Venous beading in two or more quadrants might not be a sensitive grading criterion for severe nonproliferative diabetic retinopathy

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes mellitus (DM); worldwide, DR has become the leading cause of blindness in working-age adults, especially in Asian countries due to the sharply increasing prevalence of type 2 diabetes [1‐3]. DR is a preventable blinding eye disease but is unfortunately usually overlooked at the early stages. Once the disease progresses to a severe stage, such as proliferative DR (PDR), visual impairment may be inevitable [4]. Although laser photocoagulation and anti-VEGF injections are recognized as effective treatments for PDR, these treatments rarely restore vision [5, 6]. Therefore, early screening for DR and appropriate disease severity grading as well as timely intervention are vital to reduce the incidence of sight-threatening visual impairment [7‐9].

DR severity grading was conventionally based on standard, seven-field stereoscopic photographs according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) [8]. Subsequently, the International Diabetic Retinopathy Severity Scales (IDRSS) were proposed as a simplified grading version [10] and approved as the international DR grading criterion by the Diabetic Retinopathy Preferred Practice Pattern (DR PPP) [11]. This criterion divided DR into the following levels with increasing risks of retinopathy: (1) no apparent retinopathy, (2) mild nonproliferative DR (NPDR), (3) moderate NPDR, (4) severe NPDR, and (5) PDR. The determination of severe NPDR, which is currently based on the international 4-2-1 rule (intraretinal hemorrhage (IRH), venous beading (VB), and intraretinal microvascular abnormalities (IRMA)), is quite critical due to its high probability of progressing to PDR [9]. However, we found that VB was less commonly observed in severe NPDR eyes in our clinical practice, and most eyes with VB in two or more quadrants had progressed to PDR. Moreover, the prevalence of venous abnormalities including VB in patients with type 2 diabetes reportedly varies among ethnic groups [12]. And the prevalence of retinal vascular lesions in different DR severity levels has not been reported.

In the present study, we determined the prevalence of retinal vascular lesions among different DR severity levels and assessed whether VB in two or more quadrants was an appropriate grading criterion for severe NPDR among a Chinese population with type 2 diabetes, using a combination of dilated ophthalmoscopy and fundus fluorescein angiography (FFA).

A total of 1264 DR patients were referred to the Zhongshan Ophthalmic Center for FFA examination between January 2014 and April 2017. Among them, 211 individuals were excluded due to previous laser photocoagulation, 34 individuals were excluded for previous vitrectomy, 17 individuals were excluded due to previous anti-VEGF injection, 26 individuals were excluded for poor-quality images, and 170 individuals were excluded due to other concomitant retinal diseases. In the final analysis, 806 DR patients (1612 eyes) were eligible for inclusion in this study for evaluation.

The present study determined the prevalence of retinal vascular lesions, including VB, IRMA, capillary nonperfusion, arteriovenous nicking, and DME, among different DR severity levels based on a combination of dilated ophthalmoscopy and FFA. In addition, the independent, relevant factors for VB formation and NPDR progression to PDR were assessed.

In this study, retinal vascular lesions were evaluated based on FFA, allowing the detection of subtle lesions [14]. Clinically, small retinal vascular lesions are easily overlooked by direct ophthalmoscopy [15], but FFA significantly improves the detection rate of retinal vascular lesions [16]. The prevalence of VB in our study was lower than that reported in Japanese DR patients [17]. A previous study showed that more VB was observed in Chinese DM patients than in Caucasian patients (8.7 vs. 2.1%) [12];nevertheless, there were no data regarding its prevalence among different DR severity levels. According to DR PPP, VB in two or more quadrants on dilated ophthalmoscopy is the international grading criterion for severe NPDR. However, only 2.1% of the severe NPDR eyes presented with VB in two or more quadrants in this study. We speculated that the prevalence of VB assessed by direct ophthalmoscopy would be even lower. Furthermore, among the total of 225 eyes with VB in two or more quadrants, 214 eyes (more than 95%) had entered the PDR stage. Therefore, we suggested that VB in two or more quadrants might be a too strict criterion for judging severe NPDR, at least among a Chinese population with type 2 DM. No VB was observed even with FFA in moderate NPDR eyes, indicating that once VB is observed, DR has progressed to the advanced stage (severe NPDR or PDR). Our results indicated that although VB in two or more quadrants might not be considered a sensitive criterion for judging severe NPDR, VB had a great specificity to define an advanced form of DR.

To the best of our knowledge, there were no data regarding the prevalence of IRMA among different DR severity levels. Our results showed that 53% of the severe NPDR had IRMA, which was far higher than the proportion of VB in severe NPDR. Previous clinicopathologic study demonstrated that IRMA had the particular potential for neovascularization [18]. Recent study suggested that IRMA significantly increased risk of PDR [19]. Additionally, our study also contributed data regarding the prevalence of other retinal vascular lesions, including capillary nonperfusion, arteriovenous nicking, and DME, among different DR severity levels.

In addition, our study revealed that the formation of VB was significantly correlated with age of DM onset, diabetes duration, capillary nonperfusion, and smoking, while it was not associated with drinking, hypertension, and arteriovenous nicking. VB is the chronic reactive expansion of the retinal vein in response to retinal ischemia or other abnormal situations [20], although idiopathic VB can occur in some cases [21]. As DR progresses, the death of pericytes and basement membrane thickening result in impaired perfusion and retinal ischemia, while increased ischemia leads to the formation of VB [22]. Indeed, our study suggested that the formation of VB was significantly associated with capillary nonperfusion and the disease course of DR, especially the age of DM onset and diabetes duration.

Additionally, VB, IRMA, duration of diabetes, hypertension, logMAR vision, and arteriovenous nicking were determined as independent risk factors for NPDR progression to PDR after adjustment for age and sex, while the age of DM onset was determined as an independent protective factor, which was consistent with previous studies [19, 23‐26]. Furthermore, our results indicated that VB and IRMA were important predictors of NPDR progression to PDR, and the ORs of VB were even greater than that of IRMA. Moreover, we should pay more attention to visual changes, blood pressure, and arteriovenous nicking of DR patients. And patients with a long duration of diabetes and younger age of DM onset must undergo regular fundus exams. Nevertheless, in our study, a considerable proportion of patients had progressed to PDR (49.1%) when they were referred to the ophthalmologist. Early detection for retinopathy contributes to the reduction of the occurrence of severe DR [27, 28], but unfortunately, a significant proportion of type 2 DM patients does not undergo early retinal screening in China, especially in rural areas, before the onset of severe visual impairment [29], which could explain the high proportion of severe NPDR and PDR in our study.

There are several limitations to our study that need to be considered. Firstly, as a clinic-based retrospective study, selection bias may have occurred when patients were recruited into this study. Secondly, all patients were from a single institution, so a referral bias may exist. Thirdly, we did not evaluate the prevalence of “IRH in each of four quadrants,” because FFA was mainly evaluated in our study and it showed no advantage regarding the detection of IRH. Nevertheless, our study for the first time reported the prevalence of retinal vascular lesions among different DR severity levels based on FFA. And our study also contributed to explore more appropriate DR disease severity grading criteria and disease progression relevant factors.

In conclusion, our study suggested that VB in two or more quadrants might not be a sensitive grading criterion for severe NPDR in a Chinese population with type 2 diabetes. A more sensitive criterion for severe NPDR should be explored in the future to reduce the incidence of sight-threatening visual impairment. Nevertheless, VB has a great specificity to define an advanced form of DR.