Though wet age-related macular degeneration remains a juggernaut, researchers are finding increasingly large obstacles to lay in its path. At this year's ARVO meeting, doctors from around the world will share information about the various ways they're fighting AMD and its associated pathologies, including photodynamic therapy, transpupillary therapy and the use of experimental agents. There are also new findings regarding vein occlusions and the toxicity of popular surgical adjuncts. To see what's hot this year in retinal research, read on.

Battling Inflammation
Researchers from the Netherlands found that antitumor necrosis factor can be effective in tough cases of sight-threatening uveitis.

In the study, the doctors administered anti-TNF (IV Infliximab
3-5 mg/kg body weight or subcutaneous injection of Etanercept two times 25 mg weekly) to 15 patients with refractory uveitis who had already failed treatment with agents such as steroids, cyclosporine, methotrexate and interferon-alpha. Most patients had Behçet's disease (nine). The others had sarcoidosis (one), ideopathic uveitis (two), birdshot retinochoroidopathy (one), Wegener's granulomatosis (one) or Erdheim Chester (one).

The anti-TNF therapy effectively suppressed the ocular inflammation and brought about clinical improvement in most patients, especially those with Behçet's. Treatment was discontinued in one patient due to a rash. 2399
A fluocinolone acetonide implant may be effective in suppressing inflammation in patients with severe uveitis who have to undergo cataract surgery, say researchers from Duke University and Control Delivery Systems (Watertown, Mass.), the maker of the device.

In the pilot study, eight eyes of seven patients with posterior or pan-uveitis requiring immunosuppressive therapy and/or periocular steroid injections underwent simultaneous implantation of a sustained-release fluocinolone acetonide implant (0.5 mg or 2 mg) and phaco/IOL implantation.

The mean follow-up was 58 weeks. The patients' average acuity went from 20/750 to 20/70, with seven of the eight eyes improving by four lines or more. Five of the eight now see 20/40 or better. No intraocular inflammation recurred and patients who had required systemic immuonsuppression preoperatively were able to reduce the use of such agents postoperatively. The average number of steroid drops went from 7.4 per day to 1.5. And, though 10 steroid injections were given preop, only one was needed in the same length of time postop. The most significant risk was an increase in IOP, with the mean pressure rising from 12 to 17 mmHg, which required two of the seven patients to go on IOP-lowering drops. 2410

Photodynamic Therapy
The Treatment of AMD with Photodynamic Therapy (TAP) study group will report five-year findings of a study extension evaluating verteporfin therapy in AMD patients with predominantly classic subfoveal CNV.

The study included patients who had completed two years' follow-up in the TAP investigation and whom study doctors judged might benefit from further therapy. All patients received treatment, regardless of whether they were originally in the treatment or placebo group in TAP. There were 124 patients total, or 78 percent of the original 159 verteporfin-treated patients. Ninety-three (58 percent) completed their four-year exam.

At year three, 33 (36 percent) and 40 patients (43 percent) lost at least 15 letters of vision. There were no additional cases of severe vision decrease between three and four years. Though the vision remained relatively stable in the patients, the researchers advise caution in interpreting the results, since there was no control group and not all the patients in the TAP investigation were in this extension. 1099

In another PDT-based study, researchers from New York City say that a combination of PDT and triamcinolone acetonide (Kenalog) may be effective for CNV secondary to AMD.

In the paper, 26 patients with CNV underwent PDT and then immediately received an intravitreal injection of 4 mg of Kenalog. Thirteen hadn't been previously treated, and were called the Newly Treated group. The other 13 had had prior PDT therapy and had experienced visual loss while being treated with PDT alone and were called the Prior Treatment group.

In the Newly Treated group, mean visual acuity improved by 1.9 lines, with four improving by at least three lines. Two patients (15 percent) required retreatment at three months. Among the 13 eyes in the Prior PDT group, the mean change in acuity was only 0.31 lines. No patient in the Prior group required retreatment at three months. No patients lost three or more lines. The researchers say that, though there was a limited number of patients, the improvement in acuity and lack of fluorescein leakage suggest that this combo therapy merits further investigation. 5032

In a similar study, researchers from Indiana University Medical School say it may be possible to achieve similar visual results in fewer treatments with PDT combined with a Kenalog injection than with PDT alone in patients with predominantly classic CNV due to AMD.

In the study, researchers retrospectively studied 22 patients with new subfoveal CNV. Seven had predominantly classic lesions, eight had minimally classic and seven had lesions that were purely occult. After 13 months, the subjects had received an average of 2.8 PDT treatments and 1.6 Kenalog injections. Predominantly classic patients needed fewer treatments, 2.4 on average compared to 3.6 in the occult group.

Half lost at least 15 letters of vision, and 36 percent lost 30 or more. Here again, the classic group did better, with only 40 percent losing 15 or more, versus 71 percent in the predominantly occult patients. The average logMAR acuity changed from 0.55 to 0.96, and the average greatest linear dimension of the lesions increased from 2,648 µm to 3,977 µm.

As for side effects, 60 percent of the phakic eyes had a worsening of cataract, and there was a transient intraocular pressure rise in 36 percent of patients. 1742

Also of interest in the PDT realm, at this year's meeting researchers will present data from the Verteporfin in Minimally Classic (VIM) trial 1100 and the Verteporfin with Altered (Delayed) Light in Choroidal CNV (VALIO) trial. 1101

Kenalog Highlights
Japanese researchers say it may be better to perform vitrectomy with adjunctive Kenalog in patients with proliferative vitreoretinopathy.
In the retrospective study, surgeons looked at 15 PVR eyes that underwent pars plana vitrectomy with Kenalog used as an adjunct, and 21 that had vitrectomy alone.

With an average follow-up of one year, 67 percent of the Kenalog-assisted group had achieved retinal reattachment with a single operation, compared to just 24 percent of the non-Kenalog group. The final reattachment percentages were 93 percent and 57 percent for the drug-assisted group and the non-Kenalog group, respectively. The Kenalog group also showed a statistically significantly lower rate of reoperations. One eye of each group had an intraocular pressure increase that was controllable by glaucoma drops. There were no other adverse effects. 2988

Researchers from the University of Sydney have undertaken a prospective, double-masked, placebo-controlled, randomized clinical trial looking into the efficacy and side effects of Kenalog in diabetic macular edema.

At three months, nine of the 16 eyes (56 percent) treated with Kenalog have gained five or more letters of best-corrected acuity, versus just two of the 15 eyes (13 percent) that received placebo. Only one of the Kenalog eyes (6 percent) lost five or more lines of vision, compared to five of the untreated eyes (33 percent). Though Kenalog appears to be effective, the researchers advise holding off on using it until longer-term safety data is available. 3219

Researchers from the University of Medicine and Dentistry of New Jersey and Wills Eye Hospital say that though Kenalog can reduce clinical macular edema in eyes with diabetic retinopathy, the visual acuity may not improve.

The surgeons reviewed the charts of 232 eyes of 218 patients with diabetic macular edema who were treated with intravitreal Kenalog injections. One hundred and seventy-eight eyes (77 percent) had nonproliferative disease, and 54 eyes (23 percent) had the proliferative form. One hundred and ninety-five (84 percent) underwent at least one focal laser treatment. After starting with an average acuity of 20/160 at baseline, the average acuities were 20/120, 20/120 and 20/140 at one, three and six months, respectively. Clinical resolution of macular edema occurred in 140 eyes (61 percent), and 40 (17 percent) were treated more than once. Visual outcomes were limited by subsequent development of vitreous hemorrhage and macular ischemia in some of the patients. 3220

The same group also studied the complications of Kenalog used for edema of various etiologies in a separate study. They retrospectively analyzed 387 eyes of 368 patients, with a mean follow-up of six months. The complications:

• Mean IOP went from 15 mmHg preop to 17 mmHg, 17.9 mmHg and 16.8 mmHg at one, three and six months, respectively.
• Three eyes underwent a guarded filtration procedure for a steroid response.
• Sixty-three eyes (16 percent) had pressures above 21 mmHg and 20 eyes (5.2 percent) had IOPs above
30 mmHg.
• Ten eyes (2.6 percent) developed culture-proven endophthalmitis (Staph. epidermidis).
• Seven (1.8 percent) had cataract progression.
• One eye (0.3 percent) required laser peripheral iridotomy immediately after injection due to angle closure and one eye developed herpes simplex keratitis two months after injection. 3222

Other Agents
Researchers from Alcon, the University of Iowa and the U.K.'s South Hampton Hospital say that anecortave acetate may be effective for patients with occult or minimally classic CNV.

Under an open-label, compassionate-use protocol, the researchers treated 24 patients with occult or minimally classic CNV with a posterior juxtascleral administration of anecortave acetate (15 or 30 mg). Over the follow-up period, retreatments were performed at the discretion of the treating physician based upon evidence of improvement or clinical progression of the lesion. After retreatment, the exam cycle was repeated. Three patients received PDT prior to the study, and two received it during the study when their CNV lesions progressed to the level of eligibility for the TAP study.

At one year, visual acuity improved from baseline in a quarter of the patients (6 patients). Sixty-seven percent (16 people) lost less than 15 letters of vision, and only 17 percent (four patients) experienced severe vision loss.

Clinical improvement, defined as decreased subretinal fluid, decreased subretinal hemorrhage or reduced hyperfluorescence, was evident in half of the patients. Sixteen patients needed retreatments, and adverse events were limited to discomfort in the injection area (three patients) that resolved in up to two weeks. 5039

In an open-label, randomized study sponsored by Genentech, researchers in Boston and San Francisco found that patients with wet AMD showed improvement in vision when they were treated with rhuFAB V2, a monoclonal antibody fragment that works against vascular endothelial growth factor in the eye.

In the study, researchers enrolled 64 patients in two dose groups: 300 µg and 500 µg, given every 28 days; or "usual care." The CNV was minimally classic in 39 percent and predominantly classic in 33 percent. Twenty-eight percent had had prior PDT. The number in the treatment group outnumbered the usual-care group by four to one, and each patient in the V2 group got four to eight intravitreal injections. Most usual-care subjects crossed over to rhuFAB treatment for 12 weeks after the initial study period.

In subjects with as long as seven months of follow-up (n=19) who were treated with 300 µg, the average visual acuity improved 8.5 letters from baseline on day 98, and improved an additional 4.3 letters through day 210, for an overall improvement of 12.8 letters.

Subjects who started out in the usual-care group for 98 days, then switched to rhuFAB, showed a decrease of three letters at first, followed by an improvement of 10.3 letters after switching to 300 µg rhuFAB. The researchers say there have been few drug-related serious adverse events, and that, except for reversible inflammation, the patients have tolerated the injections. They think further study is warranted. 972

Transpupillary Thermotherapy
Surgeons from France and Belgium say it may be possible to treat both a submacular hemorrhage from CNV and its cause simultaneously, using pneumatic displacement and TTT.

The doctors retrospectively analyzed data from 22 eyes of 20 patients with hemorrhage. Treatment consisted of posterior vitrectomy with removal of the posterior hyaloid. They injected pure SF6 gas through the pars plana, but no tissue plasminogen activator. Patients remained face down for eight hours. Then, patients alternated prone positioning with walking to allow active blood displacement. After an average of three weeks, surgeons performed TTT on what turned out to be predominantly occult CNV in most eyes.

At the 12-month follow-up, acuity improved by at least two lines in 18 eyes (82 percent) and worsened in two. The average improvement was 3.4 lines. Though the hemorrhage didn't recur, some CNV did, in a predominantly classic form. 1751

RAP Session
Surgeons from Manhattan Eye, Ear and Throat Hospital say that PDT may reduce the risk of visual loss in patients with retinal angiomatous proliferation, for which there currently is no established treatment. Retinal angiomatous proliferation, or RAP, is a specific type of neovascular AMD in which vascularization is intraretinal rather than choroidal.

In the study, researchers retrospectively reviewed a series of 90 patients treated with PDT for AMD, and five met the criteria for RAP. The doctors found that PDT had achieved stable vision in four of the five eyes, with only one patient losing more than three lines of vision. After six months, the average vision loss was 1.8 lines, and no patient lost more than six lines. Though the researchers say PDT appeared to reduce the risk of vision loss, more studies are needed to delineate the safety and efficacy of PDT in RAP. 1793
Researchers at the National Retina Institute in Chevy Chase, Md., say that high-speed ICG-guided focal laser photocoagulation of RAP lesions may help improve outcomes.

The researchers treated 12 eyes of 11 consecutive patients with macular degeneration and associated RAP lesions. They used clinical fundus examination, fluorescein angiography and static and high-speed ICG imaging to identify the lesions. Then, they used a confluent yellow laser (568 nm) to ablate the intraretinal neovascularization and any associated intraretinal vascular anastomoses.

An average of 2.1 laser treatments per eye was required. After a mean follow-up of 4.8 months, 92 percent of the patients had a reduction or resolution of subretinal fluid and retinal edema. Eighty-four percent had stable or improved acuity and 42 percent gained at least a line. There were no significant complications.

The researchers say that, since high-speed ICG was able to localize early RAP lesions that weren't well defined with traditional image techniques, it may enable earlier therapy that could lead to improved visual outcomes. 5034

CRVO News
Researchers from the University of Wisconsin-Madison and the Bascom Palmer Eye Institute have found that Kenalog may be an effective treatment for non-ischemic central retinal vein occlusion, though retreatments may be required.

In the retrospective study, 13 consecutive patients with macular edema associated with CRVO were treated with one or two injections of Kenalog. At six months, the average acuity had improved from 20/500 to 20/260, with an average gain of 2.2 lines. Five non-ischemic patients of the 13 gained three or more lines of vision. The rest of the patients, all with the ischemic form of the disease, saw no change in acuity.

Between the three- and six-month follow-ups, five patients developed a recurrence of the edema and four of them were retreated. All four of the retreated patients experienced a reduction in foveal thickness on optical coherence tomography and clinical exam. The average thickness decreased from 590 µm to 292 µm. One patient needed to start glaucoma medication in response to a postop pressure increase, and two patients experienced progressive lens opacification. 3217

Mexican researchers say that radial optic neurotomy is ineffective in treating ischemic CRVO.

The doctors performed RON on 10 consecutive patients with ischemic CRVO, then studied the results in a prospective, longitudinal analysis. Preoperatively, the patients' acuities ranged from 20/300 to hand motion. The procedure involved pars plana vitrectomy, followed by incision of the scleral ring, cribriform plate and adjacent sclera at the nasal edge of the optic disc with a microvitreoretinal blade. They saw the patients for six months.

Two patients improved from hand motion acuity to 20/300, three from 20/300 to 20/200 and five have shown no improvement. Their intraocular pressures, which ranged from 8 mmHg to 21 mmHg preop (mean: 16.33 mmHg) dropped to a range of 8 mmHg to 12 mmHg (mean: 11 mmHg) after surgery. Fundus exam, angiography and multifocal electroretinogram showed no improvement. Mean macular thickness as measured by OCT went from
786 µm preop to 560 µm postop, with no correlation with the visual gains. One patient suffered an intraoperative central artery perforation and two had intraoperative bleeding that resolved by raising the IOP. As a result of the outcomes, the authors conclude that RON has no benefit in ischemic CRVO. 4053

ICG Toxicity
A team of Canadian researchers has identified a clinically useful concentration of indocyanine green that's not toxic to the retina.

The researchers applied ICG dye (IC-Green, Akorn) and Trypan blue dye (MembraneBlue, Dutch Ophthalmic Research Corp.) to ARPE-19 and primary human RPE cultures at various concentrations and for different lengths of time. They also applied fiber-optic light to some tissue walls.

The researchers found that Trypan blue wasn't toxic to the RPE cell cultures in any concentration or over any time period, but ICG showed dose- and exposure-dependent toxicity. Over a three-minute exposure, ICG was toxic to the cells at the concentration of 5 mg/ml (26-percent cell survival) down to a concentration of 0.5 mg/ml (93-percent cell survival). Addition of light to the cultures increased cell death by the same proportion in controls and dye-treated cells; no increase in phototoxicity was demonstrated with the addition of either dye. Long periods of exposure—2 hours, 24 hours and 48 hours—to minute concentrations of either dye didn't produce cell death. At 60 seconds of exposure, ICG 0.5 mg/ml was not toxic to the cell cultures. The researchers say this is an amount that is both safe and clinically useful. 4043

Retinopathy of Prematurity
Two groups of researchers investigated the outcomes of surgery for late-stage retinopathy of prematurity.

The first group of researchers, hailing from Maryland and Tennessee, retrospectively reviewed the charts of 600 infants with Stage-5 ROP in at least one eye who were referred for surgery between 1977 and 2002. Vitrectomy was the main surgical approach in 96 percent of the 955 eyes.

Of the 597 eyes with a recorded anatomic outcome, 34 percent were "successes" (defined as fovea attached/stage 4A or foveal detachment/stage 5) and 66 percent "failed" (defined as total retinal detachment/stage 5, opaque cornea, secluded pupil or phthisis). Patients in whom the fellow eye was involved or who had a history of cryotherapy were a little more than twice as likely to fail anatomically. Of the 181 eyes with recorded final acuities, four had 20/200 or better, four were between 20/200 and 5/200, 18 could detect hand motions, 108 perceived light and 47 had no light perception. 2161

In a second, retrospective study of ROP, researchers from New Orleans compared retinal detachment repair with lens-sparing vitrectomy versus repair via scleral buckling in 26 eyes of 21 patients with Stage 4 ROP. Ten eyes had a vitrectomy and 16 had a buckle.

Seventy percent of the vitrectomy eyes were successfully reattached after one procedure, versus 31 percent of those that had undergone scleral buckling. Eighty percent of the vitrectomy eyes' retinas were attached at the last visit compared to 69 percent of the scleral buckle patients. Also, on average, eyes that had scleral buckling as their primary procedure required more procedures (mean: 3) than those that had undergone a vitrectomy (mean: 1.6). 608  

Dr. Regillo is an associate surgeon at the Retina Service and director of the Clinical Retina Research Unit at Wills Eye Hospital.