Treatment-specific Frontal Lobe Syndromes in CNS Lymphoma and Primary Brain Tumors: A Neuropsychiatric Lens
Tarlan Kehtari1, Beatriz De Faria Sousa1, Patricia Junquera2, Yuliya Linhares3
1FIU Herbert Wertheim College of Medicine, 2Psychiatry and Behavioral Health, FIU Herbert Wertheim College of Medicine, 3Miami Cancer Institute, Baptist Health of South Florida
Objective:
To synthesize clinical studies in patients with PCNSL and primary brain tumors evaluating treatment-related neurotoxicity, with emphasis on frontal lobe syndromes and their psychiatric manifestations.
Background:
Survivorship after primary CNS lymphoma (PCNSL) and primary brain tumors is shaped not only by disease control but also by treatment-related neuropsychiatric sequelae. Beyond diffuse "cognitive decline", apathy, executive dysfunction, and personality changes are prevalent, disabling, and often more decisive for quality of life, yet remain under-recognized and inconsistently measured.
Design/Methods:
We reviewed randomized trials, longitudinal cohorts, registry studies, and systematic reviews reporting neurocognitive and psychiatric outcomes in patients with PCNSL and primary CNS tumors. We also included voxel-based imaging studies evaluating network changes after whole-brain radiotherapy (WBRT), focal radiotherapy (fRT), chemotherapy, and autologous stem-cell transplantation (ASCT).
Results:
WBRT is strongly associated with neurotoxicity. In the PRECIS and HOVON trials, 64–88% of patients declined after WBRT, versus 20–28% with ASCT, with survivors reporting apathy, reduced initiative, and executive dysfunction. Delayed neurotoxicity affects up to 70% of long-term PCNSL survivors, including personality changes. Connectome studies show a 73% rise in limbic and 50% rise in paralimbic anomalies after WBRT, correlating with verbal recall decline (r = –0.94). Registry data likewise found 73.3% of WBRT patients versus 27.1% with focal RT declined (p = 0.001), usually in fluency and recall. fRT appears less toxic but dose-dependent, with effects on frontal networks. High-dose methotrexate carries a lower risk, though 25–30% of survivors still show deficits. Evidence for immunotherapies, CAR-T, and surgery is limited, largely case reports describing psychiatric syndromes and parkinsonism.
Conclusions:
Treatment-related neurotoxicity in PCNSL and CNS tumors manifests as modality-specific frontal lobe syndromes with psychiatric symptoms, not just ‘cognitive decline’. WBRT poses the highest risk, but psychiatric issues are rising across treatments. This highlights the need for standardized psychiatric measures and integrated survivorship strategies across neuro-oncology, psychiatry, and neuro-rehabilitation.
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