Frequency and Risk Factors for Neovascular Glaucoma After Vitrectomy in Eyes with Diabetic Retinopathy: An Observational Study

The incidence of postoperative NVG after PPV in our study was considerably lower than has been found in previously published series in which it was only 4.6% [3‐5, 7‐9]. The low incidence may be associated with significant advancements in surgical techniques, such as the use of a wide-angled viewing system, high cutter speed, minimally invasive PPV, and anti-vascular endothelial growth factor adjuvants before surgery. A recent study of 127 eyes with PDR reported that the occurrence of NVG was 11.8% after PPV [10], and this was also higher than the results of our study. The reasons may be that the inclusion criteria of our study were more stringent.

The main aim of this study was to detect the risk factors for postoperative NVG in PDR eyes after PPV. Our results show that preoperatively high IOP combined with VO, no intravitreal injection of anti-VEGF drugs, more severe PDR, and higher HbA1c levels were significant predictors of NVG (Table 3).

As many studies have reported [3, 10], a high baseline IOP is a risk factor for NVG. In the early stage, NVI usually appears as small vascular tufts that result from the leakage of protein and cells from the micro-NVI [11], and the IOP may be elevated before the NVI can be observed by gonioscope. A small NVI can sometimes be detected by iris fluorescein angiography (IFA) [12], and we will explore the significance of IFA in the early diagnosis of NVI in future studies. Many large epidemiological studies have found that diabetic patients are at high risk for glaucoma: The Rotterdam study found that diabetes is correlated with primary open-angle glaucoma [13]. The Blue Mountain study also obtained similar conclusions [14]. Finally, some scholars believe that elevated IOP may be one of the symptoms of diabetic autonomic dysfunction [15, 16].

Many studies on retinal vein occlusion (RVO) have clearly shown ischaemic RVO eyes are at risk of developing ocular neovascularization. Moreover, many studies have shown that diabetes mellitus is significantly associated with RVO [17, 18], especially when present with central retinal vein occlusion (CRVO) [19]. Diabetic patients with microvascular and microcirculatory disorders due to long-term hyperglycaemia had a higher risk than other patients of vascular occlusion. In addition, the appearance of a vascular white line is predicted to be a serious manifestation of PDR. The condition causing retinal ischaemia is aggravated, and the concentration of VEGF is increased. Studies of clinical specimens have shown that there is a strong correlation between increases in intraocular VEGF levels and the development of PDR [20], and retinal vascular occlusion often indicates poor vascular function in the whole body. Studies have shown that carotid plaque is associated with RVO [21] when vascular occlusion is found pre- or during PPV, and there is a substantial risk of ocular ischaemic syndrome, which causes NVG. Fewer studies have explored the combination of PDR with VO, and there are also few corresponding epidemiological studies. In our opinion, awareness of this syndrome needs to highlight diabetes-related ocular disease.

Our results illustrate the fact that different grades of PDR for PPV are associated with widely different results. The more serious DR, especially the detached retina, has lost its supply of blood from the choroid, is more ischaemic, and may produce greater amounts of vaso-proliferative factors. In addition, in patients with severe PDR, the systemic disease is also more severe, leading to a greater likelihood of carotid plaque, resulting in a higher occurrence of NVG [22]. An earlier study published in 1998 demonstrated that PDR patients with TRD are more prone to NVG [23], and some other studies have shown that more serious PDR is more dangerous to low vision and increases the incidence of NVG [24, 25].

Treatment with an intravitreal injection of anti-VEGF has been shown to be an efficient and safe treatment for NVG in multiple studies [26‐28]. Castillo et al. reported that 156 patients who received preoperative IV anti-VEGF drugs 5–10 days prior to PPV demonstrated significantly better BCVA and fewer postoperative complications at 6 months. Similarly, previous studies have administered preoperative IV anti-VEGF drugs from 1 to 33 days before PPV for PDR-related complications [26, 27, 29‐31]. All these results indicate that preoperative treatment with IV anti-VEGF drugs may represent a strategy to make PPV safer and more effective for severe PDR. However, few studies have reported whether preoperative IV anti-VEGF drugs are associated with postoperative NVG. To our knowledge, bevacizumab induces the regression of retinal neovascularization in patients with PDR, and the regression of the vascular component of fibrovascular complexes after treatment with IV anti-VEGF drugs facilitates the segmentation and delamination of membranes and thereby greatly reduces the likelihood of intraoperative bleeding. The resolution of VH and less intraoperative bleeding may in turn provide a clear surgical field and shorten surgical times. A clearer surgical field can reduce iatrogenic retinal breaks, improve panretinal photocoagulation (PRP), and decrease the incidence of NVG. Contrary to our conclusion, Kwon et al. reported that postoperative intravitreal bevacizumab (IVB) is a risk factor for postoperative NVG [10]; however, when comparing their and our results, it must be noted that the optimal timing of preoperative IVB is very important. Surgeons performing PPV on patients with PDR should consider administering preoperative IVB 5–10 days prior to PPV, especially in cases with severe grades of vitreoretinal adhesion, and this information was not clearly presented in their paper. Overall, further clinical trials should be performed in the future to determine the association between preoperative IV administration of anti-VEGF drugs and postoperative NVG.

Glycated haemoglobin, which has an average lifetime of 120 days and the blood level of which represents the average blood glucose concentration for that period, is an important index of systemic factors. In a previous report, when HbA1c levels were 6.5% or higher, the risk of diabetic retinopathy was exacerbated [32]. A large epidemiological survey performed in the USA, the Diabetes Control and Complications Trial (DCCT), showed that when glycosylated haemoglobin is reduced by 10% (e.g., from 7% to 6.3%), the progression of retinopathy is reduced by 35–40%, that is, patients with 10% glycosylated haemoglobin will have a risk of developing diabetic retinopathy when glycosylated haemoglobin decreases to 7% [33]. The results of the United Kingdom Prospective Diabetes Study (UKPDS) also show that for every 1% reduction in glycated haemoglobin, the complications of diabetic retinopathy were reduced by 35% [34]. Another clinical study performed in 2017 also showed that if blood glucose control is not satisfactory after PPV, the risk of postoperative neovascular glaucoma is greater [10]. This may be because PPV for PDR will cause damage to the retina, and postoperative ischaemia–reperfusion injury will also lead to increased retinal inflammation and if combined with postoperative hyperglycaemia will lead to increased microcirculatory damage to the retina, eventually leading to a large release of VEGF. In addition, in patients with proliferative diabetic retinopathy, promoting neovascularization factor functions are stronger than those of inhibiting neovascularization factors. Vitreous barrier function is weakened after vitreous surgery, resulting in faster diffusion of VEGF, making the vascular endothelium of the anterior segment an area of increased concentration of growth factor which causes neovascularization of the iris, and postoperative hyperglycaemia also exacerbates this process. Furthermore, in addition, hyperglycaemia can cause systemic microcirculatory disorders, leading to hypoperfusion retinopathy (ocular ischaemic syndrome) and causing rubeosis iridis [35].

Contrary to this work, previous studies have found that PPV combined with cataract extraction is a risk factor for postoperative NVG [4, 36‐38]. This may be because the previous research time was relatively early; during that time, cataract surgery could damage the barrier function of the posterior capsule and suspensory ligament. With the development of cataract phacoemulsification technology, surgical trauma is greatly reduced.

We also found that male sex, younger age, type 1 diabetes, and a longer duration of diabetes were also considered risk factors for postoperative neovascular glaucoma in previous studies [3, 5, 8, 10]. In this study, of the patients who developed NVG, six were male and five were female; the youngest was 42 years old and the oldest was 72; the prevalence of type 1 and type 2 diabetes was similar; and the shortest the duration of diabetes was 2 years, while the longest was 30 years. None of these results were statistically significant.