Department of Neurology, Mie University, Mie, Japan.
Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA.
Eur J Neurol. 2021 Dec;28(12):4261-4266. doi: 10.1111/ene.15120.
The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS).
Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue.
A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm.
This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.
本研究旨在确定 1 例抗 Kelch 样蛋白 11（KLHL11）相关副肿瘤性神经系统综合征（PNS）患者的长期影像学改变、自身抗体特异性和临床病程。
回顾性评估连续脑磁共振图像。为了检测 KLHL11 自身抗体，通过噬菌体展示免疫沉淀和测序（PhIP-Seq）对纵向脑脊液（CSF）和血清样本进行筛选。还进行了免疫组织化学染色，以评估患者精原细胞瘤组织中 KLHL11 的存在。
一名 42 岁男性出现进行性共济失调和感觉神经性听力损失。在神经症状出现后 11 个月发现转移性精原细胞瘤。尽管免疫治疗部分有效，但他的小脑性共济失调在接下来的 8 年中逐渐恶化。脑磁共振成像显示进行性脑桥和小脑萎缩，伴有“十字面包征”，以及黑质、红核和齿状核的磁敏感加权成像（SWI）低信号强度。PhIP-Seq 在所有样本中均富集 KLHL11 衍生肽。用患者 CSF 对小鼠脑进行免疫组织化学染色显示，在延髓和齿状核中与 KLHL11 商业抗体存在共定位。精原细胞瘤组织的免疫组织化学分析显示细胞质中存在抗 KLHL11 抗体阳性颗粒。
本研究表明，对于不仅在 T2-FLAIR 而且在 SWI 上显示脑干和小脑萎缩以及信号改变的患者，应将 KLHL11-PNS 纳入鉴别诊断，否则可能会被解释为多系统萎缩等神经退行性疾病的继发改变。
