Comparative analysis of the effectiveness of antiangiogenic therapy and vitrectomy in the treatment of diabetic macular edema occurring against the background of the vitreoretinal interface pathology

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Background

Diabetes mellitus (DM) is a disease that often results in visual function disablement among people aged 40–70 years old [1]. Diabetic macular edema (DME) is a serious diabetes complication that affects a patient’s quality of life, and the incidence of DME among diabetic patients ranges from 3%–29% [2].

Anti-angiogenic therapy by angiogenesis inhibitor intravitreal administration (AIIVA) is currently considered the “gold standard” of DME treatment. Clinical practice and data from multicenter studies prove the efficiency of this method [3–5].

Meanwhile, another manifestation of diabetic retinal disorder, which is often combined with DME, is a change in the vitreoretinal interface (VRI) [6]. Some studies have revealed the effect of VRI pathology on the efficiency of anti-angiogenic therapy for DME [7]. This determines the expediency of vitrectomy with the removal of the posterior hyaloid and the internal limiting membrane, thereby representing an effective method of treating other ophthalmic diseases with VRI pathology. Considering the data on the influence of pathological changes in VRI on the efficiency of anti-angiogenic therapy for DME, vitrectomy should be considered as an alternative and, possibly, the preferred method of treatment in DME.

This work aimed to perform a comparative analysis of the efficiency of anti-angiogenic therapy and vitrectomy in treatment of DME in case of VRI pathology.

Materials and methods

The study included 60 patients (60 eyes) with DME combined with concomitant VRI pathology, as confirmed by the data of optical coherence tomography. All patients were diagnosed with type 2 DM and compensated glycemic level (glycated hemoglobin lower than 7.5%). An optical coherence tomogram revealed one of the variants of VRI pathology (epiretinal fibrosis, vitreomacular adhesion, vitreomacular traction, and extramacular epiretinal membrane). Except for DME, any other ophthalmic pathology capable of reducing visual acuity (tractional retinal detachment, macular hole, occlusion of retinal veins or arteries, glaucoma, etc.) was used as a criterion for exclusion from the study.

The DME patients were distributed into two groups. Group 1 consisted of patients who received three AIIVAs at the start of DME therapy and continued anti-angiogenic therapy as the circumstances required. Anti-angiogenic therapy with ranibizumab administered at a dose of 0.5 mg was performed according to the standard protocol. Group 2 included patients who received three AIIVAs at the start of DME therapy and subsequently underwent surgical treatment in the scope of vitrectomy with peeling of the internal limiting membrane. Surgical techniques included subtotal three-port 25 G vitrectomy, aspiration induction of posterior hyaloid detachment followed by its elevation and removal, and staining of the internal limiting membrane and its removal with forceps. In the presence of indications due to the recurrence of macular edema, AIIVA was performed on the patients in the postoperative period.

Patients in both groups were randomized based on the baseline generally accepted indicators analyzed in the medical literature on anti-angiogenic therapy for DME, namely, visual acuity and central retinal thickness.

The follow-up period was 12 months.

Table 1 presents the main characteristics of patients in the study groups.

Table 1 / Таблица 1

Characteristics of patients in each study group

Характеристики исследуемых групп

Characteristics	Group 1	Group 2
Number of patients (eyes)	30 (30)	30 (30)
Gender (men/women)	15/15	10/20
Average age, years	71 ± 5.2	69 ± 4.4
Average visual acuity	0.30 ± 0.15	0.23 ± 0.13
Average thickness of the central retina, microns	598.5 ± 111.4	573.3 ± 123.3

Each patient underwent a monthly standard ophthalmologic examination, which included visometry according to the Snellen eye chart and spectral optical coherence tomography. The criteria for evaluating efficiency were visual acuity and thickness of the central retina at the end of the study as well as the frequency of AIIVA per year.

Results

In accordance with the aim of this study, we analyzed the changes in visual acuity in patients of the studied groups (Table 2).

Table 2 / Таблица 2

Dynamics of visual acuity in patients with diabetic macular edema under different treatment options

Динамика остроты зрения у пациентов с диабетическим макулярным отеком при различных вариантах лечения

Group	Visual acuity according to the Snellen eye chart
	Baseline	Month 1	Month 3	Month 6	Month 9	Month 12
One	0.30 ± 0.15	0.39 ± 0.21	0.34 ± 0.18	0.34 ± 0.16	0.31 ± 0.17	0.33 ± 0.19
Two	0.23 ± 0.13	0.22 ± 0.143	0.28 ± 0.15	0.32 ± 0.181	0.34 ± 0.21	0.37 ± 0.212

1 р < 0.05 compared to the baseline; 2 р < 0.001 compared to the baseline; 3 р < 0.001 compared to Group 1.

In Group 1, the visual acuity increased statistically significantly from 0.30 ± 0.15 to 0.39 ± 0.2 one month after undergoing AIIVA. In the course of further follow-up and, if necessary, another round of AIIVA, visual acuity decreased to 0.33 ± 0.19, which did not differ statistically from the initial visual acuity.

In Group 2, no statistically significant change in visual acuity was revealed 1 and 3 months after vitrectomy. However, eventually, there was a gradual statistically significant increase in visual acuity from 0.32 ± 0.18 at month 6 to 0.37 ± 0.21 at month 12.

Table 3 presents the results of the analysis of changes in the central retina thickness in the groups during the follow-up period.

Table 3 / Таблица 3

Dynamics of central retinal thickness in patients with diabetic macular edema under different treatment options

Динамика толщины центральной сетчатки у пациентов с диабетическим макулярным отеком при различных вариантах лечения

Group	Central retinal thickness, microns
	Baseline	Month 1	Month 3	Month 6	Month 9	Month 12
One	598.5 ± 111.4	486.1 ± 83.21	509.3 ± 901	506.8 ± 93.21	488.9 ± 99.61	516.8 ± 130.11
Two	573.3 ± 123.3	442.5 ± 112.61	400.3 ± 66.31.2	405.9 ± 86.91, 2	390.9 ± 85.71, 2	383.6 ± 64.91, 2

1 р < 0.001 compared to the baseline; 2 р < 0.001 compared to the group 1.

Analysis of the results presented in Table 3 indicated a statistically significant decrease in the retinal thickness in both groups during the entire follow-up period. However, starting from month 3, the decrease in the central retinal thickness in Group 2 was significantly greater than that in Group 1. By the end of the study, the retinal thickness in Group 2 was close to normal (383.6 ± 64.9), while it was statistically significantly greater in Group 1 (516.8 ± 130.1, p < 0.001).

Furthermore, the analysis of the number of injections performed showed that during the follow-up period, the frequency of AIIVA per year in Group 1 was 5.7 ± 0.9, which was significantly higher than in Group 2 (0.7 ± 1.2, p < 0.001).

Discussion

Pathological changes in VRI are not always an indication for vitrectomy. Such cases include the following:

• vitreomacular traction with an extrafoveolar location, which does not cause traction deformity of the macula;
• extrafoveolar vitreomacular adhesion, which is not considered by some authors as a pathology;
• epiretinal fibrosis, whose surface is not grossly deformed, in the presence of retinal edema; and
• extramacular epiretinal membrane, which forms tangential traction reaching the macular region.

Under the classification of The International Vitreomacular Traction Study Group [8], these changes are not considered as a separate pathology of VRI. In DME patients, these were revealed both during initial diagnostics and during regular anti-angiogenic therapy. However, they are usually not considered as invariable indications for vitrectomy. In accordance with the existing contemporary approach to the treatment of DME, such patients typically receive anti-angiogenic therapy. However, the absence of a persistent effect from the regular administration of angiogenesis inhibitors in the future suggests that there are signs of DME refractoriness in the therapy performed. The therapeutic approach can consist either in the continuation of anti-angiogenic therapy, which provides a short-term effect, or changing to other algorithms focused on alternative pathogenetic links of the disease. In our case, vitrectomy was chosen as an algorithm as part of a method of influencing the VRI pathology.

The current study’s findings revealed that the continuation of regular anti-angiogenic therapy for DME with concomitant pathology of VRI led to a short-term increase in visual acuity in month 1 after the onset of treatment. In the future, the achieved functional effect may decrease to the initial indices of visual acuity. The continuation of regular anti-angiogenic therapy with a follow-up period of up to 12 months promoted the stabilization of functional indicators. At the same time, in the group of patients who underwent vitrectomy, a progressive increase in visual acuity was registered compared to the initial values by the end of the follow-up period.

Optical coherence tomography data demonstrate clearly that, in DME with concomitant VRI pathology, the retinal thickness decreased progressively in the central zone both in the anti-angiogenic therapy group and in the vitrectomy group. This thickness was significantly less than the initial values by the end of the follow-up period. At the same time, by the end of the follow-up period, the average retinal thickness in the vitrectomy group had decreased to almost normal values, while in the anti-angiogenic therapy group, residual retinal edema was registered. Furthermore, the decrease in retinal thickness in the vitrectomy group was significantly greater than in the anti-angiogenic therapy group as early as 3 months after the case follow-up.

Moreover, a significantly greater number of intravitreal injections of an angiogenesis inhibitor were required to relieve the retinal edema in the anti-angiogenic therapy group during the entire follow-up period compared with the vitrectomy group.

The obvious efficiency of vitrectomy illustrates the importance of such a link in the DME pathogenesis as a traction component. In this regard, it can be assumed that DME is also induced by the traction component in patients with a vitreoretinal interface pathology in DM. Therefore, in the absence of efficiency of the anti-angiogenic therapy, the change to vitrectomy should be considered.

Conclusions

1. In DME patients with concomitant pathology of VRI, vitrectomy significantly improved visual acuity by the end of month 12 of the case follow-up, in contrast to patients receiving only regular anti-angiogenic therapy.
2. In DME patients with VRI pathology, comprehensive treatment (anti-angiogenic therapy + vitrectomy) resulted in a significant decrease in central retinal thickness and the number of injections of angiogenesis inhibitors.

About the authors

Ernest V. Boiko

Interindustry Research and Technology Complex “Eye microsurgery” n.a academician S.N. Fyodorov”; North-Western State Medical University named after I.I. Mechnikov; Military Medical Academy named after S.M. Kirov

Email: boiko111@list.ru

Professor, Doctor of Medical Science, Honored MD of Russian Federation, Director; Professor, Head, Ophthalmology Department

Russian Federation, Saint Petersburg

Dzhambulat H. Oskanov

Interindustry Research and Technology Complex “Eye microsurgery” n.a academician S.N. Fyodorov”

Author for correspondence.
Email: oskanovd@mail.ru
ORCID iD: 0000-0001-8842-2643

врач-офтальмолог

Russian Federation, Saint Petersburg

Sergei V. Sosnovskii

Interindustry Research and Technology Complex “Eye microsurgery” n.a academician S.N. Fyodorov”

Email: svsosnovsky@mail.ru

Assistant-Professor, PhD, MD of Highest Qualification, Ophthalmologist

Russian Federation, Saint Petersburg

References

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