Effect of Intraocular Pressure Lowering Treatment on Peripapillary and Macular Vessel Density on Normotensive Eyes with Optic Disc Drusen: A Randomized Controlled Trial

ABSTRACT

To evaluate the effect of intraocular pressure (IOP) reduction on peripapillary and macular vessel density parameters from optical coherence tomography angiography (OCT-A) in normotensive eyes with optic disc drusen (ODD). Randomized controlled trial, with 6 months of follow-up, including normotensive eyes with ODD divided into two groups: control group (lubricating eye drop) and case group (latanoprost 50mcg/ml). We used OCT-A to evaluate peripapillary and macular vessel density parameters. Data were collected at baseline and at 1, 3, and 6 months following the use of eye drops. This study included a total of 32 eyes (16 cases and 16 controls) from 19 patients. After 6 months, the group using latanoprost IOP reduced IOP to 10.8 ± 0.64 versus 13.5 ± 0.54 mmHg in the control group (p < 0.001). We observed significant changes in OCT-A vessel density peripapillary parameters. The total radial peripapillary capillary (RPC) density (%) at month 6, in the eyes using latanoprost was 55.1 ± 1.05% and control was 57.9 ± 0.88%, p = 0.033. However, no changes were observed in macular vessel density parameters as well as retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness between groups after 6 months of using latanoprost. No sight-threatening events were observed during follow-up in either group. Until now there is no evidence that just lowering IOP can benefit normotensive patients with ODD. In fact, we observed a significant decrease in RPC vessel density after 6 months of IOP reduction using latanoprost, compared to the control group.

Introduction

Optic disc drusen (ODD) are acellular deposits of calcium, amino and nucleic acids, and mucopolysaccharides.¹ They are located anterior to the lamina cribrosa in the optic nerve head of 0.3–2.4% of the population.² ODD can be buried, more prevalent in children and can mimic papilledema, or they can be superficial and become exposed with aging. Most cases are bilateral. Studies suggest that ODD arise as part of an irregular dominant inheritance pattern with incomplete penetrance.¹ Although they are frequently asymptomatic, ODD can be associated with visual field defects in 24–87% of cases, and eyes with ODD are more prone to develop vascular complications.^3,4

Nowadays, the gold standard exam for diagnosis and follow-up of ODD is optical coherence tomography (OCT) using Enhanced Depth Image (EDI) or Swept Source (SS) technology, which can provide images from deeper layers, with better image sharpness.⁵ Studies have used OCT angiography (OCT-A) to analyze the microvasculature of the optic nerve head and macular region with adequate correlation with functional parameters, such as visual field and structural measurements from retinal layers thickness.⁶ The benefit of OCT-A is not requiring intravenous contrast, as traditional fluorescein angiography, to assess retinal circulation.⁷ Patients with ODD are at risk of nerve fiber loss due to abnormal retinal circulation from congenital retinal vascular anomalies as well as decreased blood flow velocity through optic nerve arterioles, which may lead to progressive visual field loss.^8,9

Until now there is no scientific valid treatment for eyes with ODD. It has been proposed that lowering intraocular pressure (IOP) may be a neuroprotective treatment, like reducing the risk of progression in optic nerve damage in patients with ocular hypertension.¹⁰ However, there is still controversy regarding the use of hypotensive eye drops in eyes with ODD.¹¹ The purpose of the study is to evaluate the effect of IOP reduction in the ocular vascular flow measured with OCT-A in eyes with ODD.

Methods

This was a prospective randomized clinical trial study. We recruited participants from the Glaucoma Clinic at the Hospital Oftalmológico de Brasília. The Institutional Review Board at the Hospital Oftalmológico de Brasília (CAAE 48360621.1.0000.5667) approved the methods, and we obtained written informed consent from all participants. We also registered the study in the Brazilian Registry of Clinical Trials (registration 5hjbmtx). All study methods complied with the Declaration of Helsinki guidelines for human subject research. This is a longitudinal randomized clinical trial, with 6 months follow-up, which evaluated the effect of IOP reduction, with hypotensive eye drops, on the peripapillary and macular vessel density in eyes with ODD using measurements from OCT-A.

The study protocol included: a questionnaire (age, race, comorbidities, weight in kilograms, height in meters, ocular and systemic medications, discriminating the use of antihypertensive drugs and dosage; IOP measurement with a Goldman applanation tonometer (a mean between the 3 last measurements prior to the initiation of the eyedrop); biomicroscopy; gonioscopy; retinography; standard automated perimetry (SAP) with 24-2 strategy (Humphrey Field Analyzer II, model 750i, Carl Zeiss Meditec, Inc, Dublin, CA) to evaluate mean deviation (MD); Spectral Domain OCT (SD-OCT) (Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany) was used to evaluate retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) measurements. We also used OCT-A (AngioVue Avantis, Optovue, Fremont, USA) to evaluate vessel density from peripapillary, macular regions and to measure the disc area. The AngioVue characterizes vascular information at various user-defined retinal layers as a vessel density map and quantitatively as vessel density (%), which is the proportion of vessel area over the total area measured.¹² For optic nerve head cube scans, we used a 4.5 × 4.5 mm field of view (evaluating both small and all vessels) and for macular cube scans we used a 6.0 × 6.0 mm field of view. Mean arterial blood pressure was evaluated on the right-upper arm with automated device (G-Tech, Beijing Choice Electronic Technology, China).

Inclusion and exclusion criteria

The criteria used to include patients in the study were: normotensive (IOP < 21 mmHg) patients with ODD without a history of treatment with hypotensive eye drops; patients over 18 years of age; absence of macular diseases; absence of glaucoma and retinal vascular diseases; axial length less than 25 mm; open angle on gonioscopic examination. For ODD diagnosis, we used Enhanced Depth Imaging OCT (EDI-OCT) with standard protocol, previously described by Hamann and Costello (Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany).^5,13 Example of a patient is shown in Figure 1.

Figure 1.

Example of patient with optic disc drusen using Enhanced Depth Imaging Optical Coherence Tomography (EDI-OCT) (Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany).

Randomization

Block randomization was generated with a random number generator (https://www.randomizer.org/) with a block size of 30. Eyes from patients with ODD were randomized (block randomization) into two groups: control group (using lubricating eye drops) and case group (using latanoprost 50mcg/ml eye drop, once daily). In cases in which the patient had bilateral ODD, randomization was performed by eye. The periodicity of evaluation of these patients after the beginning of the use of eye drops was 1, 3, and 6 months. At each visit, the patients underwent: IOP measurement, biomicroscopy, fundoscopy, SD-OCT of macular and optic nerve (average RNFL, average GCC), OCT-A of peripapillary and macular vessels (RPC density of small and RPC density of all vessels, macular vessel density in the four quadrants).

Outcome measures

The primary outcome of the study was to compare change in IOP, RPC vessel density (small and all vessels), macular vessel density and average RNFL and GCC parameters between the 2 groups at the end of 6 months. Secondary outcomes were to evaluate the occurrence of vascular events, such as: venous and artery occlusions and non-arteritic anterior ischemic optic neuropathies.

Statistical analysis and sample size calculation

We compared OCT-A peripapillary vascular density between the different periods (before the IOP reduction, 1, 3, and 6 months after the IOP reduction) using generalized estimating equations (GEE) models to account for the dependence between eyes from the same patient.¹⁴ Based on previous studies, sample calculation (G-POWER 3.1 software) demonstrated that at least 15 eyes in each group were needed to identify a 5% difference in mean peripapillary vascular density before and after IOP reduction, considering a power of 80% and alpha error of 5%, and already considering an estimated dropout rate of 10% during follow-up.¹⁵ Demographic and clinical data of the patients were analyzed. Summary statistics (means, standard deviations, and 95% confidence intervals) were presented for continuous variables and frequencies, and percentages for categorical variables. Data were analyzed using STATA version 15.1 (StataCorp LP, College Station, TX). The type I error (alpha level) was set at 0.05.

Results

This study included a total of 32 eyes (16 cases and 16 controls) from 19 patients. 13 patients had bilateral ODD (26 eyes) and 6 patients had unilateral ODD (6 eyes). Data regarding age, body mass index, mean arterial blood pressure, values of SAP MD, and disc area are discriminated in Table 1. The initial goal was an IOP reduction of at least 30% between baseline and final measurement. We observed a significant change in IOP between groups after treatment with hypotensive drug. Baseline IOP in the latanoprost group was 15.8 ± 0.61 mmHg and control was 15.0 ± 0.58 mmHg (p = 0.500). After 6 months of treatment, IOP in the latanoprost group decreased to 10.8 ± 0.64 mmHg and in control group was 13.5 ± 0.54 mmHg, with significant statistical difference between groups (p < 0.001) (Table 2).

Table 1.

Clinical and demographic variables of subjects included in the study.

Variables	19 patients
Age (years)	58.15 ± 12.47
Mean arterial blood pressure (mmHg)	108.15 ± 16.0
Body mass index (kg/m2)	28.1 ± 4.39
SAP MD (dB)	−1.71 ± 1.96
Disc area (mm2)	1.78 ± 0.62

SAP: standard automated perimetry; dB: decibels.

Table 2.

Intraocular pressure and optical coherence tomography angiography measurements over time between case and controls.

	Baseline			Month 1			Baseline vs Month 1		Month 3			Baseline vs Month 3		Month 6			Baseline vs Month 6
	Case	Control	P value	Case	Control	P value	Case	Control	Case	Control	P value	Case	Control	Case	Control	P value	Case	Control
IOP, mmHg	15.87 ± 0.61	15.01 ± 0.58	0.500	12.32 ± 0.49	14.63 ± 0.69	<0.001	<0.001	0.472	11.03 ± 0.53	13.65 ± 0.59	<0.001	<0.001	0.005	10.83 ± 0.64	13.5 ± 0.54	<0.001	<0.001	0.024
RCP density from small vessels, (%)	51.06 ± 0.81	50.65 ± 1.02	0.756	50.53 ± 0.84	51.51 ± 0.92	0.420	0.591	1.000	50.93 ± 0.81	51.71 ± 1.21	0.591	0.826	1.000	49.29 ± 0.96	52.11 ± 0.83	0.029	0.068	0.828
RCP density from all vessels, (%)	56.65 ± 0.87	56.21 ± 0.99	0.741	56.41 ± 0.95	57.24 ± 0.89	0.498	1.000	0.620	56.65 ± 0.89	57.54 ± 1.2	0.531	1.000	0.964	55.17 ± 1.05	57.92 ± 0.88	0.033	0.134	0.395
Superior macular vessel density, (%)	49.83 ± 1.84	50.75 ± 1.61	0.560	50.69 ± 1.78	51.49 ± 1.59	0.476	1.000	1.000	52.64 ± 1.12	51.07 ± 1.46	0.237	0.586	1.000	51.55 ± 1.23	50.61 ± 1.38	0.535	1.000	1.000
Nasal macular vessel density, (%)	49.29 ± 1.37	48.34 ± 1.43	0.385	48.52 ± 1.9	50.24 ± 1.48	0.306	1.000	0.918	50.6 ± 1.31	49.57 ± 1.47	0.423	1.000	1.000	50.92 ± 1.24	49.19 ± 1.46	0.304	1.000	1.000
Inferior macular vessel density, (%)	50.26 ± 1.75	49.93 ± 1.55	0.861	50.86 ± 1.27	50.32 ± 1.66	0.686	1.000	1.000	52.04 ± 1.09	50.64 ± 1.72	0.306	1.000	1.000	51.48 ± 0.91	49.67 ± 1.22	0.241	1.000	1.000
Temporal macular vessel density, (%)	50.51 ± 1.19	49.64 ± 1.43	0.570	49.97 ± 1.78	51.29 ± 1.18	0.328	1.000	1.000	51.53 ± 1.06	49.94 ± 1.69	0.223	1.000	1.000	51.07 ± 1.14	50.7 ± 1.36	0.794	1.000	1.000
RNFL thickness, μm	94.77 ± 3.71	100.43 ± 3.13	0.016	94.64 ± 3.58	100.25 ± 3.4	0.009	1.000	1.000	94.57 ± 3.47	101.36 ± 3.08	0.002	1.000	1.000	96.67 ± 3.89	101.21 ± 3.26	0.131	0.359	1.000
GCC thickness, μm	96.36 ± 4.1	94.64 ± 2.26	0.589	97.96 ± 3.62	96.25 ± 3.91	0.476	1.000	1.000	100.02 ± 5.25	97.15 ± 5.14	0.635	1.000	1.000	93.62 ± 2.09	94.24 ± 2.76	0.736	1.000	1.000

Values showed in marginal mean ± standard error; BMI: body mass index; IOP: intraocular pressure; RPC: radial peripapillary capillary; OCT: optical coherence tomography; RNFL: retinal nerve fiber layer; GCC: ganglion cell complex.

p value from Generalized Estimated Equations.

We observed significant differences between treated and untreated eyes at the end of 6 months. The RPC density of small vessels (%) in baseline of latanoprost group was 51.0 ± 0.81% and control 56.0 ± 1.02%, (p = 0.756). At month 6, the latanoprost group was 49.2 ± 0.96% and of control was 52.1 ± 0.83%, (p = 0.029). The RPC density of all vessels (%) in baseline of latanoprost group was 56.6 ± 0.87% and control was 56.2 ± 0.99%, (p = 0.741). At month 6, the latanoprost group was 55.1 ± 1.05% and of control group was 57.9 ± 0.88%, (p = 0.033). No changes were observed in macular vessel density parameters from OCT-A measurements over time comparing baseline and 6-month evaluation (Table 2).

Average mean RNFL thickness at baseline of the latanoprost eyes was 94.7 ± 3.71 μm versus 100.4 ± 3.13 μm in control eyes (p = 0.016). Even though groups had different baseline RNFL measurements at baseline, no statistically significant changes in measurements of the RNFL and GCC were observed over time. At month 6, the latanoprost group had 96.6 ± 3.89 μm and control group had 101.2 ± 3.26 μm, (p = 0.131). The average OCT GCC thickness did not show significant differences at baseline and over time (Table 2).

When comparing changes against baseline versus month 1, 3, and 6 measurements, we found only IOP with significant changes in eyes using latanoprost (p < .001) (Table 2). However, no changes were observed regarding IOP in the control group, OCT RNFL and GCC thickness, and vessel density from OCT-A measurements for both groups. No vascular events were observed in both groups.

Discussion

Patients with ODD can develop visual field defects due to mechanical compression of RNFL, increasing the risk of visual impairment and worsening visual related quality of life.^9,16–18 In addition, eyes with ODD are more prone to develop vascular events such as ischemic optic neuropathy, arterial or venous occlusions and subretinal neovascularization.⁴ In the current study, we evaluated the relationship between IOP reduction and peripapillary and macular areas vessel density, with the hypothesis that an improvement in vascularization parameters could occur after an IOP reduction. An increase in vessel density parameters could serve as a potential biomarker for less RNFL and GCC damage due to compression of fibers in eyes with ODD. However, at the end of the study, even though the target IOP reduction was achieved, there was no statistically significant improvement in vessel density as measured by OCT-A device.

In the current study, we used the OCT-A Angiovue (Optovue, Fremont, USA) to assess peripapillary and macular vessel density. Manalastas et al. in a reproducibility study, have demonstrated that for healthy subjects, the mean RPC vessel density was 61.3% (range 60.4–62.3%) and the standard deviation between visits was 2.37% (1.99–2.94%).¹² This is important because our measurements for RPC density at 6 months for the latanoprost group was 55.1 ± 1.05% and for control group was 57.9 ± 0.88%, (p = 0.033), showing that despite statistical significance, the small difference between the 2 groups may not be clinically relevant as the range of 2–3% are still within the standard deviation of the inter-visits measurements from the device. We acknowledge that despite randomization, we found that patients in the latanoprost group had thinner RNFL measurements at baseline (94.7 ± 3.71 μm) compared to the control group (100.4 ± 3.13 μm, p = 0.016), which may be explained by the variability in the measurements due to the compression of RNFL fibers in some eyes with ODD. Nevertheless, at 6 months, no statistically significant changes in measurements of the RNFL was observed. At month 6, the latanoprost group had 96.6 ± 3.89 μm and control group had 101.2 ± 3.26 μm, (p = 0.131). As measurements from RNFL thickness seems not to have biased the vessel density measurements at baseline (Table 2), which was our primary outcome, we did not consider this as a major limitation.

Drusen has been suggested to originate from axoplasmic derivatives of disintegrated nerve fibers, secondary to altered axoplasmic transport in an anatomically small scleral canal, or from abnormal axonal metabolism leading to deposition of calcium crystals in mitochondria, axonal disruption, and mitochondrial extrusion into the extracellular space with continuous calcium apposition.^1,19 In fact in the current study, the mean disc area was 1.78 ± 0.99 mm² in the latanoprost group and 1.76 ± 0.17 mm² in the control group (Table 1), showing a small disc area. A plausible model of glaucoma pathogenesis is that a posterior translaminar pressure gradient generates mechanical strain in the lamina cribrosa that is detected by astrocytes, which become activated and toxic to the adjacent axons passing through, leading to axon degeneration.^20,21 The only established treatment for glaucoma is to lower IOP, having direct influence in the translaminar pressure gradient.²² The interaction of ODD with the remodeling and strain patterns of the lamina, or with the behavior of astrocytes are not known.²³

Disc drusen are located anterior to the lamina cribrosa, and generally are not present in the RNFL or posterior to lamina cribrosa. This indicates that the translaminar pressure gradient is relevant to the formation of ODD. Specifically, the location implies hold up of axoplasmic flow in the orthograde direction (i.e. leaving the eye, toward lateral geniculate nucleus).²³ Current hypothesis states that the primary pathology is likely to be an inherited dysplasia of the optic disc and its blood supply.²⁴ Microcirculation of structurally congested optic discs can be compromised as discs with hypolasia may present fewer nerve fibers compared to glial and other supporting cells.²⁴ Thus, the attempt to enhance microcirculation perfusion of the optic nerve by using vasoactive agents (such as Pentoxifylline) or reducing IOP may help to minimize RNFL and GCC loss.⁵ By lowering IOP through hypotensive eye drops or surgically fenestrating the optic nerve sheath, it is expected changes in translaminar pressure gradient, and thus interrupt the progression of visual field loss and RNFL thinning. To the best of our knowledge, there have not been trials or retrospective comparisons to evaluate these strategies, by which altering the translaminar gradient in either direction could be helpful or harmful, as surgical approaches for patient with ODD would impose larger risks of visual loss.^25,26

Visual field defects may occur secondary to nerve fiber layer injury or to vascular events. A crowded small disc with an anomalous vascular pattern predisposes eyes to vascular complications.^19,27 Fraser et al. demonstrated that ODD were found with much higher prevalence in young patients with non-arteritic anterior ischemic optic neuropathy than in the general population and were usually bilateral and buried.⁴ Non-arteritic anterior ischemic optic neuropathy has also been reported in patients with acute angle closure attacks, Posner-Schlossman syndrome, and neovascular glaucoma suggesting that an elevated IOP may be a risk factor in structurally congested discs.²⁴ Thus, we hypothesized that IOP lowering therapy could also benefit eyes with ODD.

The study by Grippo et al., which analyzed 103 eyes with ODD, 22 of which were hypertensive (IOP > 22 mmHg) and 81 normotensives, showed some loss of visual field in almost 91% of the hypertensive eyes and only 66% of the normotensive eyes.²⁸ The Collaborative Normal-Tension Glaucoma Study demonstrated that by reducing IOP by 30% in patients without ocular hypertension, an important difference was obtained in the progression of visual field loss, and in the group treated with hypotensive medication there was a loss of 40% and in the untreated group 80% at 5 years of follow-up, which reinforces the theory of the benefit of reducing IOP even in non-hypertensive eyes to preserve the visual field.²⁹ In our study, despite achieving statistical significant IOP reduction, no evidence of improvement in vessel density or nerve fiber thickness was found.

One might argue about the use of latanoprost in detriment to other traditional hypotensive drugs. Latanoprost is the only medication that acts exclusively on IOP and does not have significant systemic or local vasoactive effect. The choice for latanoprost was better tolerability compared to other prostaglandins analogues, such as travoprost and bimatoprost. Some studies have shown that carbonic anhydrase inhibitors, such as, dorzolamide can improve blood flow in the optic nerve head and choroid.^30,31 Brimonidine tartrate was previously used to test improvement in clinical outcomes of patients with non-arteritic anterior ischemic optic neuropathy.³² However, no statistically significant advantage was shown. In addition, the presumed neuroprotective effects of brimonidine with animal models, in treating ischemic optic nerve injury have not translated into effective clinical applications.³³ Timolol is associated with cardiovascular adverse events, such as bradycardia and tachycardia, hypotension, orthostatic hypotension, angina pectoris, myocardial infarction, heart failure, and syncope.³⁴ Future studies could evaluate the effect of latanoprostene bunod in eyes with ODD, as the nitric-oxide donating agent might have a vasoactive behavior in optic nerve blood flow.³⁵ In addition, Rho-kinase inhibitors may enhance retinal ganglion cell survival after ischemic injury and increase ocular blood flow. ^36–38 Thus, evaluating the effect of these drugs on ocular blood flow and visual field loss in eyes with ODD can be promising.

Anatomical changes in vascular density in the peripapillary and macular regions, in addition to the density of the retinal nerve fiber layer, are found in eyes with ODD when compared to healthy eyes. Engelke et al., who analyzed vascular density using OCT-A in 45 eyes with ODD compared to 50 healthy eyes, showed a significant reduction in vascular density in all peripapillary sectors in eyes with ODD.⁷ They also analyzed RNFL thickness between groups using OCT, finding no statistical difference between the general thicknesses, however, dividing into sectors, a reduction in the RNFL was evident in the upper quadrant in eyes with ODD compared to healthy eyes. GCC thickness also showed a statistically significant thinning in the study, when comparing eyes with ODD and healthy ones. Finally, Engelke et al. demonstrated a positive correlation between vascular density and GCC and vascular density and RNFL. However, it was demonstrated that the anatomical changes in eyes with ODD did not translate into changes in the visual field, probably because the origin of the axon comes from different regions, and not from just one point in the RNFL and GCC.

This study has several limitations. First, we did not used laser speckle flowgraphy to assess optic nerve head microcirculation, nor color Doppler imaging to measure retrobulbar hemodynamics as previous studies.^39,40 However, we chose to investigate vascular density parameters obtained with OCT-A as the device is more commonly used in clinical practice.^6,41 Second, we included only patients with normal IOP range. This could have partially explained the absence of significant relationship between IOP reduction and vascular density and RNFL thickness, as the magnitude of IOP reduction was limited, its impact on vascular density parameters were probably minimal.⁴² Therefore, even if microvascular variations occurred, they were too small to be detected in our OCT-A scans. Third, it is also important to understand that the parameters measured by OCT-A are inferred by detecting erythrocytes moving through the vascular lumen.⁴³ This approximate quantification of the flow area is not an exact measure of perfusion and may deviate from the anatomical parameters due to several confounders and artifacts, such as changes in vessel diameter and vascular wall thickness, that is, yet another point that may have interfered in our measurements and contributed to our study not having achieved significant changes in the analyzed vascular density. Fourth, this study was limited by the number of patients able to participate in the study, as ODD is a relatively rare disease. Thus, we have included both eyes in the study for patients with bilateral ODD. Even though a cross over effect with systemic absorption of the hypotensive drug could have occurred, we believe that randomization and the results from IOP reduction between eyes showed no bias regarding this issue. Fifth, we have not measured the size of the drusen. Since no changes in baseline measurements from vessel density was observed, we assume that they might have similar sizes, with few or no impact in vessel density measurements. Finally, the reduced follow-up time of the study may have been a factor that contributed to the non-statistical significance of the studied variables. However, as we used only prostaglandin analogues, we consider that the hypotensive effect would not benefit from a longer period, as no changes was observed after 6 months. We also highlight that within 6 months of follow-up no eyes presented vascular events, but future studies could investigate if reducing IOP can be related to lower prevalence of vascular events over a longer period of follow-up.

Until now there is no evidence that lowering IOP can benefit normotensive patients with ODD. We conducted a limited study with small numbers of patients and relatively short follow-up (6 months). The decrease observed in RPC vessel density in eyes that received latanoprost in our study may be explained by the variability in OCT measurements. Therefore, these limited conclusions cannot be extrapolated for longer periods of treatment and more studies are necessary to investigate this issue. A better understanding of the pathophysiological factors, evolution patterns, and complications of the disease will help patients with ODD, who have not yet suffered visual loss, to implement prophylactic and therapeutic strategies to reduce the effects of functional loss and avoid the vascular complications resulting from ODD.

Funding Statement

The author(s) reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/01658107.2024.2377166.