Currently, intravitreal injection of anti-VEGF drugs is the standard treatment for neovascular ARMD. Patients with neovascular ARMD require long-term repeated intravitreal injections during anti-VEGF therapy (6, 15). Repeated injections may lead to complications such as uveitis, endophthalmitis, subconjunctival haemorrhage, elevated intraoc ular pressure, retinal detachment, retinal pigment epithelium tears, corneal nerve fiber and sensitivity loss (16–18). As a common complication of ocular surgery, VMIA has been discussed as an influencing factor of anti-VEGF efficacy in previous studies (12). To assess the interrelationship between the intravitreal injection therapy and the development of VMIA, this study analyzed a cohort of ARMD eyes receiving anti-VEGF therapy. In our results, 49.4% of ARMD eyes at baseline had presented any VMIA and these were roughly equivalent to Leuschen et al. report (19). This prevalence is higher than that in controls with adjusted age. VMIA was considered to be a pathogenesis of ARMD, as traction would lead to pigment epithelial detachment and spread of VEGF (20).
In our study, 10.3% of the eyes had the occurrence or development of VMIA after receiving anti-VEGF treatment, which was lower than Chang et al.(21) and Kinra et al.(22). These two studies involved different underlying diseases, such as diabetic macular edema and retinal vein occlusion. Diabetic retinopathy and retinal vein occlusion mainly involve the inner retinal structure, the VEGF and inflammatory factors are more likely to affect the VMI. Therefore, the response of VMI to VEGF treatment is different in different clinical entities.
In this study, 13.3% of VMA eventually developed PVD, which is higher than the 5.6% incidence of PVD reported by Veloso et al.(23). The difference may be due to the small sample size. PVD occurred at very similar time points in both studies, both within three injections. Although PVD can occur spontaneously due to its natural history, the fact that PVD occurred in all eyes in these studies within a relatively short time after intravitreal injection suggests that PVD in these cases may be caused by intravitreal injection rather than coincidence. Therefore, we speculate that intravitreal injection may lead to PVD due to its mechanical effect.
It was reported that the coexistence rate of ERM accounts for 15–38% of ARMD eyes(24), which is consistent with 14.9% in our group. The incidence rate of ERM in ARMD eyes was higher than that in the normal eyes. This was thought to be due to inflammation or preretinal glial cells in ARMD than control (25). Previous studies believe that PVD was significantly associated with the formation of ERM (26). However, in our study, the original ERM was significantly thickened in 2 eyes after intravitreal injection, and 1 eye with VMA developed ERM. It seems that VMIA contribute more to the development of ERM. Some researchers believe that the chronic vitreous traction caused the migration of glial cells, macrophages, or pigment epithelial cells, and leads to ERM, which further supports our findings (27, 28).
Regarding the risk factors of VMI changes in patients treated with intravitreal injection of anti-VEGF drugs, in the report of Kinra et al. (22), VMIA, cataract extraction and age are the influencing factors of VMI changes. Stallman et al. observed differences between sexes with respect to the induction of PVD (29). Chang et al. observed that poor BCVA was an important factor associated with the development of VMIA (21). However, we did not find a correlation between cataract extraction, age, sex, BCVA, and the development of VMIA in ARMD eyes treated with intravitreal injection. In our study, pre-existing VMIA was an independent risk factor for post-injection VMI changes. Possible reasons for this phenomenon: Some VMAs are a staged state in the natural process of PVD, the perturbation during injection and the destruction of the vitreous gel collagen framework by the injection fluid accelerate the development of PVD (29); The physicochemical effects of drugs lead to immune and inflammatory responses that stimulate the migration of glial cells, macrophages or pigment epithelial cells caused by vitreous traction (27), which ultimately accelerates the occurrence and development of ERM.
This study showed that the CRT of the VMI changed group and the VMI unchanged group were significantly decreased after anti-VEGF treatment, indicating that the anti-VEGF treatment was effective in both groups. Although BCVA was improved in both groups, there was no significant difference in BCVA before and after treatment in the VMI changed group. It may be due to the small sample size and insufficient statistical effect.
The main limitation of our study is that there was no control of eyes with ARMD and without any injection, and its retrospective nature. It is necessary to conduct further prospective large sample research on these parameters.
In conclusion, intravitreal injection of anti-VEGF drugs has a certain probability to cause changes in VMI, and the risk is higher in eyes with pre-existing VMIA. The effect of intravitreal injections on VMI was concentrated in the first three injections, and subsequent increases in the number of injections did not significantly increase the risk of VMIA.