Clinical Features and Treatment of Inactive Proliferative Diabetic Retinopathy

Background To investigate the clinical features and results after vitrectomy for inactive proliferative diabetic retinopathy (IPDR). Methods Retrospective review of 40 eyes of 21 IPDR patients who underwent 23G or 25G minimally invasive vitrectomy between January 2018 and December 2019 in Tianjin Medical University Eye Hospital. The average follow-up period was 8.7 months. Outcome measures were best-corrected visual acuity (BCVA), clinical features and intraoperative ndings of IPDR. Results All eyes were performed with panretinal photocoagulation (PRP) for average 1.6 years before operation. Fundus examination showed the optic disc was pale, and a mass of yellowish-white broproliferative membrane was around the optic disc and vascular arcade. Thirty-three eyes (82.5%) were accompanied by tractional retinal detachment, and macula was involved in 9 eyes (22.5%). The vitreous adhered with the retina tightly. The mid-peripheral retina was thin. Thirty-one eyes (77.5%) were accompanied by small branch retinal artery and vein occlusion. Fourteen eyes (35.0%) occurred iatrogenic retinal break during vitrectomy. The median LogMAR of BCVA signicantly improved from 1.0 (20/200)preoperatively to 0.92 (20/167) postoperatively (P = 0.000). Conclusions The fundus manifestation of IPDR was quiet and special. Vitrectomy could improve patients’ visual acuity, but the incidence of iatrogenic retinal break was high. Vitrectomy could vitro-retinal surgeons according the minimum quantitative


Background
Proliferative diabetic retinopathy (PDR) is more active, mainly manifested as repeated vitreous hemorrhage (VH), brovascular proliferation and tractional retinal detachment (TRD), which is the leading cause of blindness in diabetic patients [1][2][3]. Vitrectomy is seen as an effective method in treating PDR [4,5]. Inactive proliferative diabetic retinopathy (IPDR) refers to PDR with "quiet" fundus performance. The clinical features of IPDR are different from traditional PDR, and the principles and e cacy of vitrectomy are also different from traditional PDR. In order to analyze the clinical features of IPDR and the e cacy of vitrectomy, we had included a group of clinical data of IPDR patients. Now the results were reported as following.

Patients
Retrospective review of 40 eyes of 21 IPDR patients who underwent 23G or 25G minimally invasive vitrectomy between January 2018 and December 2019 in Tianjin Medical University Eye Hospital.
Inclusion criteria: (1) PDR patients according to the classi cation criteria of DR recommended by the International Academy of Ophthalmology in 2003 [6]; (2) No fresh vitreous and retinal hemorrhage; (3) The broproliferative membrane is yellowish-white without active neovascularization; (4) All patients were treated with 23G or 25G minimally invasive vitrectomy.
Exclusion criteria: Patients with a clear diagnosis of retinal vascular occlusion, macular degeneration and optic neuropathy.
This study adhered to the tenets of the Helsinki Declaration and was approved by ethics committee of Tianjin Medical University Eye Hospital.
Written informed consent was obtained from all patients.

Synopsis of design
Preoperative data, including the patient's age (at operation), gender, and systemic diseases, including hypertension, cardiovascular disorders, cerebrovascular disorders and renal disorders with dialysis were collected. The blood glucose and HbA1C level measured on the day of admission for the operation were recorded. History of previous ocular procedure such as panretinal photocoagulation (PRP) was also recorded. Preoperative ocular examinations in both lesion eyes and fellow eyes included measurements of best-corrected visual acuity (BCVA), intraocular pressure, biomicroscopic examination of anterior and posterior segments, fundus examination with indirect ophthalmoscope, Bscan ultrasonography and optical coherence tomography (OCT). Funduscopic ndings including the color of optic disc, the extent of TRD and the location and extension of broproliferative membrane were recorded.
A standard 3-port 23-or 25-guage pars plana vitrectomy (PPV) was performed to all eyes by surgeons with more than 15 years of vitreoretinal surgery experience. The surgical procedures have been reported elsewhere [7,8]. In short, during the standard vitrectomy procedure, anterior-posterior vitreoretinal traction was released as much as possible. Microscissors and cutter were used for segmentation and delamination of brovascular tissue. Proliferative tissue was removed to the greatest possible extent to the periphery, with the caution to avoid inducing iatrogenic break. Laser photocoagulation was only performed around the iatrogenic retinal break. Phacoemulsi cation combined with intraocular lens implantation was performed in patients with obvious lens opacity. Silicone oil or per uoropropane (C3F8) infusion were indicated if there were multiple large retinal breaks or extensive retinectomy.
The average follow-up period was 8.7 months (6-12 months). Silicone oil removal surgery was performed for patients who had good retinal attachment at 3 months after PPV.

Statistical methods
The systemic, pre-, intra-, and post-operative data was analyzed. All visual acuity data were converted to the logarithm of minimal angle of resolution (logMAR) scale for analyses. The Wilcoxon signed-rank test was performed for non-normal continuous observations. Analyses were performed using SPSS 22.0, P values < 0.05 was considered statistically signi cant.

Results
There were 9 males (17 eyes) and 12 females (23 eyes), with an average age of 55.5 ± 9.9 years (41-73 years old). All patients were diagnosed with type 2 diabetes after examination by the department of endocrinology and met the diabetes diagnostic criteria by WHO in 1999 [9]. The average diabetic duration was 12.4 ± 5.7 years (5-25 years), and HbA1C was 7.4 ± 1.0%. The preoperative median LogMAR of BCVA was 1.0 (Snellen equivalent of 20/200). All eyes were treated with PRP 1.6 ± 1.1 years (0.5-4.0 years) before the operation under the guidance of fundus uorescein angiography (FFA). Subject characteristics are summarized in Table 1.
Clinical features of IPDR: (1) IPDR was mostly bilateral. In this study, 19 patients (90.5%) were bilateral, only 2 (9.5%) patients were unilateral. Among them, the fellow eye had received vitrectomy due to PDR in one patient, the fellow eye lost sight due to unknown reason 4 years ago in another patient; (2) IPDR occurred after PRP treatment; (3) No fresh hemorrhage was observed in vitreous and retina; (4) The broproliferative membrane was yellowish-white in appearance without active neovascularization, mainly located on the surface of the optic disc and/or around the vascular arcade. The broproliferative membrane was distributed in a circular shape in some patients (Fig. 1); (5) OCT showed that the broproliferative membrane stretched the macula, resulting in macular edema (Fig. 2), and even macular detachment; (6) TRD was limited, mostly located around the vascular arcade. Thirty-three eyes (82.5%) were accompanied by limited TRD. Macula was involved in 9 eyes (22.5%); (7) The mid-peripheral retina was pale, and mostly accompanied by small branch artery and vein occlusion. Thirty-one eyes (77.5%) were accompanied by small branch retinal artery and vein occlusion.
Features of IPDR in vitrectomy: (1) The incidence of complete posterior vitreous detachment (PVD) was low. Partial PVD occurred in 28 eyes (70%), and the broproliferative membrane adhered closely to the posterior vitreous cortex and retina around the optic disc and vascular arcade. PVD was not occurred in 12 eyes (30%), and the broproliferative membrane was integrated with the posterior vitreous cortex, and adhered closely to the retina. (2) It was relatively di cult to completely remove the broproliferative membrane during the operation, and iatrogenic retinal break was extremely prone to occur. Fourteen eyes (35.0%) occurred iatrogenic retinal break during the operation. Silicone oil infusion was performed in 8 eyes. C3F8 infusion was performed in 6 eyes. (3) The optic disc was pale, and the mid-peripheral retina was thin. Clinical features of IPDR and intraoperative ndings are depicted in Table 2.
Postoperative visual acuity in one patient worsened from the preoperative status, two patients were lost to follow-up and all others improved or were stable. The median LogMAR of BCVA was 0.92(Snellen equivalent of 20/167)at the end of follow-up, which was signi cantly improvement compared with preoperative BCVA (Z=-3.782, P = 0.000).

Discussion
All patients in this study were diagnosed with type 2 diabetes by the department of endocrinology. The average diabetes duration was 12.7 years, and all the lesion eyes met the inclusion criteria to ensure reliable case diagnosis and credible observation results.
PDR mostly manifests as fresh vitreous and retinal hemorrhage, broproliferative membrane with active neovascularization and/or TRD clinically.
We found that a small number of PDR patients had relatively "quiet" fundus performance. In order to distinguish it from traditional PDR, we de nited this type of PDR with "quiet" fundus as IPDR.
Combined with the preoperative examination and intraoperative observation, we found it has the following characteristics:(1)All occurred after PRP treatment; 2 No fresh vitreous and retinal hemorrhage; 3 The broproliferative membrane was yellowish-white in appearance without active neovascularization, mainly located on the surface of the optic disc and/or around the vascular arcade; 4 TRD was limited, and mostly located around the optic disc and/or vascular arcade; 5 The optic disc was pale. The mid-peripheral retina was thin, and mostly accompanied by small branch artery and vein occlusion; 6 The incidence of PVD was low. The vitreous and retina adhered closely. It was relatively di cult to completely remove the broproliferative membrane during the operation, and iatrogenic retinal break was extremely prone to occur.
Non-proliferative diabetic retinopathy (NPDR) often develops slowly. However, PDR develops rapidly due to the formation of neovascularization. The fundus performance of PDR is active. But, the fundus performance of IPDR is relatively quiet. We consider the reasons as follows: (1) HbA 1 C is proposed as a medium and long-term measure of average glycemia, and it is a serious risk factor for DR. Strict control of glycemia can delay the development of DR [10,11].
Patients in this study had a relatively long history of diabetes and had rich experience in controlling glycemia.
The result of HbA 1 C measurement showed that the patient's long-term glycemic control is relatively ideal.
Therefore, the progress of IPDR was relatively slow; (2) Panretinal laser photocoagulation is an effective method for treating DR. Melanosomes located within the retinal pigment epithelium (RPE) absorb the laser energy that causes a thermal injury and coagulates the adjacent photoreceptors and RPE cells. As photoreceptors are metabolically the most active cells in the retina with high oxygen consumption, photocoagulation lowers the metabolic load and reduces the ischemia and ischemia-driven angiogenic substances [12]. Photocoagulation plays an important role in controlling or delaying the development of DR [13,14]. In this study, all eyes were treated with PRP for an average of 1.6 years before surgery, which effectively alleviated the hypoxia and ischemia of the retina; (3) The occlusion of small branch arteries can cause ischemia and necrosis of retinal inner cells, and PRP can also make the neurosensory retina thin due to the damaged retinal cells including photoreceptors and ganglion cells [12]; These factors lead to thinning of the retinal tissue and reducing oxygen demand so that the oxygen demand and oxygen supply of the retina reach a relatively balance state. During the operation, we found that the retinal tissues in the middle and periphery of the IPDR eyes were relatively thin, which further con rmed the hypothesis.
The vitreous adhered tightly to the retina in the eyes of IPDR, and the vitrectomy was relatively di cult, which easily induced iatrogenic retinal break. All patients in this study were performed by surgeons with more than 15 years of experience in vitreoretinal surgery, 14 eyes (35%) still occurred iatrogenic retinal break when the retinal broproliferative membrane was removed. Considering that the fundus performance of IPDR is relatively quiet, we suggest that vitrectomy for such patients should be performed in accordance with the principle of minimal quanti cation. During the operation, we just need to remove the opaque vitreous, cut off the proliferation cord and relieve the local traction, it is not necessary to completely remove the broproliferative membrane to minimize retinal damage and avoid iatrogenic retinal break; If iatrogenic retinal break occurs inadvertently during the operation, we should remove fully the broproliferative membrane, and select the tamponade (silicone oil or C3F8) according to the condition. Considering that all the eyes in this study had been treated with PRP before surgery, and the retina had no obvious ischemia and hypoxia, if there was no iatrogenic retinal break, retinal photocoagulation was not performed, but if it occurred, photocoagulation was performed only on the edge of the break to block it.
The BCVA at the end of follow-up after vitrectomy was improved compared with that before surgery. However, postoperative visual acuity in one patient worsened from the preoperative status, two patients were lost to follow-up and all others improved or were stable. The main reasons for no improvement of visual acuity after the vitrectomy in some patients are the atrophy and thinning of the retina of the lesion eyes and the long-term macular tractional detachment.
Due to the relative unsatisfactory prognosis of IPDR and the di culty of surgery, surgeons with rich experience in vitreoretinal surgery can consider vitrectomy for patients after fully communicating with patients and obtaining the patients' consent.
The limitations of this study include its limited sample size and retrospective nature. Also, it lacks controlled observation results of long-term non-surgical treatment in IPDR. However, because of the limited previously published reports in this eld, this study provides important observations and insights on the characteristics of IPDR and the e cacy of vitrectomy.

Conclusion
In summary, the fundus performance of IPDR is relatively "quiet" and characteristic. Vitrectomy can improve the vision of some patients, but the operation is relatively di cult. It can be performed by surgeons with rich experience in vitreoretinal surgery in accordance with the principle of minimal quanti cation. Future large-scale studies that include different treatment methods are necessary to further evaluate the progress and prognosis of IPDR. This study adhered to the tenets of the Helsinki Declaration and was approved by ethics committee of Tianjin Medical University Eye Hospital. Written informed consent was obtained from all patients.

Consent for publication
Consent for publication has been obtained.

Availability of data and materials
The data used and analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. Funding