 mg at a time) nine times after initial diagnosis for CNS prophylaxis. Three days after the last intrathecal MTX injection, he suddenly developed neurological symptoms. Examination revealed difficulty in verbal fluency, dysarthria, left incomplete facial paralysis and ipsilateral upper extremity weakness. Emergent brain MRI was performed within 6 h of symptom onset. Diffusion weighted imaging (DWI) MRI showed several areas of restricted diffusion with corresponding low apparent diffusion coefficient (ADC) involving the bilateral central semiovale and frontoparietal subcortical white matter (Fig. 1A, C). T2-weighted image (T2WI) and fluidattenuated inversion recovery (FLAIR) image showed well-delineated, marked hyperintense abnormalities in the same region of diffusion restriction, and further area showed hyperintense which was not seen in DWI (Fig. 1C, E, G, yellow arrow). No abnormal contrast enhancement was observed. Cerebrospinal fluid (CSF) analysis was nonspecific (4 white blood and 0 red blood cells, protein 37.7 mg/dL, glucose 68 mg/dL, absent atypical malignant cells). CSF was sterile without microorganism. Ten days later, he had shown a complete spontaneous recovery without leucovorin treatment. However, follow-up MRI after four weeks, still showed increased signal intensity of prolonged T2 changes in areas of prior restricted diffusion and newly developed
170
J. Yang et al. / Journal of the Neurological Sciences 353 (2015) 169–171
Fig. 1. Initial (A, C, E, G) and follow-up (B, D, F, H) MRI of a patient with acute MTX neurotoxicity. Restricted diffusion and its corresponding low ADC map (A) (white solid arrow) in the bilateral central semiovale is seen, which is resolved on follow-up MRI (B). Abnormal T2 hyperintensity is seen on DWI (C) and FLAIR sequence (G) with high ADC map (E) (yellow solid arrow), suggesting vasogenic edema. Concurrently, subtle diffusion restriction (C) with low ADC map (E) involving left inferior frontal gyrus (white dashed arrow) is seen at the same axial section. It seems that cytotoxic and vasogenic edema coexists initially. Follow-up MRI shows restrictive lesion disappeared (D, F) and interval development of newly T2 hyperintense lesion (H) (yellow dashed arrow).
T2 hyperintensity was observed, with normalized DWI and ADC (Fig. 1B–F). 3. Discussion MTX competitively inhibits dihydrofolate reductase, the enzyme responsible for reducing dihydrofolic acid to tetrahydrofolic acid. Reduced folates are used for metabolic transfer of 1-carbon units in many biochemical reactions. Some of these reactions influence the synthesis of thymidylate and inosine monophosphate. The inhibition of thymidylate synthesis appears to be the most important effect of methotrexate and results in greater suppression of DNA synthesis than RNA synthesis. As a result, MTX interferes with DNA synthesis, repair, and cellular replication [1,2]. The incidence of MTX-related leukoencephalopathy ranges from 3 to 10% and the risk factors include high dosage, intrathecal administration, children and young adult, and association with cranial irradiation [3]. MTX is the most commonly implicated anticancer drug in chronic encephalopathy. Cerebral imaging shows characteristic white matter disease, often confluent, i.e. leukoencephalopathy, and progressive deep brain atrophy [4]. It causes cognitive dysfunction, behavioral
abnormalities, and spasticity rather than focal deficits and the changes are usually irreversible. A transient acute neurologic syndrome has been reported in patients receiving high-dose methotrexate. Its presentation is characteristic with clinical semblance to stroke, including hemiparesis, hemisensory change, dysarthria, or aphasia. However, in contrast to stroke, complete neurological resolution has been observed in the majority of reported cases [5]. DWI with ADC maps has been useful in the early diagnosis of ischemic stroke as it distinctively identifies cytotoxic edema secondary to acute ischemia, which is not detectable with other sequences. Therefore, DWI helps in differentiation of acute infarction from other stroke mimicking disease processes. In acute ischemic stroke, low DC values are correlated with irreversible brain damage. After a couple of weeks of the ischemic event, signal normalization of DWI and ADC occurs [6]. Several reports in the literature have described radiological features of the acute to subacute MTX-related leukoencephalopathy using DWI. In those cases, transient diffusion restriction with corresponding decreased ADC values was typically found in the periventricular white matter, particularly in the centrum semiovale, without prominent high signal changes on T2- or FLAIR sequences in the acute phase. In
J. Yang et al. / Journal of the Neurological Sciences 353 (2015) 169–171
some of these cases, interval development of increased T2 signal intensity was observed on follow-up MRI [2,5,7–9]. In our case, DWI showed round, well-demarcated, symmetric restricted diffusion in the centrum semiovale with low signal on the ADC map. It was similar to previous reports denoting cytotoxic edema relevant to acute toxicity. Abnormal hyperintensity on T2 weighted and FLAIR sequences was perceptible at the same area of DWI. Simultaneously, additional hyperintense T2 changes without diffusion restriction, however, accompanied with low ADC value were represented. It suggested that vasogenic edema also coexisted. Follow-up MRI showed resolution of the diffusion abnormality and interval development of abnormal hyperintensity on FLAIR. A distinctive point in our case is the coexistence of cytotoxic and vasogenic edema as a possible explanation for MTX-induced leukoencephalopathy. The exact pathophysiology of MTX leukoencephalopathy is unclear. Several mechanisms have been proposed, including increased adenosine accumulation, homocysteine elevation and its excitatory effect on N-methyl-D-aspartate (NMDA) receptor, small vessel vasculopathy with microinfarction, increased capillary permeability, transient vasospasm, and acute demyelinating process itself [2,10]. Neuroimaging findings of our case might provide a possible explanation for those speculations. 4. Conclusion This neuroimage case revealed that cytotoxic and vasogenic edema might co-exist in a patient with this form of methotrexate leukoencephalopathy.
171
Conflict of interest None.
References [1] Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978;41(1):36–51. [2] Agarwal A, Vijay K, Thamburaj K, Ouyang T. Transient leukoencephalopathy after intrathecal methotrexate mimicking stroke. Emerg Radiol 2011;18(4):345–7. [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(10):1688–95. [4] Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med 2001;345(6):425–32. [5] Haykin ME, Gorman M, van Hoff J, Fulbright RK, Baehring JM. Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. J Neuro-Oncol 2006;76(2):153–7. [6] Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia. Stroke 1997;28(5):1082–5. [7] Kuker W, Bader P, Herrlinger U, Heckl S, Nagele T. Transient encephalopathy after intrathekal methotrexate chemotherapy: diffusion-weighted MRI. J Neuro-Oncol 2005;73(1):47–9. [8] Salkade PR, Lim TA. Methotrexate-induced acute toxic leukoencephalopathy. J Cancer Res Ther 2012;8(2):292–6. [9] Fisher MJ, Khademian ZP, Simon EM, Zimmerman RA, Bilaniuk LT. Diffusionweighted MR imaging of early methotrexate-related neurotoxicity in children. AJNR Am J Neuroradiol 2005;26(7):1686–9. [10] Sandoval C, Kutscher M, Jayabose S, Tenner M. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003;24(9):1887–90.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
A unique radiological case of intrathecal methotrexate-induced toxic leukoencephalopathy Jiwon Yang, Gap Su Kim, Hyeon-Mi Park ⁎ Department of Neurology, Gachon University Gil Medical Center, South Korea
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 2 March 2015 Received in revised form 24 March 2015 Accepted 1 April 2015 Available online 11 April 2015 Keywords: Diffusion magnetic resonance imaging Methotrexate Leukoencephalopathy
© 2015 Elsevier B.V. All rights reserved.
1. Introduction Methotrexate (MTX) is a necessary antimetabolite for the treatment of oncological disorders in all age groups. It was first introduced in 1948 for treatment of childhood lymphocytic leukemia [1]. Intrathecal methotrexate is used for prophylaxis and treatment of meningeal leukemia. Neurological adverse effects of methotrexate are not uncommon. Chronic leukoencephalopathy is the most serious neurotoxicity, particularly when it is administered intrathecally in combination with cranial radiation therapy, and is characterized by insidious evolution of dementia, pseudobulbar palsy or ataxia with widespread white matter changes. On the other hand, acute neurological toxicity is rare and not well understood. The diagnosis of acute focal symptoms from MTX treatment is difficult and sometimes challenging in patients who show restriction on diffusion-weighted image. Herein, we report on a case of acute MTX leukoencephalopathy with a unique radiological finding. 2. Case report A 19-year old male was urgently consulted to the neurology department for sudden-onset dysarthria and weakness of left upper extremity. He had been diagnosed with acute biphenotypic leukemia five months ⁎ Corresponding author at: Department of Neurology, Gil Hospital Gil Medical Center 21, Namdong-daero 774beon-gil, Namdong-gu, Incheon, South Korea. Tel.: +82 32 460 3346; fax: +82 32 460 3344. E-mail address: [email protected] (H.-M. Park).
http://dx.doi.org/10.1016/j.jns.2015.04.001 0022-510X/© 2015 Elsevier B.V. All rights reserved.
previously. Soon afterward, he underwent induction chemotherapy using vincristine, prednisolone, daunorubicin, and L-asparaginase. However, induction treatment failed and subsequently he was treated with high-dose cytarabine and idarubicin, followed by consolidation chemotherapy using cyclophosphamide, vincristine, adriamycin, and dexamethasone. He had received intrathecal administration of MTX (15 mg at a time) nine times after initial diagnosis for CNS prophylaxis. Three days after the last intrathecal MTX injection, he suddenly developed neurological symptoms. Examination revealed difficulty in verbal fluency, dysarthria, left incomplete facial paralysis and ipsilateral upper extremity weakness. Emergent brain MRI was performed within 6 h of symptom onset. Diffusion weighted imaging (DWI) MRI showed several areas of restricted diffusion with corresponding low apparent diffusion coefficient (ADC) involving the bilateral central semiovale and frontoparietal subcortical white matter (Fig. 1A, C). T2-weighted image (T2WI) and fluidattenuated inversion recovery (FLAIR) image showed well-delineated, marked hyperintense abnormalities in the same region of diffusion restriction, and further area showed hyperintense which was not seen in DWI (Fig. 1C, E, G, yellow arrow). No abnormal contrast enhancement was observed. Cerebrospinal fluid (CSF) analysis was nonspecific (4 white blood and 0 red blood cells, protein 37.7 mg/dL, glucose 68 mg/dL, absent atypical malignant cells). CSF was sterile without microorganism. Ten days later, he had shown a complete spontaneous recovery without leucovorin treatment. However, follow-up MRI after four weeks, still showed increased signal intensity of prolonged T2 changes in areas of prior restricted diffusion and newly developed
170
J. Yang et al. / Journal of the Neurological Sciences 353 (2015) 169–171
Fig. 1. Initial (A, C, E, G) and follow-up (B, D, F, H) MRI of a patient with acute MTX neurotoxicity. Restricted diffusion and its corresponding low ADC map (A) (white solid arrow) in the bilateral central semiovale is seen, which is resolved on follow-up MRI (B). Abnormal T2 hyperintensity is seen on DWI (C) and FLAIR sequence (G) with high ADC map (E) (yellow solid arrow), suggesting vasogenic edema. Concurrently, subtle diffusion restriction (C) with low ADC map (E) involving left inferior frontal gyrus (white dashed arrow) is seen at the same axial section. It seems that cytotoxic and vasogenic edema coexists initially. Follow-up MRI shows restrictive lesion disappeared (D, F) and interval development of newly T2 hyperintense lesion (H) (yellow dashed arrow).
T2 hyperintensity was observed, with normalized DWI and ADC (Fig. 1B–F). 3. Discussion MTX competitively inhibits dihydrofolate reductase, the enzyme responsible for reducing dihydrofolic acid to tetrahydrofolic acid. Reduced folates are used for metabolic transfer of 1-carbon units in many biochemical reactions. Some of these reactions influence the synthesis of thymidylate and inosine monophosphate. The inhibition of thymidylate synthesis appears to be the most important effect of methotrexate and results in greater suppression of DNA synthesis than RNA synthesis. As a result, MTX interferes with DNA synthesis, repair, and cellular replication [1,2]. The incidence of MTX-related leukoencephalopathy ranges from 3 to 10% and the risk factors include high dosage, intrathecal administration, children and young adult, and association with cranial irradiation [3]. MTX is the most commonly implicated anticancer drug in chronic encephalopathy. Cerebral imaging shows characteristic white matter disease, often confluent, i.e. leukoencephalopathy, and progressive deep brain atrophy [4]. It causes cognitive dysfunction, behavioral
abnormalities, and spasticity rather than focal deficits and the changes are usually irreversible. A transient acute neurologic syndrome has been reported in patients receiving high-dose methotrexate. Its presentation is characteristic with clinical semblance to stroke, including hemiparesis, hemisensory change, dysarthria, or aphasia. However, in contrast to stroke, complete neurological resolution has been observed in the majority of reported cases [5]. DWI with ADC maps has been useful in the early diagnosis of ischemic stroke as it distinctively identifies cytotoxic edema secondary to acute ischemia, which is not detectable with other sequences. Therefore, DWI helps in differentiation of acute infarction from other stroke mimicking disease processes. In acute ischemic stroke, low DC values are correlated with irreversible brain damage. After a couple of weeks of the ischemic event, signal normalization of DWI and ADC occurs [6]. Several reports in the literature have described radiological features of the acute to subacute MTX-related leukoencephalopathy using DWI. In those cases, transient diffusion restriction with corresponding decreased ADC values was typically found in the periventricular white matter, particularly in the centrum semiovale, without prominent high signal changes on T2- or FLAIR sequences in the acute phase. In
J. Yang et al. / Journal of the Neurological Sciences 353 (2015) 169–171
some of these cases, interval development of increased T2 signal intensity was observed on follow-up MRI [2,5,7–9]. In our case, DWI showed round, well-demarcated, symmetric restricted diffusion in the centrum semiovale with low signal on the ADC map. It was similar to previous reports denoting cytotoxic edema relevant to acute toxicity. Abnormal hyperintensity on T2 weighted and FLAIR sequences was perceptible at the same area of DWI. Simultaneously, additional hyperintense T2 changes without diffusion restriction, however, accompanied with low ADC value were represented. It suggested that vasogenic edema also coexisted. Follow-up MRI showed resolution of the diffusion abnormality and interval development of abnormal hyperintensity on FLAIR. A distinctive point in our case is the coexistence of cytotoxic and vasogenic edema as a possible explanation for MTX-induced leukoencephalopathy. The exact pathophysiology of MTX leukoencephalopathy is unclear. Several mechanisms have been proposed, including increased adenosine accumulation, homocysteine elevation and its excitatory effect on N-methyl-D-aspartate (NMDA) receptor, small vessel vasculopathy with microinfarction, increased capillary permeability, transient vasospasm, and acute demyelinating process itself [2,10]. Neuroimaging findings of our case might provide a possible explanation for those speculations. 4. Conclusion This neuroimage case revealed that cytotoxic and vasogenic edema might co-exist in a patient with this form of methotrexate leukoencephalopathy.
171
Conflict of interest None.
References [1] Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978;41(1):36–51. [2] Agarwal A, Vijay K, Thamburaj K, Ouyang T. Transient leukoencephalopathy after intrathecal methotrexate mimicking stroke. Emerg Radiol 2011;18(4):345–7. [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(10):1688–95. [4] Filley CM, Kleinschmidt-DeMasters BK. Toxic leukoencephalopathy. N Engl J Med 2001;345(6):425–32. [5] Haykin ME, Gorman M, van Hoff J, Fulbright RK, Baehring JM. Diffusion-weighted MRI correlates of subacute methotrexate-related neurotoxicity. J Neuro-Oncol 2006;76(2):153–7. [6] Schaefer PW, Buonanno FS, Gonzalez RG, Schwamm LH. Diffusion-weighted imaging discriminates between cytotoxic and vasogenic edema in a patient with eclampsia. Stroke 1997;28(5):1082–5. [7] Kuker W, Bader P, Herrlinger U, Heckl S, Nagele T. Transient encephalopathy after intrathekal methotrexate chemotherapy: diffusion-weighted MRI. J Neuro-Oncol 2005;73(1):47–9. [8] Salkade PR, Lim TA. Methotrexate-induced acute toxic leukoencephalopathy. J Cancer Res Ther 2012;8(2):292–6. [9] Fisher MJ, Khademian ZP, Simon EM, Zimmerman RA, Bilaniuk LT. Diffusionweighted MR imaging of early methotrexate-related neurotoxicity in children. AJNR Am J Neuroradiol 2005;26(7):1686–9. [10] Sandoval C, Kutscher M, Jayabose S, Tenner M. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am J Neuroradiol 2003;24(9):1887–90.
