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  Vol. 62 No. 10, October 2005 TABLE OF CONTENTS
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Delayed Neurotoxicity in Primary Central Nervous System Lymphoma

Antonio M. P. Omuro, MD; Leah S. Ben-Porat, MS; Katherine S. Panageas, DrPH; Amy K. Kim, BA; Denise D. Correa, PhD; Joachim Yahalom, MD; Lisa M. DeAngelis, MD; Lauren E. Abrey, MD

Arch Neurol. 2005;62:1595-1600.

Background  Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown.

Objective  To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy.

Design  Retrospective review.

Setting  Department of Neurology, Memorial Sloan-Kettering Cancer Center.

Patients  One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity.

Main Outcome Measures  Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings.

Results  The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortical dementia characterized by psychomotor slowing, executive and memory dysfunction, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autopsy data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a competing risk. Older age (P = .01), mental status changes at diagnosis (P = .04), female sex (P = .05), and radiotherapy (P<.001) predicted neurotoxicity on univariate analysis, but only radiotherapy remained significant in the multivariate setting.

Conclusion  These findings suggest that the core pathophysiologic mechanism is the interruption of frontal-subcortical circuits mediated by radiation damage, possibly caused by progressive microvascular alterations, loss of oligodendrocyte progenitors, or oxidative stress.


Author Affiliations: Departments of Neurology (Drs Omuro, Correa, DeAngelis, and Abrey and Ms Kim), Epidemiology and Biostatistics (Ms Ben-Porat and Dr Panageas), and Radiation Oncology (Dr Yahalom), Memorial Sloan-Kettering Cancer Center, New York, NY.



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Neurology 2007;69:1178-1182.
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An Update on Therapy of Primary Central Nervous System Lymphoma
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ASH Education Book 2006;2006:311-316.
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