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  • NEUROTOXICITY IN CHILDREN AFTER TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKAEMIA AND METHOTREXATE NEUROTOXICITY IN A CONTROLLED ANIMAL MODEL

    SATU LEHTINEN

    Department of Paediatrics, University of Oulu

    OULU 2003

  • SATU LEHTINEN

    NEUROTOXICITY IN CHILDREN AFTER TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKAEMIA AND METHOTREXATE NEUROTOXICITY IN A CONTROLLED ANIMAL MODEL

    Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Paediatrics, on June 13th, 2003, at 12 noon.

    OULUN YLIOPISTO, OULU 2003

  • Copyright © 2003 University of Oulu, 2003

    Supervised by Docent Marjatta Lanning Docent Leena Vainionpää

    Reviewed by Docent Toivo T. Salmi Docent Tuula Äärimaa

    ISBN 951-42-7033-9 (URL: http://herkules.oulu.fi/isbn9514270339/)

    ALSO AVAILABLE IN PRINTED FORMAT Acta Univ. Oul. D 728, 2003 ISBN 951-42-7032-0 ISSN 0355-3221 (URL: http://herkules.oulu.fi/issn03553221/)

    OULU UNIVERSITY PRESS OULU 2003

  • Lehtinen, Satu, Neurotoxicity in children after treatment for acute lymphoblastic leukaemia and methotrexate neurotoxicity in a controlled animal model Department of Paediatrics, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu, Finland Oulu, Finland 2003

    Abstract

    In the Nordic countries, event-free survival (EFS) exceeds 80% in certain groups of children treated for acute lymphoblastic leukaemia (ALL). With the improved cure rates, however, there are more children suffering from neurological late effects, especially due to therapy directed at the central nervous system (CNS). The aim of this study is to examine the changes taking place in the nervous system after leukemia treatment and to evaluate the role of treatment in these changes in patients and in an animal model.

    Twenty-seven ALL survivors and healthy controls were examined by means of motor evoked potentials (MEPs). ALL survivors were also examined clinically. The children with ALL continued to show decreased motor nerve conduction in the peripheral nerves, but not within the CNS, five years after the cessation of treatment. Clinical neurological findings were obtained in 33% of the cases. The MEP results indicated reversibility of the motor injury due to CNS effects.

    Nineteen patients underwent perfusion magnetic resonance imaging (MRI) at the cessation of treatment or 4-8 years after the treatment. Seventeen of them also underwent single-photon emission computed tomography (SPECT). The studies showed small perfusion defects in SPECT, which were not visible by perfusion MRI.

    Methotrexate (Mtx) neurotoxicity was studied in a swine model using functional MRI, brain perfusion SPECT, iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl) tropane ([123I]β-CIT) SPECT and whole-hemisphere autoradiography with [125I]β-CIT in ten Mtx-treated animals and five control animals. Mtx-related changes in the brain could be detected as reduced or negative blood- oxygen-level-dependent (BOLD) responses to somatosensory activation in BOLD contrast MRI, which indicates changes in flow metabolism coupling. Perfusion defects in brain SPECT were seen in the Mtx group and the control group, which suggests that the perfusion defects seen in brain SPECT are probably multifactorial. The change in dopamine transporter (DAT) density in the Mtx group was not different from that in the controls.

    The abnormalities in nerve conduction after treatment in survivors of ALL were partly reversible years after the treatment. The patients had perfusion defects in SPECT imaging which were not seen in perfusion MRI. The clinical significance of these defects remains obscure. The animal model suggested perfusion defects to be multifactorial.

    Keywords: acute lymphoblastic leukaemia, autoradiography, brain, cerebrovascular disorders, follow-up studies, magnetic resonance imaging, methotrexate, motor evoked potentials, single-photon emission computer tomography

  • To my family

  • Acknowledgements This work was carried out at the Department of Paediatrics, University of Oulu, during the years 1998–2002.

    I wish to acknowledge Professor Mikko Hallman, M.D, Head of the Department of Paediatrics, for creating an inspiring atmosphere for scientific work during these years. I also wish to acknowledge Professor Matti Uhari, M.D., for teaching me skills in scientific research and paediatrics.

    My deepest gratitude goes to my supervisors, Docent Marjatta Lanning, M.D., and Docent Leena Vainionpää, M.D., for their comprehensive guidance and encouragement throughout these years. You have shared both the good days and the bad. Marjatta Lanning introduced me to the field of paediatric haemato-oncology during the paediatric course in the medical school and later suggested the theme of the present work. I am equally grateful to Leena Vainionpää for her interest, advice and practical help throughout these years.

    I thank my official referees, Docent Toivo T. Salmi, M.D. and Docent Tuula Äärimaa, M.D. for their valuable and constructive criticism during the preparation of the manuscript.

    My warmest thanks are also due to my co-author Docent Uolevi Tolonen, M.D., for teaching me scientific writing, and for the optimistic attitude and support during the work. I also wish to warmly thank Docent Eija Pääkkö, M.D., for very flexible co-operation. I owe my thanks to Minna Mäkiranta. M.Sc., for fruitful co-operation and enjoyable discussions about scientific work. I am grateful to Eila Kolehmainen, Ph.D., for the technical preparation of autoradiography and for very pleasant co-operation and generous support. I also wish to thank my other co-authors, Docent Aapo Ahonen, M.D., Arja Harila-Saari, M.D., Usko Huuskonen, M.D., Jukka Jauhiainen, Ph.D., Jarkko Oikarinen, Ph.D., Professor Juhani Pyhtinen, M.D., Docent Osmo Tervonen, M.D., Physicist Pentti Torniainen and Erkki Tupala, M.D. for their help during this work.

    The research laboratory staff deserve special thanks, especially Seija Seljanperä, R.N., and Veikko Lähteenmäki. I also wish to thank Aki Pulkkinen and Sirkka Vehkaperä for their great co-operation. Without your endless support, this work would not have been possible.

    I want to thank Malcolm Hicks M.A. and Sirkka-Liisa Leinonen Ph.L. for revising the language of the original papers and this thesis. I also wish to thank Ms. Maija Veikkola

  • for finding the literature and Ms. Marjatta Paloheimo for her friendly help on many occasions. I also want to thank Juha Turtinen M.Sc. and Mr. Jari Åström for their help with computer problems.

    It has been a privilege to work for years with talented colleagues who are able to create an inspiring atmosphere. We have shared many joyful moments, and I have received generous support throughout the years. My special thanks go to Docent Maila Koivisto, M.D.. I have truly enjoyed our lively discussions about scientific and clinical problems along with other interesting matters.

    Riikka Joukio has been my friend since childhood. I have shared many nice moments with your family and children, Jaakko, Jutta and Juhana. Shirley Johnson, Tuula Kaukola and Tuula Kuukasjärvi, I want to express my gratitude for our friendship. I am privileged to have such friends as you are.

    I want to thank Saima and Pekka Lehtinen for their support. During my exchange student year, I was lucky to have a host family with whom I have maintained close relations for two decades. I want to thank Jim and Jean Henry for love, support and great memories, and also for offering the best holiday spot in the world.

    This thesis would not have been accomplished without the support of my family. My sincere thanks go to my mother, Lauha Lehtinen, for her support. I also want to honor my late father, Pentti Lehtinen. I wish to thank the families of my brothers, Jouko and Kalevi. Your children have brought lots of joy into my life, too. Mika, Jenni, Riikka and Lotta, you have certainly won my heart, and I always wish to spend more time with you. Finally, I wish to express my gratitude to Juha Vuorela for giving me the support during the final years of this project. I am thankful for the years and memories we have shared.

    This research was supported by Alma and K. A. Snellman Foundation, Oulu, Finland, Nona and Kullervo Väre Foundation, Helsinki, Finland, Cancer Society of Northern Finland and Foundation for Paediatric Research, Helsinki, Finland.

    Oulu, May 2003 Satu Lehtinen

  • Abbreviations ADCz apparent diffusion coefficient ALL acute lymphoblastic leukaemia BFM Berlin-Frankfurt-Munster BOLD blood-oxygen-level-dependent CBF cerebral blood flow CBV cerebral blood volume CMC carboxymethylcellulose CNS central nervous system CRT cranial radiation therapy CSF cerebrospinal fluid CT computed tomography DAT dopamine transporter DF-ROM dorsiflexion range of motion ECD ethyl-cysteinate-dimer EEG electroencephalogram EFS event-free survival ERP event-related potential FDG fluorodeoxyglucose FSE fast spin-echo FOV field of view Gy Gray (1Gy = 100 cGy = 100 rad) HR high risk of relapse IQ intelligence quotient IR intermediate risk of relapse MEP mean evoked potential MMN mismatch negativity MRD minimal residual disease MRI magnetic resonance imaging MTT mean transit time Mtx methotrexate NEX number of excitations NLE necrotising leukoencephalopathy

  • NOPHO Nordic Society for Paediatric and Haematology and Oncology PCR polymerase chain reaction PD proton density PET positron emission tomography ROI region of interest SD standard deviation SEP somatosensory evoked potentia