屈光手术后干眼患者角膜共焦镜观察
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摘要
目的
观察LASIK术后角膜中央基底层下上皮神经丛的再生,研究其数量及形态参数与干眼指标间的关系,以及神经再生及干眼程度与术后时间、不同术式、切削深度等指标之间的相关性,从而帮助我们更全面地了解LASIK术后干眼症的病理生理机制,以期优化其治疗方案。
方法
随机入选2011年10月至2012年9月在北京协和医院眼科行传统LASIK/飞秒LASIK手术的近视患者42例(84眼)。根据患者随访时间分为LASIK术后半年组19例(38眼)和LASIK术后一年组23例(46眼)。对患者进行的术后检查主要包括干眼相关检查和角膜共聚焦显微镜检查两部分,其中前者又可分为泪液三项试验和OSDI问卷调查,后者即采用HRT III共聚焦显微镜着重对基底层下上皮神经丛进行观察,在单眼的角膜中央区域内任意选择三点行立体扫描,从中挑选出基底层下上皮神经最丰富且最清晰的三幅图像后使用ACCMetrics软件对这些图像进行神经数量及形态参数的统计并取平均值,具体参数包括神经纤维主干及主干上分支的密度(CNFD和CNBD)、神经纤维长度(CNFL)、神经总分支节点的密度(CTBN)、以及神经纤维的宽度(CNFW)和弯曲度(CNFT)等。采用独立样本t检验的方法比较术后不同随访时间组(半年组、一年组)之间,以及不同种类LASIK术式组(传统组、飞秒组)之间神经参数与干眼指标的差异；此外,根据实际情况对神经参数与干眼指标,以及两者分别与切削深度及基质层厚度之间的关系行偏相关及双变量相关性分析。
结果
1.干眼指标,LASIK术后一年组患者的Schirmer试验值和TBUT值均显著大于半年组(t=-2.340,-5.403,P<0.05),荧光素染色分值显著小于半年组(t=2.634,P<0.05),但两组间的OSDI评分未见统计学显著性差异(t=1.207,P>0.05)。神经参数,LASIK术后一年组患者的CNFD、CNBD、CNFL、CTBN值均显著大于半年组(t=-3.293,-4.501,-7.091,-4.240, P<0.01),但是两组间的CNFW、CNFT值均未见显著性差异(t=1.480,0.474,P>0.05)。
2. LASIK术后半年组,CNBD值与荧光素染色评分值呈负相关(r=-0.346,P<0.05),其余神经参数与干眼指标均无相关性(P值均>0.05)。LASIK术后一年组,CNFD值与Schirmer试验值呈正相关(r=0.321, P<0.05), CNBD、CTBN、CNFT值与Schirmer试验值呈负相关(r=-0.347,-0.340,-0.325,P<0.05),而CNFW值则与OSDI评分值呈正相关(r=0.342,P<0.05),其余神经参数与干眼指标均无相关性(P值均>0.05)。
3.无论是LASIK术后半年组还是一年组,行传统LASIK手术的患者其各项干眼主客观指标和神经数量及形态参数与行飞秒LASIK手术的患者相比不存在任何显著性差异(P值均>0.05)。
4. LASIK术后半年组,神经纤维的数量及形态参数以及干眼指标与手术切削深度及残留基质床厚度均无相关性(P值均>0.05)。LASIK术后一年组,TBUT值与手术切削深度呈负相关(r=-0.297,P<0.05),而其余神经参数及干眼指标与手术切削深度及残留基质床厚度均无相关性(P值均>0.05)。
结论
1. LASIK术后一年患者的干眼客观指标较术后半年患者显著改善,且其角膜中央基底层下上皮神经丛主干及分支的数量、神经纤维的长度均较术后半年患者显著增加。
2. LASIK术后半年及一年患者角膜中央基底层下上皮神经丛的某些神经参数与干眼指标存在相关性,尤以术后一年者较为明显。
3.传统LASIK与飞秒LASIK相比,其对术后半年及一年患者的干眼指标和神经参数所产生的影响无显著差异。
4. LASIK术后一年患者的TBUT值与手术切削深度呈负相关。
Objective
To observe the regeneration of subbasal epithelial nerve plexus in central cornea after LASIK surgery, and study the correlation between its measurements and dry eye test values, so as to promote our knowledge about the pathophysiological mechanism of post-LASIK dry eye and optimize its therapeutic options.
Methods
Forty-two myopic patients (84eyes) who had conventional LASIK/femtosecond-assisted LASIK from October2011to September2012in PUMCH were included in this cross-sectional study. Patients were divided into two groups (six-month group and one-year group) based on the post-LASIK follow-up period. Subjective and objective dry eye tests were carried out to determine patients' degree of post-LASIK dry eye, and confocal microscopy was used to observe the regeneration of subbasal epithelial nerve plexus that could then be analyzed by ACCMetrics software using quantitative parameters, such as the density, length, tortuosity and width of corneal nerve fiber. The quantitative data of the two groups was compared using an independent sample t test, and the correlation among dry eye test values, nerve fiber measurements, depth of excimer laser ablation and thickness of residual stromal bed was assessed by partial or bivariate correlation method.
Results
1. The values of Schirmer test and TBUT were higher and the score of fluorescein staining was lower in patients from the one-year group when compared with those from the six-month group (t=-2.340,-5.403,2.634, P<0.05), but there was no statistically significant difference in the OSDI score between the two groups (t=1.207, P>0.05). In terms of nerve fiber measurements, the values of CNFD, CNBD, CNFL and CTBN in patients from the one-year group were all higher than those from the six-month group (t=-3.293,-4.501,-7.091,-4.240, P<0.01), but there was no statistically significant difference in the values of CNFW and CNFT between the two groups (t=1.480,0.474, P>0.05).
2. For patients in the six-month group, the value of CNBD was negatively correlated with the score of fluorescein staining (r=-0.346, P<0.05), while none of the other nerve fiber measurements was correlated with any of the dry eye test values (P>0.05). However, for patients in the one-year group, the value of Schirmer test was positively correlated with that of CNFD (r=0.321, P<0.05), but negatively correlated with that of CNBD, CTBN, and CNFT respectively (r=-0.347,-0.340,-0.325, P<0.05), and the value of CNFW was positively correlated with the score of OSDI (r=0.342, P<0.05), while none of the other nerve fiber measurements was correlated with any of the dry eye test values (P>0.05).
3. There was no statistically significant difference in either dry eye test values or nerve fiber measurements between patients who had conventional LASIK surgery and those who had femtosecond-assisted LASIK surgery (P>0.05).
4. For patients in the six-month group, none of their nerve fiber measurements or dry eye test values was correlated with either the depth of excimer laser ablation or the thickness of residual stromal bed (P>0.05). However, for patients in the one-year group, the value of TBUT was negatively correlated with the depth of excimer laser ablation (r=-0.297, P<0.05), while none of the other nerve fiber measurements or dry eye test values was correlated with either the depth of excimer laser ablation or the thickness of residual stromal bed (P>0.05). Conclusions
1. For patients who are one-year post-LASIK, their values of objective dry eye tests
are greatly improved, and the density and length of their subbasal epithelial nerve plexus in central cornea are significantly increased when compared with those of patients who are six-month post-LASIK.2. Some measurements of subbasal epithelial nerve plexus in central cornea are
correlated with some of the dry eye test values, which are more common in one-year post-LASIK patients.3. The difference between conventional-LASIK and femtosecond-assisted LASIK
does not significantly affect the dry eye test values and nerve fiber measurements in patients who are six-month or one-year post-LASIK.4. The TBUT value of one-year post-LASIK patients is negatively correlated with
the depth of excimer laser ablation.
观察LASIK术后角膜中央基底层下上皮神经丛的再生,研究其数量及形态参数与干眼指标间的关系,以及神经再生及干眼程度与术后时间、不同术式、切削深度等指标之间的相关性,从而帮助我们更全面地了解LASIK术后干眼症的病理生理机制,以期优化其治疗方案。
方法
随机入选2011年10月至2012年9月在北京协和医院眼科行传统LASIK/飞秒LASIK手术的近视患者42例(84眼)。根据患者随访时间分为LASIK术后半年组19例(38眼)和LASIK术后一年组23例(46眼)。对患者进行的术后检查主要包括干眼相关检查和角膜共聚焦显微镜检查两部分,其中前者又可分为泪液三项试验和OSDI问卷调查,后者即采用HRT III共聚焦显微镜着重对基底层下上皮神经丛进行观察,在单眼的角膜中央区域内任意选择三点行立体扫描,从中挑选出基底层下上皮神经最丰富且最清晰的三幅图像后使用ACCMetrics软件对这些图像进行神经数量及形态参数的统计并取平均值,具体参数包括神经纤维主干及主干上分支的密度(CNFD和CNBD)、神经纤维长度(CNFL)、神经总分支节点的密度(CTBN)、以及神经纤维的宽度(CNFW)和弯曲度(CNFT)等。采用独立样本t检验的方法比较术后不同随访时间组(半年组、一年组)之间,以及不同种类LASIK术式组(传统组、飞秒组)之间神经参数与干眼指标的差异；此外,根据实际情况对神经参数与干眼指标,以及两者分别与切削深度及基质层厚度之间的关系行偏相关及双变量相关性分析。
结果
1.干眼指标,LASIK术后一年组患者的Schirmer试验值和TBUT值均显著大于半年组(t=-2.340,-5.403,P<0.05),荧光素染色分值显著小于半年组(t=2.634,P<0.05),但两组间的OSDI评分未见统计学显著性差异(t=1.207,P>0.05)。神经参数,LASIK术后一年组患者的CNFD、CNBD、CNFL、CTBN值均显著大于半年组(t=-3.293,-4.501,-7.091,-4.240, P<0.01),但是两组间的CNFW、CNFT值均未见显著性差异(t=1.480,0.474,P>0.05)。
2. LASIK术后半年组,CNBD值与荧光素染色评分值呈负相关(r=-0.346,P<0.05),其余神经参数与干眼指标均无相关性(P值均>0.05)。LASIK术后一年组,CNFD值与Schirmer试验值呈正相关(r=0.321, P<0.05), CNBD、CTBN、CNFT值与Schirmer试验值呈负相关(r=-0.347,-0.340,-0.325,P<0.05),而CNFW值则与OSDI评分值呈正相关(r=0.342,P<0.05),其余神经参数与干眼指标均无相关性(P值均>0.05)。
3.无论是LASIK术后半年组还是一年组,行传统LASIK手术的患者其各项干眼主客观指标和神经数量及形态参数与行飞秒LASIK手术的患者相比不存在任何显著性差异(P值均>0.05)。
4. LASIK术后半年组,神经纤维的数量及形态参数以及干眼指标与手术切削深度及残留基质床厚度均无相关性(P值均>0.05)。LASIK术后一年组,TBUT值与手术切削深度呈负相关(r=-0.297,P<0.05),而其余神经参数及干眼指标与手术切削深度及残留基质床厚度均无相关性(P值均>0.05)。
结论
1. LASIK术后一年患者的干眼客观指标较术后半年患者显著改善,且其角膜中央基底层下上皮神经丛主干及分支的数量、神经纤维的长度均较术后半年患者显著增加。
2. LASIK术后半年及一年患者角膜中央基底层下上皮神经丛的某些神经参数与干眼指标存在相关性,尤以术后一年者较为明显。
3.传统LASIK与飞秒LASIK相比,其对术后半年及一年患者的干眼指标和神经参数所产生的影响无显著差异。
4. LASIK术后一年患者的TBUT值与手术切削深度呈负相关。
Objective
To observe the regeneration of subbasal epithelial nerve plexus in central cornea after LASIK surgery, and study the correlation between its measurements and dry eye test values, so as to promote our knowledge about the pathophysiological mechanism of post-LASIK dry eye and optimize its therapeutic options.
Methods
Forty-two myopic patients (84eyes) who had conventional LASIK/femtosecond-assisted LASIK from October2011to September2012in PUMCH were included in this cross-sectional study. Patients were divided into two groups (six-month group and one-year group) based on the post-LASIK follow-up period. Subjective and objective dry eye tests were carried out to determine patients' degree of post-LASIK dry eye, and confocal microscopy was used to observe the regeneration of subbasal epithelial nerve plexus that could then be analyzed by ACCMetrics software using quantitative parameters, such as the density, length, tortuosity and width of corneal nerve fiber. The quantitative data of the two groups was compared using an independent sample t test, and the correlation among dry eye test values, nerve fiber measurements, depth of excimer laser ablation and thickness of residual stromal bed was assessed by partial or bivariate correlation method.
Results
1. The values of Schirmer test and TBUT were higher and the score of fluorescein staining was lower in patients from the one-year group when compared with those from the six-month group (t=-2.340,-5.403,2.634, P<0.05), but there was no statistically significant difference in the OSDI score between the two groups (t=1.207, P>0.05). In terms of nerve fiber measurements, the values of CNFD, CNBD, CNFL and CTBN in patients from the one-year group were all higher than those from the six-month group (t=-3.293,-4.501,-7.091,-4.240, P<0.01), but there was no statistically significant difference in the values of CNFW and CNFT between the two groups (t=1.480,0.474, P>0.05).
2. For patients in the six-month group, the value of CNBD was negatively correlated with the score of fluorescein staining (r=-0.346, P<0.05), while none of the other nerve fiber measurements was correlated with any of the dry eye test values (P>0.05). However, for patients in the one-year group, the value of Schirmer test was positively correlated with that of CNFD (r=0.321, P<0.05), but negatively correlated with that of CNBD, CTBN, and CNFT respectively (r=-0.347,-0.340,-0.325, P<0.05), and the value of CNFW was positively correlated with the score of OSDI (r=0.342, P<0.05), while none of the other nerve fiber measurements was correlated with any of the dry eye test values (P>0.05).
3. There was no statistically significant difference in either dry eye test values or nerve fiber measurements between patients who had conventional LASIK surgery and those who had femtosecond-assisted LASIK surgery (P>0.05).
4. For patients in the six-month group, none of their nerve fiber measurements or dry eye test values was correlated with either the depth of excimer laser ablation or the thickness of residual stromal bed (P>0.05). However, for patients in the one-year group, the value of TBUT was negatively correlated with the depth of excimer laser ablation (r=-0.297, P<0.05), while none of the other nerve fiber measurements or dry eye test values was correlated with either the depth of excimer laser ablation or the thickness of residual stromal bed (P>0.05). Conclusions
1. For patients who are one-year post-LASIK, their values of objective dry eye tests
are greatly improved, and the density and length of their subbasal epithelial nerve plexus in central cornea are significantly increased when compared with those of patients who are six-month post-LASIK.2. Some measurements of subbasal epithelial nerve plexus in central cornea are
correlated with some of the dry eye test values, which are more common in one-year post-LASIK patients.3. The difference between conventional-LASIK and femtosecond-assisted LASIK
does not significantly affect the dry eye test values and nerve fiber measurements in patients who are six-month or one-year post-LASIK.4. The TBUT value of one-year post-LASIK patients is negatively correlated with
the depth of excimer laser ablation.
引文
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[48]Sonigo B, Iordanidou V, Chong-Sit D, et al. In vivo corneal confocal microscopy comparison of intralase femtosecond laser and mechanical microkeratome for laser in situ keratomileusis [J]. Invest Ophthalmol Vis Sci,2006,47(7):2803-11.
[49]Shtein RM, Kelley KH, Musch DC, et al. In vivo confocal microscopic evaluation of corneal wound healing after femtosecond laser-assisted keratoplasty [J]. Ophthalmic Surg Lasers Imaging,2012,43(3):205-13.
[50]Patel SV, McLaren JW, Kittleson KM, et al. Subbasal nerve density and corneal sensitivity after laser in situ keratomileusis:femtosecond laser vs mechanical microkeratome [J]. Arch Ophthalmol,2010,128(11):1413-9.
[51]Zhang F, Deng S, Guo N, et al. Confocal comparison of corneal nerve regeneration and keratocyte reaction between FS-LASIK, OUP-SBK, and conventional LASIK [J]. Invest Ophthalmol Vis Sci,2012,53(9):5536-44.
[52]Rodriguez AE, Rodriguez-Prats JL, Hamdi IM, et al. Comparison of goblet cell density after femtosecond laser and mechanical microkeratome in LASIK [J]. Invest Ophthalmol Vis Sci,2007,48(6):2570-5.
[53]黄悦,赵绍贞,孙慧敏,等.两种微型角膜板层刀在准分子激光原位角膜磨镶术的效果比较[J].眼视光学杂志,2007,9(3)：169-71.
[54]De Paiva CS, Chen Z, Koch DD, et al. The incidence and risk factors for developing dry eye after myopic LASIK [J]. Am J Ophthalmol,2006,141(3):438-45.
[55]Niu LL, Zhou XT, Ding L, et al. The effects of protein-free calf blood extract for recovery of corneal nerve after LASEK and LASIK [J]. Zhonghua Yan Ke Za Zhi,2011, 47(6):539-45.
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[4]Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea,1999,18(4): 403-7.
[5]Tuominen IS, Konttinen YT, Vesaluoma MH, et al. Corneal innervation and morphology in primary Sjogren's syndrome. Invest Ophthalmol Vis Sci,2003,44(6): 2545-9.
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[7]Mokhtarzadeh M, Casey R, Glasgow BJ. Fluorescein punctate staining traced to superficial corneal epithelial cells by impression cytology and confocal microscopy. Invest Ophthalmol Vis Sci,2011,52(5):2127-35.
[8]Benitez del Castillo JM, Wasfy MA, Fernandez C, et al. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci,2004,45(9):3030-5.
[9]Erdelyi B, Kraak R, Zhivov A, et al. In vivo confocal laser scanning microscopy of the cornea in dry eye. Graefes Arch Clin Exp Ophthalmol,2007,245(1):39-44.
[10]Villani E, Galimberti D, Viola F, et al. The cornea in Sjogren's syndrome:an in vivo confocal study. Invest Ophthalmol Vis Sci,2007,48(5):2017-22.
[11]Zhang X, Chen Q, Chen W, et al. Tear dynamics and corneal confocal microscopy of subjects with mild self-reported office dry eye. Ophthalmology,2011,118(5):902-7.
[12]Villani E, Viola F, Sala R, et al. Corneal involvement in Graves' orbitopathy:an in vivo confocal study. Invest Ophthalmol Vis Sci,2010,51(9):4574-8.
[13]Villani E, Galimberti D, Viola F, et al. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci,2008,49(2):560-4.
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innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Invest Ophthalmol Vis Sci,2007,48(1):173-81.
[17]De Paiva CS, Pflugfelder SC. Corneal epitheliopathy of dry eye induces hyperesthesia to mechanical air jet stimulation. Am J Ophthalmol,2004,137(1):109-15.
[18]Tuisku IS, Konttinen YT, Konttinen LM, et al. Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Exp Eye Res,2008, 86(6):879-85.
[19]Zhang M, Chen J, Luo L, et al. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea,2005,24(7):818-24.
[20]Cruzat A, Pavan-Langston D, Hamrah P. In vivo confocal microscopy of corneal nerves:analysis and clinical correlation. Semin Ophthalmol,2010,25(5-6):171-7.
[21]Cruzat A, Witkin D, Baniasadi N, et al. Inflammation and the nervous system:the connection in the cornea in patients with infectious keratitis. Invest Ophthalmol Vis Sci, 2011,52(8):5136-43. [22] Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci, 2010,51(1):122-8.
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[24]Hong J, Zhu W, Zhuang H, et al. In vivo confocal microscopy of conjunctival goblet cells in patients with Sjogren's syndrome dry eye. Br J Ophthalmol,2010,94(11): 1454-8.
[25]Wakamatsu TH, Sato EA, Matsumoto Y, et al. Conjunctival in vivo confocal scanning laser microscopy in patients with Sjogren syndrome. Invest Ophthalmol Vis Sci, 2010,51(1):144-50.
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[27]Villani E, Beretta S, De Capitani M, et al. In vivo confocal microscopy of meibomian glands in Sjogren's syndrome. Invest Ophthalmol Vis Sci,2011,52(2):933-9.
[28]Matsumoto Y, Sato EA, Ibrahim OM, et al. The application of in vivo laser confocal microscopy to the diagnosis and evaluation of meibomian gland dysfunction. Mol Vis, 2008,14:1263-71.
[29]Ibrahim OM, Matsumoto Y, Dogru M, et al. The efficacy, sensitivity, and specificity of in vivo laser confocal microscopy in the diagnosis of meibomian gland dysfunction. Ophthalmology,2010,117(4):665-72.
[30]Matsumoto Y, Shigeno Y, Sato EA, et al. The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy. Graefes Arch Clin Exp Ophthalmol,2009,247(6):821-9.
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[57]Patel DV, McGhee CN. In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery:a review [J]. Br J Ophthalmol,2009,93(7):853-60.
[1]The definition and classification of dry eye disease:report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf, 2007,5(2):75-92.
[2]The epidemiology of dry eye disease:report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf,2007,5(2):93-107.
[3]Chiou AG, Kaufman SC, Kaufman HE, et al. Clinical corneal confocal microscopy. Surv Ophthalmol,2006,51(5):482-500.
[4]Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea,1999,18(4): 403-7.
[5]Tuominen IS, Konttinen YT, Vesaluoma MH, et al. Corneal innervation and morphology in primary Sjogren's syndrome. Invest Ophthalmol Vis Sci,2003,44(6): 2545-9.
[6]Chen JJ, Rao K, Pflugfelder SC. Corneal epithelial opacity in dysfunctional tear syndrome. Am J Ophthalmol,2009,148(3):376-82.
[7]Mokhtarzadeh M, Casey R, Glasgow BJ. Fluorescein punctate staining traced to superficial corneal epithelial cells by impression cytology and confocal microscopy. Invest Ophthalmol Vis Sci,2011,52(5):2127-35.
[8]Benitez del Castillo JM, Wasfy MA, Fernandez C, et al. An in vivo confocal masked study on corneal epithelium and subbasal nerves in patients with dry eye. Invest Ophthalmol Vis Sci,2004,45(9):3030-5.
[9]Erdelyi B, Kraak R, Zhivov A, et al. In vivo confocal laser scanning microscopy of the cornea in dry eye. Graefes Arch Clin Exp Ophthalmol,2007,245(1):39-44.
[10]Villani E, Galimberti D, Viola F, et al. The cornea in Sjogren's syndrome:an in vivo confocal study. Invest Ophthalmol Vis Sci,2007,48(5):2017-22.
[11]Zhang X, Chen Q, Chen W, et al. Tear dynamics and corneal confocal microscopy of subjects with mild self-reported office dry eye. Ophthalmology,2011,118(5):902-7.
[12]Villani E, Viola F, Sala R, et al. Corneal involvement in Graves' orbitopathy:an in vivo confocal study. Invest Ophthalmol Vis Sci,2010,51(9):4574-8.
[13]Villani E, Galimberti D, Viola F, et al. Corneal involvement in rheumatoid arthritis: an in vivo confocal study. Invest Ophthalmol Vis Sci,2008,49(2):560-4.
[14]Efron N. Contact lens-induced changes in the anterior eye as observed in vivo with the confocal microscope. Prog Retin Eye Res,2007,26(4):398-436.
[15]Hosal BM, Ornek N, Zilelioglu G, et al. Morphology of corneal nerves and corneal sensation in dry eye:a preliminary study. Eye (Lond),2005,19(12):1276-9. [16] Benitez-Del-Castillo JM, Acosta MC, Wassfi MA, et al. Relation between corneal
innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Invest Ophthalmol Vis Sci,2007,48(1):173-81.
[17]De Paiva CS, Pflugfelder SC. Corneal epitheliopathy of dry eye induces hyperesthesia to mechanical air jet stimulation. Am J Ophthalmol,2004,137(1):109-15.
[18]Tuisku IS, Konttinen YT, Konttinen LM, et al. Alterations in corneal sensitivity and nerve morphology in patients with primary Sjogren's syndrome. Exp Eye Res,2008, 86(6):879-85.
[19]Zhang M, Chen J, Luo L, et al. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocal microscopy. Cornea,2005,24(7):818-24.
[20]Cruzat A, Pavan-Langston D, Hamrah P. In vivo confocal microscopy of corneal nerves:analysis and clinical correlation. Semin Ophthalmol,2010,25(5-6):171-7.
[21]Cruzat A, Witkin D, Baniasadi N, et al. Inflammation and the nervous system:the connection in the cornea in patients with infectious keratitis. Invest Ophthalmol Vis Sci, 2011,52(8):5136-43. [22] Lin H, Li W, Dong N, et al. Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci, 2010,51(1):122-8.
[23]Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol,2013,32(1):19-41.
[24]Hong J, Zhu W, Zhuang H, et al. In vivo confocal microscopy of conjunctival goblet cells in patients with Sjogren's syndrome dry eye. Br J Ophthalmol,2010,94(11): 1454-8.
[25]Wakamatsu TH, Sato EA, Matsumoto Y, et al. Conjunctival in vivo confocal scanning laser microscopy in patients with Sjogren syndrome. Invest Ophthalmol Vis Sci, 2010,51(1):144-50.
[26]Kojima T, Matsumoto Y, Dogru M, et al. The application of in vivo laser scanning confocal microscopy as a tool of conjunctival in vivo cytology in the diagnosis of dry eye ocular surface disease. Mol Vis,2010,16:2457-64.
[27]Villani E, Beretta S, De Capitani M, et al. In vivo confocal microscopy of meibomian glands in Sjogren's syndrome. Invest Ophthalmol Vis Sci,2011,52(2):933-9.
[28]Matsumoto Y, Sato EA, Ibrahim OM, et al. The application of in vivo laser confocal microscopy to the diagnosis and evaluation of meibomian gland dysfunction. Mol Vis, 2008,14:1263-71.
[29]Ibrahim OM, Matsumoto Y, Dogru M, et al. The efficacy, sensitivity, and specificity of in vivo laser confocal microscopy in the diagnosis of meibomian gland dysfunction. Ophthalmology,2010,117(4):665-72.
[30]Matsumoto Y, Shigeno Y, Sato EA, et al. The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy. Graefes Arch Clin Exp Ophthalmol,2009,247(6):821-9.
[31]Pflugfelder SC, Solomon A, Stern ME. The diagnosis and management of dry eye:a twenty-five-year review. Cornea,2000,19(5):644-9.
[32]Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction:executive summary. Invest Ophthalmol Vis Sci,2011,52(4):1922-9.