Cerebrospinal Fluid Changes in the Excitatory Amino Acids Concentration Caused by the Standard Treatment of Acute Lymphoblastic Leukaemia in Children do not Correlate with their Later Cognitive Functioning

Abstract

The aim of this study was to ascertain whether changes in the concentrations of cerebrospinal fluid excitatory amino acids (EAAs) contribute to neurotoxicity of the standard acute lymphoblastic leukaemia (ALL) treatment protocols. We found a statistically significant increase in glutamate and aspartate in 12 ALL patients during their treatment. Cognitive functioning was examined in all patients at an average of 3.7 years after the disease diagnosis. Importantly, the levels of EAAs during the therapy were not correlated with the results of the cognitive test. This study suggests that standard ALL treatment-induced neurotoxicity may not lead to persistent neurocognitive deficits.

acute lymphoblastic leukaemia - neurotoxicity - glutamic acid - aspartic acid - cognitive functioning

References

• 1 Atlante A, Calissano P, Bobba A. et al . Glutamate neurotoxicity, oxidative stress and mitochondria.  FEBS Lett. 2001;  18 1-5
• 2 Buizer AI, de Sonneville LM, Veerman AJ. Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: a critical review of the literature.  Pediatr Blood Cancer. 2009;  52 447-454
• 3 Cole PD, Kamen BA. Delayed neurotoxicity associated with therapy for children with acute lymphoblastic leukemia.  Ment Retard Dev Disabil Res Rev. 2006;  12 174-183
• 4 Cole PD, Beckwith KA, Vijayanathan V. et al . Folate homeostasis in cerebrospinal fluid during therapy for acute lymphoblastic leukemia.  Pediatr Neurol. 2009;  1 34-41
• 5 Cronstein BN. The mechanism of action of methotrexate.  Rheum Dis Clin North Am. 1997;  23 739-755
• 6 De Braganca KC, Packer RJ. Neurotoxicity of chemotherapeutic and biologic agents in children with cancer.  Curr Neurol Neurosci Rep. 2008;  8 114-122
• 7 Glover DA, Byrne J, Mills JL. et al . Impact of CNS treatment on mood in adult survivors of childhood leukemia: a report from the Children's Cancer Group.  J Clin Oncol. 2003;  21 4395-4401
• 8 Hallböök H, Gustafsson G, Smedmyr B. et al . Treatment outcome in young adults and children >10 years of age with acute lymphoblastic leukemia in Sweden: a comparison between a pediatric protocol and an adult protocol.  Cancer. 2006;  107 1551-1561
• 9 Hill JM, Kornblith AB, Jones D. et al . A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation.  Cancer. 1998;  82 208-218
• 10 Holownia A, Trofimiuk E, Krawczuk-Rybak M. et al . Cerebrospinal fluid excitatory amino acids and tau protein in children with acute lymphoblastic leukemia treated according to the BFM protocol.  Acta Haematol. 2004;  112 222-224
• 11 Iuvone L, Mariotti P, Colosimo C. et al . Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia.  Cancer. 2002;  95 2562-2570
• 12 Kingma A, van Dommelen RI, Mooyaart EL. et al . Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only.  J Pediatr. 2001;  139 413-420
• 13 Melucci D, Xie M, Reschiglian P. et al . FMOC-Cl as derivatizing agent for the analysis of amino acids and dipeptides by the absolute analysis method.  Chromatographia. 1999;  5-6 317-320
• 14 Muszyñska-Rosłan K, Krawczuk-Rybak M, Protas PT. et al . Level of tau protein in children treated for acute lymphoblastic leukemia.  Pediatr Neurol. 2006;  34 367-371
• 15 Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia.  Lancet Oncol. 2008;  9 257-268
• 16 Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia.  Lancet. 2008;  22 1030-1043
• 17 Quinn CT, Griener JC, Bottiglieri T. et al . Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer.  J Clin Oncol. 1997;  15 2800-2806
• 18 Quinn CT, Griener JC, Bottiglieri T. et al . Effects of intraventricular methotrexate on folate, adenosine, and homocysteine metabolism in cerebrospinal fluid.  J Pediatr Hematol Oncol. 2004;  26 386-388
• 19 Rainesalo S, Keränen T, Palmio J. et al . Plasma and cerebrospinal fluid amino acids in epileptic patients.  Neurochem Res. 2004;  29 319-324
• 20 Shen EY, Lai YJ, Ho CS. et al . Excitatory and inhibitory amino acid levels in the cerebrospinal fluids of children with neurological disorders.  Acta Paediatr Taiwan. 1999;  40 65-69
• 21 Virgin Jr CE, Ha TP, Packan DR. et al . Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.  J Neurochem. 1991;  57 1422-1428
• 22 Zhang H, Zhang X, Zhang T. et al . Excitatory amino acids in cerebrospinal fluid of patients with acute head injuries.  Clin Chem. 2001;  47 1458-1462

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