Submacular surgery evaluated for CNV, macular degeneration

Dr. Pesin: At least 2 million people in the United States have evidence of ocular histoplasmosis. One hundred thousand of these are estimated to develop choroidal neovascularization (CNV) in one or both maculae. And it usually affects individuals in their 30s to 50s, obviously in the prime of their lives.

There are limitations to the current therapies. During the 1980s, the Macular Photo coagulation Study (MPS), showed that laser benefits extrafoveal and juxtafoveal membranes; however, 30% of laser cases develop recurrences.

In addition, subfoveal laser should reduce visual acuity if used. There was a variable vision loss with observation, which was sometimes severe and sometimes not. You need to know the exact boundaries to do laser, and that’s one of the things about laser: you can’t laser something that has a diffusely leaking membrane on a fluorescein and, also, if there is blood overlying the lesion, you can’t just treat that. You don’t know where the vessels actually are; you may be overtreating or undertreating.

Surgical removal of the vessels certainly may halt the ingrowth and the progression of central visual loss. It may spare the photoreceptors in the region of the vessels because we’re not actually damaging the retina itself. There is no need to identify exact boundaries; you can remove blood at the time of surgery and you can remove an occult membrane with a diffusely leaking edge. You can use it when the boundaries are obscured by blood because you’re removing blood along with the vessels.

Only retrospective studies so far

EastWest Eye Conference Panel

CLEVELAND — During the EastWest Eye Conference held here, moderator Kevin Alexander, OD, PhD, gathered a panel of experts to address new approaches to macular disease. In several articles, we present abbreviated versions of the panelists’ presentations as well as several highlights of the question-and-answer period. Starting on this page, Samuel R. Pesin, MD, a retinal specialist with Retina Vitreous Associates in Toledo, Ohio, reviews study protocols for the Submacular Surgery Trials involving patients with choroidal neovascularization due to macular degeneration, ocular histoplasmosis or idiopathic causes. Stuart P. Richer, OD, PhD, chief of the Optometry Section at the VA Medical Center in North Chicago, outlines his study of patients with dry macular degeneration who are receiving either a placebo, a lutein or a lutein and antioxidant combination (see article). David G. Miller, MD, a retinal specialist with Retina Associates of Cleveland, updates the status of the photodynamic therapy trials and introduces an experimental procedure called retinal rotation (see article). ---Kevin Alexander In accompanying articles, our panelists also address questions from the audience and from Dr. Alexander concerning the ethics of placebo-controlled trials and patients who are ineligible for laser treatment.

The benefits of submacular surgery have only been shown in retrospective studies. About 30% to 35% of patients experienced improved vision, and researchers showed that visual function was possible in an area previously occupied by the vessels. The surgical risks were low. In contrast, series of patients that were merely observed in previous retrospective studies had poor visual acuity outcomes. While there were few improvements when people were untreated, some did do well as the vessels regressed on their own.

Previous research has shown that patients’ visual outcomes can be either poor or wonderful with surgery, or in cases of observation alone. Thus, a randomized clinical trial is justified because this is a significant public health problem, the surgery is well defined, the complication rate is low and current data suggests there are some potential vision benefits. Also, current estimates of risks and benefits are imprecise, so that needs to be better defined. The target number of patients can be recruited quickly over a few years. And meaningful outcomes can be determined in 2 to 4 years.

Little data is available on the potential risks of the surgery. In published retrospective studies, there was an absence of untreated controls, a limited number of cases and short follow-up periods. Recurrences are more common over time. The retinal pigment epithelium atrophies over time. Cataracts can develop as a result of surgery. Retinal detachments can be a late complication.

Potential surgical complications

Intraoperatively, potential complications include a peripheral retinal tear, a hemorrhage under the macula upon vessel removal and an enlargement of multiple retinal incisions. We try to limit the risk of hemorrhage by raising the pressure in the eye for a short period of time on resecting the membrane. As far as retinal incisions, we make a very tiny one, but sometimes removing the vessels yields a larger one than we want. And sometimes we have to make more than one incision to remove the vessels. This isn’t really a complication, but the more incisions and the larger they are increases the risk of scar tissue developing after the procedure.

Postoperatively, the number one complication is cataract, but that’s more straightforward and can be removed over time. Retinal detachments can also occur postop. Less frequent complications can include endophthalmitis or any other problems that may occur after any eye surgery.

Choroidal neovascularization trials

The Submacular Surgery Trials (SST), which began in 1997 and are sponsored by the National Eye Institute, stemmed from clinical research of Matthew A. Thomas, MD, of the Barnes Retina Institute in St. Louis in the early 1990s. Dr. Thomas and others had found that many of their patients who had previously undergone laser photocoagulation developed subfoveal recurrences. The purpose of the initial arm of the SST (“H” group) for CNV was to determine if surgical removal of subfoveal CNV due to ocular histoplasmosis syndrome or idiopathic causes will stabilize or improve vision more often than observation.

Eligible patients in this arm of the SST must have evidence of CNV due to ocular histoplasmosis syndrome or idiopathic causes. Visual acuity has to be 20/50 to 20/800, as tested by the SST protocol. Fluorescein angiogram has to show subfoveal CNV, whether it’s new or recurrent. In other words, they could have previous laser outside of the center. The lesion has to be less than or equal to 9 MPS disc areas. And the patient has to be able to return for 4 years of follow-up.

Patients cannot have another ocular disease that compromises vision, a history of subfoveal laser, recent surgery or previous investigation. So they can’t have been in a radiation treatment study or a photodynamic therapy study.

Macular degeneration trials

The SST arm for macular degeneration has been underway since 1998. Each year it is estimated that 200,000 people over the age of 65 in the United States will develop vessels in their macula from macular degeneration, and about 30,000 of these develop it in the second eye each year. The number of people over age 65 will double over the next 25 to 30 years, making this study of paramount importance.

We know that we’re limited with our current therapy, which is, basically, laser. We have the most success treating the nonsubfoveal choroidal vessels, but few cases come in that are nonsubfoveal. They are mostly subfoveal. Of lasered extrafoveal or juxtafoveal membranes, many will eventually become subfoveal because there is a greater than 50% recurrence rate.

Only small, well-demarcated subfoveal lesions have benefited from laser treatment. The margins of lesions composed of more than 50% blood are difficult to define. Diffuse or occult membranes also make treatment more difficult.

Rationale for surgery

The rationale for submacular surgery is this: we know that removal of CNV may halt growth of the lesion and enlargement of the vision defect. We can spare the photoreceptors by not damaging the retina overlying the vessels as we remove the vessels. We don’t have to identify the exact boundaries of the vessels, and we can use it when we can’t see the borders because of blood.

Improvement in visual acuity after surgery has been documented. Vision function is possible in the area where the vessels have been removed, and the surgical risks are low. With no surgery, poor visual outcome usually occurs, with few improvements.

Some of Dr. Thomas’s data from 1998 show that about 35% of patients who underwent surgery experienced visual acuity improvement of greater than or equal to two lines.

Like the SST for subfoveal histoplasmosis CNV, this trial is justified because macular degeneration is a significant public health problem. The surgery has been used and has been effective, with few complications. Current data suggest potential vision benefits. Current estimates of risks and benefits are imprecise, so we need that data in order to recommend this. The target number of patients can be recruited in a short time interval, and meaningful outcomes can be determined in 2 to 4 years.

Patient eligibility

There are two arms of the SST for macular degeneration — the “B” and “N” groups. Patients eligible for the B group must be at least 50 years old with macular degeneration in one eye. The blood can be associated with either classic or occult CNV under the foveal avascular zone center. And at least 75% of the blood must be posterior to the equator. Patients are permitted to have undergone previous non-subfoveal laser treatment. The total lesion size should be more than or equal to 3.5 MPS disc areas, and the visual acuity can be as poor as light perception, but no better than 20/100.

Patients eligible for the N group must be at least 50 years old and have macular degeneration. The subfoveal vessels must have some classic component and be associated with less than 50% blood.

Total lesion size must be no greater than 9 MPS disc areas. No prior laser for vessels can be present in the N group. Vision must range from 20/100 to 20/800.

Requirements for both trials

Exclusion criteria for both the “H” and “B and N” arms of the SST include:

• another ocular disease that compromises vision
• glaucoma with glaucomatous field loss
• history of subfoveal laser
• recent eye surgery
• previous investigations, such as radiation treatment or photodynamic therapy
• previous submacular surgery

All patients undergo special vision testing for best-corrected visual acuity. Contrast sensitivity is performed, reading speed is measured and photographs are taken with color film and fluorescein angiography. Some patients will have lens photos because we need to study the cataract development over time. A health-related quality of life and a vision interview is performed, and eligibility is assessed through the main center in Baltimore.

Follow-up

Once patients agree they want to be in the study, they are randomized, whereby half the patients get surgery and the other half are observed. Initial follow-up for the surgery patients is 1 month, and for the observation patients it’s 3 months. Otherwise, everybody comes back at 3, 6, 12, 18, 24, 36 and 48 months after enrolling.

We’re studying the primary outcome, which is vision stabilization or improvement at 2 years, and the secondary outcome, which is a change in quality of life from baseline at the 2- to 4-year exam. We’re also looking at the change in vision over 4 years, severe vision loss and adverse ocular outcomes, such as cataract, retinal detachment or recurrences.

In the SST for macular degeneration, the goal is to enroll 360 patients for the B group and 600 for the N group; for group H, the goal is 240 patients. This study began only recently, but the hope is that by September 2000 we can get a lot of eye doctors referring patients in so we can end the trial recruitment and study these patients over 2- and 4-year periods. The study can’t end and we won’t have our gold standard information until we have everybody in and studied for 4 years.

Primary eye care continued

When practitioners refer their patients for studies such as the SST, they may wonder if their patients will be lost to the study. We request that patients continue to see their primary eye care provider for all of their eye care; we tell them we’re just conducting the study and taking care of their retinal disease. We talk to them at length regarding the importance that you all have in their vision care, especially for their better eye if their other eye hasn’t been affected, and we also counsel them regarding low vision. We’ll use the primary care giver to make the appropriate referral for low vision care, as well as cataract surgery after vitrectomy surgery, which is a common occurrence over time.

For Your Information:

• Samuel R. Pesin, MD, is a retinal specialist with Retina Vitreous Associates. He can be reached at 2213 Cherry St., Suite 400, Toledo, OH 43608; (419) 251-4367; fax: (419) 251-3571. Dr. Pesin has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.