Pediatric Hematology and Oncology
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Transient Encephalopathy Following a Single Exposure of High-Dose Methotrexate in a Child with Acute Lymphoblastic Leukemia Masako Kubo, Eiichi Azuma, Shoujiro Arai, Yoshihiro Komada, Masahiro Ito & Minoru Sakurai To cite this article: Masako Kubo, Eiichi Azuma, Shoujiro Arai, Yoshihiro Komada, Masahiro Ito & Minoru Sakurai (1992) Transient Encephalopathy Following a Single Exposure of HighDose Methotrexate in a Child with Acute Lymphoblastic Leukemia, Pediatric Hematology and Oncology, 9:2, 157-165, DOI: 10.3109/08880019209018331 To link to this article: http://dx.doi.org/10.3109/08880019209018331
Published online: 09 Jul 2009.
Submit your article to this journal
Article views: 14
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipho20 Download by: [University of California, San Diego]
Date: 31 March 2016, At: 23:30
Short Communication
TRANSIENT ENCEPHALOPATHY FOLLOWING A SINGLE EXPOSURE OF HIGH-DOSE METHOTREXATE IN A CHILD WITH ACUTE LYMPHOBIASTIC LEUKEMIA
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
Masako Kubo, MD, Eiichi Azuma, MD, Shoujiro Arai, MD, Yoshihiro Komada, MD, Masahiro Ito, MD, and Minoru Sakurai, MD 0 Department of Pediatrics, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514 Japan
0 An episode of transient encephalopathy ajier the j r s t course of intravenous high-dose mcthotrexate (HD-MTX; 1000 mg/m2) was observed in a I-ycar-old girl with acute lymphoblastic lncknnia. The neurological abnonnalitics took place 5 days after HD-MTX therapy. Shc expm'enced complex partial seuure and hji hiparesis, which resolved spontaneously in 5 days. Cranial computed tomographic scan and magnetic resonance imaging showed multiple low-density lesions in bilateral hemispheres. It is well appreciated that neurotoxicityj?om M T X follows prolonged exposures, oficn accompanying or following radiation therapy. To our knowldge, howevn, thcre have been no reports that such neurological complications developed following a single exposure o f H D - M T X in patients with A L L . Follow-up clectroencephalograms showed that shc had periodic lateralized epileptform discharges (PLEDS), sugpting functional deaffmentation of cortical neuronsfollowing HD-MTX. Moreover, the serum and CSF M T X levelsfollowing a second low-dose course and hcr clinical course suggested that shc had presumably central nervous system leukemia at the time of HD-MTX therapy, which might have been related to neurological complications. Thc pathogenesis o f MTX-induced neurotoxicity is discussed.
KEY WORLS: acu& lynphoblastic leukemia, mthotremte, transient mephalopathy
INTRODUCTION A subacute transient cerebral dysfunction and chronic leukoencephalopathy have been shown to be associated with intrathecal injection of methotrexate (IT-MTX) and intravenous high-dose methotrexate (HD-MTX). In 1978, Allen et al first reported transient cerebral dysfunction a few days after the treatment of HD-MTX and vincristine (VCR)in patients with osteogenic sarcoma.' Subsequently, several other cases of subacute transient neurotoxicity with HD-MTX have been reported in osteogenic s a r c ~ m aand ~ ' ~ in acute lymphoblastic leukemia (ALL) .6 Encephalopathy developed at various times following MTX therapy. Subacute transient neurotoxicity appeared early in the chemotherapy regimen, most commonly after the second or third course of
Pediatric Hnalology and Oncology, 9:157-165, 1992 Copyright @ 1992 by Hemisphere Publishins Corporation
157
158
M. KUBO ET A 1
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
HD-MTX except one case of osteogenic sarcoma after a single treatment of very high-dose MTX.2-6In ALL, chronic encephalopathy often follows prolonged exposure of MTX.' Usually patients with ALL received lower doses of M T X than those with osteogenic sarcoma. Following a single exposure of HD-MTX, occurrence of neurotoxicity is quite uncommon. Here we report on a girl with ALL who developed transient neurotoxicity after the first course of HD-MTX plus VCR.
CASE REPORT A 4-year-old Mexican girl was admitted to the Mie University Hospital to continue chemotherapy for ALL. Three months prior to admission to the hospital, she was admitted to a hospital in Mexico because of bleeding tendency and arthralgia. Petechiae, hepatosplenomegaly, and cervical lymphadenopathy were noted. The hemoglobin was 11.2 g/dl. The white cell count was 171,000/mm3with 90 % of lymphoblasts that were classified as L1, as defined by French-American-British (FAB) classification. The diagnosis of ALL was made, although immunophenotype and karyotype were unknown. She was started on VCR, cyclophosphamide, doxorubicin, and prednisone, and was given a course of intrathecal injection of M T X (12.5 mg/m2),cytosine arabinoside, and hydrocortisone during remission induction. She achieved complete remission after six courses of chemotherapy. She never received oral 6mercaptopurine or M T X therapy. On admission to the hospital she appeared well. Physical examination revealed nothing particular. Bone marrow aspirates showed that she was in complete remission. The hemoglobin was 10.0 g/dl; the white cell count was 4700/mm3 with 46% polys, 50% lymphocytes, 4% monocytes; the platelet count was 596,000/mm3. Blood chemistry was normal. Since she belonged to the high-risk ALL group (high initial leukocyte count), she was placed on the protocol for high-risk ALL (group study for childhood cancers at Tohkai District, Japan). This protocol consists of vincristine (1.5 mg/mm2), dexamethasone (4 mg/mm2 every 8 hours), cyclophosphamide (10 mg/kg), bleomycin (0.2 mg/kg) given together intravenously and given simultaneously with 1000 mg/m2 HD-MTX over 24-hr continuous infusion followed 12 hours later by folinic acid (CF) 15 mg i.v., 3 hourly X 9, and 6 hourly X 8. The M T X infusion was complicated by frequent vomiting and poorly localized headache that continued for as long as 4 days. Five days after the completion of MTX, she became sleepy and developed slurred speech, versive reaction to the right side, deviation of eyes to the right side, automatism, cortical blindness, and hyporeflexia of extremities. Electroencephalogram (EEG) revealed continuous a waves on left occipital region without any epileptic discharge (Fig. 1A). Cranial C T scan was normal at this
159
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
$ 3
poCv
1
FIGURE 1. EEG tracing revealed. (A) Continuous a wave on left occipital region at the onset of the encephalopathy. (B) Periodic spike discharge on the left occipital region 2 days after the onset of encephalopathy. (C) Diffuse synchronous spikes and waves on the right hemisphere after 3 days. (D) Bilateral slowing after 2 months.
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
160
M. KUBO ET A 1
time. The hemoglobin was 12.6 g/dl, the white cell count 4000/mm3with 84% neutrophils and 1696 lymphocytes. The platelet was 214,000/mm3. There was no bleeding tendency. Serum electrolytes were unremarkable. A spinal tap detected normal CSF, including cytospin preparation for leukemic cells. CSF protein was normal level, but myelin basic protein was not determined. CSF cultures were negative and viruses, especially herpes simplex virus, were not isolated. Within 2 hours she became alert without residual major neurological abnormalities. She was diagnosed as having the complex partial seizure and was begun on phenytoin intravenously. The seizure was observed 1 to 2 times daily for 3 days. Follow-up EEG tracings revealed periodic spike discharge on the left occipital lobe (Fig. 1B). Two days after the first convulsive episode left hemiparesis and left side of eye deviation developed again, and spike discharge on the right occipital lobe and diffuse synchronous spikes and waves appeared on EEG (Fig. 1C). C T scan on day 3 revealed low-density area with enhancement in the left occipital, left frontal, and right frontal lobes (Fig. 2). It could represent that the neurotoxicity was localized in the cortex and/or subcortical region. Magnetic resonance imaging (MRI) on day 11 revealed the same lesion of C T scan. Repeated
FIGURE 2. Cranial CT scan 3 days after the onset of the encephalopathy showing low-density areas with enhancement in the left occipital and left frontal lobes.
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
161
CSF studies were negative. The patient was placed on intravenous diazepam and oral carbamazepin, which were effective to suppress convulsions. The symptoms gradually abated in 5 days, but hyporeflexia continued for an additional 2 months. Two weeks after the convulsion CT scans revealed disappearance of the low-density area with enhancement. Brain scintigram with [1231]inosinemonophosphate on day 30 revealed normal blood flow in the cerebral hemisphere. However, EEG remained abnormal with bilateral 6 showing for 2 months (Fig. 1D). At 2 months after the episode of cerebral dysfunction, M T X was administered weekly as either bolus injection of 150 mg/m2or drip infusion of 200 mg/ m2 over 4 hours. Samples for serum and CSF M T X levels were obtained as 1.73 and 0.10 pM, respectively, at the end of drip infusion, and as 9.17 and 0.14 pM at 6 hours after bolus injection. M T X concentration and its clearance in serum were within normal limits. However, percent CSF/serum ratio was 5.78 (bolus injection) and 1.53 (drip infusion), which was much higher than the values of other reported cases (0.5 1-0.68) following HD-MTX therapy.' The levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acids (HVA) in CSF were within normal range. She did not experience any neurological abnormalities this time. Since then, she had been on intrathecal cytosine arabinoside and hydrocortisone for prophylaxis of CNS leukemia four times. Five months after the episode, she complained of headache and vomiting, and 2900 ALL cells/mm3 were found in CSF. M T X was again administered intrathecally, resulting in clinical improvement and normalized CSF. However, after cranial irradiation (18 Gy), slurred speech recurred. O n T2-weighted MRI, the white matter showed diffusely high-intensity lesions, suggesting leukoencephalopathy (Fig. 3). At 9 months after convulsion, she developed hematological relapse. Bone marrow cells showed common ALL phenotype with Philadelphia chromosome.
DISCUSSION The clinical neurotoxic reactions of M T X were well documented as acute and chronic cerebral disturbances.' Acute arachnoiditis was associated with intrathecal administration and acute somnolence, fatigability, confusion, disorientation, seizures, or increased intracranial pressure were observed during or within hours after several courses of intravenous administration of HDMTX. Chronic encephalopathy may become progressive and include seizures, ataxia, stupor, paraplegia, dementia, and death after several months to years of M T X therapy. Pathological changes have included multiple necrotic foci of white matter, fibrinoid changes in adjacent blood vessels, and periventricular calcification^.^'^
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
162
M. KUBO ET A1
FIGURE 3. T2-weighted magnetic resonance imaging showed diffuse high-intensity lesions in the white matter, suggesting leukoencephalopathy.
The subacute neurotoxicity had been reported as motor dysfunction of spinal cord or brain within days and weeks after starting therapy in patients receiving frequent IT-MTX.' In 1978, Allen et al reported transient focal cerebral deficit after HD-MTX therapy.' Similar cases have been reported in 16 cases of osteogenic sarcoma and 4 cases in ALL.3-6The mode of onset was abrupt, usually 4-16 days after the early courses of HD-MTX treatment with C F rescue and with or without vincristine. These patients had hemiparesis, generalized or focal seizures, aphasia, loss of consciousness, dysarthria, and emotional disturbance. In two patients hemiparesis appeared to migrate from one side to the other. The deficits fluctuated 1-10 days and resolved within 35 days. It is intriguing that these symptoms represent dysfunction of cortex and/or subcortical region of brain, and the abnormal signs of basal ganglia, cerebellum, and brain stem were rarely observed. C T scan revealed normal in 12 patients and focal leukoedema, hypodensity, periventricular hypodensity in three patients. EEG showed nonspecific diffuse slowing or focal slowing in 13 patients and in two, spike and slow were observed. The patient developed an abrupt onset of neurotoxicity 5 days after the first course of HD-MTX. The symptoms and EEG showed neurological dys-
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
163
function migrated from the left side to the right. It is interesting that periodic spikes appeared in left occipital region, since periodic lateralized epileptiform discharges (PLEDS) means a summated activity of population of cortical neurons undergoing shifts in membrane potential or partial functional deafferentation of cortical neurons." C T scan also indicated multiple foci of the lesions. The neurotoxicity was located in the multiple foci of cerebral cortex and/or subcortical region. CSF study and brain scintigram excluded any major cerebral vasculopathy. She did not have congenital heart disease, rheumatic valvular disease, or bacterial endocarditis, where cerebrovascular accident might develop. Taken together, encephalopathy due to M T X was most likely, although intracranial vasculitis and transient cerebrovascular occlusions or spasms due to destruction by leukemic infiltration cannot be completely excluded. The pathogenesis of subacute transient neurotoxicity remains to be determined. Concentration of M T X in CNS seems to be related to this neurotoxicity.1'5'7Patients with osteogenic sarcoma received as much as 6-12 g/m'. Patients with ALL usually have been given lower doses of M T X than in osteogenic sarcoma. In the present case, even at lower dose M T X administration, percent CSF/serum ratio was upper limit of the normal range (2-5)." But in other reported cases following HD-MTX therapy, the values of percent Clearance of M T X in CSF might have CSF/serum ratio was 0.51-0.68.7"2 been more delayed than in serum; hence percent CSF/serum increased during 24-hour drip infusion of MTX. I' Collectively, M T X concentration on administration of 1 g/m' HD-MTX, which had not been determined, might have induced high levels in CSF. Several factors may effect high concentration of M T X in CNS. Morse reported that in patient with ALL, CNS involvement of leukemic cells increased M T X concentration in CNS, and that in 2 of 11 patients with meningeal leukemia overt CNS leukemia was preceded by a high CSF/serum ratio 13 of M T X concentration. Leukemic cells may involve a damage of endothelial cells of capillary vessels and may increase permeability of MTX. In our case meningeal relapse occurred 5 months after the neurological dysfunction. High initial leukocyte count also suggested possible CNS involvement of leukemic cells. VCR also has neurotoxicities and increases intracellular concentration using with MTX." In all four cases of ALL with subacute transient encephalopathy VCR was administered with HD-MTX. Our patient continued to have peripheral neuropathy, suggesting that VCR may be related to neurotoxicity. Abelson indicated that M T X inhibited the synthesis of neurotransmitters. 15 It is tempting to hypothesize that an abnormally high CSF/serum ratio might affect the neurotransmitters in the brain, causing transient encephalop-
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
164
M.KUBOETA1
athy. We evaluated the major metabolites of neurotransmitters, HVA and 5H I M , in the CSF following low-dose MTX, at which a high CSF/serum M T X ratio was obtained. The result showed that there were no significant changes in the metabolites during and after M T X therapy. Prognosis has been favorable. The earlier reports described that most patients had no permanent damage and some patients developed permanent sequelae of mild hemiparesis."6 Subsequent chemotherapy was given to all these patients without appearance of abnormal neurological signs.2'6 In the current case subsequent intrathecal M T X administration for treatment of meningeal leukemia produced no neurological disturbances. However, following radiation therapy, diffuse degeneration on bilateral white matter was found in the patient. A recent report indicated high doses of CF prevented leukoencephalopathy.I6 To our knowledge, there have been no reports of high-dose leucovorin therapy for subacute transient encephalopathy. When the patient with subacute transient encephalopathy in ALL will be given additional MTX, other neurotoxicity may be prevented by high-dose CF.
REFERENCES 1. Bleyer WA. Neurological sequelae of methotrexate and ionizing radiation. Cuncn Emf Rcp. 1981 ;65:89-98. 2. Allen JC, Rosen G. Transient cerebral dysfunction following chemotherapy for osteogenic sarcoma. Ann Neurol. 1978;3:441-444.
3. Packer RJ, Grossman RI, Belasco JB. High dose systemic methotrexate-associated acute neurologic dysfunction. Mcd Pcdiutr Oncol. 1983;11:159-161. 4. Fritsh G, Urban C. Transient encephalopathy during the late course of treatment with high-dose methotrexate. Cuncn. 1984;ll:159-161. 5. Jaffe N, Takaue Y,Anzai T, et al. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cuncn. 1985;56:1356-1360. 6. Sato J, Tsuda Y, Ninomiya, et al. Transient encephalopathy during the intensive chemotherapy with high-dose methotrexate in children with acute lymphoblastic leukemia. Jpn J Pediutr H m f o l . 1989;3:20-26. 7. Matuoka H,Sasaki K, Fujimoto T. Clinical pharmacology of methotrexate (MTX). Clin Harmatof I/pn). 1986;27:1856-1861. 8. Price RA, Jamieson PA. The central nervous system in childhood leukemia. Cuncn. 1975;35:306-318. 9. Liu HM, Maurer HS, Vongsvivut S, et al. Methotrexate encephalopathy. Hum Puthol. 1978;9:635649. 10. Young GB, Goodnough P, Jacono V, et al. Periodic lateralized epileptiform discharges (PLEDS): electrographic and clinical features. Am J EEG Zchnol. 1988;28:1-13. 11. Poplack DG,Bleyer WA, Wood JN, et al. A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cuncn Res. 1977;37:1982-1985. 12. Freeman AI, Wang JJ, Sinks LF. High-dose methotrexate in acute lymphoblastic leukemia. Cancer Ecuf R q . 1977;61:727-731. 13. Morse M,Savitch J, Balis F, et al. Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Cfin Oncol. 1985;3:19-24. 14. Henderson GB, Tsuji JM. Identification of the bromosulfo-phthalein sensitive efflux route for metho-
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
165
trexate as the site of action of vincristine in the vincristine dependent enhancement of rnethotrexate uptake in L1210 cells. Cuncn Rcs. 1988;48:5995-6001. 15. Abelson HT.Methotrexate and central nervous system toxicity. Cuncn Eeuf Rep. 1978;62:1999-2001. 16. Cohen IJ, Stark B, Kaplinsky C, et al. Methotrexate-induced leukoencephalopathy is treatable with high-dose folinic acid. Pediufr Hemufol Oncol. 1990;7:79-87.
Received April 17, I991 Accepted August 16, I991
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
Address corrcspondmcc fo M . Kubo.
ISSN: 0888-0018 (Print) 1521-0669 (Online) Journal homepage: http://www.tandfonline.com/loi/ipho20
Transient Encephalopathy Following a Single Exposure of High-Dose Methotrexate in a Child with Acute Lymphoblastic Leukemia Masako Kubo, Eiichi Azuma, Shoujiro Arai, Yoshihiro Komada, Masahiro Ito & Minoru Sakurai To cite this article: Masako Kubo, Eiichi Azuma, Shoujiro Arai, Yoshihiro Komada, Masahiro Ito & Minoru Sakurai (1992) Transient Encephalopathy Following a Single Exposure of HighDose Methotrexate in a Child with Acute Lymphoblastic Leukemia, Pediatric Hematology and Oncology, 9:2, 157-165, DOI: 10.3109/08880019209018331 To link to this article: http://dx.doi.org/10.3109/08880019209018331
Published online: 09 Jul 2009.
Submit your article to this journal
Article views: 14
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipho20 Download by: [University of California, San Diego]
Date: 31 March 2016, At: 23:30
Short Communication
TRANSIENT ENCEPHALOPATHY FOLLOWING A SINGLE EXPOSURE OF HIGH-DOSE METHOTREXATE IN A CHILD WITH ACUTE LYMPHOBIASTIC LEUKEMIA
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
Masako Kubo, MD, Eiichi Azuma, MD, Shoujiro Arai, MD, Yoshihiro Komada, MD, Masahiro Ito, MD, and Minoru Sakurai, MD 0 Department of Pediatrics, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514 Japan
0 An episode of transient encephalopathy ajier the j r s t course of intravenous high-dose mcthotrexate (HD-MTX; 1000 mg/m2) was observed in a I-ycar-old girl with acute lymphoblastic lncknnia. The neurological abnonnalitics took place 5 days after HD-MTX therapy. Shc expm'enced complex partial seuure and hji hiparesis, which resolved spontaneously in 5 days. Cranial computed tomographic scan and magnetic resonance imaging showed multiple low-density lesions in bilateral hemispheres. It is well appreciated that neurotoxicityj?om M T X follows prolonged exposures, oficn accompanying or following radiation therapy. To our knowldge, howevn, thcre have been no reports that such neurological complications developed following a single exposure o f H D - M T X in patients with A L L . Follow-up clectroencephalograms showed that shc had periodic lateralized epileptform discharges (PLEDS), sugpting functional deaffmentation of cortical neuronsfollowing HD-MTX. Moreover, the serum and CSF M T X levelsfollowing a second low-dose course and hcr clinical course suggested that shc had presumably central nervous system leukemia at the time of HD-MTX therapy, which might have been related to neurological complications. Thc pathogenesis o f MTX-induced neurotoxicity is discussed.
KEY WORLS: acu& lynphoblastic leukemia, mthotremte, transient mephalopathy
INTRODUCTION A subacute transient cerebral dysfunction and chronic leukoencephalopathy have been shown to be associated with intrathecal injection of methotrexate (IT-MTX) and intravenous high-dose methotrexate (HD-MTX). In 1978, Allen et al first reported transient cerebral dysfunction a few days after the treatment of HD-MTX and vincristine (VCR)in patients with osteogenic sarcoma.' Subsequently, several other cases of subacute transient neurotoxicity with HD-MTX have been reported in osteogenic s a r c ~ m aand ~ ' ~ in acute lymphoblastic leukemia (ALL) .6 Encephalopathy developed at various times following MTX therapy. Subacute transient neurotoxicity appeared early in the chemotherapy regimen, most commonly after the second or third course of
Pediatric Hnalology and Oncology, 9:157-165, 1992 Copyright @ 1992 by Hemisphere Publishins Corporation
157
158
M. KUBO ET A 1
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
HD-MTX except one case of osteogenic sarcoma after a single treatment of very high-dose MTX.2-6In ALL, chronic encephalopathy often follows prolonged exposure of MTX.' Usually patients with ALL received lower doses of M T X than those with osteogenic sarcoma. Following a single exposure of HD-MTX, occurrence of neurotoxicity is quite uncommon. Here we report on a girl with ALL who developed transient neurotoxicity after the first course of HD-MTX plus VCR.
CASE REPORT A 4-year-old Mexican girl was admitted to the Mie University Hospital to continue chemotherapy for ALL. Three months prior to admission to the hospital, she was admitted to a hospital in Mexico because of bleeding tendency and arthralgia. Petechiae, hepatosplenomegaly, and cervical lymphadenopathy were noted. The hemoglobin was 11.2 g/dl. The white cell count was 171,000/mm3with 90 % of lymphoblasts that were classified as L1, as defined by French-American-British (FAB) classification. The diagnosis of ALL was made, although immunophenotype and karyotype were unknown. She was started on VCR, cyclophosphamide, doxorubicin, and prednisone, and was given a course of intrathecal injection of M T X (12.5 mg/m2),cytosine arabinoside, and hydrocortisone during remission induction. She achieved complete remission after six courses of chemotherapy. She never received oral 6mercaptopurine or M T X therapy. On admission to the hospital she appeared well. Physical examination revealed nothing particular. Bone marrow aspirates showed that she was in complete remission. The hemoglobin was 10.0 g/dl; the white cell count was 4700/mm3 with 46% polys, 50% lymphocytes, 4% monocytes; the platelet count was 596,000/mm3. Blood chemistry was normal. Since she belonged to the high-risk ALL group (high initial leukocyte count), she was placed on the protocol for high-risk ALL (group study for childhood cancers at Tohkai District, Japan). This protocol consists of vincristine (1.5 mg/mm2), dexamethasone (4 mg/mm2 every 8 hours), cyclophosphamide (10 mg/kg), bleomycin (0.2 mg/kg) given together intravenously and given simultaneously with 1000 mg/m2 HD-MTX over 24-hr continuous infusion followed 12 hours later by folinic acid (CF) 15 mg i.v., 3 hourly X 9, and 6 hourly X 8. The M T X infusion was complicated by frequent vomiting and poorly localized headache that continued for as long as 4 days. Five days after the completion of MTX, she became sleepy and developed slurred speech, versive reaction to the right side, deviation of eyes to the right side, automatism, cortical blindness, and hyporeflexia of extremities. Electroencephalogram (EEG) revealed continuous a waves on left occipital region without any epileptic discharge (Fig. 1A). Cranial C T scan was normal at this
159
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
$ 3
poCv
1
FIGURE 1. EEG tracing revealed. (A) Continuous a wave on left occipital region at the onset of the encephalopathy. (B) Periodic spike discharge on the left occipital region 2 days after the onset of encephalopathy. (C) Diffuse synchronous spikes and waves on the right hemisphere after 3 days. (D) Bilateral slowing after 2 months.
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
160
M. KUBO ET A 1
time. The hemoglobin was 12.6 g/dl, the white cell count 4000/mm3with 84% neutrophils and 1696 lymphocytes. The platelet was 214,000/mm3. There was no bleeding tendency. Serum electrolytes were unremarkable. A spinal tap detected normal CSF, including cytospin preparation for leukemic cells. CSF protein was normal level, but myelin basic protein was not determined. CSF cultures were negative and viruses, especially herpes simplex virus, were not isolated. Within 2 hours she became alert without residual major neurological abnormalities. She was diagnosed as having the complex partial seizure and was begun on phenytoin intravenously. The seizure was observed 1 to 2 times daily for 3 days. Follow-up EEG tracings revealed periodic spike discharge on the left occipital lobe (Fig. 1B). Two days after the first convulsive episode left hemiparesis and left side of eye deviation developed again, and spike discharge on the right occipital lobe and diffuse synchronous spikes and waves appeared on EEG (Fig. 1C). C T scan on day 3 revealed low-density area with enhancement in the left occipital, left frontal, and right frontal lobes (Fig. 2). It could represent that the neurotoxicity was localized in the cortex and/or subcortical region. Magnetic resonance imaging (MRI) on day 11 revealed the same lesion of C T scan. Repeated
FIGURE 2. Cranial CT scan 3 days after the onset of the encephalopathy showing low-density areas with enhancement in the left occipital and left frontal lobes.
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
161
CSF studies were negative. The patient was placed on intravenous diazepam and oral carbamazepin, which were effective to suppress convulsions. The symptoms gradually abated in 5 days, but hyporeflexia continued for an additional 2 months. Two weeks after the convulsion CT scans revealed disappearance of the low-density area with enhancement. Brain scintigram with [1231]inosinemonophosphate on day 30 revealed normal blood flow in the cerebral hemisphere. However, EEG remained abnormal with bilateral 6 showing for 2 months (Fig. 1D). At 2 months after the episode of cerebral dysfunction, M T X was administered weekly as either bolus injection of 150 mg/m2or drip infusion of 200 mg/ m2 over 4 hours. Samples for serum and CSF M T X levels were obtained as 1.73 and 0.10 pM, respectively, at the end of drip infusion, and as 9.17 and 0.14 pM at 6 hours after bolus injection. M T X concentration and its clearance in serum were within normal limits. However, percent CSF/serum ratio was 5.78 (bolus injection) and 1.53 (drip infusion), which was much higher than the values of other reported cases (0.5 1-0.68) following HD-MTX therapy.' The levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acids (HVA) in CSF were within normal range. She did not experience any neurological abnormalities this time. Since then, she had been on intrathecal cytosine arabinoside and hydrocortisone for prophylaxis of CNS leukemia four times. Five months after the episode, she complained of headache and vomiting, and 2900 ALL cells/mm3 were found in CSF. M T X was again administered intrathecally, resulting in clinical improvement and normalized CSF. However, after cranial irradiation (18 Gy), slurred speech recurred. O n T2-weighted MRI, the white matter showed diffusely high-intensity lesions, suggesting leukoencephalopathy (Fig. 3). At 9 months after convulsion, she developed hematological relapse. Bone marrow cells showed common ALL phenotype with Philadelphia chromosome.
DISCUSSION The clinical neurotoxic reactions of M T X were well documented as acute and chronic cerebral disturbances.' Acute arachnoiditis was associated with intrathecal administration and acute somnolence, fatigability, confusion, disorientation, seizures, or increased intracranial pressure were observed during or within hours after several courses of intravenous administration of HDMTX. Chronic encephalopathy may become progressive and include seizures, ataxia, stupor, paraplegia, dementia, and death after several months to years of M T X therapy. Pathological changes have included multiple necrotic foci of white matter, fibrinoid changes in adjacent blood vessels, and periventricular calcification^.^'^
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
162
M. KUBO ET A1
FIGURE 3. T2-weighted magnetic resonance imaging showed diffuse high-intensity lesions in the white matter, suggesting leukoencephalopathy.
The subacute neurotoxicity had been reported as motor dysfunction of spinal cord or brain within days and weeks after starting therapy in patients receiving frequent IT-MTX.' In 1978, Allen et al reported transient focal cerebral deficit after HD-MTX therapy.' Similar cases have been reported in 16 cases of osteogenic sarcoma and 4 cases in ALL.3-6The mode of onset was abrupt, usually 4-16 days after the early courses of HD-MTX treatment with C F rescue and with or without vincristine. These patients had hemiparesis, generalized or focal seizures, aphasia, loss of consciousness, dysarthria, and emotional disturbance. In two patients hemiparesis appeared to migrate from one side to the other. The deficits fluctuated 1-10 days and resolved within 35 days. It is intriguing that these symptoms represent dysfunction of cortex and/or subcortical region of brain, and the abnormal signs of basal ganglia, cerebellum, and brain stem were rarely observed. C T scan revealed normal in 12 patients and focal leukoedema, hypodensity, periventricular hypodensity in three patients. EEG showed nonspecific diffuse slowing or focal slowing in 13 patients and in two, spike and slow were observed. The patient developed an abrupt onset of neurotoxicity 5 days after the first course of HD-MTX. The symptoms and EEG showed neurological dys-
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
163
function migrated from the left side to the right. It is interesting that periodic spikes appeared in left occipital region, since periodic lateralized epileptiform discharges (PLEDS) means a summated activity of population of cortical neurons undergoing shifts in membrane potential or partial functional deafferentation of cortical neurons." C T scan also indicated multiple foci of the lesions. The neurotoxicity was located in the multiple foci of cerebral cortex and/or subcortical region. CSF study and brain scintigram excluded any major cerebral vasculopathy. She did not have congenital heart disease, rheumatic valvular disease, or bacterial endocarditis, where cerebrovascular accident might develop. Taken together, encephalopathy due to M T X was most likely, although intracranial vasculitis and transient cerebrovascular occlusions or spasms due to destruction by leukemic infiltration cannot be completely excluded. The pathogenesis of subacute transient neurotoxicity remains to be determined. Concentration of M T X in CNS seems to be related to this neurotoxicity.1'5'7Patients with osteogenic sarcoma received as much as 6-12 g/m'. Patients with ALL usually have been given lower doses of M T X than in osteogenic sarcoma. In the present case, even at lower dose M T X administration, percent CSF/serum ratio was upper limit of the normal range (2-5)." But in other reported cases following HD-MTX therapy, the values of percent Clearance of M T X in CSF might have CSF/serum ratio was 0.51-0.68.7"2 been more delayed than in serum; hence percent CSF/serum increased during 24-hour drip infusion of MTX. I' Collectively, M T X concentration on administration of 1 g/m' HD-MTX, which had not been determined, might have induced high levels in CSF. Several factors may effect high concentration of M T X in CNS. Morse reported that in patient with ALL, CNS involvement of leukemic cells increased M T X concentration in CNS, and that in 2 of 11 patients with meningeal leukemia overt CNS leukemia was preceded by a high CSF/serum ratio 13 of M T X concentration. Leukemic cells may involve a damage of endothelial cells of capillary vessels and may increase permeability of MTX. In our case meningeal relapse occurred 5 months after the neurological dysfunction. High initial leukocyte count also suggested possible CNS involvement of leukemic cells. VCR also has neurotoxicities and increases intracellular concentration using with MTX." In all four cases of ALL with subacute transient encephalopathy VCR was administered with HD-MTX. Our patient continued to have peripheral neuropathy, suggesting that VCR may be related to neurotoxicity. Abelson indicated that M T X inhibited the synthesis of neurotransmitters. 15 It is tempting to hypothesize that an abnormally high CSF/serum ratio might affect the neurotransmitters in the brain, causing transient encephalop-
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
164
M.KUBOETA1
athy. We evaluated the major metabolites of neurotransmitters, HVA and 5H I M , in the CSF following low-dose MTX, at which a high CSF/serum M T X ratio was obtained. The result showed that there were no significant changes in the metabolites during and after M T X therapy. Prognosis has been favorable. The earlier reports described that most patients had no permanent damage and some patients developed permanent sequelae of mild hemiparesis."6 Subsequent chemotherapy was given to all these patients without appearance of abnormal neurological signs.2'6 In the current case subsequent intrathecal M T X administration for treatment of meningeal leukemia produced no neurological disturbances. However, following radiation therapy, diffuse degeneration on bilateral white matter was found in the patient. A recent report indicated high doses of CF prevented leukoencephalopathy.I6 To our knowledge, there have been no reports of high-dose leucovorin therapy for subacute transient encephalopathy. When the patient with subacute transient encephalopathy in ALL will be given additional MTX, other neurotoxicity may be prevented by high-dose CF.
REFERENCES 1. Bleyer WA. Neurological sequelae of methotrexate and ionizing radiation. Cuncn Emf Rcp. 1981 ;65:89-98. 2. Allen JC, Rosen G. Transient cerebral dysfunction following chemotherapy for osteogenic sarcoma. Ann Neurol. 1978;3:441-444.
3. Packer RJ, Grossman RI, Belasco JB. High dose systemic methotrexate-associated acute neurologic dysfunction. Mcd Pcdiutr Oncol. 1983;11:159-161. 4. Fritsh G, Urban C. Transient encephalopathy during the late course of treatment with high-dose methotrexate. Cuncn. 1984;ll:159-161. 5. Jaffe N, Takaue Y,Anzai T, et al. Transient neurologic disturbances induced by high-dose methotrexate treatment. Cuncn. 1985;56:1356-1360. 6. Sato J, Tsuda Y, Ninomiya, et al. Transient encephalopathy during the intensive chemotherapy with high-dose methotrexate in children with acute lymphoblastic leukemia. Jpn J Pediutr H m f o l . 1989;3:20-26. 7. Matuoka H,Sasaki K, Fujimoto T. Clinical pharmacology of methotrexate (MTX). Clin Harmatof I/pn). 1986;27:1856-1861. 8. Price RA, Jamieson PA. The central nervous system in childhood leukemia. Cuncn. 1975;35:306-318. 9. Liu HM, Maurer HS, Vongsvivut S, et al. Methotrexate encephalopathy. Hum Puthol. 1978;9:635649. 10. Young GB, Goodnough P, Jacono V, et al. Periodic lateralized epileptiform discharges (PLEDS): electrographic and clinical features. Am J EEG Zchnol. 1988;28:1-13. 11. Poplack DG,Bleyer WA, Wood JN, et al. A primate model for study of methotrexate pharmacokinetics in the central nervous system. Cuncn Res. 1977;37:1982-1985. 12. Freeman AI, Wang JJ, Sinks LF. High-dose methotrexate in acute lymphoblastic leukemia. Cancer Ecuf R q . 1977;61:727-731. 13. Morse M,Savitch J, Balis F, et al. Altered central nervous system pharmacology of methotrexate in childhood leukemia: another sign of meningeal relapse. J Cfin Oncol. 1985;3:19-24. 14. Henderson GB, Tsuji JM. Identification of the bromosulfo-phthalein sensitive efflux route for metho-
TRANSIENT ENCEPHALOPATHY AFTER HIGH-DOSE METHOTREXATE
165
trexate as the site of action of vincristine in the vincristine dependent enhancement of rnethotrexate uptake in L1210 cells. Cuncn Rcs. 1988;48:5995-6001. 15. Abelson HT.Methotrexate and central nervous system toxicity. Cuncn Eeuf Rep. 1978;62:1999-2001. 16. Cohen IJ, Stark B, Kaplinsky C, et al. Methotrexate-induced leukoencephalopathy is treatable with high-dose folinic acid. Pediufr Hemufol Oncol. 1990;7:79-87.
Received April 17, I991 Accepted August 16, I991
Downloaded by [University of California, San Diego] at 23:30 31 March 2016
Address corrcspondmcc fo M . Kubo.
