Cognitive Performance and Magnetic Resonance
Imaging Findings After High-Dose Systemic and
Intraventricular Chemotherapy f...
mental to assess long-term neurotoxic sequelae and their
effects on cognitive performance by standardized, vali-
dated met...
• Number Connection Test19
: Test of attention. This test is
analogous to the Trail Making Test Part A, in which the sub-
and at the most recent follow-up, as judged by the Reli-
able Change Indices. For each of the 56 comparisons (6
test score...
This study evaluated cognitive function and treatment-
induced white matter changes on MRI in patients receiv-
intraventricular chemotherapy that includes methotrex-
ate and cytarabine is low. Accordingly, this treatment regi-
men se...
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Cognitive Performance and Magnetic Resonance Imaging Findings ...

  1. 1. Cognitive Performance and Magnetic Resonance Imaging Findings After High-Dose Systemic and Intraventricular Chemotherapy for Primary Central Nervous System Lymphoma Klaus Fliessbach; Horst Urbach, MD; Christoph Helmstaedter, PhD; Hendrik Pels, MD; Axel Glasmacher, MD; Ju¨rgen A. Kraus, MD; Thomas Klockgether, MD; Ingo Schmidt-Wolf, MD; Uwe Schlegel, MD Background: Long-term neurotoxicity is a frequent com- plication of combined radiotherapy and chemotherapy in patients with primary central nervous system lym- phoma. Treatment protocols without radiotherapy have been implemented to avoid this; however, little detailed neuropsychologic and neuroradiologic data exist to as- sess the frequency of long-term treatment sequelae in this patient group. Objective: To determine whether a polychemo- therapy regimen based on high-dose methotrexate re- sults in cognitive impairment and/or changes detectable by magnetic resonance imaging of the brain during long- term follow-up. Patients and Methods: Twenty patients with histo- logically proven primary central nervous system lym- phoma were treated with a novel chemotherapy proto- col that included systemic and intraventricular administration of methotrexate and cytarabine (ara-C). Standardized neuropsychologic testing and magnetic reso- nance imaging investigations were performed prior to therapy and prospectively during a median follow-up pe- riod of 36 months (range, 21-69 months). Results: Ten patients achieved durable remissions with- out relapse for more than 1 year after completion of che- motherapy. There was no gross cognitive decline in any of these patients during the follow-up period. In con- trast, magnetic resonance imaging revealed therapy- induced white matter changes in 5 of these patients. Conclusions: We conclude that chemotherapy alone is associated with a low risk of long-term neurotoxicity in primary central nervous system lymphoma. Methotrexate- induced white matter lesions detectable on magnetic reso- nance imaging are not inevitably associated with signifi- cant cognitive decline. Arch Neurol. 2003;60:563-568 P RIMARY CENTRAL nervoussys- tem lymphoma (PCNSL) is a malignant brain tumor sen- sitive to both radiotherapy and chemotherapy. While radiotherapy alone results in a median survival of only 12 to 18 months,1 a me- dian survival of more than 40 months has been achieved with combined radio- therapy and chemotherapy.2 High-dose chemotherapy protocols that include methotrexatearesimilarlyeffectiveinterms of tumor response and extension of survival.3-6 In view of the greater propor- tion of long-term survivors, long-term treatment toxicity becomes increasingly relevant. Both irradiation and methotrexate are known to be potentially neurotoxic. Com- bined therapy may cause severe leukoen- cephalopathy and deep brain atrophy, resulting in a dementing illness. This com- plication typically occurs from 4 months to several years after treatment.7 The in- cidence of severe neurotoxic events ranges from 8% to 50% in different series8-12 and is particularly high in the older popula- tion. In a study by Abrey et al,10 neuro- toxicity occurred in more than 80% of the patients older than 60 years. Besell et al12 reported that 5 (62%) of 8 patients older than 60 years developed dementia after a combined polychemotherapy-radio- therapy regimen. A major goal in introducing treat- ment regimens using chemotherapy without irradiation is to prevent late neu- rotoxic effects. To effectively control tu- mor growth, chemotherapy protocols are necessarily “aggressive,” eg, using high- dose systemic methotrexate alone or in combination with other compounds, and using intraventricular or intra-arterial ad- ministration of methotrexate. The safety of these regimens with respect to neurotoxic- ity is, thus, not a priori. Hence, it is instru- ORIGINAL CONTRIBUTION From the Departments of Neurology (Mr Fliessbach, and Drs Pels, Kraus, Klockgether, and Schlegel), Radiology (Dr Urbach), Internal Medicine (Drs Glasmacher and Schmidt-Wolf), and Epileptology (Neuropsychological Section) (Dr Helmstaedter), University of Bonn, Bonn, Germany. (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 563 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from
  2. 2. mental to assess long-term neurotoxic sequelae and their effects on cognitive performance by standardized, vali- dated methods that include neuropsychologic testing in addition to magnetic resonance imaging (MRI) of the brain. However, the availability of comprehensive neu- ropsychologic data is limited to a single institution’s ex- perience with intra-arterial chemotherapy after blood- brain barrier disruption.13 Those authors concluded that no cognitive decline was detectable in any of the 31 pa- tients examined. Sandor et al4 reported the results of a neuropsychologic assessment of 7 of 14 patients treated according to an intravenous polychemotherapy proto- col: 2 of these patients experienced severe cognitive de- terioration after treatment. Guha-Thakurta et al5 pre- sented detailed data on a quality-of-life assessment of patients after intravenous methotrexate monotherapy. In other studies,3,14,15 neurotoxicity was assessed only by means of clinical impression or by rough measures, such as the Mini-Mental State Examination or by a Karnofsky Performance Score. Consequently, the extent of cogni- tive deficits that result from different treatment regi- mens remains unclear. This holds particularly true for more subtle neuropsychologic deficits, which are ex- pected to be more frequent than severe dementia.7 There- fore, we have included longitudinal neuropsychologic test- ing in a series of 20 patients treated with a novel polychemotherapy regimen that included high-dose systemic methotrexate. Additionally, standardized MRI investigations were performed to document possible treatment sequelae, since high-dose methotrexate ad- ministered to patients with sarcomas reportedly had re- sulted in periventricular white matter changes detectable on MRI.16,17 So far, it is not clear whether these changes invariably led to neuropsychologic dysfunction. METHODS PATIENTS AND TREATMENT Between September 1995 and September 1998, 20 consecu- tive patients (human immunodeficiency virus negative) with histologically proven PCNSL were treated with a novel che- motherapy protocol consisting of combined intravenous and intraventricular administration of methotrexate and cy- tarabine in combination with intravenous application of vinca- alkaloids and alkylating agents. The chemotherapy protocol is presented in Table 1. The results of the trial with respect to treatment response (70%), median time to treatment failure (20.5 months), and median overall survival (54 months) have been published in detail.18 NEUROPSYCHOLOGIC ASSESSMENT Patients underwent a standardized neuropsychologic test bat- tery, comprising tests of attention, verbal memory, visual re- tention, word fluency, and visuoconstruction. The tests were chosen because of their known sensitivity to nonspecific changes in cognitive function that would be expected to result from treat- ment-related white matter disease. The neuropsychologic ex- aminations were performed prior to treatment or immediately after its initiation and at 4 months, 12 months, and at the most recent follow-up. The following psychometric tests were used: Bonn Chemotherapy Protocol for Primary Central Nervous System Lymphoma* Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Course A Methotrexate, 5 g/m2 † IV + Vincristine, 2 mg IV + Ifosfamide, 800 mg/m2 ‡ IV + + + + Dexamethasone, 10 mg/m2 by mouth + + + + Prednisolone, 2.5 mg ICV + + + + Methotrexate, 3 mg ICV + + + + Cytarabine, 30 mg ICV + Course B Methotrexate, 5 g/m2 † IV + Vincristine, 2 mg IV + Cyclophosphamide, 200 mg/m2 ‡ IV + + + + Dexamethasone, 10 mg/m2 by mouth + + + + Prednisolone, 2.5 mg ICV + + + + Methotrexate, 3 mg ICV + + + + Cytarabine, 30 mg ICV + Course C Ara-C, 3 g/m2 § IV + + Vindesine, 5 mg IV + Dexamethasone, 20 mg/m2 by mouth + + + + + Prednisolone, 2.5 mg ICV + + + + Methotrexate, 3 mg ICV + + + + Cytarabine, 30 mg ICV + Abbreviations: ICV, intraventricularly; IV, intravenously. *Sequence of courses: A1 (days 1-5), B1 (days 22-26), C1 (days 43-49); A2 (days 64-68), B2 (days 85-89), C2 (days 106-112). Cycles A to C (A1 to C1) are repeated once (A2 to C2). †A 0.5 g/m2 infusion over 30 minutes and 4.5 g/m2 infusion over 23.5 hours. ‡One-hour infusion. §Three-hour infusion. (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 564 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from
  3. 3. • Number Connection Test19 : Test of attention. This test is analogous to the Trail Making Test Part A, in which the sub- ject has to connect numbered circles, and the time for comple- tion is analyzed. For patients older than 60 years, a special version for elderly subjects20 was used. • Controlled Written Word Association21 : Test of word flu- ency. The subject has to write as many words as possible that begin with the letters L, P, and S (or K/L/F in a parallel ver- sion) within 1 minute for each letter. The parameter used for analysis was the number of correctly produced words. • Verbal Learning and Memory Test22 : Test of verbal memory. This is a word-list learning task analogous to the Reye Au- ditory Verbal Learning Test. A 15-item word list has to be learned during 5 learning trials and recalled after an inter- ference list and a 30-minute delay. Both learning (sum of cor- rect items in the first 5 trials) and recall (loss of learned items in delayed recall) were analyzed. • Benton Visual Retention Test23 : Test of visual retention. Ten items with a 3-figure design format are presented for 10 sec- onds, and the subjects must recall the figure immediately by drawing it. The parameter used for analysis was the number of correctly reproduced items. • Block Design Test24 : Test of visuoconstruction. The subject has to reproduce 2-dimensional colored designs using col- ored blocks. The parameter used for analysis was the raw value according to the Wechsler Adult Intelligence Scale. To prevent training effects, parallel test forms were used in repeated testing if available (Controlled Written Word Association, Verbal Learning and Memory Test, and Benton Visual Retention Test). STATISTICAL ANALYSIS All raw values were transformed into standard values accord- ing to normative test data of healthy controls that consider age and education. In healthy controls, standard values have a mean±SD of 100±10, yielding a normal range of 90 to 110. As an indicator for overall cognitive performance, a summary score was computed by calculating the arithmetic mean of the standard values of the 6 evaluated test parameters. Changes in test performance between results at 4 months and at the most recent follow-up were analyzed by calculating reliable change indices for each test score in every patient. This is an estab- lished procedure to test for the significance of individual changes by comparing them with the extent of changes ex- pected to occur in a healthy control population.25 Analogous to Hermann et al,25 a 90% change score confidence interval was computed by multiplying the SE of differences (SED) by±1.64. The SED was derived from the SE of measurement (SE=[1−rxx]1/2 ) by the formula SED=(2[SE]2 )1/2 . In this equa- tion, rxx are the published retest reliability indices of the tests. The difference between 2 individual test scores was consid- ered significant if its value exceeded the borders of this confi- dence interval. Given only statistical variation, one would ex- pect only 5% of differences outside this confidence interval in both directions. Binomial tests were applied to compare the number of observed differences with the number of expected differences. MAGNETIC RESONANCE IMAGING Each patient was studied by MRI within 72 hours prior to ini- tiation of therapy, after the second chemotherapy cycle, and after completion of therapy. Magnetic resonance imaging fol- low-up was done every 4 months within the first year after therapy and every 6 months thereafter. Magnetic resonance im- aging was performed on a 0.5-T (Gyroscan T5; Philips Medi- cal Systems, Best, the Netherlands) or a 1.5-T scanner (Gyros- can ACS-NT; Philips Medical Systems). All MRI studies were carried out using a standardized protocol that included sagit- tal T1-weighted spin echo (slice thickness, 5 mm; interslice gap, 0.5 mm), axial T2-weighted fast spin echo (5 mm; 1 mm), coro- nal fluid-attenuated inversion recovery (5 mm; 1 mm), and axial T1-weighted spin echo (5 mm; 1 mm) before and following gado- linium injection. If contrast enhancement was observed on the axial slices, additional sagittal and coronal T1-weighted spin- echo images were acquired. RESULTS PATIENT CHARACTERISTICS Of the 20 patients treated, 2 died of treatment-related complications (sepsis with multiorgan failure related to myelosuppression in both cases), 4 showed progressive disease, and 14 achieved either complete (n=12) or partial (n=2) remissions.18 Ten of these patients achieved durable remissions without relapse for more than 1 year after completion of chemotherapy (6 women, 4 men; median age, 60 years [range, 27-67 years]). In these patients, the development of cognitive performance could be evaluated with regard to potential neurotoxicity. In the 4 patients who experienced relapses within 1 year after completion of treatment, cognitive deficits result- ing from the relapse itself could not be distinguished from treatment-induced deficits. Therefore, cognitive deficits in these patients could not be directly attrib- uted to treatment-related neurotoxicity. However, neuropsychologic tests were carried out in these patients as well. NEUROPSYCHOLOGIC ASSESSMENT Follow-up of the 10 patients with long-term survival and without relapse ranged from 21 to 69 months (median, 36 months; mean, 43 months) after diagnosis. Prior to therapy, 5 of them showed cognitive impairment, 2 could not be tested (global aphasia in one, noncooperation in the other), and 3 showed normal cognitive function. The neuropsychologic summary scores of these 10 patients during follow-up are shown in Figure 1. In 4 of 5 pa- tients with cognitive impairment at the initial examina- tion, improvement was found 4 months after therapy, re- sulting in a normal summary score for 3 of them. In 1 patient, this improvement resulted from recovery of a ver- bal memory deficit; in the remaining 3 patients, there was a recovery of basic attentional functions, which affected their performance on more than 1 test. Patients with nor- mal cognitive function prior to therapy showed pre- served cognitive function 4 months after therapy and thereafter, ie, there were no significant changes in the sum- mary score during the entire follow-up period. At the most recent follow-up, the summary scores ranged from 86 to 109, with a median value of 94. Although patients older than 60 years tended to have lower test scores, the over- all development of the neuropsychologic scores during follow-up was identical in patients younger and older than 60 years. Figure 2 shows the individual performance changes for single test scores between examinations at 4 months (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 565 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from
  4. 4. and at the most recent follow-up, as judged by the Reli- able Change Indices. For each of the 56 comparisons (6 test scores for 10 patients were compared; there were 4 missing values), the number of improvements, stable scores, and deteriorations are given. In total, there were 10 improvements and 4 deteriorations. The number of observed deteriorations did not significantly exceed the number of expected deteriorations (binomial test, P=.33), whereas the number of improvements did (PϽ.001). This analysis was also carried out separately for the 5 pa- tients who were older than 60 years. In 28 comparisons (2 missing values), there were 3 deteriorations, which did not exceed the number of expected deteriorations sig- nificantly (P=.17), and 5 improvements, which ex- ceeded the number of expected improvements (P=.004). No patient experienced a decline in more than 1 test score subsequent to therapy. Neuropsychologic test results in 4 patients who re- lapsed within 1 year after treatment are of note: a 37- year-old woman re-treated with combined chemo- therapy, resulting in complete remission, showed good cognitive function at her most recent follow-up (sum- mary score, 100). Two other patients (aged 59 and 67 years), who had received either whole brain radio- therapy or chemotherapy plus ocular radiotherapy at re- lapse, developed dementia thereafter. Persistent impair- ment of cognitive function (summary score, 76 at most recent follow-up) was observed in a 62-year-old woman who had received combined chemotherapy at relapse and who had experienced serious tumor complications, in- cluding intracerebral and panventricular hemorrhage at initial examination. MAGNETIC RESONANCE IMAGING Magnetic resonance imaging revealed white matter changes that developed during therapy in 4 of 10 patients (aged 67, 65, 62, and 51 years) (Figure 3). In one of them (aged 67 years), these changes were detect- able after the third chemotherapy cycle but substantially decreased in size until completion of therapy, resulting in a few persistent periventricular white matter spots. This patient showed moderate improvement in cognitive function (summary score, 88 at most recent follow-up, 84 at initial examination). In the other 3 patients, con- fluent widespread white matter changes partly involving subcortical U fibers were progressive until the end of therapy and remained stable thereafter. In all of them, the overall cognitive function was within the normal range at the most recent follow-up (summary score, 94, 95, and 97, respectively). In another patient (aged 68 years), white matter lesions were already detectable prior to therapy (most likely representing microangio- pathic changes) and showed progression with therapy. This patient showed severe cognitive dysfunction at ini- tial examination (summary score, 73) and ongoing improvement after therapy (summary score, 86 at most recent follow-up). 110 90 100 80 70 0 6 12 18 30 36 48 5424 42 60 66 72 SummaryScore(StandardValues) Patients <60 Years Old ∗ 110 90 100 80 70 0 6 12 18 30 36 48 5424 42 60 66 72 Months SummaryScore(StandardValues) Patients >60 Years Old † B A Figure 1. Development of overall cognitive performance. The asterisk indicates patient not testable owing to aphasia; dagger, missing value owing to noncooperation. 10 Improved Steady Declined 6 8 4 2 0 ZVT WF BVRT VLMT-L VLMT-R BDT No.ofPatients Figure 2. Changes in neuropsychological test results between 4 months after therapy and last follow-up. For each test, the number of patients showing declined, stable, or improved test results are depicted. BDT indicates Block Design Test; BVRT, Benton Visual Retention Test; VLMT-L, Verbal Learning and Memory Test–Learning; VLMT-R, Verbal Learning and Memory Test–Recall; WF, Word Fluency; and ZVT, Letter Connection Test. (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 566 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from
  5. 5. COMMENT This study evaluated cognitive function and treatment- induced white matter changes on MRI in patients receiv- ing intravenous and intraventricular polychemotherapy for PCNSL. Long-term survival without relapse, de- fined as durable remission for more than 1 year after completion of therapy, was achieved in half of the pa- tients treated. In this subgroup, sensitive test proce- dures did not reveal any evidence of cognitive decline at- tributable to therapy-related neurotoxicity. Initially, successful treatment of PCNSL often resulted in signifi- cant improvement of cognitive function. As cognitive im- pairment is one of the most frequent clinical features of PCNSL,26 cognitive improvement with successful therapy is to be expected. Hence, to determine treatment- induced neurotoxicity, long-term cognitive perfor- mance has to be compared with the patients’ perfor- mance after completion of therapy and not with pretreatment performance. Four months after comple- tion of therapy, neither acute adverse treatment effects nor long-term neurotoxicity are to be expected.7 Com- parison between the patients’ cognitive performance 4 months after completion of therapy and at the most re- cent follow-up showed either preserved function or on- going recovery of primary impaired functions subse- quent to therapy. This also applied to 5 patients older than 60 years who belonged to a group at high risk for developing neurotoxicity. Two years after diagnosis (mini- mum follow-up, 21 months), none of these 5 patients showed cognitive decline. Our findings are in sharp con- trast with published long-term observations in patients after combination therapy for PCNSL. One study re- ported that 6 of 10 patients older than 60 years who had received combined radiotherapy and chemotherapy were demented 24 months after diagnosis.10 In the present series, cognitive function was signifi- cantly impaired after irradiation in 2 of 4 patients who experienced early relapses and in a third patient in this group who had tumor-related brain hemorrhage at the initial examination. In these patients, an unequivocal evaluation of chemotherapy-related neurotoxicity was not possible since the relapse itself or its treatment could have led to substantial cognitive impairment. Somewhat unexpectedly, MRI demonstrated white matter changes in 5 of the 10 long-term survivors. The temporal relationship between polychemotherapy and the development of MRI changes strongly suggests that the white matter changes were treatment induced. Strik- ingly, none of these patients experienced overall cogni- tive decline during a follow-up period of at least 16 months after the appearance of white matter changes. There- fore, methotrexate-induced leukoencephalopathy de- tectable by MRI does not inevitably lead to gross cogni- tive dysfunction. Further follow-up has to show whether there might be future deterioration of cognitive perfor- mance in these patients. The occurrence of clinical asymptomatic white mat- ter changes in patients treated with chemotherapy for PCNSL has recently been reported.27,28 In one study, 2 of 37 patients treated with systemic high-dose metho- trexate showed changes classified as “clinically asymp- tomatic leukoencephalopathy.”27 In our series, white mat- ter changes seemed to be more frequent (5 of 10 patients). Nine patients in another series who received systemic high-dose methotrexate were found to have persisting white matter lesions in “close proximity to the original enhancing masses” on MRI.28 The demyelinating effect of the brain lymphoma itself was discussed from an etio- logical viewpoint by the authors. In contrast to this, the white matter changes found in our series were more wide- spread and most probably represented a treatment- induced leukoencephalopathy. Two mechanisms may contribute to the frequent oc- currence of widespread white matter lesions in our se- ries: first, methotrexate reaches cytotoxic concentra- tions in the CSF and probably in brain parenchyma when administered in high systemic doses.29 White matter seems to be particularly sensitive to high-dose systemic metho- trexate, and clinically asymptomatic or symptomatic white matterlesionshavebeenreportedinyoungpatientstreated with high-dose or ultrahigh-dose methotrexate therapy.16,17,30 Second, in this study, methotrexate was also given intraventricularly on days 1 to 4 via an Ommaya reservoir, with single doses of 3 mg/d. Intraventricular methotrexate penetrates only a few millimeters into the surrounding parenchyma.31 Presumably, the periven- tricular white matter was exposed to a particularly high concentration of methotrexate in the patients in this study. We conclude that the risk of long-term neurotox- icity in patients treated with combined intravenous and A B C D Figure 3. Clinically asymptomatic leukoencephalopathy in a 51-year-old man 49 months after treatment. Axial fast spin-echo images (repetition time, 4849 ms; echo time, 90 ms; slice thickness, 5 mm) show confluent white matter hyperintensity involving subcortical U fibers. The patient showed no significant cognitive decline during the 49-month follow-up. (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 567 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from
  6. 6. intraventricular chemotherapy that includes methotrex- ate and cytarabine is low. Accordingly, this treatment regi- men seems to be more favorable than combined radio- therapy and chemotherapy protocols, which have a known high risk of severe neurotoxicity, particularly in older pa- tients. However, at present, a reliable prediction of the risk of long-term neurotoxicity is not possible because of the small number of patients examined. In light of the ongoing debate on treatment in PCNSL, the inclusion of appropriate assessments of cognitive function appears in- dispensable in any controlled clinical trial that com- pares different treatment modalities. Accepted for publication November 12, 2002. Author contributions: Study concept and design (Mr Fliessbach, and Drs Helmstaedter, Pels, Klockgether, and Schlegel); acquisition of data (Mr Fliessbach, and Drs Urbach, Helmstaedter, Pels, Glasmacher, Schmidt- Wolf, and Schlegel); analysis and interpretation of data (Mr Fliessbach, and Drs Urbach, Helmstaedter, Kraus, Schmidt-Wolf, and Schlegel); drafting of the manuscript (Mr Fliessbach); critical revision of the manuscript for im- portant intellectual content (Mr Fliessbach, and Drs Urbach, Helmstaedter, Pels, Glasmacher, Kraus, Klock- gether, Schmidt-Wolf, and Schlegel); study supervision (Dr Klockgether). Corresponding author: Uwe Schlegel, MD, Depart- ment of Neurology, University Hospital Bonn, Sigmund- Freud-Str. 25, D-53105 Bonn, Germany, (e-mail: uwe REFERENCES 1. Nelson DF, Martz KL, Bonner H, et al. 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Lovblad K, Kelkar P, Ozdoba C, Ramelli G, Remonda L, Schroth G. Pure metho- trexate encephalopathy presenting with seizures: CT and MRI findings. Pediatr Radiol. 1998;28:86-91. 31. Blasberg RG, Patlak CS, Shapiro WR. Distribution of methotrexate in the cere- brospinal fluid and brain after intraventricular administration. Cancer Treat Rep. 1977;61:633-641. (REPRINTED) ARCH NEUROL/VOL 60, APR 2003 WWW.ARCHNEUROL.COM 568 ©2003 American Medical Association. All rights reserved. on December 1, 2010www.archneurol.comDownloaded from