Peripapillary Vessel Density in Relation to Optic Disc Drusen: A Multimodal Optical Coherence Tomography Study

Optic disc drusen (ODD) are acellular calcified deposits within the optic nerve head known to cause visual field defects. An emerging gold standard for the diagnosis of ODD is enhanced depth imaging optical coherence tomography (EDI-OCT). The presence of ODD affects the adjacent peripapillary vasculature, which can be visualized using OCT angiography (OCTA). This study investigates the association between peripapillary vessel density and anatomical ODD location and volume using a newly developed method of multimodal OCT.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Peripapillary Vessel Density in Relation to Optic Disc Drusen: A Multimodal Optical Coherence Tomography Study Lea Lykkebirk, MD, Anne-Sofie Wessel Lindberg, PhD, Isabelle Karlesand, MD, Mathias Heiberg, MD, Lasse Malmqvist, MD, PhD, Steffen Hamann, MD, PhD Background: Optic disc drusen (ODD) are acellular calcified deposits within the optic nerve head known to cause visual field defects. An emerging gold standard for the diagnosis of ODD is enhanced depth imaging optical coherence tomography (EDI-OCT). The presence of ODD affects the adjacent peripapillary vasculature, which can be visualized using OCT angiography (OCTA). This study investigates the association between peripapillary vessel density and anatomical ODD location and volume using a newly developed method of multimodal OCT. Methods: A case–control study with 16 patients diagnosed with ODD in the period 2008–2017 and 24 healthy controls. All patients and controls had EDI-OCT, OCTA, and demographic data collected. Using EDI-OCT and the medical imaging segmentation tool ITK-SNAP, 3-dimensional (3D) visualization of ODD in patients were created. ODD 3D visualization and corresponding OCTA scans were superimposed, making it possible to correlate ODD volume to the peripapillary vessel density in the corresponding modified Garway-Heath segments of the optic disc. Results: We found that mean peripapillary vessel density across all modified Garway-Heath segments were lower in ODD patients compared with controls with significant reduction of peripapillary vessel density in the superior segment (P = 0.03) and globally (P = 0.05). A significant inverse proportionality between ODD volume and peripapillary vessel density in the corresponding segment was seen (P = 0.002). Conclusions: We found a reduced peripapillary vessel density in regions with close anatomical proximity to ODD Department of Ophthalmology (LL, IK, MH, LM, SH), Rigshospitalet, University of Copenhagen, Glostrup, Denmark; and Department of Applied Mathematics and Computer Science (A-SWL), Technical University of Denmark, Kgs. Lyngby, Denmark. Supported by The VELUX Foundations. The authors report no conflicts of interest. Address correspondence to Lea Lykkebirk, MD, Department of Ophthalmology, Rigshospitalet, Valdemar Hansens Vej 13, DK-2600 Glostrup, Denmark; E-mail: [e-mail] Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 and inverse proportionality between ODD volume and peripapillary vessel density. Journal of Neuro-Ophthalmology 2023;43:185–190 doi: 10.1097/WNO.0000000000001667 © 2022 by North American Neuro-Ophthalmology Society O ptic disc drusen (ODD) are acellular calcified deposits that accumulate within the optic nerve head (ONH) in front of lamina cribrosa in up to 2% of the population (1,2). The condition is generally considered benign, although visual field defects are usually seen on perimetric examination (3,4). Anterior ischemic optic neuropathy (AION) and vascular occlusion, with risk of irreversible severe visual loss, are known to occur as a complication of ODD (5–7). How ODD cause nerve fiber injury and ocular vascular complications is not fully understood. ODD can sometimes be visualized on the optic disc using ophthalmoscopy, but when they are buried within the ONH, diagnosis is increasingly difficult (8). The noninvasive technology enhanced depth imaging optical coherence tomography (EDI-OCT) is considered gold standard in detecting ODD (9,10). OCT angiography (OCTA) is a noninvasive technique for imaging the microvasculature of the retina. Previous studies investigating the usage of OCTA in ODD patients have found that reduction in retinal nerve fiber layer (RNFL) thickness and visual field (VF) loss are associated with decreased peripapillary vessel density (PVD) on OCTA (11,12). Case reports describing the location of ODD to correlate with focal attenuation of the vessel signal on OCTA have been published (13). Recently, Lindberg et al (14) proposed a reproducible method using multimodal OCT to analyze the correlation between ODD detected on EDI-OCT and PVD measured on OCTA. In our study, we applied this method with the aim of finding an association between ODD and PVD. We 185 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution hypothesized that PVD was reduced in areas adjacent to ODD and that an increase in ODD volume was associated with a decrease in PVD. affect the optic nerve, such as Alzheimer disease and multiple sclerosis; 4) high myopia (worse than 26.00 diopters); 5) previous injuries to the eye; and 6) poor OCTA scan quality (signal strength index below 50). METHODS Data Acquisition Study Population We performed a retrospective hospital-based case–control study of patients with ODD and a similar-sized control group with no history of ODD. ODD patients were identified by diagnostic coding in medical records from Rigshospitalet, Denmark, between 2008 and 2017. Patients were also invited to participate from their follow-up clinic appointments. Participating ODD patients were invited to a study examination. Controls were recruited among the staff at the Department of Ophthalmology, Rigshospitalet. Written informed consent was provided by all participants. The study was approved by the Scientific Ethics Committee of the Capital Region of Denmark (H-17021284), and all procedures adhered to the Declaration of Helsinki. Inclusion Criteria Inclusion criteria for patients were 1) age $18 years; 2) diagnostic coding of ODD in the medical file at Rigshospitalet; 3) contact information was available in the medical file; and 4) address in the Capital Region of Denmark. Controls were eligible for inclusion if 1) age was $18 years. Exclusion Criteria The exclusion criteria for patients and controls were as follows: 1) intraocular pressure (IOP) . 21 mm Hg; 2) other ophthalmologic diseases than ODD affecting the optic nerve or the retina; 3) neurologic diseases that may ODD patient examination was conducted by one examiner (L.L.) and healthy controls were examined by another (I.K.). Patients’ best-corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, while BCVA of controls was obtained with Snellen chart. IOP was measured using kinetic applanation or iCal tonometry. OCTA data were acquired using swept-source OCTA (Topcon DRI OCT Triton swept-source OCT, Topcon, Japan) with a pattern size of 6 · 6 mm. Furthermore, examination of ODD patients included slit-lamp examination and ophthalmoscopy following pupillary dilation with 0.5% tropicamide and automated perimetry (Octopus; Haag-Streit Diagnostics, Koeniz, Switzerland; strategy SITA-standard, 30-2 threshold). EDI-OCT (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany) of the ONH was performed according to the ODDS Consortium ODD OCT scanning guidelines (9) with a pattern size of 15° · 10°, a total of 97 B-scans distanced 30 mm between each, averaging 30 B-scans. Data Analysis We used ITK-SNAP software to manually segment ODD seen on EDI-OCT. The multimodal method of data analysis used in this study was designed and described by Lindberg et al (14). Briefly, PVD on OCTA was analyzed in an annulus surrounding the ONH. In brief, this was done by binarizing the vessels and representing them with equal FIG. 1. Illustration of the method utilized to analyze peripapillary vessel density in relation to optic disc drusen (ODD) location and volume. A. Three-dimensional segmentation of 3 differently colored ODD using ITK-SNAP based on enhanced depth imaging optical coherence tomography (EDI-OCT) of the ONH. B. OCT-angiography of the right ONH of an ODD patient shown with a heat map annulus in the region of interest. The ONH and surrounding peripapillary retina are divided into 4 segments in a modified Garway-Heath map. The margins of the ODD segmentation are demarcated with green, which is done by superimposing EDI-OCT and associated segmentation data. ONH, optic nerve head. 186 Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic characteristics of the included ODD patients and controls Number Sex (male/female), n [%] Age (IQR) Refraction (IQR) BCVA (IQR) IOP, mmHG (SD) Visual field, MD dB (IQR) ODD Patients Controls P 16 10/6 [63/37] 55 (38) 0 (1.4) 89 (1) 13.8 (2.7) 24.8 (5.5) 24 7/17 [29/71] 35 (12) 0 (1.3) 85 (4) 14.7 (2.3) — — 0.04* 0.12† 0.11† 0.14† 0.26‡ — BCVA, best-corrected visual acuity; IOP, intraocular pressure; IQR, interquartile range; MD, mean defect; ODD, optic disc drusen. *Chi-square test. † Wilcoxon rank test. ‡ Student t-test. width using skeletonization, thereby representing large vessels in the same way as other vessels. The PVD was calculated from this and illustrated locally as a heat map based on the density. EDI-OCT and OCTA were superimposed by registering to one another, making it possible to investigate PVD in relation to ODD location. We divided the ONH and surrounding peripapillary vessels into 4 segments in a modified Garway-Heath map. The method is summarily illustrated in Figure 1. Statistics Statistical analysis was performed using R (version 4.1.2) and RStudio (“Ghost Orchid” Release). If both eyes in a patient were eligible for inclusion, we chose data from the eye having the worst mean defect on automated perimetry. Data from the right eye were used for controls. To compare BCVA in patients and controls, we converted BCVA of controls to ETDRS using the formula: 85 + 50 · log (Snellen fraction). Test for normality was done using Shapiro test and visualizing the data as histograms. We used a two-sample t test to compare normally distributed numerical data presented by mean and SD. In case of skewed distribution, the Wilcox–Mann–Whitney test was utilized, and data were presented as median and interquartile range (IQR). Categoric variables were compared using Chisquare test. We used multiple regression analysis to determine if demographic characteristics and the ONH segments in controls had a significant influence on their PVD. We then utilized these results in the multiple regression analysis when determining the trend between ODD volume and PVD in patients. Two-tailed P values of ,0.05 were considered statistically significant. RESULTS Thirty ODD patients identified by diagnostic coding met the criteria for inclusion. Two of these could not be reached. An additional 2 patients were identified in the clinic and 1 control was reclassified as a patient because ODD was found during examination. Of the 31 invited patients, 28 agreed to participate. We excluded 12 patients in total due to retinal disease (n = 2), bilateral ODD-associated AION (n = 5), incomplete examination (n = 2), low image quality (n = 1), and ODD being obscured by vessels during the segmentation phase (n = 2), ending up with 16 ODD patients being included. Thirty-three controls met the inclusion criteria and were examined. We excluded 9 of these in total due to glaucoma TABLE 2. Mean peripapillary vessel density (PVD) in different regions of the optic nerve head in ODD patients vs controls ODD Patients Temporal Superior Nasal Inferior Global ODD Volume, mm3 PVD Controls PVD P 0.05 ± 0.11 0.12 ± 0.18 0.07 ± 0.11 0.10 ± 0.13 0.41 ± 0.37 91.0 ± 24.4 71.4 ± 20.5 77.9 ± 18.4 72.5 ± 17.8 78.5 ± 17.3 103.7 ± 12.3 85.7 ± 14.9 84.5 ± 11.3 80.2 ± 16.8 88.5 ± 9.8 0.07 0.03 0.22 0.17 0.05 ODD volume data are shown as median ± interquartile range, PVD data are shown as mean ± SD. Student t-test was performed to compare the regional PVD in ODD patients vs controls. Significant P values (P , 0.05) are written in bold. ODD, optic disc drusen. Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 187 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Bar plot of the peripapillary vessel density in optic disc drusen (ODD) patients (red bars) compared with controls (blue bars). Each bar represents the mean in a segment of the optic nerve head with error bars showing the standard deviation. The pale bars represent the global peripapillary vessel density in each group. *Statistically significant differences in peripapillary vessel density between ODD patients and controls. G, global; I, inferior; N, nasal; S, superior; T, temporal. (n = 1), incomplete examination (n = 3), poor image quality (n = 4), and ODD (n = 1). The latter was subsequently reclassified as a patient. We therefore ended up including 24 controls. Demographic and clinical characteristics of the included ODD patients and controls are shown in Table 1. There were no significant differences between age, refraction, BCVA, or IOP. There was a significant overrepresentation of male participants in the patient group in comparison with the controls (P = 0.04). A comparison of PVD in patients and controls is shown together with patients’ ODD volume in the corresponding segments of the ONH in Table 2. In patients, the global mean PVD across all segments was 78.5 ± 0.18. The highest mean PVD in patients was found in the temporal segment (mean 91 ± SD 24.4) and lowest in the superior segment FIG. 3. Point plot of peripapillary vessel density (PVD) in patients in relation to the optic disc drusen (ODD) volume in the corresponding segment of the optic nerve head. The 4 ONH segments of the modified Garway-Heath map are indicated by different colors as explained. I, inferior; N, nasal; S, superior; T, temporal. 188 Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (71.4 ± 20.5). The global mean PVD in controls was 88.5 ± 9.8, and the temporal segment had the highest mean PVD (103.7 ± 12.3) while the inferior segment had the lowest (80.2 ± 16.8). The PVD was lower in patients in comparison with controls in all 4 segments, with significant reduction found globally (P = 0.05) and in the superior segment (P = 0.03), illustrated in Figure 2. We found a larger ODD volume (in cubic millimeters) in the superior segment (median 0.12 ± IQR 0.18), then the inferior (0.10 ± 0.13), nasal (0.07 ± 0.11) and the temporal (0.05 ± 0.11) segments. No significant difference in ODD volume was found between the 4 ONH segments. Using multiple linear regression analysis, we found that PVD in controls was significantly higher in the temporal segments compared with the other 3 segments (estimated 23.5 ± SD 3.9, P , 0.001) and male participants had a significantly higher PVD than female participants (estimated 7.9 ± SD 3.1, P = 0.03), although age did not have a significant impact on PVD in our controls. Biological sex and ONH segments were used in the multiple linear regression model together with ODD volume to identify the effect on PVD in patients. We found that an increase in ODD volume had a significant effect on lowering the PVD in the corresponding segment (estimated 248.8 ± SD 15.0 per mm3, P = 0.002). The temporal segment had a significantly higher PVD than other segments (13.8 ± 6.8, P = 0.05), although biological sex did not affect the PVD in patients significantly. Figure 3 shows a scatterplot of PVD in individual ODD patients as a function of ODD volume colored to indicate the 4 segments of the ONH. CONCLUSIONS In this study, we examined the microvasculature of the ONH using multimodal OCT imaging in 16 ODD eyes and 24 control eyes. We investigated the effect of ODD on PVD and found a reduced PVD in ODD patients compared with controls and an inverse proportionality between ODD volume and neighboring PVD. Male participants were overrepresented in the patient group in comparison with the control group (P = 0.04). Furthermore, we found that male participants in the control group had a significantly higher PVD than control female participants (P = 0.03), but this association was not significant in the patient group. If male sex were indeed associated with higher PVD, our study would have underestimated the difference of PVD in patients vs controls because male participants were overrepresented in the patient group. However, large OCTA studies conducted on healthy people have previously found no or the opposite association between biological sex and PVD (15). Whether the significantly different distribution of male participants and female participants in the 2 groups had an impact on our results therefore remains uncertain. The global PVD in patients was significantly reduced in comparison with controls (P = 0.05). In a recent study by Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 Yan et al (16), they concluded that peripapillary vessel density and vessel complexity potentially were the best OCTA measures to segregate ODD eyes from control eyes. Even though we found a significant difference in global PVD, we only found a significant reduction in 1 of the 4 segments of the modified Garway-Heath map. This might be due to interpatient variation of ODD location. If a patient did not have ODD in all segments, then all 4 segments were still included in the statistical analysis. The variation in ODD location did not affect the range of global ODD volume and PVD as much as that of the individual ONH segments. The superior segment where PVD was found to be significantly reduced (P = 0.03) in patients was also the segment with the largest median ODD volume. In the study by Yan et al (16), a quadrant analysis of the PVD was performed because a previous study had described ODD as more commonly located in the superior and nasal portion of the ONH (17). Although this assumption was made, they found that not only the superior and nasal segment but also the inferior segment had significantly reduced PVD in ODD eyes compared with controls. This discovery is consistent with our findings where the inferior segment showed the second-largest median of ODD volume. In both the patient group and control group, we saw that the temporal PVD was significantly greater than the other 3 ONH segments. The same was seen in the study by Yan et al (16), where a modified Garway-Heath map was also used, although they did not analyze whether the difference was statistically significant. The reason for this is probably the data analysis method in which big vessels are either removed completely or, as in this case, reduced by skeletonization. Large retinal vessels more commonly span over the superior, nasal, and inferior peripapillary retina and spare the temporal region. When large vessels are removed or reduced to thin lines by skeletonization, it leaves blank spaces, and information about the underlying microvasculature is not possible to obtain. We found the smallest median ODD volume in the temporal region and therefore chose to include the ONH regions as a factor in our multivariable statistical analysis. Otherwise, we would have overestimated the effect of the ODD volume on PVD. We found a significant inverse proportionality (P = 0.002) between ODD volume and reduction of PVD in ODD patients. ODD location and large volume have previously been shown to cause RNFL thinning and VF loss (18). Furthermore, OCTA parameters have been shown to correlate with RNFL and VF loss (11,12,16). The chronological order of the pathology behind these findings is still unknown. Whether ODD cause nerve fiber injury directly through axonal compression resulting in regression of blood vessels due to lower metabolic demand or indirectly through vascular compression and ischemia remains unanswered. A third option is that poor blood supply leads to disturbances in axonal metabolism, which is thought to be a pathophysiological mechanism of ODD themselves (19). The 189 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution pathophysiologic relation between ODD and PVD needs to be investigated further. This study has some limitations. The major limitation is the small sample size making it difficult to prove significant differences between the PVD of patients and controls, but we did still find some significant differences. The manual segmentation of ODD on EDI-OCT is a time-consuming process that constitutes a limitation for utilizing the method in daily clinic, but the method is necessary when wanting to calculate ODD volume. Furthermore, when manually segmenting ODD, the investigator must make assumptions about the delineation of ODD where vessels are obscuring underlying tissue. These assumptions make the method susceptible to low inter- and intrarater reliability. Deep learning looks promising as a tool to overcome these limitations and replace manual segmentation in the future (20). This study supports the relevance of OCTA when investigating ODD and potentially also other ONH diseases. 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Lykkebirk et al: J Neuro-Ophthalmol 2023; 43: 185-190 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.