the future of diabetic retinopathy treatment

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40 I RETINA TODAY I SEPTEMBER 2009

COVER STORY

Diabetic retinopathy (DR) is the leading causeof blindness among working-aged adults inthe United States. It is estimated that morethan 4 million Americans are affected by DR,

and that number is expected to increase to 7.2 million by2020.1 The availability of efficacious treatments for dia-

betic retinopathy will be a substantial public health con-cern in the coming years, of great interest to ophthalmol-ogists and millions of their patients.

This article reviews some of the prospects for futuredevelopments in medical and surgical treatments for DR.

It is useful to think of DR in terms of two critical

abnormal processes in diabetic blood vessels: vascularincompetence and vascular occlusion. Vascular incompe-tence leads to leakage of blood and blood products intothe retina, while vascular occlusion leads to patches of ischemia in the retinal capillary bed and to the eventualsequela of neovascularization.

The anatomic substrate for vascular incompetence isthe appearance of microaneurysms. Intact retinal vesselsrarely leak, but when they are complicated by micro-aneurysms they produce profuse leakage, the hallmark of nonproliferative macular edema (Figures 1-3).

Microaneurysms have a life cycle, typically lasting

The Future of Diabetic Retinopathy

TreatmentAdvances in pharmacologic and surgical treatment optionswill be needed as the prevalence of this condition increases.

BY DONALD J. D’AMICO, MD; AND R. V. PAUL CHAN, MD

Figure 1. Color fundus photograph (left) and red free photograph (right) of the right eye.There are scattered dot blot hemor-

rhages, hard exudates,and microaneurysms evident nasal to the fovea.



SEPTEMBER 2009 I RETINA TODAY I 41

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approximately 3 months: They bloom, they grow, theyfill with leukocytes and become autoinfarcted. This lifecycle is often underemphasized; I have never been con-vinced that treating microaneurysms in the retina withlaser does anything more than create incidental retinaldamage on the way to the therapeutic RPE lesion.

ANTIINFLAMMATORY THERAPY

Vascular incompetence in DR leads secondarily toprofound ischemia. The work of Joussen and col-leagues2 suggests that antiinflammatory strategies may

be important in the treatment of this component of the disease. Those researchers showed that the earliestsign of the development of DR in animals is themigration of leukocytes into the retinal capillary bed.They pointed out that vascular endothelial growth fac-tor (VEGF) induces the expression of ICAM-1 andeNOS in the retina and initiates early diabetic retinalleukocyte adhesion in vivo, and they concluded thatinhibition of VEGF may be useful in the treatment of early DR. The same may also be true for diabetic mac-ular edema (DME).

The recent publication of a randomized trial compar-

ing intravitreal injection of triamcinolone acetonidewith grid laser cyclophotocoagulation in patients withDME,3 I believe, heralds the end of a period of intenseinterest in and use of intravitreal steroids as a treatmentfor this condition. Nevertheless, we may be able to learnsomething from the “Wow” effect seen immediatelyafter steroid injection in many patients. Inflammationsurely plays a role or roles in DR, and important antiin-flammatory targets remain to be explored.

Steroids can have toxic effects in the retina. Kwak andD’Amico4 showed that dexamethasone causedincreased staining and disorganization of Müller cells in

the rabbit retina. Dexamethasone-induced alterations in

retinal glutamate synthetase activity or glucose metabo-lism were proposed as mechanism for the interferencein Müller cell function. Müller cells, also called Müllerglia, are the metabolic supporting cells in the retina.There may be Müller-cell–related strategies that can beexploited in the future for DR therapy.

VEGF INHIBITION

Vascular endothelial growth factor is produced by gan-glion and photoreceptor cells in the retina in response toischemia. It induces profound leakage from existing ves-

sels and the growth of new, immature vessels. It works inconjunction with multiple factors, includingangiopoeitin, erythropoetin, and others, to producemature blood vessels. VEGF inhibition has been used suc-cessfully as a strategy in the treatment of retinal patholo-gies including, notably, age-related macular degeneration.

Trials of anti-VEGF agents in patients with DME haveshown efficacy, with incidental regression of neovascu-larization. In an open-label study, Nguyen and col-leagues5 demonstrated reduction in foveal thicknessand improvement in visual acuity in 10 patients withDME after a series of injections of ranibizumab 0.5 mg

(Lucentis, Genentech, Inc.). Visual acuity improved by amean 12.3 letters from baseline.

While this is a promising result—and does, as theauthors assert, demonstrate that VEGF is an importanttherapeutic target in DME—it suggests that more workis needed. With only 12.3 letters gained in a small non-randomized series, it remains to be seen what the bene-fit would be in a randomized trial.

Even if these anti-VEGF drugs were shown to be effi-cacious against DME, the prospect of 7.2 million peoplelining up in retinal practices for monthly intravitrealinjections is daunting. Platforms for extended drug

delivery will surely be needed in order for this type of

Figure 2. HRA fluorescein angiograms of the right eye at 19 seconds (left), 44 seconds (middle), 3 minutes (right) show punc-

tate progressive hyperfluorescence with late leakage consistent with microaneurysms.



42 I RETINA TODAY I SEPTEMBER 2009

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therapy to balance the cost and benefits of treatmentfor this chronic life-long disease.

When I was a resident, we longed for the day wewould have a magic drug that could undo neovascular-ization. In a sense, we now have it, with the advent of VEGF-blocking drugs. And yet we still treat proliferativeDR (PDR) with panretinal photocoagulation. We havepowerful pharmacologic tools that have been shown toregress rubeosis, surface neovascularization, and cer-

tainly retinal and subretinal neovascularization, but wecannot use them in many situations because of issuesrelated to drug delivery, as well as concerns aboutapplying anti-VEGF strategies to a severely ischemic reti-na. It is to be hoped that further research in this fieldwill lead to wider utility for these agents.

ERYTHROPOEITIN

Other angiogenic factors in addition to VEGF areinduced in the retina by ischemia. One of them, ery-thropoeitin (EPO), was shown by Watanabe and col-leagues6 to be more strongly associated with the pres-

ence of PDR than is VEGF. The researchers concludedthat EPO is a potent ischemia-induced angiogenic fac-tor that acts independently of VEGF during retinalangiogenesis in PDR.

We evaluated the levels of VEGF and EPO in a nondi-abetic patient who presented to our practice with achronic rhegmatogenous retinal detachment withextensive retinal neovascularization.7 We compared theresults of enzyme-linked immunosorbent assays of asample of that patient’s vitreous with those of a smallseries of patients with other retinal conditions. His EPOlevel was higher than those of patients with PDR. His

VEGF level was lower than those of patients with PDR

but higher than those of patients without neovascular-ization. We concluded that vitreous concentrations of EPO and VEGF can be elevated in patients with neovas-cularization secondary to a rhegmatogenous retinaldetachment of long duration.

If EPO inhibition is a potential target in the treat-ment of DR or DME, why do we not have anti-EPOdrugs? Research is ongoing. EPO is complex; in addi-tion to being an angiogenic factor, it is also a survivalfactor for photoreceptors. Simply blocking it may notbe the best strategy. No doubt research into the

potential of EPO as a target in diabetes-related oculardisease will continue.

VITREOUS SURGERY

Vitreous surgery has evolved to include less invasivetransconjunctival modes, including 25-gauge and 23-gauge vitrectomy systems. These smaller-gauge instru-ments have offered surgeons a new subtlety andsophistication in the ability to handle tissues.Nevertheless, dissection of the thickened, taut, vascu-larized posterior hyaloid from the underlying ultradeli-cate, often sick and ischemic retina is still extremely

challenging, one of the most difficult dissections in

[Laser] technology shows promise for

removal of vitreous and other posterior

segment tissues, including epiretinalmembrane and posterior hyaloid,

without damaging the retinal surface.

Figure 3. Infrared fundus photograph (left) and OCT (right) show intraretinal cystoid changes and punctate hyperreflective

areas consistent with hard exudates seen on the fundus photograph.The arrowed line across the infrared photograph corre-

lates with the macular section seen on the OCT.



SEPTEMBER 2009 I RETINA TODAY I 43

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ophthalmology. I liken it to trying to pry bubble gumoff wet tissue paper without tearing the tissue paper.

We have been exploring the application of

erbium:YAG (Er:YAG) laser technology, which is cur-rently used primarily for skin resurfacing, to performretinal dissection for a number of years. These effortshave been temporarily suspended due to corporaterearrangements among the laser manufacturers, butwe have the Er:YAG laser technology at Weill CornellMedical Center and are building a new microsurgicalarea in which to explore it further.

With a high repetition rate, the Er:YAG laser canablate very gradually with a precision approaching thatof the excimer.8 With the laser connected to a sapphirefiber and set at pulse energies between 1.0 and 21.2 mJ

and pulse repetition rates between 10 and 200 Hz, wedocumented clinically useful vitreous ablation rates thatscaled linearly with high repetition rates. We believe thistechnology shows promise for removal of vitreous andother posterior segment tissues, including epiretinalmembrane and posterior hyaloid, without damagingthe retinal surface. The Er:YAG laser wavelength can betransmitted across perfluoro-octane as well as air. Onecan imagine a variety of strategies in contact and non-contact modes to use this tool.

I am convinced this technology will be used in thefuture, although currently it is impractical. We have no

way to visualize the depth of a dissection, so we do notknow when to stop. Also the laser technology must becombined with proper fluidics for intraocular use.Nevertheless, there is great potential for laser dissectionof intraocular tissues.

RETINAL MICROVASCULAR SURGERY

We have investigated in animal eyes the feasibility of microvascular surgery to revascularize the retina.9,10

In porcine eyes under an operating microscope,several classic microvascular maneuvers were possible,including vascular puncturing, catheterization, mobi-

lization, and intravascular injections of retinal arteriesand veins. Two remote retinal vessels were connectedwith a fine tube using a combination of these maneu-vers. Instrumentation used included disposable 30-gauge needles, fine polyimide tubes, custom-madefine glass tubes, and the Er:YAG laser.

In the human the larger retinal vessels range fromapproximately 80 to 125 µm, and we can achievecatheterization, anastomoses, and other procedures, inthe scale of the human hand. One can envision tech-niques by which an ischemic retina could be revascu-larized. This type of procedure has been successful in

other parts of the body, so why not in the retina?

CONCLUSIONS

I noted above the two fundamental abnormalprocesses at work in diabetic blood vessels: vascular

incompetence and vascular occlusion. The basic chal-lenges in DR therapy flow from these critical vascularabnormalities. We must find therapies that prevent orreverse retinal vascular leakage, retinal ischemia andatrophy, and resulting neovascularization.

The future of DR therapy will be filled with innovation,

both pharmacologic and surgical. Antiinflammatory

approaches will be at the fore in pharmacology. Extended

delivery vehicles will provide a foundation for multidrug mul-

titreatment; an intraocular implant could potentially allow

delivery of more than one drug to the retina. Laser technolo-

gy holds promise for delicate, controlled ablation of tissues in

the posterior segment, and true retinal vascular surgery mayallow us to restore blood flow in ischemic tissues. ■

Donald J. D’Amico, MD, is Professor and

Chairman of the Department of Ophthalmology

at Weill Cornell Medical College and

Ophthalmologist-in-Chief at New York-

Presbyterian Hospital, New York, NY. He may be

reached at 1 646 962 2865; e-mail: djdamico@

med.cornell.edu Dr. D’Amico states that he is a consultant for Alcon Laboratories, and Neurotech, and a Scientific

Advisory Board member and equity holder in OptiMedica,

Ophthotech, and Jerini Ophthalmic.R. V. Paul Chan, MD, is an Assistant Professor of

Ophthalmology and the St. Giles Assistant

Professor of Pediatric Retina at Weill Cornell

Medical College. Dr. Chan states that he has no

financial interests or relationships to disclose.

Acknowledgements: Figures courtesy of Dr. Minhee Cho.

1. Centers for Disease Control and Prevention. Improving the Nation’s Vision Health: ACoordinatedPublic Health Approach. http://www.cdc.gov/diabetes/pubs/pdf/vision.pdf. Published July 13, 2007.Accessed August 18, 2009.2. Joussen AM, Poulaki V, Qin W, et al. Retinal vascular endothelial growth factor induces intercellularadhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic reti-

nal leukocyte adhesion in vivo.Am J Pathol. 2002;160(2):501–509.3. Diabetic Retinopathy Clinical Research Network. Arandomized trial comparing intravitreal triamci-nolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology.2008;115(9):1447–1449.4. Kwak HW, D’Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasoneafter intravitreal injection. Arch Ophthalmol. 1992;110(2):259–266.5. Nguyen QD, Tatlipinar S, Shah SM, et al. Vascular endothelial growth factor is a critical stimulus fordiabetic macular edema. Am J Ophthalmol.2006;142(6):961–969.6. Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferativediabetic retinopathy. N Engl J Med. 2005;353(8):782–792.7. Kim BJ, Waheed NK, Romano M, ScottiF, Hafezi-Moghadam A, D’Amico DJ. Elevated erythropoi-etin and vascular endothelial growth factor levels in an adolescent with retinal neovascularization froma chronic rhegmatogenous retinal detachment. Retin Cases Brief Rep. 2008(2);2:117–120.8. Krause MH, D’Amico DJ. Ablation of vitreous tissue with a high repetition rate erbium:YAG laser.Eur J Ophthalmol. 2003;13(5):424–432.9. Christoforidis JB, Warden SM, Demattia M, D’Amico DJ. In vivo redirection of retinal blood flow intoborosilicate micro-cannulas in rabbits. Graefes Arch Clin Exp Ophthalmol. 2006;244(8):1022-–1025.10. Tsilimbaris MK, Lit ES, D’Amico DJ. Retinal microvascular surgery: a feasibility study. Invest Oph-

thalmol Vis Sci. 2004;45(6):1963–1968.

the future of diabetic retinopathy treatment

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