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远视儿童短期使用 1% 阿托品凝胶后脉络膜厚度的变化

Choroidal thickness changes in hyperopia children after short-term use of 1% atropine gel

来源期刊: 眼科学报 | 2023年8月 第38卷 第8期 564-570 发布时间:2023-10-26 收稿时间:2023/10/26 9:04:01 阅读量:3385
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关键词:
阿托品脉络膜厚度远视儿童
atropine choroidal thickness hyperopia children
DOI:
10.12419/2303190001
目的:评估远视儿童使用1%阿托品凝胶1周后脉络膜厚度(choroidal thickness,CT)的变化。方法:选择42例4~7岁的远视儿童,予每天使用1%阿托品凝胶两次,持续7d。使用光学相干断层成像扫描测量视网膜及CT,并分析使用1%阿托品凝胶前后中心凹以及距中心凹处间隔1.0 mm的上、下、鼻和颞侧(最多3.0mm)CT的变化。结果:在远视儿童中,基线CT随位置而变化(F=27.08, P<0.05),与中心凹相比,鼻侧及距中心凹上方2 mm、3 mm及距中心凹颞侧3 mm处的CT较薄(P<0.05)。使用1%阿托品凝胶后,中央凹及旁中心凹CT改变比较差异无统计学意义(P>0.05)。使用1%阿托品凝胶前后视网膜厚度无明显变化(P>0.05)。结论:短期使用1%阿托品凝胶并没有改变远视儿童的脉络膜和视网膜厚度。
Objective: To assess changes of choroidal thickness (CT) in hyperopia children after 1 week using of 1% atropine.Methods: A total of 42 hyperopia children aged 4–7 years were included into the study.A single drop of 1% atropinegel was used twice a daily for 7 days in the subjects.The thickness of retina and choroid was measured by OCT, and the changes before and after using 1% atropine gel were analyzed at the subfovea and at 1.0 mm intervals (up to3.0 mm) from the fovea at superior, inferior, nasal, and temporal locations. Results: In the hyperopia children, baselineCT parameters were varied with the location(F=27.08,P<0.05).Compared with the fovea, the CT at the nasal side,2 mm and 3 mm above the fovea and 3 mm from the temporal side of the fovea were thinner (P<0.05).After using 1%atropine gel, there was no significant difference in the CT changes of subfoveal choroidal thickness and other sites ofparafovea (P> 0.05). There was no significant change in retinal thickness before and after using 1% atropine gel (P > 0.05).Conclusion: No changes were found in the thickness of choroid and retina in hyperopia children after short-term use of1% atropine gel.
阿托品在小儿眼科领域应用十分广泛。目前,阿托品被认为是控制儿童近视进展最有效的药物,在国内外的临床试验中有着强有力的证据支持[1-2]。在屈光门诊的工作中,1.0%阿托品仍然是年幼远视儿童及内斜视儿童初次睫状肌麻痹验光的首选[3]。在中度弱视儿童的治疗中,阿托品抑制疗法与遮盖疗法一样有效[4]。此外,为降低儿童斜视手术中眼心反射的发生率,阿托品也常常被联合使用[5]
脉络膜是一种高度血管化的结构,其每单位血流量比其他身体组织都要高[6]。脉络膜厚度(choroidal thickness,CT)被认为是脉络膜血流的替代标志物,CT改变(ΔCT)可能成为量化肥厚脉络膜谱系疾病[7]和涉及血管系统全身疾病[8]的重要测量指标。既往的研究中,我们观察到了使用1%阿托品后虹膜和睫状体的改变[9]。同样作为葡萄膜的一部分,脉络膜在使用阿托品后也可能会出现某些变化,在近视儿童中,使用不同浓度的阿托品进行近视防控,脉络膜出现了不同程度的增厚[10-12]。而在远视儿童中,阿托品用药前后CT相关研究未见报道。本研究的目的是评估远视儿童使用1%阿托品1周前后的ΔCT,这将有助于更好地了解阿托品的作用机制。

1 资料与方法

1.1 研究对象

本研究纳入2021年5月南通大学第二附属医院就诊的远视儿童42例,其年龄4~7岁,平均(5.90±0.85)岁,女性20例,均取右眼相关数据进行分析。纳入标准:初次检查等效球镜(spherical equivalent,SE)+0.5 D < SE ≤ +5.0 D;散光≤2.0 D;排除标准:除屈光不正外,有任何其他重大眼科疾病史、眼部手术或受伤史、框架及隐形眼镜佩戴史、存在局部或全身可能导致CT变化的用药史、患有可能影响视力发展的系统性疾病,不能配合光学相干断层成像扫描(optical coherence tomography,OCT)检查者,对阿托品眼膏过敏者。本研究遵循赫尔辛基宣言,经南通大学第二附属医院伦理委员会批准(批件号:2020KT068),患儿监护人均签署知情同意书。

1.2 处理方法

所有患儿均行裂隙灯显微镜、直接检眼镜、Topcon自动验光仪(KR-800)验光,以获得睫状肌麻痹前后的屈光状态。SE=球镜度数+l/2柱镜度数。所有患儿在初次检查后使用1%阿托品凝胶,每天2次,持续7 d。如果参与患儿出现严重过敏反应,立刻终止研究并安排适当的治疗。

1.3 脉络膜、视网膜厚度测量

同一名经验丰富的研究人员使用SD-OCT(Spectralis HRA+OCT;德国海德堡工程公司)进行检查,并使用增强深度成像(enhanced depth imaging,EDI)模式优化脉络膜的可见度。利用仪器的自动实时眼球跟踪功能,对每个径向平均进行30次扫描。每个扫描线都是使用仪器的高分辨率扫描模式捕获的,这种高分辨率扫描会产生一个由1 536×3 496像素组成的B超图像。以被检查者黄斑中心凹为中心,对眼底水平及竖直两个方向上的视网膜、脉络膜进行扫描。第二次扫描是通过Follow-up模式从之前的位置采集图像。选取清晰度最高的图像资料进行厚度测量(图1)。为避免昼夜节律影响,由同一位操作员于每日9:00至14:00进行测量[13]。获得OCT图像后,根据扫描结果使用仪器自带的测量系统测量视网膜厚度(retinal thickness,RT),RT是指内界膜至视网膜色素上皮层外缘之间的垂直距离。为了确定测量的重复性,检查者进行用药前后两次黄斑中心凹CT(subfoveal choroidal thickness,SFCT)测量。CT需使用仪器自带的软件进行手动测量,定义为从视网膜色素上皮高反射线的最外边缘到脉络膜巩膜界面内表面的距离[14-15]。每次测量进行3次,取平均值进行记录。分别记录黄斑中心凹RT(subfoveal retinal thickness, SFRT)、SFCT以及距离黄斑中心凹1 mm、2 mm、3 mm上方、下方、鼻侧、颞侧共13个点位的RT及CT(图2),其中SFCT测量值取两次测量的平均值。所有测量结果在所有OCT图像中都得到了很好的识别。
20231026153404_4325.png
图1 CT的测量
Figure 1 Measurement of CT
CT定义为视网膜色素上皮外界与脉络膜巩膜交界处的垂直距离值。
CT was defined as the vertical distance between the outer surface of the retinal pigment epithelium and the junction of the choroid and  sclera.
20231026153544_6358.png
图2 视网膜和脉络膜的光学相干断层扫描
Figure 2 Measurement of Optical Coherence Tomography of the Retina and Choroid
(A)黄斑中心凹及距离黄斑中心凹1 mm、2 mm、3 mm 鼻侧、颞侧的RT及CT测量位点(绿色水平线);(B)黄斑中心凹及距离黄斑中心凹1 mm、2 mm、3 mm 上方、下方的RT及CT测量位点(绿色垂直线)。
(A) The central fovea of the macula and the RT and CT measurement sites 1 mm, 2 mm, and 3 mm away from the central fovea of the macula on the nasal and temporal sides (green horizontal line); (B) The central fovea of the macula and the RT and CT measurement sites 1 mm, 2 mm, and 3 mm above and below the central fovea of the macula (green vertical line).

1.4 统计学方法

    数据均使用SPSS 22.0进行统计学分析。正态分布的计量资料均以(x±s)表示。使用Bland-Altman分析进行观察者内部一致性测量,使用组内相关系数(intraclass correlation coefficient,ICC)评估2次SFCT测量之间的重复性。局部使用1%阿托品凝胶治疗1周后,将SE、CT、RT与基线值进行比较。使用Kolmogorov-Smirnov检验计量资料的正态性,其中,基线SE、用药前后TRT 2.0 mm、用药前后TRT 3.0 mm、用药前后SRT 3.0 mm测量位点测量值系非正态分布,其余测量参数符合正态分布。正态分布的数据组内比较采用配对样本t检验,非正态分布数据用M(P25,P75)表示,采用Wilcoxon符号秩检验。采用单因素方差分析比较不同象限(颞、鼻、上、下)CT的差异。P<0.05表示差异有统计学意义。

2 结果

2.1 一致性分析

经过观察者内部一致性测量(图3),ICC分别为0.962、0.973(P<0.05)。
20231026153852_9783.png
图3 Bland-Altman分析进行观察者内部一致性测量
Figure 3 Blank-Altman analysis for internal consistency measurement of observers
使用1%阿托品凝胶前(A)和1周后(B)进行两轮中心凹下CT测量的Bland-Altman图。实线表示平均差异,而虚线表示95%的一致性极限(1.96×SD)。检查者在两次检查中均未发现出现差异的趋势。
The Bland-Altman diagram of two rounds of central concave CT measurement before (A) and after (B) 1% atropine gel was used. The solid line represents the average difference, while the dashed line represents the 95% consistency limit (1.96 × SD). The examiner did not find any trend of difference in both examinations.

2.2 远视患儿使用1%阿托品凝胶前后CT的变化

使用1%阿托品凝胶后,SE从1.13 D(0.75 D, 1.50 D)变化为2.76 D(1.75 D, 3.56 D)(Z=-5.57, P<0.05)。表1总结了患者SFCT以及距离黄斑中心凹1 mm、2 mm、3 mm上方(SCT 1 mm、SCT 2 mm、SCT 3 mm)、下方(ICT 1 mm、ICT 2 mm、ICT 3 mm)、鼻侧(NCT 1 mm、NCT 2 mm、NCT 3 mm)、颞侧(TCT 1 mm、TCT 2 mm、TCT 3 mm)共13个点位的CT以及以类似方式标注的RT。使用1 %阿托品凝胶后,SFCT及旁中心凹其余位点CT改变差异无统计学意义(P>0.05)。单因素方差分析比较显示,基线C T随位置比较差异有统计学意义(F=27.08, P<0.05),与SFCT(376.98±68.86 μm)比较,鼻侧(NCT 1 mm、NCT 2 mm、NCT 3 mm)测量位点CT[(334.90±74.48)μm,(258.17±73.77) μm,(199.40±59.85)μm]及TCT 3 mm、ICT 2 mm、ICT 3 mm处[(346.48±70.95)μm,(337.40±60.76)μm,(305.86±60.25)μm]更薄(P<0.05),其余位点CT与SFCT比较差异无统计学意义(P>0.05)。使用1%阿托品凝胶后,CT随位置改变差异有统计学意义(F=34.31, P<0.05),与SFCT[(385.52±57.91)μm]比较,鼻侧(NCT 1 mm、NCT 2 mm、NCT 3 mm)测量位点CT[(341.17±62.09)μm,(263.57±68.74)μm,(378.36±62.26)μm]及NCT 3 mm、ICT 2 mm、ICT 3 mm处[(200.17±53.46)μm,(336.02±58.42)μm,(309.67±54.97)μm]更薄(P<0.05)。使用1%阿托品凝胶前后各测量位点RT改变差异均无统计学意义(P>0.05)。

表1 使用1%阿托品凝胶前后CT的变化 单位:μm
Table 1 CT changes before and after the use of 1% atropine gel Unit: μm

20231026153952_9941.png

3 讨论

脉络膜在近视发生、发展中的作用得到了越来越多的研究,但起源于视网膜的信号如何穿过高度血管化的脉络膜影响巩膜等方面仍然进展缓慢[16]。有研究认为CT的变化可能在响应视觉刺激与调节巩膜生长中发挥了重要作用[17]。CT的变化是近视进展的潜在生物学标志,并且被认为可以作为治疗期间调整阿托品浓度的参考[18]。目前明确的是,在近视儿童中,使用不同浓度的阿托品后脉络膜会出现不同程度的增厚[10-12]。在既往的研究中常常以SFCT的变化进行比较。在Zhang等[11]的研究中,每日两次使用1%阿托品眼膏,连续1周,SFCT出现了15μm的脉络膜增厚。在另一项使用1%阿托品眼膏的研究中[19],观察到SFCT增加了(26±14)μm。在一项连续两年的研究中,Yam等[18]发现与基线相比,0.05%、0.025%阿托品组的SFCT在2年后分别增厚了(21.15±32.99)μm、(3.34±25.30)μm。在Sander等[20]的研究中使用了0.01%阿托品滴眼液,60 min后20例年轻近视成年人观察到平均6μm的脉络膜增厚。可见使用较高浓度的阿托品后脉络膜增厚更多,但同样是使用1%阿托品眼膏,在不同的研究中脉络膜增厚程度也有不同。在Zhang等[11]的研究中,使用阿托品后SFCT增加了15μm。在Ye等[19]的研究中,近视组在使用1%阿托品1周后,SFCT的厚度增加了(26±14)μm。而在本研究中,远视儿童在使用1%阿托品1周后CT没有显著增厚。结合本研究,我们认为既往研究中SFCT增厚程度的不同与纳入研究儿童的屈光状态有关。在Ye等[19]的研究中仅纳入了近视儿童,而Zhang等[11]的研究纳入30例有近视、正视和远视的儿童,使用1%阿托品1周后的SE为(?3.50±4.63)D,因此在Zhang等[11]研究中使用阿托品后SFCT增厚程度要小于Ye等[19]的研究。
目前,阿托品引起脉络膜增厚的机制尚不明确。既往有研究认为,阿托品引起的睫状肌麻痹被认为是CT升高重要原因[21-22]。然而,本研究中,在远视儿童中使用1%阿托品1周后,尽管得到了足够的睫状肌麻痹,脉络膜并没有增厚,这一发现颠覆了既往相关研究的部分结论[21-22],并且提示睫状肌麻痹可能并不是阿托品引起脉络膜增厚的原因。Ye等[19]也认为睫状肌麻痹可能不是主要机制,在他们的研究中发现ΔCT和晶状体度数变化之间并不相关,0.01%阿托品持续1周也会导致CT增厚,但不会导致睫状肌麻痹。其他可能的作用机制包括阿托品作为毒蕈碱受体的拮抗作用[23]、阿托品引起的一氧化氮增多[24]、阿托品通过刺激多巴胺的释放而导致脉络膜增厚等[25-26],对此还需要进一步的研究进行确定。
在本研究中,使用1%阿托品凝胶前后脉络膜并没有增厚。既往的研究证实,近视患者呈现更加远视的相对周边屈光度,远视患者的周边屈光状态则以近视性离焦为主[27-29]。与传统上认为近视和远视离焦是在相同的基因和通路中引发相反变化的观点不同,近期有研究显示近视和远视离焦信号通过不同的途径传播[30],而阿托品可以消除儿童远视离焦引起的脉络膜变薄[31],这可能是阿托品能增加近视儿童CT,而并没有引起远视儿童脉络膜增厚的重要原因。此外,既往有研究[32]显示,阿托品减缓近视进展的部分是由其脉络膜增厚介导的,考虑到本研究提示,远视儿童使用阿托品后并没有引起CT增厚,因此我们推测对远视儿童使用阿托品并不能降低近视发病率。
综上所述,1%阿托品凝胶局部给药1周后并没有增加远视儿童的CT。本研究存在一些潜在的局限性。首先,本研究纳入的样本量相对较小,因此并不能进一步研究使用阿托品后对低度、中度、高度远视儿童CT的影响。其次,仅纳入了4~7岁的儿童,阿托品对其他年龄组远视儿童脉络膜的影响尚不清楚。第三,仅观察使用阿托品7 d后CT的变化,阿托品对远视儿童CT影响的长期随访仍需进一步研究。

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1、南通市科技计划(MS2020035)。This work was supported by Nantong Science and Technology plan (MS2020035).()
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