Abstract
Purpose
High-dose (HD) cytosine arabinoside (ara-C) is a major treatment in acute myeloblastic leukemia (AML) that can lead to cerebellar complications, although electroencephalogram, computed tomography, and magnetic resonance imaging remain normal. We conducted a prospective study to evaluate brain perfusion with single-photon emission computed tomography (SPECT) in adult patients before and after receiving ara-C.
Procedures
Forty-three patients were pre-included, and 20 reached a complete remission. These 20 patients were definitively included and underwent three technetium-99m hexamethyl-propylene-amine oxime (HMPAO) SPECT acquisitions with a double-head camera: SPECT1 at AML diagnosis, SPECT2 after induction (conventional ara-C dose), and SPECT3 during HD ara-C treatment. All the included patients underwent six series of neurological and cognitive examinations: N1, N2, and N3 at the time of SPECT1, SPECT2, and SPECT3, respectively; N4 during HD ara-C treatment; N5 (at 10 days); and N6 during follow-up (at 6 months). Statistical parametric mapping (SPM2) was used to test perfusion changes. A specific method based on random walk (RW) was used to analyze diffuse brain perfusion heterogeneity.
Results
No neurological adverse effect was observed, and all neurological and cognitive examinations remained normal. Between SPECT1 and SPECT2, SPM2 analysis showed a decrease in cerebral blood flow, i.e., in the cerebellum, in the occipitoparietal cortex, and in the thalamus. No significant difference was observed between SPECT2 and SPECT3 or between SPECT1 and SPECT3. RW analysis showed no significant difference in perfusion heterogeneity between the three SPECTs.
Conclusions
HMPAO SPECT demonstrated a decrease in thalamus, cerebellar, and parieto-occipital perfusion after conventional doses of ara-C in AML patients, although the neurological examinations were normal and the patients had no neurological adverse effects.
Similar content being viewed by others
References
Rudnick SA, Cadman EC, Capizzi RL, Skeel RT, Bertino JR, McIntosh S (1979) High dose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44:1189–1193
Cole N, Gibson BE (1997) High-dose cytosine arabinoside in the treatment of acute myeloid leukaemia. Blood Rev 11:39–45
Bishop JF, Matthews JP, Young GA et al (1996) A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87:1710–1717
Mayer RJ, Davis RB, Schiffer CA et al (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 331:896–903
Stentoft J (1990) The toxicity of cytarabine. Drug Saf 5:7–27
Baker WJ, Royer GL Jr, Weiss RB (1991) Cytarabine and neurologic toxicity. J Clin Oncol 9:679–693
Russell JA, Powles RL (1974) Letter: neuropathy due to cytosine arabinoside. Br Med J 4:652–653
Barrios NJ, Tebbi CK, Freeman AI, Brecher ML (1987) Toxicity of high dose Ara-C in children and adolescents. Cancer 60:165–169
Winkelman MD, Hines JD (1983) Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study. Ann Neurol 14:520–527
Chim CS, Kwong YL (1996) Cerebellar toxicity with medium-dose cytarabine in a young patient with renal insufficiency. Am J Hematol 53:208
Penta JS, Von Hoff DD, Muggia FM (1977) Hepatotoxicity of combination chemotherapy for acute myelocytic leukemia. Ann Intern Med 87:247–248
Bolwell BJ, Cassileth PA, Gale RP (1988) High dose cytarabine: a review. Leukemia 2:253–260
Vaughn DJ, Jarvik JG, Hackney D, Peters S, Stadtmauer EA (1993) High-dose cytarabine neurotoxicity: MR findings during the acute phase. AJNR Am J Neuroradiol 14:1014–1016
Vera P, Rohrlich P, Stievenart JL et al (1999) Contribution of single-photon emission computed tomography in the diagnosis and follow-up of CNS toxicity of a cytarabine-containing regimen in pediatric leukemia. J Clin Oncol 17:2804–2810
Vera P, Farman-Ara B, Stievenart JL et al (1996) Proportional anatomical stereotactic atlas for visual interpretation of brain SPET perfusion images. Eur J Nucl Med 23:871–877
Trouillas P, Takayanagi T, Hallett M et al (1997) International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci 145:205–211
Bisiach E, Vallar G, Perani D, Papagno C, Berti A (1986) Unawareness of disease following lesions of the right hemisphere: anosognosia for hemiplegia and anosognosia for hemianopia. Neuropsychologia 24:471–482
Mathiowetz V, Volland G, Kashman N, Weber K (1985) Adult norms for the box and block test of manual dexterity. Am J Occup Ther 39:386–391
Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382–389
Schmidt R, Freidl W, Fazekas F et al (1994) The Mattis Dementia Rating Scale: normative data from 1,001 healthy volunteers. Neurology 44:964–966
Van Der Linden M, Coyette F, Poitrenaud J (2004) L’épreuve de rappel libre/rappel indicé à 16 items (RL/RI-16) [serial (book, monograph)]. In: Van Der Linden M (ed) L’évaluation des troubles de la mémoire. Solal, Marseille, pp 25–47
Weschler D (2009) Weschler Adult Intelligence Scale-III [serial (book, monograph)]. The Psychological Corporation, San-Antonio
Tombaugh TN (2004) Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 19:203–214
Friston KJ, Holmes AP, Worsley KJ, Poline JB, Frakowiak RSJ (1995) Statistical parametric maps in functional imaging: a general linear approach [generic]. Hum Brain Mapp 2:189–210
Friston KJ, Ashburner J, Poline JB, Frith CD, Heather JD, Frakowiak RSJ (1995) Statistical registration and normalization of images [generic]. Hum Brain Mapp 2:165–189
Holmes A, Friston KJ, Poline JB (1997) Characterising brain images with the general linear model [generic]. In: Frackowiak RSJ (ed) Human brain function. Academic, New York, pp 59–84
Modzelewski R, de la Rue T, Janvresse E et al (2008) Development and validation of the random walk algorithm: application to the classification of diffuse heterogeneity in brain SPECT perfusion images. J Comput Assist Tomogr 32:651–659
Lill DW, Mountz JM, Darji JT (1994) Technetium-99 m-HMPAO brain SPECT evaluation of neurotoxicity due to manganese toxicity. J Nucl Med 35:863–866
Wallace EA, Wisniewski G, Zubal G et al (1996) Acute cocaine effects on absolute cerebral blood flow. Psychopharmacology (Berl) 128:17–20
Denays R, Makhoul E, Dachy B et al (1994) Electroencephalographic mapping and 99mTc HMPAO single-photon emission computed tomography in carbon monoxide poisoning. Ann Emerg Med 24:947–952
Osterlundh G, Bjure J, Lannering B, Kjellmer I, Uvebrant P, Marky I (1997) Studies of cerebral blood flow in children with acute lymphoblastic leukemia: case reports of six children treated with methotrexate examined by single photon emission computed tomography. J Pediatr Hematol Oncol 19:28–34
Karabacak NI, Ozturk G, Gucuyener K, Gokcora N, Gursel T (1997) Assessment of brain perfusion by 99mTc-HMPAO SPECT in akinetic mutism due to high-dose intravenous methotrexate therapy. Childs Nerv Syst 13:560–562
Ansar MA, Osaki Y, Kazui H et al (2006) Effect of linearization correction on statistical parametric mapping (SPM): a 99mTc-HMPAO brain perfusion SPECT study in mild Alzheimer’s disease. Ann Nucl Med 20:511–517
Choi JY, Lee KH, Na DL et al (2007) Subcortical aphasia after striatocapsular infarction: quantitative analysis of brain perfusion SPECT using statistical parametric mapping and a statistical probabilistic anatomic map. J Nucl Med 48:194–200
Guedj E, Allali G, Goetz C et al (2008) Frontal assessment battery is a marker of dorsolateral and medial frontal functions: a SPECT study in frontotemporal dementia. J Neurol Sci 273:84–87
Herzig RH, Hines JD, Herzig GP et al (1987) Cerebellar toxicity with high-dose cytosine arabinoside. J Clin Oncol 5:927–932
Salinsky MC, Levine RL, Aubuchon JP, Schutta HS (1983) Acute cerebellar dysfunction with high-dose ARA-C therapy. Cancer 51:426–429
Sylvester RK, Fisher AJ, Lobell M (1987) Cytarabine-induced cerebellar syndrome: case report and literature review. Drug Intell Clin Pharm 21:177–180
Levy-Cooperman N, Burhan AM, Rafi-Tari S et al (2008) Frontal lobe hypoperfusion and depressive symptoms in Alzheimer disease. J Psychiatry Neurosci 33:218–226
Talairach J, Tornoux P (1988) Co-planar stereotaxic atlas of human brain [generic]. Thieme, New York
Acknowledgments
The authors wish to thank the Scientific Committee of the CIC-INSERM Rouen University for reviewing the protocol 98-037 HP corresponding to this study.
R. Modzelewski was partially supported by grants from the “Comité de Seine-Maritime de la Ligue Contre le Cancer”.
We also would like to thank Dilys Moscato, Département de Langues et Communication, Rouen University, for reviewing the English.
Conflict of Interest Disclosure
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Modzelewski, R., Lepretre, S., Martinaud, O. et al. Brain Perfusion in Adult Patients with Acute Myeloblastic Leukemia before and after Cytosine Arabinoside. Mol Imaging Biol 13, 747–753 (2011). https://doi.org/10.1007/s11307-010-0409-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11307-010-0409-7