disc hm. 위치와 peripheral lamina cribrosa의 recent structural alteration에 관한 연구입니다. Ap.홍승우/R4 박하나

Introduction Disc hemorrhage (DH) is an important risk factor for development and progression of glaucoma. It often precedes nerve fiber layer damage, optic disc changes, or visual field defects. location of DH is highely correlated with the location of the RNFL defect or neural rim notches, and predicts the location of RNFL defect which develops later in eyes which had DH. Quigley et al. suggested that DH results from microvascular disruption which occurs in the process of backward bowing of the lamina cribrosa. Nitta et al. proposed that the degenerative changes of retinal nerve fiber layer and damage to the capillary network surrounding the border of retinal nerve fiber layer defect could produce DH.  DH results from the mechanical disruption of the capillaries secondary to stretching or degenerative change. disc hm.는 glaucoma progression의 중요한 risk factor로 NFL damage, optic disc change, visual field defect에 선행하여 나타나기도 합니다. disc hm.위치는 RNF L defect나 neural rim notch의 위치와 높은 연관성을 가져 이후 RNFL defect 가 발생할 위치를 예상할 수 있습니다. quigley 등은 disc hm.가 lamina cribrosa의 backward bowing에 따른 microvascular disruption으로 생긴다고 하였고 nitta 등은 RNFL degenerative change와 defect border 주변의 capillary network의 손상이 disc hm.를 발생시킨다고 하였는데 이는 stretch나 degenerative change에 따른 capillay의 mechanical disruption의 결과라고 제시하였습니다.

Introduction Yang et al. demonstrated the posterior migration of the LC insertion in early experimental glaucomatous monkey eyes, an observation in support of DH being derived from the microvascular disruption. In addition, other investigators suggested that the DH is derived from the hemodynamic disturbance including microinfarction in the optic disc, disorder of retinal circulation, or decrease in capillary perfusion. Increased levels of circulating endothelin-1 and matrix metalloproteinase-9, which may disturb the blood-retinal barrier, have also been suggested to be involved in the development of DH. Using EDI-OCT, several studies have demonstrated localized structural alteration of the peripheral LC, including focal LC defect and pit. An association of DH with focal LC defects has also been reported. They demonstrate that the glaucomatous optic neuropathy involves not only the loss of retinal nerve fibers and prelaminar tissue but also the damage of the underlying LC, as demonstrated in the histologic studies. yang등은 early experimental glaucomatous monkey eye에서 LC insertion의 post. migration을 증명하였고 이는 microvascular disruption으로인해 disc hm,가 발생된다는 것을 뒷받침해주었습니다. 또한 다른 연구들에서도 disc hm.는 optic disc 의 microinfarction, retinal circulation의 disorder나 capillary perfusion감소등의 hemodynamic disturbance로 부터 발생된다고 제시하였습니다. 또한 endothelin-1, matrix metalloproteinase-9의 증가또한 관여한다고 하였습니다. EDI OCT를 사용하여 몇몇 연구에서는 focal Lamina cribrosa defect와 pit등 localized structural alteration에 대해 보여주었고 disc hm.와 focal lamina cribrosa의 연관성에 대해서도 histologic study로써 이미 보고된바 있습니다.

Purpose To investigate whether disc hemorrhage (DH) is associated with the recent structural alteration of the peripheral LC as assessed by enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT). 이 연구에서는 EDI OCT를 이용하여 DISC HM이전과 이후를 비교함으로써 DISC HM.에 따른 peripheral lamina cribrosa의 recent alteration의 여부를 조사하고자 하였습니다.

Methods Based on the Lamina Cribrosa Exploration Study (LCES) and Investigating Glaucoma Progression Study (IGPS), ongoing prospective studies, in the Seoul National University Bundang Hospital Glaucoma Clinic. Study Subjects underwent a complete ophthalmic examination including visual acuity assessment, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, and dilated stereoscopic examination of the optic disc. central corneal thickness measurement, axial length measurement, stereo disc photography, SD-OCT and standard automated perimetry (Humphrey Field Analyzer II 750; 24-2 Swedish interactive thresholdalgorithm; Carl-Zeiss Meditec, Dublin, CA, USA). inclusion criteria : best corrected visual acuity of ≥ 20/40, spherical refraction of -8.0 to +3.0 diopters and cylinder correction of ≤ ±3.0 diopters. - DH group: required to have POAG, and to have at least one DH observed with photography between serial EDI SD-OCT optic disc scans. - non-DH group : required to have had regular follow-up with less than 4 months inter-visit interval, and no observable DH during the scan interval. - exclusion criteri : history of ocular surgery other than cataract extraction and glaucoma surgery and intraocular disease (e.g., diabetic retinopathy or retinal vein occlusion) or neurologic disease. 이 연구는 lamina cribrosa exploration study와 investigating glaucoma progression study에 enroll된 환자를 대상으로 시력, refraction gonioscopy goldmann applanation tonometry CCT, axial length 측정, stereo disc photography SD OCT, 24-2 standard automated perimetry를 시행하였습니다. inclusion criteria에 만족하는 환자 중 disc hm. group은 POAG를 진단받고 EDI OCT scan사이에 적어도 한번의 disc hm.가 photography상 보였던 환자를 대상으로 하였고 non disc hm. group는 disc hm.가 보이지 않았던 환자중에 4개월 이하 간격으로 regular f/u 을 했던 환자를 대상으로 하였습니다. ocular surgery를 받거나 intraocular disease, neurologic disease의 hx.가 있으면 제외하였습니다.

Methods All patients were followed up every 3 to 6 months with regular follow-up fundus photography, SD-OCT retinal nerve fiber layer thickness measurement and visual field testing being performed at 6 month to 1 year intervals. Optic disc scan using EDI SD-OCT was performed at 1-2 year intervals. Non-DH group was matched with DH group for age, visual field MD, IOP at baseline and follow-up scans, and IOP fluctuation (standard deviation of IOPs obtained during the scan interval). Optic discs are routinely examined opthalmoscopically using noncontact fundus examination lens, and a DH recorded when observed. Enhanced Depth Imaging Optical Coherence Tomography of the Optic Disc optic nerve was imaged using the EDI technique. Approximately 65 horizontal B-scan section images covering the optic disc, 30–34 μm apart, were obtained from each eye. The images are obtainable only when the quality score is higher than 15. 모든환자는 3-6개월간격으로 f/u하며 fundus photo를 시행하였으며 RNFL OCT와 VF를 6개월에서 1년마다 시행하고 EDI OCT를 1-2년마다 시행하였습니다. non disc hm. group은 disc hm. group과 age, VF MD, IOP등을 match시켰습니다. EDI OCT는 optic disc를 30-34um간격으로 대략65 horizontal section image로 얻었으며 quality score가 15이상일때만 image를 사용하였습니다.

Methods 3-D Construction of the Optic Disc Images and Generation of Radial Images 11 radial OCT images centered on the optic disc were generated to examine the temporal periphery of the LC. Each image was radially equidistant and separated by 15 degrees. direction of radial images was aligned based on the right eye orientation. The superior clock hour was 12 o’clock and the others were assigned accordingly in a clockwise manner in the right eye and counterclockwise in the left. Disc photograph of an eye having DH in the inferotemporal quadrant (arrow). (B) temporal periphery lamina cribrosa를 검사하기 위해 optic disc를 중심으로 15도 간격으로 radial한 11개의 image를 만들었습니다. (C) 는 3D image를 정면으로 보았을때 이며 이 이미지에 fundus photograph를 겹쳐 disc hm.의 위치를 결정하였습니다

Methods Defining the Recent Structural Alteration of the Lamina Cribrosa LC alteration occurred either vertically (outward deformation of the LC surface) or radially (radial disruption of the LC) at the temporal periphery near the neural canal opening. a outward deformation was defined when the difference in the depth of the visible end of anterior LC surface between the baseline (α1) and follow-up images (α2). A radial disruption was defined when a new cleft or the enlargement of the existing cleft. lamina cribrosa alteration은 outward deformation또는 radial disruption으로 나타날 수 있는데 outward deformation은 ant.lamina surface end의 baseline(α1)과 f/u image(α2)의 depth차로 결정하였고 radial disruption은 새롭게 cleft가 생기거나 이미 존재하던 cleft가 커졌을때로 정의하였습니다. depth를 결정하기 위해서 두개의 bruch’s memb. opening point를 연결하는 선으로 reference line으로 정하였고 ant. laminar surface의 endpoint에서 refence line에 평행하게 그려 그거리를 측정하였습니다. 같은 방법으로 disc hm.가 발생한 meridian에서 outward deformation과 radial disruption을 관찰할 수 있습니다.

Methods Data Analysis To calculate the test-retest variability for the depth of the visible end of anterior LC surface measurement -> intersession variability of the measurements -intraclass correlation coefficient and intersession standard deviation (SD) was calculated. A significant change was accepted with an intersession SD of 1.96 times because it corresponds to the 95% confidence interval for the true value of the measurement. To define the radial disruption, repeated measure variability was used. A significant change was accepted with a repeat measure SD of 1.96 times. Clinical charactertics and OCT measurements between the groups were compared using independent samples t-test and chi-square test for continuous variables and categorical variables, respectively. Factors influencing the recent structural alteration of the LC was assessed using logistic regression analysis. P value of less than 0.05 was considered statistically significant. ant. lamina cribrosa surface depth를 측정시 발생하는 test retest variability를 계산하기 위해 intersession variability를 측정하였는데 intersession SD은 1.96배로 95% 신뢰구간안에 있었으며 radial disruption 측정시 발생하는 repeated measure variability또한 SD 1.96배로 95%신뢰구간안에 있었습니다. 그룹간 임상특정과 OCT 측정에서 연속변수와 categori별 변수를 각각 independent samples t-test and chi-square test를 사용하여 비교하였고 recent structural alteration에 영향을 주는 factor는 logistic regression analysis를 사용하였습니다. p value는 0.05이하일때 유의하다고 하였습니다.

v Results disc hm.를 가진 60안중 poor image quality로 인해 15안이 제외되어 최종적으로 45안이 포함되었고 non disc hm. 그룹도 같은 이유로 제외된 13안을 제외하고 36안이 포함되었습니다. 두그룹간에 age, intitial & f/u scan시 iop, VF MD 등 baseline clinical characteristic사이에 유의한 차이는 보이지 않았습니다. There were no differences in the baseline clinical characteristics between the two groups including age, untreated IOP, IOPs at the initial scan and follow-up scan, IOP fluctuation during the study period, and visual field MD

In DH group, the recent LC alteration exceeding the test-retest or repeated measure variability was found in 40 eyes (88.9%). recent LC alteration was found in a total of 95 merdians. Of the 95 meridians, 15 meridians had both outward deformation and radial disruption, 48 meridans outward deformation only, 32 meridians radial disruption only. In the non-DH group, the recent LC alteration was found in 4 eyes (11.1%). - Recent LC alteration was found in a total of 7 meridians, of which 5 meridians had outward deformation only and 2 meridians had radial disruption only. DH group에서 recent LC alteration은 40안에서 나타났으며 이중 11안은 1meridian, 15안은 2meridian, 7안은 3meridian, 3안은 4meridian, 4안은 5meridian이상에서 recent alteration을 보여 총 95meridian에서 변화를 볼 수 있었으며 이중 15meridian은 outward deformation과 radial disruption 둘다 나타났으며 48meridian은 outward deformation만, 32meridian은 radial disruption만 나타났습니다. non disc hm.그룹에서는 4안에서만 recent alteration을 보였으며 총 7meridian에서 변화를 볼 수 있었습니다.

central LC depth at the meridians that showed outward deformation did not differ between the initial and follow-up examinations both in DH group (274.91 ± 76.23 vs.275.41± 77.13 μm, P = 0.721) and non-DH group (301.86 ± 76.61 vs. 301.64 ± 75.16μm, P = 0.893) In eyes with recent LC alteration, the amount of maximum outward deformation was larger in the DH group (n=33; 55.82±34.60 μm, range, 17.0 – 178.7 μm) than in the non-DH group (n=3; 20.15±4.28 μm, range, 16.9 – 25.0 μm). - The amount of maximum radial disruption was also larger in the DH group (n= 28; 69.87±46.74 μm, range, 16.2 – 173.7 μm) than in the non-DH group (n=2, 18.31±1.17 μm, range 17.5 – 19.1 μm). central lamina cribrosa depth는 disc hm. 그룹과 non disc hm.그룹에서 initial 과 f/u시 두군간의 유의한 차이를 보이지 않았습니다. recent lamina cribrosa alteration을 보이는 환자중 disc hm. 그룹이 maximum outward deformation의 정도가 더 컸으며 maximal radial disruption또한 disc hm. 그룹이 더 많았습니다.

- maximum LC alteration (outward deformation or radial disription) was observed at the same location as DH in 21 eyes, 0.5 clock-hour apart from the DH in 15 eyes, and 1 clock hour apart from the DH in 4 eyes maximum lamina cribrosa alteration위치가 disc hm. 위치와 같은 경우가 21안에서 보였습니다.

recent alteration을 보인 그룹과 보이지 않은 그룹을 비교했을때 disc hm. 의 hx recent alteration을 보인 그룹과 보이지 않은 그룹을 비교했을때 disc hm.의 hx.가 있거나 axial length가 두군간의 유의한 차이를 보였습니다. Eyes with recent LC alteration had a more frequent prevalence of DH (P<0.001) and a longer axial length (P=0.040) than eyes without LC alteration

Univariate logistic regression analysis showed a significant influence of a history of DH (Odds ratio = 64.0, P<0.001) and longer axial length (Odds ratio = 1.371, P=0.049) on the recent structural LC alteration. In the multivariate analysis, only the history of DH was statistically significant (Odds ratio = 59.186, P<0.001). recent alteration에 변화를 주는 factor들에 대해 univariate regression analysis시 disc hm. history와 axial length가 더 길때 유의한 영향을 주는것으로 나타났으며 이를 multivatiate analysis를 했을대 disc hm. hx.만이 통계적으로 유의한 값을 보였습니다.

A Representative Case disc hm.가 있는 환자의 radial b scan image를 얻어 disc hm.가 발생되기 전후의 이미지를 비교한 것으로 disc hm. 위치 부근의 temporal lamina cribrosa의 변화를 볼 수 있습니다.

Discussion ischemic microinfarction at the optic disc, blood retinal barrier dysfunction related with an increased circulating cytokines (endothelin-1 or matrix metalloproteinases-9), and mechanical rupture of small blood vessels have been proposed to explain the cause of DH in glaucoma. mechanical stress and strain can result in activation of LC astrocytes, which may initiate an immunologic cascade leading to neural and LC tissue degeneration. Because of the inhomogenous microarchitecture of the LC, the localized strain on the LC may affect its periphery in particular, and lead to alteration of the peripheral LC. However, there was no difference between the IOPs at the basal ONH scanning and at the follow-up ONH scanning which was taken after the observation of DH in eyes with recent stuructural LC alteration. 2 possibilities - First, it is possible that the eyes had undetected IOP fluctuation at the time of DH or LC alteration. - Second, the LC alteration is not principally resulted from the IOP related mechanical stress but is related with a degenerative process of LC induced by other insults.  impaired blood supply to the laminar region may be another factor that can lead to structural changes of the LC, weakening the laminar beams and making them prone to collapse even within a statistically normal range of IOP. optic disc에서 ischemic microinfarction, blood retinal barrier dysfunction, small blood vessel의 mechanical rupture등이 disc hm.의 원인으로 설명되고 있는데 mechanical stress와 strain은 astrocyte의 activation시켜 neural&lamina tissue degeneration을 유발시킨다는 mechanical 이론에서는 lamina의 inhomogenous한 구조가 localized strain시 특히 periphery에 더 영향을 주어 peripheral lamina의 alteration을 유발한다고 제시하였습니다. 그러나 이 연구에서 recent alteration을 보인 disc hm.그룹에서 basal&f/u scan시 IOP간에 유의한 차이가 없었습니다. 따라서 2가지 가능성을 생각할 수 있는데 먼저 disc hm.나 lamina alteration시 detect되지 않은 iop fluctuation의 가능성, 두번째로 lamina alteration이 iop와 연관된 mechanical stress가 주로 작용하기보다는 lamina의 degenerative process를 유발하는 다른 factor를 고려할 수 있다는 것입니다. laminar region에 impaired blood supply시 structural change, laminar beam의 약화등이 정상 range의 iop시에도 발생할 수 있어 another factor로 생각할 수 있습니다.

Discussion another scenario involving the ischemic process can be considered. It is possible that DH resulted from microvascular infarction, then caused harmful effect in the lamina cribrosa. 13 SD-OCT scans were obtained at the time of first DH after the baseline SD-OCT scan. Of these, 10 eyes showed the recent LC alteration. This finding suggests that DH may be an effect of the LC alteration rather than a cause. Several studies have demonstrated focal LC defect spacially correlated with neuroretinal rim loss, visual field defects and retinal nerve fiber layer defects in glaucomatous eyes. Park et al reported that DH was associated with focal LC defects. Our finding suggests that the structural alteration observed in the cross-sectional studies are the result of acquired change rather than congenital deformation. 또다른 원인으로 ischemic process를 고려할 수 있는데 microvascular infarction으로 부터 disc hm.가 발생가능하며 lamina cribrosa에 영향을 주게 됩니다. 그러나 이과정에서는 disc hm.시에는 lamina의 변화가 발견되지 않을 수 있습니다. disc hm.발견시 시행한 13안의 OCT중 10안에서 recent alteration을 발견할 수 있었는데 이는 disc hm.는 변화의 원인이라기 보다는 lamina alteration의 영향일 수도 있다는 것을 의미하지만 이에대해서는 prospective한 연구가 필요할 것입니다. 그동안의 몇몇 스터디에서 focal lamina defect와 neuroretinal rim loss, VF defect, RNF L defect와의 연관성에 대해 입증해 보였고 disc hm.와 focal lamina defect와의 연광성에 대해서도 보고된바 있습니다.

Discussion In the present study, axial length was significantly associated with LC alteration in the univariate analysis.  This finding is in line with previous observations where the relationship between the myopia and structural defect of the LC was demonstrated. Ohno-Matsui et al. and Takayama et al. reported that optic nerve pit or LC defects are more common in eyes with longer axlial length. increased scleral tension derived from axial elongation might impose mechanical stress on the LC and lead to LC alteration in myopic eyes. the outward deformation of the LC observed in the present study may be an epiphenomenon of backward bowing of the LC. It is possible that the peripheral LC moves toward posterior when the LC bows posteriorly.  the central LC should have been displaced of larger degree than the amount of outward deformation of the peripheral LC. However, the depth of the central LC was not different between the baseline and follow-up images in eyes showing the outward deformation in the present study.  the outward deformation of the peripheral LC is a primary event that dynamically occurs at the peripheral LC, independently of the entire LC movement. 이 연구에서는 axial length와 lamina cribrosa의 alteration사이에 significant한 연관성을 보였는데 이것은 이전에 myopia와 lamina cribrosa의 structural decfect와의 관계에 대해서 증명된것과 같은 맥락을 보입니다. axial length가 길수록 optic nerve pit이나 lamina defect가 더 흔하다고 보고된바 있는데 이는 axial elogation으로 scleral tension 증가로 인한 mechanical stress가 원인일 수 있다고 하였습니다. 또한 이 연구에서 보인 lamina cribrosa의 outward deformation이 lamina의 backward bowing에 의한 부가 현상일수 있다는 주장이 있을 수 있는데 이때는 central lamina cribrosa의 displace 정도가 peripheral outward deformation 양보다 더 커야하는데 이 연구에서는 central lamina depth에 유의한 차이를 보이지 않았기 때문에 peripheral lamia의 outward deformation은 전체 lamina movement와 관계없이 일어 날 수 있다고 제시하였습니다.

Discussion Limitations First, the sample size was small. Second, 25% of eyes with DH, and 27% of eyes without DH were excluded because of the poor visualization of the temporal periperhy. Third, only temporal LC periphery was considered for evaluation in the radial images. This was because of the poor visualization of the nasal half of the LC due to thick neuroretinal rim or overlying large retinal vessels. Fourth, non-DH group was matched with DH group for age, visual field MD and IOP parameters. Lastly, the Fo-BMO axis was not applied to determine the location of the DH. this limitation does not affect our study conclusion because the disc photograph and EDI-OCT scan was aligned within each eye. 이 연구의 한계점으로는 sample size가 작고 poor visualization으로 많은 비율이 제외가 되었다는 것, 또한 오직 temporal 쪽만 측정하였다는것, fovea-BMO axis를 적용하지 못했다는 것입니다.

conclusion recent structural alteration of the peripheral LC was associated with DH, and that the LC alteration and DH were spatially correlated. While our findings suggest that DH occurs secondary to structural LC alteration, a prospective study is required to elucidate the precise relationship between the DH and the LC alteration. 결론적으로 peripheral lamina cribrosa의 recent structure alteration은 disc hm.와 연관되어 있으며 alteration과 disc hm.위치는 일치하는 경향을 보였습니다. 또한 disc hm.는 lamina의 alteration으로 인한 microvascular damage로 인해 이차적으로 일어날 수 있다고 하였으나 이들의 관계에 대해서는 prospective한 스터디를 통해 명확히 밝혀져야 할 것입니다.

lamina cribrosa의 focal defect가 glaucomatous visual field progression에 미치는 영향에 대해 연구한 논문입니다.

Introduction Risk factors for the development and progression of glaucoma include elevated intraocular pressure (IOP), older age, lower central corneal thickness (CCT),decreased ocular perfusion pressure, disc hemorrhage, and beta-zone parapapillary atrophy, among others. LC, an array of collagen beams with intervening pores, serves as a conduit for retinal ganglion cell (RGC) axons and retinal blood vessels through the scleral canal. Normal LC had a smooth, curvilinear anterior surface with a flat or slightly upward sloping as it approaches the laminar insertion, whereas some glaucomatous eyes had localized irregularities of various shapes and sizes in the anterior LC surface. Focal LC defects at the laminar insertion area also have been identified in a histologic study of glaucomatous optic nerve head. These focal LC defects likely represent localized loss of laminar tissue and correlate spatially with ophthalmoscopic structural glaucomatous changes, such as neuroretinal rim loss and acquired pits of the optic nerve. the relationship between focal LC defects and glaucoma progression is unclear. glaucoma progression의 risk factor로는 iop 증가, 연령 증가, 낮은 CCT, Disc hm.등 다양한 요인이 있습니다. 앞선 논문과 비슷하게 normal lamina cribrosa는 smooth, curvilinear ant. surface가 flat 하거나 sl.하게 upward sloping을 가지는데 glaucomatous eye에서는 이러한 surface의 localized irregular한 변화를 보이고 focal lamina defect가 neuroretial rim loss와 acquired pit과 구조적으로 연관성을 보입니다. 그러나 focal lamina defect와 glaucoma progression사이의 연관성에 대해서는 아직 명확하지 않습니다

Purpose we assessed the association between focal LC defects and glaucomatous visual field (VF) progression and compared VF progression rates between glaucomatous eyes with and without focal LC defects. 따라서 이연구에서는 focal lamina cribrosa defect와 glaucomatous vf progression간의 관계에 대해 focal lamina defect가 있는 그룹과 없는 그룹에서 vf progression rate를 비교하여 평가하고자 하였습니다.

Methods prospectively enrolled patients with glaucoma who had undergone at least 5 VF tests of either eye using standard automated perimetry (Humphrey VF Analyzer, 24-2 Swedish Interactive Threshold Algorithm Standard strategy; Carl Zeiss Meditec, Inc, Dublin, CA). Enhanced-Depth Imaging Optical Coherence Tomography serial horizontal and vertical cross sectional scans (interval between scans, ~30 um) of the optic nerve head were obtained for both eyes of each participant using EDI OCT. excluded eyes with previous posterior segment intraocular surgery, nonglaucomatous ocular or systemic diseases known to affect optic nerve head structure or VF, or poor quality OCT images because of media opacity, irregular tear film, or inadequate patient cooperation. For the eyes with 5 or more VFs, the EDI OCT images were carefully reviewed for the presence of laminar holes and laminar disinsertions violating the smooth curvilinear U- or W-shaped cross-sectional contour. A laminar hole was defined as a localized discontinuity of the LC tissue (a punched-out or hole-like LC defect). A laminar disinsertion was defined as a posteriorly displaced laminar insertion with downward sloping at the far periphery of the LC toward the neural canal wall. The LC lesions with combined features of a laminar hole and a laminar disinsertion were classified as focal LC defects. laminar hole laminar disinsertion laminar disinsertion 적어도 5번의 VF를 시행한 glaucoma를 진단받은 환자를 대상으로 prospectively 하게 enroll하였습니다. EDI OCT를 사용하여 연속적인 horizontal & vertical cross sectional scan을 시행하였으며 이전 안내 수술을 받거나 optic n. head structure나 VF에 영향을 줄 수 있는 nonglaucomatous ocular disease나 systemic disease시 제외하엿습니다. laminar hole은 laminar tissue의 localized defect로 정의하였고 disinsertion은 downsloping을 보이며 post. 쪽으로 displace로 정의 하였습니다.

Methods Clinical Parameters At the initial visit, all participants provided a detailed medical history and underwent slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, CCT measurement using ultrasonic pachymetry , simultaneous color optic disc stereophotography, and standard automated perimetry. Typical examination intervals before EDI OCT ranged from 3 to 6 months: Slit-lamp biomicroscopy, Goldmann applanation tonometry, and optic disc examination for disc hemorrhage detection were repeated for each visit. Optic disc stereophotography and standard automated perimetry were repeated usually at 6- to 12-month intervals. Visual Field Progression Analysis Automated pointwise linear regression (PLR) analysis was performed using Progressor software. Significantly progressing VF test points were defined as those having a progression rate (slope of VF sensitivity) over time worse than -1.0 dB/year with P<0.01, which is a commonly used criterion for trend-based PLR analysis of VF progression. global VF progression rate of each eye was calculated by averaging the progression rates of all test points for the entire follow-up period. localized VF progression rate of each eye was calculated by averaging the progression rates of significantly progressing test points based on the PLR criteria described. 처음 방문시 모든 환자들은 medical history와 함께 slit lamp exam, goldmann applanation tonometry, gonioscopy, CCT, disc photo, SAP를 시행하였고 3-6개월마다 정기검사를 시행하고 6-12개월마다 DISC photo와 시야검사를 시행하였습니다. Visual field progression analysis는 automated pointwise linear regression analysis를 사용하였으며 significant하게 progressing하는 VF test point는 1년에 -1.0 데시벨이상 악화되는 progressing rate를 보일때로 정의하였으며 gloval VF progression rate는 전체 f/u 기간중에 모든 test point의 progression rate를 평균하여 계산하였으며 localized VF progression rate는 significant한 progressing test point의 progression rate를 평균하여 계산하였습니다.

v Results A total of 169 eyes of 169 patients with glaucoma (97 women) were included. Mean VF MD and age at the time of EDI OCT were -11.49±6.87 (range, -28.70 to -0.46) dB and 69±12 (range, 25-91) years, respectively. mean number of evaluated VFs was 10.3±5.3 (range, 5-36), spanning a mean of 8.1±4.0 (range, 2.1-21.8) years. interval between the last VF examination and EDI OCT was 5.2±3.4 (range, 0-12) months. There were 125 eyes with primary open-angle glaucoma, 20 eyes with exfoliative glaucoma, 11 eyes with pigmentary glaucoma, and 13 eyes with chronic angle-closure glaucoma. Sixty eyes (36%) progressed on the basis of PLR criteria (at least 2 VF test points progressing faster than 1.0 dB/year at P<0.01). Eyes with focal LC defects progressed more frequently than eyes without focal LC defects (38/81 eyes [47%] vs. 22/88 eyes [25%],P < 0.003). 총 169명의 169안을 대상으로 시행하였고 EDI OCT 시행시의 mean VF MD값은 -11.49±6.87데시벨, 나이는 69±12세였습니다. last VF exam과 EDI OCT간의 interval은 5.2±3.4개월이었으며 125안은 POAG, 20안은 exfoliative glaucoma, 11안은 pigmentary glaucoma, 13안은 CACG였습니다. VF progression은 60안에서 나타났으며 focal lamina defect가 있는 그룹이 없는 그룹보다 progression율이 높았습니다.

significantly more eyes with disc hemorrhage in the VF progression group than in the group with no VF progression (19/60 [32%] vs. 10/109 [9%] eyes; P<0.001). the mean number of VFs (13.0±6.5 vs.8.7±3.8) and follow-up period (10.0±4.2 vs. 7.1±3.5 years) were significantly greater in the progression group than in the group with no progression (P<0.001). - There was no difference in CCT, baseline VF MD, peak IOP, or SD IOP (IOP fluctuation) between the 2 groups (P>0.3). progression 그룹과 non progression 그룹을 비교하였을때 disc hm.가 VF progression group에서 유의하게 더 많았으며 VF의 mean number와 f/u period가 progression 그룹에더 유의하게 컸음을 알 수 있었습니다. CCT, baseline VF MD, peak IOP, SD IOP는 두그룹간에 유의한 차이는 없었습니다.

presence of focal LC defects, disc hemorrhage, mean follow-up IOP, number of VFs, and follow-up period were significantly associated with VF progression in the univariable analysis (odds ratios [ORs], 2.65, 4.59, 1.13, 1.19, and 1.21, respectively; P = 0.003, P<0.001, P<0.021, P<0.001, and P<0.001, respectively). - presence of focal LC defects, disc hemorrhage, mean follow-up IOP, number of VFs, and follow-up period remained significantly associated with VF progression in the multivariable analyses (ORs, 2.90, 4.66, 1.22,1.25, and 1.27, respectively; P = 0.010, P = 0.002, P = 0.002, P<0.001, and <0.001, respectively). univariable analysis와 mutivariable analysis모두에서 focal LC defect존재, disc hm. mean f/u IOP, VF number, f/u period가 VF progression과 significant한 연관성을 보였습니다.

v Results There were no differences in the baseline clinical characteristics between the two groups including age, untreated IOP, IOPs at the initial scan and follow-up scan, IOP fluctuation during the study period, and visual field MD mean global VF progression rate among all 169 eyes was -0.40±0.79 (range, -6.43 to 1.03) dB/year. Mean global progression rate was significantly faster in the focal LC defect group than in the group with no focal LC defect (-0.54±0.99 vs. -0.28±0.52 dB/year; P= 0.031). - mean localized progression rate was significantly faster in the progressing eyes with focal LC defects than in the progressing eyes with no focal LC defects (-2.85±1.85 vs. -1.75±0.56 dB/year; P = 0.009) mea global VF progression rate와 mean localized progression rate모두 focal lamina cribrosa defect가 있는 그룹에서 유의하게 진행이 더 빨랐음을 알 수 있었습니다.

Discussion Ocular Hypertension Treatment Study and the European Glaucoma Prevention Study identified older age, higher IOP, smaller CCT, greater cup-to-disc ratio, and greater pattern standard deviation as risk factors for the development of open-angle glaucoma. Early Manifest Glaucoma Trial identified factors for VF progression, which included age, IOP, CCT, VF MD, and disc hemorrhage. In the multivariable analysis of the present study, in addition to the known risk factors of mean follow-up IOP and disc hemorrhage, we found that focal LC defects were independently associated with VF progression with ORs of 2.90 and 3.73. Our result suggests that certain structural features of the LC may affect glaucoma progression, and thus its structure as evaluated by EDI OCT may serve as a useful risk assessment tool in the management of glaucoma. Our study demonstrated the association between the presence of focal LC defects and previous VF progression, but the temporal sequence between the 2 phenomena is still unclear. Focal LC defects may have led to progressive RGC and VF loss, but it is also possible that progressive RGC loss has caused focal LC defects. OHTS와 EGPS에서 OAG 발생의 risk factor에 대해 연구하였고 EMGT에서는 VF progression factor로 age, IOP, CCT, VF MD, DISC HM를 제시하였습니다. 이연구에서는 이미 알려진 risk factor 이외에 focal LC defect 또한 VF progression에 영향을 미친다고 하엿습니다. 이러한 구조적 변화는 EDI OCT를 이용하여 평가할 수 있으며 이는 glaucoma management에서 risk를 평가하는 유용한 진단 tool로써 사용할 수 있다고 하엿습니다. focal lamina defect는 retinal ganglion cell loss와 vf loss를 일으킬 수 있으나 또한 retinal ganglion cell loss로 인해 focal lamina defect가 일어날 수 있습니다. 따라서 vf progression과 focal lamina defect의 발생의 관련성에 대해서는 prospective한 study가 필요합니다.

Discussion APON has been associated with an increased risk of progressive optic disc damage and VF loss in glaucoma. Ugurlu et al demonstrated VF progression in 56%(14/25) of patients with open-angle glaucoma with APON and in 25% (6/24) of age-, IOP-, and glaucoma severitye matched patients without APON during a 4- to 12-year follow-up period. in our study, significant progression was detected in 47% of the eyes with focal LC defects and in 25% of the eyes with no focal LC defects. Our results are consistent with this previous article because an APON is a clinical manifestation of laminar holes and disinsertions, as evidenced in our previous article. Reasons for the increased risk and faster rate of VF progression in the eyes with focal LC defects compared with those in the eyes without are unclear. laminar tissue is lost or damaged, RGC axons may lose their structural and functional support. This may lead to RGC axon compression, extension, or shearing or impairment in nutrient delivery. once a localized area of the LC is damaged and deformed, that area with the focal LC defect and its adjacent areas may become more vulnerable to glaucomatous damage and enter a vicious cycle, leading to progressive RGC and VF loss. APON은 progressive optic disc damage와 VF loss를 증가시키는 risk와 연관되어 있고 한 연구에서는 APON을 보인 그룹에서 VF progression의 비율이 더 높았다는 보고가 있습니다. 이 연구에서는 focal lamina defect를 보인 군에서 47%가 significant한 progression을 보였는데 이는 laminar hole과 disinsertion의 clinical한 형태가 APON 이라는 이저자들의 이전 논문의 결과와 일치한다고 하였습니다. focal defect가 있는 그룹에서 vf progression의 risk 증가와 더 빠른 진행율을 보인 이유는 아직 명확하지 않은데 lamina tissue가 damage를 받으면 ganglion cell axon의 구조적 기능적 support를 잃게 되고 axon의 compression, extension 등이 일어나며 이러한 focal defect 부위는 glaucomatous damage에 더 vulnerable하고 progressive한 retinal cell ganglion과 vf loss를 유발하게 된다고 가정하였습니다.

conclusion focal LC defects were strongly associated with past glaucomatous VF progression, and the eyes with focal LC defects tended to progress faster than the eyes without them. This suggests that RGC function is tied to the LC and is consistent with the hypothesis that the LC is the principal site of glaucoma injury. Focal LC defects may be an independent risk factor for glaucomatous VF progression. focal lamina cribrosa defect는 VF progression과 강한 연관성을 가지며 더 fast한 progression을 보였습니다. 이것은 retinal ganglion cell function이 lamina와 연관이 있으며 lamina cribrosa가 glaucoma injury의 주요한 site라는 가정과 일치합니다. 또한 focal lamina cribrosa defect는 VF progression에 independent한 risk factor로 작용한다고 하였습니다.