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重视对髓鞘少突胶质细胞糖蛋白抗体阳性视神经炎的再认识

Pay attention to the re-understanding of myelin oligodendrocyte glycoprotein antibody-positive optic neuritis

来源期刊: 眼科学报 | 2023年3月 第38卷 第3期 175-180 发布时间:2023-03-01 收稿时间:2023/3/24 16:56:54 阅读量:7646
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髓鞘少突胶质细胞糖蛋白抗体视神经炎临床特征治疗进展
myelin oligodendrocyte glycoprotein antibody optic neuritis clinical characteristics treatment advancement
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10.12419/j.issn.1000-4432.2023.03.01
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视神经炎(optic neuritis,ON)是指视神经的炎性脱髓鞘病变,是引起中青年人视力下降的主要原因。近年来,髓鞘少突胶质细胞糖蛋白抗体阳性视神经炎(myelin oligodendrocyte glycoprotein antibody-positive ON,MOG-ON)成为神经眼科领域的研究热点,国内外报道不断增加。2021年3月,中华医学会眼科学分会神经眼科学组制定了《中国脱髓鞘性视神经炎诊断和治疗循证指南(2021年)》,将MOG-ON作为新的视神经炎亚型纳入脱髓鞘性视神经炎的诊疗体系,给广大眼科医生提供了新的参考依据。因此,临床医生需要充分认识MOG抗体相关疾病和MOG-ON的临床特征和治疗进展,努力提高其诊断和治疗水平,使此类患者能够得到更多的获益,造福于更多的视神经疾病患者。
Optic neuritis(ON)is an inflammatory demyelinating disease of the optic nerve, which is the main cause of vision loss in young and middle-aged people. In recent years, myelin oligodendrocyte glycoprotein antibody-positive ON(MOG-ON)has become a research hotspot in the field of neuro-ophthalmology, and reports at home and abroad are increasing.In March 2021, the Neuro-ophthalmology Group of Ophthalmology Branch of Chinese Medical Association formulated the Evidence-Based Guidelines for the Diagnosis and Treatment of Demyelinating Optic Neuritis in China(2021) , and included MOG-ON as a new optic neuritis subtype in the diagnosis and treatment system of myelinating optic neuritis providing a new reference for the majority of ophthalmologists. Therefore, clinicians need to fully understand the clinical features and treatment progress of MOG antibody-related diseases and MOG-ON, and strive to improve the level of diagnosis and treatment, so that such patients can get more benefits and benefit more patients with optic nerve diseases.
    视神经炎(optic neuritis,ON)是指视神经的炎性脱髓鞘病变,可导致急性或亚急性视力下降,是引起中青年人视功能损害的主要原因。水通道蛋白4(aquaporin 4,AQP4)抗体和髓鞘少突胶质细胞糖蛋白(myel in oligodendrocyte glycoprotein,MOG)抗体成为ON诊断必不可少的生物标志物,改变了眼科医生对于典型性ON的理解和认识[1]。近几年,MOG抗体阳性视神经炎(MOG antibody-positive ON,MOG-ON)成为神经眼科领域的研究热点,国内外报道不断增加[2-5]。2021年3月,中华医学会眼科学分会神经眼科学组制定了《中国脱髓鞘性视神经炎诊断和治疗循证指南(2021年)》[6],将MOG-ON作为新的ON亚型纳入脱髓鞘性视神经炎的诊疗体系,给广大眼科医生提供了新的参考依据。因此,临床医生需要充分认识MOG-ON的临床特征,努力提高对该病的诊断和治疗水平,使患者能够得到更多的获益,造福于更多的视神经疾病患者。

1 MOG抗体与MOG抗体相关疾病

    MOG抗原是一种1型跨膜蛋白,表达于少突胶质细胞的细胞膜上,属于免疫球蛋白超家族[7]。虽然,MOG仅占中枢神经系统(central nervous system,CNS)髓鞘蛋白成分的0.05%,但又是CNS髓鞘成分中抗原性最强的蛋白[8]。21世纪初,MOG抗体曾被误认为是多发性硬化(multiple sclerosis,MS)的特异性生物标志[9],早期MOG抗体的检测方法是酶联免疫吸附实验(enzyme linked immunosorbent assay,ELISA)法,随着检测技术的发展出现了灵敏度和特异度更高的基于细胞的检测(cell-based assays,CBA)法[10]。ELISA法能识别的线性表位的MOG抗体不具有致病性,而CBA法能识别构象表位的MOG抗体具有致病性,通过CBA法检测MOG抗体证实了MS患者的MOG抗体阳性率极低,由此确定MOG抗体阳性与MS发生无直接的关系。
    目前,主流观点认为MOG抗体是MOG抗体相关疾病(MOG antibody-associated disease,MOGAD)主要的生物标志物,MOGAD是一种不同于MS和视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)的独立的疾病谱[11-12]。2015年,国际NMOSD诊断标准是在MOGAD被确认为一个独立疾病实体之前制定的,约21%~42%的AQP4抗体阴性NMOSD患者的MOG 抗体呈阳性[13-14]。MOGAD的临床表型比NMOSD更加广泛,仅有约1/3的MOGAD患者符合AQP4抗体阴性的NMOSD诊断标准[15-16]AQP4抗体和MOG抗体同时阳性NMOSD病例极为罕见,表明了NMOSD和MOGAD并非由共同的病理生物学机制介导[17]。另外,MOGAD病理标本显示的脱髓鞘病灶不伴有星形胶质细胞变性,这与NMOSD并不相同[18]。MOGAD病灶可广泛累及CNS,临床表现多样化,包括ON、横贯性脊髓炎、急性播散性脑脊髓炎(acute disseminated encephalomyelitis, AEDM)和脑干脑炎等[15, 19],可为单一症状或者以上症状的多种组合。

2 MOG-ON临床特征

    ON是MOGAD最常见的临床分型,ADEM在儿童患者中更常见。MOG-ON患者男女比例相当,临床表现多种多样,主要特征包括视盘水肿多见、容易双眼发病和复发率较高[2-3]。MOG-ON更常见于儿童患者[4-5],与中青年患者相比,儿童患者具有不同的临床特征,具有更好的视力恢复、更低的年复发率和更多的颅内段视神经受累[20]。MOG-ON和AQP4-ON急性期引起的视力下降通常都很严重,但MOG-ON患者的视力恢复结局明显优于AQP4-ON患者[2, 21]仅有6%~10%MOG-ON患者的最终视力低于0.1,而AQP4-ON患者的最终视力低于0.1的比例通常超过1/3[2, 21-22]。笔者团队的一项最新研究结果显示:首次发病时有73.2%MOG-ON患者伴视盘水肿(AQP4-ON占比为38.2%),45.0%MOG-ON患者首次发病即表现为双眼同时受累或短期内双眼先后受累(AQP4-ON占比为12.6%);随访结束时MOG-ON患者出现严重视力下降(BCVA≤0.1)比例(15/254;5.9%)明显低于AQP4-ON(236/550;42.9%)和双抗体阴性ON组(68/218;31.2%)[5]
    部分MOG-ON患者对于糖皮质激素(激素)治疗反应敏感,但又存在着明显的激素依赖性,表现为激素减量或者停用后容易复发,这一特征符合慢性复发性炎性视神经病变(chronic relapsing inflammatory optic neuropathy,CRION)诊断标准[23-24],而AQP4-ON患者很少出现这类情况[25]。MOG抗体阳性可以表现为短暂性或者一过性,约63%MOG-ON患者的抗体水平在发病14个月后降至检测线以下[26],而AQP4抗体一旦阳性,通常会持续多年。MOG抗体持续阳性的患者更易复发,并且MOG抗体滴度的降低与疾病的单时相病程有关[27]。使用免疫抑制剂治疗期间,血清MOG抗体滴度可以降低或者转阴[28]。MOG抗体可以在其他CNS炎症性疾病中检测到,例如与抗N-甲基-D-天冬氨酸受体(anti-N-methyl-D-aspartate receptor,NMDAR)抗体共存[29]
    不同亚型ON的眼眶MRI检查表现存在差异性。在MOG-ON患者中,视神经增强信号可以发生在视神经周围,甚至延续到眶内组织,这在其他亚型的ON中很少见到[2, 30-31]。AQP4-ON常有长节段的视神经受累,其中视交叉和视束受累相对常见[31]。近期一项研究表明MOG-ON患者视交叉受累的比例高达16%,在这些患者中约54%存在长节段广泛的视神经增强信号[32]。由于MRI视神经受累特点不同,可以为不同亚型ON诊断及鉴别提供线索,建议对所有非典型ON患者进行眼眶MRI检查[6]

3 MOG-ON治疗进展

    目前,MOG-ON治疗研究数据有限,治疗推荐多来自一些小样本、回顾性研究,缺乏统一治疗方案,参考和借鉴专家共识和相关疾病的治疗指南具有重要意义[6, 11-33]。MOG-ON的治疗通常分为两个阶段:急性期治疗和缓解期治疗。急性期治疗的目的是最大限度地挽救视功能,防止或减少对CNS的进一步损害;维持期治疗主要目的是为了减少疾病的复发,降低失明和致残的严重程度。
    大剂量甲泼尼龙冲击治疗(intravenous methyl-prednisolone,IVMP)是MOG-ON患者急性期的一线治疗。最近的一项回顾性研究表明,早期IVMP治疗可以改善MOG-ON患者的视力预后[34]。对于部分IVMP治疗不敏感的患者,可使用血浆置换(plasma
exchange,PE)治疗。国外研究表明,对于IVMP治疗无效的MOGAD患者经PE治疗后的预后有改善[28]。笔者研究表明,PE治疗可以有效改善ON患者的视力[35]。因此,当伴有严重视力下降的MOG-ON患者经IVMP治疗效果欠佳时,PE是一种可行的治疗选择。对于IVMP治疗无反应或反应差,或病情逐渐恶化的MOGAD患者,静脉注射免疫球蛋白(intravenous immunoglobulin,IVIG)治疗有助于快速控制症状并减少复发[36]。日本学者进行的一项多中心、前瞻性、双盲、随机对照试验表明,IVIG可作为IVMP治疗不敏感ON急性期患者安全有效的治疗选择[37]
    MOG-ON患者的维持期治疗的最佳方案还不确定,期待着国内外同行开展更多的“头对头”(直接比较研究)的临床试验,筛选更优的治疗方案。多项研究表明,MOG-ON加用经典的免疫抑制治疗,包括小剂量激素、硫唑嘌呤、吗替麦考酚酯(mycophenolate mofetil,MMF)、利妥昔单抗(rituximab,RTX)和定期IVIG,可以降低疾病复发的频率,但不能完全预防复发[38-43]。一项来自13个国家29个中心的回顾性研究发现,RTX降低了MOGAD的复发率,尽管B淋巴细胞显著减少(血液中CD19+B淋巴细胞比例<1%),但仍有不少患者继续复发[44]。笔者研究发现,MMF和RTX均能降低MOG-ON患者的疾病活动程度,RTX表现出比MMF更好的耐受性;因为不加用免疫抑制治疗的MOG-ON患者中仅有不到一半会复发[45],因此,首次发病后暂时不推荐免疫抑制剂治疗仍然是一个不错的选择。据报道,托珠单抗有助于稳定复发性MOG-ON患者的病情[46-47],还需要开展更多的高质量临床研究来验证。最后还需要指出,传统的MS疾病修饰治疗对MOG-ON患者无效,甚至可能使患者的病情加重或恶化[40-41]

4 展望

    AQP4抗体和MOG抗体的发现加深了眼科医生对ON的认识,两种特异性抗体的检测有助于不同亚型ON患者的诊断、治疗和随访。推荐非典型ON患者进行AQP4抗体和MOG抗体筛查。针对NMOSD发病机制中的关键环节的新型的免疫靶向药物研发,比如选择性补体C5抑制剂、IL-6受体抑制剂、B淋巴细胞消耗剂,这些药物的上市已成为治疗AQP4-ON的里程碑事件。新型免疫靶向药物的成功上市为我们深入研究MOGAD发病机制提振了信心,坚信在不久的将来就会出现针对MOG-ON发病机制中的特异性靶向药物;此外,干细胞治疗、抗VEGF治疗、基因治疗可能会是潜在有效的措施,有待于更加深入的基础和临床研究;同时呼吁国内从事神经眼科的医生齐心协力、通力合作,积极开展和参与国际和国内的多中心视神经疾病的临床研究项目,尽快搭建和完善我国的神经眼科疾病数据库平台,积累更多的国人自己的循证医学证据,更好地服务于MOG-ON患者。

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1、国家重点研发计划项目(2018YFE0113900);国家自然科学基金面上项目(81870662)。
This work was supported by the National Key Research and Development Program (2018YFE0113900);National Natural Science Foundation of China (81870662).()
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