Delayed neurotoxicity in primary central nervous system lymphoma.
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.


METHODS
Retrospective review.


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


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


METHODS
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.


CONCLUSIONS
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.
Omuro
Antonio M P
AM
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Ben-Porat
Leah S
LS
Panageas
Katherine S
KS
Kim
Amy K
AK
Correa
Denise D
DD
Yahalom
Joachim
J
Deangelis
Lisa M
LM
Abrey
Lauren E
LE
D000367:Age Factors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D001927:Brain Diseases / Q000453:epidemiology / Q000209:etiology* / Q000628:therapy; D016543:Central Nervous System Neoplasms / Q000628:therapy*; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000453:epidemiology / Q000209:etiology* / Q000503:physiopathology; D011878:Radiotherapy / Q000009:adverse effects*; D012189:Retrospective Studies; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors