Clinical Manifestations, Tumor Associations, and Long-Term Outcomes of Anti-KLHL11 Encephalitis

BACKGROUND AND OBJECTIVES: Anti-Kelch-like protein 11 (KLHL11) encephalitis was discovered in middle-aged men with testicular seminoma and rhombencephalitis, defining a new type of paraneoplastic neurologic syndrome (PNS), but diagnostic criteria and treatment outcomes remain largely unclear. This study aimed to comprehensively describe the initial presentations and subsequent clinical courses, ancillary findings, treatments, and outcomes of patients with anti-KLHL11 encephalitis. METHODS: We tested 1,361 patients with clinical features or tumors that could be associated with anti-KLHL11 encephalitis (1,164 CSF and 680 serum). The retrospective analysis included 458 serum and 288 CSF samples from 473 patients between January 2010 and July 2020, while prospective screening for anti-KLHL11 antibodies was regularly performed since July 2020. Anti-KLHL11-abs was screened using KLHL11 overexpression cell-based assay. Detailed clinical and paraclinical information was collected. RESULTS: Seventeen anti-KLHL11 encephalitis patients were identified. The median age of patients was 59 (IQR 48-72; range 28-76) years, and 12 individuals (n = 12, 71%) were male. Common phenotypes were cerebellar ataxia (n = 12, 71%), brainstem encephalitis (n = 12, 71%), opsoclonus-myoclonus syndrome (n = 8, 47%), and limbic encephalitis (n = 3, 18%). Meningitis was observed in one patient. Concurrent antibodies included those against N-methyl-D-aspartate receptor (n = 2), glial fibrillary acidic protein (n = 1), and contactin-associated protein-like 2 (n = 1). MRI was abnormal in 8 cases (47%), showing T2/FLAIR hyperintensity in the rhombencephalon (n = 3, 18%), limbic system (n = 4, 24%), or cerebellar atrophy (n = 2, 12%). Tumors were identified in 10 cases (59%), including seminoma (n = 5, 29%), ovarian teratoma (n = 1, 6%), urological (renal cell carcinoma and urothelial cell carcinoma, both n = 1, 12%), small-cell lung cancer, and carcinoma of unknown primary (all n = 1). Fifteen patients received first-line immunotherapies (88%), and 6 patients also received second-line immunotherapy (35%). Improvement or stabilization was achieved in 10 (7 and 3, respectively, 67%) patients. The median follow-up duration was 20 months (range 1.5-180). Six patients died within the first 12 months, related to encephalitis (n = 3, 18%) or cancer (n = 3, 18%). DISCUSSION: Anti-KLHL11 encephalitis mainly related to infratentorial encephalitis but can also present as limbic encephalitis and rarely as meningitis. Early diagnosis enables early oncological and immunologic treatment, hopefully improving outcomes.