Short-term effects of intravitreal dexamethasone implant on choroidal structure in eyes with refractory diabetic macular edema Contributors

doi:10.21203/rs.3.rs-2100030/v1

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Short-term effects of intravitreal dexamethasone implant on choroidal structure in eyes with refractory diabetic macular edema Contributors

https://doi.org/10.21203/rs.3.rs-2100030/v1

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Purpose

To evaluate choroidal structural changes after intravitreal dexamethasone implant (IDI) in eyes with diabetic macular edema (DME) refractory to anti-vascular endothelial growth factor (VEGF) therapy.

Methods

Twenty-three eyes of 14 patients with DME refractory to anti-VEGF therapy were included in this retrospective study. Detailed ophthalmological examinations were recorded and optical coherence tomography (OCT) images were obtained before and 3 months after IDI. Choroidal images were binarized into the luminal area and total choroidal area. Subfoveal choroidal thickness (SFCT) and choroidal vascularity index (CVI) were calculated.

Results

The mean best-corrected visual acuity (BCVA) and central macular thickness (CMT) were improved significantly (from 0.94 to 0.81 LogMAR, p = 0.02, and from 464 to 371 µ, p = 0.01, respectively) after IDI. There were no significant changes in both SCFT and CVI at the end of the follow-up period (from 446.3 to 428.8 µ, p = 0.51 and from 63.1 to 63.7 p = 0.35, respectively).

Conclusion

IDI in eyes with DME refractory to anti-VEGF therapy improves BCVA and CMT but has no significant effect on SCFT and CVI in short term.

Choroidal thickness

Choroidal vascularity index

Diabetic macular edema

Intravitreal injection

Ozurdex

Diabetic macular edema (DME) is a leading cause of vision loss in the working-age population [1] and anti-vascular endothelial growth factor (VEGF) agents have been widely used as the first-line therapy for DME [2–3]. However, a considerable proportion of patients (19.7–66%) had an inadequate response to anti-VEGF treatment [4, 5]. The pathogenesis of DME is multifactorial and complex and besides VEGF other inflammatory mediators such as interleukin (IL)-6, IL-8, matrix metalloproteinase, angiopoietin-2, tumor necrosis factor-alfa, and intercellular adhesion molecule-1 are also involved in it [6, 7]. Therefore, in case of poor response to anti-VEGF treatment switching to alternative or adjunctive treatment strategies such as intravitreal steroids should be considered [3]. Recent multicenter studies showed that intravitreal dexamethasone implant (IDI) (Ozurdex; Allergan, Irvine, CA, USA) is an effective treatment method for DME [8, 9].

The choroidal vasculature provides an important blood supply to the outer retina and choroidal abnormalities occurring in diabetic patients may cause severe functional damage to the retina and lead decrease in visual acuity [10, 11]. The newly developed marker of the choroidal vascularity index (CVI), which provides information on the proportion of the luminal area (LA) to the total choroidal area (TCA), has been widely used to assess the vascular status of the choroid in many ocular diseases [12–15]. The CVI shows a good correlation with the severity of diabetic retinopathy (DR) and may be a sensitive marker of choroidal vascular change in DME [13, 14]. Although some studies evaluated CVI changes with anti-VEGF or steroid treatments in DME, to the best of our knowledge, only one study has previously evaluated the effect of IDI on CVI in eyes with DME resistant to anti-VEGF agents [16–19]. Thus, in this study, we aimed to investigate the short-term effect of IDI on choroidal structural changes in eyes with refractory DME.

This retrospective study was conducted with 23 eyes of 14 patients who were treated with IDI due to refractory DME despite at least 3 consecutive monthly intravitreal anti-VEGF therapy at Zonguldak Bulent Ecevit University Hospital between September 2021 and June 2022. The study was approved by the Ethics Committee of Zonguldak Bulent Ecevit University and adhered to the tenets of the declaration of Helsinki. All patients were informed about the potential side effects, and their consent was taken before the procedure.

All participants underwent an ophthalmic evaluation before and 3-months after IDI, including the measurement of best-corrected visual acuity (BCVA) in LogMAR units, slit-lamp biomicroscopy, fundoscopy, fluorescein angiography, and enhanced depth imaging – optical coherence tomography (EDI-OCT) imaging (Spectralis®, Heidelberg Engineering Inc., Heidelberg, Germany). All EDI-OCT images were obtained between 10:00 and 12:00 hours to minimize the effect of diurnal variations in the choroidal structures. Evidence of macular ischemia, history of any systemic disease other than diabetes, previous ocular surgery and/or laser photocoagulation, epiretinal membrane, vitreomacular traction or adhesion, glaucoma/ ocular hypertension, presence of media opacities that could distort image quality were determined as exclusion criteria. The diagnosis of DME was based on the results of OCT and fluorescein angiography. Refractory DME is defined as central macular thickness (CMT) of 300 µm with persistent increased intraretinal fluid and no morphological improvement of DME on OCT despite at least 3 consecutive monthly anti-VEGF therapy. CMT was measured manually as the distance from the outer border of the hyper-reflective line corresponding to the retina pigment epithelium, perpendicular to the choroidal-scleral interface. Subfoveal choroidal thickness (SFCT) was measured vertically from the outer surface of the retinal pigment epithelium to the choroidal-scleral interface.

All dexamethasone implants were injected under sterile conditions in an outpatient operating room. The implant was inserted into the vitreous cavity through the pars plana using a single-use applicator. Patients were treated with a topical ophthalmic antibiotic for five days after treatment.

Binarization of EDI-OCT images was performed with Image-J software (Version 1.50a; National Institutes of Health, Bethesda, MD, USA). 3000 µm wide area with the margins of 1500-µm nasal and 1500-µm temporal from the fovea was selected. Borders of the choroidal area were set manually with the Image-J ROI Manager. The image was adjusted by the Niblack auto-local threshold. TCA, LA, and stromal area (SA) were measured (Fig. 1) [12]. CVI was the ratio between LA and TCA.

Statistical Analysis

The analysis of the data was done using IBM SPSS 22.0 (SPSS Inc., Chicago, IL, USA) software. Descriptive statistics were defined as mean ± standard deviation for variables with normal distribution, median (min-max) for variables with non-normal distribution, and the number of cases (%) for nominal variables. To evaluate the differences in BCVA, CMT, SFCT, CVI, TCA, LA, and SA before and after IDI, paired t-tests were performed. A p-value of ˂0.05 was considered statistically significant.

Baseline Characteristics

A total of 23 eyes of 14 patients with refractory DME were enrolled in this study. Of 14 patients, 5 (35.7%) were males and 9 (64.3%) were females and the mean age was 64.7 ± 7.7 years. The mean number of previous intravitreal anti-VEGF injections was 7.5 ± 3.9. (Table 1)

Table 1

Demographics and Baseline Characteristics of the Patients
Eyes/Patients (n)	23 / 14
Mean age (years)	64.78 ± 7.71
Male/Famele (n)	5 / 9
Mean number of anti-VEGF injections	7.56 ± 3.92

Visual Acuity

The mean BCVA before and after IDI were 0.94 ± 0.4 and 0.81 ± 0.3 LogMAR, respectively. There was a statistically significant improvement in BCVA after IDI in the short-term (p = 0,02). (Table 2)

Table 2

Comparison of visual acuity and EDI-OCT parameters during the follow-up period
	Before Dex Implant	At 3 Month	p
BCVA (LogMAR)	0.94 ± 0.4	0.81 ± 0.3	0.02
CMT (µ)	464.9 ± 168.3	371 ± 127	0.01
SFCT (µ)	446.3 ± 150.6	428.8 ± 122.6	0.052
CVI (%)	63.1 ± 2.2	63.8 ± 2.8	0.35
TCA (mm²)	1.15 ± 0.45	1.10 ± 0.36	0.25
LA (mm²)	0.73 ± 0.28	0.70 ± 0.23	0.29
SA (mm²)	0.42 ± 0.17	0.40 ± 0.14	0.21
BCVA: Best corrected visual acuity; CMT: Central macular thickness; SFCT: Subfoveal choroidal thickness; CVI: Choroidal vascular index; TCA: Total choroidal area; LA: Luminal area; SA: Stromal area

Central Macular Thickness

The mean CMT for all eyes decreased significantly from 464.9 ± 168.3 µm at baseline to 371.0 ± 127.0 µm at the final visit after IDI (p = 0,01). (Table 2)

Choroid Thickness

The mean SFCT before and after IDI were 446.3 ± 150.6 and 428.8 ± 122.6, respectively. There was a slight decrease in SFCT after IDI but it wasn’t statistically significant (p = 0,51). (Table 2)

Choroidal Vascularity Index

The mean CVI of eyes with refractory DME was 63.3 ± 2.3 at baseline and 63.7 ± 2.8 at the final visit. There was no significant change in CVI (p = 0,35). There were also no significant differences between initial and final visit means of the TCA (1.15 ± 0.45 vs 1.10 ± 0.36 mm², p = 0,25), LA (0.73 ± 0.28 vs 0.70 ± 0.23 mm², p = 0,295), and SA (0.42 ± 0.17 vs 0.40 ± 0.14 mm², p = 0,21), respectively. (Table 2)

DME has complex pathogenesis involving VEGF and other inflammatory mediators [7]. Unlike anti-VEGF therapy, steroids can reduce levels of other inflammatory cytokines in addition to VEGF levels [20]. Thus, steroids should be considered for some cases that are refractory to anti-VEGF therapy. Among steroids, 0.7 mg intravitreal dexamethasone implant (Ozurdex, Allergan; Irvine, CA) has shown efficacy in DME treatment, specifically in improving visual acuity and decreasing retinal thickness in eyes with anti–VEGF-resistant DME [3]. In this study, there were significant improvements in CMT and BCVA after switching to IDI and, no systemic or ocular complications, especially cataract progression. However, the short follow-up period and small sample size in this study may also have contributed to the results.

Diabetes is a metabolic disorder mainly affecting the systemic vasculature. Although the primary changes in diabetic eyes occur in the retinal vasculature, accompanying changes are also observed in the choroidal layer, which is essential in providing nutrients and oxygenation to the outer retina layers. Histopathologic studies showed vascular dropout, areas of vascular nonperfusion, and choroidal neovascularization in diabetic cases [11]. Postmortem studies reported choroids of diabetic subjects had more focal choriocapillaris degeneration areas than nondiabetic choroids [21]. Those structural changes in choroid vessels may affect choroidal blood flow. Laser Doppler flowmetry and OCT angiography measurements revealed that patients with DME had significantly decreased choriocapillaris blood flow in the foveal region [22, 23]. However, the exact role of choroidal abnormalities in the pathology of DME and its impact on the response to treatment modalities remain unclear.

In recent years, SFCT has been commonly used to evaluate the choroid in DR or DME. However, the results of SFCT in DR or DME in different studies are controversial, since it’s an unstable factor affected by various systemic and ocular factors, such as age, axial length, IOP, or systolic blood pressure [24]. Kim et al. reported that SFCT was increased in eyes with DME than in those without [14]. In contrast, Gerendas et al. revealed that SFCT was significantly decreased in eyes with DME and in nonedematous fellow eyes [25]. Similarly, Esmaeelpour et al. reported a decrease in SFCT in eyes with DME [26]. In this study, there was also no significant change in SCFT although there were significant changes in VA and CMT. We thought that previously received anti-VEGF therapy may have affected choroidal layers.

Unlike SFCT, CVI discriminates between the luminal and stromal areas, providing more detailed information about changes in the choroidal vessels and showing less variability under the above-mentioned physiological factors. Changes in the CVI in DR have been reported in several recent studies. Gupta et al. reported that the CVI was significantly decreased in eyes with DME and DR compared to controls [13]. A decrease in the CVI was observed in patients with diabetes even in the absence of DR, and a further decrease occurred along with the severity of DR [14]. Okamoto et al showed that even a single injection of ranibizumab decreased CVI in DME patients [27]. Recently Liu et al revealed that CVI and SCFT decrease by subtenon triamcinolone treatment in eyes with DME refractory anti-VEGF therapy [18]. Kocamis et al also reported a decrease in CVI after IDI in eyes with DME [19]. They both attributed that to the decreased vasodilatation in choroidal vessels. On the other hand, Rishi et al claimed that IDI has no short-term influence on SCFT and CVI in eyes with DME [16]. The absence of CVI and SCFT changes after IDI in our study may reflect that IDI has a greater effect on retinal layers than choroidal structures in eyes with resistant DME which previously received anti-VEGF therapy.

Our study had several limitations including its retrospective design, relatively small number of patients and short duration of follow-up. Therefore, a prospective multicenter clinical study larger sample size and longer follow-up period may be warranted in the future to reveal the longitudinal effect of intravitreal dexamethasone on choroidal vasculature.

In conclusion, switching to IDI may improve BCVA and CMT in DME eyes refractory to anti-VEGF injections. However, it has no significant influence on SFCT or CVI in the short-term. This result may indicate that IDI affects the retinal layers rather than the choroid layer in eyes with previously received anti-VEGF therapy.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Serdar Bilici and Suat Hayri Ugurbas contributed to the study’s conception and design. Material preparation and data collection were performed by Enes Serbest. Data analysis was performed by Serdar Bilici. The first draft of the manuscript was written by Serdar Bilici and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Zonguldak Bulent Ecevit University (06/07/2022 – 2022/13).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish

The authors affirm that human research participants provided informed consent for the publication of the images in Figure 1.

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No competing interests reported.

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Short-term effects of intravitreal dexamethasone implant on choroidal structure in eyes with refractory diabetic macular edema Contributors

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