Michael Gilligan1, Connie Lesnick1, Michael Bradshaw3, Shafeeq Ladha4, Maulik Shah5, John Wittenborn6, Shannon Hinson1, Divyanshu Dubey2, John Mills1, Sean Pittock2, Anastasia Zekeridou1, Andrew McKeon2
1Department of Laboratory Medicine and Pathology, 2Department of Neurology, Mayo Clinic, 3Department of Neurology, Billings Clinic, 4Barrow Neurological Institute, 5Department of Neurology, University of California, San Francisco, 6Neurology, Robert Wood Johnson University Hospital
Objective:
To report a novel paraneoplastic encephalitis associated with calmodulin kinase-like vesicle associated (CAMKV)-IgG antibody.
Background:
Uterine cancer is historically associated with paraneoplastic cerebellar ataxia but not encephalitis. High-throughput protein microarrays expedite novel neural antibody discovery.
Design/Methods:
Unclassified antibodies identified by murine brain-based indirect immunofluorescence assay (IFA) October 2022-September 2023 with cerebrum-restricted IgG staining (cerebellum negative) were screened by protein microarray and CAMKV identified as a high-ranking candidate antigen. Additional patient samples with an identical staining pattern were obtained retrospectively (serum, 3; CSF, 3). Western blot, confocal microscopy, immune-absorption and mass spectrometry were performed to elucidate CAMKV specificity further. Recombinant antigen-specific assays (cell-based assay [CBA], western blot) provided additional molecular confirmation.
Results:
Five patients with CAMKV-IgG were identified, 3 women; 2 men (median symptom-onset age was 59 years; range, 53-74). All samples (serum 4, CSF 3) were tissue IFA and CAMKV CBA positive. Onset was subacute (4) or acute (1). All had encephalitis manifesting with ≥1 of: behavioral change (3), seizures (3), psychosis (2), amnesia (2), hyperkinetic movements (tremor [1], choreiform movements [1]), insomnia (2). None had cerebellar ataxia. CSF revealed lymphocytic pleocytosis (median, 17; range, 8-74 [normal, ≤5]) in all 4 available. EEG was abnormal in 3 of 4 (subclinical electrographic seizures [2], bilateral epileptiform discharges [1]). T2 hyperintensities present in all patients were: mesial temporal (4), bilateral basal ganglia (3). Diffusion weighted lesions affected right paramedian frontal and parietal lobes (1), and bilateral anterior cingulate gyri (1). Cancers detected were uterine (3 patients: adenocarcinoma [2; 1 poorly differentiated], neuroendocrine [1]), bladder (1), non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All 5 demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]); 3 patients died from cancer.
Conclusions:
CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis (limbic and extra-limbic) notably associated with uterine cancer.