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July 2009 Newsletter

My Two Cents: The Macuflow Online Vision Test

A new online vision test for macular degeneration, called Macuflow, is described in the June 2009 edition of the British Journal of Ophthalmology. The test is a modification of the Amsler grid, and is designed to overcome some of the known shortcomings of the traditional Amsler grid vision test.

Macuflow consists of a series of concentric lines that sweep from the periphery of the vision test toward its center. The sweeping motion of the lines provides seamless coverage of the central visual field, and encourages stable fixation. The test is able to detect both scotomas ("blind sports") and metamorphopsia ("distortions"). These appear as discontinuities of the grid and deformations of the lines, respectively. A link to the vision test can be found on myvisiontest.com.

There is a growing interest in designing effective vision tests for patients with macular degeneration. A variety of computerized tests are now available, including Preferential Hyperacuity Perimetry, entoptic perimetry, Macular Mapping, Threshold Amsler Grid, Rarebit, and now Macuflow. Each test has its own strengths and weaknesses. Head to head comparisons not yet been published, so we do not know at this time if one test is superior to the other.

I encourage my patients to test their vision in a variety of ways. It is possible that for a given patient certain vision defects may be detected earlier on one test or another. By checking their vision in a variety of ways they will be more likely to detect a change should it occur. We welcome this new vision test, and hope you find it useful.

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Avastin For Retinal Angiomatous Proliferation

A new study finds that intravitreal Avastin (bevacizumab) is a safe and effective treatment for retinal angiomatous proliferation.

Retinal angiomatous proliferation (RAP) is a distinct form of neovascular AMD associated with angiomatous proliferation that originates from the retina and extends posteriorly into the subretinal space, eventually communicating in some cases with new choroidal vessels. There is a poor visual prognosis and rapid vision loss is common.

In this study 17 eyes from 16 patients with newly diagnosed RAP underwent intravitreal Avastin therapy. The patients received three monthly Avastin injections and were then followed-up for 12 months.

The mean best-corrected visual acuity (BCVA) at baseline was 20/42. At 12 months after treatment the mean BCVA improved significantly to 20/28. BCVA improved 3 ETDRS lines or more in 18% (3 of 17) treated eyes, and 88% (15 of 17) eyes gained 1 or more ETDRS lines. At 12 months after treatment, the mean central macular thickness was reduced significantly from 297 um at baseline to 237 um. At the 12-month follow-up visit, absence of fluorescein leakage was demonstrated in 82% (14 of 17) treated eyes. No ocular or systemic adverse effects were encountered.

The investigators conclude that intravitreal Avastin is very promising for RAP with no apparent safety concerns after 12-months of follow-up.

WHAT IT MEANS TO YOU: Retinal angiomatous proliferation is an uncommon variant of neovascular AMD that, because of an extensive and complex network of intraretinal blood vessels, has traditionally been associated with a poor visual prognosis. However, with the advent of anti-VEGF therapies these patients have faired much better. In fact, a recent paper has documented an association between VEGFA genotype and risk of developing RAP, suggesting that VEGF is at least in part responsible for the formation of RAP, and suggesting that anti-VEGF therapies may be an effective treatment option. This small case series lends support to this view.

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Desensitization Occurs After Long-term Use Of Avastin

Researchers describe their clinical experience with desensitization (tachyphylaxis) to intravitreal Avastin in patients undergoing treatment for exudative AMD.

Desensitization is a commonly encountered problem in drug therapy, such that a medication loses its effectiveness over time; a phenomena known as tachyphylaxis. This is a major problem that can be encountered anytime a drug needs to be taken over a prolonged period of time.

The investigators retrospectively reviewed the records of 59 consecutive patients treated with Avastin at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment effect. The researchers defined tachyphylaxis as an absence of therapeutic response to Avastin 21-35 days after an injection when the patient had previously has a successful therapeutic response.

Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with Avastin. High-dose Avastin (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to Avastin was seen after an episode of unilateral post-injection anterior uveitis. The median time taken to develop tachyphylaxis was 100 weeks (range: 31-128 weeks) after the initial Avastin injection, and the median number of Avastin injections to the development of tachyphylaxis was 8 (range: 5-10 injections).

The researchers conclude that tachyphylaxis can occur after long-term intravitreal use of Avastin in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.

WHAT IT MEANS TO YOU: There is great concern that patients needing to continue on long-term anti-VEGF therapy will develop drug resistance. This is why, in addition to cost and convenience, it is so important that the number of injections be kept to the absolute minimum necessary to keep the macula dry. Generally speaking, tachyphylaxis occurs less frequently when a drug has multiple biologic targets. For example, if a drug interferes with multiple stages of a biologic process, then resistance will be less common than if it interferes with only one. All currently available anti-VEGF drugs have just a single therapeutic target. Earlier research found that it was possible to decrease desensitization by combining Avastin with an intravitreal steroid.

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Two Year Results Of The PrONTO Study

Two year results from the PrONTO study show that as-needed treatment of wet age-related macular degeneration (AMD) with intravitreal Lucentis (ranibizumab) that can achieve visual results comparable to monthly treatments with fewer injections.

The Lucentis phase III clinical trials required monthly injections for all patients, but it was unclear if monthly dosing was the best dosing interval. The PrONTO study was designed to investigate whether a variable-dosing OCT-guided regimen with Lucentis could result in similar clinical outcomes over a 2-year period using fewer injections.

AMD patients with subfoveal neovascularization and a central retinal thickness (CRT) of at least 300 um received 3 consecutive monthly intravitreal injections of Lucentis (0.5 mg). During the first year, retreatment with Lucentis was performed if specific criteria was fulfilled. During the second year, retreatment was performed if any qualitative increase in the amount of fluid was detected using OCT.

Forty patients were enrolled in PrONTO and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters and the CRT decreased by 212 um. VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months.

The final VA outcomes in the PrONTO Study were comparable with the results from the phase III clinical trials. The final mean VA improved by 7.2 letters in the MARINA trial, and 11.3 letters in the ANCHOR trial. Whereas patients in these trials received 24 injections over 24 months, the patients in the PrONTO Study received an average of just 9.9 injections.

WHAT IT MEANS TO YOU: The PrONTO study clearly demonstrates that OCT-guided retreatment of neovascular AMD with Lucentis can achieve visual outcomes that are non-inferior to monthly dosing. Interestingly, a study in the same copy of this journal found this is also true of Avastin – patients achieved excellent visual outcomes using half the number of injections as was used in PrONTO! Unfortunately, monthly office visits with careful examination are necessary to achieve these results. This can pose a significant burden for many patients and their families. Alternative follow-up strategies, such as "treat-and-extend," are still untested. While home vision tests may provide an effective means of detecting recurrence, we would ideally like to detect recurrence before vision is affected. Perhaps someday home testing of biomarkers, such as activated VEGF receptors, can be used to detect CNV recurrence at an earlier stage. More likely, better drugs will become available. The holy grail is a drug (or drug combination) that eradicates existing CNV, deters recurrence, combats the dry component of AMD, and can be administered topically as an eye drop. Such drugs are already on the horizon.

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Polypoidal Choroidal Vasculopathy Responsible For AMD Anti-VEGF Treatment Failure

A new study reports that polypoidal choroidal vasculopathy (PCV) is a common cause of Lucentis and Avastin treatment failure of neovascular AMD.

Lucentis and Avastin are highly effective in the treatment of neovascular AMD. However, there is a small number of patients who will continue to lose vision despite treatment with Lucentis or Avastin. One possible cause of poor response to anti-VEGF therapy is the development of PCV.

PCV is a distinct clinical entity that is characterized by interconnected polypoidal choroidal vessels. It has been proposed that PCV may be a variant of neovascular AMD. The prevalence of PCV among white patients previously diagnosed with AMD is between 4% to 14%. PCV is more common in Asians that Caucasians. It is unclear why some AMD patients are prone to developing PCV. PDT has been reported to be an effective and safe treatment for PCV. Anti-VEGF therapy is also frequently used for PCV patients but with mixed results.

In this study, the records of 12 eyes of 12 patients with neovascular AMD and PCV that responded poorly to anti-VEGF monotherapy were retrospectively reviewed. All of the patients in this study initially presented with typical neovascular AMD and only later during the course of the treatment were found to have developed PCV. All patients demonstrated increasing macular exudation despite regular intravitreal Lucentis or Avastin injections for a minimum of 6 months. All but 2 patients underwent PDT following diagnosis of PCV, with 2 patients continuing on anti-VEGF monotherapy. All patients responded to treatment with resolution of hemorrhages and improvement in edema, exudates, and stabilization of VA.

This study highlights the importance of considering the presence of PCV in AMD patients who fail to respond to standard anti-VEGF therapy.

WHAT IT MEANS TO YOU: PCV, like retinal angiomatous proliferation, may arise as a variant of the typical neovascularization associated with neovascular AMD. It is unclear why certain patients develop these variations. The pathogenesis of PCV is controversial. It has been suggested that there are several types of PCV, including polypoidal CNV and polypoidal inner choroidal vessel abnormalities. It appears that treatment with existing anti-VEGF agents may actually trigger the development of PCV in certain patients, although we do not currently know why this occurs or have any way to predict which patients may be at risk for developing PCV. It is possible that an imbalance of various cytokines (including VEGF and others) are responsible for the development of these vascular abnormalities, just as they are likely to be involved in the pathogenesis of conventional CNV. This case series reminds us to look for the development of PCV in those patients with typical neovascular AMD that fail to respond to anti-VEGF therapy in a timely manner.

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Four-year Follow-up Of Photodynamic Therapy For AMD

A long-term study of patients with exudative AMD undergoing standard-fluence PDT finds that visual acuity remained stable between years 2 and 4 years following treatment.

PDT is performed by intravenous administration of a drug know as verteporfin, then activating the drug within the retina using a laser. Upon activation verteporfin generates singlet oxygen and free radicals, leading to occlusion of the CNV membrane and surrounding blood vessels. A number of studies have reported favorable results using PDT in combination with intravitreal steroid. A 24-month follow-up study of PDT-steroid combination therapy found a visual acuity benefit that lasts for 1 year, but at the end of 2 years vision was worse than at the time of the treatment. Reduced-fluence PDT attempts to reduce the risk of vision decline by cutting the dose of verteporfin and decreasing the laser energy.

This study included 262 patients with exudative AMD who were treated with standard-fluence PDT and then followed for 48 months. There was a steep loss of visual acuity 3 months after the first PDT treatment, followed by a slow decline until month 12, and then visual acuity remained stable from months 24 to 48. Best corrected visual acuity dropped from 6 lines at the time of treatment to 4.8 lines at 48 months. The CNV size increased during the first 12 months, particularly the first 3 months after PDT.

The investigators conclude that PDT is a safe, long-term treatment for exudative AMD, but it is not definitive because this treatment cannot stop the initial growth of the CNV lesion.

WHAT IT MEANS TO YOU: This study confirms that standard-fluence PDT results in vision loss. It is reassuring to see that vision loss stabilizes after 2 years, and then remains unchanged for at least 2 additional years. The poor visual outcomes following standard-fluence PDT has lead to many practitioners embracing "safety-enhanced" variations of the original PDT protocol, although these have not yet been tested in clinical trials. However, it seems the best we can hope for from PDT monotherapy is less loss of vision. Therefore, the most appropriate use of PDT for most patients is as an adjunctive to anti-VEGF drugs, such as in the RADICAL trials.

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Reduced-fluence PDT Plus Lucentis Combo Therapy

QLT has announced positive 12-month results from its phase 2 RADICAL study of reduced-fluence photodynamic therapy PDT plus Lucentis combination therapy for neovascular AMD, according to a press release from the company.

The RADICAL study is comparing retreatment rates and visual outcomes of three therapies: 1) reduced-fluence PDT, Lucentis, dexamethasone combination therapy, 2) reduced-fluence PDT, Lucentis combination therapy, and 3) Lucentis monotherapy among 162 patients with choroidal neovascularization (CNV) due to AMD.

Patients were randomized into one of four treatment groups: 1) Quarter-fluence PDT, Lucentis, dexamethasone. 2) Half-fluence PDT, Lucentis, dexamethasone. 3) Half-fluence PDT, Lucentis. 4) Lucentis monotherapy. After a mandatory treatment period, all groups received subsequent treatment on an as-needed basis.

Twelve-month results showed that statistically significantly fewer re-treatments were required with the combination therapies than with Lucentis monotherapy. Of the four treatment groups, the half-fluence triple therapy group demonstrated superior results, with the fewest re-treatment visits (3 total) and mean visual acuity improvement most comparable to Lucentis monotherapy, according to the press release.

While the study will continue for 24-months, QLT plans to present the 12-month primary analysis at a scientific meeting later this year.

WHAT IT MEANS TO YOU: PDT/anti-VEGF combination therapies hold promise of decreased risk of recurrence, but at the expense of poorer visual outcome than can usually be achieved with anti-VEGF monotherapy. The disappointing visual outcomes following PDT monotherapy has lead to investigation of so-called reduced-fluence PDT, utilizing less verteporfin and less laser energy, in an attempt to decrease collateral damage to the retinal pigment epithelium, photoreceptors, and adjacent normal choroidal vessels. Most studies have also found that the concomitant administration of intravitreal steroids will improve the visual outcome following PDT. Patients in the PrONTO study of as-needed Lucentis monotherapy required approximately 5 treatments per year, whereas patients in the RADICAL study required 3 treatments over a 12 month period. While that difference may seem minimal, a 40% decrease in the number of required treatments could over time become sizable. The real question is: what is price in terms of vision loss?

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CCR3 Is A Target For AMD Diagnosis And Therapy

A research study using laboratory rats has identified the eosinophil/mast cell chemokine receptor CCR3 as a new biologic marker for CNV that has strong potential as a new target for therapeutic intervention. The researchers have discovered that CCR3 is expressed on the surface of CNV vessels in humans but is absent from normal retinal vascular tissue.

CCR3 is a receptor found on the surface of a variety of cells, including white blood cells, for a class of chemical messengers ("cytokines") known as eotaxins. CCR3 is most frequently associated with eosinophils and mast cells, white blood cells that play a major role in allergic reactions. However, recent research has found that eotaxin and its receptor, CCR3, are overexpressed in human atherosclerosis, suggesting that eotaxin participates in vascular inflammation.

The research team was able to detect CCR3 receptors on laser-induced CNV in mice by attaching anti-CCR3 antibodies to tiny semiconductor nanocrystals called "quantum dots" and injecting these into the mice. The antibodies cause the quantum dots to attach to CCR3 on the surface of the choroidal neovascular blood vessels, making them visible with conventional ocular angiography techniques, even before the CNV has penetrated into the retina. Such imaging techniques utilizing CCR3-targeting quantum dots is able to visualize CNV invisible to standard fluorescein angiography.

Furthermore, genetic or pharmacological targeting of CCR3 or eotaxins inhibited the development of laser-induced CNV in mice. CCR3 blockade was more effective at inhibiting CNV development than VEGF-A neutralization.

WHAT IT MEANS TO YOU: CCR3 is a new biomarker for CNV and a potential new therapeutic target. Early detection of CNV, prior even to the lesion entering the subretinal space, could permit therapy to be initiated before vision has been compromised. In this way risk of vision loss from CNV is minimized. Apparently, CNV is dependent upon CCR3 and blocking it causes regression of CNV in much the same way as will blocking VEGF. This has not yet been tested in humans, but is a very promising development.

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Bilateral Simultaneous Intravitreal Injections

A small retrospective series of patients with limited follow-up undergoing simultaneous bilateral intravitreal injections reports that the procedure was well tolerated by all patients, and that given a choice none of the patients requested alternating unilateral injections after receiving bilateral injections. The records of 35 patients receiving simultaneous bilateral intravitreal injections were reviewed. A total of 208 injections were administered to the patients, with a mean of 5.9 injections per patient. The indication for initiating therapy included CNV from AMD (49 eyes), diabetic macular edema (13 eyes), and proliferative diabetic retinopathy (4 eyes). Drugs used included Avastin alone (133 eyes), Lucentis alone (56 eyes), Avastin plus triamcinolone (14 eyes), and Avastin plus dexamethasone (5 eyes). Mean time of postinjection follow-up was 39 days. A separate povidone-iodine preparation, speculum, needle, and syringe were used for each eye. None of the patients requested alternating unilateral injections, after receiving bilateral injections. Patients should be counseled as to the risk of complications. The study was published in the American Journal of Ophthalmology.

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Avastin For Acute Central Serous Chorioretinopathy

A new study finds that intravitreal Avastin results in prompt resolution of acute central serous chorioretinopathy (CSCR). Though the cause of CSCR remains unknown, it is believed that abnormalities in choroidal circulation make the overlying retinal pigment epithelium dysfunctional, resulting in the development of a serous retinal detachment. Photodynamic therapy, laser photocoagulation and pharmacological agents have been used to treat CSCR. However, these treatment options serve only to shorten the duration of symptoms and have no effect on the recurrence rate or the final visual acuity. In this study 10 eyes of 10 patients with acute central serous chorioretinopathy received an intravitreal Avastin injection. All patients showed prompt resolution of neurosensory detachment, and improvement in visual acuity and symptoms within 1 month. At 6 months the mean VA (LogMAR) had improved from 0.32 to 0.04, which was statistically significant. The investigators conclude that intravitreal Avastin for acute central serous chorioretinopathy results in prompt resolution of neurosensory detachment and reduction of angiographic leakage. These short-term results suggest that intravitreal Avastin injection is a promising therapeutic option for this condition. Published in the June 2009 edition of Ophthalmologica.

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Ozurdex Implant Approved For Macular Edema From Retinal Vein Occlusion

The U.S. Food and Drug Administration has approved Allergan's dexamethasone intravitreal implant for reducing macular edema due to branch retinal vein occlusion or central retinal vein occlusion, the company announced in a press release. Administered intravitreally, Ozurdex (dexamethasone intravitreal implant 0.7 mg) delivers an extended release dose of the corticosteroid through Allergan's proprietary Novadur solid polymer delivery system. The FDA approval follows positive results from two clinical trials of the implant that enrolled approximately 1,300 patients. In both studies, as well as in a pooled analysis, patients treated with the drug achieved a 3-line improvement in best corrected visual acuity significantly faster than patients who received sham treatment. The duration of effect lasted approximately 1 to 3 months thereafter, according to the release. Ozurdex is the first therapy indicated for macular edema secondary to retinal vein occlusion to receive FDA approval.

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Endophthalmitis After Anti-VEGF Injections

A new study reporting on the largest series of presumed endophthalmitis cases following intravitreal anti-VEGF injection published to date finds an incidence of 0.049%, and that 20% of cases have a very poor visual outcome. This study is a retrospective analysis of 30,736 injections performed in 5 community-based retinal practices around the country. There were a total of 15 cases of presumed endophthalmitis (0.049%): Avastin (5/8039 = 0.062%), Lucentis (10/22579 = 0.044%), and Macugen (0.00%). Endophthalmitis rates for these 3 types of intravitreal injections did not differ significantly. Mean time to diagnosis was 3.5 days (range, 1–8 days). Six of 13 (46%) cases were culture positive. Only gram positive organisms were isolated. Two patients lost between 3 and 5 lines of vision. One patient dropped from 20/30 to hand motions vision. Two patients lost all vision (no light perception). This study found an incidence of presumed endophthalmitis similar to previous studies. Some earlier reports had suggested that patients with endophthalmitis following anti-VEGF agents do well, typically with a return to baseline vision. Unfortunately, this does not seem to be the case in this series wherein 20% of patients had very poor outcomes. Published in the June 2009 edition of Ophthalmology.

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The Vitreous In AMD

Vitreomacular adhesion (VMA) is a risk factor for exudative AMD, and posterior vitreous detachment (PVD) may protect against wet AMD, according to a paper appearing in the July 2009 edition of the American Journal of Ophthalmology. PVD is a common condition, occurring in about 75% of people over the age of 65. PVD occurs because the central part of the vitreous becomes more liquid with age causing the outer part (cortex) to eventually peel away from the retina. Occasionally, the vitreous cortex will remain adherent to the macula (vitreomacular adhesion) and exert traction upon it. This study consisted of 29 previously untreated subjects with active exudative AMD in one eye and dry AMD in the fellow eye. The incidence of PVD in eyes with dry AMD was 69% (20 of 29), compared with 21% (6 of 29) with active exudative AMD (P = .002). VMA was present in 38% (11 of 29) of eyes with exudative AMD and in only 10% (3 of 29) eyes with dry AMD (P = .008). The results of this study demonstrate that in active AMD, PVD is highly associated with dry AMD, whereas VMA is strongly related to exudative AMD. Thus, VMA may be an important risk factor for progression of nonexudative AMD to exudative AMD. These findings suggest that vitrectomy or pharmacologic vitreolysis may be valuable in preventing exudative AMD.

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Assisting The Vision Impaired With Digital Audio Broadcasting

A move from analogue to digital audio broadcasting (DAB) radio may leave people with vision problems left out of Britain's digital revolution if steps are not taken to assist in the switchover, as laid out in the communications Minister Lord Carter's Digital Britain report. DAB is a digital radio technology for broadcasting radio stations. Radio is repeatedly cited as one of the most important pastimes by blind and partially sighted people. A Digital Help Scheme similar to that used for switchover to digital television has been proposed. The Royal National Institute of Blind People (RNIB) believes such a scheme is absolutely essential. The Digital Britain report also states that steps will have to be taken to ensure that DAB equipment that meets the needs of people with sight and dexterity problems is available at an affordable price. RNIB is calling for a help scheme to provide equipment to this effect, and for a usability standard mark to be provided on all products.

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PDT Plus Lucentis: 12-month Results

QLT, maker of the drug Visudyne used during PDT, announced that 12-month results from the Phase II Mont Blanc study showed that patients treated with PDT plus Lucentis combination therapy had non-inferior visual acuity to patients treated with Lucentis alone. Mont Blanc is a 24-month trial investigating the safety and efficacy of combining standard-fluence PDT and Lucentis in patients with subfoveal neovascular AMD, and represents the European arm of the global Summit clinical trial program. At the Month 12 examination, mean VA in the combination therapy group improved 2.5 letters from baseline compared with a 4.4 letter improvement in the Lucentis monotherapy group. In the combination therapy group, 96% of patients had a three-month treatment-free interval, compared with 92% in the Lucentis monotherapy group. "Mont Blanc provided the first data within the Summit clinical trial program and showed that patients treated with Visudyne combination therapy had non-inferior visual acuity to patients treated with Lucentis monotherapy," said Bob Butchofsky, CEO of QLT Inc.

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Octreotide Inhibits Choroidal Neovascularization In Rats

A study published in the journal Ophthalmic Research finds that octreotide, a synthetic version of the hormone somatostatin (growth hormone inhibiting hormone), is able to inhibit choroidal neovascularization in rats. Somatostatin is produced by numerous organs throughout the body, including the digestive system, the brain, and the eye. Growing evidence suggests that in the retina, somatostatin acts both as a neuromodulator and an antiangiogenic factor. Currently available data suggest that somatostatin analogues might inhibit angiogenesis directly through somatostatin receptors present on endothelial cells and also indirectly through the inhibition of growth factor secretion such as insulin-like growth factor (IGF-I) and vascular endothelial growth factor (VEGF) and reducing monocyte chemotaxis. In the current study CNV was induced in rats by laser photocoagulation. The rats were divided into two groups which were retrobulbarly injected with octreotide or buffered saline. Octreotide treatment significantly inhibited fluorescein leakage, decreased growth of CNV, and lowered levels of VEGF and insulin-like growth factor mRNA. The researchers conclude that octreotide may be an effective therapeutic strategy for CNV.

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