To describe phenotypic presentations, outcomes and histopathological features and T cell responses in Kelch-like protein 11 (KLHL11) encephalitis.

Clinical features and outcomes of KLHL11-IgG seropositive cases identified in the Mayo Clinic Neuroimmunology Laboratory (confirmed by transfected-cell and tissue-based immunofluorescence assays) were reviewed. Peripheral blood mononuclear cells (PBMCs) from two KLHL11-IgG-seropositive patients were exposed in vitro to KLHL11 recombinant protein and T cell activation was analyzed by flow cytometry.

Thirty-eight KLHL11-IgG-seropositive patients were identified, all men. Initial clinical presentations were: ataxia (81%), diplopia (55%), vertigo (50%), hearing loss (39%), tinnitus (34%), dysarthria (30%) and seizures (23%). Hearing loss or tinnitus preceded other neurological deficits by 1-8 months in 10 patients (26%).  Among patients screened for malignancy, testicular germ-cell tumors (63%) or testicular microlithiasis and fibrosis (16%) were found.  In another two patients, lymph node biopsy yielded different cancer diagnoses (metastatic lung adenocarcinoma and chronic lymphocytic leukemia). Initial brain MRIs revealed T2-hyperintensities in temporal lobe (10), cerebellum (7), brainstem (3) or diencephalon (4). A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and non-necrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and two autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early stage active inflammation and later extensive neuronal loss.  Compared to non-autoimmune control PBMCs, CD8⁺ and CD4⁺ T cells were significantly activated (surface-CD69 upregulation) when patient PBMCs were cultured with KLHL11 protein. Most patients (59%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [11] or improved [9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. 

KLHL11-IgG is a biomarker of paraneoplastic encephalitis that is highly associated with testicular germ-cell tumors. Neuropathological findings and the demonstrated KLHL11 specific T-cell responses support a CD8⁺-T cell-mediated cytotoxic pathogenesis.