Visual Field Progression Patterns in the Ocular Hypertension Treatment Study Correspond to Vulnerability Regions of the Disc

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Based on a structural model of superior and inferior areas of relative vulnerability at the optic disc, we hypothesized that the nasal and paracentral regions are more prone to show a reduction in sensitivity. Methods This is a posthoc analysis of the data from a randomized controlled clinical trial. Data collected from patients enrolled in the Ocular Hypertension Treatment Study (OHTS) Phases 1 and 2 were used. A pointwise analysis was applied to determine the progression patterns in the early and delayed treatment groups. Each group's progression rate and frequency were calculated for each of the 52 locations corresponding to the 24-2 VF strategy, using trend- and event-based analyses, respectively. Results For the event-based analysis, the events were most commonly found in the nasal and paracentral regions. The same regions, with some modest variation, were found to have the fastest rates of progression (ROP) measured with trend analysis. A similar pattern of progression was observed in both the early and delayed treatment groups. Conclusions Development of VF loss in ocular hypertensive eyes is consistent with the vulnerability zones previously described in glaucomatous eyes with established VF loss. This suggests that these locations need to be most carefully monitored. Health sciences/Diseases/Eye diseases/Ocular hypertension/Glaucoma Health sciences/Signs and symptoms/Eye manifestations Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Structurally, glaucomatous optic neuropathy has a characteristic loss of the retinal ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) which results in corresponding patterns of visual field (VF) loss. Hood et al. examined the location of local glaucomatous damage around the optic disc among eyes with early glaucoma (i.e., VF 24 − 2 mean deviation (MD) better than − 6dB) and identified areas of relative vulnerability to glaucomatous damage. 1 Consistent with previous histology and optical coherence tomography (OCT) measurements by others, 2 – 6 they found that damage is most likely to occur in the major RNFL bundles within the superior and inferior quadrants, particularly in the temporal half of these quadrants. Based on these findings, Hood et al. 7 developed a schematic model for early glaucomatous damage, in which these regions were referred to as the superior vulnerability zone (SVZ) and inferior vulnerability zone (IVZ), respectively (Fig. 1 a). Although the model has been consistent in multiple studies, to the best of our knowledge, this theoretical pattern of progression has not been validated in eyes that were initially healthy (based on optic-disc and VF examination) at baseline and later developed glaucomatous damage. Furthermore, it is unclear how intraocular pressure (IOP)-lowering treatment affects the rates of change corresponding to these most vulnerable regions. Ocular hypertension (OHTN) is one of the most important risk factors for developing primary open-angle glaucoma (POAG). More importantly, lowering the IOP is currently the only proven treatment method to slow or halt the rate of progression (ROP) in glaucoma. Although patients with OHTN do not have evidence of optic neuropathy nor any detectable perimetric defect using conventional methods (i.e., optic disc examination and standard automated perimetry), they are considered at higher risk for developing glaucoma. The Ocular Hypertension Treatment Study (OHTS) was a landmark clinical trial that helped better describe the natural history of OHTN and conversion to POAG while demonstrating that treatment to lower IOP could reduce the risk for conversion to POAG by 50%. 9 The OHTS data offers a unique opportunity to determine patterns of VF loss for several reasons. First, it is the most extensive randomized-control study to date on OHTN with a very long duration of follow-up. Second, the study employed repeated standard automated perimetry (SAP), considered the reference standard for assessing functional damage in glaucoma. As per the study design, all participants had to have repeated normal VF tests at the beginning of the study (defined as a Glaucoma Hemifield Test [GHT] 10 and Corrected Pattern Standard Deviation [CPSD] within normal limits 11 , 12 ), thereby allowing for identification of very early VF loss. The purpose of this study is to utilize the OHTS dataset (from Phases 1 and 2) to determine the pattern of VF loss by identifying the locations on the 24 − 2 VF grid that progress most rapidly and frequently. Methods Subjects This study included data collected in the first two phases of the OHTS study through December 30, 2008. The design of the OHTS has been described previously (www.clinicaltrials.gov, registration number NCT00000125). 1 Briefly, the study was conducted in three phases: the first phase (OHTS Phase 1) was a randomized clinical trial conducted from February 28, 1994, to June 2, 2002. Between February 1994 and October 1996, 1636 participants with OHT were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). The second phase (OHTS Phase 2) was conducted from June 3, 2002, to December 30, 2008. During this phase, both groups received treatment: the original medication group continued to receive treatment (early medication group), and hypotensive treatment was offered to the original observation group (delayed medication group). In the third phase (OHTS Phase 3), treatment was no longer determined by the study protocol and was not included in our analysis. All participants in the OHTS signed a statement of informed consent approved by the institutional review board of each participating clinic. The study adhered to the tenets of the Declaration of Helsinki and was in compliance with the Health Insurance Portability and Accountability Act. Visual field data We included 2,749,398 test points from 58,115 visual fields of 1,188 patients (2,369 eyes) that participated in the OHTS and met the following criteria: 1) a series of at least six reliable visual fields which were performed over at least six years of follow-up and 2) each eye was required to have at least two qualifying visual field tests with normal GHT, normal PSD (P < 5%), and less than 33% fixation losses, false positive results, and false negative (as per the OHTS criteria). 13 Since the early visual field testing paradigm used the 30-2 pattern and did not use the SITA algorithm, to maintain consistency the 52 locations of the 24-2 grid (54 minus 2 points for the blind spot) were retained from the 30-2 grid. A correction factor of +1.0 dB was applied to threshold sensitivities measured using the Full Threshold algorithm to permit a comparison to those measured with the SITA family of algorithms. 14 The number of VF tests and length of follow-up for the early and delayed medication groups are presented in Figure 2. Schematic model to predict the points most likely to progress on the 24-2 The vulnerability regions described by Hood et al. include the temporal half of the superior and inferior quadrants of the disc (i.e., 45 to 90 degrees and -45 to -90 degrees in figure 1a.), defined as the SVZ and IVZ, respectively. Although the SVZ and IVZ represent a relatively small (45°) region of the disc, defects in these regions can still vary in location, depth, and width, as well as homogeneity. Thus, the corresponding VF defects seen on a 24-2 VF can show a wide range of patterns. 13 Based on previous work by Janosnious et al. 8 we identified for each hemifield the points on the 24-2 that are expected to have the greatest overlap (top quartile) with the corresponding disc vulnerability zone. As depicted in figure 1b (orange circles), the points are located in the nasal and paracentral region. We hypothesize that these locations would show progression more commonly than other VF points. Identifying Vulnerability Regions on the 24-2 using the OHTS dataset Data cleaning, analysis, summarization, visualization, and manuscript preparation were performed using the R statistical programming language. 15–21 In order to identify the regions vulnerable for progression on the 24-2 VF, two independent endpoints were devised to define pointwise progressive loss using both event-based and trend-based analysis. In an event-based analysis, each observation is compared to a reference, and a binary event occurrence is determined. In this study, threshold sensitivity cutoffs were defined by the 5% limit of variability within all OHTS patients using the qualification test and test retest for each point (Figure 3). A pointwise event was defined as a single field point having three consecutive threshold sensitivity observations below the respective pointwise cut off, and the time of the event was defined as the time of the first observation in the triplet (Figure 4). As follows from this definition, one eye was permitted to have multiple pointwise events (e.g., two separate points satisfying the above criteria). Trend analysis with pointwise linear regression utilizes all eligible data and their relationship to time to determine the rate of change. For every eye, the rate of change in threshold sensitivity was determined at each of the 52 test points by extracting the slope from a linear regression model of threshold (dB) versus time. Figure 5 provides an example of this analysis for one eye. The mean slope (dB/year) was calculated and compared between the two groups for each VF point. Results Event-based analysis In the event-based analysis, at least one pointwise event occurred in 1547 (65.3%) of the 2369 eyes included in the study. The frequency of pointwise events varied across the 52 visual field points from 0.9% to 5.2% in the early medication group (median: 2.1%, IQR: 1.5-3.0%) and from 1.5% to 6.4% in the delayed medication group (median: 3.1%, IQR: 2.4-4.0%). Figure 5 shows the mean percentage of pointwise events within each field point for the delayed and early medication groups. The events were concentrated in the nasal and paracentral regions in both groups. Trend-based analysis In the trend-based analysis, the slopes of pointwise threshold sensitivity varied among individuals from -3.47 to 1.23 dB/year (median: -0.13, IQR: -0.23 to -0.05 dB/year) across the 52 visual field points. The distribution and mean pointwise slopes for each of the 52 visual field points for the early and late medication groups are shown in figure 7. In both groups, the mean pointwise slopes were steeper (i.e., more negative) in the nasal and paracentral regions, mainly in the superior hemifield. Discussion This study aimed to determine which 24-2 VF grid locations change most rapidly and frequently in eyes with OHTN. As the schematic structural model predicted, in both the delayed and early medication groups of the OHTS, the nasal and paracentral regions were found to be most vulnerable to progression, corresponding to the IVZ and SVZ of the optic disc. Our findings were consistent with both the trend and event analyses and are in agreement with previous reports on most common locations of VF defects in early glaucoma. 22 The appearance of an isolated, asymmetric scotoma in the peripheral nasal region, commonly referred to as the “nasal step,” has been described previously and is considered a common feature of early glaucomatous damage. 23–25 The presence of paracentral scotoma in the early stages of the disease has also been described. 26–28 Using conventional thresholding white-on-white perimetry with regionally enhanced spatial resolution, Schiefer et al. found a paracentral defect in over 50% of glaucoma eyes with predominantly mild to moderate field loss. 29 Heijl and Lunqvist used supralinimal threshold related screening technique to determine the most frequent locations of new defects in OHTN eyes. 30 Out of a cohort of 2907 eyes, 45 developed new defects and those occurred most frequently in the nasal and paracentral regions. However, to our knowledge, the frequency and progression rates for each of the 24-2 VF points during the transition from a normal field to a confirmed glaucomatous defect has not been reported. The pointwise analysis we applied was chosen to maximize sensitivity for progression detection. In the OHTS, progressive VF damage endpoints were defined by event-based criteria based on reproducible abnormal summary metrics (e.g., glaucoma hemifield test [GHT] result of Outside Normal Limits or a corrected pattern standard deviation [CPSD] with a p-value <5%). These criteria were mainly devised to provide high specificity and had to be confirmed by an Endpoint Committee. However, it can easily miss early focal changes and obscure progression patterns. 31 Also, the abnormalities were defined based on comparison to age-matched controls rather than an intrasubject longitudinal variability, which might have affected the observed incidence of progressive VF changes. On the one hand, participants whose VF sensitivities were closer to the lower boundaries of abnormality were more likely to develop the OHTS VF endpoint, leading to confirmed VF abnormalities by even small amounts of subsequent deterioration. On the other hand, eyes or test locations with higher VF threshold sensitivity at baseline required more significant loss or needed to be followed for longer periods of time to reach the endpoint. The novel approach used herein for pointwise detection of progression has several advantages for the detection of patterns of progression. First, the process is automated and objective, eliminating the risk of subjective interpretation and providing a reliable measure of the changes in VF over time. Second, the pointwise analysis offers an exact and detailed measurement of the VF with progression endpoints determined by the individual patient’s change in threshold sensitivity and is not subject to comparison with a normative database. This allows accurate detection of subtle progressive changes in the VF, which may not be noticeable when relying on overall averages or generalized trends subjected to the population variability. Third, the technique enabled us to summarize the progression events and trends for each point on the VF. This provided an overview of the patterns of overall changes in VF loss throughout the entire study population over time. It is important to note that this method was used here with the sole purpose of identifying patterns of VF progression. The present study did not address whether the amount of VF change detected has significant implications on vision-related quality of life, nor did it aim to compare these methods with other alternative endpoints in terms of sensitivity and specificity. As the structural model predicted, the progression was most apparent in the nasal and paracentral field points. These progression patterns were consistent in both the trend and event progression analyses. Each method we used to determine progression has its strengths and weaknesses. The event-based analysis is helpful for detecting rapid, stepwise changes in loss of threshold sensitivity. In contrast, the trend-based analysis is useful for detecting slow, sustained progression, albeit some milder acute changes could be missed. This is especially true for eyes with long stable history during follow-up in which the trend is flat over long period of time and eventually experience a sudden decline in threshold sensitivity, which may not be sufficient to change the steepness of the slope. In such cases, only substantial changes over time will significantly affect the overall trend. Despite these differences, overall, the patterns of VF threshold sensitivity loss were very similar in both approaches, further confirming our hypothesis. Limitations Although the findings of this study offer valuable insights into glaucoma progression, it is important to acknowledge some limitations. First, our results are based on progression patterns among ocular hypertensive patients, most of whom did not develop manifest glaucoma during the study period. This could have affected the average progression rates, possibly affecting the pattern of progression as well. Specifically, the fact that all subjects received treatment (either early or delayed) suggests that the natural history might differ. In addition, the OHTS findings do not necessarily reflect the progression patterns in the general population. It should also be noted that the frequency and rates of progression do not reflect the natural course of the disease as both groups received hypotensive treatment during the study period. Nevertheless, our findings are consistent with the structural model of areas of vulnerability and with typical patterns of VF loss among glaucoma patients. Second, our analysis of patterns of VF loss was bounded by the data obtained in the OHTS. Since the study did not include testing directed at the central VF (e.g., 10-2 standard automated perimetry), our ability to ascertain the patterns of loss in the macular region was limited. Specifically, the low resolution of the 24-2 in the central 10 degrees of the VF might have resulted in greater variability obscuring the progression in this region. Lastly, it would have been interesting to confirm our functional findings with changes in the RNFL and GCL over time. Unfortunately, structure-function conformation is limited by the lack of OCT scans in the OHTS. Summary Based on the structural model of the areas of vulnerability at the disc, we hypothesized that VF loss would be commonly seen in the nasal and paracentral regions among OHTN patients. The pointwise methods applied to data collected during the first two phases of the OHTS confirmed this hypothesis through two independent analyses. Our findings suggest that these locations need to be carefully monitored to facilitate early detection of progression. Abbreviations intraocular pressure, IOP; ocular hypertension treatment study, OHTS, primary open-angle glaucoma, POAG; ocular hypertension, OHT; visual field, VF; Mean deviation, MD; ganglion cell layer, GCL; retinal nerve fiber layer, RNFL; Corrected Pattern Standard Deviation, CPSD; Glaucoma Hemifield Test, GHT; Standard automated perimetry, SAP; Inferior vulnerability zone, IVZ; Superior vulnerability zone, SVZ; References Hood DC, Wang DL, Raza AS, de Moraes CG, Liebmann JM, Ritch R. The Locations of Circumpapillary Glaucomatous Defects Seen on Frequency-Domain OCT Scans. Invest Ophthalmol Vis Sci . 2013;54(12):7338. doi:10.1167/iovs.13-12680 Nouri-Mahdavi K, Hoffman D, Tannenbaum DP, Law SK, Caprioli J. Identifying early glaucoma with optical coherence tomography. Am J Ophthalmol . 2004;137(2):228-235. doi:10.1016/j.ajo.2003.09.004 Medeiros FA, Zangwill LM, Bowd C, Vessani RM, Susanna R, Weinreb RN. Evaluation of retinal nerve fiber layer, optic nerve head, and macular thickness measurements for glaucoma detection using optical coherence tomography. Am J Ophthalmol . 2005;139(1):44-55. doi:10.1016/j.ajo.2004.08.069 Kanamori A, Nakamura M, Escano MFT, Seya R, Maeda H, Negi A. Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography. Am J Ophthalmol . 2003;135(4):513-520. doi:10.1016/s0002-9394(02)02003-2 Budenz DL, Michael A, Chang RT, McSoley J, Katz J. Sensitivity and specificity of the StratusOCT for perimetric glaucoma. Ophthalmology . 2005;112(1):3-9. doi:10.1016/j.ophtha.2004.06.039 Quigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology . 1979;86(10):1803-1830. doi:10.1016/s0161-6420(79)35338-6 Hood DC. Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT). Prog Retin Eye Res . 2017;57:46-75. doi:10.1016/j.preteyeres.2016.12.002 Jansonius NM, Schiefer J, Nevalainen J, Paetzold J, Schiefer U. A mathematical model for describing the retinal nerve fiber bundle trajectories in the human eye: average course, variability, and influence of refraction, optic disc size and optic disc position. Exp Eye Res . 2012;105:70-78. doi:10.1016/j.exer.2012.10.008 Gordon MO. The Ocular Hypertension Treatment Study: Baseline Factors That Predict the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol . 2002;120(6):714. doi:10.1001/archopht.120.6.714 Asman P, Heijl A. Glaucoma Hemifield Test. Automated visual field evaluation. Arch Ophthalmol . 1992;110(6):812-819. doi:10.1001/archopht.1992.01080180084033 Gordon MO. The Ocular Hypertension Treatment Study: Design and Baseline Description of the Participants. Arch Ophthalmol . 1999;117(5):573. doi:10.1001/archopht.117.5.573 Johnson CA, Keltner JL, Cello KE, et al. Baseline visual field characteristics in the ocular hypertension treatment study. Ophthalmology . 2002;109(3):432-437. doi:10.1016/s0161-6420(01)00948-4 Keltner JL, Johnson CA, Cello KE, et al. Classification of visual field abnormalities in the ocular hypertension treatment study. Arch Ophthalmol . 2003;121(5):643-650. doi:10.1001/archopht.121.5.643 De Moraes CG, Demirel S, Gardiner SK, et al. Effect of Treatment on the Rate of Visual Field Change in the Ocular Hypertension Treatment Study Observation Group. Invest Ophthalmol Vis Sci . 2012;53(4):1704. doi:10.1167/iovs.11-8186 R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2019. Available at: https://www.R-project.org/. Wickham H, François R, Henry L, Müller K. Dplyr: A grammar of data manipulation.; 2019. Available at: https://CRAN.R-project.org/package=dplyr. Wickham H, Henry L. Tidyr: Easily tidy data with ’spread()’ and ’gather()’ functions.; 2019. Available at: https://CRAN.R-project.org/package=tidyr. Wickham H, Chang W, Henry L, et al. Ggplot2: Create elegant data visualizations using the grammar of graphics.; 2019. Available at: https://CRAN.R-project.org/package=ggplot2. Wilke CO. Cowplot: Streamlined plot theme and plot annotations for ’ggplot2’.; 2019. Available at: https://CRAN.R-project.org/package=cowplot. Xie Y. Knitr: A general-purpose package for dynamic report generation in r.; 2019. Available at: https://CRAN.R-project.org/package=knitr. Xie Y. Bookdown: Authoring books and technical documents with r markdown.; 2018. Available at: https://CRAN.R-project.org/package=bookdown. Germano RAS, Germano CS, Susanna FN, Susanna R. Patterns of Visual Field Loss in Early, Moderate, and Severe Stages of Open Angle Glaucoma. Journal of Glaucoma . 2022;31(7):609-613. doi:10.1097/IJG.0000000000001986 Werner EB, Beraskow J. Peripheral nasal field defects in glaucoma. Ophthalmology . 1979;86(10):1875-1878. doi:10.1016/s0161-6420(79)35335-0 Lau LI, Liu CJ ling, Chou JCK, Hsu WM, Liu JH. Patterns of visual field defects in chronic angle-closure glaucoma with different disease severity. Ophthalmology . 2003;110(10):1890-1894. doi:10.1016/S0161-6420(03)00666-3 Bonomi L, Marraffa M, Marchini G, Canali N. Perimetric defects after a single acute angle-closure glaucoma attack. Graefes Arch Clin Exp Ophthalmol . 1999;237(11):908-914. doi:10.1007/s004170050385 Park SC, De Moraes CG, Teng CCW, Tello C, Liebmann JM, Ritch R. Initial Parafoveal Versus Peripheral Scotomas in Glaucoma: Risk Factors and Visual Field Characteristics. Ophthalmology . 2011;118(9):1782-1789. doi:10.1016/j.ophtha.2011.02.013 Park SC, Kung Y, Su D, et al. Parafoveal Scotoma Progression in Glaucoma. Ophthalmology . 2013;120(8):1546-1550. doi:10.1016/j.ophtha.2013.01.045 De Moraes CG, Sun A, Jarukasetphon R, et al. Association of Macular Visual Field Measurements With Glaucoma Staging Systems. JAMA Ophthalmol . 2019;137(2):139-145. doi:10.1001/jamaophthalmol.2018.5398 Schiefer U, Papageorgiou E, Sample PA, et al. Spatial pattern of glaucomatous visual field loss obtained with regionally condensed stimulus arrangements. Invest Ophthalmol Vis Sci . 2010;51(11):5685-5689. doi:10.1167/iovs.09-5067 Heijl A, Lundqvist L. The frequency distribution of earliest glaucomatous visual field defects documented by automatic perimetry. Acta Ophthalmol (Copenh) . 1984;62(4):658-664. doi:10.1111/j.1755-3768.1984.tb03979.x Hood DC, La Bruna S, Tsamis E, et al. The 24-2 Visual Field Guided Progression Analysis Can Miss the Progression of Glaucomatous Damage of the Macula Seen Using OCT. Ophthalmol Glaucoma . 2022;5(6):614-627. doi:10.1016/j.ogla.2022.03.007 Additional Declarations There is conflict of interest Cite Share Download PDF Status: Published Journal Publication published 14 Feb, 2024 Read the published version in Eye → Version 1 posted Editorial decision: revise 29 Aug, 2023 Review # 1 received at journal 24 Aug, 2023 Review # 2 received at journal 28 Jul, 2023 Reviewer # 2 agreed at journal 28 Jul, 2023 Reviewer # 1 agreed at journal 27 Jul, 2023 Reviewers invited by journal 27 Jul, 2023 Editor assigned by journal 20 Jul, 2023 Submission checks completed at journal 22 Jun, 2023 First submitted to journal 21 Jun, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3094148","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":222109559,"identity":"094ba26c-b8a9-447f-a747-f758acf9225e","order_by":0,"name":"Ari Leshno","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYFACxsYDDAxAxN4A5BhYEKWlAaKF5wBIiwRx9kC0SCSA2ERo4Z99uOHAhz938vgln1/d8KNAgoG/vTsBrxaJc4kNB2e2PSuWnJ1TdrMH6DCJM2c34LfmDGPDYd6Gw4kbbuek3eABajGQyMWvRR6k5c8foJabZ9Ju/iFGiwFICwMbUMsN9mO3ibLFEKjlYG/b4cSZPTlst2UMJHgI+kXuDPvDBz+ADutnP/7s5ps/NnL87b0EvI8APAZgkljlIMD+gBTVo2AUjIJRMIIAAEVpUqBrAJIDAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8717-1659","institution":"Columbia University Irving Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ari","middleName":"","lastName":"Leshno","suffix":""},{"id":222109560,"identity":"12e60d4b-6415-45d4-90b7-582fb48cf22a","order_by":1,"name":"Nikhil Bommakanti","email":"","orcid":"","institution":"Columbia University Irving Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nikhil","middleName":"","lastName":"Bommakanti","suffix":""},{"id":222109561,"identity":"db15f61e-e9e0-4346-a1f9-fce0bda9feae","order_by":2,"name":"Carlos Gustavo De Moraes","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"Gustavo","lastName":"De Moraes","suffix":""},{"id":222109562,"identity":"6d73aba7-9b2c-492b-903d-c3fab70ee931","order_by":3,"name":"Mae Gordon","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mae","middleName":"","lastName":"Gordon","suffix":""},{"id":222109563,"identity":"8bf02663-0d01-4e1e-b273-5d0380f86e9a","order_by":4,"name":"Michael Kass","email":"","orcid":"","institution":"Washington University School of Medicine in St Louis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Kass","suffix":""},{"id":222109564,"identity":"90f08a81-20d9-479e-bfff-6712d0049645","order_by":5,"name":"George Cioffi","email":"","orcid":"","institution":"Columbia University Irving Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Cioffi","suffix":""},{"id":222109565,"identity":"fedeb10a-e1d2-42f1-a48f-2812e87a556a","order_by":6,"name":"Jeffrey Liebmann","email":"","orcid":"https://orcid.org/0000-0002-5663-0533","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"","lastName":"Liebmann","suffix":""}],"badges":[],"createdAt":"2023-06-22 01:15:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3094148/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3094148/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41433-024-02949-x","type":"published","date":"2024-02-14T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":40911347,"identity":"8ef806b7-e1a2-486b-8ae4-2a0d43906537","added_by":"auto","created_at":"2023-08-01 22:45:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1496378,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe vulnerability zones model: \u003c/strong\u003ea. The original schematic model (right eye orientation) published by Hood et al.\u003csup\u003e7 \u003c/sup\u003eshowing the location of the superior vulnerability zone (SVZ, orange) and the inferior vulnerability zone (IVZ, green) on the temporal half of the disc. b. Schematic model (right eye in field view orientation) highlighting the 24-2 visual field regions of vulnerability based on spatial correspondence to the IVZ and SVZ at the disc. The borders of the superior (red) and inferior (blue) regions supplying input to the temporal half of the disc are superimposed on retinal nerve fiber layer tracings modified from Figure 3 by Jansonius et al.,\u003csup\u003e8\u003c/sup\u003e with permission. The points on each hemifield on the 24-2 that are expected to have the greatest overlap (top quartile) with the corresponding disc vulnerability zone are marked by an orange circle.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/8a7c36bcfaf499176d9ca220.png"},{"id":40911349,"identity":"a01c6ef8-61ce-4dfc-8bde-0a4cbefd51e7","added_by":"auto","created_at":"2023-08-01 22:45:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":205343,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003enumber of fields (a) and follow-up duration (b) for the delayed and medication groups\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/ba74796de70cda9c3b7e0917.png"},{"id":40913384,"identity":"4bc427f3-8670-4a15-ae62-1bb529a5f96c","added_by":"auto","created_at":"2023-08-01 22:53:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":162661,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003edistribution of 24-2 pointwise (right eye orientation) total deviation (TD) and lowest fifth percentiles (dashed red line) from the qualifying data\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/c23355f65f452f934ed007d2.png"},{"id":40911351,"identity":"adec22ff-d63d-4b7f-a43f-80068d48e9cd","added_by":"auto","created_at":"2023-08-01 22:45:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":150385,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eexample of pointwise event-based analysis in one eye: \u003c/strong\u003ea. Example of event analysis in a single eye. The threshold sensitivity values for each field point are distributed along the time axis. The points in each location were color-coded based on the 5\u003csup\u003eth\u003c/sup\u003e percentile threshold: blue outline = above the threshold; red outline at or below the threshold. Three consecutive threshold sensitivity measures below the threshold was defined as an event (red-filled). b. Distribution of threshold sensitivity values over time for the (-21,-3) field-point. Note that although there were 2 values below the threshold after 2 year, those did not pass for an event as the following value was above the threshold.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/8f9fc75c5c3a7a1e544778ab.png"},{"id":40911350,"identity":"31f155e1-a68d-47a4-b96a-803eb13a6648","added_by":"auto","created_at":"2023-08-01 22:45:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":141836,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExample of trend analysis for one eye: \u003c/strong\u003eThe threshold sensitivity values for each field point are distributed along the time (years) axis (blue outline circles). The rate of change in threshold sensitivity was determined at each of the 52 test points by extracting the slope from a linear regression model of threshold (dB) versus time (red line).\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/0ce56b2ecf9e80012c777bc6.png"},{"id":40914533,"identity":"7f85af09-6def-440b-af8a-fe7f377700e1","added_by":"auto","created_at":"2023-08-01 23:01:45","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":655540,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe mean percentage of pointwise events in the delayed (a) and early (b) medication groups: \u003c/strong\u003eThe frequency of pointwise events varied across the 52 visual field points for the delayed (a) and early (b) medication groups. Locations with higher frequency of event are shown in darker background.\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/2b07e911ee5721ec64a6bd67.png"},{"id":40911354,"identity":"cafa1e16-209e-4d0a-8324-6407ae9ab293","added_by":"auto","created_at":"2023-08-01 22:45:45","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":300029,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003edistribution and mean threshold sensitivity rates for each point in the medication (a) and delayed medication groups (b):\u003c/strong\u003e The distribution of progression slopes within each of the 52 field-points pointwise events varied across the 52 visual field points for the delayed (a) and early (b) medication groups. Locations with higher frequency of event are shown in darker colors.\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/bcb7d8bb725b102c412a24e9.png"},{"id":51162747,"identity":"fbb5a92e-c6e9-4fa0-b192-8e92675d0d01","added_by":"auto","created_at":"2024-02-15 08:11:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2295532,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3094148/v1/1f1e32e6-4069-4965-aac6-2928efb2ac44.pdf"}],"financialInterests":"There is conflict of interest","formattedTitle":"Visual Field Progression Patterns in the Ocular Hypertension Treatment Study Correspond to Vulnerability Regions of the Disc","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStructurally, glaucomatous optic neuropathy has a characteristic loss of the retinal ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) which results in corresponding patterns of visual field (VF) loss. Hood et al. examined the location of local glaucomatous damage around the optic disc among eyes with early glaucoma (i.e., VF 24\u0026thinsp;\u0026minus;\u0026thinsp;2 mean deviation (MD) better than \u0026minus;\u0026thinsp;6dB) and identified areas of relative vulnerability to glaucomatous damage.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Consistent with previous histology and optical coherence tomography (OCT) measurements by others,\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e they found that damage is most likely to occur in the major RNFL bundles within the superior and inferior quadrants, particularly in the temporal half of these quadrants. Based on these findings, Hood et al.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e developed a schematic model for early glaucomatous damage, in which these regions were referred to as the superior vulnerability zone (SVZ) and inferior vulnerability zone (IVZ), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Although the model has been consistent in multiple studies, to the best of our knowledge, this theoretical pattern of progression has not been validated in eyes that were initially healthy (based on optic-disc and VF examination) at baseline and later developed glaucomatous damage. Furthermore, it is unclear how intraocular pressure (IOP)-lowering treatment affects the rates of change corresponding to these most vulnerable regions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOcular hypertension (OHTN) is one of the most important risk factors for developing primary open-angle glaucoma (POAG). More importantly, lowering the IOP is currently the only proven treatment method to slow or halt the rate of progression (ROP) in glaucoma. Although patients with OHTN do not have evidence of optic neuropathy nor any detectable perimetric defect using conventional methods (i.e., optic disc examination and standard automated perimetry), they are considered at higher risk for developing glaucoma. The Ocular Hypertension Treatment Study (OHTS) was a landmark clinical trial that helped better describe the natural history of OHTN and conversion to POAG while demonstrating that treatment to lower IOP could reduce the risk for conversion to POAG by 50%.\u003csup\u003e9\u003c/sup\u003e The OHTS data offers a unique opportunity to determine patterns of VF loss for several reasons. First, it is the most extensive randomized-control study to date on OHTN with a very long duration of follow-up. Second, the study employed repeated standard automated perimetry (SAP), considered the reference standard for assessing functional damage in glaucoma. As per the study design, all participants had to have repeated normal VF tests at the beginning of the study (defined as a Glaucoma Hemifield Test [GHT]\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and Corrected Pattern Standard Deviation [CPSD] within normal limits\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e), thereby allowing for identification of very early VF loss.\u003c/p\u003e \u003cp\u003eThe purpose of this study is to utilize the OHTS dataset (from Phases 1 and 2) to determine the pattern of VF loss by identifying the locations on the 24\u0026thinsp;\u0026minus;\u0026thinsp;2 VF grid that progress most rapidly and frequently.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cu\u003eSubjects\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThis study included data collected in the first two phases of the OHTS study through December 30, 2008. The design of the OHTS has been described previously (www.clinicaltrials.gov, registration number NCT00000125).\u003ca href=\"#ref-gordon_ocular_1999\"\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/a\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eBriefly, the study was conducted in three phases: the first phase (OHTS Phase 1) was a randomized clinical trial conducted from February 28, 1994, to June 2, 2002. Between February 1994 and October 1996, 1636 participants with OHT were randomized to receive either topical ocular hypotensive medication (medication group) or close observation (observation group). The second phase (OHTS Phase 2) was conducted from June 3, 2002, to December 30, 2008. During this phase, both groups received treatment: the original medication group continued to receive treatment (early medication group), and hypotensive treatment was offered to the original observation group (delayed medication group). In the third phase (OHTS Phase 3), treatment was no longer determined by the study protocol and was not included in our analysis.\u003c/p\u003e\n\u003cp\u003eAll participants in the OHTS signed a statement of informed consent approved by the institutional review board of each participating clinic. The study adhered to the tenets of the Declaration of Helsinki and was in compliance with the Health Insurance Portability and Accountability Act.\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eVisual field data\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eWe included 2,749,398 test points from 58,115 visual fields of 1,188 patients (2,369 eyes) that participated in the OHTS and met the following criteria: 1) a series of at least six reliable visual fields which were performed over at least six years of follow-up and 2) each eye was required to have at least two qualifying visual field tests with normal GHT, normal PSD (P \u0026lt; 5%), and less than 33% fixation losses, false positive results, and false negative (as per the OHTS criteria).\u003csup\u003e13\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSince the early visual field testing paradigm used the 30-2 pattern and did not use the SITA algorithm, to maintain consistency the 52 locations of the 24-2 grid (54 minus 2 points for the blind spot) were retained from the 30-2 grid. A correction factor of +1.0 dB was applied to threshold sensitivities measured using the Full Threshold algorithm to permit a comparison to those measured with the SITA family of algorithms.\u003csup\u003e14\u003c/sup\u003e The number of VF tests and length of follow-up for the early and delayed medication groups are presented in Figure 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSchematic model to predict the points most likely to progress on the 24-2\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe vulnerability regions described by Hood et al. include the temporal half of the superior and inferior quadrants of the disc (i.e., 45 to 90 degrees and -45 to -90 degrees in figure 1a.), defined as the SVZ and IVZ, respectively. Although the SVZ and IVZ represent a relatively small (45\u0026deg;) region of the disc, defects in these regions can still vary in location, depth, and width, as well as homogeneity. Thus, the corresponding VF defects seen on a 24-2 VF can show a wide range of patterns.\u003csup\u003e13\u003c/sup\u003e Based on previous work by Janosnious et al.\u003csup\u003e8\u003c/sup\u003e we identified for each hemifield the points on the 24-2 that are expected to have the greatest overlap (top quartile) with the corresponding disc vulnerability zone. As depicted in figure 1b (orange circles), the points are located in the nasal and paracentral region. We hypothesize that these locations would show progression more commonly than other VF points. \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cu\u003eIdentifying Vulnerability Regions on the 24-2 using the OHTS dataset\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eData cleaning, analysis, summarization, visualization, and manuscript preparation were performed using the R statistical programming language.\u003csup\u003e15\u0026ndash;21\u003c/sup\u003e In order to identify the regions vulnerable for progression on the 24-2 VF, two independent endpoints were devised to define pointwise progressive loss using both event-based and trend-based analysis. In an event-based analysis, each observation is compared to a reference, and a binary event occurrence is determined. In this study, threshold sensitivity cutoffs were defined by the 5% limit of variability within all OHTS patients using the qualification test and test retest for each point (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA pointwise event was defined as a single field point having three consecutive threshold sensitivity observations below the respective pointwise cut off, and the time of the event was defined as the time of the first observation in the triplet (Figure 4). As follows from this definition, one eye was permitted to have multiple pointwise events (e.g., two separate points satisfying the above criteria).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrend analysis with pointwise linear regression utilizes all eligible data and their relationship to time to determine the rate of change. For every eye, the rate of change in threshold sensitivity was determined at each of the 52 test points by extracting the slope from a linear regression model of threshold (dB) versus time. Figure 5 provides an example of this analysis for one eye. The mean slope (dB/year) was calculated and compared between the two groups for each VF point.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003e\u003cu\u003eEvent-based analysis\u003c/u\u003e\u003c/h2\u003e\n\u003cp\u003eIn the event-based analysis, at least one pointwise event occurred in 1547 (65.3%) of the 2369 eyes included in the study. The frequency of pointwise events varied\u0026nbsp;across the 52 visual field points\u0026nbsp;from\u0026nbsp;\u003cspan dir=\"RTL\"\u003e0.9%\u003c/span\u003e to 5.2% in the early medication group (median: 2.1%, IQR: 1.5-3.0%) and from 1.5% to 6.4% in the delayed medication group (median: 3.1%, IQR: 2.4-4.0%). Figure 5 shows the mean percentage of pointwise events within each field point for the delayed and early medication groups. The events were concentrated in the nasal and paracentral regions in both groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTrend-based analysis\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn the trend-based analysis, the slopes of pointwise threshold sensitivity varied among individuals from -3.47 to 1.23 dB/year (median: -0.13, IQR: -0.23 to -0.05 dB/year) across the 52 visual field points. The distribution and mean pointwise slopes for each of the 52 visual field points for the early and late medication groups are shown in figure 7. In both groups, the mean pointwise slopes were steeper (i.e., more negative) in the nasal and paracentral regions, mainly in the superior hemifield.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to determine which 24-2 VF grid locations change most rapidly and frequently in eyes with OHTN. As the schematic structural model predicted, in both the delayed and early medication groups of the OHTS, the nasal and paracentral regions were found to be most vulnerable to progression, corresponding to the IVZ and SVZ of the optic disc. Our findings were consistent with both the trend and event analyses and are in agreement with previous reports on most common locations of VF defects in early glaucoma.\u003csup\u003e22\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe appearance of an isolated, asymmetric scotoma in the peripheral nasal region, commonly referred to as the \u0026ldquo;nasal step,\u0026rdquo; has been described previously and is considered a common feature of early glaucomatous damage.\u003csup\u003e23\u0026ndash;25\u003c/sup\u003e The presence of paracentral scotoma in the early stages of the disease has also been described.\u003csup\u003e26\u0026ndash;28\u003c/sup\u003e Using conventional thresholding white-on-white perimetry with regionally enhanced spatial resolution, Schiefer et al. found a paracentral defect in over 50% of glaucoma eyes with predominantly mild to moderate field loss.\u003csup\u003e29\u003c/sup\u003e Heijl and Lunqvist used supralinimal threshold related screening technique to determine the most frequent locations of new defects in OHTN eyes.\u003csup\u003e30\u003c/sup\u003e Out of a cohort of 2907 eyes, 45 developed new defects and those occurred most frequently in the nasal and paracentral regions. However, to our knowledge, the frequency and progression rates for each of the 24-2 VF points during the transition from a normal field to a confirmed glaucomatous defect has not been reported.\u003c/p\u003e\n\u003cp\u003eThe pointwise analysis we applied was chosen to maximize sensitivity for progression detection. In the OHTS, progressive VF damage endpoints were defined by event-based criteria based on reproducible abnormal summary metrics (e.g., glaucoma hemifield test [GHT] result of Outside Normal Limits or a corrected pattern standard deviation [CPSD] with a p-value \u0026lt;5%). These criteria were mainly devised to provide high specificity and had to be confirmed by an Endpoint Committee. However, it can easily miss early focal changes and obscure progression patterns.\u003csup\u003e31\u003c/sup\u003e Also, the abnormalities were defined based on comparison to age-matched controls rather than an intrasubject longitudinal variability, which might have affected the observed incidence of progressive VF changes. On the one hand, participants whose VF sensitivities were closer to the lower boundaries of abnormality were more likely to develop the OHTS VF endpoint, leading to confirmed VF abnormalities by even small amounts of subsequent deterioration. On the other hand, eyes or test locations with higher VF threshold sensitivity at baseline required more significant loss or needed to be followed for longer periods of time to reach the endpoint.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe novel approach used herein for pointwise detection of progression has several advantages for the detection of patterns of progression. First, the process is automated and objective, eliminating the risk of subjective interpretation and providing a reliable measure of the changes in VF over time. Second, the pointwise analysis offers an exact and detailed measurement of the VF with progression endpoints determined by the individual patient\u0026rsquo;s change in threshold sensitivity and is not subject to comparison with a normative database. This allows accurate detection of subtle progressive changes in the VF, which may not be noticeable when relying on overall averages or generalized trends subjected to the population variability. Third, the technique enabled us to summarize the progression events and trends for each point on the VF. This provided an overview of the patterns of overall changes in VF loss throughout the entire study population over time. It is important to note that this method was used here with the sole purpose of identifying patterns of VF progression. The present study did not address whether the amount of VF change detected has significant implications on vision-related quality of life, nor did it aim to compare these methods with other alternative endpoints in terms of sensitivity and specificity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs the structural model predicted, the progression was most apparent in the nasal and paracentral field points. These progression patterns were consistent in both the trend and event progression analyses. Each method we used to determine progression has its strengths and weaknesses. The event-based analysis is helpful for detecting rapid, stepwise changes in loss of threshold sensitivity. In contrast, the trend-based analysis is useful for detecting slow, sustained progression, albeit some milder acute changes could be missed. This is especially true for eyes with long stable history during follow-up in which the trend is flat over long period of time and eventually experience a sudden decline in threshold sensitivity, which may not be sufficient to change the steepness of the slope. In such cases, only substantial changes over time will significantly affect the overall trend. Despite these differences, overall, the patterns of VF threshold sensitivity loss were very similar in both approaches, further confirming our hypothesis.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eLimitations\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the findings of this study offer valuable insights into glaucoma progression, it is important to acknowledge some limitations. First, our results are based on progression patterns among ocular hypertensive patients, most of whom did not develop manifest glaucoma during the study period. This could have affected the average progression rates, possibly affecting the pattern of progression as well. Specifically, the fact that all subjects received treatment (either early or delayed) suggests that the natural history might differ. In addition, the OHTS findings do not necessarily reflect the progression patterns in the general population. It should also be noted that the frequency and rates of progression do not reflect the natural course of the disease as both groups received hypotensive treatment during the study period. Nevertheless, our findings are consistent with the structural model of areas of vulnerability and with typical patterns of VF loss among glaucoma patients. Second, our analysis of patterns of VF loss was bounded by the data obtained in the OHTS. Since the study did not include testing directed at the central VF (e.g., 10-2 standard automated perimetry), our ability to ascertain the patterns of loss in the macular region was limited. Specifically, the low resolution of the 24-2 in the central 10 degrees of the VF might have resulted in greater variability obscuring the progression in this region. Lastly, it would have been interesting to confirm our functional findings with changes in the RNFL and GCL over time. Unfortunately, structure-function conformation is limited by the lack of OCT scans in the OHTS.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSummary\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eBased on the structural model of the areas of vulnerability at the disc, we hypothesized that VF loss would be commonly seen in the nasal and paracentral regions among OHTN patients. The pointwise methods applied to data collected during the first two phases of the OHTS confirmed this hypothesis through two independent analyses. Our findings suggest that these locations need to be carefully monitored to facilitate early detection of progression.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eintraocular pressure, IOP; ocular hypertension treatment study, OHTS, primary open-angle glaucoma, POAG; ocular hypertension, OHT; visual field, VF; Mean deviation, MD; ganglion cell layer, GCL; retinal nerve fiber layer, RNFL; Corrected Pattern Standard Deviation, CPSD; Glaucoma Hemifield Test, GHT; Standard automated perimetry, SAP; Inferior vulnerability zone, IVZ; Superior vulnerability zone, SVZ;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHood DC, Wang DL, Raza AS, de Moraes CG, Liebmann JM, Ritch R. The Locations of Circumpapillary Glaucomatous Defects Seen on Frequency-Domain OCT Scans. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e. 2013;54(12):7338. doi:10.1167/iovs.13-12680\u003c/li\u003e\n\u003cli\u003eNouri-Mahdavi K, Hoffman D, Tannenbaum DP, Law SK, Caprioli J. Identifying early glaucoma with optical coherence tomography. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2004;137(2):228-235. doi:10.1016/j.ajo.2003.09.004\u003c/li\u003e\n\u003cli\u003eMedeiros FA, Zangwill LM, Bowd C, Vessani RM, Susanna R, Weinreb RN. Evaluation of retinal nerve fiber layer, optic nerve head, and macular thickness measurements for glaucoma detection using optical coherence tomography. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2005;139(1):44-55. doi:10.1016/j.ajo.2004.08.069\u003c/li\u003e\n\u003cli\u003eKanamori A, Nakamura M, Escano MFT, Seya R, Maeda H, Negi A. Evaluation of the glaucomatous damage on retinal nerve fiber layer thickness measured by optical coherence tomography. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2003;135(4):513-520. doi:10.1016/s0002-9394(02)02003-2\u003c/li\u003e\n\u003cli\u003eBudenz DL, Michael A, Chang RT, McSoley J, Katz J. Sensitivity and specificity of the StratusOCT for perimetric glaucoma. \u003cem\u003eOphthalmology\u003c/em\u003e. 2005;112(1):3-9. doi:10.1016/j.ophtha.2004.06.039\u003c/li\u003e\n\u003cli\u003eQuigley HA, Green WR. The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. \u003cem\u003eOphthalmology\u003c/em\u003e. 1979;86(10):1803-1830. doi:10.1016/s0161-6420(79)35338-6\u003c/li\u003e\n\u003cli\u003eHood DC. Improving our understanding, and detection, of glaucomatous damage: An approach based upon optical coherence tomography (OCT). \u003cem\u003eProg Retin Eye Res\u003c/em\u003e. 2017;57:46-75. doi:10.1016/j.preteyeres.2016.12.002\u003c/li\u003e\n\u003cli\u003eJansonius NM, Schiefer J, Nevalainen J, Paetzold J, Schiefer U. A mathematical model for describing the retinal nerve fiber bundle trajectories in the human eye: average course, variability, and influence of refraction, optic disc size and optic disc position. \u003cem\u003eExp Eye Res\u003c/em\u003e. 2012;105:70-78. doi:10.1016/j.exer.2012.10.008\u003c/li\u003e\n\u003cli\u003eGordon MO. The Ocular Hypertension Treatment Study: Baseline Factors That Predict the Onset of Primary Open-Angle Glaucoma. \u003cem\u003eArch Ophthalmol\u003c/em\u003e. 2002;120(6):714. doi:10.1001/archopht.120.6.714\u003c/li\u003e\n\u003cli\u003eAsman P, Heijl A. Glaucoma Hemifield Test. Automated visual field evaluation. \u003cem\u003eArch Ophthalmol\u003c/em\u003e. 1992;110(6):812-819. doi:10.1001/archopht.1992.01080180084033\u003c/li\u003e\n\u003cli\u003eGordon MO. The Ocular Hypertension Treatment Study: Design and Baseline Description of the Participants. \u003cem\u003eArch Ophthalmol\u003c/em\u003e. 1999;117(5):573. doi:10.1001/archopht.117.5.573\u003c/li\u003e\n\u003cli\u003eJohnson CA, Keltner JL, Cello KE, et al. Baseline visual field characteristics in the ocular hypertension treatment study. \u003cem\u003eOphthalmology\u003c/em\u003e. 2002;109(3):432-437. doi:10.1016/s0161-6420(01)00948-4\u003c/li\u003e\n\u003cli\u003eKeltner JL, Johnson CA, Cello KE, et al. Classification of visual field abnormalities in the ocular hypertension treatment study. \u003cem\u003eArch Ophthalmol\u003c/em\u003e. 2003;121(5):643-650. doi:10.1001/archopht.121.5.643\u003c/li\u003e\n\u003cli\u003eDe Moraes CG, Demirel S, Gardiner SK, et al. Effect of Treatment on the Rate of Visual Field Change in the Ocular Hypertension Treatment Study Observation Group. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e. 2012;53(4):1704. doi:10.1167/iovs.11-8186\u003c/li\u003e\n\u003cli\u003eR Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2019. Available at: https://www.R-project.org/.\u003c/li\u003e\n\u003cli\u003eWickham H, Fran\u0026ccedil;ois R, Henry L, M\u0026uuml;ller K. Dplyr: A grammar of data manipulation.; 2019. Available at: https://CRAN.R-project.org/package=dplyr.\u003c/li\u003e\n\u003cli\u003eWickham H, Henry L. Tidyr: Easily tidy data with \u0026rsquo;spread()\u0026rsquo; and \u0026rsquo;gather()\u0026rsquo; functions.; 2019. Available at: https://CRAN.R-project.org/package=tidyr.\u003c/li\u003e\n\u003cli\u003eWickham H, Chang W, Henry L, et al. Ggplot2: Create elegant data visualizations using the grammar of graphics.; 2019. Available at: https://CRAN.R-project.org/package=ggplot2.\u003c/li\u003e\n\u003cli\u003eWilke CO. Cowplot: Streamlined plot theme and plot annotations for \u0026rsquo;ggplot2\u0026rsquo;.; 2019. Available at: https://CRAN.R-project.org/package=cowplot.\u003c/li\u003e\n\u003cli\u003eXie Y. Knitr: A general-purpose package for dynamic report generation in r.; 2019. Available at: https://CRAN.R-project.org/package=knitr.\u003c/li\u003e\n\u003cli\u003eXie Y. Bookdown: Authoring books and technical documents with r markdown.; 2018. Available at: https://CRAN.R-project.org/package=bookdown.\u003c/li\u003e\n\u003cli\u003eGermano RAS, Germano CS, Susanna FN, Susanna R. Patterns of Visual Field Loss in Early, Moderate, and Severe Stages of Open Angle Glaucoma. \u003cem\u003eJournal of Glaucoma\u003c/em\u003e. 2022;31(7):609-613. doi:10.1097/IJG.0000000000001986\u003c/li\u003e\n\u003cli\u003eWerner EB, Beraskow J. Peripheral nasal field defects in glaucoma. \u003cem\u003eOphthalmology\u003c/em\u003e. 1979;86(10):1875-1878. doi:10.1016/s0161-6420(79)35335-0\u003c/li\u003e\n\u003cli\u003eLau LI, Liu CJ ling, Chou JCK, Hsu WM, Liu JH. Patterns of visual field defects in chronic angle-closure glaucoma with different disease severity. \u003cem\u003eOphthalmology\u003c/em\u003e. 2003;110(10):1890-1894. doi:10.1016/S0161-6420(03)00666-3\u003c/li\u003e\n\u003cli\u003eBonomi L, Marraffa M, Marchini G, Canali N. Perimetric defects after a single acute angle-closure glaucoma attack. \u003cem\u003eGraefes Arch Clin Exp Ophthalmol\u003c/em\u003e. 1999;237(11):908-914. doi:10.1007/s004170050385\u003c/li\u003e\n\u003cli\u003ePark SC, De Moraes CG, Teng CCW, Tello C, Liebmann JM, Ritch R. Initial Parafoveal Versus Peripheral Scotomas in Glaucoma: Risk Factors and Visual Field Characteristics. \u003cem\u003eOphthalmology\u003c/em\u003e. 2011;118(9):1782-1789. doi:10.1016/j.ophtha.2011.02.013\u003c/li\u003e\n\u003cli\u003ePark SC, Kung Y, Su D, et al. Parafoveal Scotoma Progression in Glaucoma. \u003cem\u003eOphthalmology\u003c/em\u003e. 2013;120(8):1546-1550. doi:10.1016/j.ophtha.2013.01.045\u003c/li\u003e\n\u003cli\u003eDe Moraes CG, Sun A, Jarukasetphon R, et al. Association of Macular Visual Field Measurements With Glaucoma Staging Systems. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e. 2019;137(2):139-145. doi:10.1001/jamaophthalmol.2018.5398\u003c/li\u003e\n\u003cli\u003eSchiefer U, Papageorgiou E, Sample PA, et al. Spatial pattern of glaucomatous visual field loss obtained with regionally condensed stimulus arrangements. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e. 2010;51(11):5685-5689. doi:10.1167/iovs.09-5067\u003c/li\u003e\n\u003cli\u003eHeijl A, Lundqvist L. The frequency distribution of earliest glaucomatous visual field defects documented by automatic perimetry. \u003cem\u003eActa Ophthalmol (Copenh)\u003c/em\u003e. 1984;62(4):658-664. doi:10.1111/j.1755-3768.1984.tb03979.x\u003c/li\u003e\n\u003cli\u003eHood DC, La Bruna S, Tsamis E, et al. The 24-2 Visual Field Guided Progression Analysis Can Miss the Progression of Glaucomatous Damage of the Macula Seen Using OCT. \u003cem\u003eOphthalmol Glaucoma\u003c/em\u003e. 2022;5(6):614-627. doi:10.1016/j.ogla.2022.03.007\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3094148/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3094148/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e\n\u003cp\u003eTo determine the locations on the 24-2 visual field (VF) testing grid that are most likely to progress in patients with ocular hypertension (OHTN). Based on a structural model of superior and inferior areas of relative vulnerability at the optic disc, we hypothesized that the nasal and paracentral regions are more prone to show a reduction in sensitivity.\u003c/p\u003e\n\u003ch2\u003eMethods\u003c/h2\u003e\n\u003cp\u003eThis is a posthoc analysis of the data from a randomized controlled clinical trial.\u0026nbsp;Data collected from patients enrolled in the Ocular Hypertension Treatment Study (OHTS) Phases 1 and 2 were used. A pointwise analysis was applied to determine the progression patterns in the early and delayed treatment groups. Each group's progression rate and frequency were calculated for each of the 52 locations corresponding to the 24-2 VF strategy, using trend- and event-based analyses, respectively.\u003c/p\u003e\n\u003ch2\u003eResults\u003c/h2\u003e\n\u003cp\u003eFor the event-based analysis, the events were most commonly found in the nasal and paracentral regions. The same regions, with some modest variation, were found to have the fastest rates of progression (ROP) measured with trend analysis. A similar pattern of progression was observed in both the early and delayed treatment groups.\u003c/p\u003e\n\u003ch2\u003eConclusions\u003c/h2\u003e\n\u003cp\u003eDevelopment of VF loss in ocular hypertensive eyes is consistent with the vulnerability zones previously described in glaucomatous eyes with established VF loss. This suggests that these locations need to be most carefully monitored.\u003c/p\u003e","manuscriptTitle":"Visual Field Progression Patterns in the Ocular Hypertension Treatment Study Correspond to Vulnerability Regions of the Disc","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-01 22:45:40","doi":"10.21203/rs.3.rs-3094148/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2023-08-29T07:42:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-08-24T18:34:20+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2023-07-29T01:58:35+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-07-29T01:56:29+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2023-07-27T19:07:10+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2023-07-27T16:46:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-20T09:58:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-06-22T08:16:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2023-06-22T01:14:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3d3a54c4-52e7-49ed-8870-937bb0c78d48","owner":[],"postedDate":"August 1st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":23613571,"name":"Health sciences/Diseases/Eye diseases/Ocular hypertension/Glaucoma"},{"id":23613572,"name":"Health sciences/Signs and symptoms/Eye manifestations"}],"tags":[],"updatedAt":"2024-02-15T08:11:08+00:00","versionOfRecord":{"articleIdentity":"rs-3094148","link":"https://doi.org/10.1038/s41433-024-02949-x","journal":{"identity":"eye","isVorOnly":false,"title":"Eye"},"publishedOn":"2024-02-14 05:00:00","publishedOnDateReadable":"February 14th, 2024"},"versionCreatedAt":"2023-08-01 22:45:40","video":"","vorDoi":"10.1038/s41433-024-02949-x","vorDoiUrl":"https://doi.org/10.1038/s41433-024-02949-x","workflowStages":[]},"version":"v1","identity":"rs-3094148","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3094148","identity":"rs-3094148","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}