Prevalence of focal lamina cribrosa defects in eyes with pachychoroid disease spectrum

INTRODUCTION

Pachychoroid disease spectrum (PDS) is a recently defined clinical entities characterized by retinal pigment epithelium (RPE) abnormalities overlying areas of choroidal thickening. PDS occurs due to pachychoroid-driven processes involving choroidal congestion and choroidal hyperpermeability, manifested in choroidal thickening and dilated choroidal vessels. The current definition of PDS includes central serous chorioretinopathy (CSC), pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy,and polypoidal choroidal vasculopathy (PCV).

A number of studies have shown disease characteristics,suitable treatment strategies, and possible pathogenesis of PDS, however, still various aspects of PDS such as optic nerve head (ONH) structures remain to be uncovered. A few studies have presented ONH structures in the PDS. One study demonstrated that lamina cribrosa (LC) disinsertion or LC defect is associated with peripapillary retinoschisis in PDS as well as with glaucoma. Increased leakage from the hyperpermeable choroidal vessels may lead to greater inflow of fluid to the ONH from the subarachnoid space through peripheral LC disinsertion or from the vitreous region through central LC defects in eyes with PDS; however, the study only included cases with PDS having peripapillary retinoschisis. Recently, one study defined peripapillary pachychoroid syndrome (PPS)as a distinct variant of PDS,in which peripapillary choroidal thickening is associated with intraretinal and/or subretinal fluid in the nasal macula and occasional ONH edema. In that study, all eyes showed intraretinal fluid and cysts extending from the temporal disc margin, with associated atrophy of the RPE, photoreceptor ellipsoid zone, and external limiting membrane. However,they suggested that peripapillary intraretinal fluid resembling peripapillary retinoschisis can occur in the eyes with PDS that do not show LC disinsertion.

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Despite several studies have suggested the possible correlation of LC disinsertion/defect in the patients with PDS, there has been no study investigating the prevalence of focal LC defect among the patients with PDS. Based on these studies,we intended to examine the prevalence of focal LC defect among the patients with pachychoroid diseases, but without peripapillary retinoschisis. We also compared the prevalence of focal LC defects between the eyes with PDS in the absence of peripapillary retinoschisis and that of the normal control group.

SUBJECTS AND METHODS

This study was approved by the Institutional Review Board of International St. Mary’s Hospital and adhered to the tenets of the Declaration of Helsinki. Due to the retrospective nature of the study, the requirement for informed consent was waived.

仿制药企业所提的专利挑战中，大多数针对的是非活性成分专利。极高的专利挑战成功率激励更多的仿制药企业对非活性成分专利提出专利挑战。而从原研药企业角度而言，非活性成分专利极高的挑战成功率又“迫使”其在桔皮书登记更多的专利，从而通过数量的优势来弥补非活性成分专利在保护效果上的不足。桔皮书中更多的非活性成分专利又必然会导致更多的针对非活性成分专利的挑战。这样就形成了一个“怪圈”，使得双方都需要付出更多的精力和资源来维护或挑战改进型的非活性成分专利。

Three-dimensional computed tomography reconstruction indicating a rich collateral renal blood supply and confirming the origins and extent of the renal artery stenosis.

However, based on our findings, we discarded the primary hypothesis that increased hydrostatic pressure of PDS may be associated with development of LC disinsertion/defect. At least the eyes with PDS but without peripapillary retinoschisis,it seems that increased hydrostatic pressure does not have significant impact on the development of LC alteration.Simply, the presence of focal LC defect among the patients with PDS may be just accidental findings of normal ONH variants in this study.Previously, our study group investigated the prevalence of focal LC defects in the patients with unilateral branch retinal vein occlusion (BRVO), those with normal tension glaucoma(NTG), and the normal control group. In that study,prevalence of focal LC defects were significantly higher in the eyes with BRVO and those with NTG than that of the normal control group: the prevalence of focal LC defects was 38.9%in the BRVO group, 41.7% in the NTG group, and none in the control group. In addition, the mean peripapillary choroidal thickness was significantly thinner in the eyes with focal LC defects than those without in both the BRVO group and the NTG group. Based on these results, our study group assumes the possible pathophysiologic correlation between BRVO and NTG. Although this study lacks of the NTG group, we could infer that focal LC defects in the patients with PDS may not be significantly correlated with pathologic changes of ONH,because there was no significant difference in the prevalence of focal LC defects between the PDS group and the normal control group.

Our study had several limitations, including a relatively small study population. Moreover, due to the retrospective nature of the study, the control group was relatively heterogeneous.Further investigations with larger populations, a longitudinal design should enhance our understanding of LC disinsertion in patients with PDS.

Ophthalmologic examination was performed for each patient according to our clinic’s standard retinochoroidal evaluation procedure, as described previously. Routine ophthalmologic evaluation included slit lamp examination, intraocular pressure measurement using a non-contact tonometer, and fundus examination after dilation. The refractive error was measured for each eye using an autorefractor followed by conversion to the spherical equivalent [diopters (D)]. For the diagnosis of CSC, PCV, and pachychoroidal neovasculopathy, fluorescein angiography and indocyanine green angiography were conducted with a Heidelberg Retina Angiograph System (HRA-2; Heidelberg Engineering, Heidelberg, Germany) with a confocal scanning laser ophthalmoscope.

Spectral-domain optical coherence tomography (SD-OCT; Spectralis/Heidelberg Engineering)with EDI modality was used to examine the ONH and macula. For LC analysis, serial horizontal cross-sectional scans, approximately 30 µm apart and coering the ONH, were obtained (Figure 1A). EDI-OCT images of the ONH were reviewed by experienced glaucoma specialist (Lee NE), who was blinded to the retinal status; the presence of alterations in the LC was evaluated. Focal LC defect was defined as an anterior laminar surface irregularity violating the normal smooth curvilinear U- or W-shaped contour. To avoid falsepositives, defects needed to be >100 μm in diameter, >30 μm in depth, and present in at least one additional raster scan, as suggested by a previous study.

The mean subfoveal choroidal thickness (SFCT) was also measured using the Spectralis SD-OCT system with EDI.Choroidal thickness was defined as the perpendicular distance between the outer border of the hyperreflective line corresponding to the RPE, and the chorio-scleral interface.For macular evaluation, serial cross-sectional horizontal scans were obtained, approximately 121 μm apart in a 30°×15°macular area. Single horizontal and vertical scans across the fovea were acquired separately. To measure SFCT, at least two horizontal and vertical high-quality scans throughout the fovea were obtained from each eye. Utilizing the digital calipers in the Heidelberg Spectralis OCT software, the choroidal thickness was measured horizontally and vertically at the subfoveal region in each trans-sectional image, and the average measurement was calculated (Figure 1B). Three CharacteristicsPatients with PDS (=180)Patients without PDS (=236)independent observers (Kang HM, Lee NE, and Choi JH)blinded to the clinical data (including the ONH status of each patient) measured the choroidal thicknesses.For statistical analysis, eyes with PDS, including CSC, PCV,and pachychoroid neovasculopathy, were included in the study.In cases with bilateral PDS eyes, the right eye was analyzed.

分析工具 本研究采用CiteSpace 5.0对数据进行分析：从CNKI下载检索数据并在CiteSpace中进行数据转换，导入数据并进行参数设置，运行软件进行图谱绘制。

RESULTS

We retrospectively reviewed 180 consecutive patients with PDS and 236 patients without PDS, who met the study criteria.Among the patients with PDS, 118 (65.6%) were male and the mean age at the time of examination was 57.4±11.1y (range:34-80y). There were no significant differences in clinical characteristics between the patients with PDS and the control group, including age (=0.710) and sex (=0.248). The mean SFCT was significantly higher in the PDS group than in the control group (<0.001). A detailed comparison of the clinical characteristics between the two groups is shown in Table 1.Among the patients with PDS, the primary diagnosis was CSC in 73 (40.6%), PCV in 75 (41.7%), and pachychoroidal neovasculopathy in 32 (17.8%); all patients underwent intravitreal anti-vascular endothelial growth factor injections.

Among 180 patients with PDS, 6 (3.3%) showed focal LC defects in the absence of peripapillary retinoschisis. No patients in the control group showed focal LC defect. Diabetic retinopathy(DR) was not observed in any patient. The prevalence of focal LC defect was not significantly different between patients with and without PDS (=0.318). Among the six patients with PDS and focal LC defects, four eyes had PCV, one eye was the fellow eye of the PCV eye, and one eye showed pachychoroidal neovasculopathy. The detailed characteristics of the six patients with focal LC defects are listed in Table 2,and representative images are shown in Figures 2-6.

目前,由于一维混沌映射其产生方式简单,生成序列众多而被广泛应用于扩频通信中,现在比较常见的、统计性能较好的一维混沌映射主要有以下3种,其表达式以及初值和系统参数的取值范围如下。

DISCUSSION

If focal LC defect in the eyes with PDS but without peripapillary retinoschisis is simply one of the normal ONH variants, there would be no significant impact of focal LC defect on disease activity and treatment response in the patients with PDS. However, we cannot confirm the underlying pathogenesis of focal LC defects in patients with PDS based on the results of this cross-sectional study, where it was difficult to determine the precise time at which focal LC defects occurred in the PDS patients. If focal LC defect is one of normal ONH variants, it may be observed before disease onset. Further studies on peripapillary structures are necessary to broaden our understanding of PDS. In addition,further longitudinal studies on the association between focal LC defects and the development of peripapillary retinoschisis may provide more insight to this structural change of ONH in PDS. Thus, we suggest that future investigations examine peripapillary choroidal structures and determine ONH status in patients with PDS.

It has been suggested previously that hydrostatic pressure leads to LC disinsertion/defect in PDS. Based on this hypothesis, we assumed that LC disinsertion/defect and subsequent peripapillary retinoschisis may reflect higher hydrostatic pressure, disease activity, and further treatment response.

In the study group with PDS, CSC is characterized by choroidal congestion and choroidal hyperpermeability,which causesfocal RPE defects and serous pigment epithelial detachment. PPE has features characteristic of RPE disturbances such as CSC, but lacks clinical or imaging evidence of acute or chronic subretinal fluid. Pachychoroid neovasculopathy is a type-1 neovascularization that occurs in overlying focal areas of choroidal thickening in patients without a history of acute CSC and no evidence of chronic subretinal fluid, age-related macular degeneration, or other degenerative changes. PCV is defined as the presence of abnormal branching vascular networks with polypoidal lesions shown by indocyanine green angiography.

Unless indicated otherwise, data are presented as the mean±standard deviation (range). Baseline characteristics included age, sex, the cup/disc ratio, refractive error, and SFCT. IBM SPSS Statistics software for Windows(version 22.0; IBM Corporation, Armonk, NY, USA) was used for the statistical analyses. Student’s-test and the Kruskal-Wallis test were used for analyzing continuous variables and the Chi-square test was used for the analysis of categorical variables. Mauchly’s test of sphericity and Kolmogorov-Smirnov analyses were also applied.-values <0.05 were considered statistically significant.

In this study, we examined the prevalence of focal LC defect patients with PDS in the absence of peripapillary retinoschisis;six patients (3.3%) showed focal LC defect. Although the majority of focal LC defect occurred in active PDS-affected eyes, focal LC defect was also found in the contralateral eye of ahemorrhagic PCV. However, further comparison showed no significant difference in the prevalence of focal LC defect between patients with and without PDS.

The primary outcome measure was the prevalence of focal LC defect among patients with PDS in the absence of peripapillary retinoschisis.

This retrospective, observational study was conducted at the Catholic Kwandong University College of Medicine, International St. Mary’s Hospital. We reviewed the medical records of patients who were diagnosed with PDS and underwent ONH evaluation by enhanced depth imaging optical coherence tomography (EDI-OCT) between October 2017 and August 2019 retrospectively. Patients who underwent ophthalmologic evaluation for vitreous floaters but not presenting obvious ocular disease were included in the control group. During the study period, ONH evaluation by EDI-OCT was included in the routine ophthalmologic evaluation for testing purposes in our vitreoretinal clinic. The exclusion criteria were as follows: 1) eyes with glaucoma or history of intraocular pressure ≥22 mm Hg; 2) patients with family history of glaucoma; and 3) eyes with severe media opacity, for example caused by vitreous hemorrhage,which obscured EDI-OCT images of the retina and choroidal structures.

Although our study has several limitations, our study is the first attempt to investigate the prevalence of focal LC defects in the patients with PDS but without peripapillary retinoschisis.We could assume that the presence of focal LC defect in the patients with PDS but without peripapillary retinoschisis is accidental finding of normal ONH variants, rather than pathophysiological change associated with increased hydrostatic pressure.

In conclusion, focal LC defect was observed in patients with PDS in the absence of peripapillary retinoschisis, in both diseased eyes and disease-free contralateral eyes. However, the prevalence of LC disinsertion was not significantly different between patients with PDS and the control group.

因为以上方面考虑的是三个完全没有重叠的方面，Eggleston把它们放在一个“三维”的立体图上，如图1所示。

Supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT)(No.2018R1C1B5085620); the Korea Health Technology R& D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare,Republic of Korea (No.HI21C1251).

Kang HM designed and conducted the study. Kang HM, Lee NE, and Choi JH collected the data.Kang HM, Lee NE, Choi JH, Koh HJ, and Lee SC managed,analyzed, and interpreted the data. Kang HM, Lee NE, Choi JH, Koh HJ, and Lee SC prepared, reviewed, and approved the manuscript.

图6为类方形蜂窝夹芯壁厚在0.01～0.4 mm内变化时，改变等壁厚类方形蜂窝夹芯等效剪切模量得到的四边简支类方形蜂窝夹层结构固有频率变化曲线。从图6可见，不论是双壁厚还是等壁厚类方形蜂窝夹层结构，在不同剪切模量下，其固有频率均随着壁厚的增大，呈现先增大后减小的趋势，这与图5中情况类似。

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