【作者】 黄鑫；

【导师】 戚晓昆；

【作者基本信息】 南方医科大学 ， 神经病学（专业学位）， 2016， 硕士

【摘要】 背景视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders, NMOSD)属于中枢神经系统(central nervous system, CNS)特发性炎性脱髓鞘疾病,主要以视神经和脊髓同时或相继受累为主要表现,临床具有显著的复发特征。2004年首次提出NMO免疫球蛋白G (NMO immunologlobulin G, NMO-IgG)是一种主要与CNS水通道蛋白4 (water channel aquaporin-4, AQP4)结合的特异性血清学标记物,对于诊断NMOSD具有高度特异性,又称之为水通道蛋白-4抗体(water channel aquaporin-4 antibody, AQP4-Ab)。2015年NMOSD诊断指南更加注重临床症状、实验室及磁共振成像(magnetic resonance imaging, MRI)等综合临床资料,并提出重视NMOSD的复发病程。因此,如何更加全面的研究NMOSD的临床特征及复发的相关因素是一个关键问题。目的1.分析NMOSD的一般临床特点2.分析NMOSD的血清、脑脊液(cerebrospinal fluid, CSF)实验室检查特点3.分析NMOSD的视神经、脊髓、颅脑MRI特点4.比较血清AQP4-Ab阳性与阴性的临床、实验室及影像学特征5.比较CSF AQP4-Ab阳性与阴性的临床、实验室及影像学特征6.比较血清AQP4-Ab不同滴度水平的临床特点7.分析不同临床因素对NMOSD发病3年内复发的影响方法1.收集2009.07.29-2015.12.31就诊于我院神经内科确诊NMOSD患者73例,所有患者均具备完整的临床、实验室及影像学(视神经、脊髓及颅脑MRI)资料,采集急性期和缓解期的血清及同期CSF,检测血清及CSF AQP4-Ab,血清其他自身免疫抗体,包括抗核抗体、抗SS-A抗体、抗SS-B抗体、抗Ro-52抗体等,CSF常规、生化、细胞学,血清及CSF寡克隆区带(oligo clonal bands,OB)、髓鞘碱性蛋白(myelin basic protein, MBP),计算CSF 24 h IgG合成率、IgG合成指数、血脑屏障指数,记录入组时及随访期的扩展残疾状态量表(expanded disability status scale, EDSS)评分,建立NMOSD数据库。2.所有患者诊断均符合2015年NMOSD国际共识诊断标准。否认合并其他自身免疫性疾病(如系统性红斑狼疮、白塞氏病、干燥综合征等)及肿瘤病史。3.采用基于细胞的间接免疫荧光法检测AQP4-Ab,采用SPSS19.0统计软件进行统计学分析。结果1. NMOSD的一般临床资料：(1)人口学资料：①73例患者中,男12例,女性61例,男女比例约1：5。首次发病中位年龄38岁；②随访时间：所有患者均接受随访(随访时间2009.09.01-2016.04.20),中位随访时间3年;③EDSS评分：急性期平均EDSS6.2±1.9分；缓解期中位EDSS3分。(2)病程最短3年,最长27年,中位病程7年。第一次复发距首次发病的中位时间间隔6个月,第二次复发与首次复发的中位时间间隔5个月。中位复发次数4次,年平均复发次数0.8次/年。1年内复发率91.8%,2年内复发率93.2%,3年内复发率94.5%,5年内复发率100%；(3)首次发病临床表现：视力下降22例,肢体麻木17例,肢体疼痛13例,肢体无力10例,呃逆9例,皮肤瘙痒11例,肢体或躯干异常感觉6例,束带感4例,低头屈颈触电样征(Lhermitte’s征)2例,心动过缓1例,腹胀便秘1例,复视1例；(4)核心临床症状：首次发病：视神经炎(optic neuritis,ON)22例、长节段贯性脊髓炎(longitudinally extensive transverse myelitis, LETM)40例、极后区综合征5例、急性脑干综合征4例、ON合并LETM2例；多次复发病程：复发性ON合并LETM26例,复发性LETM26例,复发性ON 6例,极后区综合征2例,LETM合并极后区综合征5例,复发性ON合并极后区综合征2例,其他大脑受损表现2例,ON、LETM合并极后区综合征4例。2. NMOSD的实验室检查特点：①血清免疫检验：急性期AQP4-Ab中位滴度(1：80)显著高于缓解期(1：20),差异具有统计学意义(P=0.000)。血清MBP升高15.8%(9/57),其他自身免疫抗体阳性72.6%(53/73)；②CSF免疫检验：CSF蛋白升高43.1%(25/58),白细胞升高39.7%(23/58),24h IgG合成率升高22.8%(13/57),IgG合成指数升高28.1%(16/57),血脑屏障指数升高24.6%(14/57)；③51例血清AQP4-Ab阳性患者的CSF AQP4-Ab阳性检出率为45.1%(23/51)。3. NMOSD的视神经、脊髓及颅脑MRI特点：(1)视神经MRh①视神经MRI异常82.3%(51/62),累及单侧视神经41.2%(21/51),双侧视神经58.8%(30/51)。其中,9.8%(5/51)累及视神经前段1/2,88.2%(45/51)累及视神经后段1/2,2.0%(1/51)累及视交叉；②急性期视神经水肿、增粗92.2%(47/51)；③末次随访发现视神经萎缩39.2%(20/51),其中单侧萎缩40.0%(8/20),双侧萎缩55.0%(11/20),视交叉萎缩5.0%(1/20)；(2)脊髓MRI病灶分布特点：①脊髓病灶节段数：83.3%(60/72)病灶≥3椎体节段,16.7%(12/72)病灶<3个椎体节段；②脊髓MRI病灶形态呈条片样77.8%(56/72),小片状6.9%(5/72),团块样5.6%(4/72),弥漫分布4.2%(3/72),细长不均匀2.8%(2/72),大片状1.4%(1/72),类圆形1.4%(1/72)；③脊髓MRI病灶部位：累及颈髓38.9%(28/72),颈髓合并胸髓34.7%(25/72),胸髓18.1%(13/72),延髓合并颈胸髓2.8%(2/72),颈胸腰髓均受累2.8%(2/72),延髓合并颈髓1.4%(1/72),全脊髓1.4%(1/72)。病灶居于脊髓中央73.6%(53/72),居中偏后8.3%(6/72),居中偏前4.2%(3/72),偏向一侧13.9%(10/72)；④脊髓MRI强化类型：斑片状强化41.7%(30/72),环形强化4.2%(3/72),线样强化4.2%(3/72),环形强化伴斑点样强化4.2%(3/72),条形强化5.6%(4/72),结节样伴条形强化2.8%(2/72),余37.5%(27/72)未见强化；(3)脑MRI病灶特点：颅脑可见异常脱髓鞘病灶53.4%(39/73),病灶形态均呈斑片样,主要分布于脑室旁病灶33例(其中侧脑室旁21例、四脑室旁10例、三脑室旁2例),半卵圆中心28例,基底节区22例,脑干14例,额叶12例。4.血清AQP4-Ab阳性与阴性患者的临床、实验室及影像学特点：(1)急性期血清AQP4-Ab阳性患者的EDSS评分、总病程复发次数均高于阴性患者,差异具有统计学意义(P=0.019,P=0.001)：(2)血清AQP4-Ab阳性患者的其他自身免疫抗体、CSF AQP4-Ab阳性检出率显著高于阴性患者,差异具有统计学意义(P=0.028、P=0.001)。5. CSF AQP4-Ab阳性与阴性患者的临床、实验室及影像学特点：CSFAQP4-Ab阳性患者的白细胞数、MBP和24h IgG合成率均显著高于阴性患者,差异具有统计学意义(P=0.008,P=0.043,P=0.012)。6.比较血清AQP4-Ab不同滴度水平的临床特点：(1)23例CSF AQP4-Ab阳性患者的血清AQP4-Ab滴度的几何均数(1：111.4)显著高于28例CSF AQP4-Ab阴性患者(1：29.0),差异具有统计学意义(Z=-4.400,P=0.000)；(2)20例患眼永久性失明患者的AQP4-Ab滴度的几何均数(1：105.6)显著高于42例非失明患者(1：64.0),差异具有统计学意义(Z=-2.199,P=0.028)；(3)12例脊髓萎缩患者的AQP4-Ab滴度的几何均数(1：56.6)与50例无脊髓萎缩患者(1：72.9)比较,差异无统计学意义(Z=-0.626,P=0.532)；(4)32例伴颅内病灶患者的AQP4-Ab滴度的几何均数(1：57.8)与30例无颅内病灶患者(1：74.6)比较,差异无统计学意义(Z=-0.903,P=0.366)；(5)60例脊髓病变节段≥3的AQP4-Ab滴度均数(几何均数1：64.3)与12例脊髓病变节段<3的患者(几何均数1：63.9)比较,差异无统计学意义(Z=-0.178,P=0.859)。7.单因素分析发现,血清AQP4-Ab、其他自身免疫抗体不同临床亚组患者的发病3年内复发次数差异具有统计学意义。有序Logistic回归分析,发现血清AQP4-Ab、其他自身免疫抗体是影响NMOSD发病3年内复发次数的独立危险因素,其中血清AQP4-Ab阳性(OR=14.556>1)、自身免疫抗体阳性(OR=4.328>1)可能与NMOSD发病3年内的复发次数呈正相关。结论1.本组NMOSD好发于女性,男女比例约1：5,首次发病中位年龄38岁。2.血清AQP4-Ab阳性患者总病程复发次数较阴性患者高,提示血清AQP4-Ab阳性患者临床更易复发。3.NMOSD发病临床表现多样,主要为视力下降、肢体麻木、肢体疼痛、肢体无力、皮肤瘙痒、呃逆、感觉异常、束带感等,一些非特异性症状如皮肤瘙瘁、束带感或顽固性呃逆均仅见于血清AQP4-Ab阳性患者,临床误诊率高达54.8%,往往以消化内科、皮肤科甚至心内科首诊,误诊诊断包括多发性硬化(multiple sclerosis, MS)、胃食管返流病、周围神经病、脑梗死、脊髓空洞症、躯体化形式障碍、窦性心动过缓、颅内占位、ADEM及其他(过敏性皮炎、神经性呕吐等)。此类患者应当引起神经内科临床医师重视,仔细查体,结合病史及EDSS评分,尽早完善血清AQP4-Ab检测,减少漏诊。4. NMOSD急性发作期血清AQP4-Ab滴度高于缓解期,依然说明AQP4-Ab在NMOSD发病及复发中的重要作用。血清AQP4-Ab阳性患者的其他自身免疫抗体阳性检出率显著高于阴性患者,提示血清其他自身免疫抗体可能参与NMOSD的体液免疫。血清AQP4-Ab阳性患者的急性期EDSS评分显著高于阴性患者,提示血清AQP4-Ab阳性患者的神经系统功能缺损症状较阴性患者更重。此外,AQP4-Ab滴度较高的患者临床结局更易发生患眼失明。5. CSF AQP4-Ab阳性患者的CSF白细胞、MBP及24hIgG合成率显著高于阴性患者,往往提示脱髓鞘疾病急性期活动性。6. CSF AQP4-Ab阳性可见于血清AQP4-Ab>1:160的患者,血清AQP4-Ab滴度<1：20时,CSF AQP4-Ab多为阴性。7.血清AQP4-Ab阳性、其他自身免疫抗体阳性是影响NMOSD发病3年内复发次数的独立危险因素。更多还原

【Abstract】 BackgroundNeuromyelitis optica spectrum disorders (NMOSD) is an idiopathic, inflammatory, demyelinating diseases of the central nervous system (CNS), which characterized by involvement of optic nerve and spinal cord simultaneously or sequentially. NMOSD is relapsing and aggressive. In 2004, NMO-immunologlobulin G (NMO-IgG) was reported, which was combined with water channel aquaporin-4 (AQP4) which mainly expressed in CNS. The target antigen of NMO-IgG thus also called water channel aquaporin-4 antibody (AQP4-Ab). NMO-IgG was a highly specific serum autoantibody marker for diagnosis of NMOSD. With the constant updating of diagnostic criteria of NMOSD in 2015, the core clinical characteristics, laboratory data, magnetic resonance imaging (MRI) and the recurrence become more valued. Consequently, it is a very key problem how to analysis the clinical characteristics and relapse correlation factors of NMOSD.Objective1. To analysis the general clinical characteristics of NMOSD.2. To summarize serum and cerebrospinal fluid (CSF) laboratory statistics of NMOSD.3. To analysis the optic nerve, spinal cord, and brain MRI characteristics of NMOSD.4. To compare the clinical, laboratory and MRI characteristics of serum AQP4-Ab positive and negative.5. To compare the clinical, laboratory and MRI characteristics of CSF AQP4-Ab positive and negative.6. To compare the clinical characteristics of serum AQP4-Ab positive at different titer levels.7. To observe the relapse correlation factors of NMOSD in the 3 years.Methods1. The clinical data of 73 cases who visited the Department of Neurology at our hospital from July 29th 2009 to December 31th 2015, including clinical material, laboratory statistics and neuroimaging features (optic nerve, spinal cord and brain MRI). Serum and period cerebrospinal fluid (CSF)both in acute and remission period were collected. The CSF specimens were collected for the count of routine examination, biochemical detection, cytology, myelin basic protein (MBP), oligo clonal bands (OB).24 hours IgG synthesis rate, IgG index and Blood brain barrier index were calculated. The serum and CSF AQP4-Ab were detected. The serum examinations were detected for includes OB, MBP, and autoimmune antibodies, such as serum ANA, anti-SSA, anti-SSB and anti-Ro-52 antibody. The expanded disability status scale (EDSS) scores were recorded and then building database.2. NMOSD was defined as cases fulfilling all items of 2015 NMOSD criteria. None of cases was complicated other autoimmune diseases, such as Systems Lupus Erythematosus, Behcet’s Disease and Sjogren Syndrome, and cancer-free.3. Positive test for AQP4-Ab using best available detection method (cell-based assay strongly recommended). Statistical analysis was done by SPSS 19.0.Results1. Clinical characteristics:(1)General clinical data:①Patients included 12 males,61 females. Male to female ratio was 1 to 5 among the patients. The median onset age of NMOSD was 38 years old; ②Follow up:All patients were followed up (from September lth 2009 to April 20th 2016, the median follow-up time was 3 years);③EDSS:The mean of EDSS score was 6.2±1.9 of NMOSD in acute exacerbation. The median EDSS score of NMOSD was 3 in remission stage. (2) To all the patients, the longest disease course was 27 years and the shortest was 3 years, the median course of NMOSD was 7 years. The duration from the first relapse to the onset was 6 months. The duration from the second relapse to the first relapse was 5 months. The median recurrence rate was 4. The median recurrent times per years was 0.8. The average annual recurrence rate was 91.8%. Two years later, the recurrent rate of NMOSD had come to 93.2%.Three years later, the recurrent rate of NMOSD had come to 94.5%. Five years later, the recurrent rate of NMOSD had come to 100%; (3) The initial clinical symptoms was visual loss (n=22), numbness of the limbs (n=17), limb pain (n=13), neuropathic pruritus (n=11), limb paresthesia (n=10), hiccup (n=9), trunk or four limbs paresthesia (n=6), zonesthesia (n=4), Lhermitt’s sign (n=2), bradycardia (n=1), abdominal distension and constipation (n=1), diplopia (n=1); (4) The core clinical characteristics had ON (n=22), LETM (n=40), area postrema syndrome (n=5), acute brainstem syndrome e(n=4), ON combined LETM (n=2)at onset. In relapse stage, the core clinical symptoms include recurrent ON combined LETM (n=26), recurrent LETM (n=26), recurrent ON (n=6), area postrema syndrome (n=2), LETM combined area postrema syndrome (n=5), recurrent ON combined area postrema syndrome (n=2),symptomatic cerebral syndrome with NMOSD-typical brain lesions (n=2),ON combined LETM and area postrema syndrome (n=4).2. Laboratory examination:①Serum immunologic test:There was a remarkable difference (P=0.000)in AQP4-Ab titres between with the acute and remission period (median titer of 1:20 to 1:40).The positive rate of serum MBP was 15.8%(9/57). The positive rate of autoimmune antibodies positive was 72.6%(53/73);②CSF immunologic test:The positive rate of CSF protein was 43.1%(25/58). The positive rate of CSF white blood cells was 39.7%(23/58). The positive rate of 24h IgG synthesis rate was 22.8%(13/57). The positive rate of IgG index was 28.1%(16/57). The positive rate of blood brain barrier index was 24.6%(14/57). ③The CSF AQP4-Ab was positive rate 45.1%(23/51) in serum AQP4-Ab positive patients.3. Neuroimaging Features:(1)Optic nerve MR:①The detection rate of optic nerve MRI lesion was82.3%(51/62).Optic nerve MRI lesion were detectable in unilateral 41.2%(21/51)and bilateral 58.8%(30/51). The optical nerve MRI lesion were located at posterior 1/2 of optic nerve 88.2%(45/51), frontier 1/2 of optic nerve 9.8%(5/51)and involving optic chiasm 2.0%(1/51);②Optic nerve edema and thickening was 92.2%(47/51) cases in acute period;③The last follow-up showed optic atrophy in 39.2%(20/51), including unilateral atrophy 40.0%(8/20), bilateral atrophy 55.0%(11/20)and optic chiasm atrophy 5.0%(1/20);(2)Spnial cord MRI:① 82.2%(60/72)of NMOSD have>3 contiguous segments and 16.7%(12/72)in the onset<3 contiguous segments of LETM;②Lesions of LETM were sliver 77.8% (56/72), litter patch 6.9%(5/72), roundish5.6%(4/72), slender 2.8%(2/72), diffuse 4.2%(3/72), large patch 1.4%(1/72)and quasi-circular 1.4%(1/72);③Spinal cord lesions:Lesions were involved the cervical spinal cord 38.9% (28/72), cervical spinal cord combined with thoracic spinal cord 34.7%(25/72), thoracic spinal cord 34.7%(13/72), medulla oblongata combined with cervical and thoracic spinal cord 2.8%(2/72), cervical combined with thoracic and thoracic cord 2.8%(2/72), medulla oblongata combined with cervical spinal cord 1.4%(1/72), craniospinal cord 1.4%(1/72). Lesions living in the spinal cord central 73.6%(53/72), center leans to back 8.3%(6/72), leans to front 4.2%(3/72)and slants 13.9%(10/72); @The characteristic of enchanced lesions of LETM are patchy enchancement 41.7% (30/72), ring-like enchancement 4.2%(3/72), linear enchancement 4.2%(3/72), ring-like combined with apot enchancement 4.2%(3/72), sliver enchancement 5.6% (4/72), nodule-like combined with sliver enchancement 2.8%(2/72)and 37.5%(27/72) lack of enhancement. (3)The positive rate of NMOSD brain lesions was 53.4% (39/73).The patchy lesions were located at around ventricles (n=33), near the outer wall of periventricular (n=21), along the fourth ventricle (n=10), along the third ventricle (n=2), centrum semiovale (n=28), basal ganglia (n=22), brainstem (n=14), the frontal lobe (n=12).4. The Clinical, laboratory and imaging characteristics of serum AQP4-Ab with positive and negative:(1)There was a remarkable difference (P=0.001)in ESSS ans total recurrence between with serum AQP4-Ab with positive and negative;(2) The positive rate of autoimmune antibodies positive and CSF AQP4-Ab in serum AQP4-Ab positive was statistically significant difference with and serum AQP4-Ab negative group (P=0.028、P=0.001).5. The Clinical, laboratory and imaging characteristics of CSF AQP4-Ab with positive and negative:White blood cells, MBP and 24h IgG synthesis rate of CSF AQP4-Ab in positive patients were slightly higher than that of negative patients, the difference was statistically significant (P=0.008, P=0.043, P=0.012).6. The clinical features of AQP4-Ab positive cases at different titer levels:(1) There was a remarkable difference (Z=-4.400,P=0.000)in geometric mean of serum AQP4-Ab titres between with CSF AQP4-Ab positive (1:111.4)and CSF AQP4-Ab negative (1:29.0). (2) There was a remarkable difference (Z=-2.199,P=0.028)in geometric mean of serum AQP4-Ab titres between with permanent complete blindness (1:105.6)and without permanent complete blindness (1:64.0). (3)There was no statistical significance (Z=-0.626, P=0.366)in the of geometric mean serum AQP4-Ab titres compared with or without spine shrinked and became thin. (4)The of geometric mean serum AQP4-Ab titres was 1:57.8 in large cerebral lesions on MRI groups and the group without cerebral lesions (1:74.6)was no statistically significant difference with cerebral lesions group (Z=-0.903, P=0.366). (5)We also compared the serum AQP4-Ab titres (n=60, 1:64.3)with>3 VS spinal cord lesions and those<3 VS spinal cord lesions on MRI (n=12,1:63.9). Of the 29 patients with myelitis, there was no statistic difference among them (Z=-0.178, P=0.859).5. Single factor analysis showed that there was significant statistically significant difference between the serum AQP4-Ab and other autoimmune antibody positive and negative for the recurrence times in three years. Serum AQP4-Ab and other autoimmune antibodies positive is independent risk factors for affecting the incidence of NMOSD 3 years recurrence times proved by ordinal logistic regression analysis, which serum AQP4-Ab positive (OR=14.556>1)and autoimmune antibodies positive (OR=4.328>1)are positive correlated with NMOSD onset within 3 years recurrence times.Conclusion1. NMOSD were predominantly woman with an median age 38 (years old and has a 5:1 F:M ratio.2. The characteristic of serum AQP4-Ab positive patients which is abundant with higher recurrence suggests that serum AQP4-Ab plays a crucial role in relapse again.3. NMOSD had various clinical manifestations and initial symptoms was visual loss, numbness, pain and weakness of the limbs, hiccup, and pruritus. Some nonspecific clinical symptom that neuropathic pruritus, zonesthesia and intractable hiccup appear only for serum AQP4-Ab positive. The misdiagnosis rate was 54.8%. Erroneous diagnoses includes Multiple sclerosis, reflux esophagitis, peripheral neuropathy, cerebral infarction, syringomyelia, somatization disorders, sinus bradycardia, space occupying lesion, ADEM and other (allergic dermatitis, nervous vomiting). Most patients with nonspecific clinical symptom should be paid more attention by neurologist. Careful medical examination and serum AQP4-Ab should be checked as sooner as possible including CSF OB and CSF white blood cells. Examinations might be repeated when necessary in order to reduce misdiagnosis of NMOSD.4. Serum AQP4-Ab titres of NMOSD in acute stage was higher than in remission. It is confirmed that the AQP4-Ab were increased in the acute phase. The positive rate of autoimmune antibodies in serum AQP4-Ab positive was significant higher suggests that other autoimmune antibodies in serum may be involved in the humoral immunity of NMOSD. The EDSS and nervous system disability status of patients with serum AQP4-Ab positive was seriously than that in negative patients. Morever, the titres were significantly higher in the patients with permanent complete blindness.5. White blood cells, MBP and 24h IgG synthesis rate of CSF AQP4-Ab in positive patients were slightly higher than negative patients suggests that the activity of the demyelinating disease.6. AQP4 Ab was consistently positive in CSF when the serum AQP4-Ab titres > 1:160. AQP4-Ab weren’t detectable in CSF samples when matched serum titres were<1:20.7. The onset of serum AQP4-Ab and other autoimmune antibody positive is independent risk factors for affecting the incidence of NMOSD 3 years recurrence times.更多还原