Lowering Intraocular Pressure: A Potential Approach for Controlling High Myopia Progression

High myopia is among the most common causes of vision impairment, and it is mainly characterized by abnormal elongation of the axial length, leading to pathologic changes in the ocular structures. Owing to the close relationship between high myopia and glaucoma, the association between intraocular pressure (IOP) and high myopia progression has garnered attention. However, whether lowering IOP can retard the progression of high myopia is unclear. On reviewing previous studies, we suggest that lowering IOP plays a role in progressive axial length elongation in high myopia, particularly in pathologic myopia, wherein the sclera is more remodeled. Based on the responses of the ocular layers, we further proposed the potential mechanisms. For the sclera, lowering the IOP could inhibit the activation of scleral fibroblasts and then reduce scleral remodeling, and a decrease in the scleral distending force would retard the ocular expansion like a balloon. For the choroid, lowering IOP results in an increase in choroidal blood perfusion, thereby reducing scleral hypoxia and slowing down scleral remodeling. The final effect of these pathways is slowing axial elongation and the development of scleral staphyloma. Further animal and clinical studies regarding high myopia with varied degree of IOP and the changes of choroid and sclera during IOP fluctuation in high myopia are needed to verify the role of IOP in the pathogenesis and progression of high myopia. It is hoped that this may lead to the development of a prospective treatment option to prevent and control high myopia progression.     

Structural and ultrastructural changes to the sclera in a mammalian model of high myopia

PURPOSE: The development of high myopia is associated with scleral thinning and changes in the diameter of scleral collagen fibrils in humans. In the present study, the association between these scleral changes and the losses in scleral tissue that have previously been reported in animal models were investigated to determine the relationship between changes in collagen fibril architecture and thinning of the sclera in high myopia. METHODS: Myopia was induced in young tree shrews by monocular deprivation of pattern vision for short-term (12 days) or long-term (3-20 months) periods. Scleral tissue from normal animals over a wide age range (birth to 21 months) was also collected to provide data on the normal development of the sclera. Light and electron microscopy were used to measure scleral thickness and to determine the frequency distribution of collagen fibril diameters in the sclera. Tissue loss was monitored through measures of scleral dry weight. RESULTS: Significant scleral thinning and tissue loss, particularly at the posterior pole of the eye, were associated with ocular enlargement and myopia development after both short- and long-term treatments. However, collagen fibril diameter distribution was not significantly altered after short-term myopia treatment, whereas, from 3 months of monocular deprivation onward, significant reductions in the median collagen fibril diameter were noted, particularly at the posterior pole. CONCLUSIONS: The results of this study demonstrated that loss of scleral tissue and subsequent scleral thinning occurred rapidly during development of axial myopia. However, this initial tissue loss progressed in a way that did not result in significant alterations to the collagen fibril diameter distribution. In the longer term, there was an increased number of small diameter collagen fibrils in the sclera of highly myopic eyes, which is consistent with findings in humans and is likely to contribute to the weakened biomechanical properties of the sclera that have previously been reported.     

近视巩膜组织重塑与相关基因研究进展

近视严重威胁着儿童的视力健康,高度近视可以导致多种并发症,甚至视力完全丧失。近年来随着近视发病率的持续增加,人们对近视认知水平的持续提升,儿童近视问题受到了广泛关注。目前近视发生和发展的具体机制尚不清楚,人们普遍认为巩膜是近视发生的效应器。随着近视不断发展,眼轴逐渐拉长,眼球的结构和功能随之发生改变,其中,眼轴过度延长导致巩膜重塑,后极部巩膜加速变薄,巩膜的组织结构和生物力学特性发生了重要改变,而相关基因表达的调控则是视觉信号引起巩膜重塑的关键。大量研究者借助于近视动物模型和基因测序技术发现,巩膜细胞外基质重塑与近视的发生和发展密切相关。文章就目前巩膜在近视发生发展中组织结构及相关基因的变化进行综述,为深入探究近视的巩膜重塑机制和寻找新的近视治疗靶点提供思路。     

Scleral structure and biomechanics

As the eye's main load-bearing connective tissue, the sclera is centrally important to vision. In addition to cooperatively maintaining refractive status with the cornea, the sclera must also provide stable mechanical support to vulnerable internal ocular structures such as the retina and optic nerve head. Moreover, it must achieve this under complex, dynamic loading conditions imposed by eye movements and fluid pressures. Recent years have seen significant advances in our knowledge of scleral biomechanics, its modulation with ageing and disease, and their relationship to the hierarchical structure of the collagen-rich scleral extracellular matrix (ECM) and its resident cells. This review focuses on notable recent structural and biomechanical studies, setting their findings in the context of the wider scleral literature. It reviews recent progress in the development of scattering and bioimaging methods to resolve scleral ECM structure at multiple scales. In vivo and ex vivo experimental methods to characterise scleral biomechanics are explored, along with computational techniques that combine structural and biomechanical data to simulate ocular behaviour and extract tissue material properties. Studies into alterations of scleral structure and biomechanics in myopia and glaucoma are presented, and their results reconciled with associated findings on changes in the ageing eye. Finally, new developments in scleral surgery and emerging minimally invasive therapies are highlighted that could offer new hope in the fight against escalating scleral-related vision disorder worldwide.     

The sclera and myopia

Myopia is a very common ocular problem, affecting perhaps one billion people worldwide. Most myopia is produced by lengthening of the vitreous chamber of the ocular globe. High myopia is characterized by scleral thinning and localized ectasia of the posterior sclera. The sclera is a dense, fibrous, viscoelastic connective tissue that forms the outer coat of the eye and consists of irregularly arranged lamellae of collagen fibrils interspersed with proteoglycans and non-collagenous glycoproteins. Scleral fibroblasts are located between scleral lamellae, and are responsible for synthesizing the extracellular matrix in which they reside. Research highlighted in this review clearly demonstrates that the sclera is not a static container of the eye, but rather is a dynamic tissue, capable of altering extracellular matrix composition and its biomechanical properties in response to changes in the visual environment to regulate ocular size and refraction. Based on these studies, a strategy directed at reversing myopia-associated scleral extracellular matrix remodeling events would be warranted, particularly in cases of high myopia in humans.     

Pirenzepine affects scleral metabolic changes in myopia through a non-toxic mechanism

Whilst the precise mechanism regulating ocular growth is unknown, it has been shown that various pharmacological agents, including the muscarinic receptor antagonists, atropine and pirenzepine, are effective at preventing the development of myopia. A recent study, which demonstrated that muscarinic antagonists reduce the synthesis of glycosaminoglycans and DNA in chick sclera in vitro, led to the suggestion that such drugs may act directly on the sclera, possibly through a toxic mechanism. Accepted markers of scleral metabolism and cell viability were used in conjunction with a non-invasive, physiological method of ocular growth regulation to determine whether the selective muscarinic antagonist pirenzepine inhibits the development of myopia via toxicity to the sclera. Chicks were monocularly deprived (MD) of pattern vision and given daily intravitreal injections of either pirenzepine (700 microg) or saline vehicle into the deprived eye over 5 days. Unoccluded animals also received intravitreal injections of either pirenzepine or saline into one eye (n=6, all groups). The contralateral eye of all animals was left untreated for comparison. Optical and ocular biometric measures were collected on the final experimental day. Following in vivo delivery of [(35)S] labelled sulphate, levels of sulphate incorporation into scleral glycosaminoglycans were measured in proteinase K digests following selective precipitation with alcian blue dye. The DNA content was also assessed through luminescence spectrometry after binding to Hoechst 33258 dye. To allow comparison with an accepted non-invasive, physiological method of ocular growth regulation, myopia was prevented in additional groups of MD animals by allowing 3hr of unoccluded vision each day, over 5 days, before levels of sulphate incorporation were measured. Scleral DNA content, a marker of cell viability, was not significantly altered between treated and control eyes in any injected group. Relative levels of sulphate incorporation (% difference between treated and contralateral control eyes) were significantly lower in the cartilaginous sclera of pirenzepine-MD animals, compared to saline-MD controls (+35.9 +/- 10.1% vs +121.2 +/- 28.6%, P<0.05), after 2hr of incorporation. However, after 6hr incorporation, there was no significant difference in sulphate incorporation in the cartilaginous sclera between the two groups (+87.2 +/- 33.1% vs +111.0 +/- 14.4%, P=0.53). No significant change was found in the levels of glycosaminoglycan synthesis in the fibrous sclera of any pirenzepine treated group, when compared to the appropriate saline control. Relative patterns of sulphate incorporation, between treatment and control groups, were essentially identical at both time points examined, regardless of whether myopia was prevented through pirenzepine injection or periods of unoccluded vision. The present study shows that, at a dose of pirenzepine sufficient to prevent experimentally-induced axial myopia, glycosaminoglycan synthesis in the cartilaginous sclera was significantly reduced for a transient period following the injection. These pirenzepine-induced reductions in glycosaminoglycan synthesis were not caused by direct drug toxicity to scleral cells as these changes were reversible and no significant reduction in DNA content was observed in pirenzepine treated eyes. Similar patterns of scleral glycosaminoglycan synthesis changes were found following the provision of brief periods of unoccluded vision further demonstrating that pirenzepine is effective in myopia prevention via a non-toxic mechanism. Consequently, the prevention of myopia development in chicks, with either pirenzepine or brief periods of unoccluded vision, is associated with the transient modulation of scleral glycosaminoglycan synthesis in the cartilaginous sclera.     

Scleral remodeling during the development of and recovery from axial myopia in the tree shrew

PURPOSE: Recent investigations have suggested that scleral thinning in mammalian eyes with axial myopia is a consequence of the loss of scleral tissue, rather than the redistribution of existing tissue as the eye enlarges. The present study investigated whether further changes in the distribution and metabolism of scleral tissue occur during the process of recovery from axial myopia. Scleral glycosaminoglycan (GAG) synthesis and content as well as scleral dry weight changes were monitored as indicators of remodeling in myopic and recovering tree shrew sclerae. METHODS: Myopia was induced in tree shrews by monocularly depriving them of pattern vision. Some animals then had the occluder removed and were allowed to recover from the induced myopia for periods of 1, 3, 5, 7, and 9 days. Newly synthesized GAGs were radiolabeled in vivo with [(35)S]sulfate. Sulfate incorporation and total GAG content in the sclera was measured through selective precipitation of GAGs from proteinase K digests with alcian blue dye. Dry weights of the sclerae were also determined. Changes in ocular refraction and eye size were monitored using retinoscopy, keratometry, and ultrasonography. RESULTS: Eyes developing myopia showed a significant reduction in scleral GAG synthesis, particularly in the region of the posterior pole (-36% +/- 7%) compared with contralateral control eyes. Scleral dry weight was also significantly reduced in these eyes (-3.7% +/- 1.2%). In recovering eyes, significant changes in GAG synthesis were apparent after 24 hours of recovery. After 3 days of recovery, significantly elevated levels of GAG synthesis were found (+79% +/- 15%), returning to contralateral control eye values after 9 days of recovery. Interocular differences in scleral dry weight were shown to follow a similar pattern to that observed for GAG synthesis. CONCLUSIONS: Active remodeling, resulting in either the loss or replacement of scleral tissue and not passive redistribution of scleral tissue, is associated with changes in eye size during both myopia development and recovery. Regulatory changes in scleral metabolism can be rapidly evoked by a change in visual conditions and the direction of regulation is related to the direction of change in eye size.     

高度近视眼轴的初步研究

本文观测了高度近视５６例１１２眼的前房深度、眼轴长度、后巩膜形态、屈光状态、眼内压及巩膜壁硬度，并与正常对照组６２眼比较。高度近视的眼轴明显延长，主要是眼球后部扩张。这种变化在发生后巩膜葡萄肿的病例更为显著。高度近视组巩膜壁硬度下降，眼内压无明显改变，提示眼球壁抗力降低似为眼轴延长的重要因素。     

Optical correction of induced axial myopia in the tree shrew: implications for emmetropization.

PURPOSE: To determine whether an active emmetropization mechanism is involved in the recovery from axial myopia through the use of a mammalian model of refractive development. Specifically, we sought to establish whether the emmetropization mechanism is visually guided by the level of clarity of the image falling on the retina, or if recovery is driven by a mechanism sensitive to abnormal eye shape. METHODS: Young tree shrews had axial myopia induced by monocular deprivation (MD) of pattern vision and then the myopic eye was either: (1) accurately corrected with a negative lens or (2) had a zero-powered lens placed in front of it. Their emmetropization response was monitored, both through the use of ocular refractive and biometric measures, as well as through the assessment of scleral dry weight and glycosaminoglycan synthesis, as indicators of scleral metabolism. RESULTS: Corrective lenses prevented recovery from induced myopia (-6.8 +/- 0.7 D after 5 days MD vs. -6.6 +/- 0.6 D after 5 days of lens wear), whereas animals fitted with zero-powered lenses displayed near full recovery from the induced myopia (-6.6 +/- 0.6 D vs. -1.7 +/- 0.3 D). Significant reductions in scleral dry weight (-4.6 +/- 1.3%) and glycosaminoglycan synthesis (-28.6 +/- 7.3%) were found in the posterior sclera of animals wearing corrective lenses. Conversely, animals wearing zero-powered lenses displayed elevated levels of glycosaminoglycan synthesis (+62.3 +/- 11.1%) in conjunction with scleral dry weights that did not differ significantly between treated and fellow control eyes (-1.5 +/- 2.6%). CONCLUSIONS: Accurate correction of induced axial myopia prevents the refractive, biometric and scleral metabolic responses that are normally observed in tree shrew eyes recovering from induced myopia. These findings support the hypothesis that recovery is driven by an active emmetropization response dependent on the clarity of image falling on the retina and not by a mechanism that is sensitive to abnormal eye shape.     

HA/CD44与病理性近视巩膜改变的研究进展

近视是一种常见的眼部疾病,其特征是眼轴增长。近视患者因眼轴不断延长及巩膜变薄会引起黄斑变性、视网膜下出血、视网膜脱离等并发症,最终导致视力下降甚至失明。透明质酸（hyaluronic acid,HA）是细胞外基质（extracellular matrix,ECM）的重要糖胺聚糖成分。它在细胞衰老、癌症和组织稳态中起着重要的作用。CD44是透明质酸的主要细胞表面受体,广泛分布于人体眼组织和体液中的一种黏附因子,参与多种重要的生理功能,包括细胞增殖、黏附、迁移、造血和淋巴细胞活化。HA通过与CD44相互作用参与近视巩膜的病理改变,对于预防近视以及延缓近视的发展具有指导意义。     

Modulation of scleral DNA synthesis in development of and recovery from induced axial myopia in the tree shrew

Visually modulated scleral extracellular matrix remodelling is associated with the development of, and recovery from, induced axial myopia in the tree shrew, a commonly used mammalian model of refractive error development. The involvement of scleral cell proliferation in this process was investigated using [3H] thymidine. Tree shrews were monocularly deprived of pattern vision, using translucent occluders, or the retinal image was optically defocused, using negative lenses, over a period of 5 days. A further group was monocularly deprived for 5 days, then allowed 3 days of binocular recovery. A control group of binocularly open animals was employed to establish normal parameters. On the final day of the experimental period, [3H] thymidine was administered by intraperitoneal injection, then optical and biometric measures were taken and tissue samples collected for assay. Incorporation of [3H] thymidine into cellular DNA was measured in proteinase K digests, following precipitation with trichloroacetic acid. After 5 days, significant amounts of myopia were present in the treated eyes of both form-deprived [-7. 0+/-0.7 Dioptres (D), group mean+/-s.e.m.; P<0.01] and lens-defocused animals (-6.2+/-0.9 D;P<0.01). After 3 days of recovery, 50% of the refractive error had been compensated for, predominantly through shortening of the vitreous chamber in the treated eye. Reduced levels of [3H] thymidine incorporation were observed in sclera from both groups of myopic animals (form-deprived, -34.3+/-9.9%;P<0.05 and lens-defocus, -32.8+/-4.5%;P<0.005). Increased levels of [3H] thymidine incorporation were found in the sclera of recovering animals (+144.0+/-43.2%;P<0.05). The results show that changes in regulation of cell proliferation, during the development of myopia, are visually mediated and inversely related to the direction of change in ocular size. This implies that alterations in the scleral fibroblast population are involved in the modulation of scleral matrix turnover during myopia development.     

Induced myopia associated with increased scleral creep in chick and tree shrew eyes

PURPOSE: To investigate the role of scleral creep in the axial elongation of chick and tree shrew eyes with induced myopia. METHODS: Form-deprivation myopia was induced with a diffusing occluder worn over one eye. Scleral samples from the posterior pole and equatorial regions of myopic, contralateral (control), and age-matched normal chick and tree shrew eyes were loaded in vitro with a force of 5 g for 20 minutes while creep extension was monitored. The elastic behavior of sclera from myopic, control, and normal chick eyes was also compared. RESULTS: In both chick and tree shrew, posterior and equatorial scleral samples from myopic eyes had significantly (P < 0.05) greater creep extensions than equivalent samples from control and normal eyes (n = 10, each group). Among individual tree shrews the difference in creep rate between the sample from the myopic eye and that from the control eye correlated with vitreous chamber elongation (r = 0.746, P < 0.05) and development of myopia (r = 0.792, P < 0.01) in the deprived eye. No such association was found in the data from chicks. The elastic properties of chick sclera were unaffected in form-deprivation myopia. CONCLUSIONS: In chick and tree shrew, form-deprivation myopia is associated with increased creep rate of posterior and equatorial sclera. In tree shrew, the correlation between increased scleral creep rate and vitreous chamber elongation in myopic eyes supports the hypothesis that induced changes in the axial length of the mammalian eye are mediated by changes in the creep properties of the sclera.     

Measurement of retinal thickness by ocular coherence tomography in a case of scleral transparency in high myopia

PURPOSE: Staphylomatous thinning of the sclera and retina are among the numerous changes associated with the elongated eye of high myopia. We report a case of scleral and retinal transparency in high myopia in which ocular coherence tomography was used to measure retinal and scleral thickness in vivo. DESIGN: Observational case report. METHODS: The clinical presentation and evaluation of a case of scleral transparency in high myopia are presented. RESULTS: This case demonstrates numerous anatomical changes to the sclera and retina known to occur in association with high myopia. Initial evaluation by optical coherence tomography demonstrated a retinal thickness of 74 microm and a scleral thickness of 80 microm. CONCLUSIONS: Optical coherence tomography can be used to measure scleral and retinal thickness in vivo in a patient with high myopia. It is not known at this time what precautions are necessary in such a patient should intraocular surgery be required.     

高度近视眼巩膜细胞外基质中相关胶原分子机制的研究进展

高度近视眼是目前为止全球范围内主要的不可逆性致盲性眼部疾病之一。高度近视眼在发生和发展的过程中,眼球后部巩膜可能异常薄变或扩展。巩膜薄变、脉络膜萎缩性薄变及不同程度的眼轴延长,且伴有巩膜细胞外基质(ECM)的过度降解是高度近视眼不断发展的根本原因。近年来,随着相关研究的不断深入,国内外学者发现巩膜ECM生化特性的改变与近视眼的发展有着十分密切的关系,而胶原作为巩膜ECM的重要组成部分,其表达和积聚的改变与病理性近视眼的发展呈显著正相关的关系。目前,临床医学领域对此尚无有效的治疗方法,常用的药物及手术疗法的疗效尚未确定且毒副作用较大,并不适合在临床上进行大范围的推广和使用。本文就目前高度近视眼巩膜ECM中胶原分子机制的研究进展进行综述。     

色觉在眼屈光发育中的作用

作为视觉重要组成部分的色觉在屈光发育中的作用应引起我们的重视。有研究发现,不同单色光与眼球的增长发育和屈光的变化密切相关,长波长光能促进眼球的增长形成相对近视,短波长光能抑制眼球的增长产生相对远视。研究还发现,短波长蓝光可阻止豚鼠光学离焦性近视进展。色光干预引起屈光发育异常的作用机制除了纵向色像差作用外,还可能存在其他作用机制。作为色觉通路第一站的视锥细胞可能在屈光发育及近视形成过程中发挥重要作用,视色素的代谢产物视黄酸可能是影响屈光发育的重要信号因子。研究色觉在眼屈光发育中的作用有助于进一步探讨近视发病机制,也为近视防治研究提供了新的方向。本文对色觉在眼屈光发育中的作用进行综述。     

病理性近视后巩膜葡萄肿的研究进展

我国近视眼患者超过3亿,其中高度近视患者已超过一千万,高度近视中很大一部分为病理性近视(pathological myopia,PM),其并发的眼底病变已成为眼底病中不可逆致盲的首位眼病.在病理性近视眼底一系列退行性病变中,后巩膜葡萄肿(posterior staphyloma,PS)是最基础的病变之一,其发病原因仍无定论,可能是眼轴不断延长、巩膜中胶原的合成及分解紊乱造成胶原蛋白减少共同造成巩膜变薄而不能抵抗眼压的结果.目前病理性近视后巩膜葡萄肿的唯一治疗手段为后巩膜加固术.对于无临床症状或者因PS而产生的并发症需要定期观察,手术时机仍需要大量的临床研究进行评估.     

形觉剥夺性近视中巩膜变化的生物学机制

近视眼的发病机制不明，形觉剥夺可以诱导典型的近视动物模型，形成形觉剥夺性近视眼(form—deprivationmyopia，FDM)。通过细胞和分子水平的研究发现，FDM的变化主要表现在眼球局部，形觉剥夺可诱导巩膜软骨细胞增殖，细胞外基质(extracellularmaterial，ECM)基因表达异常，ECM增加，巩膜胶原纤维改变等引起巩膜重塑，导致眼轴延长，近视屈光度增加。本文就FDM巩膜变化生物学机制的研究进展作一综述。     

碱性成纤维细胞生长因子与转化生长因子β在近视眼巩膜中作用的研究进展

近视是世界最常见眼病之一,其发病机制尚不完全清楚。有研究发现,细胞生长因子与近视的发生发展密切相关,其中碱性成纤维细胞生长因子（bFGF）与转化生长因子β（TGF-β）作为关键的信号分子可以通过调控巩膜细胞外基质的合成与降解参与近视眼巩膜重塑,但具体转导途径和机制还不十分清楚。现就bFGF和TGF-β在近视眼巩膜中的表达及其调控巩膜重塑的可能机制进行综述。     

Dynamic changes of ocular biometric parameters: a modified form-deprivation myopia model of young guinea pigs

AIM: To evaluate the dynamic ocular biometric changes of a modified form-deprivation myopia model in young guinea pigs. METHODS: The animals were randomly assigned to two groups: the monocularly deprived facemask group (MDF, with all the right eyes covered, n=24) and the normal control group(free of facemask, n=24). Each group was then equally divided into four subgroups which were followed up for 2, 4, 6 and 8 weeks, respectively. Parameters measured from every eye included refraction, corneal curvature, axial length and the dry weight of sclera at the posterior pole. RESULTS: All the facemasks remained in place during the follow-up. The covered eyes developed myopia with the vitreous chamber lengthening and the dry weight of posterior sclera reduced at each time point compared with the contralateral uncovered(P<0.05 at all time points). The changes had a linear correlation with the deprivation time (P<0.05). There were no significant differences in all the parameters between the uncovered eyes of MDF group and the normal control group (P>0.05 at all time points). CONCLUSION: Monocular form deprivation with the facemask is highly effective and non-invasive in inducing axial myopia in guinea pigs. The axial myopia is mainly caused by the increased vitreous chamber length and the weakened posterior sclera rigidity. The form-deprivation eye didn't interfere with the natural development of the contralateral eye.     

Dynamic changes of ocular biometric parameters:a modified form-deprivation myopia model of young guinea pigs

AIM:To evaluate the dynamic ocular biometric changes of a modified form-deprivation myopia model in young guinea pigs.METHODS:The animals were randomly assigned to two groups:the monocularly deprived facemask group(MDF,with all the right eyes covered,n =24) and the normal control group(free of facemask,n =24).Each group was then equally divided into four subgroups which were followed up for 2,4,6 and 8 weeks,respectively.Parameters measured from every eye included refraction,corneal curvature,axial length and the dry weight of sclera at the posterior pole.RESULTS:All the facemasks remained in place during the follow-up.The covered eyes developed myopia with the vitreous chamber lengthening and the dry weight of posterior sclera reduced at each time point compared with the contralateral uncovered(P <0.05 at all time points).The changes had a linear correlation with the deprivation time(P <0.05).There were no significant differences in all the parameters between the uncovered eyes of MDF group and the normal control group(P >0.05 at all time points).CONCLUSION:Monocular form deprivation with the facemask is highly effective and non-invasive in inducing axial myopia in guinea pigs.The axial myopia is mainly caused by the increased vitreous chamber length and the weakened posterior sclera rigidity.The form-deprivation eye didn’t interfere with the natural development of the contralateral eye.