Gelpi Ellen, Höftberger Romana, Graus Francesc, Ling Helen, Holton Janice L, Dawson Timothy, Popovic Mara, Pretnar-Oblak Janja, Högl Birgit, Schmutzhard Erich, Poewe Werner, Ricken Gerda, Santamaria Joan, Dalmau Josep, Budka Herbert, Revesz Tamas, Kovacs Gabor G
Neurological Tissue Bank of the Biobanc-Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Acta Neuropathol. 2016 Oct;132(4):531-43. doi: 10.1007/s00401-016-1591-8. Epub 2016 Jun 29.
We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB11001 and HLA-DQB10501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB11001 and HLA-DQB10501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.
我们最近报道了一种新型神经综合征，其特征为独特的非快速眼动（NREM）和快速眼动（REM）睡眠行为障碍，伴有睡眠呼吸暂停和喘鸣，同时伴有延髓功能障碍，并与抗神经元细胞黏附蛋白IgLON5抗体存在特定关联。所有患者均携带HLA - DRB11001和HLA - DQB10501等位基因。两名患者的神经病理学检查结果显示一种新型的tau蛋白病，局限于神经元，主要累及下丘脑和脑干被盖。本研究的目的是描述抗IgLON5综合征的神经病理学特征，并根据相关临床和免疫学数据的存在提供诊断确定性水平。对6例患者的大脑进行了检查，并通过共识确定了神经病理学诊断所需的特征。使用额外的临床和免疫学标准来定义“确诊”“很可能”和“可能”的诊断类别。所有患者的大脑均显示出显著相似的特征，符合神经退行性疾病，伴有神经元丢失和胶质细胞增生，且无炎症浸润。最相关的发现是由三重复（3R）和四重复（4R）tau蛋白异构体组成的高度磷酸化tau蛋白在神经元中的积累，优先累及下丘脑，更严重的是脑干被盖核，从颅端到尾端存在严重程度梯度，直至颈髓上段。当这些神经病理学特征与血清或脑脊液中IgLON5抗体的检测同时出现时，可确诊为抗IgLON5相关tau蛋白病。当抗体状态未知时，“很可能”的诊断需要神经病理学检查结果以及相符的临床病史，或确认携带HLA - DRB11001和HLA - DQB10501等位基因。对于神经病理学相符但缺乏相关临床表现和免疫学状态信息的病例，应考虑“可能”的诊断。这些标准应有助于在存档组织中识别未确诊的病例，并将有助于对这种新型疾病进行未来的临床病理学研究。
