Correlation between AI-measured lacquer cracks extension and development of myopic choroidal neovascularization

doi:10.21203/rs.3.rs-2011276/v1

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Correlation between AI-measured lacquer cracks extension and development of myopic choroidal neovascularization

https://doi.org/10.21203/rs.3.rs-2011276/v1

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published 01 Mar, 2023

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Objectives

To investigate the correlation between the AI-measured area of the lacquer cracks (LC) at their first detection and the occurrence of a choroidal neovascularization (CNV) during the follow up in patients affected by pathologic myopia. Secondary outcome was the detection of a correlation between the time to onset of CNV with both baseline LC area and LC area increase during follow up.

Methods

Optical coherence tomography (OCT) acquisitions of patients diagnosed with LC were retrospectively analyzed. The study population was divided in a CNV group (showing documented onset of a CNV) and a n-CNV group (no CNV development during follow-up). LC area was measured using MatLab software after application of a customized method for LC segmentation on infrared (IR) enface images.

Results

Fifty-five (55) patients with a mean follow-up of 5.1 ± 1.4 years were included. LC area at baseline was 2.82 ± 0.54 mm² and 1.57 ± 0.55 mm² in CNV (20 patients) and n-CNV group (35 patients) group respectively (p < 0.001). LC area increase was significantly higher in CNV group (p = 0.009). Time to onset of CNV was linearly correlated with both LC area at baseline (p = 0.006) and LC area increase (p < 0.001).

Conclusions

Myopic CNV development is associated with lager LC areas and higher LC area increase during time. Earlier CNV onset is inversely correlated with LC area and LC area increase.

Lacquer cracks

image processing

artificial intelligence

myopia

choroidal neovascularization

Pathological myopia is defined as the coexistence of a high myopia and anatomical characteristics predisposing to atrophic, traction, or neovascular myopic maculopathy, such as posterior staphyloma and elongation of the axial lenght.(1) Bulbar elongation is responsible not only for anomalies in posterior pole retinal adherence (determining complications such as dome shape macula, full thickness macular hole, myopic foveoschisis and posterior pole detachment) but also for choroidal and retinal thinning, that are associated to atrophic degeneration and neovascular membranes formation in pathologic myopia. Myopic choroidal neovascularization (CNV) is the second most common cause of CNV after age-related macular degeneration (AMD). It occurs in 5 to 11% of patients with pathological myopia, being responsible for a high socioeconomic impact and determining a high degree of disability in everyday life activities in these patients. Its development has been directly correlated to the relative height of posterior staphyloma and inversely correlated to choroidal thickness (CT).(2) In fact, according to the mechanical theory of myopic CNV formation, mechanical choroidal and scleral strain induced by elongation of the eyeball produces zones of fragility of the RPE-Bruch membrane complex facilitating retinal ingrowth of neovessels from the underlying choriocapillaris.(3) Lacquer cracks (LC) are linear atrophic lesions believed to be the manifestation of acute ruptures in the RPE-Bruch's membrane-choriocapillaris complex caused by the stretching effect of bulbar elongation.(4) They occur at the posterior pole in 4.2–15.7% of highly myopic eyes, especially in patients with posterior staphyloma, male sex and younger age.(5) The higher prevalence of LC both in affected and fellow eye of patients developing a myopic CNV is among the elements supporting the mechanical theory of CNV formation.(6) In a large series from Ohno-Matsui et al.(7), myopic CNV developed in around 10% of highly myopic eyes and specifically in 3.7% of eyes with diffuse chorioretinal atrophy, in 20.0% of eyes with patchy atrophy, and in 29.4% of eyes with LC. Nevertheless, the poor specificity of the association detected to the present date impairs the use of LCs as predictors of CNV development in pathologic myopia. Recent development of image processing and artificial intelligence (AI) techniques made it possible to extract unprecedented qualitative and quantitative information from imaging acquisitions, that have already shown surprising efficacy in unrevealing hidden characteristics of other retinal diseases.(8, 9) The purpose of this study was to investigate the presence and the relevance of a correlation between the AI-measured area of the LC at the moment of their first detection and the occurrence of a CNV during the follow up in patients affected by pathologic myopia. Moreover, we aimed to find a correlation between the baseline LC area and time to onset of CNV after LC first detection.

Patients affected by pathologic myopia and showing lacquer cracks in at least one eye were retrospectively selected from databases of two specialized retina centers (Department of Ophthalmology of the University Paris Est Créteil and Department of Ophthalmology of IRCSS San Raffaele Milano) among records from July 2007 to August 2022. Inclusion criteria were availability of high quality (Q > 15) OCT acquisitions documenting the first appearance of LC (acquisitions before and after their appearance) and age older than 18 years. A minimum follow up of 2 years was required for inclusion in n-CNV group. LC presence was assessed by three experienced graders (E.C., M.B. and S.F) based on the examination of high resolution (1536 x 1536 pixels) 30°x30° fovea-centered enface infrared (IR) and late phase ICGA images.(10–12) All images from both centers were acquired using Spectralis spectral domain (SD) OCT (Heidelberg Engineering, Heidelberg, Germany). LC were defined as hyperreflective linear lesions, in and around the macula, on a 30°x30° IR acquisition. LC presence was confirmed with late-phase ICGA imaging when available, and they were identified as hypocianescent linear lesions due to choroidal filling defects.(13) Exclusion criteria were diffuse choroidal atrophy at the moment of appearance of LC preventing accurate full evaluation of the LC area, concomitance of other retinal diseases and interval between follow up visits > 6 months. The development of a myopic CNV during the follow up was registered and the study population was divided in two groups: a CNV group, showing OCT documented onset of a CNV during the follow up time, and a n-CNV group, in which no CNV developed according to available records. Relevant risk factors for the development of CNV in myopic patients were registered so to consider potential confounding factors. Considered factors included best corrected visual acuity (BCVA), spherical equivalent, axial length, absolute height of posterior staphyloma, CT, central macular thickness, the presence of patchy choroidal atrophy, familiarity for myopic CNV, previous cataract surgery. (2)^,(14) Axial length was derived from optical biometry calculations performed with IOL Master 700 (Carl Zeiss Meditec AG, Jena, Germany) when available. The height of posterior staphyloma was calculated on B-scan OCT images as the perpendicular distance between RPE-Bruch junction at 3000 mm superior, nasal, temporal and inferior to the fovea and a line drawn tangential to the foveal RPE-Bruch junction. The mean of the 4 distances expressed in absolute positive value was defined as absolute posterior staphyloma height, as previously described in literature (Fig. 1).(2) CT was defined as the distance from the RPE line to the hyperrefractive line posterior to the large vessel layers of the choroid. Subfoveal CT was measured on OCT B-scan images. Mean of CT at 1500 mm from the fovea in the superior, nasal, inferior, and temporal sector was also calculated as parafoveal CT. The aim of the study was to investigate the presence and the relevance of a correlation between AI-measured baseline LC area and CNV formation in myopic maculopathy patients with LC. Secondary outcomes were the assessment of a correlation between LC area at baseline and time to CNV onset and the assessment of an association between LC area increase during follow up and time to CNV onset. For LC area calculation, IR images were first cropped using an open-source image processing software (ImageJ, NIH, Bethesda, MD)(Fig. 1A). LC segmentation was performed with MatLab software (Mathworks, Natick, MA) using a manual threshold of 185 and an adaptive threshold of 35% sensitivity (Fig. 1B). Erosion for disc shapes with radius = 2 was then performed to refine the segmentation. Validation of the segmentation from a human grader was necessary to ensure that segmented images matched the real shape and dimensions of the lacquer cracks as seen by human eye. Spurious and patch atrophy areas were excluded (Fig. 1C). Areas of the segmented regions was than calculated and converted to mm^{2 (}Fig. 1 D). The difference between LC area at baseline and LC area at final follow up acquisition was calculated and defined as D LC area (mm²). The study was conducted in accordance with the tenets of the Declaration of Helsinki and with French and Italian legislation and was approved from the Ethics Committee of the Federation France Macula 2018-27.

Statistical analysis

Statistical analysis was conducted using SPSS v.26 (IBM SPSS statistics). Normal distribution of the quantitative variables was assessed with Shapiro-Wilk test and variables were described using mean and standard deviation. Qualitative variables were described with number of cases over total and percentage. Comparison of quantitative variables was performed using C² test while qualitative variables were compared using two-tail T test for independent samples. Linear regression was performed using CNV development during follow up as a dependent variable and all quantitative variables resulting as statistically significant at univariate analysis as independent variables. Linear correlation between LC area and time to onset of CNV and between D LC area and time to onset of CNV was assessed using Spearman correlation. A p value < 0.05 was considered as statistically significant.

A total of 55 patients was included with a mean follow up of 5.1 ± 1.4 years. Twenty (20) patients with a mean age of 66 ± 8.7 years developed a CNV during the follow up (CNV group), with a mean time to onset of CNV of 10.4 ± 8.1 months and a mean follow up of 4.9 ± 1.7 years. Mean number of intravitreal injections (IVI) per person was 4.2 ± 2.6 and all 20 patients were treated with ranibizumab injections. Patients included in n-CNV group were 35 and were followed for 5.3 ± 1.1 years, which was not statistically different from follow up of CNV group (p = 0.671). No significant differences in terms of age and sex compositions were detected between the two groups (see Table 1). LC area at baseline was 2.82 ± 0.54 mm² and 1.57 ± 0.55 mm² in CNV and n-CNV group respectively (p < 0.001, B = 0.167)(see Figs. 2 and 3). LC area at baseline showed a significant linear correlation with time to onset of CNV (R = -0.87 (CI from − 0.94 to -0.69), p = 0.006, see Fig. 4). Similarly, the LC area increase during follow up (D LC area) was significantly higher in CNV group (p = 0.009, B = 0.136)(see Figs. 2 and 3) and linearly correlated with time to onset of CNV (R= -0.81 (CI from − 0.92 to -0.73)), p < 0.001) (see Fig. 4). Patchy choroidal atrophy was detected in 12/20 patients in CNV group (60.0%) and 10/35 (28.6%) patients in n-CNV group (p = 0.022, OR = 3.57). Both subfoveal CT and parafoveal CT were significantly lower in CNV group (respectively p = 0.024, B= -0.06 and p < 0.001, B=-0.02). Absolute height of posterior staphyloma was 550.1 ± 29.6 mm in CNV group and 454.8 ± 22.5 mm in n-CNV group (p = 0.001, B = 0.03). No significant differences in central macular thickness were detected between groups (p = 0.799). The linear regression model aiming to predict CNV development based on LC area, D LC area, absolute staphyloma height, subfoveal CT and parafoveal CT resulted as statistically significant (p < 0.001) and showed a high degree of correlation (R = 0.957, R² = 0.915, F = 106.045). Moreover, LC area showed a significant positive correlation with D LC area (LC area increase during follow-up) (R = 0.72) and absolute staphyloma height (R = 0.62) (Fig. 5). Similarly, D LC area showed a significant positive correlation with LC area (R = 0.72) and absolute staphyloma height (R = 0.77). Both LC area and D LC area were negatively correlated with subfoveal CT and parafoveal CT (see Fig. 5).

Table 1

Results of inferential statistic comparing the two study groups. BCVA = best corrected visual acuity; CNV = choroidal neovascularization; LC = lacquer cracks; OR = odds ratio; SE = spherical equivalent
	CNV group (20 pts)	n-CNV group (35 pts)	p	Coefficient/OR
Age (years)	66 ± 8.7	64 ± 10.2	0.438
Sex (male)	9/20 (45.0%)	18/35 (51.4%)	0.573
Follow up duration (years)	4.9 ± 1.7	5.3 ± 1.1	0.671
LC area at baseline (mm²)	2.82 ± 0.54	1.57 ± 0.55	< 0.001	0.167
D LC area (mm²)	0.93 ± 0.33	0.33 ± 0.19	0.009	0.136
BCVA at baseline (logMAR)	0.15 ± 0.05	0.13 ± 0.06	0.802
SE (D)	-10.2 ± 2.5	-9.9 ± 2.9	0.735
Axial length (mm)	27.8 ± 1.6	28.1 ± 1.4	0.790
Absolute posterior staphyloma height (mm)	550.1 ± 29.6	454.8 ± 22.5	0.001	0.03
Subfoveal choroidal thickness (mm)	54.5 ± 6.9	72.4 ± 8.4	0.024	-0.06
Parafoveal choroidal thickness (mm)	60.3 ± 10.6	76.5 ± 6.4	< 0.001	-0.02
Central macular thickness (mm)	269.8 ± 30.5	277.2 ± 32.1	0.799
Patchy choroidal atrophy	12/20 (60.0%)	10/35 (28.6%)	0.022	3.57

Myopic macular degeneration accounts for up to 7.8% of causes of severe vision loss in European countries(15) and significantly impacts public health’s costs and patients’ quality of life, particularly as concerns vision-related activity limitation.(16) Myopic CNV accounts for a major part of critical VA loss cases in pathologic myopia and refinement of predictors of its onset may prompt indications for a closer follow up in selected patients and help earlier identification of CNV. LC have been associated to higher risk of CNV in past literature, with up to 30% of LC patients developing a CNV within 3 years from identification.(7) Ikuno et al.(17) found that 94% of CNV in myopic patients developed from LC regions with all CNV being of classic type. This supports the theory of the pathogenesis of myopic CNV being linked to areas of RPE fragility predisposing intraretinal migration and ingrowth of choroidal neovassels. Nevertheless, lack of characterization of the type of LC lesions conferring the highest risk for CNV onset impaired their specificity as a prognostic factor. Some attempts have been made to correlate morphology of the LCs to the risk of CNV, with conflicting results: while in some series no differences were found between linear and stellate LCs(17), others identified a higher risk associated to crossing LCs compared to linear ones.(2) The advancements of technology made possible to overcome limitations given by shape-based classification allowing precise and automated measurements of LC area. Using this method, we identified LC area at baseline examination as being significantly associated to CNV onset on a 5 year follow up retrospective investigation. Not only patients that developed a CNV during follow up (CNV group) showed a higher LC area at baseline, but they were also characterized by a higher increase in LC area between first and last examination (D LC area), thus showing a progression of the pathological process over time. Moreover, both LC area and D LC area displayed an inverse linear correlation with time to CNV onset from baseline examination, meaning that larger and more progressing lesions are correlated to a faster development of CNV. Consistently with previous findings(2) and with the theory of LC being induced by bulbar elongation, LC area and LC progression were positively correlated with absolute staphyloma height and negatively correlated with subfoveal and parafoveal choroidal thickness. Interestingly, according to our findings, higher LC area at baseline was correlated to higher increase in LC area during the follow up. Both features might be manifestations of a more active bulbar strain process, leading to choroidal thinning, higher staphyloma height and faster CNV development. Lastly, our findings confirmed lower subfoveal and parafoveal CT, higher absolute staphyloma height and patchy choroidal atrophy to be associated to CNV development. By contrast, patients that developed CNV did not show differences in terms of axial length, SE and BCVA at baseline compared to patients who did not develop CNV within 5 years from examination. The reported findings are limited by the retrospective nature of the study, in particular as concerns assumptions on time of onset of CNV. Nevertheless, the high performances of the linear regression model based on LC area, D LC area, subfoveal CT, parafoveal CT and absolute staphyloma height revealed that these parameters are likely to provide a good prediction of myopic eyes at higher risk for CNV development. ICGA was available for 40 out of 55 patients. Past literature(11, 18) demonstrated high performances of N-IR imaging in LC detection (92.9% concordance with ICGA) and showed how hyperreflective lines on N-IR corresponded to hypocianescent lines on late-phase ICGA. Considering the high reliability in LC measurement and detection showed in background literature(5, 11, 13, 19) and the scope of our study, the availability of a higher number of cases and the higher generalizability of results obtained using IR images rather than ICGA made us choose IR as a method for LC area measurement. In fact, ICGA is not routinely performed in myopic patients, due to invasiveness of the exam and scarce availability of the dye in tertiary care centers. In agreement with current literature and as highlighted in Fig. 2, LC profile shown by ICGA images in closely similar to the one shown by IR images. Consequently, even though ICGA remains the gold standard for LC detectability, IR can provide good performance il LC area progression calculation. To the best of our knowledge, it is the first report in literature to provide measurement of LC area and LC area progression and to highlight its importance as a prognostic factor in pathologic myopia. We found that larger LC areas and higher LC area increase during time are associated to CNV onset in pathologic myopia population. Moreover, the onset is faster in patients showing large LC areas at baseline and a large LC area progression at follow-up examinations. Lastly, we included both LC area and LC area increase in a high performing for CNV risk assessment. We hope that our findings might stimulate further prospective research to confirm our hypothesis and to provide personalized screening of CNV development in myopic population.

Conflicts of interest: No conflicting of interest exists for any author

Funding: The authors did not receive support from any organization for the submitted work.

Ruiz-Medrano J, Montero JA, Flores-Moreno I, Arias L, García-Layana A, Ruiz-Moreno JM. Myopic maculopathy: Current status and proposal for a new classification and grading system (ATN). Progress in Retinal and Eye Research. 2019 Mar 1;69:80–115.
Ikuno Y, Jo Y, Hamasaki T, Tano Y. Ocular Risk Factors for Choroidal Neovascularization in Pathologic Myopia. Investigative Ophthalmology & Visual Science. 2010 Jul 1;51(7):3721–5.
Noble KG, Carr RE. Pathologic Myopia. Ophthalmology. 1982 Sep 1;89(9):1099–100.
Klein RM, Green S. The Development of Lacquer Cracks in Pathologic Myopia. American Journal of Ophthalmology. 1988 Sep 1;106(3):282–5.
Xu X, Fang Y, Uramoto K, Nagaoka N, Shinohara K, Yokoi T, et al. CLINICAL FEATURES OF LACQUER CRACKS IN EYES WITH PATHOLOGIC MYOPIA. RETINA. 2019 Jul;39(7):1265–77.
Neelam K, Cheung CMG, Ohno-Matsui K, Lai TYY, Wong TY. Choroidal neovascularization in pathological myopia. Progress in Retinal and Eye Research. 2012 Sep 1;31(5):495–525.
Ohno-Matsui K, Yoshida T, Futagami S, Yasuzumi K, Shimada N, Kojima A, et al. Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia. British Journal of Ophthalmology. 2003 May 1;87(5):570–3.
Crincoli E, Zhao Z, Querques G, Sacconi R, Carlà MM, Giannuzzi F, et al. Deep learning to distinguish Best vitelliform macular dystrophy (BVMD) from adult-onset vitelliform macular degeneration (AVMD). Sci Rep. 2022 Jul 26;12(1):12745.
Catania F, Allegrini D, Nembri A, Confalonieri F, Zollet P, Crincoli E, et al. Macular Microvascular Modifications in Progressive Lamellar Macular Holes. Diagnostics (Basel). 2021 Sep 19;11(9):1717.
Brancato R, Trabucchi G, Introini U, Avanza P, Pece A. Indocyanine Green Angiography (Icga) in Pathological Myopia. European Journal of Ophthalmology. 1996 Jan 1;6(1):39–43.
Liu CF, Liu L, Lai CC, Chou JC, Yeh LK, Chen KJ, et al. Multimodal imaging including spectral-domain optical coherence tomography and confocal near-infrared reflectance for characterization of lacquer cracks in highly myopic eyes. Eye. 2014 Dec;28(12):1437–45.
Axer -Siegel Ruth, Cotlear D, Priel E, Rosenblatt I, Snir M, Weinberger D. Indocyanine Green Angiography in High Myopia. Ophthalmic Surgery, Lasers and Imaging Retina. 2004 Mar;35(2):139–45.
Sayanagi K, Ikuno Y, Uematsu S, Nishida K. Features of the choriocapillaris in myopic maculopathy identified by optical coherence tomography angiography. British Journal of Ophthalmology. 2017 Nov 1;101(11):1524–9.
Young TL. DISSECTING THE GENETICS OF HUMAN HIGH MYOPIA: A MOLECULAR BIOLOGIC APPROACH. Trans Am Ophthalmol Soc. 2004 Dec;102:423–46.
Cedrone C, Nucci C, Scuderi G, Ricci F, Cerulli A, Culasso F. Prevalence of blindness and low vision in an Italian population: a comparison with other European studies. Eye (Lond). 2006 Jun;20(6):661–7.
Chiang PPC, Fenwick E, Cheung CMG, Lamoureux EL. Public Health Impact of Pathologic Myopia. In: Spaide RF, Ohno-Matsui K, Yannuzzi LA, editors. Pathologic Myopia [Internet]. New York, NY: Springer; 2014 [cited 2022 Aug 19]. p. 75–81. Available from: https://doi.org/10.1007/978-1-4614-8338-0_6
Ikuno Y, Sayanagi K, Soga K, Sawa M, Gomi F, Tsujikawa M, et al. LACQUER CRACK FORMATION AND CHOROIDAL NEOVASCULARIZATION IN PATHOLOGIC MYOPIA. RETINA. 2008 Sep;28(8):1124–31.
Hung KC, Chen MS, Yang CM, Wang SW, Ho TC. Multimodal imaging of linear lesions in the fundus of pathologic myopic eyes with macular lesions. Graefes Arch Clin Exp Ophthalmol. 2018 Jan 1;256(1):71–81.
Bontzos G, Xirou T, Gkiala A, Smoustopoulos G, Gkizis I, Kontou E, et al. Long-term progression of myopic maculopathy in degenerative myopia as imaged by SD-OCT and IR imaging. Clinical and Experimental Optometry. 2022 Jan 2;105(1):26–31.

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You are reading this latest preprint version

Correlation between AI-measured lacquer cracks extension and development of myopic choroidal neovascularization

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