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

Autor: Dubey D; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Department of Immunology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Wilson MR; Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco., Clarkson B; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Giannini C; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Gandhi M; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Cheville J; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Lennon VA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Department of Immunology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Eggers S; Department of Neurology, Mayo Clinic, Rochester, Minnesota., Devine MF; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Mandel-Brehm C; Department of Biochemistry and Biophysics, University of California, San Francisco., Kryzer T; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Hinson SR; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Khazaie K; Department of Immunology, Mayo Clinic, Rochester, Minnesota., Hales C; Department of Neurology, Emory University School of Medicine, Atlanta, Georgia., Kattah J; Department of Neurology, University of Illinois College of Medicine, Peoria., Pavelko KD; Department of Immunology, Mayo Clinic, Rochester, Minnesota., Andrews P; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Eaton JE; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee., Jitprapaikulsan J; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mahidol University, Bangkok, Thailand., Mills JR; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Flanagan EP; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Zekeridou A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Leibovich B; Department of Urology, Mayo Clinic, Rochester, Minnesota., Fryer J; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Torre M; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Kaufman C; Louisiana Neurologic Consultants, Baton Rouge, Louisiana., Thoreson JB; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Sagen J; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Linnoila JJ; Department of Neurology, Massachusetts General Hospital, Boston., DeRisi JL; Department of Biochemistry and Biophysics, University of California, San Francisco.; Chan Zuckerberg Biohub, San Francisco, California., Howe CL; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Department of Immunology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., McKeon A; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota., Pittock SJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.; Department of Neurology, Mayo Clinic, Rochester, Minnesota.; Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota.
Jazyk: angličtina
Zdroj: JAMA neurology [JAMA Neurol] 2020 Nov 01; Vol. 77 (11), pp. 1420-1429.
DOI: 10.1001/jamaneurol.2020.2231
Abstrakt: 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.
Databáze: MEDLINE
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