Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis

Michael Gilligan; Connie E Lesnick; Yong Guo; Michael J Bradshaw; Shafeeq S Ladha; Mihaela Nowak; Maulik P Shah; John R Wittenborn; Eati Basal; Shannon Hinson; Binxia Yang; Divyanshu Dubey; John R Mills; Sean J Pittock; Anastasia Zekeridou; Andrew McKeon

doi:10.1002/ana.26943

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis

Ann Neurol. 2024 Apr 18. doi: 10.1002/ana.26943. Online ahead of print.

Authors

Michael Gilligan^{1

2}, Connie E Lesnick¹, Yong Guo³, Michael J Bradshaw⁴, Shafeeq S Ladha⁵, Mihaela Nowak⁶, Maulik P Shah⁷, John R Wittenborn⁸, Eati Basal¹, Shannon Hinson¹, Binxia Yang¹, Divyanshu Dubey^{1

3}, John R Mills¹, Sean J Pittock^{1

3}, Anastasia Zekeridou^{1

3}, Andrew McKeon^{1

3}

Affiliations

¹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
² Department of Neurology, University College Dublin, St Vincent's Hospital Elm Park, Dublin, Ireland.
³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Neurology, University of Washington and Billings Clinic, Billings, MT, USA.
⁵ Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.
⁶ Department of Neurology, Jefferson Hospital, Jefferson Hills, PA, USA.
⁷ Department of Neurology, University of California, San Francisco, CA, USA.
⁸ Department of Neurology, Robert Wood Johnson University Hospital, New Brunswick, NJ, USA.

PMID: 38634529
DOI: 10.1002/ana.26943

Abstract

Objectives: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV).

Methods: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation.

Results: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer.

Interpretation: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024.

Grants and funding

RO1NS126227/NH/NIH HHS/United States