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Original Investigation
August 3, 2020

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

Author Affiliations
  • 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 3Department of Immunology, Mayo Clinic, Rochester, Minnesota
  • 4Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota
  • 5Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco
  • 6Department of Biochemistry and Biophysics, University of California, San Francisco
  • 7Department of Neurology, Emory University School of Medicine, Atlanta, Georgia
  • 8Department of Neurology, University of Illinois College of Medicine, Peoria
  • 9Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee
  • 10Department of Neurology, Mahidol University, Bangkok, Thailand
  • 11Department of Urology, Mayo Clinic, Rochester, Minnesota
  • 12Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 13Louisiana Neurologic Consultants, Baton Rouge, Louisiana
  • 14Department of Neurology, Massachusetts General Hospital, Boston
  • 15Chan Zuckerberg Biohub, San Francisco, California
JAMA Neurol. 2020;77(11):1420-1429. doi:10.1001/jamaneurol.2020.2231
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.


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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