FP370 : Ultrawidefield FA Guided Targeted Retinal Photocoagulation in Diabetic Retinopathy

Dr. Pallavi Singh, S19000, Dr. Vinod Kumar, Dr. Parijat Chandra, Dr. Atul Kumar

Abstract 

Background: Diabetic retinopathy is a leading cause of avoidable blindness in the world. Adverse effects associated with conventional scatter laser techniques have necessitated the use of newer laser techniques to tackle this inflating health epidemic.

Aim: To assess the effects of ultra-wide field fluorescein angiography (UWFFA) guided targeted retinal photocoagulation (TRP) in diabetic retinopathy.

Settings and Design: Prospective interventional study. 

Methods: Thirty eyes with severe NPDR and PDR without HRC were subjected to TRP of only capillary non-perfusion (CNP) areas as seen on UWFFA. The patients were followed up for a minimum of six months. Visual acuity, contrast sensitivity, central macular thickness, visual fields and disease regression were assessed at baseline, 6 weeks, 3 months and 6 months after laser photocoagulation. 

Results: There was a significant improvement in visual acuity, contrast sensitivity and mean deviation (p <0.01) at 6 weeks as compared to baseline, which remained stable at 3 and 6 months. Eight eyes required additional laser and two eyes required injection of anti-VEGF at 3 months. Disease regression was seen in 93.3% eyes at 6 months.

Conclusion: UWFFA guided TRP is an effective treatment modality in eyes with severe NPDR and PDR without HRC. It results in disease regression in a good percentage of cases without any detrimental effects of laser induced worsening of macular edema and function. 

Keywords: Targeted retinal photocoagulation, Ultra wide field angiography, Diabetic retinopathy, Panretinal photocoagulation, Capillary non-perfusion, Macular edema 

Introduction

Diabetic retinopathy is one of the leading causes of avoidable blindness in the world currently attributing to 1% of the global blindness.^[1] Conventional full scatter retinal laser photocoagulation has been the mainstay for the treatment of high-risk proliferative diabetic retinopathy (PDR)since its development.^[2] The Early Treatment Diabetic Retinopathy Study (ETDRS) suggested that patients with severe nonproliferative diabetic retinopathy (NPDR) or PDR without high risk characteristics (HRC) might also benefit from an early scatter photocoagulation.^[3]Full scatter laser has been shown to reduce the risk of severe vision loss in PDR, however it is associated with side effects such as constriction of visual fields and  worsening of macular edema that can result in a decrease in visual acuity, color vision and contrast sensitivity.^[2[,[4],[5].

Wide-field images can be obtained by three methods; creating montage images, using a special lens with a traditional fundus camera and using a specially-designed wide-angle camera. Although 7-field photography is a reliable method for assessment of diabetic retinopathy, it is a time-consuming examination requiring skilled photographers and pharmacological pupil dilation. Ultra-wide field (UWF) imaging, which can visualize up to 200º of the retina in a single field helps in localizing the capillary non-perfusion areas (CNP) with high accuracy even in the far retinal periphery.^[6]The 200° field of view of the Optos images covers 82% of the retinal surface (compared to 15% for the 45° images) thus providing  an advantage over conventional fluorescein angiography (FA) techniques which are highly dependent on the accurate time of image acquisition which may be compromised in a montage image, which itself provides a maximum view of 140 degrees.^[7] As compared to conventional FA, UWF imaging shows 3.2 times greater retinal area, 3.9 times more non-perfusion and 1.9 times more neovascularization, thus providing a definitive advantage.^[6]

Targeted retinal photocoagulation (TRP), introduced recently with the availability of UWF imaging, may be able to overcome the side effects seen with scatter laser. TRP refers to selective photocoagulation of the non-perfused areas of the retina while leaving out the better perfused ones. This is governed by the rationale that directing therapy specifically at ischemic parts of retina will eliminate the source of anti-VEGF, while minimizing the retinal damage and inflammation caused by conventional full scatter laser.^[8]

Probability of suboptimal treatment of PDR with conventional FA guided TRP due to inadequate unmasking of all the CNP areas is a major concern. TRP with the help of UWF imaging aims at treating all the CNP areas of the retina which might get missed with conventional FA thus giving outcomes similar to full scatter laser without its undesirable side effects.

To the best of our knowledge, a single pilot study has been neverconducted till date to evaluate the safety of TRP in previously untreated patients with PDR showing favorable outcomes. In our study, we intend to assess the efficacy and outcomes of TRP in both the treatment naïve as well as previously treated patients with severe NPDR and PDR without HRC. 

Methods and Materials

This was a prospective, interventional study carried out on diabetic patients recruited from the Retina Clinic at a tertiary eye center. Institutional review board approval was obtained. The study adhered to the tenets of the Declaration of Helsinki.

Patients with age >18 years with non-insulin dependent diabetes mellitus (NIDDM), severe NPDR or PDR without HRC, ETDRS corrected distance visual acuity (CDVA) of 1 logarithm of minimum angle of resolution (logMAR) or better (Snellen equivalent 6/60 or better), central macular thickness (CMT) less than 300 microns measured on spectral domain optical coherence tomography (SD-OCT) with absence of central intra- and ⁄ or subretinal fluid, treatment naïve eyes or eyes with previous laser done three months back and/ or received anti-VEGF treatment more than six weeks back were recruited for the study. Patients with diabetic macular edema (DME), PDR with HRC, poor glycemic control (HbA1C > 8.0%), coexisting hypertensive retinopathy, previously vitrectomized eyes, presence of cataract, glaucoma, age related macular degeneration, optic atrophy and other concurrent conditions that could lead to diminution of vision were excluded from the study. Informed consent was obtained from all the enrolled participants.

The parameters studied at baseline were CDVA (ETDRS), contrast sensitivity (Pelli-Robson Chart, Haag-Streit, UK), 30-2 Swedish Interactive Threshold Algorithm (SITA) Standard visual fields (Humphrey Field Analyzer Model 750i, Carl Zeiss Meditec Inc., Dublin) and central macular thickness (Cirrus HD-OCT Model 5000, Carl Zeiss Meditec Inc., Dublin). 6 mm macular cube scan was done and the central 1 mm thickness value was analyzed. Blood investigations were carried out including fasting and post-prandial blood sugars, renal function tests and glycosylated hemoglobin (HbA1c).

All patients were subjected to FFA using the Optos UWF imaging (Optos Tx200, Dunfermline, Scotland, UK). The principal treating physician (AK) evaluated all fundus photographs and fluorescein angiograms delineating CNP areas, perivascular leakage and neovascularization. TRP was performed for all patients using Pattern Scan Laser (PASCAL, Topcon, Santa Clara, CA, USA, Fig 1 and 2). The CNP areas were selectively lasered using Pascal 5 X 5 array with 20 ms pulse duration using QuadrAspheric lens (Volk Optical Inc., OH, USA) with a magnification factor of 0.51 and retinal spot size of 400µm. Laser burns were applied to all the CNP areas as well as at the junction of ischemic and non-ischemic areas. The laser spots were placed 0.75 burn width apart and the end point of laser was taken to be moderate grey burns.^[9]

The follow up evaluation was done at six weeks, three and six months post laser application. The primary outcomes assessed were the changes in visual acuity, contrast sensitivity, visual fields, central macular thickness and disease progression or regression over six months. Secondary outcome measures included the number of patients requiring additional laser and/or anti-VEGF injections due to development of DME or new areas of peripheral ischemia. 

Statistical Analysis

Statistical analysis was performed using SPSS (Version 22.0). Paired t- test was used to evaluate the changes in CMT. For non- parametric data i.e. visual acuity, contrast sensitivity and mean deviation on visual fields, Wilcoxon signed-rank test was used. Subgroup analysis for treatment naïve and previously treated eyes was carried out using Mann Whitney test. The null hypothesis was rejected for p values less than 0.05.

 Results

Thirty eyes of 19 patients with Diabetic retinopathy were subjected to TRP following evaluation on UWF fluorescein angiography. The mean age of the patients was 56.67 ± 7.31 years (Range 42- 68 years). There were 11 males (57.8%) and 8 females (42.1%) included in the study. The mean HbA1c was 7.8 ± 2.1%. Out of all eyes, 33.3% (10/30) eyes were treatment naïve (Group 1) and 66.7% eyes (20/30) were previously treated with laser photocoagulation (Group 2) elsewhere. In patients with bilateral TRP, 63.6% (7/11) patients were previously treated and 36.4% (4/11) were treatment naïve. Among the patients who underwent unilateral treatment, 25% (2/8) had undergone laser treatment earlier and the remaining 75% (6/8) were untreated before.

Visual Acuity

The median CDVA at baseline was 0.45 (min-0.1, max-1), which improved significantly (p = 0.001) to 0.25 (min- 0, max- 1) at 6 weeks after TRP. This amounted to a mean of 10-letter improvement. The CDVA slightly reduced at 3 months to 0.3 (min-0.1, max-0.8, p value= 0.003) and remained stable at 6 months. Though there was a minimal decrease in CDVA on follow up, the overall improvement remained significant as compared to baseline. There was no significant difference in CDVA between the treatment naive and previously treated eyes (Table 1).

Contrast Sensitivity

At baseline, the median contrast sensitivity was 1.05 (min- 0, max– 1.35), which improved to 1.2 at 6 weeks (min-0.45, max-1.35, p = 0.001). Like visual acuity, this decreased at 3 months to 1.05 (min- 0.45, max- 1.35, p= 0.03) and remained stable at 6 months. However, there was no significant intergroup difference at baseline, 6 weeks, 3 months and 6 months (Table 1).

Central Macular Thickness

The mean CMT was 255.33 ± 35.67 microns at baseline, 257 ± 37.72 microns at 6 weeks post laser, 259.73 ± 43.81 microns at 3 months and 249.5 ± 32.1 microns at 6 months. There was a slight increase in CMT over the first 3-month follow up, with a decrease in thickness seen at 6 months. However, all the changes were insignificant statistically over the course of follow up and between the two groups as well (p<0.05, Table 1).

Two eyes (6.7 %) developed macular edema (CMT 350 microns and 379 microns with central cystic spaces) at the 3-month follow up and required intravitreal anti-VEGF injection (Lucentis, Genentech Inc., San Francisco, CA). Both these eyes belonged to the group previously treated with laser.

Visual Fields

On Humphrey visual fields, the mean deviation at baseline was -8.72dB (min-3.5, max-17.43), which improved significantly post-laser at 6 weeks to -6.96dB (min-2.89, max-11.82, p = 0.008). This dropped to -7.98dB (min-2.06, max- 14.54, p  =0.006) at 3 months but remained significantly better than baseline at 6 months at -7.44dB (min-3.01, max 11.21, p = 0.002). Statistically, there was no difference between both the groups (Table 1).

Figure 3 depicts the changes in visual acuity, contrast sensitivity, mean deviation on visual fields and central macular thickness in eyes with diabetic retinopathy undergoing TRP over a 6 month follow up.

Disease Regression

Disease regression was defined as disappearance of leaks and areas of neovascularization and no development of new CNP areas. Disease progression was defined as development of macular edema, vitreous hemorrhage, tractional retinal detachment or progression to PDR in eyes with severe NPDR.^[10] Out of 30 eyes, 20 (66.7%) eyes showed complete disease regression at the 3-month follow up. Eight eyes (26.7%) needed additional laser over the course of follow-up at 3 months due to development of new areas of capillary non-perfusion. Out of these, two eyes (25%) were treatment naïve and 6 eyes (75%) were previously treated. Two eyes that developed macular edema at 3 months were subsequently excluded from the analysis. However, all remaining 28 eyes (93.3%) showed complete disease regression at 6 months. There was no significant difference in the visual acuity, contrast sensitivity, central macular thickness and visual fields between eyes with PDR and NPDR. 

Discussion

With a growing trend in the incidence and prevalence of diabetic retinopathy over the recent years, its management protocols have also taken a significant leap from the yesteryears. It has been shown that the mid peripheral retina is more likely to have capillary non-perfusion as opposed to the posterior retina.^[11] Studies indicate that patients with retinal ischemia have a 3.75 times greater probability of developing diabetic macular edema.^[12] Clinical comparisons between central and peripheral argon laser panretinal photocoagulation (PRP) have shown peripheral PRP to be superior to central PRP in terms of visual outcomes.^[13]

Few studies evaluated ultra-wide-field FA-guided targeted laser photocoagulation of the peripheral non-perfusion in eyes with diabetic retinopathy. Reddy et alreported 2 patients with proliferative diabetic retinopathy in which targeted retinal photocoagulation resulted in regression of retinal neovascularization. ^[8] The concept of TRP has brought about a significant improvement in patient comfort and minimization of complications associated with conventional scatter laser without compromising the therapeutic outcomes seen with the latter. Also, single session TRP may theoretically reduce the treatment time.  However, it might show inferior results unless all areas of CNP are delineated before laser photocoagulation. This becomes impossible with conventional FFA cameras capable of capturing retinal images only till the mid-periphery. UWF imaging leads to early and complete detection of all CNP areas and peripheral areas of neovascularization. Thus, the various adverse effects associated with full scatter photocoagulation, coupled with improved detection of peripheral retinal ischemia have set the premise for laser strategies other than conventional PRP for the management of diabetic retinopathy.

Our study showed an improvement in contrast sensitivity and visual fields, which was consistent at 6 months. The central macular thickness did not increase or decrease significantly over the course of follow up. Thus, the complication of macular edema noted with scatter photocoagulation is negligible with TRP. This stands in contrast with the previously observed adverse effects of scatter laser on macular function such as decrease in visual acuity, constriction of visual fields, drop in color vision and increase in central macular thickness, as elucidated by the DRS and ETDRS groups. ^[2],[3] Our study indicated a significant improvement in visual acuity and visual fields for most patients similar to earlier work on TRP .^[14],[15] This could be attributed to decreased load of VEGF and its harmful effects on the macula. Also, laser of retinal non-perfusion areas reduces retinal edema and ischemia of the surrounding areas leading to possible improvement of retinal function. However, it is most important to note that targeted laser performed using UWF imaging leads to ablation of all CNP areas and preserves functional retina. This in turn leads to decreased VEGF production, along with much lesser inflammation as compared to traditional scatter laser, which could account for the preservation, and even improvement of macular function.

Though Reddy et al discussed the concept of targeted retinal laser in 2009, but it was not until 2013 that Muqit et alassessed the effect of single-session targeted laser photocoagulation guided by ultra-wide-field FA in 28 eyes.^[14] At 24 weeks, complete disease regression was found in 37% and additional panretinal laser photocoagulation was planned for active proliferative diabetic retinopathy in 30%. ^[14],[16] Further work by Sato et al showed that selective photocoagulation of non-perfusion areas of the retina in preproliferative diabetic retinopathy led to decreased progression to PDR as compared to no laser.^[17]Takamura et al demonstrated that additional TRP is beneficial in maintaining reduced macular thickness after intravitreal Bevacizumab injections as compared to injection alone.^[18]

Though Muqit et al showed that following primary TRP using UWF imaging, there was PDR regression, severe NPDR cases were excluded in their study. We included cases of severe NPDR and PDR without HRC to establish the effects of TRP in early stages of the disease as well. Further, in their study they used a pre-fixed number of laser spots in all the patients, thus leaving the possibility of leaving some non-perfusion areas un-lasered in certain patients and performing excess laser in others. The latter may defy the very purpose of TRP. As opposed to this, our study involved laser of all visible CNP with no preset number of laser spots, which could result in the higher regression rates seen in our study.

To conclude, our study demonstrates the beneficial effects of UWFA guided targeted retinal photocoagulation on the macular edema and its function in the setting of PDR and severe NPDR cases. Future studies may focus on the automated detection of the peripheral lesions on the ultra-wide-field images as well and long term efficacy of TRP with larger sample sizes with longer follow up. . Nonetheless, initial results with targeted retinal laser are encouraging and it can prove to be a useful alternative to the well-established existing conventional laser photocoagulation for the treatment of diabetic retinopathy. References

1. World Health Organization. Global data on visual impairments.World Health Organization, Geneva, 2012.
2. Diabetic Retinopathy Study Research Group.Photocoagulation treatment of proliferative diabetic retinopathy: Clinical application of Diabetic Retinopathy Study (DRS) findings. DRS Report Number 8. Ophthalmology. 1981; 88: 583-600.
3. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy: ETDRS Report Number 9. Ophthalmology.1991; 98: 766-785.
4. Early Treatment Diabetic Retinopathy Study Research Group. Techniques for scatter and local photocoagulation treatment of diabetic retinopathy: Early Treatment Diabetic Retinopathy Study Report Number 3. IntOphthalmolClin. 1987;27: 254-264.
5. Early Treatment Diabetic Retinopathy Study Research Group.Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report Number 2. Ophthalmology. 1987;94: 761-774.
6. Wessel MM, Aaker GD, Parlitsis G, Cho M, D’amico DJ, Kiss S. Ultra–wide-field angiography improves the detection and classification of diabetic retinopathy. Retina. 2012;32: 785-91.
7. Patel M, Kiss S. Ultra-wide-field fluorescein angiography in retinal disease. CurrOpinOphthalmol.2014; 25, 213-20.
8. Reddy S, Hu A, Schwartz SD. Ultra wide field fluorescein angiography guided targeted retinal photocoagulation (TRP). SeminOphthalmol. 2009;24:9-14.
9. 9.Muqit MM, Denniss J, Nourrit V, Marcellino GR, Henson DB, Schiessl I et al. Spatial and spectral imaging of retinal laser photocoagulation burns. Invest Ophthalmol Vis Sci. 2011;52:994-1002.
10. Muqit MMK, Marcellino GR, Henson DB, Young L B, Turner GS, Stanga PE. Pascal panretinal laser ablation and regression analysis in proliferative diabetic retinopathy: Manchester Pascal Study Report 4. Eye. 2011; 25: 1447-56.
11. Shimizu K, Kobayashi Y, Muraoka K. Midperipheral fundus involvement in diabetic retinopathy. Ophthalmology. 1981;88: 601-612
12. Wessel MM, Nair N, Aaker GD, Ehrlich JR, D’Amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol. 2012; 96:694-8.
13. Blankenship GW. A clinical comparison of central and peripheral argon laser panretinal photocoagulation for proliferative diabetic retinopathy. Ophthalmology. 1988; 95:170-7.
14. MuqitMM, Marcellino, GR, HensonDB, Young LB, PattonN, Charles SJ et al.Optos‐guided pattern scan laser (Pascal)‐targeted retinal photocoagulation in proliferative diabetic retinopathy. ActaOphthalmol. 2013; 91: 251-8.
15. Wang Y, MuqitMM, Stanga PE, Young LB, Henson DB. Spatial changes of central field loss in diabetic retinopathy after laser. Optom Vis Sci. 2014;91: 111-20.
16. Muqit MM, Young LB, McKenzie R, John B, Marcellino GR, Henson D. B. et al. Pilot randomized clinical trial of Pascal TargETEd Retinal versus variable fluencePANretinal 20 ms laser in diabetic retinopathy: PETER PAN study. BrJOphthamol. 2013; 97(2): 220-27.
17. Japanese Society of Ophthalmic Diabetology: Subcommittee on the Study of Diabetic Retinopathy Treatment. Multicenter randomized clinical trial of retinal photocoagulation for preproliferative diabetic retinopathy. Jpn J Ophthamol. 2012;56: 52-9.
18. Takamura Y, Tomomatsu T, Matsumura T, Arimura S, Gozawa M, Takihara Yet al. The effect of photocoagulation in ischemic areas to prevent recurrence of diabetic macular edema after intravitreal bevacizumab injectionPC for NPAs to prevent DME progression after IVB. Invest OphthalmolVis Sci. 2014;55: 4741-6.