GQ1b-Seronegative Miller Fisher Syndrome Associated With Pembrolizumab.
GQ1b-Seronegative Miller Fisher Syndrome Associated With Pembrolizumab.
复制标题
GQ1b-血清阴性米勒费希尔综合征与派姆单抗相关。
DOI：
10.1097/wno.0000000000000755
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发表时间：
2019
影响因子：
2.9
通讯作者：
D. Kaufman
中科院分区：
文献类型：
--
作者：
K. Green;A. Levine;Jayne Ward;D. Kaufman
一例62岁男性，有头皮转移性鳞状细胞癌（SCC）病史，最近完成了5个周期的帕博利珠单抗治疗，因进行性步态共济失调、构音障碍、吞咽困难和复视2周就诊于急诊科。体格检查时，患者出现深度反射消失、下肢共济失调、双侧面部麻痹和眼肌麻痹。脑部MRI正常。腰椎穿刺显示白细胞分离，7个白色血细胞/mL，蛋白质为236 mg/dL（正常：15-45 mg/dL）。其他脑脊液（CSF）检查（包括细胞学和流式细胞术）均正常。初步诊断为米勒费舍尔综合征（MFS），并开始静脉注射免疫球蛋白（IVIg）治疗5天。在2天内，面部无力和眼肌麻痹明显改善。苷脂（去唾液酸-GM 1、GM 1、GM 2、GD 1a、GD 1b和GQ 1b），乙酰胆碱受体（阻断、结合和调节）和副肿瘤（抗神经元核I/II/III型，抗神经胶质细胞核I型，浦肯野细胞胞质I/II/Tr型，两栖激素，CRMP-5，纹状体，P-/Q-型钙通道，N-型钙通道，AChR神经节神经元，和神经元[V-G]钾通道）抗体在正常范围内。2个月后的门诊随访显示眼肌麻痹已消退，步态有所改善，残留轻度左侧面瘫。未给予帕博利珠单抗进一步治疗。米勒费希尔综合征是一种罕见的格林-巴利综合征，其特征是典型的共济失调、反射消失和眼肌麻痹三联征（1）。这种疾病主要是周围神经功能障碍之一;然而，罕见的变体表现为中枢功能障碍-通常限于菱脑（2）。发病机制被认为是由于分子模拟引起的感染后自身免疫性疾病（3）。抗GQ 1b抗体最常在高达80%的病例中检测到（2）。GQ 1b表位在中枢和外周均有发现，在第三、第四和第六脑神经的郎维氏结周围具有显著丰度（4，5）。肌梭内神经末梢的缺陷富含GQ 1b表位，这与共济失调和反射消失相关（6）。眼外肌中存在的其他不太丰富的神经节苷脂抗体（GT 1a和GD 1b）（7），部分解释了少数GQ 1b抗体阴性的MFS患者。大多数对其他神经节苷脂抗体的单一和/或复合形式呈阳性（8，9）。一小部分GQ 1b血清阴性病例与其他抗体相关。抗谷氨酸脱羧酶（10）和电压门控钾通道（11）抗体已在文献中报道。有一个真正的血清阴性病例组甚至更少，其中没有检测到抗体（8）。我们的转移性SCC患者在完成5轮新型PD-1抑制剂pembrolizumab治疗后不久发生血清阴性MFS。他有典型的MFS临床表型和典型的CSF表现，提示外周脱髓鞘。通过血清学标志物、CSF检测和神经影像学检查排除了副肿瘤疾病和/或软脑膜转移的可能性。未发现典型的前驱感染和神经节苷脂抗体阳性。由于这对于MFS是非典型的，考虑到治疗与症状发作之间的时间相关性，我们质疑与帕博利珠单抗的相关性。免疫检查点抑制剂pembrolizumab与几种神经免疫相关事件有关（12）。该药物通过激活T细胞功能调节宿主保护自身免受自身免疫的能力（13）-这是一种有益于肿瘤治疗的反应，但可能是致命的免疫介导的不良事件的来源。有与帕博利珠单抗相关的格林-巴利综合征的报告，均为神经节苷脂抗体阴性（表1）。在报告的病例中，只有停药后接受IVIg治疗的患者临床症状改善（12、14、15）。与pembrolizumab相关的外周神经自身免疫的病理生理学尚未完全了解。所有3例报告的患者均有不同程度的面神经受累;或许，pembrolizumab对面神经上的神经节苷脂表位簇有潜在的偏好。这个病例增加了密歇根州东兰辛市密歇根州立大学神经病学和眼科学系（KEG，JHW和DIK）和密歇根州东兰辛市密歇根州立大学骨科医学院（AML）的无数不良自身免疫性疾病。
A 62-year-old man with a history of metastatic squamous cell carcinoma (SCC) of the scalp, who recently completed 5 cycles of pembrolizumab, presented to the emergency department with 2 weeks of progressive gait ataxia, dysarthria, dysphagia, and diplopia. On physical examination, he had profound areflexia, lower-extremity ataxia, facial diplegia, and ophthalmoplegia. Brain MRI was normal. Lumbar puncture showed albuminocytologic dissociation of 7 white blood cells/mL and protein of 236 mg/dL (normal: 15–45 mg/dL). Additional cerebrospinal fluid (CSF) studies including cytology and flow cytometry were normal. A tentative diagnosis of Miller Fisher syndrome (MFS) was made, and a 5-day course of intravenous immunoglobulin (IVIg) therapy was initiated. Within 2 days, there was marked improvement in facial weakness and ophthalmoplegia. Ganglioside (Asialo-GM1, GM1, GM2, GD1a, GD1b, and GQ1b), acetylcholine receptor (blocking, binding, and modulating), and paraneoplastic (antineuronal nuclear type I/II/III, antiglial nuclear type I, purkinje cell cytoplasmic types I/II/Tr, amphiphysin, CRMP-5, striational, P-/Q-type calcium channel, N-type calcium channel, AChR ganglionic neuronal, and neuronal [V-G] potassium channel) antibodies sent before starting IVIg were within the normal range. Outpatient follow-up 2 months later showed that ophthalmoplegia had resolved, and there was improvement in gait and residual mild left facial palsy. No further treatment with pembrolizumab has been administered. Miller Fisher syndrome is a rare form of Guillain–Barre syndrome characterized by a classic triad of ataxia, areflexia, and ophthalmoplegia (1). The disorder primarily is one of peripheral nerve dysfunction; however, rare variants manifest as central dysfunction—usually limited to the rhombencephalon (2). The pathogenesis is believed to be a postinfectious autoimmune disorder due to molecular mimicry (3). Anti-GQ1b antibody is most frequently detected in up to 80% of cases (2). The GQ1b epitope is found both centrally and peripherally, with significant abundance around nodes of Ranvier of the third, fourth, and sixth cranial nerves (4,5). Defects in the nerve terminals inside muscle spindles are rich in GQ1b epitopes, which correlate with ataxia and areflexia (6). Other less-abundant ganglioside antibodies (GT1a and GD1b) that are present in extraocular muscles (7), partly account for a minority of patients with MFS that are GQ1b antibody–negative. The majority are positive for a single and/or a complexed form of other ganglioside antibodies (8,9). A small subset of the GQ1b-seronegative cases is associated with other antibodies. Anti–glutamic acid decarboxylase (10) and voltage-gated potassium channel (11) antibodies have been reported in the literature. There is an even smaller group of truly seronegative cases, where no antibodies are detected (8). Our patient with metastatic SCC developed seronegative MFS, shortly after completing 5 rounds with a novel PD-1 inhibitor, pembrolizumab. He had the classic clinical phenotype of MFS and the typical CSF findings indicative of peripheral demyelination. The possibility of a paraneoplastic disease and/or leptomeningeal metastasis was excluded with serologic markers, CSF testing, and neuroimaging. The typical antecedent infection and ganglioside antibody seropositivity were not present. As this is atypical for MFS, we questioned an association with pembrolizumab, given the temporal association between therapy and onset of symptoms. The immune checkpoint inhibitor pembrolizumab has been linked to several neurological immune-related events (12). The drug modulates the host’s ability to protect itself from autoimmunity by activating T-cell functionality (13)— a response that is beneficial in oncotherapy yet the source of potentially fatal immune-mediated adverse events. There are reports of Guillain–Barre syndrome associated with pembrolizumab, all negative for ganglioside antibodies (Table 1). Of the reported cases, only those treated with IVIg after discontinuation of the drug had clinical improvement (12,14,15). The pathophysiology of the peripheral nerve autoimmunity related to pembrolizumab is not fully understood. All 3 of the reported patients had varying degrees of facial nerve involvement; perhaps, pembrolizumab has an underlying predilection for ganglioside epitopes clustering on the facial nerve. This case adds to the myriad of adverse autoimmune Department of Neurology and Ophthalmology (KEG, JHW, and DIK), Michigan State University, East Lansing, Michigan; and Michigan State University College of Osteopathic Medicine (AML), East Lansing, Michigan.