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. 2021 Jan 14;16(1):e0244281. doi: 10.1371/journal.pone.0244281

Factors correlated with visual outcomes at two and four years after vitreous surgery for proliferative diabetic retinopathy

Katsuhiro Nishi 1,#, Koichi Nishitsuka 1,*,#, Teiko Yamamoto 1,¤, Hidetoshi Yamashita 1
Editor: Andrzej Grzybowski2
PMCID: PMC7808600  PMID: 33444332

Abstract

Proliferative diabetic retinopathy (PDR) is the most severe case of diabetic retinopathy that can cause visual impairment. This study aimed to reveal the factors correlated with better postoperative visual acuity after a long follow-up in patients who underwent vitrectomy for PDR. We retrospectively analyzed the data set including systemic findings, ocular findings, and surgical factors from registered patients who could be completely followed up for 2 or 4 years after vitrectomy. We ultimately enrolled 128 eyes from 100 patients who underwent vitrectomy for PDR between January 2008 and September 2012 and were followed up for >2 years. Among them, 91 eyes from 70 patients could be followed up for 4 years. Factors related to the postoperative visual acuity of ≥20/40 and ≥20/30 after 2 and 4 years were investigated by logistic regression analysis. Better postoperative visual acuity correlated with the following factors: no rubeosis iridis ([≥20/40 at 2 years; odds ratio {OR}, 0.068; 95% confidence interval {CI}, 0.012–0.39; P = 0.003], [≥20/30 at 2 years; OR, 0.07; 95% CI, 0.01–0.40; P = 0.03], [≥20/30 at 4 years; OR, 0.078; 95% CI, 0.006–0.96; P = 0.04]), no fibrovascular membrane [(≥20/40 at 2 years; OR, 0.22; 95% CI, 0.061–0.81; P = 0.02), (≥20/40 at 4 years; OR, 0.26; 95% CI, 0.07–0.94; P = 0.04), (≥20/30 at 4 years; OR, 0.14; 95% CI, 0.04–0.52; P = 0.004)], existing vitreous hemorrhage (≥20/30 at 2 years; OR, 9.55; 95% CI, 1.03–95.27; P = 0.04), and no reoperation ([≥20/40 at 4 years; OR, 0.15; 95% CI, 0.03–0.78; P = 0.02], [≥20/30 at 4 years; OR, 0.06; 95% CI, 0.07–0.54; P = 0.01]). Treatment provision before disease severity and treatment without complications were associated with good postoperative visual acuity.

Introduction

Diabetic retinopathy is the leading cause of visual impairment worldwide [1]. In Japan, it accounts for 12.8% of all newly certified visual impairment cases [2]. Its most severe condition is proliferative diabetic retinopathy (PDR), which can cause visual acuity decrement or visual loss in patients with diabetic retinopathy [3,4]. Vitrectomy is indicated for nonclearing vitreous hemorrhage (VH) or traction retinal detachment [5,6]. The clinical endpoints of PDR treatment were vitreoretinal lesion removal and blindness prevention.

Generally, patients with PDR undergo surgery in their 40s to 60s [7]. Considering that the average life expectancy of patients with diabetes mellitus (DM) is approximately 70 years, those who have undergone vitreous surgery for PDR will live roughly 10–30 years [8]. Hence, the goal for PDR treatment should not only to prevent blindness but also to maintain visual acuity after vitrectomy.

Although the factors correlated with the postoperative visual outcome of PDR have been reported extensively [7,9–11], the postoperative follow-up period varies in each case. To examine PDR cases more accurately, we need to continually assess the postoperative course as long as possible. Treatments for PDR should aim to improve as well as maintain patient’s visual acuity. In this study, we aimed to build a data set that mainly included cases that could be completely followed up 2 or 4 years after a primary surgery and to reveal the factors correlated with the visual outcomes after vitrectomy for PDR.

Materials and methods

This retrospective study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Yamagata University Faculty of Medicine (approval number: H26-21). All data were fully anonymized before we accessed them and the IRB waived the requirement for informed consent. This study investigated 147 eyes from 116 patients with PDR who underwent primary vitreous surgery at Yamagata University Hospital between January 2008 and September 2012. We retrospectively reviewed the medical records of these patients. A total of 106 eyes from 82 patients who had been attending only to Yamagata University Hospital were examined. We also collected the information of patients who had been attending to other hospitals after vitreous surgery. All patients with persistent VH and traction retinal detachment underwent three-port 20-gauge (G) pars plana vitrectomy or microincision vitreous surgery (MIVS) (23-G or 25-G); the 20-, 23-, and 25-G system was used for 71, 45, and 12 eyes, respectively (MIVS for 57 eyes). Two vitreoretinal surgeons performed all the surgical procedures. However, surgical cases of only diabetic macular edema were excluded. All patients did not receive anti-vascular endothelial growth factor (VEGF) therapy as a preoperative adjunct. Pan retinal photocoagulation was cautiously performed before or during vitrectomy on all patients. Participants were treated for vision-affecting lesions such as posterior capsular opacification, progressed cataract, neovascular glaucoma, and diabetic macular edema (DME) during the postoperative course.

Data collected

The systemic factors collected were as follows: age, sex, duration from visual loss awareness to the primary vitreous surgery, hypertension history, DM duration, preoperative glycosylated hemoglobin (HbA1c), oral DM medication, insulin treatment, diabetic nephropathy history, coronary heart disease and/or stroke history, anticoagulant and/or antiplatelet agent administration, preoperative systolic and diastolic blood pressure, heart rate, and blood biochemical examination.

Moreover, the ophthalmologic findings were categorized into three sections: preoperative, intraoperative, and postoperative. The preoperative ophthalmologic findings were as follows: intraocular lens implantation, retinal photocoagulation, the history of intravitreal injection of triamcinolone acetonide, rubeosis iridis, ocular hypertension (>21 mmHg), VH, posterior vitreous detachment, fibrovascular membrane, retinal detachment, and macular detachment. The intraoperative ophthalmologic findings were the following: cataract surgery, intraoperative retinal photocoagulation, gas tamponade, silicone oil tamponade, intraoperative complications (iatrogenic retinal break and retinal dialysis), and the number of used gauge (20-G or MIVS). Lastly, the postoperative ophthalmologic findings were as follows: reoperation and postoperative complications (VH, retinal detachment, and neovascular glaucoma).

For visual acuity measurement, we used a Japanese decimal visual acuity chart placed 5 m away from the patient. We measured decimal visual acuity preoperatively and 3 months, 6 months, 1 year, 2 years, 3 years, and 4 years after the primary vitreous surgery. The decimal visual acuity was converted into Snellen visual acuity and logarithmic minimum angle of resolution (logMAR) to examine visual acuity change.

We compared the decimal visual acuity distribution as well as the amount of vision change between the preoperative period and 2 years postoperatively and between 2 and 4 years postoperatively. An increase of ≥0.3 logMAR unit, a change of <0.3 logMAR unit, and a decrease of ≥0.3 logMAR unit in comparison with the preoperative value were defined as “improvement,” “invariant,” and “worsening,” respectively. We then examined statistically the factors correlated with visual acuity of ≥20/40 Snellen (0.5 Japanese decimal visual acuity) or ≥20/30 Snellen (0.7 Japanese decimal visual acuity) at 2 and 4 years after a primary surgery for PDR. In Japan, driver's license can only be renewed if at least one eye has a visual acuity of ≥20/30.

Statistical analysis

Fisher’s exact test, chi-square test, Mann-Whitney U test and analysis of variance (ANOVA) were used for the statistical analysis. For the factors of P < 0.1, we employed stepwise forward logistic regression analysis. For all the analyses, P < 0.05 was considered to be statically significant. All statistical data were analyzed using the PASW Statistics 18 (SPSS Inc., Chicago, IL, USA).

Results

A total of 128 eyes from 100 patients (87.1%) could be followed up for >2 years after a primary surgery. In total, 91 eyes from 70 patients could be followed-up 4 years after the primary surgery. However, 37 eyes from 30 patients could not be evaluated 4 years after the primary surgery. Therefore, 37 eyes were categorized under the 2–3-year follow-up group. Tables 1 and 2 summarize the demographics of patients. Furthermore, 91 eyes were from 68 men, and 37 eyes were from 32 women. Their mean age was 55.7 ± 9.1 years. Regarding patients’ age during the primary surgery, 29% (37 eyes) of the patients aged <50 years, whereas 61% (78 eyes) aged <60 years. No significant difference was found between the backgrounds of patients that could be followed up for 4 years and of those that could be followed up for 2–3 years postoperatively. In total, 11 patients presented with diabetic macular edema that required additional treatment after vitrectomy. During the research period, VEGF treatment was not approved in Japan, and patients were treated with retinal photocoagulation and local steroid. Seven eyes presented with neovascular glaucoma that required additional treatment after vitrectomy.

Table 1. Patient demographics.

Total 4 years follow-up 2–3 years follow-up P valuea
N = 128 N = 91 N = 37
Age (years) 55.7 ± 9.1 55.1 ± 9.0 57.4 ± 9.1 0.29
Sex (male) 91 66 25 0.67
Duration from visual loss awareness to the primary surgery (months) 3.9 ± 3.8 4.3 ± 4.3 2.9 ± 2.6 0.62
Hypertension 76 53 23 0.84
Diabetes mellitus duration (years) 12.1 ± 6.8 12.1 ± 6.6 11.8 ± 7.3 0.7
HbA1c (%) 7.4 ± 1.3 7.3 ± 1.1 7.7 ± 1.5 0.35
Oral medication for diabetes mellitus 64 43 21 0.44
Insulin treatment 76 55 21 0.84
Diabetic nephropathy 88 57 31 0.12
History of coronary heart disease and/or stroke 23 16 7 1
Anticoagulant and/or antiplatelet agent administration 28 20 8 1
Intraocular lens implantation 38 25 13 0.4
Preoperative retinal photocoagulation 111 81 30 0.26
Intravitreal injection of triamcinolone acetonide 1 1 0 1
Rubeosis iridis 16 13 3 0.4
Ocular hypertension 10 8 2 0.72
Vitreous hemorrhage 102 73 29 1
Posterior vitreous detachment 32 22 10 0.48
Fibrovascular membrane 72 55 17 0.17
Retinal detachment 30 24 6 0.26
Macular detachment 18 14 4 0.78
Cataract surgery 63 45 18 1
Intraoperative retinal photocoagulation 111 76 35 0.15
Gas tamponade 24 20 4 0.21
Silicone oil tamponade 3 2 1 1
Intraoperative complications 15 10 5 1
MIVS 57 54 13 0.24
Reoperation 23 16 7 1
Postoperative complications 32 21 11 0.5
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HbA1c: Glycosylated hemoglobin; BCVA: Best corrected visual acuity; logMAR: Logarithmic minimum angle of resolution; MIVS: Microincision vitrectomy surgery.

a Comparison of patients followed up for >4 years vs. 2–3 years.

Table 2. Demographics of systemic factors in patients.

Total 4 years follow-up 2–3 years follow-up P valuea
N = 128 N = 91 N = 37
Systolic BP (mmHg) 138.9 ± 17.7 138.1 ± 17.7 140.9 ± 17.7 0.79
Diastolic BP (mmHg) 78.5 ± 11.5 78.0 ± 12.1 79.7 ± 10.0 0.63
Heart rate (beats/min) 74.8 ± 9.8 74.0 ± 10.2 77.0 ± 7.9 0.67
TP (g/dl) 6.9 ± 0.5 7.0 ± 0.5 6.9 ± 0.5 0.87
Alb (g/dl) 4.0 ± 0.4 4.0 ± 0.4 3.9 ± 0.5 0.63
T.Bil (mg/dl) 0.6 ± 0.2 0.6 ± 0.2 0.6 ± 0.1 0.26
AST (IU/L) 20.0 ± 6.3 20.4 ± 6.5 19.0 ± 5.7 0.42
ALT (IU/L) 23.6 ± 11.5 24.4 ± 12.3 21.6 ± 9.3 0.52
LDH (IU/L) 204.6 ± 34.8 205.3 ± 36.3 202.8 ± 31.3 0.95
BUN (mg/dl) 21.7 ± 8.7 21.5 ± 8.9 22.2 ± 8.4 0.63
Crea (mg/dl) 1.5 ± 1.0 1.5 ± 1.0 1.5 ± 0.9 0.73
eGFR (ml/min/1.73 m2) 62.6 ± 27.0 64.1 ± 28.0 59.0 ± 24.5 0.54
UA (mg/dl) 5.8 ± 1.3 5.8 ± 1.3 5.8 ± 1.3 0.72
Na (mEq/L) 140.5 ± 1.8 140.6 ± 1.8 140.4 ± 1.9 0.55
K (mEq/L) 4.4 ± 0.4 4.4 ± 0.3 4.5 ± 0.4 0.46
Cl (mEq/L) 104.3 ± 2.5 104.2 ± 2.2 104.5 ± 3.3 0.96
TG (mg/dl) 175.6 ± 88.4 158.2 ± 70.7 221.0 ± 126.1 0.62
TC (mg/dl) 205.4 ± 39.1 201.6 ± 36.4 215.6 ± 45.4 0.25
WBC (/μl) 6708 ± 1564 6725 ± 1745 6668 ± 1128 0.6
RBC (/μl) 428 ± 53.1×104 430 ± 49.7 × 104 421 ± 61.4 × 104 0.62
Hb (g/dl) 12.7 ± 1.6 12.8 ± 1.5 12.6 ± 1.8 0.6
Ht (%) 38.2 ± 4.4 38.5 ± 3.9 37.5 ± 5.3 0.39
Plat (/μl) 23.0 ± 4.8 22.9 ± 5.1 23.4 ± 4.2 0.55
PT (%) 11.1 ± 0.6 11.0 ± 0.5 11.4 ± 0.9 0.28
PT-INR 0.93 ± 0.06 0.92 ± 0.05 0.98 ± 0.11 0.34
APTT (seconds) 28.9 ± 2.9 29.1 ± 2.9 28.2 ± 3.0 0.21
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BP, blood pressure; TP, total protein; Alb, albumin; T.Bil, total bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; BUN, blood urea nitrogen; Crea, creatinine; eGFR, estimated glomerular filtration rate; UA, uric acid; Na, sodium; K, potassium; Cl, chlorine; TG, triglyceride; TC, total cholesterol; WBC, white blood cell; RBC, red blood cell; Hb, hemoglobin; Ht, hematocrit; Plat, platelet; PT, prothrombin time; PT-INR, prothrombin time–internationalized normalized ratio; APTT, activated partial thromboplastin time.

a Comparison of patients followed up for 4 years vs. 2–3 years.

Comparison of the visual outcomes between preoperative and 2 and 4 years after primary vitreous surgery is illustrated in Fig 1. Both distributions of visual acuity at 2 and 4 years after primary vitreous surgery were more significantly improved than the distribution of preoperative visual acuity (P < 0.0001). The distribution of visual acuity between 2 and 4 years postoperatively was not significantly different (P = 0.59). Two years after surgery, the visual acuity values in 64.0% (82 of 128 eyes) and 39.8% (50 eyes of 128 eyes) of patients were ≥20/40 and ≥20/30, respectively. Four years after surgery, the visual acuity values in 53.8% (49 of 91 eyes) and 46.1% (42 of 91 eyes) of patients were ≥20/40 and ≥20/30, respectively.

Fig 1. Comparison of the visual outcomes between preoperative period and at 2 and 4 years after primary vitreous surgery.

Fig 1

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The transition and change in the amount of postoperative visual acuity are depicted in Fig 2. As observed, the mean logMAR visual acuity changed during the preoperative period and 3 months, 6 months, 1 year, 2 years, 3 years, and 4 years postoperatively. Compared with the preoperative visual acuity, the visual activity in each subsequent observation point was significantly improved (P < 0.0001; ANOVA). Table 3 shows the distribution of visual acuity improvement, invariance, and worsening at 2 and 4 years postoperatively. At 2 years after surgery, the percentage of visual acuity improvement (logMAR ≤ −0.3), invariance (−0.3 < logMAR < 0.3), and worsening (logMAR ≥ 0.3) was 74.2% (95 of 128 eyes), 13.3% (17 of 128 eyes), and 12.5% (16 of 128 eyes), and at 4 years postoperatively, 69.2% (63 eyes of 91 eyes), 16.5% (15 eyes of 91 eyes), and 14.3% (13 eyes of 91 eyes) were obtained, respectively. Nonetheless, the distribution of visual acuity improvement, invariance, and worsening between 2 and 4 years after surgery was not significantly different (P = 0.710).

Fig 2. Transition and change in the amount of postoperative visual acuity.

Fig 2

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Mean BCVA (logMAR) ± standard error of the means (± SEM) during the preoperative period and 3 months, 6 months, 1 year, 2 years, 3 years, and 4 years after the primary vitrectomy. *P < 0.001 compared with preoperative mean BCVA (logMAR) based on the ANOVA test with Bonferroni correction.

Table 3. Distribution of visual acuity improvement, invariance, and deterioration at 2 and 4 years after surgery.

Improvement* Invariant** Worsen*** P value
2 years after surgery (N = 128) 95 (74.2%) 17(13.3%) 16(12.5%) 0.710
4 years after surgery (N = 91) 63 (69.2%) 15(16.5%) 13(14.3%)
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* Postoperative BCVA improved by ≥0.3 LogMAR unit compared with preoperative BCVA.

** Postoperative BCVA changed within 0.3 LogMAR unit compared with preoperative BCVA.

*** Postoperative BCVA worsened by ≥0.3 LogMAR unit compared with preoperative BCVA.

BCVA: Best corrected visual acuity; LogMAR: Logarithmic minimum angle of resolution.

Table 4 lists the factors correlated with the visual acuity of ≥20/40 at 2 years after surgery for PDR. Multivariate analysis showed that patients who achieved ≥20/40 at 2 years after the primary surgery for PDR had no rubeosis iridis (P = 0.003) and no fibrovascular membrane (P = 0.02) preoperatively.

Table 4. Analysis of the factors correlated with the visual acuity of ≥20/40 at 2 years after surgery.

Univariate analysis Multivariate analysis
P value OR 95% CI P value
Rubeosis iridis 0.001 0.068 0.012–0.39 0.003
Ocular hypertension 0.004 0.42 0.048–3.71 0.43
Vitreous hemorrhage 0.001 0.86 0.24–3.01 0.81
Fibrovascular membrane <0.001 0.22 0.061–0.817 0.02
Retinal detachment 0.001 1.23 0.00 0.99
Macular detachment <0.001 0.25 0.04–1.46 0.12
Intraoperative retinal photocoagulation 0.001 0.52 0.11–2.36 0.39
Gas tamponade <0.001 0.39 0.07–2.1 0.28
Silicone oil tamponade 0.04 0.00 0.00 0.99
Intraoperative complications 0.01 0.18 0.03–1.02 0.06
Reoperation <0.001 0.21 0.04–1.17 0.07
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OR: Odds ratio; CI: Confidence interval.

Table 5 summarizes the factors correlated with the visual acuity of ≥20/30 at 2 years postoperatively. According to the multivariate analysis, patients who achieved ≥20/30 at 2 years after primary surgery for PDR had no rubeosis iridis (P = 0.03) but had VH (P = 0.04) preoperatively.

Table 5. Analysis of the factors correlated with the visual acuity of ≥20/30 at 2 years after surgery.

Univariate analysis Multivariate analysis
P value OR 95% CI P value
PT-INR value 0.029 0.08 0.00–233.09 0.54
APTT 0.003 0.89 0.76–1.04 0.14
Rubeosis iridis 0.026 0.07 0.01–0.40 0.03
Vitreous hemorrhage < 0.001 9.55 1.03–95.27 0.04
Fibrovascular membrane 0.001 0.52 0.18–1.51 0.23
Retinal detachment 0.003 1.01 0.18–5.51 0.99
Macular detachment 0.002 0.25 0.04–1.46 0.12
Intraoperative retinal photocoagulation 0.001 0.58 0.22–1.48 0.25
Gas tamponade 0.002 0.29 0.06–1.45 0.13
Reoperation 0.001 0.08 0.05–1.18 0.07
Postoperative complications 0.04 0.45 0.11–1.89 0.28
PT-INR value 0.029 0.08 0.00–233.09 0.54
APTT 0.003 0.89 0.76–1.04 0.14
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OR: Odds ratio; CI: Confidence interval.

Table 6 presents the factors correlated with the visual acuity of ≥20/40 at 4 years postoperatively. Multivariate analysis showed that patients who achieved ≥20/40 at 4 years after surgery for PDR had no fibrovascular membrane (P = 0.04) and no reoperation (P = 0.02) preoperatively.

Table 6. Analysis of the factors correlated with the visual acuity of ≥20/40 at 4 years after surgery.

Univariate analysis Multivariate analysis
OR 95% CI P value
Ocular hypertension 0.02 0.15 0.01–2.31 0.17
Fibrovascular membrane 0.003 0.26 0.07–0.94 0.04
Retinal detachment 0.002 0.85 0.18–4.07 0.84
Macular detachment 0.005 0.11 0.01–1.20 0.07
Gas tamponade 0.006 0.84 0.17–4.22 0.84
Reoperation 0.005 0.15 0.03–0.78 0.02
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OR: Odds ratio; CI: Confidence interval.

Table 7 presents the factors correlated with visual acuity of ≥20/30 at 4 years postoperatively. According to the multivariate analysis, patients who achieved ≥20/30 at 4 years after surgery for PDR had no rubeosis iridis (P = 0.04), no fibrovascular membrane (P = 0.004), and no reoperation (P = 0.01) preoperatively.

Table 7. Analysis of the factors correlated with the visual acuity of ≥20/30 at 4 years after surgery.

Univariate analysis Multivariate analysis
OR 95% CI P value
Rubeosis iridis 0.001 0.078 0.006–0.96 0.04
Ocular hypertension 0.004 1.01 0.05–20.59 0.99
Vitreous hemorrhage 0.001 0.66 0.1–4.41 0.67
Fibrovascular membrane <0.001 0.14 0.04–0.52 0.004
Retinal detachment 0.001 0.61 0.12–3.22 0.57
Macular detachment <0.001 0.18 0.01–3.41 0.25
Intraoperative retinal photocoagulation 0.001 0.24 0.05–1.28 0.96
Gas tamponade <0.001 0.67 0.09–4.59 0.69
Reoperation <0.001 0.06 0.07–0.54 0.01
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OR: Odds ratio; CI: Confidence interval.

Discussion

This study demonstrated that the absence of rubeosis iridis and fibrovascular membrane before the surgery for PDR correlated with the visual acuity of ≥20/40 at 2 years postoperatively, whereas the absence of rubeosis iridis and the presence of VH preoperatively correlated with the visual acuity of ≥20/30 at 2 years postoperatively. At 4 years postoperatively, the preoperative absence of fibrovascular membrane and reoperation correlated with the visual acuity of ≥20/40, whereas the preoperative absence of rubeosis iridis, fibrovascular membrane, and reoperation correlated with ≥20/30. Furthermore, the distribution of visual acuity at 2 years after the primary vitreous surgery was more significantly improved than that of preoperative visual acuity. However, such distribution between 2 and 4 years postoperatively had no significant difference.

Rubeosis iridis is the neovascularization of the iris as a result of severe retinal ischemia. When neovascularization progresses to the angle between the iris, the intraocular pressure increases, leading to angiogenic glaucoma [12]. Many people who are in this condition have poor prognosis even after undergoing glaucoma surgery, often resulting in blindness [13]. Mason et al. [14] reported that preoperative and postoperative iris neovascularization, postoperative macular ischemia, and postoperative VH were risk factors for light perception or no light perception vision after vitrectomy in patients with diabetic retinopathy. In our study, the absence of preoperative rubeosis iridis is associated with visual acuities of ≥20/40 and ≥20/30 at 2 years and ≥20/30 at 4 years after the primary vitrectomy for PDR.

Moreover, VH may occur from the neovascularization in the eye. Retinal function is not necessarily impaired by VH itself and is often maintained if no retinal detachment occurs. However, considering that the eye can hardly be observed because of VH occurrence, panretinal laser photocoagulation could not be performed [13]. VH is one of the factors to consider when making early decision to undergo vitreous surgery for PDR [15]. In the current study, the presence of VH is associated with the visual acuity of ≥20/30 at 2 years after the primary vitrectomy for PDR. This result may suggest that surgery without hesitation will provide a better therapeutic effect.

Meanwhile, fibrovascular membrane is formed with the neovascularization in contact with the retina through the epicenters. When the retina is pulled to the tangential direction by the fibrovascular membrane, tractional retinal detachment and macular detachment occur. When the traction in a thinned ischemic retina is excessive, retinal break may form, resulting in a combined tractional and rhegmatogenous retinal detachment. Hence, vitreous surgery should be performed as soon as possible [13]. La Heij et al. [16] observed 44 cases of 33 patients with tractional retinal detachment and macular detachment of PDR for median follow-up of 10 months retrospectively; they found that 22 eyes (50%) achieved a visual acuity of >20/200. In the present study, fibrovascular membrane correlated with the visual acuity of ≥20/40 after 2 years, and ≥20/40 and ≥20/30 after 4 years postoperatively. Conversely, retinal detachment and macular detachment did not correlate with postoperative visual acuity, as confirmed by multivariate analysis. Considering that fibrovascular membrane is the cause of tractional retinal detachment and macular detachment, this condition might correlate with postoperative visual acuity stronger than retinal detachment and macular detachment.

Furthermore, the absence of reoperation only correlated with the visual acuity at 4 years postoperatively in this study. Vitreous surgery for PDR can lead to various complications in which the most common were corneal epithelial defects, elevated intraocular pressure, cataract formation, recurrent VH, rhegmatogenous retinal detachment, and neovascular glaucoma [17]. In this study, those with recurrent VH, retinal detachment, or neovascular glaucoma after primary vitrectomy for PDR underwent reoperation, indicating that performing minimal activity after surgery for PDR is required to maintain visual acuity from 2 years to 4 years.

The relationship between systemic factors and diabetic retinopathy has been reported extensively. Gupta et al. [9] showed that the factors related to poor visual outcome were longer duration of DM, use of insulin, delay in surgery, presence of ischemic heart disease, and failure to attend clinical appointments. According to Yorston et al. [11], systemic factors were not related to visual outcome in cases with vitrectomy for PDR. However, our study found an association between systemic factors and visual acuity at 2 and 4 years after a primary vitreous surgery for PDR. Therefore, the progress of vitreous surgery has improved the treatment results of PDR without being greatly affected by systemic factors.

Furthermore, visual acuity results after vitreous surgery for PDR had been previously reported. G Ratnarajan et al. [10] observed the VH cases of PDR in which 88 eyes of 80 patients (type 2 DM: 69 eyes of 62 cases, type 1 DM: 19 eyes of 18 cases) underwent 20-G vitreous surgery 44 months after the primary surgery. They found that the postoperative mean logMAR visual acuity was significantly improved (type 2 DM: logMAR from 0.64 to 0.46, type 1 DM: logMAR from 0.37 to 0.47). In addition, B Gupta et al. [9] observed the 346 eyes of 249 patients with traction retinal detachment and VH of PDR; the patients underwent 20-G vitreous surgery and were followed up for a mean of 1.44 years, and 39.4% of them achieved a final visual acuity of ≥20/40. D Yorston et al. [11] observed the 174 eyes of 148 patients who underwent 20-G vitreous surgery and were followed up for 8 months; an improvement in logMAR visual acuity of >0.3 was found in 74.4%. In our study, we included not only 20-G cases but also MIVS cases. The percentage of cases with a visual acuity of ≥20/40 was 64.0% (82 eyes), and that of cases with ≥20/30 visual acuity was 39.8% (51 eyes). This study also showed that an improvement in logMAR visual acuity of >0.3 was found in 74.2% and 69.2% of patients at 2 and 4 years after a primary surgery, respectively. This result is similar to the result obtained from a previous study [11].

Although the number of cases in our study is smaller than that in previous reports, the original objectives of our study are to examine cases that could be completely followed up 2 or 4 years after a primary surgery and to reduce the number of dropout cases by collecting information on patients who have visited other ophthalmology clinics. No bias occurred because patient backgrounds had no significant difference between cases that could be followed up for 4 years and cases that could be followed up for 2–3 years after a primary surgery (Tables 1 and 2).

However, the current study has several limitations. This study has a retrospective design, and the surgical procedures were performed by two surgeons. Verification at another facility and prospective study are necessary to prove the usefulness of the factors clarified in this research. The surgical techniques of the two vitreoretinal surgeons might have minor differences, which may have introduced bias into the anatomic results and visual outcomes. Differences in therapeutic effects between 20, 23, and 25 gauges, which could not be examined in this study and in treatment outcomes due to proliferative membrane grading should be further evaluated.

In summary, the factors correlated with better postoperative visual acuity in PDR cases were as follows: no rubeosis iridis, no fibrovascular membrane, presence of VH, and no reoperation. Provision of treatment before the condition became severe and the lack of treatment complications were associated with good postoperative visual acuity. Furthermore, patients with PDR need to be treated at an early stage without missing the timing of surgical treatment.

Supporting information

S1 File. Supplementary excel file with raw data.

(XLSX)

Click here for additional data file. (51.3KB, xlsx)

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was supported by JSPS KAKENHI Grant Numbers JP25462704, JP20K18373.

References

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Decision Letter 0

Andrzej Grzybowski

5 Oct 2020

PONE-D-20-28142

Factors correlated with visual outcomes at two and four years after vitreous surgery for proliferative diabetic retinopathy

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Partly

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: THis is a nice set of data regarding long-term outcomes for patients undergoing vitrectomy surgery for proliferative diabetic retinopathy. A few clarifications would be helpful:

1) Can the authors please describe the lens status of the patients? Did all patients receive cataract surgery at the time of vitrectomy? Were some already pseudophakic? Did any receive cataract surgery at a later time after the vitrectomy? (I ask, because cataract progression could affect final outcomes).

2) Did any patients receive anti-VEGF as a pre-operative adjunct to the surgery to reduce bleeding?

3) Did any patients develop macular edema after the vitrectomy requiring anti-VEGF therapy?

4) Of the patient with pre-operative rubeosis, did any need to go on to glaucoma surgery? What was the pre-vitrectomy stage of the rebeosis (early versus late stage)?

5) Can the authors provide some level of quantification of the proliferative membranes, and whether the extent of proliferation correlated with outcomes?

Reviewer #2: Dear authors

I would like to congratulate you on your work. The findings and results are important and can help surgeons make the right decisions. The advantages of the study are: large cohort of patients, long follow up and the fact that only two vitreoretinal surgeons performed surgeries.

The study has some major limitations:

• Effect of gauges on vitreoretinal surgery: There is considerable talk about functional and morphological results after vitreoretinal surgery performed with the help of 20G, 23 G , 25 G but no analysis on the effect of the different gauges. Did the evolution of vitreoretinal surgery have any effect on the results?

• No information on treatment regiments before and after surgery: Patients with PDR will most certainly need treatment with injection and perhaps laser treatment before and after surgery. There is only one short mention on the use of Triamncinolone before surgery but no mention on the use of injections or laser before and after surgery. I believe this is a very important part that will judge the anatomical and functional results and has to be mentioned with sub-analysis in each group. (lower initial BCVA means more or less post OP treatment with injections or laser?)

• Did the status of the fibrovascular membranes and the status of the posterior hyaloid play a role in the functional and morphological results? Did the manipulation of these mambranes have an effect on the RD rate and final BCVA?

• Lines 111 and 112 Explain: Among them, 91 eyes of 70 patients could be followed up for 4 years after 112 a primary surgery, and 37 eyes of 30 patients could be followed up for 2-3 years How is it possible to have data on 91 eyes with a 4 year follow up and only 37 eyes with a follow up up to 2-3 years. Is it opposite correct? What do you mean with 2-3 years? Not precise enough

• Lines 153 to 160: A statistical association between initial BCVA and improvement of vision after 2-3 year and 4 year is essential! Which patients profited more from surgery? Does initial BCVA is a prognostical factor?

• Discussion Line 214-220: Important and helpful results but these results are incomplete if the treatment regiments before and after surgeries are not elaborated (did patients with rubeosis iridis receive any or more post OP injections or laser treatments compared to patients with no rubeosis?)

**********

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Reviewer #2: No

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Attachment

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Click here for additional data file. (14.5KB, docx)
PLoS One. 2021 Jan 14;16(1):e0244281. doi: 10.1371/journal.pone.0244281.r002

Author response to Decision Letter 0

14 Nov 2020

Reviewer #1: THis is a nice set of data regarding long-term outcomes for patients undergoing vitrectomy surgery for proliferative diabetic retinopathy.

Response: Thank you for cautiously reviewing our manuscript. We found that there was a minor error in Figure 1. Hence, it was modified. Moreover, some data in the Result section were revised. Nevertheless, the changes did not affect the multivariate analysis in this study.

Two years after surgery, the visual acuity values in 64.0% (82 of 128 eyes) and 39.8% (50 eyes of 128 eyes) of patients were ≥20/40 and ≥20/30, respectively. Four years after surgery, the visual acuity values in 53.8% (49 of 91 eyes) and 46.1% (42 of 91 eyes) of patients were ≥20/40 and ≥20/30, respectively (page 13, lines 149–152).

A few clarifications would be helpful:

1) Can the authors please describe the lens status of the patients? Did all patients receive cataract surgery at the time of vitrectomy? Were some already pseudophakic? Did any receive cataract surgery at a later time after the vitrectomy? (I ask, because cataract progression could affect final outcomes).

Response: Thank you for the valuable comment. The lens status of patients is presented in Table 1. In total, 63 of 128 eyes underwent cataract surgery during vitrectomy. Moreover, 38 of 128 eyes were pseudophakic during treatment. This study mainly assessed factors correlated to long-term visual acuity prognosis and the initial treatment of PDR. During the course, the attending physician treated macular edema, cataract, and late cataract if necessary. The following data were added in the Material and Methods section:

Participants were treated for vision-affecting lesions such as posterior capsular opacification, progressed cataract, neovascular glaucoma, and diabetic macular edema (DME) during the postoperative course (page 5, lines 73–75).

2) Did any patients receive anti-VEGF as a pre-operative adjunct to the surgery to reduce bleeding?

Response: Thank you for this valuable comment. As shown in page 5, line 70, all patients did not receive anti-vascular endothelial growth factor (VEGF) therapy during vitrectomy. This information was modified as follows:

All patients did not receive anti-vascular endothelial growth factor (VEGF) therapy as a preoperative adjunct (page 5, lines 70–72).

3) Did any patients develop macular edema after the vitrectomy requiring anti-VEGF therapy?

Response: Thank you for this valuable comment. In total, 11 patients presented with DME that required additional treatment after vitrectomy. During the research period, VEGF therapy was not approved in Japan and patients were treated with retinal photocoagulation and local steroid. The following data were added in the Result section:

In total, 11 patients presented with diabetic macular edema that required additional treatment after vitrectomy. During the research period, VEGF treatment was not approved in Japan, and patients were treated with retinal photocoagulation and local steroid (page 8, lines 124–127).

.

4) Of the patient with pre-operative rubeosis, did any need to go on to glaucoma surgery? What was the pre-vitrectomy stage of the rebeosis (early versus late stage)?

Response: Thank you for this valuable comment. This study investigated the relationship between preoperative rubeosis and long-term visual acuity prognosis. PRP was cautiously performed during vitrectomy for rubeosis in PDR. Postoperatively, NVG was found in seven eyes and glaucoma surgery was performed. Postoperative NVG eye counts and treatment policies are described as follows:

Pan retinal photocoagulation was cautiously performed before or during vitrectomy on all patients (page 5, lines 72–73).

Seven eyes presented with neovascular glaucoma that required additional treatment after vitrectomy (page 8, lines 127–128).

5) Can the authors provide some level of quantification of the proliferative membranes, and whether the extent of proliferation correlated with outcomes?

Response: Thank you for this valuable comment. The relationship between proliferative membrane grading and surgical outcomes is also interesting. This association could not be assessed using the current data. However, our protocols could be modified for a follow-up study. This information has been acknowledged and it can be used as a topic in further research. These data were included in the Discussion section of the revised manuscript.

Differences in therapeutic effects between 20, 23, and 25 gauges, which could not be examined in this study and in treatment outcomes due to proliferative membrane grading should be further evaluated (page 24, lines 307–309).

Reviewer #2: Dear authors

I would like to congratulate you on your work. The findings and results are important and can help surgeons make the right decisions. The advantages of the study are: large cohort of patients, long follow up and the fact that only two vitreoretinal surgeons performed surgeries.

Response: Thank you for cautiously reviewing our manuscript. We found that there was a minor error in Figure 1. Hence, it was revised. Moreover, some data in the Result section were modified. However, these changes did not affect the multivariate analysis in this study.

Two years after surgery, the visual acuity values in 64.0% (82 of 128 eyes) and 39.8% (50 of 128 eyes) of patients were ≥20/40 and ≥20/30, respectively. Four years after surgery, the visual acuity values in 53.8% (49 of 91 eyes) and 46.1% (42 of 91 eyes) of patients were ≥20/40 and ≥20/30, respectively (page 13, lines 149–152).

.

The study has some major limitations:

• Effect of gauges on vitreoretinal surgery: There is considerable talk about functional and morphological results after vitreoretinal surgery performed with the help of 20G, 23 G , 25 G but no analysis on the effect of the different gauges. Did the evolution of vitreoretinal surgery have any effect on the results?

Response: Thank you for this valuable comment. The effect of vitreoretinal surgery (MIVS) evolution is also interesting. In this study, the number of cases in each gauge was not sufficient. Hence, we are considering 57 eyes in MIVS (23G + 25G) and 71 eyes in 20 gauge. Tables 4–7 show the factors correlated to postoperative visual acuity based on the univariate and multivariate analyses. However, MIVS did not affect visual acuity. In future studies, the number of cases should be increased, and each gauge must be analyzed. This information has been acknowledged and it can be used as a topic in further research. These data were included in the Discussion section of the revised manuscript.

Differences in therapeutic effects between 20, 23, and 25 gauges, which could not be examined in this study and in treatment outcomes due to proliferative membrane grading should be further evaluated. (page 24, lines 307–309).

• No information on treatment regiments before and after surgery: Patients with PDR will most certainly need treatment with injection and perhaps laser treatment before and after surgery. There is only one short mention on the use of Triamncinolone before surgery but no mention on the use of injections or laser before and after surgery. I believe this is a very important part that will judge the anatomical and functional results and has to be mentioned with sub-analysis in each group. (lower initial BCVA means more or less post OP treatment with injections or laser?)

Response: Thank you for the valuable comment. The protocol for PDR surgery in this study is depicted in the Material and Methods section.

All patients did not receive anti-vascular endothelial growth factor (VEGF) therapy as a preoperative adjunct. Pan retinal photocoagulation was cautiously performed before or during vitrectomy on all patients. Participants were treated for vision-affecting lesions such as posterior capsular opacification, progressed cataract, neovascular glaucoma, and diabetic macular edema (DME) during the postoperative course (page 5, lines 70–75).

One patient who received preoperative injection of triamcinolone had a history of using triamcinolone for diabetic macular edema before PDR treatment. This information was revised as follows:

Moreover, the ophthalmologic findings were categorized into three sections: preoperative, intraoperative, and postoperative. The preoperative ophthalmologic findings were as follows: intraocular lens implantation, retinal photocoagulation, the history of intravitreal injection of triamcinolone acetonide, rubeosis iridis, ocular hypertension (>21 mmHg), VH, posterior vitreous detachment, fibrovascular membrane, retinal detachment, and macular detachment (page 6, lines 83–88).

.

The low preoperative visual acuity may be attributed to PDR or vitreous hemorrhage. Vitreous hemorrhage affecting long-term visual acuity may be attributed to mild conditions, and the surgery was timely performed. These data were added in the Discussion section (page 21, lines 242–249).

• Did the status of the fibrovascular membranes and the status of the posterior hyaloid play a role in the functional and morphological results? Did the manipulation of these mambranes have an effect on the RD rate and final BCVA?

Response: Thank you for the valuable comment. Tables 4–7 show the factors correlated to postoperative visual acuity based on the univariate and multivariate analyses. However, posterior vitreous detachment did not affect visual acuity. The relationship between proliferative membrane grading and surgical outcomes is also interesting. This association could not be assessed using the current data. However, protocols could be modified for a follow-up study. This information has been acknowledged, and it can be used as a topic in further research. These data were added in the Discussion section of the revised manuscript.

Differences in therapeutic effects between 20, 23, and 25 gauges, which could not be examined in this study and in treatment outcomes due to proliferative membrane grading should be further evaluated (page 24, lines 307–309).

• Lines 111 and 112 Explain: Among them, 91 eyes of 70 patients could be followed up for 4 years after 112 a primary surgery, and 37 eyes of 30 patients could be followed up for 2-3 years How is it possible to have data on 91 eyes with a 4 year follow up and only 37 eyes with a follow up up to 2-3 years. Is it opposite correct? What do you mean with 2-3 years? Not precise enough

Response: Thank you for the valuable comment. As depicted in the first paragraph of the Result section, 128 eyes from 100 patients could be followed-up for >2 years after the primary surgery. That is, 91 eyes from 70 patients could be evaluated 4 years after the primary surgery. However, 37 eyes from 30 patients could not be followed-up 4 years after the primary surgery. Therefore, 37 eyes were categorized under the 2–3-year follow-up group. This information was revised as follows:

In total, 91 eyes from 70 patients could be followed-up 4 years after the primary surgery. However, 37 eyes from 30 patients could not be evaluated 4 years after the primary surgery. Therefore, 37 eyes were categorized under the 2–3-year follow-up group (page 8, lines 116–118).

• Lines 153 to 160: A statistical association between initial BCVA and improvement of vision after 2-3 year and 4 year is essential! Which patients profited more from surgery? Does initial BCVA is a prognostical factor?

Response: Thank you for this valuable comment. The low preoperative visual acuity might be attributed to PDR or vitreous hemorrhage. Vitreous hemorrhage affecting long-term visual acuity might be caused by mild conditions, and surgery was timely performed. These data were included in the Discussion section. The current study showed that a low preoperative visual acuity is not a serious condition.

• Discussion Line 214-220: Important and helpful results but these results are incomplete if the treatment regiments before and after surgeries are not elaborated (did patients with rubeosis iridis receive any or more post OP injections or laser treatments compared to patients with no rubeosis?)

Response: Thank you for this valuable comment. During the research period, VEGF therapy was not approved in Japan, and patients were treated with retinal photocoagulation and local steroid treatment. The protocol for PDR surgery in this study is depicted in the Method and Materials section.

All patients did not receive anti-vascular endothelial growth factor (VEGF) therapy as a preoperative adjunct. Pan retinal photocoagulation was cautiously performed before or during vitrectomy on all patients. Participants were treated for vision-affecting lesions such as posterior capsular opacification, progressed cataract, neovascular glaucoma, and diabetic macular edema (DME) during the postoperative course (page 5, lines 70–75).

Attachment

Submitted filename: response to reviewer for submitt final.docx

Click here for additional data file. (27.7KB, docx)

Decision Letter 1

Andrzej Grzybowski

8 Dec 2020

Factors correlated with visual outcomes at two and four years after vitreous surgery for proliferative diabetic retinopathy

PONE-D-20-28142R1

Dear Dr. Nishitsuka,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Andrzej Grzybowski

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I agree with Reviewer 3, who confirms the original concerns noted by the reviewers have been adequately addressed.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for addressing my comments. I appreciate the clarifications and feel that your work adds new information to the literature.

Reviewer #2: Dear authors.

Thank you for the revision of your work. One major limitation of the work is the absence of anti VEGF parameters. The injection of steroids is not up to date. The major advantage of the work is the long term follow up. I regret to inform you that i would not recommend this papaer to be published.

Reviewer #3: This revised manuscript explores factors associated with better vision outcomes after vitrectomy for proliferative diabetic retinopathy (PDR). As the authors point out, patients with PDR often have vitrectomy in their 50's, but go on to live to an average age of 70. Therefore it is important to determine factors associated with preserved vision after vitrectomy for PDR. A total of 128 eyes in 100 patients operated between January 2008 and September 2012, followed for 2 to 4 years or more were evaluated. Of these, 91 eyes from 70 patients were followed for 4 years. Those followed for more than 2 years, but less than 4 years were described as a group followed for 2-3 years. Factors associated with better vision included:

1. No preoperative rubeosis, which, if present, would be a sign of severe retinal ischemia.

2. No preoperative fibrovascular membrane.

3. Preoperative vitreous hemorrhage did not adversely affect vision.

4. No reoperation.

Questions from two reviewers of the original manuscript were answered satisfactorily. The study was carried out in Japan, where anti-VEGF therapy was not approved, and was therefore unavailable during the study. Panretinal photocoagulation was utilized for retinal neovascularization and rubeosis. Triamcinolone and focal macular laser were used for diabetic macular edema.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Acceptance letter

Andrzej Grzybowski

6 Jan 2021

PONE-D-20-28142R1

  Factors correlated with visual outcomes at two and four years after vitreous surgery for proliferative diabetic retinopathy

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