Management of stage IV neovascular glaucoma in proliferative diabetic retinopathy with single step pars plana vitrectomy + endolaser + trabeculectomy + mitomycin C versus 2-step approach, i.e., pan retinal photocoagulation followed by trabeculectomy + mitomycin C

Shilpi Narnaware; Prashant Bawankule; Dhananjay Raje; Anju Bansal; Richa Gupta

doi:10.4103/erj.erj_9_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 9 | Issue : 1 | Page : 1-7

Management of stage IV neovascular glaucoma in proliferative diabetic retinopathy with single step pars plana vitrectomy + endolaser + trabeculectomy + mitomycin C versus 2-step approach, i.e., pan retinal photocoagulation followed by trabeculectomy + mitomycin C

Shilpi Narnaware¹, Prashant Bawankule¹, Dhananjay Raje², Anju Bansal³, Richa Gupta⁴
¹ VItreo Retinal Surgeon, Sarakshi Netralaya, Nagpur, Maharashtra, India
² Statistician MDS Bio-Analytics Pvt Ltd, Nagpur, Maharashtra, India
³ DNB 2^nd Year, Sarakshi Netralaya, Nagpur, Maharashtra, India
⁴ Glaucoma Specialist, Sarakshi Netralaya, Nagpur, Maharashtra, India

Date of Submission	14-Oct-2021
Date of Acceptance	22-Jul-2022
Date of Web Publication	11-May-2023

Correspondence Address:
Dr. Shilpi Narnaware
Sarakshi Netralaya, 19, Rajiv Nagar, Wardha Road, Nagpur - 440 025 Maharashtra
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/erj.erj_9_21

Abstract

Purpose: To compare the success between single-step pars plana vitrectomy (PPV) + Endolaser (EL) + Trabeculectomy + mitomycin C (MMC) and 2-step approach, i.e., pan-retinal photocoagulation (PRP) followed by Trabeculectomy + MMC in cases of stage IV neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). Methods: Prospective, interventional study including 16 eyes of 16 patients with stage 4 NVG in cases of PDR between July 2019 and December 2020. Depending on the type of surgery, patients were divided into two groups. Group I: PRP followed by Trabeculectomy + MMC (n = 8), Group II: Combined PPV + EL + Trabeculectomy + MMC (n = 8). All patients received intravitreal bevacizumab 3 days before the surgery in both groups. Success criteria were postoperative intraocular pressure (IOP) of <20 mm Hg with or without antiglaucoma medication. Results: Postoperative IOP decreased significantly in both groups, but the mean IOP after 6 months was lower in combined group (17 mm Hg) than trabeculectomy group (22.25 mm Hg; P = 0.204). Combined group required fewer anti-glaucoma medications (mean: 0.88) than trabeculectomy group (mean: 1.38). Cumulative surgical success rates for combined group and Trabeculectomy groups were 100% and 75% respectively. No significant differences in intraoperative complications were observed between the groups. Conclusion: In stage 4, NVG secondary to PDR, single step combined approach including PPV + EL + Trabeculectomy + MMC could be more effective in controlling IOP with better visual outcome than Trabeculectomy + MMC.

Keywords: Intravitreal bevacizumab, mitomycin, pars plana vitrectomy, proliferative diabetic retinopathy, stage 4 neovascular glaucoma, trabeculectomy

How to cite this article:
Narnaware S, Bawankule P, Raje D, Bansal A, Gupta R. Management of stage IV neovascular glaucoma in proliferative diabetic retinopathy with single step pars plana vitrectomy + endolaser + trabeculectomy + mitomycin C versus 2-step approach, i.e., pan retinal photocoagulation followed by trabeculectomy + mitomycin C. Egypt Retina J 2022;9:1-7

How to cite this URL:
Narnaware S, Bawankule P, Raje D, Bansal A, Gupta R. Management of stage IV neovascular glaucoma in proliferative diabetic retinopathy with single step pars plana vitrectomy + endolaser + trabeculectomy + mitomycin C versus 2-step approach, i.e., pan retinal photocoagulation followed by trabeculectomy + mitomycin C. Egypt Retina J [serial online] 2022 [cited 2023 Jun 7];9:1-7. Available from: https://www.egyptretinaj.com/text.asp?2022/9/1/1/376076

Introduction

Neovascular glaucoma (NVG) is a type of secondary glaucoma which is characterized by fibrovascular proliferation in anterior chamber causing pull of peripheral iris into the anterior chamber angle.^[1] This is usually seen secondary to posterior segment ischemia or vaso-occlusive processes which upregulates the expression of vascular endothelial growth factor (VEGF)^[2] that promotes the development of neovascularisation on iris (NVI) and angle.^[3] Proliferative diabetic retinopathy (PDR) is one of the most common causes^[4],[5] contributing to approximately 33% of cases of NVG.^[5] In pre-VEGF era, the incidence of NVI varies from 1 to 17% in diabetic patients^[6] with PDR contributing to 65%^[7] of cases.

Secondary glaucoma causes an increase in intraocular pressure (IOP) which causes reduced ocular perfusion and further increase in retinal ischemia. This vicious cycle should be tackled at the earliest and very judiciously.

The management of NVG should aim at (1) reduction of inflammation, (2) reduction of IOP, and (3) treatment of ischemia can be done using any of the two approaches. The first approach is to tackle ischemic with pan-retinal photocoagulation (PRP) ± anti-VEGF later by glaucoma surgery. The second approach is to deal with ischemia and reduce the IOP simultaneously and aggressively by doing pars plana vitrectomy (PPV) +Endolaser (EL) + Glaucoma surgery.

Since decades, PRP is considered as standard early treatment^[8] in cases of NVG which destroys ischemic retina and decreases the production of VEGF, causing regression of both anterior and posterior segment NV.^[9] However, a response is often not adequate^[10] because of incomplete PRP due to corneal edema, hyphema, cataract, and/or vitreous hemorrhage (VH)^[11] especially in stage IV. Although the effect of PRP is long-lasting, it often takes several weeks,^[12] so the valueable time is lost leading to progressive angle closure and optic nerve damage from elevated IOP, resulting in loss of vision.^[13]

In stage 4 NVG cases, medical treatment is often inadequate with poor success rates^[14] and surgical treatment is mandatory. Previous studies have shown that trabeculectomy with mitomycin C (MMC) usually does not yield desirable results because of high chances of failure.^[14],[15] But with the advent of PRP and perioperative use of anti-VEGF, studies^[16],[17] have shown better results in patients undergoing glaucoma surgeries. Furthermore, Kiuchi et al.^[18] showed better success and reduced complications with PPV + Trabeculectomy + PRP when compared with Trabeculectomy alone.^[19]

Recently, glaucoma drainage implants ± vitrectomy have revealed variable success rates in different studies,^{[20],[21],[22]} but none of the previous studies, directly compared the success rate of PRP followed by Trabeculectomy with MMC versus PPV + EL + Trabeculectomy + MMC in a single sitting in cases of stage 4 NVG secondary to PDR. In this study, we aim to compare between two modalities of treatment and the outcome in terms of final IOP, postoperative need of anti-glaucoma medication (AGM), and gain in visual acuity (VA).

Methods

Study design

Prospective, interventional study on 16 eyes with stage 4 NVG secondary to PDR between July 2019 and December 2020. Eyes were divided into 2 groups depending on the type of surgical procedure. Group I: PRP followed by Trabeculectomy + MMC, Group II: PPV + EL + Trabeculectomy + MMC. Patients with stage 4 NVG secondary to PDR were included while patients with stage other than stage 4, Stage 4 NVG secondary to other vascular retinopathies, history of trauma or any previous retinal or glaucoma surgery, and patients with incomplete followup period were excluded. All patients underwent thorough preoperative ophthalmological examination, including bestcorrected visual acuity (BCVA), IOP, slit lamp examination, gonioscopy [Figure 1]a, and dilated indirect ophthalmoscopy examination. Preoperative lens status and number of AGM were noted. The color photo was taken preoperatively [Figure 1]a and 6 months later [Figure 1]b. IOP was recorded at @ week 1, month 1, 3, and 6 postoperatively. BCVA and number of AGM were recorded at 1 and 6 months. The study was performed according to the ethical standards of the Declaration of Helsinki and was approved by the institutional ethics committee.

Figure 1: (a)Preoperative colour showing NVI, shallow anterior chamber and corneal edema. (b) Preoperative gonioscopy photo showing bleeding, NVA and closed angles. (c)Postoperative photo showing clear cornea and patent PI. (d)Postoperative photo showing bleb, NVA: Neo vascularization of angles

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Surgical success was divided into complete success (IOP <20 mm Hg without AGM) and qualified success (IOP <20 mm Hg with AGM). Failure was defined as uncontrolled IOP despite maximum AGM, persistent hypotony, choroidal detachment, need of re-surgery or loss of perception of light.

Surgical procedure

In group I, after relative control of IOP and corneal edema (approximately 3–5 days) by using topical steroids, mydriatics, and topical and systemic anti-glaucoma medications patients first underwent PRP. Two weeks later, intravitreal bevacizumab (IVB) was given and 3 days later patients underwent Trabeculectomy with MMC. In group II, 3 days after IVB, patients underwent PPV + EL + Trabeculectomy with MMC. Surgical consent was taken from all the patients after explaining all the pros and cons. In group I, after taking corneal stay sutures, fornix-based conjunctival flap was created. Partial thickness (½–1/3^rd thickness) 4 mm × 4 mm scleral flap was created. MMC (0.02%) soaked in the surgical sponge was placed under conjunctival flap for 3 min followed by a thorough saline wash. Kelly's punch was used to create an inner window (2.25 mm²), followed by peripheral iridectomy. Scleral flaps were sutured with one non-releasable 10-0 nylon suture followed by conjunctival suturing. In group II, after partial thickness scleral flap, 23G cannulae were placed. 23G PPV was performed using a noncontact wide-angle viewing system. Following core vitrectomy, the posterior hyaloid was removed by posterior vitreous detachment induction. Membranes were peeled and aggressive PRP (up to ora-serrata) was completed with curved EL 23G probe. The remaining steps of glaucoma surgery were completed. Three sutures were placed on the scleral flap. Following surgery, patients were examined postoperatively at day 1, week 1, month 1, 3, and 6. Patients were considered “lost to follow up” if they did not turn up till 3 months after surgery. After surgery, all patients received topical steroids in tapering doses, mydriatics, and antibiotics for 32-3 weeks. AGM was adjusted according to postoperative IOP.

Statistical methods

Data on various demographic and clinical parameters were summarized according to the measurement scale. Continuous parameters were expressed in terms of mean, standard deviation (SD), and median, while discrete parameters were summarized in terms of numbers and percentages. Parameters such as age, preoperative IOP, and preoperative medication between two groups were tested for statistical significance of difference using Wilcoxon rank sum test, while gender distribution, lens status, and retinal ablation in two groups were compared using Pearson's Chi-square test. Comparison of IOP and number of medications at different postsurgical times between groups were tested using Wilcoxon rank sum test. Within the group comparison of IOP across times was performed using Friedman analysis of variance, while the number of medication between two-time points in each group was compared using Wilcoxon signed rank test. Change in VA, reduction in IOP, and number of medications between two surgical groups was compared using Wilcoxon rank sum test. The success achieved in either group (IOP ≤ 20 mmHg) was compared using Kaplan–Meier analysis.

All analyses were performed using SPSS ver 20.0 (IBM Corp., USA) and statistical significance was tested at 5% level.

Results

[Table 1] provides the descriptive statistics for demographical and clinical parameters of patients in two study groups. The mean age of patients in Group I was 55.87 (SD: 14.9) years, while that in Group II was 64.27 (SD: 5.32) years and the difference of age distribution was statistically insignificant. Gender distribution was the same in both the groups. Moreover, the lens status and retinal ablation in patients from two groups was insignificantly different. Before treatment, the difference in the distribution of IOP in patients, as well as number of medications used by patients from two groups were also insignificant.

Table 1: Descriptive statistics for demographic and clinical parameters of patients in two groups

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Descriptive statistics for IOP and number of medications used were obtained according to time for two groups as shown in [Table 2]. Postsurgical difference in IOP distribution of two groups was statistically insignificant at different times except at 3 months (P = 0.044). One month onward till 6 months, the mean IOP in Group II was lower than that of Group I; although the difference was statistically insignificant. Change in IOP from baseline to 6 months was statistically significant in both the groups (P < 0.0001) using Friedman ANOVA. Reduction in IOP at 6 months in Group II was higher (26 [SD: 6.59] mmHg) than Group I [(20.5 [SD: 8.2]), but this difference was insignificant. Further, the change of VA at 6 months in Group II was higher (4.38 [SD: 3.5] lines) as compared to Group I (1.13 [SD: 2.1] lines); however, the difference was insignificant. The number of medications used by patients at 6 months in two groups differed insignificantly. Change in number of medications used at 6 months as compared to baseline was statistically significant in Group I with P = 0.028 and in Group II with P = 0.011, using Wilcoxon signed rank test. However, the reduction in number of medication used at 6 months was more in Group II (2.13 [SD: 0.83]), as compared to Group I (1.5 [SD: 1.31]), but the difference was insignificant.

Table 2: Comparison of ocular parameters and medications in two treatment groups

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The success achieved in both groups was defined in terms of IOP ≤20 mmHg at end of 6 months. It is evident from [Table 3] that complete, qualified, and overall success in two groups was same in both the groups. Success rates in two groups were also analyzed using nonparametric Kaplan–Meier (KM) analysis. [Figure 2] provides KM plots showing cumulative success rates, using the same success criterion, achieved in two groups across time. The mean time to success in Group I was 96.37 (SE: 29.7) days, while in Group II was 41.87 (SE: 20.7) days. However, the difference in two success rates was statistically insignificant as indicated by log–rank test (2.173) with P = 0.14.

Table 3: Different types of success achieved in two treatment groups at 6 months

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Figure 2: Kaplan–Meier plots showing cumulative success rates (IOP ≤ 20 mmHg) in two treatment groups. IOP: Intraocular pressure

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Discussion

NVG is an aggressive variant causing severe loss of vision in majority of cases. Posterior segment diseases such as PDR, central retinal vein occlusion, and ocular ischemic syndrome can cause extensive ischemia and hypoxia leading to the development of NVG. Hypoxia causes ischemia leading to the liberation of VEGF. Studies^[23] have shown a high level of VEGF in ocular fluids and its inhibition plays an important therapeutic role in the treatment of NVG. Hence, the first step in the management of NVG is, tackling VEGF. This VEGF load can be tackled by two ways: (1) Anti-VEGF, (2) PRP.

According to Yazdani et al.,^[24] anti-VEGF not only reduces VEGF load, but also lowers IOP, but this effect is temporary and therefore requires additional definitive treatment i. e. PRP and surgery.^[16],[25] Studies have shown the beneficial adjunctive role of anti-VEGF in increasing success rate of Trabeculectomy/Ahmed glaucoma valve (AGV) placement/PPV.^[16],[26] According to Chen et al.,^[27] patients who received IVB before Trabeculectomy, encountered decreased rates of intra and postoperative complications and improved final VA.

PRP is another, but more definitive and permanent way of treating VEGF load. Alone PRP^[28] and also when combined with anti-VEGF^[24] has caused a reduction in IOP and regression of NV,^[25] especially so if PRP is done before IOP elevation and only when NV at angle is minimal^[29] i.e., up to stage 2–3.

Second principle in the management of a NVG case is control of IOP. In stage 4, when patients presents with persistent high IOP, PRP ± anti-VEGF is not sufficient to prevent the progression of disease and in such cases, procedures like trabeculectomy with anti-metabolites/shunts are needed to prevent glaucomatous damage to the optic nerve.

The role of PPV in the management of NVG has been studied by Venkat et al.^[30] PPV, not only clears media and decreases VEGF and inflammatory cytokines load, but also increases clearance of VEGF that is produced afterward.^[18] Besides this, vitrectomy facilitates definitive management of posterior segment ischemia by completion of lasers and re-appositioning of retinal layers. It also removes VH and can prevent ghost cell glaucoma. PPV if combined with glaucoma surgeries facilitates all the steps in a shorter time frame.^[31]

In stage 4 NVG, corneal edema secondary to IOP elevation, inflammation, cataractous changes and/or VH precludes good view of retina^[11] and thereby decrease chances of adequate and aggressive PRP. Precious time is lost to control these parameters to facilitate lasers leading to irreversible loss to optic nerve head. It is a vicious circle, where high IOP does not permit lasers and as lasers are not possible, IOP remains high.

In our study, patients were divided into two groups. In group I, the patient underwent PRP after control of inflammation, IOP, and corneal edema. They underwent Trabeculectomy with MMC 2 weeks later. In Group II, PRP was not possible because of persistent high IOP and corneal edema and patients underwent PPV + EL + Trabeculectomy + MMC within 5–7 days of presentation. Both groups received IVB 3 days before the surgery.

Before the advent of anti-VEGF's and anti-fibrotic agents, the failure rate of Trabeculectomy was high in NVG.^[15] But with anti-fibrotic agents, success rate of Trabeculectomy has improved^[18],[32] as these agents blunt the proliferative phase of fibroblast and endothelial cell growth and thereby their replication.^[33] Also adding anti-VEGF 3–7 days before the surgery further increases the success rate of Trabeculectomy + MMC.^[25] However, in spite of anti-metabolites and anti-VEGF, the success rate of Trabeculectomy is less^[14],[34] in NVG when compared to other types of glaucoma.

In our study, in group I, the mean preoperative IOP value of 42.75 mm Hg reduced to mean IOP of 11.8, 20.1, 19.3 and 22.5 mm Hg at 1 week, months 1, 3, and 6, respectively. Need of AGM which was average 2.88 preoperatively (with mean IOP of 42.75 mm Hg), reduced to mean 1.38 post-surgery (mean IOP 22.25 mm Hg) at 6 months. Overall success (Qualified success and complete success) in terms of IOP control was achieved in 62.5% of cases. The mean improvement in BCVA was 1.13 at 6 months. 37.5% of patients showed improvement in vision by >2 lines. In group 1, out of eight patients 3 had GOA, leading to no visual gain. Of these 3 patients, 2 had significant glaucomatous disc damage preceding the surgery itself but achieved good control of IOP postoperatively. One patient had failed bleb with uncontrolled IOP postoperatively. Surgical failure was seen in two cases. The first case had failed bleb within 1 month, while second case had hypotony at 2 weeks and recurrence of NV at 3 months follow up, for which the patient underwent fillin PRP. In group 1, our results are comparable to the results shown by Takihara et al.^[35] who reported success of IOP control in around 62.6%.

In group II, the mean preoperative IOP of 43 mm Hg reduced to mean 15, 16.63, 14.38 and 17 mm Hg at week 1 week, month 1, 3 and 6 respectively. Need of AGM which was average 3 preoperatively (with mean IOP of 43 mm Hg), reduced to mean 0.88 post combined procedure (mean IOP 17 mm Hg) at 6 months. Overall success (Qualified success and complete success) in terms of IOP control was achieved in 62.5% of cases. However, all 8 cases (100%) had near normal IOP (</=24) with or without medication. The mean improvement in BCVA was 4.38 at 6 months. Out of these 62.5% patients showed improvement in vision by >4 lines. One patient out of 8, had GOA preceding the surgery itself, leading to no visual gain but achieved good control of IOP (22 mm Hg) postoperatively.

Combined surgeries have shown a better success rate in various studies.^{[33],[34],[36]} Combined surgery attacks the causative disease aggressively and immediately halts the vicious cycle of inflammation, IOP rise, and source of VEGF leading to better success. One study,^[18] in which PPV and PRP are combined with Trabeculectomy, success was achieved in 55.6% after 1 year.

Combination surgeries involving PPV and shunt surgery have shown conflicting result in different studies. A study by Wang et al.^[31] showed success rates in IOP control of 71.3 with reduction of IOP to 16.9 mm Hg and VA improvement in 38.9% of cases. In another study,^[20] 95.8% patients achieved IOP <21 mm Hg with significant improvement in BCVA. However, this study included >50% cases of steroid-induced glaucoma, with around 12% having post-operative complications. Another study^[37] has reported a significant reduction in IOP after combined PPV + pars plana Baerveldt tube placement, but, experienced decrease in vision in 38% of cases.

Our study differs from all the previously quoted studies in that we had only included Stage 4 NVG secondary to PDR. At par with various studies done with AGV, in Group II of our study, 100% of patients had IOP </=24 mm Hg @ 6 months and 62.5% of patients gained >4 line improvement postsurgery.

In this study, IOP decreased significantly in both the groups, while it was significantly lower in combined group. We also found that fewer AGM is needed in combined group. Out of 8 patients in group II, 3 needed no AGM, 4 needed only 1 AGM and only 1 needed >1AGM post-operatively; compared to group I, where 50% of patients needed 2 or more AGM postoperatively. There was no case of failure in Group II, while 2 failures were seen in group I. Only 1 patient in group II developed GOA compared to 3 in Group I. VA improvement of approximately >4 lines was seen in 5 out of 8 of patients in combined group, while only one patient in group I showed more than 4 line improvement. This unremarkable improvement in vision is explained by the onset of optic atrophy due to long-term raised IOP before surgery in Group I

In our study, like previous studies,^[31],[38] we encountered transient complications which resolved spontaneously in both groups. In group II, there were no intraoperative or severe postoperative complications such as nonresolving hyphema, VH, shallow anterior chamber, choroidal detachment, encysted bleb or severe hypotony. While, 2 cases in Group I, 1 had encapsulated bleb and 1 had hypotony and recurrence of NV.

Hence, in our study, we achieved better results in terms of lowering IOP, number of postoperative medications and VA gain, in combined group. However, the difference in surgical success between two groups is not statistically significant and may be contributed to small sample size and short follow-up.

Conclusion

Early diagnosis and aggressive management to control underlying etiology and high IOP simultaneously is crucial in the management of NVG secondary to PDR. In stage 4, timely aggressive surgical treatment along with medical management is the only way to salvage such eyes. In the stepped approach, PRP is followed by Trabeculectomy + MMC few weeks down the line, leading to periods of uncontrolled IOP, which can compromise visual success. The advent of MMC, anti-VEGF's and safety and predictability of minimally invasive vitreous surgery has revolutionized the management of NVG. Early and combined surgical procedures is safe and better option in controlling IOP and underlying disease simultaneously, thereby preventing further damage caused by loss of golden time in the stepped approach.

Limitations of study

Small sample size
Short Follow up.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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