Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
Department of Neurology, Oxford University Hospitals, John Radcliffe Hospital, Oxford, UK.
J Neurol Neurosurg Psychiatry. 2018 May;89(5):526-534. doi: 10.1136/jnnp-2017-315720. Epub 2017 Oct 21.
Recent biochemical observations have helped redefine antigenic components within the voltage-gated potassium channel (VGKC) complex. The related autoantibodies may be now divided into likely pathogenic entities, which target the extracellular domains of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), and species that target intracellular neuronal components and are likely non-pathogenic. This distinction has enhanced clinical practice as direct determination of LGI1 and CASPR2 antibodies offers optimal sensitivity and specificity. In this review, we describe and compare the clinical features associated with pathogenic LGI1 and CASPR2 antibodies, illustrate emerging laboratory techniques for antibody determination and describe the immunological mechanisms that may mediate antibody-induced pathology. We highlight marked clinical overlaps between patients with either LGI1 or CASPR2 antibodies that include frequent focal seizures, prominent amnesia, dysautonomia, neuromyotonia and neuropathic pain. Although occurring at differing rates, these commonalities are striking and only faciobrachial dystonic seizures reliably differentiate these two conditions. Furthermore, the coexistence of both LGI1 and CASPR2 antibodies in an individual occurs surprisingly frequently. Patients with either antibody respond well to immunotherapies, although systematic studies are required to determine the magnitude of the effect beyond placebo. Finally, data have suggested that CASPR2 and LGI1 modulation via genetic or autoimmune mechanisms may share common intermediate molecules. Taken together, the biochemical distinction of antigenic targets has led to important clinical advances for patient care. However, the striking syndrome similarities, coexistence of two otherwise rare antibodies and molecular insights suggest the VGKC complex may yet be a common functional effector of antibody action. Hence, we argue for a molecular evolution alongside a clinical and phenotypic re-evaluation.
近期的生化观察结果有助于重新定义电压门控钾通道 (VGKC) 复合物中的抗原成分。相关的自身抗体现在可能分为可能致病的实体，这些实体靶向富含亮氨酸的胶质瘤失活 1 (LGI1) 和接触蛋白相关蛋白样 2 (CASPR2) 的细胞外结构域，以及靶向细胞内神经元成分且可能非致病性的实体。这种区分提高了临床实践水平，因为直接确定 LGI1 和 CASPR2 抗体可提供最佳的敏感性和特异性。在这篇综述中，我们描述并比较了与致病性 LGI1 和 CASPR2 抗体相关的临床特征，阐述了新兴的抗体测定实验室技术，并描述了可能介导抗体诱导病理的免疫机制。我们强调了具有 LGI1 或 CASPR2 抗体的患者之间存在明显的临床重叠，包括频繁的局灶性发作、突出的健忘症、自主神经功能障碍、肌强直和神经病理性疼痛。尽管发生的频率不同，但这些共同之处非常引人注目，只有面肩肱型肌营养不良性发作才能可靠地区分这两种情况。此外，个体中同时存在 LGI1 和 CASPR2 抗体的情况出人意料地频繁。具有任何一种抗体的患者对免疫疗法反应良好，尽管需要进行系统研究以确定免疫疗法相对于安慰剂的效果幅度。最后，数据表明，通过遗传或自身免疫机制调节 CASPR2 和 LGI1 可能共享共同的中间分子。总之，抗原靶点的生化区分导致了患者护理的重要临床进展。然而，惊人的综合征相似性、两种罕见抗体的共存以及分子见解表明，VGKC 复合物可能仍然是抗体作用的常见功能效应物。因此，我们主张在临床和表型重新评估的同时进行分子进化。
