Abstract 703: An inflammatory leptomeningeal signature in cancer patients with neurologic manifestations of COVID-19
Authors: Wilcox Jessica A. , Remsik Jan , Babady N. Esther , McMillen Tracy A. , Vachha Behroze A. , Halpern Neil A. , Dhawan Vikram , Rosenblum Marc , Iacobuzio-Donahue Christine A. , Avila Edward K. , Santomasso Bianca , Boire Adrienne 
Published: July 2021

Abstract
Background: COVID-19 is associated with a wide spectrum of neurologic manifestations, which can emerge weeks to months after the initial infection. Cancer patients are at a heightened risk of severe infections due to their immunocompromised status. Leading hypotheses predict that SARS-CoV-2 neuroinvasion or neurologic toxicity from the systemic cytokine storm may account for neurologic dysfunction.
Methods: We prospectively evaluated cancer patients with confirmed SARS-CoV-2 infection and subsequent neurologic manifestations at an NCI-designated cancer center. Evaluations included neurologic examinations, brain imaging, electroencephalogram, and cerebrospinal fluid (CSF) analysis for SARS-CoV-2 detection by RT-PCR for viral RNA and ELISA for nucleocapsid (N) and spike (S2) proteins. Additional proteomic analysis compared the CSF of patients with COVID-19 (CoV+) to cancer- and brain metastasis-matched COVID-19-negative controls (CoV-), and to patients with other cancer-associated neuroinflammatory conditions, including immune effector cell-associated neurotoxicity syndrome (ICANS) and autoimmune encephalitis.
Results: Between May and July 2020, we evaluated 18 COVID-19-positive cancer patients with a wide range of solid tumor and hematologic malignancies. Thirteen (72.2%) of our patients received tumor-directed treatment within 30 days of SARS-CoV-2 infection. Neurologic diagnoses include protracted critical care delirium (N=10), limbic encephalitis (N=4), refractory headaches (N=2), rhombencephalitis (N=1), and large-territory infarctions (N=1). A median delay of 19 days (range 0-77) existed between onset of respiratory symptoms and neurologic manifestations. Among 13 patients who underwent CSF analysis, there was no evidence of SARS-CoV-2 neuroinvasion by RT-PCR in the CSF (N=13) or by N and S2 protein detection (N=10). Targeted proteomic analysis detected a significant accumulation of IL-6 and -8, IFN-gamma, CXCL-1, -6, -9, -10, and -11, CCL-8 and -20, MMP-10 and 4E-BP1 in the CSF of CoV+ patients (N=10) relative to matched CoV- controls (pooled, p=0.029). Combined analysis of these 12 inflammatory mediators revealed CoV+ cytokine levels approaching that of ICANS. CSF MMP-10, a marker of neurodegeneration, correlated with neurologic dysfunction by Karnofsky performance status (p=0.011) and by disability rating scale (p=0.086) at the time of lumbar puncture.
Conclusion: A durable accumulation of IFN-gamma-mediated cytokines is detected in the CSF of cancer patients with neurologic manifestations of COVID-19, in the absence of detectable neuroinvasion. We hypothesize that cytokine-mediated neuroinflammation is responsible for the prolonged neurologic sequela of COVID-19. Our findings suggest a potential role for anti-inflammatory treatments in the management of such patients.
Citation Format: Jessica A. Wilcox, Jan Remsik, N. Esther Babady, Tracy A. McMillen, Behroze A. Vachha, Neil A. Halpern, Vikram Dhawan, Marc Rosenblum, Christine A. Iacobuzio-Donahue, Edward K. Avila, Bianca Santomasso, Adrienne Boire. An inflammatory leptomeningeal signature in cancer patients with neurologic manifestations of COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 703.