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

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 PARTICIPANTSThis 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 MEASURESOutcome 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. IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatm...

Paraneoplastic Myeloneuropathies

“… 15 , 25 KLHL11 IgG detected on tissue immunofluorescence was confirmed by KLHL11 HEK293 overexpression cell-based assay. 22 , 26 …”

New Technique, New Antibody: Phage Display Identifies Kelch‐Like Protein‐11 Antibodies

“…The core phenotype is rhombencephalitis, most frequently presenting with cerebellar signs, often with additional brainstem findings (eg vertigo, tinnitus, hearing loss, diplopia); with subsequently identified cases, there is a widening spectrum including also opsoclonus‐myoclonus, encephalopathy, myeloneuropathy, and cervical amyotrophy 3, 5 …”

“…There is a strong tumor association, mostly with germ cell tumors, especially (extra‐)testicular seminomas. Much more rarely, lung cancer and chronic lymphocytic leukemia are found 3, 5 . MRI findings are diverse, ranging from normal to cerebellar atrophy, cerebellar nuclei T2‐hyperintensities, leptomeningeal enhancement, or mesiotemporal abnormalities.…”

“…Median serum and CSF titers of KHLH11 autoantibodies are high (1:30,720, range: 1:960–1:245,760) and greater than 1:640, respectively 5 . KLHL11 autoantibodies target an intracellular protein and, just as the classic paraneoplastic autoantibodies (eg Hu, Yo, Ri), are an epiphenomenon of a T‐cell mediated process.…”

“…KLHL11 autoantibodies target an intracellular protein and, just as the classic paraneoplastic autoantibodies (eg Hu, Yo, Ri), are an epiphenomenon of a T‐cell mediated process. Biopsied, actively inflammatory lesions show a T cell‐predominant inflammation and non‐necrotizing granulomas, while autopsy material with Purkinje neuronal loss and Bergmann gliosis shows subsequent extensive neuronal loss 5 …”