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According to a presentation at the 2009 ARVO meeting, the Foresee Home preferential hyperacuity perimeter was able to detect early choroidal neovascularization (CNV) in patients using the device at home (without supervision) with a sensitivity of 85% and specificity of 84%. The results of this study demonstrate that it is possible to design a home vision test that significantly improves upon the ability of the Amsler grid to detect early CNV. The device is expected to be available in the U.S. in 2010.
Recently, there have been an exciting growth in the number of scientific publications that explore the ability of new vision tests to detect early CNV. While the technology is marching forward, we still face what is perhaps the most daunting challenge to any successful home vision testing program: the difficulty in motivating many patients to make a long-term commitment to using the test on a regular basis.
My experience over the past several years at MyVisionTest is that most persons use the test only very infrequently. This is consistent with experience using the Amsler grid as a home monitoring device - only about half of patients instructed to do so will actually use it regularly. This is disappointing because the ability of a vision test to detect early changes is contingent upon it being used frequently.
The effectiveness of any home vision testing program will be severely limited until we have figured out how to address the human factor.
Three studies published last month report on the important influence that diet has on the risk of AMD.
In the first study, researchers using data from the AREDS study find that a low glycemic index diet, rich in vitamins C and E, zinc, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and lutein/zeaxanthin was associated with a lower risk of early and late AMD.
The glycemic index (GI) is a measure of the glycemic quality of carbohydrate-containing foods. It was devised to measure how fast a food raises blood glucose. A higher glycemic index indicates that the body will more quickly turn the carbohydrates into sugar. DHA and EPA are omega-3 fatty acids and are the key constituents of fish oil.
In the second report, researchers find that fish oil and olive oil are protective against AMD and trans-fat increases the risk of AMD. Higher trans-unsaturated fat intake was associated with an increased prevalence of late AMD; the odds ratio comparing the highest with the lowest quartile of trans fat was 1.76. Higher omega-3 fatty acid intake (highest quartile vs lowest quartile) was inversely associated with early AMD (odds ratio, 0.85). Olive oil intake (100 ml/week vs <1 ml/week) was associated with decreased prevalence of late AMD (odds ratio, 0.48).
Trans-unsaturated fatty acids (TFA) are formed when liquid vegetable fats are hardened through a process of partial hydrogenation and are commonly found in shortenings and processed foods. Studies have shown trans-fat to increase the risk of coronary heart disease. Numerous studies have found omega-3 fatty acids to be inversely associated with AMD. Olive oil is rich in antioxidants and anti-inflammatory compounds. Olive oil may also be a proxy for certain healthy lifestyles that may be associated with a decreased risk of AMD.
In the third report, researchers from the Blue Mountains Eye Study finds that eating fish and nuts decreases the risk of early AMD, especially in people who avoid foods containing linoleic acid (an omega-6 fatty acid).
After adjusting for age, sex, and smoking, 1 serving of fish per week was associated with reduced risk of incident early AMD (relative risk, 0.69), primarily among participants with lower than average linoleic acid consumption (relative risk 0.57). There was no additional risk reduction for more than one serving of fish a week. One to 2 servings of nuts per week was also associated with reduced risk of incident early AMD (relative risk 0.65).
WHAT IT MEANS TO YOU: All three of these studies found that fish or fish oil to be protective against AMD. We will have to await results of the AREDS-2 study for definitive proof that fish oil supplementation can prevent AMD progression. Meanwhile, aside from the AREDS vitamin-mineral supplement, fish consumption and fish oil supplementation has the strongest research evidence to date of any intervention designed to decrease the risk of AMD progression. The other findings from these studies, that a low glycemic index diet, olive oil, and nuts are protective and that trans-fat increases risk of AMD, fits with the widely held belief that a heart-healthy diet can have a favorable effect on AMD risk.
Intravitreal injections have become a routine practice in ophthalmology, with more than 10,000 injections performed per month, according to a speaker at the meeting of the French Society of Ophthalmology.
Controversy exists on the use of preoperative topical antibiotics. Dr Salomon Yves Cohen said the use of preoperative topical antibiotics is "not strictly necessary, and many surgeons don't use them." Three days of postoperative topical administration of antibiotic drops is sufficient to prevent complications. Bilateral injection, he said "is not advisable, but possible, provided that two separate sets of instruments and materials are used, as if it dealing with two separate procedures."
A new study finds that the rate of infectious endophthalmitis following intravitreal injection of anti-VEGF agents is 0.077%. A retrospective review of patients who received intravitreal injections of Avastin, Lucentis, and Macugen (pegaptanib sodium) was undertaken. The risk per injection was 0.077%. The rate of endophthalmitis was 1 per 1,291 injections.
Contamination of intravitreal injection needles is more common than post-injection endophthalmitis, according to a a poster presented by Dr Henry D. Perry at the 2009 Association for Research in Vision and Ophthalmology meeting.
The study included 200 needle cultures from 178 injections and 22 controls. Patients received intravitreal injections of Avastin or Lucentis. Pre-injection prophylaxis comprised moxifloxacin 0.5% and povidone iodine 5%. Researchers found that 12 needles (6.7%) tested positive for bacteria.
WHAT IT MEANS TO YOU: As surgeons have become more familiar with giving intravitreal injections, the risk of complications has fallen. However, there remains a small but important risk of endophthalmitis (intraocular infection). It is unlikely that preoperative prophylaxis and postoperative care will be able to completely eliminate the risk of endophthalmitis. Hence the importance of dosing regimens that decrease the number of injections as much as possible without sacrificing visual outcomes. Combination therapies, for example combining photodynamic therapy with anti-VEGF, is one strategy that is being explored as a means to decrease the need for retreatment. New therapies, such as VEGF-Trap, holds promise of requiring significantly fewer injections than currently available medications. Finally, topical (eye drop) agents currently in the drug pipeline may be able to completely eliminate the need for intravitreal injection in the treatment of neovascular AMD.
A series of three patients with neovascular age-related macular degeneration (AMD) have been successfully treated off-label with Remicade (infliximab), an anti-tumor necrosis factor (TNF) monoclonal antibody.
Remicade has been approved by the US FDA for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, sarcoidosis and ulcerative colitis. It works by blocking tumor necrosis factor alpha (TNFa). TNFa is a chemical messenger (cytokine) and a key part of the autoimmune reaction. Remicade blocks the action of TNFa by preventing it from binding to its receptor.
In this study 3 patients previously treated unsuccessfully with Lucentis (ranibizumab) received 2 intravitreal injections of Remicade spaced 2 to 3 months apart.
In the first patient, best corrected visual acuity (BCVA) increased from 20/200 to 20/100 and central retinal thickness (CRT) decreased from 462 to 386 um after the first injection. Additional improvement occurred after the second injection, but recurrence was seen 7 months post-baseline. In the second patient, BCVA improved from 20/200 to 20/70 and CRT decreased from 512 to 184 um at 4 months post-baseline. In the third patient BCVA improved from 20/100 to 20/30 and CRT decreased from 388 to 282 um 2 months after the second injection.
The researchers conclude that TNF plays a role in neovascular AMD development. Whether Remicade can be viewed as an alternative treatment for AMD deserves further investigation. They speculate that Remicade might prove a useful adjunct treatment, especially in cases refractory to anti-VEGF agents, or when anti-VEGF agents are contraindicated.
WHAT IT MEANS TO YOU: Although too small a study to permit any firm conclusions to be drawn, this series of three patients offers a tantalizing glimpse at the potential anti-TNF agents may hold to treat choroidal neovascularization. It is described as a potential "breakthrough treatment" in an accompanying editorial. Anti-TNF therapy could decrease the need for reinjection with Lucentis, and possibly even improve visual outcomes beyond what is possible with Lucentis alone. Off-label use of Remicade for neovascular AMD cannot be recommended on the basis of this study alone. However, anti-TNF agents are a promising new treatment modality that deserves further study.
No statistically significant difference in best corrected visual acuity (BCVA) at 12 months in patients with early AMD taking oral supplements containing lutein, zeaxanthin, and other antioxidants, according to data from the Carotenoids and Co-Antioxidants in Age-Related Maculopathy (CARMA) study presented at the 2009 ARVO annual meeting.
The CARMA study examined the effects of supplementation with lutein and zeaxanthin plus coantioxidants (vitamins C and E and zinc) on visual function and progression from early to late stages of AMD in 433 study participants.
The primary outcome was BCVA at 12 months. Results from this study showed that although the mean change in BCVA at 12 months favored the group taking the supplement, the difference was not statistically significant. Stronger differences were found in the study's later stages, especially at the 36-month mark. However, at 36 months, there were only 21 participants left in the experimental group and 20 in the control group.
ARVO session moderator Antonio Capone Jr, said "They didn't meet their primary outcome at 12 months, but did at later months. However, as a study cohort starts to diminish in size, attrition ends up having a significant impact on outcome and decreases the power of any study. So I'm encouraged and it sounds hopeful, but I'm looking for something that's a better hope to hang my hat on from a therapeutic perspective."
WHAT IT MEANS TO YOU: This is yet another in a long line of studies that fails to find a benefit of lutein supplementation on AMD risk. Most epidemiologic and interventional studies that have investigated this question have failed to find that a diet high in lutein/zeaxanthin consumption or use of lutein/zeaxanthin supplements decreases the risk of AMD progression. The AREDS-2 study is investigating the value of fish oil and lutein supplementation on the risk of AMD progression, and should, once and for all, settle the question. Until then, lutein supplementation is still recommended because of the small possibility that it may have a beneficial effect, and because there are no known serious adverse effects of lutein supplementation.
Researchers find that elderly persons with low cognitive test scores are twice as likely to have early AMD, suggesting that cognitive impairment may share common age-related pathogenic mechanisms and risk factors with AMD.
Alzheimer disease and AMD have long been hypothesized to share a common pathogenesis based on several lines of evidence. First, both conditions have similar histopathologic changes. Both are associated with the accumulation of extracellular waste products that lead to cellular malfunction and eventual death. Second, clinical studies suggest that AMD and Alzheimer disease share similar vascular risk factors, such as hypertension and cigarette smoking. Finally, there is evidence of shared genetic loci, such as the apolipoprotein E (APOE) 4 allele.
The Cardiovascular Health Study (CHS) is a population-based prospective study of coronary heart disease and stroke in adults 65 years and older. The cohort includes 2088 persons aged 69 to 97 years. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia and Alzheimer disease using detailed neuropsychological testing.
After controlling for age, sex, race, and study center, persons with low DSST scores were more likely to have early AMD (odds ratio, 1.38) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD.
The researchers conclude that AMD and cognitive impairment may share similar complex pathogenesis and risk factors.
WHAT IT MEANS TO YOU: This study suggests that cognitive impairment - including impaired thinking, learning and memory - may represent a new risk factor for AMD. It also provides evidence that AMD may represent one manifestation of a much broader systemic disorder that includes mental impairment. There is growing evidence that cardiovascular disease and inflammatory dysfunction contributes to the onset of AMD. It is certainly possible that these same factors could promote cognitive decline. If future research confirms the finding of this study, then there may be value in training psychologists and other mental health professional to screen at-risk persons for AMD, and likewise, for eye care professionals to screen patients with AMD for cognitive impairment.
A new study finds that baseline activated VEGF receptor levels within the vitreous correlate with response to Avastin (bevacizumab) treatment.
This research study investigates a novel biomarker of CNV - the VEGF receptor. It appears that vascular endothelial cells may shed VEGF receptors into the vitreous. Just as a blood sample may contain markers for a heart attack, markers within the vitreous could provide unprecedented information about the pathogenesis of AMD and treatment opportunities.
When VEGF receptors are activated they become phosphorylated. Successful blockade of VEGF with Avastin or Lucentis will suppress the phosphorylated state of the VEGF receptor. In this way, the phosphorylated form of the receptor may provide an indicator of how well a therapy is working. This could have major clinical significance if the need for treatment could be predicted prior to the recurrence of edema, hemorrhage, and tissue damage.
In this study vitreous samples obtained immediately prior to Avastin injection from 11 patients with CNV were analyzed using reverse-phase microarrays. Two of the 11 patients had samples collected at the time of Avastin injection and 1 month later. Control samples from 5 patients were collected prior to vitrectomy for macular hole, epiretinal membrane, or retinal detachment.
Protein microarray immunostaining revealed that phosphorylated forms of VEGF receptor (VEGFR Y996 and Y1175), platelet-derived growth factor receptor beta (PDGFR-beta Y716 and Y751), and c-KIT (Y703) were present in the vitreous. A significant difference in PDGFR-beta Y751 (P<.002), VEGFR Y996 (P<.04), and VEGFR Y1175 (P<.006), but not c-KIT Y703 (P<.05) or PDGFR-beta Y716 (P<.96), was noted for the responders to treatment (n=5) compared with nonresponders (n=6) and controls (n=5). Patients were characterized as responders or nonresponders based upon their response to Avastin 1 month after intravitreal injection.
Vitreous levels of phosphorylated VEGFR Y1175 were elevated in patients with wet AMD that responded to Avastin therapy, but not in patients that failed to respond to Avastin. Nonresponders had VEGFR Y1175 levels similar to control samples. Furthermore, the pattern of changes in the levels of analyzed receptors varied considerably in the responder and nonresponder samples 1 month after Avastin injection. These data suggest that patients who have minimal or no response to anti-VEGF therapies may have other pathways responsible for neovascularization and exudation.
The researchers conclude that their study shows that activated receptor levels within the vitreous correlate with treatment response. They speculate that measurement of specific phosphorylation patterns of targets, such as VEGFR Y1175, and other signal pathway proteins in the vitreous could become the basis for early detection, prognostic determinations, and individualized timing of therapy for patients with AMD.
WHAT IT MEANS TO YOU: Vitreous levels of activated receptors constitute a new class of biomarkers. This study found that activated forms of VEGF and PDGF receptors, previously not known to exist in the vitreous, correlate with response to anti-VEGF therapy. This could represent a major breakthrough in understanding the biology of AMD. In the future, drug treatments could be tailored for individual patients based upon which angiogenic pathways are activated in their eye. Furthermore, the timing of retreatment could be based upon changes in biochemical activity prior to the actual onset of exudation, as reflected by increased macular thickness on optical coherence tomography (OCT) and decreased visual acuity. By identifying which activated receptors are present in the vitreous of patients not responding to anti-VEGF therapy, it may be possible to discover which biochemical pathways are responsible for neovascularization in these patients, and new drugs could be specifically designed to suppress these pathways.
Using a modified spectral-domain OCT technique that enhances the visibility of choroidal details, a researcher has defined a new clinical entity characterized by decreased choroidal thickness, macular pigmentary changes, peripapillary atrophy, and moderate reduction of visual acuity.
Choroidal atrophy is not uncommon in clinical practice. The appearance of vascular sheathing or obliteration of the choroidal vascular channels has been called senile choroidal sclerosis. Fundus tessellation (tigroid fundus) may also be the result of choroidal atrophy with baring of larger vessels deep in the choroid.
In this retrospective study of patients who underwent enhanced depth imaging spectral-domain OCT (EDI OCT) of the choroid the mean subfoveal choroidal thickness was 287 um. An arbitrary lower limit of normal choroidal thickness of 125 um was chosen. Patients were included in this study if at least 1 eye had a choroidal thickness of less than 125 um.
There were 28 eligible eyes of 17 patients with a mean age 80.6 years. All patients had a tessellated appearance of the peripheral fundus. The mean subfoveal choroidal thickness was 69.8 um. Of the 18 eyes without late AMD, the mean visual acuity was 20/40. Peripapillary atrophy was seen in 72% of eyes. Macular pigmentary changes were either an extension of the tessellated fundus appearance into the central macular region, or pigment clumping deep to the retina. Concurrent late AMD was found in 10 of 28 eyes (35.7%). Glaucoma was present in 6 of 17 patients (35.3%), all of whom had peripapillary atrophy.
The proportion of patients with glaucoma was higher than similarly aged groups of patients. The researchers speculate that eyes with choroidal atrophy are likely to have profound decreases in the choroidal contribution of blood supply to the prelaminar optic nerve.
The investigators conclude that age-related choroidal atrophy affects older individuals in whom posterior pole abnormalities develop that may mimic AMD. Patients with age-related choroidal atrophy may be at higher risk for glaucoma.
WHAT IT MEANS TO YOU: Given that there is considerable overlap in the clinical picture of the two conditions, it appears likely that at least some people with age-related choroidal atrophy are misdiagnosed as having AMD. It may take considerable clinical expertise to correctly differentiate some cases. We do not yet know anything about the pathogenesis of this condition, much less an effective treatment for it. It would be surprising if this condition shares many common pathogenic factors with AMD. Yet, until we know more about age-related choroidal atrophy and have specific treatment recommendations for it, recommendations similar to those offered for patients with AMD would be appropriate: maintain tight control of any systemic disorders (diabetes, hypertension, etc), eat a heart-healthy diet (including plenty of fish), exercise regularly, maintain an ideal body weight, don't smoke, and see your eye doctor regularly.
Acucela presented new data on ACU-4429, an investigational therapy for dry AMD at the 2009 ARVO meeting. Study participants tolerated ACU-4429 well in single-dose tests conducted with healthy volunteers age 55-80, said Ryo Kubota, founder and CEO of Acucela. ACU-4429 is a new therapeutic class of drugs known as "visual cycle modulators," which are designed to prevent or inhibit generation of by-products that can lead to degenerative eye conditions such as dry AMD and Stargardt's Disease. Preclinical data indicated that ACU-4429 slows the rod visual cycle, resulting in decreased accumulation of a toxic byproduct that is the precursor of lipofuscin. Acucela is developing ACU-4429 as a single-dose daily oral treatment for dry AMD. Data shows ACU-4429 may potentially slow or halt the progression of dry AMD, Kubota said. ACU-4429 is in Phase I trials, and a Phase II trial is expected to begin later this year.
Positive results of a phase 1 clinical study evaluating E10030, an anti-platelet derived growth factor (anti-PDGF) agent, in conjunction with an anti-VEGF agent to treat wet AMD were reported at the 2009 ARVO meeting. 59% percent of patients treated with anti-PDGF/anti-VEGF combination therapy gained significant vision (3-line gain) at week 12 after therapy. 100% of treated patients demonstrated neovascular regression. E10030 was well tolerated with no evidence of drug-related adverse events. Anti-VEGF monotherapy results in 3-line visual gain in approximately one third of patients and without significant neovascular regression. "Marked neovascular regression, a first in any study, with an outstanding level of visual gain, is very promising for our patients," said Dr. Lawrence J. Singerman of Case Western Reserve University. E10030 is an aptamer targeting PDGF, a key molecule involved in the recruitment and maturation of pericytes. Pericytes in neovascular tissue have been shown to be protective and play a major role in anti-VEGF treatment resistance. E10030 strips the pericytes from the neovascular tissue rendering it highly sensitive to an anti-VEGF attack.
Though many retinal specialists have begun using only OCT for monitoring patients with AMD, a presenter at the joint meeting of the Asia-Pacific Academy of Ophthalmology and American Academy of Ophthalmology said that fluorescein angiography (FA) should not be discounted and should be used in conjunction with OCT. "Personally, I think it is critically important that we do fluorescein angiography on a regular basis," Dr Alexander J. Brucker said. Dr. Brucker discussed a small study of 321 patients in which 2.2% of patients who appeared to be dry on OCT were found to be wet on fluorescein angiography. Dr. Brucker showed cases where patients were treated or not treated solely on OCT images and went on to lose vision because underlying disease was not discovered by OCT. In his practice, Dr. Brucker said they perform a fluorescein angiography exam every 12 weeks, even in cases of dry OCT images.
TM601 binding co-localizes with annexin A2 on the surface of activated vascular endothelial cells in CNV lesions, induces apoptosis, and causes CNV regression according to a poster presented at the 2009 ARVO meeting. TM601 is a wholly synthetic peptide, found to have robust anti-angiogenic activity in neovascular diseases. According to the poster, intraocular injection of 50 ug of TM601 at the time of and one week after laser-induced rupture of Bruch's membrane resulted in a 50.4% reduction in CNV area, compared to vehicle-injected eyes. When 50 ug was injected one week after rupture, the CNV area regressed by 62.4%. Daily periocular injections caused reductions of 65-70%. "For the first time, our scientists and academic collaborators have shown that annexin A2 is over-expressed in neovascular diseases in the eye," said Alison O'Neill, Vice President of Medical Affairs at TransMolecular. "As a result of its selective binding to annexin A2, we believe that TM601 not only potentially causes the regression of existing new blood vessels, but also prevents new blood vessel formation," she said.
Potentia Pharmaceuticals has successfully completed a phase 1 clinical trial of a complement factor C3 inhibitor for treating wet AMD, the company announced in a press release. The ASaP (Assessment of safety of intravitreal POT-4 therapy for patients with neovascular age-related macular degeneration) study showed that the drug was well-tolerated by all patients at all doses with no serious adverse events or inflammation. Additionally, serum analyses showed that significant sustained levels of POT-4 were consistently measured in patients who received the highest dose studied. The current POT-4 formulation is expected to provide sustained therapeutic ocular levels of the drug for several months after a single injection, the release said. Based on these data, Potentia plans to implement a phase 2 study of POT-4 for treating wet and dry AMD. "The safety and pharmacokinetic data strongly support the further development of POT-4 as a first-in-class treatment for patients with AMD," Cedric Francois, president and CEO of Potentia Pharmaceuticals, said in the release.
A census of low-vision providers in the United States characterizes the scope of low vision services available to non-veteran adults. A total of 1228 low-vision rehabilitation service entities were identified, with 608 surveyed (49.5% response rate). Almost half (42.7%) were private optometry practices. State agencies had the highest number of clients per week (45 clients per week) whereas private optometry practices had the lowest (4 clients per week). Central vision impairment was the most common deficit (74% of clients), with AMD being the most common cause (67%). Private optometry practices rarely include orientation and mobility training, psychological and social work services, driving rehabilitation, and home visits. A high percentage of government agencies provide these services. Fewer than one-quarter of all entities provided psychological services. Driving rehabilitation is also poorly represented among services at entities, available at only 11.4% of entities surveyed. The census was published in the May 2009 edition of Archives of Ophthalmology.
Volociximab, an alpha-5 beta-1 integrin antagonist, combined with Lucentis treatments for wet AMD is showing a favorable safety profile in early phase 1 studies, according to a poster presentation at the 2009 ARVO meeting. Baruch D. Kupperman reported on completed dose escalation results for 10 subjects enrolled in the study. Patients received three monthly intravitreal injections of volociximab in treatment-naive eyes at one of three doses in combination with Lucentis. "Dose escalation was completed without evidence of dose-limiting toxicity or drug-related adverse events," Dr. Kupperman said. "Results to date... suggest that volociximab has a favorable safety profile," he said.
Second Sight Medical Products announced that the FDA has granted approval for up to 20 people who are blind or who have severely impaired vision due to retinitis pigmentosa (RP) to participate in a feasibility study for its retinal implant (Argus II Retinal Implant) in the United States. Currently, 10 RP volunteers are participating in the U.S. study and an additional 12 RP volunteers are participating in similar studies throughout Europe and Mexico. The retinal implant is a three-part system designed to transmit information about the physical environment directly to an individual's retina - bypassing the photoreceptors that have been damaged by RP. The device consists of a 60-electrode grid that is implanted surgically and attached to the retina. The electrodes transmit information acquired from an external video camera that is mounted on a pair of eyeglasses worn by study volunteers. The implant has been designed to last for several years, but can be safely removed if necessary, according to the company.
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