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 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.

Figure 1.. Examples of Magnetic Resonance Image (MRI) Abnormalities Found in the Central Nervous System, Cranial Nerves, and Spinal Nerve Roots of Patients With Autoimmune Kelch-like Protein-11 (KLHL11) Encephalitis

T2 hyperintensity involving the left medullary olive (arrowhead; A). Fluid-attenuated inversion recovery (FLAIR) hyperintensity involving the pons (B). FLAIR hyperintensity involving the midbrain (arrowhead, C). Leptomeningeal enhancement (arrowhead) around the vermis on T1 postgadolinium images (D). T2 hyperintensity involving the right medial temporal lobe and atrophy of the left medial temporal lobe (E). Bilateral medial temporal hyperintensities (right greater than left; F). Gadolinium enhancement of the left trigeminal nerve (arrowhead) on axial and coronal sections (G). Gadolinium enhancement of the lumbosacral roots (arrowhead; H).

Figure 2.. Kelch-like Protein-11 (KLHL11)–Specific T-cell Response

Schematic of peripheral blood mononuclear cell–derived DC-T cell coculture assay (A). Flow cytometry at 72 hours following treatment demonstrated that (compared with vehicle treated cells) KLHL11 antigen–treated cells exhibited an increased frequency of CD69 expressing CD8+ and CD4+ T cells in KLHL11 immunoglobulin G seropositive (KLHL11+) patients but not healthy control (HC) individuals (B). Representative flow plots shown on left. Cytometry by time of flight immunophenotyping demonstrated an increased frequency of CD25 expressing CD4+ and CD8+ T cells following antigen treatment (C). Heat map shows expression of the indicated markers for each cluster. Rphenograph scatterplots show clusters generated by T-distributed stochastic neighbor embedding plots for all conditions (right) and for each condition (bottom panels). ^aP < .001.

Figure 3.. Immunohistochemical Staining of Brain Biopsy (A-F) and Testicular Seminoma (G-I)

Temporal lobe biopsy demonstrates nonnecrotizing granulomas, prominent lymphocytic infiltrates, and neuronal loss (A). Immunophenotyping demonstrated CD68-positive macrophages (B), fewer CD20-positive B cells (C) compared with numerous CD3+ T lymphocytes (D). Lymphocytes are both CD4+ (E) and CD8+ T cells (F). Hematoxylin-eosin (G) and CD3 (H) staining of a testicular seminoma from a patient with autoimmune Kelch-like protein 11 encephalitis demonstrates collection of inflammatory cells in the seminoma. Kelch-like protein 11 IgG binds to the cytoplasm of the seminomatous cells (I). Magnification 10× for panels A through F and 20× for G through I.

Figure 4.. Clinical Outcomes Assesed Based on Wheelchair Dependence

Kaplan-Meier curves show cumulative probability of ability to ambulate without wheelchair at last follow-up. A, Log-rank test: P = .01. B, Log-rank test: P = .93. KLHL11 indicates Klech-like protein 11.