Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.

Surtees, Robert; Clelland, James D.; Hann, IM

doi:10.1200/jco.1998.16.4.1505

Cited by 65 publications

(38 citation statements)

References 32 publications

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“…Both patients had low 5-methyl-THF and considerably decreased SAM concentrations shortly after toxicity episodes indicating that these patients exhibited biochemical disorders possibly related to MTX administration. Decreased CSF 5-methyl-THF or SAM levels similar to our patients were also reported in other cases of subacute neurotoxicity [30,42].…”

Section: Discussionsupporting

confidence: 91%

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Vezmar

Schüsseler

Becker

et al. 2008

Pediatric Blood & Cancer

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BackgroundSevere neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.ProcedureMTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m2) followed by calcium folinate rescue (3 × 15 mg/m2) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.ResultsIn non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.ConclusionIntrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 91%

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Vezmar

Schüsseler

Becker

et al. 2008

Pediatric Blood & Cancer

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“…Methotrexate is the cytostatic drug mostly implicated in central neurotoxicity in children with ALL (Shuper et al, 2000). Cerebral white matter changes (Chu et al, 2003;Dambska & Laure-Kamionowska, 1999;Surtees et al, 1998), neuronal damage (Chu et al, 2003;Quinn et al, 1998;Van Gool et al, 2000) and neurotransmitter abnormalities (Madhyastha et al, 2002) have been described in children treated with chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…CNSdirected chemotherapy for ALL, consisting of intrathecal methotrexate, alone or in combination with cytarabine and corticosteroids, and of systemic methotrexate and corticosteroids, is associated with central neurotoxicity (Kerr et al, 2001;Surtees et al, 1998). Various studies have demonstrated visuomotor deficits in relationship with other cognitive impairments in children with ALL after treatment with chemotherapy only (Copeland et al, 1996;Kingma et al, 2001;Lesnik et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Buizer

Sonneville

Heuvel‐Eibrink

et al. 2005

J. Inter. Neuropsych. Soc.

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Treatment for childhood acute lymphoblastic leukemia (ALL), which includes CNS prophylaxis, is associated with central and peripheral neurotoxicity. The purpose of the present study was to analyze the effects of chemotherapy on various levels of visuomotor control in survivors of childhood ALL treated without cranial irradiation, and to identify risk factors for possible deficits. Visuomotor function was compared between children after treatment for ALL (n 5 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n 5 38), and healthy controls (n 5 151). Three tasks were administered: a simple visual reaction time task and two tasks measuring visuomotor control with one requiring a higher level of cognitive control than the other. Visuomotor deficits were detected only in the ALL group, with poorer performance restricted to the condition requiring the highest level of control. Significant risk factors for poorer performance were female gender and a short time since end of treatment, and a trend was found for a young age at diagnosis. A high cumulative methotrexate dose was an adverse predictive factor in girls. The results indicate that chemotherapy-induced central neurotoxicity in childhood ALL treatment is associated with higher order visuomotor control deficits. Girls appear to be particularly vulnerable. (JINS, 2005, 11, 554-565.)

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“…Since severe demyelination and white matter changes are main features of chronic MTX-associated neurotoxicity, an impairment of the methyl-transfer pathway may be involved in its pathogenesis. Moreover, decreased SAM levels in the CSF were associated with demyelination reported in patients with MTX-related subclinical and clinical leukoencephalopathy (13,14). Furthermore, it was suggested that the SAM/SAH ratio may be a better marker for leukoencephalopathy than SAM alone (15).…”

Section: Case Reportmentioning

confidence: 99%

Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity

Vezmar¹,

Bode²,

Jaehde³

2009

Journal of Medical Biochemistry

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Kratak sadr`aj: Primena metotreksata (MTX) u viso kim dozama i/ili intratekalno u terapiji malignih obo ljenja poput akutne limfoblasti~ne leukemije (ALL) povezana je sa pojavom blagih ili te{kih oblika neuro toksi~nosti. Patogeneza neurotoksi~nosti nije u potpu nosti razja{njena, ali se va`na uloga pripisuje biohe mijskim promenama folatnog i metiltransfernog meta boli~kog puta za koje se smatra da su uzrokovane dejstvom MTX. Opisujemo slu~aj odrasle pacijen tkinje na terapiji recidiva ALL sa simptomima hroni~ne leukoencefalopatije najverovatnije uzrokovane primenom MTX. U cilju procene folatnog i metil-transfernog puta u cere brospinalnoj te~nosti (CST) pacijentkinje merene su koncentracije 5-metiltetrahidrofolata (5-metil-THF), S-adenozilmetionina (SAM) i S-adenozilhomocisteina (SAH). Tri uzorka CST su dobijena lumbalnom punkcijom u periodu od ~etiri meseca. Koncentracije su merene pomo}u validiranih bioana liti~kih metoda zasnovanih na primeni HPLC sa ultraljubi~astom i fluorescentnom detekcijom. Rezultati su pokazali dvostruko sni`enje koncentracije 5-metil-THF (29.3-31.8 nmol/L) u pore|enju sa referentnim vrednostima u svim uzor cima, dok su koncentracije SAM bile pet puta manje u dva uzorka (5-34.2 nmol/L). Koncentracije SAH su bile u rasponu 7.5-14.3 nmol/L. Na{a pacijentkinja je imala izra`ene promene u folatnom i metil-transfernom metaboli~kom putu koje uka zuju na to da biohemijske promene ovih metaboli~kih puteva za koje se smatra da su uzrokovane dejstvom MTX mogu igrati va`nu ulogu u razvoju leuko encefalopatije.Klju~ne re~i: metotreksat, cerebrospinalna te~nost, 5-metiltetrahidrofolat, S-adenozilmetionin, neurotoksi~nost Summary: Intrathecal and/or high-dose intravenous administration of methotrexate (MTX) in the treatment of malignancies such as acute lymphoblastic leukaemia (ALL) has been associated with cases of mild to severe neurotoxicity. The pathogenic mechanism of neurotoxicity is not clear, possibly MTX-associated biochemical alterations of the folate and methyl-transfer metabolic pathways play an important role. We report a case of an adult patient treated for ALL relapse with signs of chronic leukoencephalopathy associated with MTX administration. In order to assess alterations in the folate and methyl-transfer pathway we determined 5-methylte trahydrofolate (5-methyl-THF), S-adenosylmethi onine (SAM) and S-adenosylhomocysteine (SAH) in the cerebrospinal fluid (CSF) of the patient. Three CSF samples were obtained by lumbar punction within a four-month period. Concentrations of the metabolites were measured using validated bioanalytical methods based on HPLC with UV and fluorescence detection. The results showed two-fold lower 5-methyl-THF levels (29.3-31.8 nmol/L) in all obtained sam ples compared to reference values. SAM concentrations were even more than five-fold lower in two samples (5-34.2 nmol/L). SAH concentrations were in the range 7.5-14.3 nmol/L. Our patient had pronounced alterations in the folate and methyltransfer pathway which indicate that MTX-associated biochemical alter...

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Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.

Abstract: Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Cited by 65 publications

References 32 publications

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity

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