Ischemia and VEGF in Different Retinal Diseases and Therapies: How Does One Influence the Other?

Michael A. Singer, MD • Darren J. Bell, MD • Salman Porbandarwalla, MD

Retinal diseases have undergone a metamorphosis over the last seven years. Age-related macular degeneration, retinal vein occlusion and diabetic macular edema, which once were primarily treated with laser, are now predominantly being treated with anti-VEGF or corticosteroid-based therapies.

This switch to newer treatments is due to our better understanding of free intraocular VEGF levels and the role they play in retinal diseases. Currently, there are four different anti-VEGF medications to choose from. If we include the three major corticosteroids — triamcinolone, dexamethasone and fluocinolone — our armamentarium is significantly enhanced.

However, despite all of the new therapies available to us, the specific duration of action of a single injection in a given patient and its efficacy are unknown. There have been many studies in the literature comparing one anti-VEGF medication to another, yet there are many questions that remain unanswered.

The one-year results of the CATT study showed that monthly injections of bevacizumab vs. ranibizumab were equally efficacious when treating wet AMD.¹ These findings, although true for AMD, are not consistent with other retinal diseases, such as RVO and DME, which have much higher levels of free intraocular VEGF. Case reports in the literature have also suggested that persistent macular edema due to vein occlusions that are nonresponsive to one anti-VEGF agent can have complete resolution if switched to another agent with a higher affinity for VEGF.^2,3 In the coming years, studies such as CRAVE for RVO and the DRCR.net Protocol T for DME may answer these questions.

VEGF LEVELS IN ISCHEMIA

Why would there be differences among these diseases when they share abnormal VEGF levels as a basis for their pathology? The answer may lie in the degree of ischemia, as well as in the corresponding levels of VEGF. As seen in Figure 1, the levels of VEGF in central RVO are higher than in branch RVO and are almost 100 times higher than the VEGF levels in wet AMD.⁴ This fact demonstrates that diseases with higher levels of ischemia result in higher intraocular levels of free VEGF.

Figure 1. Meta-analysis of VEGF levels among different diseases as determined by vitreous sampling.

Given that the levels of VEGF differ among different retinal diseases, the molecules that have a greater affinity for VEGF might respond to macular edema in RVO/DME patients much differently than in patients with wet AMD.

A recent study was carried out at our institution analyzing the short-term effects of ranibizumab vs bevacizumab on the resolution of macular edema in patients with RVO. The study consisted of 50 patients — 32 treated with bevacizumab and 18 with ranibizumab.

The OCT measurements taken at two and four weeks showed a greater reduction in central macular thickness with statistical significance (P < .001)="" with="" ranibizumab="" compared="" to="" bevacizumab.="" the="" visual="" acuity="" in="" patients="" who="" received="" ranibizumab="" was="" also="" maintained="" better="" than="" in="" patients="" given="" bevacizumab,="" and="" statistical="" significance="" was="" found="" at="" both="" time="" points="" (p=""><>⁵

These results further exemplify the importance of assessing retinal diseases with higher free VEGF levels earlier and of treating them with agents with higher affinity for VEGF.

VEGF AND REBOUND EDEMA

The exact duration of effect of these anti-VEGF medications on any given retinal disease is still unknown. Case reports by Matsumoto et al. illustrated the concept of rebound edema in RVO patients. They showed that rebound edema, when occurring after injections with anti-VEGF agents, tends to be much greater than on initial presentation.⁶ In our study, 41% of our patients who responded to bevacizumab at two weeks rebounded by four weeks.⁵ In many instances, the edema may be related to significant peripheral ischemia, which is often difficult to image. Using widefield fluorescein angiography, such as the Optos device, may provide clues about some of these diseases, as well as potential therapies to block this cycle of rebound edema going forward.

Figure 2 illustrates a patient with an RVO and active macular edema. After a single anti-VEGF injection, the retinal edema is improved on OCT, and the image shows increased peripheral circulation and decreased ischemia.

Figure 2. A 39-year-old man with CRVO OD who received IVT ranibizumab. A. OCT central subfield thickness of 412 µm prior to injection; B. Optos ultra-widefield imaging (orange = perfused, blue = ischemic) prior to injection; C. OCT central subfield thickness = 277 µm and reduction of macular edema after injection; D. Optos ultra-widefield imaging (orange = perfused, blue = ischemia) with increases in circulation after injection.

CONCLUSION

Do anti-VEGF agents work by binding to VEGF, resulting in improved circulation, or do they decrease inflammation/edema so that the ischemic retina can reperfuse? In either of these scenarios, is there a threshold of ischemia that is reached when the medicine wears off that causes upregulation of VEGF and, hence, rebound edema? If this is so, will peripheral ablation using targeted panretinal photocoagulation directed by widefield angiography eradicate the cause of the ischemia, so the VEGF signal is no longer sent to the peripheral retina?

These are questions that are waiting to be answered, and future studies may provide insight into the pathogenesis and treatment of these conditions. RP

REFERENCES

1. CATT Research Group; Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897-1908.
2. Labriola LT, Sadda SR. Rapid resolution of macular edema associated with central retinal vein occlusion using ranibizumab after failure with multiple bevacizumab injections. Semin Ophthalmol. 2011;26:387-391.
3. Kaiser RS, Gupta OP, Regillo CD, et al. Ranibizmab for eyes previously treated with pegaptanib or bevacizumab without clinical response. Ophthalmic Surg Lasers Imaging. 2012;43:13-19.
4. Celia F. The consequences of CATT: Will it change your practice? Retin Physician. 2001;8(5):21-25.
5. Singer MA, Bell DJ, Woods P, et al. Effect of combination of therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion. Retina. 2012 Mar 29. [Epub ahead of print]
6. Matsumoto Y, Freund KB, Peiretti E, Cooney MJ, Ferrara DC, Yannuzzi LA. Rebound macular edema following bevacizumab (Avastin) therapy for retinal venous occlusive disease. Retina. 2007;27:426-431.