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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Journal	Annals of neurology
DOIs	https://doi.org/10.1002/ana.26943
State	Accepted/In press - 2024

ASJC Scopus subject areas

Neurology
Clinical Neurology

Access to Document

10.1002/ana.26943

Cite this

Gilligan, M., Lesnick, C. E., Guo, Y., Bradshaw, M. J., Ladha, S. S., Nowak, M., Shah, M. P., Wittenborn, J. R., Basal, E., Hinson, S., Yang, B., Dubey, D., Mills, J. R., Pittock, S. J., Zekeridou, A., & McKeon, A. (Accepted/In press). Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis. Annals of neurology. https://doi.org/10.1002/ana.26943

@article{233c04839a9d41a1a9b3af0277a4a8b3,

title = "Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis",

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.",

author = "Michael Gilligan and Lesnick, {Connie E.} and Yong Guo and Bradshaw, {Michael J.} and Ladha, {Shafeeq S.} and Mihaela Nowak and Shah, {Maulik P.} and Wittenborn, {John R.} and Eati Basal and Shannon Hinson and Binxia Yang and Divyanshu Dubey and Mills, {John R.} and Pittock, {Sean J.} and Anastasia Zekeridou and Andrew McKeon",

note = "Publisher Copyright: {\textcopyright} 2024 American Neurological Association.",

year = "2024",

doi = "10.1002/ana.26943",

language = "English (US)",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis

AU - Gilligan, Michael

AU - Lesnick, Connie E.

AU - Guo, Yong

AU - Bradshaw, Michael J.

AU - Ladha, Shafeeq S.

AU - Nowak, Mihaela

AU - Shah, Maulik P.

AU - Wittenborn, John R.

AU - Basal, Eati

AU - Hinson, Shannon

AU - Yang, Binxia

AU - Dubey, Divyanshu

AU - Mills, John R.

AU - Pittock, Sean J.

AU - Zekeridou, Anastasia

AU - McKeon, Andrew

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85190793788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85190793788&partnerID=8YFLogxK

U2 - 10.1002/ana.26943

DO - 10.1002/ana.26943

M3 - Article

AN - SCOPUS:85190793788

SN - 0364-5134

JO - Annals of neurology

JF - Annals of neurology

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this