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Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis

Educational Objective
To determine the clinical, radiologic, immunopathologic, and human leukocyte antigen features of Kelch-like protein-11 encephalitis?
1 Credit CME
Key Points

Question  What are the clinical, radiologic, immunopathologic, and human leukocyte antigen features of Kelch-like-protein-11 (KLHL11) encephalitis?

Findings  In this case series, the common presenting feature of KLHL11 encephalitis is a rhombencephalitis phenotype with ataxia, diplopia, dysarthria, vertigo, hearing loss, and tinnitus. A strong oncologic association, KLHL11-specific T-cell response, human leukocyte antigen associations, and brain histopathology supports an immunopathologic basis.

Meaning  Recognizing presenting features of KLHL11 encephalitis may aid in early diagnosis of this paraneoplastic syndrome and immunopathologic findings may guide immunotherapeutic management.

Abstract

Importance  Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management.

Objective  To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis.

Design, Setting, and Participants  This retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays).

Main Outcomes and Measures  Outcome variables included modified Rankin score and gait aid use.

Results  All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell–predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis.

Conclusions and Relevance  Kelch-like protein-11 IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatment. Described expanded neurologic phenotype and paraclinical findings may aid in its early diagnosis and treatment.

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Article Information

Accepted for Publication: April 1, 2020.

Published Online: August 3, 2020. doi:10.1001/jamaneurol.2020.2231

Correction: This article was corrected on September 14, 2020, to fix errors in Figures 2, 3, and 4.

Corresponding Author: Divyanshu Dubey, MD, Department of Neurology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (dubey.divyanshu@mayo.edu).

Conflict of Interest Disclosures: Dr Dubey has received research support from Center of Multiple Sclerosis and Autoimmune Neurology, Center for Clinical and Translational Science, and Grifols pharmaceuticals. He has consulted for UCB and Astellas Pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. Dr Dubey has a patent pending for Kelch-like protein 11 (KLHL11) IgG as a marker of neurological autoimmunity. Dr Wilson has received grants from Roche/Genentech, Sandler Foundation, William K. Bowes, Jr. Foundation, and from National Institutes of Health/National Institute of Neurological Disorders and Stroke (K08NS096117) during the conduct of the study; in addition, Dr Wilson had a patent to KLHL11 as neurological autoimmunity and paraneoplastic marker issued. Dr Clarkson reported grants from Mayo Clinic during the conduct of the study. Dr Lennon receives royalties from Mayo Clinic licensing of diagnostic tests for AQP4-IgG and is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. She has a patent pending for KLHL11, Septin 5 and MAP1B IgGs as markers of neurological autoimmunity and paraneoplastic disorders. Dr Mandel-Brehm has a patent pending for Kelch-like protein 11 IgG as a marker of neurologic autoimmunity. Dr Kryzer is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. He has a patent pending for KLHL11, Septin 5, and MAP1B IgGs as markers of neurological autoimmunity and paraneoplastic disorders. Dr Hales reported grants from the National Institutes of Health, BrightFocus Foundation, and the US Department of Defense during the conduct of the study. Dr Kattah reported other support from Otometrics during the conduct of the study. Dr Flanagan reported other support from Viela Bio outside the submitted work. Dr Zekeridou reported a patent to PDE10A-IgG as a biomarker of neurological autoimmunity pending. Dr Torre is currently supported by a T32 Training grant through the Pathology Department at Brigham and Woman's Hospital (T32 HL007627). Dr Linnoila is funded by National Institutes of Health/National Institute of Neurological Disorders and Stroke grant K08 NS101084, serves as an expert respondent for the National Vaccine Injury Compensation Program, and received honoraria from the American Academy of Neurology and the Massachusetts Neurologic Association for lectures on autoimmune neurology. Dr DeRisi has a patent pending for KLHL11 as a marker of neurologic autoimmunity. Dr McKeon has patent pending for KLHL11, Septin 5, and MAP1B as markers of neurological autoimmunity and paraneoplastic disorders. Dr Pittock is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. He has a patent pending for Septin 5 and MAP1B IgGs as markers of neurological autoimmunity and paraneoplastic disorders. He has consulted for Alexion and Medimmune. He has received research support from Grifols, Medimmune, and Alexion. All compensation for consulting activities is paid directly to Mayo Clinic. Dr Pittock has a patent pending for KLHL11-IgG as a marker of neurological autoimmunity. No other disclosures were reported.

Additional Contributions: We thank J. Schmeling, BS, and R. Johnson, MS, for technical support; S. Bryant, MS, and C. Smith for statistical support; and M. Curtis and S. Vinje for secretarial assistance. All are affiliated with the Mayo Clinic, and no compensation was received from a funding sponsor.We thank the Center for Multiple sclerosis and Autoimmune Neurology for storing and providing biospecimens for analysis. We thank the patients and their families for participation in this study.

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