Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Department of Neurology, Mayo Clinic, Rochester, Minnesota.
JAMA Neurol. 2020 Nov 1;77(11):1420-1429. doi: 10.1001/jamaneurol.2020.2231.
Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management.
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).
Outcome variables included modified Rankin score and gait aid use.
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-DQB102:01 (n = 7; 70%) and HLA-DRB103:01 (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.
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.
识别 Kelch-like protein-11 免疫球蛋白 G 阳性 (KLHL11 IgG+) 患者的表现和免疫病理学特征可能有助于早期诊断和治疗。
描述 KLHL11 脑炎不断扩大的神经表型、癌症相关性、结局和免疫病理学特征。
设计、地点和参与者：这项回顾性的三级保健中心研究于 1998 年 10 月 15 日至 2019 年 11 月 1 日进行，前瞻性地在神经免疫实验室中确定了 31 例 KLHL11 IgG+病例。其中 8 例是通过对脑炎患者（通过组织基于免疫荧光和转染细胞的检测证实）的回顾性检测发现的。
结局变量包括改良 Rankin 评分和步态辅助使用。
所有 39 例 KLHL11 IgG+患者均为男性（中位年龄 46 岁；范围 28-73 岁）。初始临床表现为共济失调（n=32；82%）、复视（n=22；56%）、眩晕（n=21；54%）、听力损失（n=15；39%）、耳鸣（n=14；36%）、构音障碍（n=11；28%）和癫痫发作（n=9；23%）。不典型的神经表现包括神经精神功能障碍、骨髓神经病和颈肌萎缩。10 例患者（26%）在其他神经功能缺损前 1 至 8 个月出现听力损失或耳鸣。在筛查恶性肿瘤的 36 例患者中（n=30），发现 23 例（64%）睾丸生殖细胞肿瘤或 7 例（19%）睾丸微石症和纤维化提示退化的生殖细胞肿瘤。在 2 例患者中，淋巴结活检诊断为 1 例肺腺癌转移和 1 例慢性淋巴细胞白血病。初始脑磁共振成像显示颞叶（n=12）、小脑（n=9）、脑干（n=3）或间脑（n=3）存在 T2 高信号。在接受 HLA Ⅰ类和Ⅱ类基因分型的 KLHL11 IgG+患者中（n=10），大多数患者存在 HLA-DQB102:01（n=7；70%）和 HLA-DRB103:01（n=6；60%）关联。活检增强的颞叶病变显示 T 细胞为主的炎症和非坏死性肉芽肿。小脑活检（慢性共济失调患者）和 2 例尸检脑显示浦肯野神经元丢失和 Bergmann 胶质增生，支持早期活跃的炎症和晚期广泛的神经元丢失。与非自身免疫性对照外周血单核细胞相比，当患者外周血单核细胞与 KLHL11 蛋白共培养时，CD8+和 CD4+T 细胞明显被激活。大多数患者（58%）受益于免疫治疗和/或癌症治疗（神经功能障碍稳定[n=10]或改善[n=9]）。Kaplan-Meier 曲线显示，没有检测到睾丸癌的患者更有可能依赖轮椅。KLHL11-IgG+患者的长期结局与 Ma2 脑炎相似。
Kelch-like protein-11 免疫球蛋白 G 是睾丸生殖细胞肿瘤和副肿瘤性神经综合征的生物标志物，通常对治疗有抗性。描述的扩大的神经表型和临床前发现可能有助于其早期诊断和治疗。
