Efficacy of Subthreshold Photocoagulation for Persistent Diabetic Macular Edema After Internal Limiting Membrane Peeling: A Retrospective Comparative Study

doi:10.21203/rs.3.rs-243863/v1

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Efficacy of Subthreshold Photocoagulation for Persistent Diabetic Macular Edema After Internal Limiting Membrane Peeling: A Retrospective Comparative Study

https://doi.org/10.21203/rs.3.rs-243863/v1

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Background

Subthreshold photocoagulation is one of the therapeutic options for treating diabetic macular edema, and have characteristic advantages, which are the lack of chorioretinal damage and the repeatability of the treatment. However, the effect of subthreshold photocoagulation is thought to be minimal among these options. In this study, we retrospectively examined the efficacy of repeated subthreshold photocoagulation for persistent diabetic macular edema after vitrectomy with peeling of the internal limiting membrane.

Methods

We enrolled ten consecutive eyes of eight patients who underwent monthly Endpoint Management™ (EpM) six times for diabetic macular edema that persisted for more than 3 months after vitrectomy with internal limiting membrane peeling for epiretinal membrane, and classified according to the interval between vitrectomy and initial EpM (Group A: within 6 months, Group B: beyond 6 months). Two type of retinal thickness (central macular thickness and macular thickness within 3mm diameter of the fovea) were measured monthly using optical coherence tomography.

Results

Mean intervals between vitrectomy and initial EpM were 4.0 ± 1.2 months (range 3–6 months) in Group A (six eyes of five patients) and 17.3 ± 7.5 months (range 10–27 months) in Group B (four eyes of four patients). No other treatments were performed between vitrectomy and initial EpM in Group A, while triamcinolone acetonide injection in the sub-Tenon’s capsule was performed in two eyes in Group B (one eye was injected thrice, the other eye received a single injection). Improvement rates of mean central macular thickness after 6 months were 18.2% in all eyes, 10.8% in Group A, and 28.7% in Group B, and improvement rates of mean macular thickness within 3mm diameter of the fovea after 6 months were 8.5% in all eyes, 4.1% in Group A, and 15.3% in Group B.

Conclusions

Monthly EpM treatment was efficacious against persistent diabetic macular edema after internal limiting membrane peeling. In particular, the efficacy was greater in eyes in which the initial EpM was performed more than 6 months after vitrectomy. Furthermore, residual efficacy of triamcinolone acetonide, which was injected at the end of vitrectomy, might have contributed to the results.

Ophthalmology

Subthreshold photocoagulation

Diabetic macular edema

Internal limiting membrane

Triamcinolone acetonide

Vitrectomy

Diabetic macular edema (DME) is a commonly-faced problem in ophthalmology practice. There are several therapeutic options for treating DME, such as photocoagulation, triamcinolone acetonide injection, anti-vascular endothelial growth factor injection, and vitrectomy, and most patients require individualized treatment using a combination of these therapies. Photocoagulation is the most friendly DME treatment from the ophthalmologists viewpoint, but conventional photocoagulations, such as panretinal photocoagulation and grid photocoagulation, have certain disadvantages, including the destructiveness of the procedure [1]. Conversely, the principle of subthreshold photocoagulation, which is considered a tissue-sparing procedure, is “stimulation” rather than “coagulation” [1], thus avoiding the risk of destruction. Lavinsky et al. demonstrated that subthreshold photocoagulation retreatment to the same areas, even the fovea, was possible due to the lack of chorioretinal damage [2], and Ohkoshi et al. described that one of the advantages of subthreshold photocoagulation was the repeatability of the treatment [3]. This is the most notable advantage of subthreshold photocoagulation. However, the effect of the treatment is thought to be minimal among the several procedures available for DME, because subthreshold photocoagulation alone might not be able to preserve visual acuity [3]. Therefore, combined treatment with other therapies [3, 4] or retreatment using subthreshold photocoagulation [5] have been reported. On the other hand, because the scars resulting from subthreshold photocoagulation are invisible, the judgment of “barely visible” photocoagulation scar at titration, which is used to determine the threshold energy, is very important. Since the judgment might be affected by transparency of the ocular media [2], such as the presence of a cataract or physiological vitreous opacity, a more exact performance of subthreshold photocoagulation is thought to be possible in cases who have previously undergone both cataract surgery and vitrectomy. Furthermore, even if subthreshold photocoagulation is performed exactly, resolution of vitreomacular traction, which is one of the factors influencing DME [6] and that cannot be treated by photocoagulation, is desirable to maximize the effect of subthreshold photocoagulation. In this study, we retrospectively examined the efficacy of repeated Endpoint Management™ (EpM), which is a type of subthreshold photocoagulation using the PASCAL laser method (Topcon Medical Laser Systems, Santa Clara, CA, USA), for persistent DME after both cataract surgery and vitrectomy with peeling of the internal limiting membrane (ILM).

This retrospective study was approved by the ethics committee of Tokyo Rosai Hospital and complied with the tenets of the Declaration of Helsinki. Ten consecutive eyes of eight patients who underwent monthly EpM six times for DME that persisted for more than 3 months after vitrectomy with ILM peeling for epiretinal membrane at Tokyo Rosai Hospital were evaluated. In all cases, the initial EpM (In-EpM) was performed between April and October 2019. The inclusion criteria were: (1) type 2 diabetes; (2) completion of panretinal photocoagulation at the end of vitrectomy; (3) presence of intraocular lens at the end of vitrectomy; (4) use of the yttrium-aluminum-argon laser for an after cataract if needed; (5) no avascular area within 6 mm diameter of the fovea on fluorescein angiography examination performed just before In-EpM. The exclusion criteria were: (1) central macular thickness within 1mm diameter of the fovea (CMT) of more than 600 µm at In-EpM; (2) history of multiple vitrectomy surgeries; (3) history of other vitreoretinal diseases, uveitis, glaucoma and corneal disease. Each patient underwent 25-gauge transconjunctival sutureless vitrectomy with ILM peeling for epiretinal membrane, with additional panretinal photocoagulation being performed during the surgery as necessary, and was given an injection of 4 mg triamcinolone acetonide into the vitreous cavity at the end of vitrectomy. In patients in whom cataract surgery and lens implantation had not previously performed, vitrectomy and cataract surgery were performed simultaneously. DME in each case was evaluated using fluorescein angiography just before the In-EpM. Titration to determine the threshold energy was performed at an area without retinal edema outside the vascular arcade, and threshold energy was determined based on the appearance of a “barely visible” lesion within 3 seconds after irradiation. In this study, 50% of the threshold energy was applied for EpM, which was performed using only a “Macular Grid” pattern with a spot diameter of 200 µm, spacing of 0.5 times of spot diameter, inner radius of 500 µm, and outer radius of 2500 µm. Since monthly EpMs were planned, the “landmark” spot was not used. All treatments were performed by a single surgeon (H.T.). Macular thickness was measured using optical coherence tomography (OCT) (Triton plus®, Topcon Medical Laser Systems, Santa Clara, CA, USA) at each monthly visit (In-EpM, EpM-1-6M), and two parameters of macular thickness, CMT and 3mMT (macular thickness within 3 mm diameter of the fovea), were assessed. The endpoint of this study was the rate of improvement in mean CMT and mean 3mMT over 6 months (from In-EpM to EpM-6M). Eyes were retrospectively classified according to the time interval between vitrectomy and In-EpM (Group A: within 6 months, Group B: beyond 6 months), and mean CMT and mean 3mMT were compared between the two groups by the t-test using Excel software (Microsoft, Redmond, WA, USA). Differences with p-values of less than 0.05 were considered statistically significant.

Mean values of age, HbA1c, and axial length in all cases were 63.4 ± 11.9 years (range 50–79), 6.5 ± 0.3% (range 5.9-7.0), and 23.77 ± 0.94 mm (range 22.23–25.51), respectively (Table 1).

Table 1

Mean values of variables
	Age (years)	HbA1c (%)	Axial length (mm)
All eyes	63.4 ± 11.9	6.5 ± 0.3	23.77 ± 0.94
Group A	61.5 ± 11.5	6.4 ± 0.3	24.03 ± 0.97
Group B	66.3 ± 11.8	6.6 ± 0.4	23.37 ± 0.73

The diabetic status of all the patients remained stable under the care of their attending physician, and none of them developed complications related to cataract surgery and vitrectomy. DME was identified by the presence of sponge-like retinal swelling and cystoid macular edema, and serous retinal detachment was not detected in any of the OCT images. Mean intervals between vitrectomy and In-EpM were 4.0 ± 1.2 months (range 3–6 months) in Group A (six eyes of five patients) and 17.3 ± 7.5 months (range 10–27 months) in Group B (four eyes of four patients). No other treatments were performed between vitrectomy and In-EpM in Group A, while triamcinolone acetonide injection in the sub-Tenon’s capsule [7] was performed in two eyes in Group B (one eye was injected thrice, the other eye received a single injection). The interval between the last triamcinolone acetonide injection and In-EpM was over 12 months in both eyes. No other treatment except EpM was performed after In-EpM in all eyes. CMTs at each evaluation period (In-EpM, EpM-1-6M) are shown in Table 2. The rates of improvement in CMT after 6 months were as follows: 18.2% in all eyes, 10.8% in Group A, and 28.7% in Group B. In the examination of all eyes, although only mean CMT at EpM-6M was significantly different from mean CMT at In-EpM (P = 0.02), all the mean CMTs at EpM-1-6M were lower than mean CMT at In-EpM, decreasing over time except for a temporary relapse at EpM-3M and EpM-4M (Table 2). There were no significant differences in mean CMT at In-EpM between Group A and Group B. In intra-group comparisons, although only mean CMT at EpM-2M in Group A was significantly different from mean CMT at In-EpM (P = 0.04), all mean CMTs at EpM-1-6M were lower than mean CMT at In-EpM, decreasing over time except for a temporary relapse at EpM-3M and EpM-4M in Group A (Table 2).

Table 2

Progression of mean central macular thickness within 1mm diameter of the fovea (CMT) over time
	In-EpM	EpM-1M	EpM-2M	EpM-3M	EpM-4M	EpM-5M	EpM-6M	IR
All eyes	403.7 ± 59.7	374.6 ± 49.5	350.1 ± 59.5	356.0 ± 51.8	364.8 ± 58.0	344.3 ± 65.4	330.2 ± 61.4*	18.2%
Group A	394.3 ± 36.8	360.5 ± 31.9	330.0 ± 50.2*	364.5 ± 53.8	385.2 ± 59.6	370.2 ± 65.4	351.7 ± 62.1	10.8%
Group B	417.8 ± 80.9	395.8 ± 62.0	380.3 ± 59.6	343.2 ± 45.8	334.3 ± 39.1	305.5 ± 41.9	298.0 ± 43.8	28.7%
Values represent mean ± standard deviation (in µm)
IR = improvement rate of mean thickness after six months from the initial Endpoint Management™
*statistical significance according to the t-test

Mean 3mMT at each evaluation period is shown in Table 3. Improvement rates in 3mMT after 6 months were as follows: 8.5% in all eyes, 4.1% in Group A, and 15.3% in Group B. In the evaluation of all eyes, although mean 3mMTs at EpM-1-6M were not significantly different from mean 3mMT at In-EpM, all the values were lower than mean 3mMT at In-EpM, decreasing over time except for a temporary relapse at EpM-4M (Table 3). There were no significant differences in mean 3mMT at In-EpM between Group A and Group B. In intra-group comparisons, although only mean 3mMT at EpM-6M in Group B was significantly different from mean 3mMT at In-EpM (P = 0.04), all the mean 3mMT values at EpM-1-6M were lower than mean 3mMT at In-EpM, decreasing over time except for a temporary relapse at EpM-3M and EpM-4M in Group A (Table 3).

Table 3

Progression of mean macular thickness within 3 mm diameter of the fovea (3mMT) over time
	In-EpM	EpM-1M	EpM-2M	EpM-3M	EpM-4M	EpM-5M	EpM-6M	IR
All eyes	362.1 ± 30.0	351.2 ± 27.0	341.6 ± 20.0	340.2 ± 24.8	345.7 ± 38.4	335.9 ± 33.3	331.5 ± 38.8	8.5%
Group A	368.5 ± 25.6	358.8 ± 23.1	343.8 ± 16.1	350.5 ± 22.0	363.8 ± 37.0	356.2 ± 26.6	353.5 ± 34.1	4.1%
Group B	352.5 ± 33.2	339.8 ± 28.6	338.2 ± 24.3	324.8 ± 20.5	318.5 ± 19.8	305.5 ± 13.1	298.5 ± 14.2*	15.3%
Values represent mean ± standard deviation (in µm)
IR = improvement rate of mean thickness after six months from the initial Endpoint Management™
*statistical significance according to the t-test

Mean values of best-corrected visual acuity (BCVA) (Log MAR) at In-EpM and EpM-6M are shown in Table 4. There were no significant differences between mean values of BCVA at In-EpM and EpM-6M in all eyes, Group A, and Group B.

Table 4

Mean values of best-corrected visual acuity (Log MAR)
	In-EpM	EpM-6M
All eyes	0.50 ± 0.28 (0.0–1.0)	0.45 ± 0.28 (0.05-1.0)
Group A	0.57 ± 0.28 (0.1-1.0)	0.54 ± 0.30 (0.05-1.0)
Group B	0.40 ± 0.25 (0.0-0.7)	0.31 ± 0.17 (0.05–0.5)
Values represent mean ± standard deviation

In this study, since subthreshold photocoagulation is inadequate for treating severe macular edema [8], we excluded cases in whom CMT at In-EpM was more than 600 µm. However, even if CMT is less than 600 µm, presence of a thickened retina due to DME can result in insufficient efficacy of EpM. Hence, we performed EpM every month to obtain sufficient effect of EpM. Transparency of ocular media (performance of cataract surgery and vitrectomy) and absence of vitreomacular traction (performance of vitrectomy with ILM peeling) contributed to attainment of the maximal efficacy of EpM. Existence of a significant difference in mean CMT in all eyes between In-EpM and EpM-6M suggests the efficacy of EpM in this study. Although the possibility of a natural but unexpected self-resolution in increased retinal thickness cannot be ruled out, better improvement of mean CMT from In-EpM to EpM-6M was detected in Group B, which had a longer interval of persistent DME after vitrectomy as compared to Group A. This fact supports the efficacy of EpM in this study. Additionally, because mean CMT decreased steadily in Group B, the efficacy of monthly EpM was noticeable right from EpM-1M. Based on the report by Terasaki et al. showing that approximately 3–4 months are required for macular edema to stabilize after vitrectomy [7], we expected that the improvement in macular thickness in Group A would be better than that in Group B due to the continuing efficacy of vitrectomy. However, we observed the opposite outcome, despite the absence of a significant difference between the groups in mean CMT at In-EpM. We attribute this phenomenon to the influence of triamcinolone acetonide. Massin et al. reported a significant transient reduction in CMT in intravitreal triamcinolone acetonide treated eyes at 1 and 3 months, which was no longer significant at 6 months [9], suggesting that the efficacy of triamcinolone acetonide might be evident at In-EpM, but might no longer be significant at EpM-6M in Group A. In other words, the improvement in macular thickness caused by triamcinolone acetonide was present at In-EpM, but had diminished by EpM-6M. This could explain the temporary relapse and lower rate of improvement in retinal thickness in Group A in comparison to Group B, and the significant improvement in mean CMT at EpM-2M in Group A might have mainly been the effect of triamcinolone acetonide. On the other hand, we evaluated not only mean CMT but also mean 3mMT, which represents a 9-fold increase in the area evaluated. Since DME typically spreads over multiple subfields in the retinal thickness map, more exact assessment of the efficacy of EpM requires examination of a wider area around the fovea. In each examination (all eyes, Group A, and Group B), mean 3mMT was improved at EpM-6M, but the improvement rate was lower than that in mean CMT. Because DME in almost cases is asymmetrical clinically, the rate of normal retinal thickness area within 3 mm diameter of the fovea could be greater than that within 1 mm diameter of the fovea in patients with DME. This might have led to the lower improvement rate in mean 3mMT, because macular thickness does not decrease in the area without thickened retina.

This study has certain limitations. First, since there are only a limited number of articles related to subthreshold photocoagulation in the literature and details of the treatments are not completely resolved, we used articles related to subthreshold micropulse as references in this study, although EpM and subthreshold micropulses, despite being similar, are not identical. Second, the small number of cases evaluated might have influenced the statistical results in this study. Studies including a larger number of cases might help to clearly identify the effect of EpM. Third, we did not evaluate BCVAs. BCVA and central subfield thickness cannot always be used interchangeably as indicators of clinical efficacy of treatment [5]. Future studies evaluating BCVA will be important.

In conclusion, monthly EpM treatment was efficacious against persistent DME after ILM peeling. In particular, the efficacy was greater in eyes in which the time interval between vitrectomy and initial EpM was greater than 6 months. Furthermore, continuing efficacy of triamcinolone acetonide, which was injected at the end of vitrectomy, might have contributed to the improvement in macular thickness in the eyes in which the initial EpM was performed within 6 months after vitrectomy. Mean macular thickness within 1 mm diameter of the fovea was a better indicator of improvement in macular thickness in DME, compared with mean macular thickness within 3 mm diameter of the fovea.

DME

Diabetic macular edema, EpM:Endpoint Management™, ILM:Internal limiting membrane, CMT:Central macular thickness within 1mm diameter of the fovea, 3mMT:Macular thickness within 3mm diameter of the fovea, OCT:Optical coherence tomography, BCVA:Best-corrected visual acuity.

Authors’ contributions

H.T. carried out all treatments. H.T. and A.W. performed the statistical analysis and wrote the main manuscript text. H.T. and K.K. prepared the clinical data. T.N. participated in the design and coordination of the study and helped to draft the manuscript. All authors read and approved the manuscript.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Tokyo Rosai Hospital (IRB No.02-11, September 23th, 2020). Written informed consent was obtained from each patient.

Consent for publication

Written informed consent for publication was obtained from each patient.

Availability of data and materials

The data sets generated and/or analysed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.

Competing interests

The authors declare no financial interests in the publication of this manuscript.

Funding

No funding was received for this study.

Acknowledgments

The authors thank the orthoptists at Tokyo Rosai Hospital, Hiroyuki Naruke, Yuka Yanagisawa, and Yuka Kobayashi, for their helpful discussions.

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No competing interests reported.

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Efficacy of Subthreshold Photocoagulation for Persistent Diabetic Macular Edema After Internal Limiting Membrane Peeling: A Retrospective Comparative Study

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Methods

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Background

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