Prognostic Evaluation of Vitrectomy Assisted by Lucentis in Diabetic Retinopathy and Neovascular Glaucoma.

For verifying the prognosis of Lucentis-assisted vitrectomy (PPV) in diabetic retinopathy (DR) and neovascular glaucoma (NVG), a retrospective analysis of DR and NVG patients who were admitted to our hospital from July 2019 to December 2020 was conducted. According to the treatment protocol, subjects who had PPV intervention were in the control group (CG; n = 38) and those receiving Lucentis adjunctive PPV were included in the intervention group (RG; n = 40). The indicators between groups were listed: treatment success rate, postoperative complication rate, surgical outcome indicators, BCVA, intraocular pressure (IOP) change, foveal thickness, and VEGF level in aqueous humor. Indicators in RG were obviously higher than in CG, such as treatment success rate and surgical outcome indicators. Conversely, lower postoperative complication rate, postoperative BCVA, IOP, retinal fovea thickness, and VEGF level in aqueous humor were found in RG than in CG. Therefore, the study reached the following conclusions about vitrectomy assisted by Lucentis: (1) it effectively increases the success rate of treatment, decreases postoperative complications as well as surgical risks, and improves patients' vision; (2) it promotes the recovery of IOP, reduces macular edema and VEGF levels in aqueous humor, and inhibits the neonatal formation of blood vessels. It is finally confirmed that Lucentis adjuvant PPV in the treatment of DR complicated with NVG is safe and feasible.

1. Introduction

Diabetes, a commonly seen chronic disease in clinics, will trigger multiple complications if blood sugar is not well controlled, among which diabetic retinopathy (DR) is the dominant one [1]. And, DR is often accompanied by neovascular glaucoma (NVG) with the deterioration of the disease [2]. The occurrence of NVG is due to the decrease in retinal blood supply, which triggers retinal ischemia and hypoxia, resulting in elevated vascular endothelial growth factor (VEGF) production in the retina. As such, a massive wide variety of new blood vessels are formed in the iris, chamber angle, and trabecular meshwork, which causes obstruction of the trabecular meshwork and the progressive closure of the chamber angle, thus preventing the normal outflow of aqueous humor, increasing intraocular pressure (IPO), and causing severe eye pain [3-5]. With the continuous increase of IOP, ocular ischemia and hypoxia cannot be controlled, contributing to optic nerve damage and visual impairment, which not only brings enormous damage to patients' bodies and minds but also greatly reduces their quality of life [6]. NVG has become a very common refractory glaucoma due to its severe clinical symptoms, great harm to the visual function of patients, and high blindness rate [7]. Currently, most scholars believe that its pathogenesis is mainly associated with retinal hypoxia and ischemia caused by ocular tissue diseases and a series of changes due to VEGF overexpression [8]. Therefore, the key to the treatment of NVG is to start from the pathogenesis, reduce and control the excessive IOP quickly, save the existing visual function, and make an early diagnosis and treatment of primary diseases [9]. At this stage, the treatment methods for DR with NVG include drug therapy and surgery [10]. Single drug treatment or surgical treatment cannot fundamentally treat NVG, and the characteristic of easy rupture and bleeding of new blood vessels also increases the difficulty of surgery. Hence, it is of great significance to explore a safe and effective treatment in the clinic [11].

Pars plana vitrectomy (PPV) is a commonly used surgical procedure in ophthalmology for patients with DR and NVG. It can effectively remove hematocele in the vitreous and improve the retinal traction force, which is conducive to retinal repositioning and vision restoration [12]. However, this surgical scheme can only solve the problem of hematocele but cannot ameliorate the formation of new blood vessels from the source. Meanwhile, this operation can easily cause retinal damage, macular edema, and other complications, which are detrimental to the postoperative recovery of patients [13]. With the deepening of the understanding of NVG's pathogenesis, anti-VEGF drugs have gradually become a hot spot for treating NVG [14]. Lucentis, a recombinant clonal antibody fragment against VEGF, has a slightly higher affinity for all isomers of VEGF [15]. Besides, it is shown that Lucentis can avoid complications such as hyphema while creating better conditions for further surgery and improving the success rate of surgical treatment [16]. However, there is relatively little research regarding the employment of Lucentis-assisted PPV for the treatment of DR with NVG [17].

Therefore, the purpose of this study was to explore the clinical efficacy of Lucentis-assisted PPV in the treatment of DR and NVG.

2. Materials and Methods

2.1. General Data

The hospital Ethics Committee agreed on the study, and the patients and corresponding dependents signed knowledgeable consent. The patients with DR and NVG admitted to our hospital between July 2019 and December 2020 were analyzed retrospectively. According to the treatment plan, patients intervened with PPV as the control group (CG; n = 38) and those receiving Lucentis and PPV as the research group (RG; n = 40). Inclusion criteria are as follows: all subjects met the diagnostic criteria of NVG [18] and were diagnosed for the first time and eligible for surgical indications, with the DR stages IV-V and NVG stages I-II. Exclusion criteria are as follows: history of ocular trauma or severe ocular infection; retinal detachment; history of eye surgery; history of Lucentis treatment or drug allergy; serious blood system diseases; cognitive dysfunction, and neurological damage; extreme major organ injury; blood coagulating defects.

2.2. Treatment Methods

Preoperative IOP was measured for all patients, and local or systemic IOP lowering treatment was used for those with high IOP so that the preoperative IOP was controlled within the normal range. All participants were followed up for 6 months after the operation.

Patients in CG underwent PPV operation directly. Before surgery, the eyeballs were anesthetized with a 1 : 1 mixture of 0.02 g/mL lidocaine hydrochloride (Rongsheng Pharmaceutical, Sinopharm Group, Henan, China, H20043676) and 7.5 g/L bupivacaine (Zhaohui Pharmaceutical, Shanghai, China, H20056442), and three-channel PPV was performed after the anesthesia took effect. During the operation, the IOP was maintained, most of the vitreous body was resected, and the neovascularization membrane was cleared to relieve peripheral and retinal traction, so as to reattach the retina and perform pan-retinal photocoagulation. No special treatment was required for minor intraoperative bleeding. In case of massive bleeding, electrocoagulation was used to stop bleeding. The intraoperative movement was gentle to prevent choroid detachment.

Patients in RG were pretreated with Lucentis. Three days before the injection of Lucentis, 5 g/L levofloxacin eye drops (Nengden Factory, Osaka, Japan, J20150106) were administered four times a day for three days. On the day of Lucentis injection, topical anesthesia was performed with proparacaine hydrochloride eye drops (S.A.AlconCouvrourN.V, 2870 Puurs, Belgium, H20160133). The conjunctival sac was rinsed, and the needle was inserted vertically at 11 : 00, about 4 mm behind the corneal limbus. Afterward, 0.5 mg Lucentis (Novartis Pharma Schweiz AG, Switzerland, s20170003) was slowly injected into the vitreous cavity, once only. IOP was strictly controlled 1 hour after injection, and PPV was performed 7 days after injection, which was the same as that of CG.

Patients in both groups were sutured with absorbable thread after the operation and were given tobramycin and dexamethasone eye ointment (ALCON CUSI s.a, Barcelona, Spain, HJ20181126). Stage II surgery (implantation of aqueous humor drainage valve) was performed for patients who failed to control IOP after PPV. 10–15 days after PPV, stage II Ahmed aqueous humor drainage valve implantation was performed after iris neovascularization basically subsided and anterior chamber inflammation was obviously alleviated. Posterior peribulbar anesthesia was used during the operation. A conjunctival flap based on the fornix was made in the superior temporal quadrant, and the drainage disc was fixed on the superficial sclera 9-10 mm behind the corneal limbus. The Ahmed glaucoma valve (AGV) drainage tube was trimmed to a suitable length and inserted into the anterior chamber and fixed on the superficial sclera. After suture, the eyes were coated with tobramycin and dexamethasone eye ointment. Postoperatively, tobramycin and dexamethasone eye drops were used 4 times a day and compound tropicamide eye drops (Santen Pharmaceutical, Suzhou, Japan, J20180051) 2 times a day.

2.3. Outcome Measures

2.3.1. Primary Outcome Measures

Treatment Success Rate. Efficacy evaluation criteria: complete success: IOP < 21 mmHg without any IOP lowering drugs; partial success, IOP < 21 mmHg with IOP lowering drugs; failure: after maximum use of drugs for glaucoma, IOP >21 mmHg or complications occurred during maximum use of glaucoma medications, requiring additional ocular surgery. Treatment success rate = (complete successful cases + partial successful cases)/total cases ×100%. Basic indicators of operation: operation time, neovascular bleeding times, and the use of electrocoagulation were recorded. Best corrected visual acuity (BCVA): the BCVA was detected before and 6 months after the operation in both arms. IOP: before and 6 months after surgery, the IOP was measured with a Topcon CT80 A noncontact tonometer (Topcon, Japan, CT80 A). Fovea thickness: six months after the operation, the fovea thickness of the two groups was measured by optical coherence tomography.

2.3.2. Secondary Outcome Measures

VEGF level in aqueous humor: the aqueous humor was collected before and 6 months after surgery, for measuring the VEGF content using ELISA according to the instructions of the human VEGF ELISA kit (Jingkang Bioengineering, Shanghai, China, JK-ELISA-00407). Incidence of complications: vitreous hemorrhage, retinal detachment, and transient intraocular hypotension were recorded.

2.4. Emergency Treatment during Operation

There were often some emergencies during operation. When this happened, vitrectomy was performed for the preretinal proliferative membrane. Retinal hemorrhage is treated with laser photocoagulation, and neovascularization can be treated with anti-VEGF.

2.5. Statistical Methods

Data were analyzed using SPSS24.0. Enumeration data (n (%)) were tested between groups via the Chi-square test. Quantitative data, recorded in mean ± standard deviation ( ± SD), were analyzed between groups by the t-test of independent samples and before and after treatment within the group by the paired t-test. The difference was deemed remarkable when P < 0.05.

3. Results

3.1. Medical Statistics

There were 24 males and 16 females in RG and 20 males and 18 females in CG (P=0.511). The average age in RG and CG was 53.16 ± 14.04 and 52.64 ± 13.75 years (P=0.869). The clinical data, for instance, BMI, course of diabetes, NVG staging, and marriage, differed insignificantly between RG and CG (P > 0.05), as shown in Table 1.

Table 1

General clinical information.

Category	Research group (n = 40)	Control group (n = 38)	t/χ2 value	P value
Sex
Male	24 (60.00)	20 (52.63)	0.430	0.511
Female	16 (40.00)	18 (47.37)
Age (years)	53.16 ± 14.04	52.64 ± 13.75	0.165	0.869
BMI (kg/m2)	23.62 ± 2.13	23.55 ± 2.25	0.141	0.888
Course of diabetes	9.86 ± 3.14	9.21 ± 3.38	0.880	0.381
NVG staging
I	28 (70.00)	25 (65.79)	0.158	0.690
II	12 (30.00)	13 (34.21)
Marital status
Married	24 (60.00)	26 (68.42)	0.600	0.438
Single	16 (40.00)	12 (31.58)
Residence
Urban	18 (45.00)	17 (44.74)	0.001	0.981
Rural	22 (55.00)	21 (55.26)
Educational background
≥ High school	9 (22.50)	10 (26.32)	0.154	0.694
< High school	31 (77.50)	28 (73.68)
History of smoking
Yes	14 (35.00)	15 (39.47)	0.167	0.682
No	26 (65.00)	23 (60.53)
History of hypertension
Yes	29 (72.50)	25 (65.79)	0.412	0.521
No	11 (27.50)	13 (34.21)

3.2. Treatment Success Rate

After treatment, the treatment success rate was notably higher in RG (38/40, 95.00%) than in CG (30/38, 78.95%) (P < 0.05), as indicated in Table 2.

Table 2

Treatment success rate.

Groups	Complete success	Partial success	Failure	Success rate
Research group (n = 40)	23 (57.50)	15 (37.50)	2 (5.00)	38 (95.00)
Control group (n = 38)	14 (36.84)	16 (42.11)	8 (21.05)	30 (78.95)
χ 2	—	—	—	4.493
P	—	—	—	0.034

3.3. Basic Information about Operation

The operation time in RG was shorter than in CG (1.61 min vs. 2.17 min, P < 0.01). Similarly, the neovascular bleeding time and electrocoagulation use time were also markedly lower in RG than in CG during operation, as indicated in Figure 1(.

Figure 1

Basic operation information. Operation time (a), neovascular bleeding time (b), and electrocoagulation use time (c). P < 0.01.

3.4. BCVA

The BCVA was not evidently different between RG and CG preoperatively (P > 0.05). However, 6 months after surgery, the BCVA was noticeably reduced in both arms, with a significantly lower reduction in RG (P < 0.05), as suggested in Figure 2.

Figure 2

BCVA. P < 0.01.

3.5. IOP

The IOP differed insignificantly between the two arms preoperatively (46.7 mmHg vs. 47.3 mmHg, P > 0.05). After surgery, the IOP was dramatically reduced in the two groups (17.3 mmHg vs. 19.1 mmHg, P < 0.01), which was lower in RG (P < 0.05), as indicated in Figure 3. Six months after the operation, the intraocular pressure decreased significantly in both groups, which was significantly lower in the RG than in CG (P < 0.01).

Figure 3

Intraocular pressure. P < 0.01.

3.6. Fovea Thickness

The fovea thickness was 245 µm in RG and 291 µm in CG, indicating that the fovea thickness was statistically lower in RG than in CG after surgery (P < 0.05), as indicated in Figure 4.

Figure 4

Fovea thickness. P < 0.01.

3.7. VEGF Level in Aqueous Humor

The VEGF level in aqueous humor was similar in RG and CG before surgery (P > 0.05). Six months after surgery, the VEGF level in aqueous humor reduced remarkably in both arms, which was lower in RG (P < 0.05), as suggested in Figure 5.

Figure 5

VEGF levels in aqueous humor. P < 0.01.

3.8. Incidence of Complications

After treatment, the complication mainly included vitreous hemorrhage, retinal detachment, and transient intraocular hypotension. The complication rate was 10.00% in RG and 28.95% in CG (P < 0.05), as suggested in Table 3.

Table 3

The incidence of complications.

Groups	Vitreous hemorrhage	Retinal detachment	Transient intraocular hypotension	Incidence of complications
Research group (n = 40)	1 (2.50)	0 (0.00)	3 (7.50)	4 (10.00)
Control group (n = 38)	4 (10.53)	2 (5.26)	5 (13.16)	11 (28.95)
χ 2	—	—	—	4.504
P	—	—	—	0.033

4. Discussion

NVG is often secondary to severe ischemic retinal disease of the whole body or eyes [19]. PPV is one of the most commonly used surgical methods to treat NVG patients [20]. However, during the operation, many thorny problems are often encountered, such as difficulty in stripping the anterior proliferative membrane of the retina, macular edema, and retinal hemorrhage, which bring great difficulties to the operation and affect patient outcomes. A study shows that inhibiting the secretion of angiogenic factors and preventing vascular proliferation is the key to treating NVG [21]. Hence, in this study, we combined Lucentis with PPV for the treatment of DR and NVG to explore its clinical efficacy.

Guan et al. [22] found that PPV with Lucentis preconditioning internal limiting membrane (ILM) peeling for severe proliferative DR complicated with macular edema (ME) could significantly ameliorate BCVA and CMT of patients and reduce postoperative complications such as operation time and intraoperative bleeding risk. Li et al. [23] found that the combination of Lucentis and surgery for NVG can significantly control IOP and improve BCVA without serious complications. In this study, we found that RG had a higher treatment success rate and lower postoperative complication rate than CG, indicating that the treatment of DR with Lucentis combined with PPV could significantly improve the clinical efficacy, which was similar to the research results of Guan J. Besides, the operation time, neovascular bleeding time, and electrocoagulation use time in RG were notably lower, which indicated that the treatment scheme of Lucentis combined with PPV could significantly improve the operation effect and reduce surgical complications. According to Chen et al. [24], pretreatment with intravitreal injection of Lucentis can reduce bleeding and shorten operation time during and after PPV in young patients with proliferative DR, and it is the same as ours. Besides, there were notably lower BCVA and IOP in RG, suggesting that the combination of Lucentis and PPV could significantly improve the patients' visual acuity and relieve IOP, which may be due to the inhibition of neovascularization by Lucentis, thus ameliorating the patients' visual acuity and IOP. In the study of Shen et al. [25], it was found that intravitreal injection of Lucentis as an adjuvant therapy for NVG with PDVH can validly improve the treatment success rate and control the IOP of patients, which is similar to our research results. This study also determined evidently lower fovea thickness and VEGF level in aqueous humor in RG, indicating that the combination of Lucentis and PPV could significantly ameliorate the macular edema and the VEGF level in aqueous humor, which may be due to the selective combination of Lucentis with VEGF to play a role in inhibiting angiogenesis. Katsanos et al. [26] found in their study that Lucentis can improve the prognosis of glaucoma filtering surgery and NVG, which agrees with our research results.

5. Strengths and Limitations

There are still some deficiencies. For example, there is no animal experiment to verify the mechanism of action. In addition, follow-up can be performed to collect risk factors and provide useful value for postoperative recovery of patients.

6. Conclusion

In conclusion, it is safe and feasible to treat DR with NVG with the combination of Lucentis and PPV, as the treatment plan can significantly improve the success rate of treatment, reduce the surgical risk and postoperative complication rate, and improve the operation effect. Moreover, it can improve the patient's vision, promote the recovery of IOP, reduce macular edema and VEGF of aqueous humor, and inhibit neovascularization.