• Diabetic Retinopathy: Six Doctors Target Three Cases

    By Miriam Karmel, Contributing Writer

    This article is from March 2007 and may contain outdated material.

    Macular edema. Proliferative retinopathy. Vitreous hemorrhage. The ophthalmic complications of diabetes can dog both physicians and their patients. Here is how six experienced retina specialists would handle three trying situations.

    Neither diabetes nor its related retinal diseases can be cured in today’s medical practice. But collaborative treatment by diabetes specialists and ophthalmologists can certainly slow the progression of diabetic retinopathy, which affects at least 5.3 million American adults.

    The dilemma for ophthalmologists: Which treatment? The only proven treatments are laser photocoagulation for diabetic macular edema (DME), panretinal photocoagulation for the proliferative form of the disease (PDR), and, of course, medical control of the diabetes-related metabolic disorders. But that hasn’t stopped doctors from reaching for new anti-VEGF agents and intravitreal steroids. Though the level of evidence to support their use is only emerging, today almost anything goes. “All the injectables have blown the traditional thinking out of the water,” said Nancy M. Holekamp, MD, associate professor of clinical ophthalmology at Washington University in St. Louis. “I’ve seen people in Missouri treat PDR with Kenalog injection alone, and that’s just nonsense. Everyone is doing everything,” she said. “It’s the Wild, Wild West out there.”

    Though their use is widespread, Donald S. Fong, MD, MPH, said the role of intravitreal steroids and anti-VEGF agents is still unclear. “Laser is actually much more effective than we had given it credit for,” Dr. Fong said. “Because the laser is so good, it means that every other treatment has to be substantially better. The laser has set a pretty high bar.” Dr. Fong is director, clinical trials research, Southern California Kaiser Permanente Medical Group.

    Ongoing investigations, many under the auspices of the Diabetic Retinopathy Clinical Research Network (DRCR.net), will ultimately clarify which, if any, off-label treatments belong in the ophthalmologist’s armamentarium. As Dr. Fong sees it: “We’re in a time of evolving management, and what is evolving is our use of the variety of treatments out there and sorting out which are better than laser.”

    In the meantime, here’s what a panel of experts had to say about treating three challenging, but not uncommon, cases. The cases and images were supplied by Dr. Holekamp. Each panelist also examined the accompanying clinical images.

    Case One: Diabetic Macular Edema Refractory to One Focal Laser Treatment

    Patient: A 52-year-old diabetic male recently diagnosed with diabetes mellitus, following many years of symptoms.

    Presents: Currently being treated with rosiglitazone (Avandia) and has good blood glucose control. After undergoing one focal laser surgery, he returns for a three-month follow-up visit. Visual acuity is 20/80. A fluorescein angiogram obtained at the pre-laser visit showed a combination of microaneurysms and diffuse leakage, and no macular ischemia.

    Problem: How to proceed? Would any of the following play a role: additional laser, intravitreal injections of triamcinolone (Kenalog) or bevacizumab (Avastin), or vitrectomy?

    Dr. Bhavsar: I would first consider discontinuing rosiglitazone, which is known to be associated with macular edema or worsening of macular edema. Patients can be controlled with therapies other than glitazones.

    Then I would check that his blood pressure is under control. And I would consider grid focal laser treatment. If the patient had persistent edema, I would then consider intravitreal triamcinolone. My next option would be intravitreal bevacizumab followed by vitrectomy.

    Dr. Capone: I would repeat the angiogram to assess whether residual focal leakage was present and repeat laser accordingly for that component.

    For the diffuse edema, the oral rosiglitazone is a potential concern. I also routinely inquire about a patient’s total body fluid/renal status when there is diffuse edema.

    For this patient, I’d contact the internist to consider discontinuing the rosiglitazone and raise the issue of tighter control of the patient’s fluid status and blood pressure. I would not inject steroid unless these measures fail.

    Dr. Flynn: This patient has persistent diffuse clinically significant diabetic macular edema (CSME) as manifested by widespread exudates throughout the posterior pole, scattered microaneurysms, and only localized evidence of the previous macular grid laser treatment. The OCT shows no vitreomacular traction, but does show persistent cystoid changes in the retina without visible subretinal fluid.

    Based simply on the persistent visual loss, presence of CSME, and OCT showing prominent cystoid changes, I would recommend treatment with intravitreal triamcinolone in the right eye. The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a phase 3, multicenter randomized prospective clinical trial for patients with CSME. One part of this study is evaluating Early Treatment Diabetic Retinopathy Study (ETDRS) modified grid laser treatment compared with treatment with intravitreal triamcinolone. Although the trial is not yet completed, the use of triamcinolone is a common clinical practice today. Safety issues with this treatment include endophthalmitis, glaucoma and cataract.

    Dr. Campochiaro: The patient has severe DME and is a good candidate for intraocular injection of a VEGF antagonist, either ranibizumab in the READ-2 clinical trial or off-label use of bevacizumab.

    Dr. Fong: I would apply additional laser treatment to all areas of thickened retina, using the modified ETDRS technique. I would treat leaky microaneurysms, especially the large “juicy” one inferior to the center. After directly treating the microaneurysms, I would apply some grid laser to fill in areas between the direct treatments.

    In my experience and in case series in the literature, triamcinolone can reduce retinal thickening from diabetic macular edema. However, retinal thickening is only partially correlated with visual acuity. And although triamcinolone may have some efficacy, safety is also important. We do not have a good assessment of the frequency of adverse events, which include cataract formation, glaucoma and endophthalmitis.

    Bevacizumab has been reported in small series to be effective in reducing diabetic macular edema. How good is it compared with laser? The effect of laser can be quite long. Some believe that improvement can occur three to six months after treatment. If bevacizumab for DME resembles ranibizumab’s effect for AMD—that is, treatment every four weeks—there is likely going to be the need for frequent re-treatment.

    In my practice, laser treatment is very effective. I consider pharmacologic treatment only as second line. If, after the patient receives additional laser and there is persistent or recurrent thickening, triamcinolone and bevacizumab should be considered.

    The evidence for vitrectomy surgery for treating macular edema is weak. I might consider its use earlier if the OCT shows definite vitreomacular traction or a thickened surface membrane. Given that the OCT demonstrates neither of these findings, I think that it is not indicated.

    Since the patient is taking rosaglitazone, I would explain the potential association with macular edema, but I would advise the patient to not worry about this treatment if his endocrinologist believes that the patient needs this drug to control his diabetes.

    Dr. Holekamp: This patient has macular edema that has failed one focal laser treatment. He has visual acuity below the level required for reading comfortably and driving. My goal would be to stabilize his diabetic retinopathy and improve his vision as much as possible. I would obtain another fluorescein and if there were microaneurysms, additional focal laser would be reasonable. However, in the presence of diffuse leakage, I am doubtful this would result in improved vision. My treatment algorithm for diffuse diabetic macular edema is focal laser according to ETDRS guidelines, a trial of intravitreal bevacizumab and a trial of intravitreal triamcinolone, with both injection procedures being preceded by good informed consent. At present, I favor bevacizumab before triamcinolone because the latter has a 30 percent chance of elevated intraocular pressure requiring treatment, a 50 percent chance of progressive cataract within one year, and recent data from small randomized clinical trials showing very little sustained visual benefit at one year.

    Case Two: Proliferative Diabetic Retinopathy Presenting With Macular Edema

    Patient: A 32-year-old white male with a 20-year history of poorly controlled insulin-dependent diabetes and systemic hypertension. He has not seen a retina specialist in three years, but had mild panretinal photocoagulation (PRP) surgery placed in one eye at that time.

    Presents: Visual acuity of 20/50, with retinal neovascularization and macular edema.

    Problem: Do you see any role for protecting the eye from worsening macular edema with intravitreal injections while administering PRP laser surgery? How is the diffuse late macular edema best treated?

    Dr. Capone: He obviously needs more scatter laser in the setting of diffuse macular edema.The question is: How do you add scatter laser in the gentlest manner? I would split the laser in two or three sessions to minimize the risk of the scatter laser worsening the macular edema.

    If that were not effective in the first eye, I’d consider intravitreal steroid injection, and concomitant steroid in the second eye, in addition to laser. I don’t see much added value to injecting an anti-VEGF agent in this scenario because of the short duration of effect and the potential rebound worsening of edema.

    Dr. Bhavsar: I would communicate directly with his internist and endocrinologist regarding optimizing blood glucose control, hypertension control, renal function and fluid balance. I would stress the importance of compliance with medical and retina care, and then I would perform focal grid laser. Approximately four weeks later, I would proceed with PRP divided into three sessions, approximately three to four weeks apart, to decrease the risk of increasing the macular edema.

    If the macular edema worsened during the PRP, I would consider treatment with intravitreal triamcinolone. If the proliferative disease were resistant to PRP treatment, I would consider intravitreal bevacizumab.

    Dr. Holekamp: This man needs to get his diabetes and systemic hypertension under control. And he has a definite need for extensive PRP laser surgery in an eye with macular edema and vision that is borderline for reading and driving. To avoid worsening of the DME and vision, it could be reasonable to inject intravitreal Avastin to reduce the intraocular VEGF load and possibly protect the macula while PRP was placed. The intravitreal bevacizumab would also likely result in regression of the retinal neovascularization, possibly reducing the chances of a post-laser vitreous hemorrhage. Bevacizumab is a temporary adjunct treatment for enhancing the outcome of laser surgery, which is still the standard of care and only long-term fix.

    The pattern of diffuse macular edema does not respond well to ETDRS-type focal laser treatment, but may respond to vitrectomy with triamcinolone-assisted peeling of the internal limiting membrane. The chronic, cystic spaces can often be the result of a taut posterior hyaloid or epiretinal membrane, which are often not appreciated until one is inside the eye doing a vitrectomy. Even in the absence of obvious traction, vitrectomy improves intraocular oxygen tension and may serve to reduce the VEGF load within the eye, thereby reducing macular edema.

    Dr. Fong: The most pressing threat to the patient’s vision is the proliferative diabetic retinopathy, which untreated has a high risk of leading to severe vision loss. Given that PRP is the only proven therapy for PDR, I would initiate PRP.

    I would definitely treat the macular edema, probably starting with focal laser treatment of the DME. Although focal laser treatment is the only proven therapy for DME, I am concerned that the PRP would lead to significant worsening of the macular edema and loss of vision.

    Given these concerns, my timing for laser treatment would be at the initial visit: focal treatment followed by PRP. I would probably divide the PRP in two sessions, one week apart. I would probably inject an anti-VEGF drug such as triamcinolone or bevacizumab. Although both are unproven, I might be more inclined to inject bevacizumab because I am not concerned about the duration of effect. Macular edema from PRP is a transient phenomenon and I have already placed focal laser treatment, which has a much longer effect.

    I would also discuss the need for improved glycemic control and urge the patient to visit his internist to control blood sugars, blood pressure and cholesterol.

    Dr. Campochiaro: It would be reasonable to treat the patient with intraocular bevacizumab, which would likely cause regression of the retinal neovascularization and also provide benefit for the macular edema. If cost of the bevacizumab were not an issue—at my institution an injection costs about $600 and is generally not covered by insurance—I would treat with monthly injections until there is resolution of the thickening or it reaches a plateau and then perform supplemental PRP.

    Case Three: Proliferative Diabetic Retinopathy With Macular Traction

    Patient: A 43-year-old white male with a 25-year history of insulin-dependent diabetes and hypertension that until recently has been poorly controlled.

    Presents: Despite extensive PRP laser surgery for aggressive PDR, he has persistent disease. Visual acuity, which was 20/20 until a recent hemorrhage with macular traction, is now 20/100.

    Problem: How to proceed with surgical or pharmaceutical management of this situation?

    Dr. Fong: The fundus photograph shows vitreous hemorrhage, fibrous proliferation and full-pattern PRP. Vitreous hemorrhage can occur from active neovascularization or from traction secondary to vitreous syneresis and contraction. My inspection of the vessels shows that there is minimal activity in the neovascular vessels; there are no fine vessels that show fine red capillaries, suggesting the vitreous hemorrhage is from contraction of the vitreous on the fibrous proliferation and not from continued neovascular activity.

    I would recommend vitrectomy to delaminate and remove the fibrovascular proliferation. Use of an anti-VEGF agent is probably not necessary because the neovascularization is already in a fibrovascular stage, rather than the active proliferation stage.

    Dr. Capone: The eye is still actively vascular in spite of the fact that he’s had good laser. And he needs a vitrectomy for traction maculopathy with vision loss.

    I’d consider off-label bevacizumab to quiet his proliferative disease so he’s more likely to have an uncomplicated vitreous surgery. You’re using it to buy a time window for surgical intervention where the eye will hopefully be less prone to intraoperative, or postoperative, bleeding.

    Dr. Flynn: The management decision will be influenced by the status of the fellow eye. If the patient is unable to work or drive, I would consider early vitrectomy for the right eye. If the patient already had a poor outcome from vitrectomy in the left eye, I would be more cautious in proceeding with surgery for the right eye. Traditional thinking held that major vitreous hemorrhage occurred as an isolated event. We now believe there may be a series of small vitreous hemorrhages in PDR. Anti-VEGF agents are frequently utilized to induce regression of neovascularization, reduce bleeding events and help with clearing of the media to allow PRP.

    Another question is when to stop applying PRP in the setting of recurrent vitreous hemorrhage. Historically, some ophthalmologists recommended 4,000 or more laser burns to accomplish the goal of regressing neovascularization. In more recent years, early vitrectomy is more often recommended rather than application of heavy confluent PRP.

    In this patient, more than adequate PRP has already been applied. Macular traction and organizing subhyaloid hemorrhage is the current concern in this patient. If no clearing has occurred in two weeks, I would proceed with early vitrectomy using 25-gauge surgery and removal of the posterior hyaloid. Limited additional endolaser treatment would be necessary.

    Dr. Campochiaro: Based upon the description and appearance, vitrectomy is indicated. I think it is reasonable to consider an injection of bevacizumab prior to surgery for PDR when there are extensive, highly vascularized membranes that will require a lot of dissection, because it can reduce bleeding and facilitate the dissection. However, in this particular case, it looks like a straightforward vitrectomy and the added expense to the patient of bevacizumab is not warranted.

    Dr. Bhavsar: I would consider pars plana vitrectomy surgery with membrane dissection by delamination techniques. If the neovascularization was particularly active, I might consider off-label intravitreal bevacizumab to help decrease the neovascular drive prior to vitrectomy surgery. However, in this case, since the macula is involved with acute traction, I would proceed promptly to vitrectomy surgery.

    Dr. Holekamp: This eye has undergone extensive PRP laser surgery. Now the eye needs a vitrectomy. Many retina specialists have reported the use of intravitreal Avastin about one week prior to vitrectomy, to reduce the vascularity of the retinal neovascularization, possibly making the vitrectomy less “bloody” and less difficult. I have done this with success. The goal of vitrectomy would be to delaminate cortical vitreous off the surface of the retina out to the vitreous base. This can be challenging in young patients without a posterior vitreous detachment. The intraoperative use of a dilute solution of triamcinolone can help identify the cortical vitreous and allow for complete peeling. Finally, in insulin-dependent young males with highly ischemic eyes, I worry about postoperative anterior hyaloidal proliferation and would follow them closely.

    Meet the Experts

    Abdish R. Bhavsar, MD
    Director, clinical research, Retina Center in Minneapolis; adjunct assistant professor of ophthalmology at the University of Minnesota; chairman, Minnesota Diabetes Eye Exam Initiative.

    "This is an era in which we have multiple treatments within our arsenal for DME and diabetic retinopathy. But the level of evidence varies between the treatments. At present, all of the pharmacotherapeutic agents that we can consider for clinical use in treating DME are to be used as off-label agents.”

    Peter A. Campochiaro, MD
    Professor of ophthalmology, Wilmer Eye Institute, Baltimore.

    "There are many patients who do not respond well to focal/grid laser photocoagulation, and I try to provide such patients with an opportunity to enter trials investigating VEGF antagonists. When they are not eligible for such trials, I consider off-label use of Avastin when appropriate.”

    Antonio Capone Jr., MD
    Clinical associate professor of ophthalmology, Oakland University, Royal Oak, Mich.

    “With the easy availability of Kenalog and the prompt response when patients are treated with it, it’s my sense that folks are less likely to pursue focal laser to its full conclusion than in the past. The only DME therapy for which there is top-tier evidence-based support is focal laser.”

    Harry W. Flynn Jr., MD
    Professor of ophthalmology, Bascom Palmer Eye Institute, Miami.

    “In the more advanced DME cases, laser treatment is often not successful at improving or stabilizing vision, and that’s where combination therapy with either intravitreal injection of triamcinolone or intravitreal of an anti-VEGF drug is under study. It’s not like the options are unlimited.”

    Donald S. Fong, MD, MPH
    Director, clinical trials research, Southern California Kaiser Permanente Medical Group, Pasadena.

    “When evaluating new therapies, do not underestimate the safety and efficacy of laser photocoagulation. “The effect of laser can be quite long. Some believe that improvement can occur three to six months after treatment. I consider pharmacologic treatment only as second line.”

    Nancy M. Holekamp, MD
    Associate professor of clinical ophthalmology, Washington University, St. Louis; partner, Barnes Retina Institute

    “The only thing we have evidence-based medicine to support is laser for macular edema and proliferative diabetic retinopathy. You’d be surprised how many people don’t practice that way anymore. “Everyone is doing everything. It’s the Wild, Wild West out there.”


    Dr. Bhavsar has received consulting fees and research funds from Genentech, Eyetech, ISTA, Novartis, Allergan and QLT. Dr. Campochiaro has consulted for Alimera Sciences, L-Path Pharmaceuticals, Potentia Pharmaceuticals and GlaxoSmithKline, and has received grants or research support from Alcon, Alimera Sciences, Athenagen, Cellgate, GlaxoSmithKline, Genentech, L-Path Therapeutics and Oxford Biomedica. Dr. Capone has received travel reimbursement and honoraria for advisory board work from Alcon and Genentech. Dr. Flynn has consulted for Alcon, Eyetech, Genentech, Eli Lilly, Novartis and Optimedica, and is a DRCR Network-Data Safety Monitoring committee member. Dr. Fong has consulted for Eli Lilly and Allergan. Dr. Holekamp has consulted for Genentech, Alcon and Pfizer.

    You’ve Got a Letter! (From Bristol-Myers Squibb)

    Treating diabetic retinopathy got a bit more complicated after Bristol-Myers Squibb sent out a “Dear Healthcare Provider” letter, which warned that triamcinolone acetonide (Kenalog) is not for intraocular use.

    The Nov. 22, 2006, letter was generated, apparently at the urging of the FDA, in response to reports of endophthalmitis, eye inflammation, increased IOP and visual disturbances (including vision loss) possibly associated with the administration of Kenalog. While the letter heightened anxiety among ophthalmologists, it isn’t likely to affect clinical practice.

    The Academy’s executive vice president, H. Dunbar Hoskins Jr., MD, expressed concern about the letter and questioned its timing. In a Dec. 8 response to Bristol-Myers Squibb, Dr. Hoskins wrote, “This places our member ophthalmologists in a very difficult position, perhaps an untenable position.” He requested copies of the safety reports that were submitted to the company, and asked the company to manufacture a preservative-free formulation, “which might address some of these safety issues.”

    In the meantime, the Ophthalmic Mutual Insurance Company (OMIC) advised that ophthalmologists, as part of “the practice of medicine,” may legally administer triamcinolone by the routes not endorsed by Bristol-Myers: intraturbinal, subconjunctival, sub-Tenon’s, retrobulbar, nasal turbinates and intralesional about the head (visit www.omic.com).

    Doctors say they will continue to use the steroid injection. “The use of intravitreal Kenalog is widespread in the ophthalmology community,” particularly in patients with vision loss where other options have failed, said Dr. Flynn.

    “I think everyone plans on continuing using it both now and in the future. So we’re doing it in a truly off-label method,” he added.

    In fact, all of the pharmacotherapeutic agents employed in the treatment of DME are used as off-label agents, said Dr. Bhavsar, who recommends a thorough discussion with patients when using off-label treatments.