Clinical and Paraclinical Features Distinguishing Paraneoplastic from Immune Checkpoint Inhibitor-induced Encephalitis
Sophia Zhao1, Jordan Benderoth1, Ralph Habis2, Roba El Zibaoui1, Arun Venkatesan3, John Probasco4
1The Johns Hopkins University School of Medicine, 2Johns Hopkins School of Medicine, 3Johns Hopkins Hospital, 4The Johns Hopkins Hospital
Objective:
To characterize clinical and paraclinical differences between pnEncephalitis and irEncephalitis to facilitate diagnosis and inform management.
Background:
Encephalitis can occur as a paraneoplastic syndrome (pnEncephalitis) or as a neurologic immune-related adverse event following immune checkpoint inhibitor therapy (irEncephalitis). Clinical differentiation between these cancer-associated encephalitides remains challenging.
Design/Methods:
From a prospective outpatient tertiary cohort (2006–2022), we retrospectively identified patients meeting criteria for pnEncephalitis or irEncephalitis and compared clinical presentations, paraclinical findings, and outcomes using nonparametric methods.
Results:

From the cohort (N=340), 26 patients with pnEncephalitis and 11 with irEncephalitis were identified. Common malignancies included ovarian teratoma (29.7%), lung cancer (18.9%), and Hodgkin's lymphoma (5.4%). In irEncephalitis patients, encephalitis developed a median of 22 days after ICI initiation.

Clinical presentations including memory deficits, focal neurologic deficits, fever, and altered mental status were similar between groups (p>0.05). Seizures were more common in pnEncephalitis (65.4% vs 18.2%, p=0.02).

MRI abnormalities occurred in both groups (42.3% vs 72.7%, p=0.18). Vascular or dural involvement was exclusive to irEncephalitis (0% vs 50%, p=0.02), including leptomeningeal enhancement, multifocal white matter hyperintensities, and chronic microvascular changes. Hippocampal and limbic involvement was primarily observed in pnEncephalitis (54.5% vs 12.5%, p=0.15). CSF parameters were similar (p>0.05): WBC, protein, IgG index, and oligoclonal bands.

Nearly all received corticosteroids (92.3% vs 100%, p=1.0); plasmapheresis was used more frequently in pnEncephalitis (57.7% vs 9.1%, p=0.01). IVIG, rituximab, and cyclophosphamide use was similar. Readmission and mortality rates were comparable.

Conclusions:
Despite similar clinical presentations, distinct paraclinical differences distinguish irEncephalitis from pnEncephalitis. Limbic system involvement and higher seizure rates characterize pnEncephalitis, consistent with the epileptogenic nature of these regions, while vascular/dural abnormalities are exclusive to irEncephalitis. These patterns suggest distinct immunopathological mechanisms that may guide diagnosis and treatment selection.
10.1212/WNL.0000000000216553
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