Skip to main content

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


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 = 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n = 38), and healthy controls (n = 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.)

Corresponding author
Reprint requests to: Annemieke Buizer, M.D., Department of Pediatrics, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail:
Hide All


Aiken, L.S. & West, S.G. (1991). Multiple regression: Testing and interpreting interactions. Newbury Park, CA: Sage Publications.
Anderson, V.A., Godber, T., Smibert, E., Weiskop, S., & Ekert, H. (2000). Cognitive and academic outcome following cranial irradiation and chemotherapy in children: A longitudinal study. British Journal of Cancer, 82, 255262.
Brown, R.T., Madan-Swain, A., Pais, R., Lambert, R.G., Baldwin, K., Casey, R., Frank, N., Sexson, S.B., Ragab, A., & Kamphaus, R.W. (1992). Cognitive status of children treated with central nervous system prophylactic chemotherapy for acute lymphocytic leukemia. Archives of Clinical Neuropsychology, 7, 481497.
Brown, R.T., Madan-Swain, A., Walco, G.A., Cherrick, I., Ievers, C.E., Conte, P.M., Vega, R., Bell, B., & Lauer, S.J. (1998). Cognitive and academic late effects among children previously treated for acute lymphocytic leukemia receiving chemotherapy as CNS prophylaxis. Journal of Pediatric Psychology, 23, 333340.
Butler, R.W., Hill, J.M., Steinherz, P.G., Meyers, P.A., & Finlay, J.L. (1994). Neuropsychologic effects of cranial irradiation, intrathecal methotrexate, and systemic methotrexate in childhood cancer. Journal of Clinical Oncology, 12, 26212629.
Carbone, P.P., Bono, V., Frei, E., III, & Brindley, C.O. (1963). Clinical studies with vincristine. Blood, 21, 640647.
Chaminade, T. & Fonlupt, P. (2003). Changes of effective connectivity between the lateral and medial parts of the prefrontal cortex during a visual task. European Journal of Neuroscience, 18, 675679.
Chu, W.C., Chik, K.W., Chan, Y.L., Yeung, D.K., Roebuck, D.J., Howard, R.G., Li, C.K., & Metreweli, C. (2003). White matter and cerebral metabolite changes in children undergoing treatment for acute lymphoblastic leukemia: Longitudinal study with MR imaging and 1H MR spectroscopy. Radiology, 229, 659669.
Ciesielksi, K.T., Harris, R.J., Hart, B.L., & Pabst, H.F. (1997). Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood. Neuropsychologia, 35, 643655.
Ciesielski, K.T., Lesnik, P.G., Benzel, E.C., Hart, B.L., & Sanders, J.A. (1999). MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: Multivariate models of early and late developing memory subsystems. Behavioral Neuroscience, 113, 439450.
Cohen, J. (1988). Statistical power analysis for the behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Earlbaum Associates.
Copeland, D.R., Moore, B.D., Francis, D.J., Jaffe, N., & Culbert, S.J. (1996). Neuropsychologic effects of chemotherapy on children with cancer: A longitudinal study. Journal of Clinical Oncology, 14, 28262835.
Cousens, P., Waters, B., Said, J., & Stevens, M. (1988). Cognitive effects of cranial irradiation in leukaemia: A survey and meta-analysis. Journal of Child Psychology and Psychiatry, 29, 839852.
D'Angio, G.J. (1983). SIOP (International Society of Paediatric Oncology) and the management of Wilms' tumor. Journal of Clinical Oncology, 1, 595596.
Dambska, M. & Laure-Kamionowska, M. (1999). Brain damage in children in course of neoplastic diseases. Folia Neuropathologica, 37, 133137.
De Bellis, M.D., Keshavan, M.S., Beers, S.R., Hall, J., Frustaci, K., Masalehdan, A., Noll, J., & Boring, A.M. (2001). Sex differences in brain maturation during childhood and adolescence. Cerebral Cortex, 11, 552557.
De Sonneville, L.M.J. (1999). Amsterdam Neuropsychological Tasks: A computer-aided assessment program. In B.P.L.M. den Brinker, P.J. Beek, A.N. Brand, S.J. Maarse, & L.J.M. Mulder (Eds.), Cognitive ergonomics, clinical assessment and computer-assisted learning: Computers in psychology (pp. 187203). Lisse, The Netherlands: Swets & Zeitlinger.
De Sonneville, L.M.J. (2003). Amsterdam Neuropsychological Tasks, Manual: Database and Appendix. Amstelveen, The Netherlands: SONAR.
De Sonneville, L.M.J., Boringa, J.B., Reuling, I.E.W., Lazeron, R.H.C., Adèr, H.J., & Polman, C.H. (2002). Information processing characteristics in subtypes of multiple sclerosis. Neuropsychologia, 40, 17511765.
DeAngelis, L.M., Gnecco, C., Taylor, L., & Warrell, R.P., Jr. (1991). Evolution of neuropathy and myopathy during intensive vincristine/corticosteroid chemotherapy for non-Hodgkin's lymphoma. Cancer, 67, 22412246.
Diamond, A. (2000). Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex. Child Development, 71, 4456.
Downie, A.L.S., Jakobson, L.S., Frisk, V., & Ushycky, I. (2003). Periventricular brain injury, visual motion processing, and reading and spelling abilities in children who were extremely low birthweight. Journal of the International Neuropsychological Society, 9, 440449.
Erickson, K., Baron, I.S., & Fantie, B.D. (2001). Neuropsychological functioning in early hydrocephalus: Review from a developmental perspective. Child Neuropsychology, 7, 199229.
Frank, E.G., Foley, G.M., & Kuchuk, A. (1997). Cognitive functioning in school-age children with human immunodeficiency virus. Perceptual and Motor Skills, 85, 267272.
Fuster, J.M. (2002). Frontal lobe and cognitive development. Journal of Neurocytology, 31, 373385.
Galea, V., Wright, M.J., & Barr, R.D. (2004). Measurement of balance in survivors of acute lymphoblastic leukemia in childhood. Gait & Posture, 19, 110.
Gatta, G., Capocaccia, R., Coleman, M.P., Ries, L.A., & Berrino, F. (2002). Childhood cancer survival in Europe and the United States. Cancer, 95, 17671772.
Gidding, C.E., Kellie, S.J., Kamps, W.A., & de Graaf, S.S. (1999). Vincristine revisited. Critical Reviews in Oncology/Hematology, 29, 267287.
Glickstein, M. (2000). How are visual areas of the brain connected to motor areas for the sensory guidance of movement? Trends in Neuroscience, 23, 613617.
Hamzei, F., Dettmers, C., Rijntjes, M., Glauche, V., Kiebel, S., Weber, B., & Weiller, C. (2002). Visuomotor control within a distributed parieto-frontal network. Experimental Brain Research, 146, 273281.
Harila-Saari, A.H., Huuskonen, U.E.J., Tolonen, U., Vainionpaa, L.K., & Lanning, B.M. (2001). Motor nervous pathway function is impaired after treatment of childhood acute lymphoblastic leukemia: A study with motor evoked potentials. Medical and Pediatric Oncology, 36, 345351.
Harila-Saari, A.H., Vainionpaa, L.K., Kovala, T.T., Tolonen, E.U., & Lanning, B.M. (1998). Nerve lesions after therapy for childhood acute lymphoblastic leukemia. Cancer, 82, 200207.
Heitger, M.H., Anderson, T.J., Jones, R.D., Dalrymple-Alford, J.C., Frampton, C.M., & Ardagh, M.W. (2004). Eye movement and visuomotor arm movement deficits following mild closed head injury. Brain, 127, 575590.
Huijbregts, S.C., De Sonneville, L.M., Van Spronsen, F.J., Berends, I.E., Licht, R., Verkerk, P.H., & Sergeant, J.A. (2003). Motor function under lower and higher controlled processing demands in early and continuously treated phenylketonuria. Neuropsychology, 17, 369379.
Jakobson, L.S., Frisk, V., Knight, R.M., Downie, A.L.S., & Whyte, H. (2001). The relationship between periventricular brain injury and deficits in visual processing among extremely-low-birthweight (< 1000 g) children. Journal of Pediatric Psychology, 26, 503512.
Jankovic, M., Brouwers, P., Valsecchi, M.G., Van Veldhuizen, A., Huisman, J., Kamphuis, R., Kingma, A., Mor, W., Van Dongen-Melman, J., & Ferronato, L. (1994). Association of 1800 cGy cranial irradiation with intellectual function in children with acute lymphoblastic leukaemia. ISPACC. International Study Group on Psychosocial Aspects of Childhood Cancer. Lancet, 344, 224227.
Kalff, A.C., de Sonneville, L.M., Hurks, P.P., Hendriksen, J.G., Kroes, M., Feron, F.J., Steyaert, J., van Zeben, T.M., Vles, J.S., & Jolles, J. (2003). Low- and high-level controlled processing in executive motor control tasks in 5–6-year-old children at risk of ADHD. Journal of Child Psychology and Psychiatry, 44, 10491057.
Kamps, W.A., Bokkerink, J.P., Hahlen, K., Hermans, J., Riehm, H., Gadner, H., Schrappe, M., Slater, R., van den Berg-de Ruiter, E., Smets, L.A., De Vaan, G.A., Weening, R.S., van Weerden, J.F., Van Wering, E.R., & van der Does-van den Berg, A. (1999). Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: Results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988–1991). Blood, 94, 12261236.
Kamps, W.A., Bokkerink, J.P., Hakvoort-Cammel, F.G., Veerman, A.J., Weening, R.S., Van Wering, E.R., van Weerden, J.F., Hermans, J., Slater, R., van den Berg, E., Kroes, W.G., & van der Does-van den Berg, A. (2002). BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: Results of DCLSG protocol ALL-8 (1991–1996). Leukemia, 16, 10991111.
Kellie, S.J., Barbaric, D., Koopmans, P., Earl, J., Carr, D.J., & de Graaf, S.S.N. (2002). Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing—A surrogate marker of brain penetration. Cancer, 94, 18151820.
Kerr, J.Z., Berg, S., & Blaney, S.M. (2001). Intrathecal Chemotherapy. Critical Reviews in Oncology/Hematology, 37, 227236.
Kingma, A., Van Dommelen, R.I., Mooyaart, E.L., Wilmink, J.T., Deelman, B.G., & Kamps, W.A. (2001). Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only. Journal of Pediatrics, 139, 413420.
Klingberg, T., Vaidya, C.J., Gabrieli, J.D.E., Moseley, M.E., & Hedehus, M. (1999). Myelination and organization of the frontal white matter in children: A diffusion tensor MRI study. Neuroreport, 10, 28172821.
Lehtinen, S.S., Huuskonen, U.E., Harila-Saari, A.H., Tolonen, U., Vainionpaa, L.K., & Lanning, B.M. (2002). Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia. Cancer, 94, 24662473.
Lesnik, P.G., Ciesielski, K.T., Hart, B.L., Benzel, E.C., & Sanders, J.A. (1998). Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia—Enhanced data analysis using an effect size model. Archives of Neurology, 55, 15611568.
Madhyastha, S., Somayaji, S.N., Rao, M.S., Nalini, K., & Bairy, K.L. (2002). Hippocampal brain amines in methotrexate-induced learning and memory deficit. Canadian Journal of Physiology and Pharmacology, 80, 10761084.
Meadows, A.T., Gordon J., Massari D.J., Littman P., Fergusson J., & Moss K. (1981). Declines in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet, 318, 10151018.
Miall, R.C., Reckess, G.Z., & Imamizu, H. (2001). The cerebellum coordinates eye and hand tracking movements. Nature Neuroscience, 4, 638644.
Moleski, M. (2000). Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Archives of Clinical Neuropsychology, 15, 603630.
Mullenix, P.J., Kernan, W.J., Schunior, A., Howes, A., Waber, D.P., Sallan, S.E., & Tarbell, N.J. (1994). Interactions of steroid, methotrexate, and radiation determine neurotoxicity in an animal model to study therapy for childhood leukemia. Pediatric Research, 35, 171178.
Muller, R.A., Kleinhans, N., Kemmotsu, N., Pierce, K., & Courchesne, E. (2003). Abnormal variability and distribution of functional maps in autism: An FMRI study of visuomotor learning. American Journal of Psychiatry, 160, 18471862.
Ochs, J., Mulhern, R., Fairclough, D., Parvey, L., Whitaker, J., Ch'ien, L., Mauer, A., & Simone, J. (1991). Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parenteral methotrexate: A prospective study. Journal of Clinical Oncology, 9, 145151.
Postma, T.J., Benard, B.A., Huijgens, P.C., Ossenkoppele, G.J., & Heimans, J.J. (1993). Long-term effects of vincristine on the peripheral nervous system. Journal of Neurooncology, 15, 2327.
Pui, C.H., Mahmoud, H.H., Rivera, G.K., Hancock, M.L., Sandlund, J.T., Behm, F.G., Head, D.R., Relling, M.V., Ribeiro, R.C., Rubnitz, J.E., Kun, L.E., & Evans, W.E. (1998). Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood, 92, 411415.
Quinn, C.T., Griener, J.C., Bottiglieri, T., & Kamen, B.A. (1998). Methotrexate, homocysteine, and seizures. Journal of Clinical Oncology, 16, 393394.
Reinders-Messelink, H.A., Schoemaker, M.M., Hofte, M., Goeken, L.N.H., Kingma, A., van den Briel, M.M., & Kamps, W.A. (1996). Fine motor and handwriting problems after treatment for childhood acute lymphoblastic leukemia. Medical and Pediatric Oncology, 27, 551555.
Reinders-Messelink, H.A., Schoemaker, M.M., Snijders, T.A.B., Goeken, L.N.H., van den Briel, M.M., Bokkerink, J.P.M., & Kamps, W.A. (1999). Motor performance of children during treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 33, 545550.
Reinders-Messelink, H.A., Schoemaker, M.M., Snijders, T.A.B., Goeken, L.N.H., Bokkerink, J.P.M., & Kamps, W.A. (2001). Analysis of handwriting of children during treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 37, 393399.
Richer, F., Chouinard, M.J., & Rouleau, I. (1999). Frontal lesions impair the attentional control of movements during motor learning. Neuropsychologia, 37, 14271435.
Shuper, A., Stark, B., Kornreich, L., Cohen, I.J., Aviner, S., Steinmetz, A., Stein, J., Goshen, Y., & Yaniv, I. (2000). Methotrexate treatment protocols and the central nervous system: Significant cure with significant neurotoxicity. Journal of Child Neurology, 15, 573580.
Surtees, R., Clelland, J., & Hann, I. (1998). Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies. Journal of Clinical Oncology, 16, 15051511.
Tournade, M.F., Com-Nougue, C., de Kraker, J., Ludwig, R., Rey, A., Burgers, J.M., Sandstedt, B., Godzinski, J., Carli, M., Potter, R., & Zucker, J.M. (2001). Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months: Results of the Ninth International Society of Pediatric Oncology Wilms' tumor trial and study. Journal of Clinical Oncology, 19, 488500.
Touwen, B.C.L. (1979). Examination of the child with minor neurological dysfunction. Clinics in Developmental Medicine (2nd ed.), Vol. 71. London: Heineman.
Tubergen, D.G., Gilchrist, G.S., O'Brien, R.T., Coccia, P.F., Sather, H.N., Waskerwitz, M.J., & Hammond, G.D. (1993). Prevention of CNS disease in intermediate-risk acute lymphoblastic leukemia: Comparison of cranial radiation and intrathecal methotrexate and the importance of systemic therapy: A Childrens Cancer Group report. Journal of Clinical Oncology, 11, 520526.
Uitenbroek, D.G. (2003). SISA Bonferroni. Southampton, UK: D.G. Uitenbroek. Retrieved July 01, 2004, from the World Wide Web:
Vainionpaa, L. (1993). Clinical neurological findings of children with acute lymphoblastic-leukemia at diagnosis and during treatment. European Journal of Pediatrics, 152, 115119.
Vainionpaa, L., Kovala, T., Tolonen, U., & Lanning, M. (1997). Chemotherapy for acute lymphoblastic leukemia may cause subtle changes of the spinal cord detectable by somatosensory evoked potentials. Medical and Pediatric Oncology, 28, 4147.
Van Gool, S.W., Van Kerschaver, E., Brock, P., Pottel, H., Hulstaert, F., Vanmechelen, E., Uyttebroeck, A., Van De Voorde, A., & Vanderstichele, H. (2000). Disease- and treatment-related elevation of the neurodegenerative marker tau in children with hematological malignancies. Leukemia, 14, 20762084.
Veerman, A.J.P., Hahlen, K., Kamps, W.A., van Leeuwen, E.F., De Vaan, G.A., Solbu, G., Suciu, S., van Wering, E.R., & van der Does-Van den Berg, A. (1996). High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia. Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. Journal of Clinical Oncology, 14, 911918.
Verstappen, C.C.P., Heimans, J.J., Hoekman, K., & Postma, T.J. (2003). Neurotoxic complications of chemotherapy in patients with cancer—Clinical signs and optimal management. Drugs, 63, 15491563.
Vezmar, S., Becker, A., Bode, U., & Jaehde, U. (2003). Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy, 49, 92104.
Von der Weid, N., Mosimann, I., Hirt, A., Wacker, P., Nenadov, B.M., Imbach, P., Caflisch, U., Niggli, F., Feldges, A., & Wagner, H.P. (2003). Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: Age- and sex-related differences. European Journal of Cancer, 39, 359365.
Waber, D.P., Tarbell, N.J., Kahn, C.M., Gelber, R.D., & Sallan, S.E. (1992). The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia. Journal of Clinical Oncology, 10, 810817.
Wise, S.P., Boussaoud, D., Johnson, P.B., & Caminiti, R. (1997). Premotor and parietal cortex: Corticocortical connectivity and combinatorial computations. Annual Review of Neuroscience, 20, 2542.
Wright, M.J., Halton, J.M., Martin, R.F., & Barr, R.D. (1998). Long-term gross motor performance following treatment for acute lymphoblastic leukemia. Medical and Pediatric Oncology, 31, 8690.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of the International Neuropsychological Society
  • ISSN: 1355-6177
  • EISSN: 1469-7661
  • URL: /core/journals/journal-of-the-international-neuropsychological-society
Please enter your name
Please enter a valid email address
Who would you like to send this to? *