Taking a Wider View In the Treatment of DME

Ultrawidefield fluorescein angiography will improve our ability to identify untreated peripheral pathology.

RAVI D. PATEL, MD · SEENU M. HARIPRASAD, MD

Diabetic macular edema continues to be a common cause of vision loss in patients with diabetic retinopathy and decreased vision-related quality of life in working-aged Americans.¹ Studies have predicted that the prevalence of diabetes will grow by 50% worldwide to more than 300 million by 2025.²

In the United States, the incidence of DME approaches 30% in adults who have had diabetes for 20 years or more.³ It can occur at any stage of diabetes and can predate the appearance of other findings of diabetic retinopathy. In eyes with mild nonproliferative diabetic retinopathy, the prevalence of DME is 3%, rising to 38% in eyes with moderate to severe NPDR, and reaches 71% in eyes with proliferative diabetic retinopathy.⁴

PAST AND PRESENT TREATMENTS

For nearly three decades, the standard therapy for DME has been focal/grid laser photocoagulation.⁵ The Early Treatment Diabetic Retinopathy Study found a 50% reduction in the likelihood of severe vision loss with focal/grid macular laser.⁶

In 2010, The Diabetic Retinopathy Clinical Research Network reported that with this treatment approach, while one-third of patients recorded a 10-letter gain, 19% still experienced progressive visual loss.⁷ These results revealed the need for more efficient treatment alternatives.

Several clinical trials, including READ-2,⁸ RISE, and RIDE,⁹ have investigated the use of anti-VEGF for DME and have shown rapid, sustained visual improvement. Given the favorable results of these trials, the FDA recently approved ranibizumab (Lucentis, Genentech, South San Francisco, CA) for the treatment of DME.

However, despite improvements in treatment options over the years, patients who experience persistent or recalcitrant DME remain continue to present for treatment.

Positive new disease markers have emerged, as have efforts to quantify peripheral pathology.

THE EVOLUTION OF PERIPHERAL RETINAL IMAGING

Diagnostic imaging has played an increasing role in eye care in recent years. Until recently, the retinal periphery went largely unimaged. Under optimal conditions, traditional angiographic methods, employing film or digital fundus cameras, can capture 50° views.

With a compliant patient, a contact lens system, such as the Ocular Staurenghi 230 SLO Retina Lens (Ocular Instruments, Bellevue, WA), can image out to the 120° range. None of these modalities can compare to the ultra-wide views of up to 200° provided by the Optos 200Tx scanning laser ophthalmoscope (Optos PLC, Dunfermline, United Kingdom) or the Heidelberg Spectralis noncontact ultrawidefield (UWF) module (Heidelberg Engineering, Heidelberg, Germany).

But perhaps even more valuable than the wider range of field, the Heidelberg UWF module captures images simultaneously. To understand why this ability is important, we should remember that each neovascular focus may have different levels of dye leakage when viewed at the same time point (Figure 1, page 28).

Enhanced viewing of the periphery has resulted in several exciting new clinical findings, most in the past few years. The technology has unveiled new insights regarding the role of peripheral pathology in retinal vascular, degenerative, and inflammatory diseases. Potential new disease markers have emerged, as have efforts to quantify peripheral pathology.^10-12

CLASSIFICATION OF DME

The pathophysiology of DME is always an important factor when evaluating a patient with this complex disease. A few causes of DME are pathologic permeability of retinal vasculature, elevated intravitreal VEGF levels, localized retinal ischemia, and mechanical vitreoretinal traction.

Figure 1. Ultrawidefield FA of a patient with diffuse DME with PDR and extensive peripheral capillary nonperfusion and peripheral vascular leakage.

Figure 2. Ultrawidefield fluorescein angiogram demonstrating how ischemic index is calculated. The total fundus area was encircled (solid line), and the area of nonperfusion was delineated (dotted line). Ischemic index was the ratio of the area of nonperfusion over the total fundus area. This eye has an ischemic index of 59%.

The literature has commonly used the terms diffuse and focal macular edema to characterize DME as a guide in planning focal/grid laser treatment.¹³ Despite current practice patterns, a subset of patients with DME continues to have persistent or recalcitrant DME despite several sessions focal/grid macular photocoagulation or monthly intravitreal injections of VEGF inhibitors and/or intravitreal steroids.

Over the past three decades, many theories have arisen regarding why recalcitrant DME persists despite aggressive conventional treatments. Currently, with the aid of UWF fluorescein angiography (UWFFA), some authors have hypothesized that peripheral retinal pathology exists that conventional diagnostic imaging and treatment for DME had not detected.

Patel and colleagues¹² demonstrated this correlation, showing that eyes with untreated nonperfusion, on average, had a stronger correlation with diffuse recalcitrant DME (69%), compared to focal recalcitrant DME (31%). A number of biologically plausible explanations exist for this observation.

First, the unique anatomy of the macula — namely, the configuration of the photoreceptors and associated neural cells of the Henle’s layer — makes it especially susceptible to diffuse edema. Second, VEGF is a potent vasodilator produced by ischemic retina that weakens the walls of the macular capillaries. Increasing intraocular VEGF levels enhances vascular permeability, inviting leakage of lipid and diffuse edema.¹⁴

CLINICAL UTILITY OF UWFFA IN DME

In recent years, the clinical study of the retinal periphery using widefield imaging has exploded and begun to show promising results in the management and treatment of DR and DME.

Silva and colleagues¹⁵ recently found an association of the presence of peripheral retinal vascular lesions visualized on color images with increased grading of severity. At three years of follow up, they found that these lesions may impact the progression of disease.¹⁶

Another study found UWFFA imaged 3.2 times more retinal area than the ETDRS standard of seven fields, accounting for nearly four times more area of retinal nonperfusion. As a result of this increased area, patients with peripheral retinal ischemia had 3.75 times increased odds of having DME, compared with those without retinal ischemia.¹⁷

ISCHEMIC INDEX

The ischemic index has been established as a grading system for retinal vascular disease, in which a ratio is calculated to provide an indication of the perfusion status of the peripheral retina. UWFFA images are captured and the areas of interest are isolated; a ratio is calculated by dividing the nonperfused retinal areas over the total retinal area.^11,18 The doctor can then use the ischemic index as a biomarker for retinal perfusion status pre- and post-treatment.

Several studies have sought to characterize the ischemic index in different vascular disease states. One study of central RVO found that the ischemic index was significantly correlated with neovascularization, and eyes that had evidence of neovascularization had an index >45%.¹¹ More recently, a study found that eyes with a greater severity of DR and larger areas of nonperfusion had the most recalcitrant DME, with a mean index of 45% (Figure 2).

These findings support the hypothesis that untreated retinal vascular nonperfusion may be associated with recalcitrant DME, demonstrating that 80% of patients with recalcitrant DME showed evidence of untreated peripheral retinal nonperfusion.¹²

Figure 3. Ultrawidefield FA of PDR with diffuse temporal recalcitrant DME, demonstrating neovascularization at the border between perfused and nonperfused retina, along with extensive peripheral nonperfusion and peripheral vascular leakage.

CREDIT: JOHN W. KITCHENS, MD

Figure 4. Ultrawidefield fluorescein angiogram of the patient in Figure 3 after targeted retinal photocoagulation precisely applied to the areas of retinal nonperfusion with regression of retinal neovascularization and resolution of recalcitrant DME.

CREDIT: JOHN W. KITCHENS, MD

TARGETED RETINAL PHOTOCOAGULATION

Studies have explored the concept of targeted retinal photocoagulation (TRP) in PDR^19-21 (Figure 3, page 29) and RVO²² using an UWFFA image to target laser to peripheral areas of nonperfusion. In one study, the effects of TRP on PDR resulted in regression in 76% of patients at 12 weeks and complete disease regression in 37% and partial regression in 33% at 24 weeks.²¹

The theory is that areas of poor perfusion may be sources of biochemical mediators that promote neovascularization. Targeted PRP laser may decrease the ischemic drive and cytokine release and ultimately reduce retinal vascular leakage and DME.²³

Using TRP to ablate the peripheral areas of nonperfusion, in combination with an antagonist to block existing VEGF, may enhance the ability to alleviate DME by suppressing the permeability of the vasculature (Figure 4).

Paul Tornambe, MD, presented a case series at the Macula Society, in which he proposed that DME is fundamentally a peripheral retinal disease manifesting secondarily in the macula. In the series, several cases of recalcitrant DME resolved after laser to the mid- and far peripheral retina.

Several ongoing pilot studies are investigating the utility of UWFFA and TRP in combination with anti-VEGF agents. The DAVE study is also evaluating the combined use of TRP and ranibizumab for clinically significant DME.

CONCLUSION

In summary, innovation in technology has greater value if we can apply it in ways that add insight to our understanding of diseases and improve our therapeutic outcomes. UWFFA has been shown to play a significant role in visualizing peripheral retinal pathology in DR and DME.

The detection and delineation of vascular nonperfusion in the retinal periphery may be of clinical value. The association between retinal capillary nonperfusion and recalcitrant DME supports the hypothesis that zones of untreated retinal nonperfusion may stimulate production of biochemical mediators, leading to recalcitrant DME and a suboptimal response to therapeutic treatments.

Ultrawidefield FA may be a valuable tool for identifying therapeutic target areas for photocoagulation, allowing for efficient treatment of ischemic retina and potentially decreasing the production of VEGF and of the cytokines that play a role in recalcitrant DME. RP

REFERENCES

1. Hariprasad SM, Mieler WF, Grassi M, et al. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol. 2008;92:89-92.

2. Sjostrand J, Popovic Z, Conradi N, Marshall J. Morphometric study of the displacement of retinal ganglion cells subserving cones within the human fovea. Graefes Arch Clin Exp Ophthalmol. 1999;237:1014-1023.

3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-1474.

4. Javadzadeh A. The effect of posterior subtenon methylprednisolone acetate in the refractory diabetic macular edema: a prospective nonrandomized interventional case series. BMC Ophthalmol. 2006;6:15-19.

5. American Academy of Ophthalmology. Preferred Practice Patterns: Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2003.

6. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:1796-1806.

7. Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2010;117:946-953.

8. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146-2151.

9. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.

10. Oliver SC, Schwartz SD. Peripheral vessel leakage (PVL): a new angiographic finding in diabetic retinopathy identified with ultra wide-field fluorescein angiography. Semin Ophthalmol. 2010;25:27-33.

11. Tsui I, Kaines A, Havunjian MA, et al. Ischemic Index and neovascularization in central vein occlusion. Retina. 2011; 31:105-110.

12. Patel RD, Messner LV, Teitelbaum B, et al. Characterization of ischemic index using ultra-widefield fluorescein angiography in patients with focal and diffuse recalcitrant diabetic macular edema. Am J Ophthalmol. 2013 Jun;155:1038-1044.

13. Browning DJ, Altaweel MM, Bressler NM, Bressler SB, Scott IU; Diabetic Retinopathy Clinical Research Network. Diabetic macular edema: what is focal and what is diffuse? Am J Ophthalmol. 2008;146:649-655.e6.

14. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445-450.

15. Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology. 2013 Jun 15. [Epub ahead of print]

16. Silva PS, Cavallerano JD, Sun JK, Aiello LM, Aiello LP. Peripheral diabetic retinal lesions identified on ultrawide field imaging (UWF) may predict 3-year diabetic retinopathy progression. Invest Ophthalmol Vis Sci. 2013;54:ARVO E-Abstract 1725.

17. Wessel MM, Nair N, Aaker GD, et al. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macularoedema. Br J Ophthalmol. 2012;96:694-698.

18. Prasad PS, Oliver SC, Coffee RE, Hubschman JP, Schwartz SD. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology. 2010;117:780-784.

19. Reddy S, Hu A, Schwartz SD. Ultra wide field fluorescein angiography guided targeted retinal photocoagulation (TRP). Semin Ophthalmol. 2009;24:9-14.

20. Kaines A, Oliver S, Reddy S, et al. Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthalmol Clin. 2009;49:53-59.

21. Muqit MM, Marcellino GR, Henson DB, et al. Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy. Acta Ophthalmol. 2013;91:251-258.

22. Spaide RF. Peripheral areas of nonperfusion in treated central retinal vein occlusion as imaged by wide-field fluorescein angiography. Retina. 2011;31:829-837

23. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480-1487.