Article(id=1208518758956659280, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208518757253779608, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.12.15, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1614960000000, receivedDateStr=2021-03-06, revisedDate=1630166400000, revisedDateStr=2021-08-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1766062925298, onlineDateStr=2025-12-18, pubDate=1640620800000, pubDateStr=2021-12-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766062925298, onlineIssueDateStr=2025-12-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766062925298, creator=13701087609, updateTime=1766062925298, updator=13701087609, issue=Issue{id=1208518757253779608, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='12', pageStart='1167', pageEnd='1267', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766062924920, creator=13701087609, updateTime=1766062998332, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208519065233125464, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208518757253779608, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208519065233125465, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208518757253779608, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1263, endPage=1267, ext={EN=ArticleExt(id=1208518759267037780, articleId=1208518758956659280, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research status of overlap syndrome of myelin oligodendrocyte glycoprotein-antibody disease and anti-N-methyl-D-aspartate receptor encephalitis, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

In recent years, there have been increasing reports of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and myelin oligodendrocyte glycoprotein-antibody disease (MOG-Ab disease) appearing simultaneously or sequentially in the same patient. Some scholars have collectively referred to this kind of disease as the overlapping syndrome of MOG-Ab disease and anti-NMDAR encephalitis (MNOS). The clinical manifestations, treatment and prognosis of these syndromes are different from simple anti-NMDAR encephalitis or MOG-Ab disease. However, due to lack of understanding, clinicians tend to diagnose these syndromes as simple anti-NMDAR encephalitis or MOG-Ab disease, resulting in delayed the disease and affected prognosis. In order to strengthen the understanding of MNOS, this paper reviews MNOS from etiological hypothesis, characteristics of affected population, clinical manifestations, imaging manifestations, antibody characteristics in disease progression and treatment, so as to provide reference for the diagnosis and treatment in the future.

, correspAuthors=Zhao-Ming Ge, authorNote=null, correspAuthorsNote=
*E-mail:
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近年来,抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎及髓鞘少突胶质细胞糖蛋白(MOG)抗体相关疾病在同一患者体内同时或先后出现的报道逐渐增多,学者们将这类疾病统称为MOG抗体病及抗NMDAR脑炎重叠综合征(MNOS)。MNOS在临床表现、治疗、预后等方面不同于单纯的抗NMDAR脑炎或MOG抗体病,但因缺乏认识,临床医师往往容易忽视患者的一些临床表现,将这类综合征诊断为单纯的抗NMDAR脑炎或MOG抗体病,以致延误病情,影响预后。为加强对MNOS的认识,该文从MNOS的病因假说、发病人群特征、临床表现、影像学表现、疾病进程中的抗体特征、治疗方法等方面进行综述,以期为今后对该疾病的诊断及治疗提供参考。

, correspAuthors=葛朝明, authorNote=null, correspAuthorsNote=
葛朝明,E-mail:
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何亚玲,硕士研究生,主要从事神经免疫方面的研究

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MOG抗体病及抗NMDAR脑炎重叠综合征研究现状
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何亚玲 , 沈雪阳 , 葛朝明 *
解放军医学杂志 | 综述 2021,46(12): 1263-1267
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解放军医学杂志 | 综述 2021, 46(12): 1263-1267
MOG抗体病及抗NMDAR脑炎重叠综合征研究现状
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何亚玲, 沈雪阳, 葛朝明*
作者信息
  • 兰州大学第二医院神经内科/甘肃省神经内科临床医学研究中心/甘肃省神经病学重点实验室,兰州 730030
  • 何亚玲,硕士研究生,主要从事神经免疫方面的研究

通讯作者:

葛朝明,E-mail:
Research status of overlap syndrome of myelin oligodendrocyte glycoprotein-antibody disease and anti-N-methyl-D-aspartate receptor encephalitis
Ya-Ling He, Xue-Yang Shen, Zhao-Ming Ge*
Affiliations
  • Department of Neurology, the Second Hospital of Lanzhou University/Clinical Research Center of Neurology of Gansu Province/Key Laboratory of Neurology of Gansu Province, Lanzhou 730030, China
出版时间: 2021-12-28 doi: 10.11855/j.issn.0577-7402.2021.12.15
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近年来,抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎及髓鞘少突胶质细胞糖蛋白(MOG)抗体相关疾病在同一患者体内同时或先后出现的报道逐渐增多,学者们将这类疾病统称为MOG抗体病及抗NMDAR脑炎重叠综合征(MNOS)。MNOS在临床表现、治疗、预后等方面不同于单纯的抗NMDAR脑炎或MOG抗体病,但因缺乏认识,临床医师往往容易忽视患者的一些临床表现,将这类综合征诊断为单纯的抗NMDAR脑炎或MOG抗体病,以致延误病情,影响预后。为加强对MNOS的认识,该文从MNOS的病因假说、发病人群特征、临床表现、影像学表现、疾病进程中的抗体特征、治疗方法等方面进行综述,以期为今后对该疾病的诊断及治疗提供参考。

髓鞘少突胶质细胞糖蛋白  /  受体,N-甲基-D-天冬氨酸  /  脑炎

In recent years, there have been increasing reports of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and myelin oligodendrocyte glycoprotein-antibody disease (MOG-Ab disease) appearing simultaneously or sequentially in the same patient. Some scholars have collectively referred to this kind of disease as the overlapping syndrome of MOG-Ab disease and anti-NMDAR encephalitis (MNOS). The clinical manifestations, treatment and prognosis of these syndromes are different from simple anti-NMDAR encephalitis or MOG-Ab disease. However, due to lack of understanding, clinicians tend to diagnose these syndromes as simple anti-NMDAR encephalitis or MOG-Ab disease, resulting in delayed the disease and affected prognosis. In order to strengthen the understanding of MNOS, this paper reviews MNOS from etiological hypothesis, characteristics of affected population, clinical manifestations, imaging manifestations, antibody characteristics in disease progression and treatment, so as to provide reference for the diagnosis and treatment in the future.

myelin oligodendrocyte glycoprotein  /  receptor, N-methyl-D aspartate  /  encephalitis
何亚玲, 沈雪阳, 葛朝明. MOG抗体病及抗NMDAR脑炎重叠综合征研究现状. 解放军医学杂志, 2021 , 46 (12) : 1263 -1267 . DOI: 10.11855/j.issn.0577-7402.2021.12.15
Ya-Ling He, Xue-Yang Shen, Zhao-Ming Ge. Research status of overlap syndrome of myelin oligodendrocyte glycoprotein-antibody disease and anti-N-methyl-D-aspartate receptor encephalitis[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (12) : 1263 -1267 . DOI: 10.11855/j.issn.0577-7402.2021.12.15
抗N-甲基-D-天冬氨酸受体(N-methy-l D-aspartate receptor,NMDAR)脑炎是NMDAR抗体介导的自身免疫性脑炎,儿童期最为常见,临床表现为迅速进展的精神行为异常,记忆力减退,运动、语言、意识、睡眠障碍,癫癎发作,低通气及自主神经功能紊乱等[1-2]。髓鞘少突胶质细胞糖蛋白(myelin oligodendrocyte glycoprotein,MOG)抗体存在于中枢神经系统脱髓鞘疾病患者体内,该抗体导致的脱髓鞘疾病是不同于多发性硬化(multiple sclerosis,MS)及视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)的独立疾病[3],有学者提出将MOG抗体导致的脱髓鞘疾病统称为MOG抗体相关疾病[4-5]。MOG抗体病可广泛累及中枢神经系统,临床表现多样,包括视神经炎、皮质脑炎、脑干脑炎、脊髓炎等,可为单一症状或以上症状的多种组合,这些症状的诊断需要相应的影像学支持[4,6]。最近,学者们发现抗NMDAR脑炎与MOG抗体病存在一定的联系,二者可在同一患者体内同时或先后重叠出现。Titulaer等[7]最先注意到一些抗NMDAR脑炎患者会出现脱髓鞘疾病的相关症状,在回顾性分析了691例抗NMDAR脑炎患者的资料后发现,23例(3.3%)存在共患脱髓鞘疾病,因此提出抗NMDAR脑炎患者可能并发脱髓鞘疾病,而有视神经脊髓炎(neuromyelitis optica,NMO)症状且出现非典型脱髓鞘疾病症状(如运动障碍、精神症状)的患者可能发生抗NMDAR脑炎。此后,Fan等[8]发现,11.9%的MOG抗体阳性脱髓鞘疾病患者及0.6%的NMOSD患者同时或相继罹患抗NMDAR脑炎,前者与抗NMDAR脑炎重叠出现的概率明显大于后者,该研究将这类MOG抗体病及抗NMDAR脑炎重叠出现的情况统称为MOG抗体病及抗NMDAR脑炎重叠综合征(overlapping syndrome of MOG-Ab disease and anti-NMDAR encephalitis,MNOS)。这类综合征通常为复发-缓解病程,首次发病或单次复发病程中可表现为抗NMDAR脑炎与中枢神经系统脱髓鞘疾病共存,也可只表现为单纯抗NMDAR脑炎或中枢神经系统脱髓鞘疾病[9-10]。与单纯MOG抗体病及单纯抗NMDAR脑炎不同,MNOS有其独特的临床表现、治疗方法及预后特征。随着抗体检测水平的提高,对该综合征的报道逐渐增多,但MNOS仍是临床中少见甚至罕见的疾病。本文对MNOS的病因假说、发病人群特征、临床表现、影像学特征、抗体特征、治疗方法等进行综述,旨在加强对该类疾病的认识,为以后的诊断及治疗提供参考。
目前抗NMDAR脑炎及MOG抗体病重叠出现的具体机制尚不明确,学者们提出的可能机制有以下几种。
MOG是一种表达于中枢神经系统少突胶质细胞及髓磷脂表面的蛋白,有研究表明NMDAR同样存在于少突胶质细胞表面[11]。MOG抗体及NMDAR抗体在同一患者体内重叠出现,可能是由针对少突胶质细胞的自身免疫性疾病引起的,当受到异常免疫攻击时,免疫细胞可能错误地攻击处于同一位置的MOG及NMDAR自身抗原,使二者同时或相继受累,从而在脑脊液及血清中产生NMDAR抗体及MOG抗体,这些自身免疫抗体可能最终导致MNOS[7,12]
MOG抗体及NMDAR抗体的重叠出现可能与免疫重建有关。不同类型的免疫治疗可能会影响机体的免疫状态,在减少免疫治疗药物用量或停药时,免疫系统会从免疫抑制中恢复[13],并进行自身重建,在此过程中可能会引起免疫细胞攻击自身抗原[14-16],从而造成多种抗体重叠出现并最终导致相关疾病。文献报道,有部分最初诊断为单纯抗NMDAR脑炎的患者,在激素减量过程中出现脱髓鞘疾病的临床和(或)影像学表现,且MOG抗体转为阳性[12]。同样,一些最初诊断为MOG抗体病的患者在激素减量过程中出现非特征性临床表现(如精神、行为异常,记忆力减退等),且NMDAR抗体转为阳性,最终被诊断为MNOS[17],此类患者病情复发及新抗体的出现可能与免疫重建有关,但需要进一步研究证实。
早期的病毒感染可能会诱导产生不同类型的抗体[18-19]。Zhou等[20]报道了1例31岁男性MNOS患者,其最初症状为发热、头痛及癫癎发作,脑脊液中单纯疱疹病毒(herpes simplex virus,HSV)、巨细胞病毒(cytomegalovirus,CMV)及风疹病毒(rubella virus,RV)抗体均为阳性,在第3次发病时,同时检测到了NMDAR抗体及MOG抗体。Hou等[21]报道的7例儿童MNOS中,1例在发病前1年被确诊为病毒性脑炎。也有一些患者在就诊时虽无病毒感染证据,但有前驱感染史,不排除前期存在病毒感染的可能。这些均提示病毒感染可能与双抗体的产生有一定关联。Cao等[18]认为,MNOS可能的机制为当人体感染嗜神经病毒后,血脑屏障遭到破坏,MOG及NMDAR抗原渗漏到外周血中,辅助性T细胞被激活,从而增加了对MOG及NMDAR特异性B细胞的招募及激活,最终导致MOG抗体及NMDAR抗体的产生,但具体机制仍有待进一步研究。
一些学者提出,抗NMDAR脑炎及MOG抗体病可能存在共同的发病机制,当某些诱因导致体液免疫紊乱时,会产生同时针对神经元及神经胶质细胞的自身抗体,从而引起神经系统异常[7,22]
多数MNOS患者的发病年龄较小,男性发病率高于女性。Du等[23]通过病例总结及既往文献分析发现,32例MNOS患者的发病年龄为3~48岁,其中男性占62%。Fan等[8]报道,MNOS的发病年龄为3~25岁,男性多于女性,儿童多于成人。曹丽萍等[24]发现,临床上抗NMDAR脑炎及MOG抗体病并存的患者平均发病年龄为22岁,且成人多于儿童,与Fan等[8]的报道不同。目前关于MNOS的报道主要为个案及小样本研究,这可能是成人与儿童发病率高低存在争议的原因,因此,尚需开展大样本研究及对既往报道的系统性综述。
MNOS患者的临床表现多样,且当抗NMDAR脑炎及MOG抗体病同时出现时,临床医师往往容易忽视其中一种疾病的临床表现,从而增加了MNOS的诊断难度。根据不同临床表现对MNOS进行分类,依据抗NMDAR脑炎及MOG抗体病出现的时间顺序不同,可分为两类:(1)MOG抗体病及抗NMDAR脑炎同时发生;(2)MOG抗体病及抗NMDAR脑炎先后发生。根据首发或单次复发病程中抗NMDAR脑炎及MOG抗体病是否并存,可将MNOS分为三类:(1)抗NMDAR脑炎型;(2)MOG抗体病型;(3)抗NMDAR脑炎及MOG抗体病重叠出现型。在疾病首次发作时,首发临床表现以抗NMDAR脑炎症状多见[8,23],其中最常见的是精神行为异常或认知功能障碍,但与单纯抗NMDAR脑炎相比,上述症状通常更轻微,较少进展为低通气等严重症状[9]。此外,与单纯抗NMDAR脑炎患者相比,MNOS患者以脑炎发病时,通常会出现不典型症状,如共济失调、单侧偏瘫或幕下磁共振成像(magnetic resonance imaging,MRI)异常[25]。因此,当抗NMDAR脑炎患者合并其他非典型症状时,需及时检测MOG抗体等指标。在MNOS的发病过程中,癫癎发作、精神行为异常、意识水平下降是最常见的症状[21,26],且整个病程中脑炎的表现均较单纯抗NMDAR脑炎更轻微。
不同于抗NMDAR脑炎发病与肿瘤相关,MNOS患者常不伴有肿瘤出现[7,27],表明其发病与肿瘤无明显关联,可能涉及自身免疫异常。
文献报道,MNOS容易复发[19,28-29]。巩帅等[26]对11例儿童MNOS的回顾性分析显示,至末次随访时,11例患儿中8例呈复发-缓解病程,复发率为72.7%,复发间隔时间为3~60个月。而既往研究表明,抗NMDAR脑炎的复发率为4%~26%[30-31],MOG抗体病的复发率为60%~90%[32-35],提示MNOS有复发风险,且更接近MOG抗体病的复发率,MOG抗体可能在MNOS患者的复发中起主要作用。因此,对于初次诊断为抗NMDAR脑炎或MOG抗体病的患者,有必要对其进行长期随访。
与单纯抗NMDAR脑炎及单纯MOG抗体病相比,MNOS有其独特的影像学特征。除少数患者单次发病时无明显影像学异常外[10],MNOS患者通常会出现幕上病灶,少数患者还会出现幕下及脊髓病灶[8]。而在幕上病灶中,最常累及的部位是皮质、皮质下白质、基底节区[24,26]。此外,有文献报道MNOS患者可出现软脑膜强化[36-37],Cherian等[36]提出双侧扣带回病变伴强化可能是MOG抗体及NMDAR抗体共存的影像学表现。因此,对于抗NMDAR脑炎伴有软脑膜强化的患者,应考虑到MNOS的可能,并同时检测MOG抗体。
在MNOS的整个病程中,可先后或同时检测到NMDAR抗体及MOG抗体,但二者在病程中的具体作用尚不清楚。有研究表明,在MNOS患者中,两种抗体的滴度与病情严重程度及预后无明显相关性[24]。但更多研究结果显示,在MNOS的发病过程中,抗体滴度随病情变化处于波动中[21,38-41],推测其与疾病复发、对治疗的反应及预后相关。有研究发现,随着发病或疾病复发,NMDAR抗体及MOG抗体滴度可升高,病情好转则会降低甚至消失[38],因此,抗体滴度可反映疾病的进展情况。有学者认为,NMDAR抗体滴度、阳性持续时间与神经系统后遗症有关[21],NMDAR抗体的去除对改善预后有很大帮助[39]。MOG抗体还可能与疾病复发及对治疗的反应有关,持续MOG抗体阳性的患者更有可能复发,且最有可能从长期免疫调节治疗中获益[40]。此外,这两种抗体的存在可能还与一些特殊的影像学表现有关。Amano等[41]报道了1例共发病4次且后3次影像学表现均有软脑膜或皮质强化的MNOS患者,回顾性分析其MOG抗体及NMDAR抗体检测结果显示,随时间推移,患者脑脊液NMDAR抗体滴度持续下降,第4次发病时几乎为阴性,但MOG抗体滴度则逐渐上升,在第4次病程中为强阳性,作者推测该患者第4次脑膜强化可能是由于MOG抗体而不是NMDAR抗体所致,提示MOG抗体可能与脑膜强化有关。此外,该病例血清MOG抗体一直维持在低水平,但脑脊液MOG抗体水平波动较大,因此,对于怀疑MNOS的患者应同时检测血清及脑脊液MOG抗体,因为复发时血清中有时检测不到MOG抗体,而在脑脊液中可检测到,这与单纯MOG抗体病的MOG抗体通常在血清中检测到,而很少在脑脊液中检测到不同[42]。在MNOS患者中,脑脊液白细胞介素-6(interleukin-6,IL-6)及CXC亚家族趋化因子13(chemokine CXC subfamily 13,CXCL13)与抗体的生成相关[43-44],这两项指标可能为该疾病的标志物,因此,在检测抗体时对其进行检测可能有助于评估疾病的进展情况。
目前尚无MNOS的治疗指南及统一治疗方法,患者发病后首选的一线治疗为激素、静脉注射用人免疫球蛋白、血浆置换或三者的组合,当一线治疗无效时则需要额外的二线免疫治疗,如利妥昔单抗或环磷酰胺等[45]。由于MNOS的复发率更接近MOG抗体病,目前普遍认为急性期治疗后需要进行免疫维持治疗,但其具体方案及疗程尚无定论。此外,根据文献报道,MNOS对激素治疗敏感[10],但一些患者在激素减量过程中易复发[12,38]。因此,可能需要更长时间的免疫维持治疗,且应减缓激素减量速度。另外,对于自身免疫性脑炎患者,从出现症状到开始治疗的时间越短,预后越好,治疗不应延迟到自身抗体检测结果报告后[25]
综上,抗NMDAR脑炎及MOG抗体病可在同一患者体内同时或先后出现,因此,当抗NMDAR脑炎患者出现脱髓鞘疾病并累及视神经或出现其他与自身免疫性脑炎不一致的特征时,应进行脑脊液及血清MOG抗体检测。同样,当MOG抗体病或其他脱髓鞘疾病患者出现非典型症状(如精神症状或癫癎发作)时,应考虑同时存在免疫介导性脑炎的可能。此外,与单发疾病患者相比,双抗体阳性患者的病理生理机制、治疗策略及对治疗的反应等均有所不同,这突出了诊断MNOS的重要性。未来应针对此类疾病进行更多前瞻性多中心研究,并对此类患者进行长期随访,以指导临床诊治。
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2021年第46卷第12期
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doi: 10.11855/j.issn.0577-7402.2021.12.15
  • 接收时间:2021-03-06
  • 首发时间:2025-12-18
  • 出版时间:2021-12-28
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  • 收稿日期:2021-03-06
  • 修回日期:2021-08-29
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    兰州大学第二医院神经内科/甘肃省神经内科临床医学研究中心/甘肃省神经病学重点实验室,兰州 730030

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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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