Saturday, November 22, 2008

Brain Reorganizes To Adjust For Loss Of Vision

Article Date: 21 Nov 2008

A new study from Georgia Tech shows that when patients with macular degeneration focus on using another part of their retina to compensate for their loss of central vision, their brain seems to compensate by reorganizing its neural connections. Age related macular degeneration is the leading cause of blindness in the elderly. The study appears in the December edition of the journal Restorative Neurology and Neuroscience.

"Our results show that the patient's behavior may be critical to get the brain to reorganize in response to disease," said Eric Schumacher, assistant professor in Georgia Tech's School of Psychology. "It's not enough to lose input to a brain region for that region to reorganize; the change in the patient's behavior also matters."

In this case, that change of behavior comes when patients with macular degeneration, a disease in which damage to the retina causes patients to lose their vision in the center of their visual field, make up for this loss by focusing with other parts of their visual field.

Previous research in this area showed conflicting results. Some studies suggested that the primary visual cortex, the first part of the cortex to receive visual information from the eyes, reorganizes itself, but other studies suggested that this didn't occur. Schumacher and his graduate student, Keith Main, worked with researchers from the Georgia Tech/Emory Wallace H. Coulter Department of Biomedical Engineering and the Emory Eye Center. They tested whether the patients' use of other areas outside their central visual field, known as preferred retinal locations, to compensate for their damaged retinas drives, or is related to, this reorganization in the visual cortex.

The researchers presented 13 volunteers with a series of tests designed to visually stimulate their peripheral regions and measure brain activity with functional magnetic resonance imaging. They found that when patients visually stimulated the preferred retinal locations, they increased brain activity in the same parts of the visual cortex that are normally activated when healthy patients focused on objects in their central visual field. They concluded that the brain had reorganized itself.

The parts of the visual cortex that process information from the central visual field in patients with normal vision were reprogrammed to process information from other parts of the eye, parts that macular degeneration patients use instead of their central visual areas.

While there is evidence with other tasks that suggests that the brain can reorganize itself, this is the first study to directly show that this reorganization in patients with retinal disease is related to patient behavior.

The research group is currently studying how long this reorganization takes and whether it can be fostered through low-vision training.

The research was funded in part by a seed grant from the Georgia Tech/Emory Health Systems Institute

StemCells, Inc. Announces Preclinical Results Showing its Proprietary Human Neural Stem Cells Can Prevent Vision Loss

StemCells, Inc reported today that its proprietary HuCNS-SC(R) product candidate (purified human neural stem cells), when transplanted into a well-established animal model, can protect the retina from progressive degeneration. Retinal degeneration leads to loss of vision in diseases such as age-related macular degeneration and retinitis pigmentosa. This promising study was conducted by Dr. Raymond Lund, a researcher and professor at the Casey Eye Institute at Oregon Health & Science University (OHSU) and his research team. Dr. Lund will present the study results at a seminar sponsored by the Foundation Fighting Blindness on Saturday, November 1, 2008. The seminar is scheduled to begin at 9:00 a.m. and will be held at the University of California -- San Francisco, Cole Hall (Medical Sciences Building on Parnassus Campus) in San Francisco, California.

"This study confirms the results of previously published academic studies evaluating neural stem cell transplantation into the retina and provides us with the rationale to pursue clinical testing of HuCNS-SC cells for retinal disorders," said Stephen Huhn, MD, FACS, FAAP, Vice President and Head of the CNS Program at StemCells, Inc. "We are already conducting additional preclinical studies and a pre-IND meeting has been scheduled with the FDA for December of this year to determine the pathway to a successful IND filing."

In this preclinical study, Dr. Lund and his co-investigator at OHSU, Dr. Peter Francis, transplanted HuCNS-SC cells into the Royal College of Surgeons (RCS) rat, a well established animal model of retinal degeneration. In the RCS model, a genetic mutation causes dysfunction of the retinal pigmented cells. Dysfunction in these cells, whose normal function is to support photoreceptors in the eye, causes progressive loss of the photoreceptors and degeneration of the retina, and ultimately, loss of visual function. Photoreceptor loss in the RCS rat begins as early as three weeks of age and by 24 weeks all photoreceptors are typically lost. In the study, the researchers transplanted HuCNS-SC cells into one eye of 21-day-old RCS rats while keeping the opposite eye as the control. Animals were evaluated starting at day 40 (19 days post transplant) and then at routine intervals up to 150 days post transplant. The evaluations showed that the HuCNS-SC cells survived the transplants and engrafted, and the eyes transplanted with the cells showed preservation of the photoreceptors and stabilization of visual function.

"The HuCNS-SC cell has proven to have very robust survival, preserving vision in our rat model at time points beyond six months," commented Dr. Lund. "These data are very encouraging and suggest cell-based therapies for retinal degeneration can be a viable treatment approach."

Dr. Francis, a retina specialist and researcher, added, "I am excited by our burgeoning collaboration with StemCells. The results of the early preclinical studies support the potential for these cells to treat retinal degenerative disease. I am especially excited by the fact that the cell is currently being tested in a clinical trial for Batten disease, a disorder of the central nervous system, which should make the transition from the laboratory to clinical use in retinal disease that much easier."

Dr. Lund received his PhD in Anatomy from University College London, after which he joined the faculty and received tenure within two years. Shortly thereafter, he moved to the United States, joining the faculty at Stanford University. Throughout his career, Dr. Lund has held several impressive academic positions including Chair of the Anatomy Department at the Medical University of South Carolina, Chair of the Neurobiology and Anatomy Department at the University of Pittsburgh, chair of the Anatomy Department at the University of Cambridge in England, the Duke Elder Professorship at the Institute of Ophthalmology in London, and the Calvin and JeNeal Hatch Chair of Ophthalmology at the Moran Eye Center at the University of Utah. In 2005, he was appointed Vice Chair of research at the Moran Eye Center in Utah. In 2007, Dr. Lund was recruited to join the faculty of the Oregon Retinal Degeneration Center at the Casey Eye Institute.

Throughout his career, Dr. Lund's research has centered on the response of the central nervous system to injury and mechanisms of rescue and repair. Focusing on the retina and its connections with the brain, he pioneered eye transplants in mammals in the late 1970s. Currently, he is investigating the use of cell-based therapies for photoreceptor degeneration in animal models of human disease.

Dr. Francis is an ophthalmologist and retina specialist at the Casey Eye Institute, and an Associate Professor, Oregon Health & Science University. Dr. Francis received his MD from University of Southampton, Southampton, England, and his PhD in molecular genetics at the Institute of Ophthalmology in London. He co-directs the Casey Macular Degeneration and Oregon Retinal Degeneration Centers. His clinical and research interests have focused on age-related macular degeneration and inherited retinal disorders.

About Retinal Degeneration
The retina is a thin layer of neural cells that lines the back of the eye and is responsible for converting external light into neural signal processed by the brain. The loss of function in retinal cells leads to an impairment or loss of vision. The macula, one of the most critical parts of the retina, is responsible for processing detailed vision. The most common forms of retinal degeneration are age-related macular degeneration and retinitis pigmentosa. In the United States, age-related macular degeneration affects over 1.7 million people in the over-65 population and is the leading cause of blindness in that group. Retinitis pigmentosa is a class of hereditary diseases that also leads to progressive degeneration of retinal cells. In the United States, the most common types of retinitis pigmentosa affect approximately 65,000 people. Preventative measures for both age-related macular degeneration and retinitis pigmentosa have limited impact on the disease and current treatments are not curative.

About HuCNS-SC Cells
StemCells' lead product candidate, HuCNS-SC cells, is a purified composition of normal human neural stem cells that are expanded and stored as banks of cells. The Company's preclinical research has shown that HuCNS-SC cells can be directly transplanted; they engraft, migrate, differentiate into neurons and glial cells; and they survive for as long as one year with no sign of tumor formation or adverse effects. These findings show that HuCNS-SC cells, when transplanted, act like normal stem cells, suggesting the possibility of a continual replenishment of normal human neural cells.

About StemCells, Inc.
StemCells, Inc. is a clinical-stage biotechnology company focused on the discovery, development and commercialization of cell-based therapeutics to treat diseases of the central nervous system and liver. The Company's product development programs seek to repair or repopulate CNS and liver tissue that has been damaged or lost as a result of disease or injury. StemCells has pioneered the discovery and development of HuCNS-SC(R) cells, its highly purified, expandable population of human neural stem cells. StemCells has completed enrollment and dosing of a six patient Phase I clinical trial of its proprietary HuCNS-SC product candidate as a treatment for neuronal ceroid lipofuscinosis (NCL) and expects the trial to be completed in January 2009. NCL, which is often referred to as Batten disease, is a rare and fatal neurodegenerative disease that affects infants and young children. StemCells owns or has exclusive rights to more than 50 issued or allowed U.S. patents and more than 150 granted or allowed non-U.S. patents. Further information about the Company is available on its web site at: www.stemcellsinc.com.

About OHSU and Casey Eye Institute
Oregon Health & Science University is Oregon's only health and research university and the state's only academic health center. OHSU is Portland's largest employer and the fourth largest in Oregon (excluding government), with more than 12,400 employees. OHSU's size contributes to its ability to provide many services and community support activities not found anywhere else in the state. It serves patients from every corner of the state, and is a conduit for learning for more than 3,400 students and trainees. OHSU is the source of more than 200 community outreach programs that bring health and education services to every county in the state.

The Casey Eye Institute, named after the founders of United Parcel Service, opened on the OHSU Marquam Hill Campus in 1991. The Casey Eye Institute is an academic regional eye center dedicated to preventing blindness through research, and to bringing advanced technology to the Pacific Northwest through continuing education of physicians. Casey is the seventh and final regional eye research center in the nation sponsored by Research to Prevent Blindness, the world's leading voluntary organization in support of eye research.

Research in mice raises question about macular degeneration drugs

Posted by Elizabeth Cooney November 7, 2008 11:05 AM

A drug used to choke new blood vessel growth in the eye disease macular degeneration may damage cells crucial to vision, if research done in mice carries over to humans, Harvard researchers report in the online journal PLoS One.

A team from the Schepens Eye Research Institute and Harvard Medical School studied what happened when levels of vascular endothelial growth factor, or VEGF, were tamped down in they eyes of adult mice. Drugs that block VEGF reduce the excess blood vessel growth and leakage that characterize macular degeneration. The researchers also found that lowering VEGF affected cells not involved in blood vessel growth but in visual function.

“The take-home message of this study is that physicians should be vigilant in monitoring patients undergoing anti-VEGF treatments for any possible signs of these side effects,” senior author Dr. Patricia D’Amore said in a statement. “Drugs such as Lucentis are very good at reducing the edema (fluids) and eliminating the abnormal blood vessels that characterize wet macular degeneration, but our results suggest that there could be unanticipated side effects.”

Glycemic Control Appears to Reduce Type 1 Diabetics’ Retinopathy Risk; Night Vision Symptoms May Predict Macular Degeneration Progression

Highlights of the November 2008 issue of “Ophthalmology”

This month’s Ophthalmology, the journal of the American Academy of Ophthalmology, reports on the conclusions from a population-based study of risk factors related to progression or regression of diabetic retinopathy over a 25 year period in people with Type 1 diabetes, and on the associations found between night vision symptoms and progression of age-related macular degeneration (AMD) in a cohort study within the Complications of Age-related Macular Degeneration Prevention Trial (CAPT), a multi-center randomized clinical trial.

Risk Factors for Retinopathy in Persons with Type 1 Diabetes
Many people who have Type 1 or Type 2 diabetes develop retinopathy, a serious disorder that damages the eye’s retina, the area of the back of the eye where images are focused and relayed to the brain’s visual cortex. Ophthalmologists (Eye M.D.s) monitor their diabetic patients for signs of retinopathy and use lifestyle recommendations, medications, and surgical approaches as appropriate to reduce the risk that diabetic retinopathy (DR) will progress to the proliferative stage (PDR), in which abnormal blood vessel growth leads to visual impairment. In recent years the diagnosis, prevention and treatment of DR and PDR have improved markedly.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is a large, long-term study that confirmed and expanded on results of other significant DR studies such as the Diabetes Control and Complications Trial. Ronald Klein, MD, and colleagues evaluated factors associated with the progression or regression of retinopathy over a 25 year period in people who had been diagnosed with Type 1 diabetes before the age of 30 years. The key finding was that glycemic control--assessed via blood levels of glycosylated hemoglobin A1, a reliable measure of average blood sugar--at the time of the baseline exam and throughout the study was strongly related to whether a patient’s DR worsened or improved. This confirmed findings of a number of earlier large studies. Better glycemic control was associated with significant reduction in DR progression and increased improvement in DR independent of how long the patient had had Type 1 diabetes and the level of DR at the baseline exam. Other risk factors found by the WESDR to be associated with progression to PDR included male gender, higher blood pressure level, presence of protein in urine (a manifestation of diabetic kidney disease) and a greater body mass index as measured at baseline.

WESDR participants were 955 insulin-taking Type 1 diabetics who received baseline exams between 1980 and 1982 and were either evaluated again four years later or died before the four-year follow up. Additional follow up exams were done at 10, 14 and 25 years post-baseline, and 520 of the original participants completed the 25-year follow-up.

Based on WESDR findings, the researchers estimate that over a 25-year period, 185,000 to 466,000 Americans with Type 1 diabetes will develop PDR. Dr. Klein adds the caution that these numbers may be an overestimation, because PDR incidence has declined in people diagnosed with Type 1 diabetes in recent years, possibly due to proactive and improved treatment of glycemia and blood pressure.

What Might Declining Night Vision Mean for AMD Patients?
The Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) Research Group assessed night vision in a cohort of 1,052 CAPT patients. The main purpose of CAPT, a National Eye Institute-sponsored multicenter randomized clinical trial conducted from 1999 to 2005, was to investigate whether low-intensity laser treatment could prevent vision loss in patients with early stage age-related macular degeneration (AMD). In advanced stages, AMD destroys the macula in the eye’s retina, the area that normally provides the detailed, central vision we rely on for reading, driving and other daily tasks. The CAPT results did not show that the laser treatment prevented vision loss, but data from the CAPT cohort did identify a new way to predict AMD progression.

Earlier studies had shown that loss of photoreceptor (light sensitive) cells, particularly “rod” cells involved in night vision, occurs before the disease progresses to advanced AMD in the retina, which indicated that assessing night vision might be a good way to track AMD progression. In the CAPT, patients with signs of early AMD, defined as 10 or more large deposits known as drusen on the retina and vision 20/40 or better, initially completed a 10-item night vision self-assessment questionnaire that rated difficulties with night driving and problems with vision deficits during low-light activities like reading or watching movies. The patients were followed-up annually up to five or six years. Data analyses led by Gui-shuang Ying, PhD, showed that those who had the worst night vision at baseline were the most likely to develop geographic atrophy (GA), or choroidal neovascularization (CNV) and to experience reduced visual acuity. GA is also known as advanced “dry” AMD, and CNV as “wet” AMD.

Since the association of night vision symptoms and AMD progression is clear and the 10-item questionnaire is simple and inexpensive to administer, Dr. Ying concludes that this could be a useful way for ophthalmologists to identify patients at high risk and intervene early to prevent vision loss and the progression to advanced AMD.

Eds: Full texts of the studies are available from the Academy’s media relations department.
About the American Academy of Ophthalmology

AAO is the world's largest association of eye physicians and surgeons—Eye M.D.s—with more than 27,000 members worldwide. Eye health care is provided by the three “O’s” – opticians, optometrists and ophthalmologists. It is the ophthalmologist, or Eye M.D., who can treat it all: eye diseases and injuries, and perform eye surgery. To find an Eye M.D. in your area, visit the Academy's Web site at www.aao.org.

Anti-VEGF Drugs For Retinal Diseases Could Have Serious Side Effects, Scientists Caution

ScienceDaily (Nov. 5, 2008) — Scientists at Schepens Eye Research Institute have found that reducing the levels of vascular endothelial growth factor (VEGF), which is best known as a stimulator of new blood vessel growth, in adult mice causes the death of photoreceptors and Muller glia - cells of the retina that are essential to visual function.

This finding holds implications for the chronic use of promising new anti-VEGF drugs such as Lucentis, which eliminate abnormal and damaging blood vessel growth and leakage in the retina by neutralizing VEGF.

"The take home message of this study is that physicians should be vigilant in monitoring patients undergoing anti-VEGF treatments for any possible signs of these side effects," says Principal Investigator Patricia D'Amore, Senior Scientist at Schepens Eye Research Institute. "Drugs such as Lucentis are very good at reducing the edema (fluids) and eliminating the abnormal blood vessels that characterize wet macular degeneration, but our results suggest that there could be unanticipated side effects."

Scientists have long known that VEGF is essential for normal development of the vascular system and for wound healing. It triggers the formation of new blood vessels that nourish the growing body and heal organs and tissues. VEGF also stimulates--in an apparent misguided attempt to heal perceived damage in the retina--the growth of abnormal blood vessels that leak and damage delicate retinal tissue.

However, a growing body of evidence also indicates that beyond its impact on blood vessel growth, VEGF may play other vital roles in the adult body and eye, so that eliminating the growth factor might lead to unexpected consequences.

Given the popularity and promise of the new anti-VEGF drugs for the treatment of macular degeneration, D'Amore and her team believed that investigating the broader role of this growth factor in the normal adult retina was critical. She and her laboratory mimicked the action of the anti-VEGF drugs by introducing into adult mice a soluble VEGF receptor, known as sFlt1, which binds and neutralizes the VEGF-- in much the same way that Lucentis does in the eye.

After two weeks, the team found no effect on blood vessels of the inner retina, but did find a significant increase in the number of dying cells of the inner and outer nuclear layers which include amacrine cells that participate in transmitting the visual signal; Muller cells that also participate in the visual signal and support the photoreceptors; and, photoreceptors, which are responsible for color and night vision. The team then used electroretinograms to measure visual function and found a significant loss in visual function. Consistent with these observations, they discovered that both photoreceptors and Muller cells express VEGFR2, the major VEGF signaling receptor and they found that neighboring Muller cells express VEGF.

Parallel studies in tissue culture demonstrated that suppressing VEGF in Muller cells led to Muller cell death, indicating an autocrine role for VEGF in Muller cells (i.e. Muller cells both make VEGF and use it for survival). Further, they used cultures of freshly isolated photoreceptors to show that VEGF can act as a protectant for these cells.

"Insight into the complex role of VEGF in the eye and in other parts of the body indicates that increased care should be taken in the long-term use of these drugs and that this new information should be considered in the design of future clinical studies to ensure that these possible side effects are taken into account," says D'Amore.

"Mice eyes differ from human eyes in many ways, so we cannot directly extrapolate these results to humans, but this study is an important heads-up that clinical application of anti-VEGF therapy in the eye needs to proceed with caution," she adds.

From a clinical perspective, Dr. Delia Sang of Ophthalmic Consultants of Boston points out that the use of anti-VEGF therapy in the treatment of patients with wet macular degeneration has revolutionized outcomes in this disease. However, in light of the work of Dr. D'Amore and others, in elucidating possible systemic and ocular side effects of these drugs, "caution must be exercised in identifying patients at increased risk of problems with long-=term VEGF blockade, and potential side effects must be detected early in the assessment of patients who will require repeated dosages of anti-VEGF agents."

The study is also relevant to the drug Avastin, which was initially approved for intravenous use as an anti-angiogenic agent in the treatment of cancer, but is also widely used intravitreally for the treatment of wet AMD because of its similar mode of action and much lower cost.

The next steps in D'Amore's research will include investigating the specific functions of VEGF in the eye.

This research is published in the November 3, 2008 PLoS ONE. Authors of the study include: Magali Saint-Geniez, Arindel S. R. Maharaj, Tony E. Walshe, Budd A. Tucker, Eiichi Sekiyama, Tomoki Kurihara, Diane C. Darland, Michael J. Young, Patricia A. D'Amore

Adapted from materials provided by Schepens Eye Research Institute, via EurekAlert!, a service of AAAS.

Anti-VEGF Drugs for Retinal Diseases Could Have Serious Side Effects, Scientists Caution

BOSTON, Nov 03, 2008 /PRNewswire via COMTEX/ -- Scientists at Schepens Eye Research Institute have found that reducing the levels of vascular endothelial growth factor (VEGF), which is best known as a stimulator of new blood vessel growth, in adult mice causes the death of photoreceptors and Muller glia -- cells of the retina that are essential to visual function. This finding, published in the November 3, 2008 PLoS ONE, holds implications for the chronic use of promising new anti-VEGF drugs such as Lucentis, which eliminate abnormal and damaging blood vessel growth and leakage in the retina by neutralizing VEGF.

"The take home message of this study is that physicians should be vigilant in monitoring patients undergoing anti-VEGF treatments for any possible signs of these side effects," says Principal Investigator Patricia D'Amore, Senior Scientist at Schepens Eye Research Institute. "Drugs such as Lucentis are very good at reducing the edema (fluids) and eliminating the abnormal blood vessels that characterize wet macular degeneration, but our results suggest that there could be unanticipated side effects."

Scientists have long known that VEGF is essential for normal development of the vascular system and for wound healing. It triggers the formation of new blood vessels that nourish the growing body and heal organs and tissues. VEGF also stimulates -- in an apparent misguided attempt to heal perceived damage in the retina -- the growth of abnormal blood vessels that leak and damage delicate retinal tissue.

However, a growing body of evidence also indicates that beyond its impact on blood vessel growth, VEGF may play other vital roles in the adult body and eye, so that eliminating the growth factor might lead to unexpected consequences.

Given the popularity and promise of the new anti-VEGF drugs for the treatment of macular degeneration, D'Amore and her team believed that investigating the broader role of this growth factor in the normal adult retina was critical. She and her laboratory mimicked the action of the anti-VEGF drugs by introducing into adult mice a soluble VEGF receptor, known as sFlt1, which binds and neutralizes the VEGF -- in much the same way that Lucentis does in the eye.

After two weeks, the team found no effect on blood vessels of the inner retina, but did find a significant increase in the number of dying cells of the inner and outer nuclear layers which include amacrine cells that participate in transmitting the visual signal; Muller cells that also participate in the visual signal and support the photoreceptors; and, photoreceptors, which are responsible for color and night vision. The team then used electroretinograms to measure visual function and found a significant loss in visual function. Consistent with these observations, they discovered that both photoreceptors and Muller cells express VEGFR2, the major VEGF signaling receptor and they found that neighboring Muller cells express VEGF.

Parallel studies in tissue culture demonstrated that suppressing VEGF in Muller cells led to Muller cell death, indicating an autocrine role for VEGF in Muller cells (i.e. Muller cells both make VEGF and use it for survival). Further, they used cultures of freshly isolated photoreceptors to show that VEGF can act as a protectant for these cells.

"Insight into the complex role of VEGF in the eye and in other parts of the body indicates that increased care should be taken in the long-term use of these drugs and that this new information should be considered in the design of future clinical studies to ensure that these possible side effects are taken into account," says D'Amore.

"Mice eyes differ from human eyes in many ways, so we cannot directly extrapolate these results to humans, but this study is an important heads-up that clinical application of anti-VEGF therapy in the eye needs to proceed with caution," she adds.

From a clinical perspective, Dr. Delia Sang of Ophthalmic Consultants of Boston points out that the use of anti-VEGF therapy in the treatment of patients with wet macular degeneration has revolutionized outcomes in this disease. However, in light of the work of Dr. D'Amore and others, in elucidating possible systemic and ocular side effects of these drugs, "caution must be exercised in identifying patients at increased risk of problems with long-term VEGF blockade, and potential side effects must be detected early in the assessment of patients who will require repeated dosages of anti-VEGF agents."

The study is also relevant to the drug Avastin, which was initially approved for intravenous use as an anti-angiogenic agent in the treatment of cancer, but is also widely used intravitreally for the treatment of wet AMD because of its similar mode of action and much lower cost.

The next steps in D'Amore's research will include investigating the specific functions of VEGF in the eye.

Authors of the study include: Magali Saint-Geniez (1,2), Arindel S. R. Maharaj (1), Tony E. Walshe (1,2), Budd A. Tucker (1,2), Eiichi Sekiyama (1,2), Tomoki Kurihara (1), Diane C. Darland (4), Michael J. Young (1,2), Patricia A. D'Amore (1,2,3)
(1) Schepens Eye Research Institute
(2) Department of Ophthalmology, Harvard Medical School
(3) Department of Pathology, Harvard Medical School
(4) University of North Dakota, Grand Forks, North Dakota

Ten Years of Data on Studies of Age-Related Eye Disease Now Available to Researchers

Looked at progression of age-related macular degeneration and age-related cataract in 4,757 older adults

Nov. 11, 2008 - Ten years of data collected during the Age-Related Eye Disease Study (AREDS), which looked at the progression of age-related macular degeneration and age-related cataract, has been released by the National Eye Institute (NEI). Researchers can apply for access to this complete set of medical history records and clinical trial results, as well as select genetic information to gain a better understanding of two complicated vision conditions that affect aging adults.

"This vast pool of data is now at the fingertips of scientists, which is an unprecedented occurrence in the field of ophthalmology," said Frederick L. Ferris III, M.D., clinical director of the NEI, which is, part of the National Institutes of Health (NIH).

"Now that the entire AREDS database is available to the global research community, we hope that researchers will be inspired to delve more deeply into analyzing the genetic and environmental factors involved in the onset and progression of age-related macular degeneration and age-related cataract."

The AREDS data are accessible through the online database of Genotypes and Phenotypes, known as dbGaP, which archives and distributes data from studies that explore the relationships between genetic variations (genotypes) and observable traits (phenotypes).

The NEI-supported AREDS was one of two studies included in the December 2006 launch of dbGaP. The National Library of MedicineÅfs National Center for Biotechnology Information (NCBI) created and operates dbGaP, which includes two levels of access.

>> Study descriptions and documents such as protocols can be found in the public, open-access section.

>> In the controlled-access section, approved researchers can view genotype and phenotype data from individual AREDS participants, though the information is coded to protect patientsÅf identities.

The first version of controlled-access AREDS data became available through dbGaP in June 2007. It included selected phenotypic data and information gathered from a genome-wide scan of DNA samples collected from 600 AREDS participants.

The updated version now incorporates the complete information obtained from all 4,757 AREDS participants during trial enrollment and follow-up visits, including data from photographs of the patients' eyes and information regarding their nutritional intake, quality of life, and rates of illness and death.

"Providing this new set of AREDS data through dbGaP will benefit researchers worldwide who are investigating genetic factors in age-related macular degeneration and other conditions," said David Lipman, M.D., director of the NCBI.

"AREDS was one of two founding studies in dbGaP, and its availability over the last year and a half has enabled many research teams to conduct their own analyses of these important data. We are delighted to have received, and to make available, this even more extensive set of data, further enhancing the possibilities for research and discovery."

AREDS began in 1992 as a long-term, multi-center, prospective study designed to evaluate the progression of age-related macular degeneration and age-related cataract. Participants were also enrolled in a clinical trial of high-dose vitamin and mineral supplements. They were followed for a median of 6.5 years during the trial and an additional five years after the trial's conclusion.

In addition, DNA was isolated from blood samples taken from more than 3,700 AREDS participants beginning in 1998. DNA from many of these participants is currently being stored in the NEI-AREDS Genetic Repository. Access to these DNA samples for research purposes is available for a fee through the Coriell Institute for Medical Research at http://ccr.coriell.org/Sections/Collections/AREDS/?SsId=68.

"Genetic testing has become crucial in the advancement of science, both for understanding the progression of diseases and for determining appropriate research directions for treatments," said Paul A. Sieving, M.D., Ph.D., director of the NEI. "With the AREDS data available through dbGaP, vision researchers can continue to identify genetic factors that may play a role in eye conditions such as age-related macular degeneration and cataract."

The public, open-access AREDS data can be viewed on the dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000001.v2.p1. Researchers can find a link to the application for controlled access to individual-level data on the same site.

More information about AREDS (NCT00000145) can be found at www.clinicaltrials.gov.

The National Eye Institute (NEI), a component of the National Institutes of Health, is the federal government's lead agency for vision research that leads to sight-saving treatments and plays a key role in reducing visual impairment and blindness. For more information, visit the NEI Web site at www.nei.nih.gov.

The National Center for Biotechnology Information (NCBI) was established in 1988 as a national resource for molecular biology information. NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing molecular and genomic data, and disseminates biomedical information, all for the better understanding of processes affecting human health and disease. NCBI is a division of the National Library of Medicine, the world's largest library of the health sciences. For more information, visit www.nlm.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Retinal Imaging: The Future is Bright with New Technologies

By John W. Kitchens, MD

Introduction
There have been certain major “eras” in ophthalmology. These could include: the phaco era, the refractive era, the anti-VEGF era, among others. I believe we are about to enter into “the imaging era”, specifically in regard to the management of retinal diseases. At no time in the history of ophthalmology have more companies come forth to develop and market the same technology as spectral domain OCT. Although this technology is exciting and is taking “center stage”, other interesting imaging techniques are beginning to develop.

Autofluorescence utilization is becoming more and more common and the information that it yields may play an important role by improving our understanding of AMD and other hereditary retinal disorders. The technology that forms the foundation of autofluorescence has improved rapidly in the last few years and this imaging modality is about to enter “prime time” in the retina world.

Ultrawide angle imaging is another exciting technology that may have retina specialists rethinking some of their understanding and approaches to retinal vascular diseases (e.g, diabetic retinopathy, vascular occlusions, etc), uveitis, and heritable retinal diseases. It is a revolutionary system that can improve our understanding of many common retinal diseases. In this article, I hope to provide a brief overview to some of the technologies that may develop alongside spectral domain OCT.

Autofluorescence (AF)
Although fundus autofluorescence has received particular attention recently, it has actually been around for some time.. Autofluorescence was initially described prior to initiating the dye injection in fluorescein angiography. At that time, it was described as “pseudofluorescence” [1]. With the advent of the confocal scanning laser ophthalmascope (cSLO) [2,3], autofluorescence has become much more functional as a tool for evaluating the health of the RPE (among other things). Autofluorescence can also be performed with a standard fundus camera incorporating special filters [4]. Images obtained using this technique are of lower quality due to the presence of naturally occurring fluorophores in the lens and other structures of the eye. Also, because of the low levels of illumination created by autofluorescence, multiple images (usually 4-16) are obtained and are averaged with normalized pixel values represented in the final image.

Autofluorescence of the fundus is primarily due to the presence of lipofuscin (along with other fluorophores) in the RPE. Lipofuscin accumulates in aging RPE cells and represents the incomplete degradation of photoreceptor outer segments [5]. Increased autofluorescence can be seen with RPE dysfunction representing a decreased ability of the RPE to metabolize or eliminate the byproducts of phototransduction. Decreased autofluorescence occurs with the loss of photoreceptor outer segments. Hence autofluorescence can give information regarding the health of the RPE and outer retina in various disorders.

Autofluorescence adds insight into various disease states. Diseases characterized by the accumulation of fluorophores (Best disease and Stargardt’d disease) shows characteristically intense autofluorescence [6.7]. Autofluorescent findings may also help to explain the lack of visual recovery in some cases of central serous chorioretinopathy [8]. AMD demonstrates autofluorescent findings that can predict progression of geographic atrophy [9], as well as help characterize drusen and pigment epithelial detachments. Most interesting in “wet” AMD is the use of autofluorescent characteristics as a possible predictor of visual acuity improvement with the use of anti-VEGF therapy [10].

Currently, the only cSLO-based system available for obtaining autofluorescent images is the Heidelberg Retina Angiograph (the HRA classic, HRA 2, and Spectralis HRA; Heidelberg Engineering, Heidelberg, Germany). The Spectralis is a unique device that is essentially the “Swiss Army Knife” of retinal imaging. This device has the ability to perform 6 different imaging modalities including: fluorescein angiography, ICG, autofluorescence, high speed/resolution OCT, red-free, and infrared imaging. Not only can the Spectralis perform all of these different imaging modalities (some at the same time), but it creates a reference point for location and correction of these various images to ensure that the same points are being imaged from visit to visit. It should also be noted that cSLO instuments from both Rodenstock (Rodenstock, Weco, Dusseldorf, Germany) and Zeiss (Zeiss, Oberkochen, Germany) are in development.

Ultrawide Angle Imaging
Fluorescein angiography has been fundamental to the understanding of vascular disorders affecting the retina and choroid. Since it was first described in 1961 [11], arguably, no diagnostic procedure has led to a better understanding of diseases that affect the posterior pole than angiography. From A-to-Z (or AMD to AZOOR), fluorescein angiography was essential in our understanding of the most common and the rarest of retinal disorders. Since its inception, fluorescein angiography has undergone incremental improvements in camera systems, image processing, and the transition to digital angiography. The gradual evolution in angiography has led to higher quality images in a more patient-friendly (quicker) method.

The next step in this evolution is that of ultrawide angle angiography. The Optos P200A (Optos Inc., Dunfermline, Scotland) is the first noncontact system that offers up to a 200 degree view of the retina in a single image. I have had the opportunity to utilize this system over the last 6 months and must admit that it has changed my approach to many retinal diseases. In no disease was imaging of the retinal periphery more valuable than diabetic retinopathy.

Initially, I began obtaining ultrawide angle angiography in patients with proliferative diabetic retinopathy. My intent was to identify the area of neovascularization (NVE) and degree of nonperfusion in patients presenting with mild vitreous hemorrhage. While imaging these (affected) eyes, I was astounded to see that, often, the fellow (asymptomatic) eye had more profound changes than the eye with hemorrhage. This is particularly important in diabetic patients due to the fact that a hemorrhage in their fellow eye would leave them unable to drive, dose their insulin, and perform other vital activities of daily living. These findings led me to perform earlier panretinal laser in the fellow eye in an effort to “head-off” any problems that may develop.

Patients with clinically significant diabetic macular edema also demonstrated a wide variety of peripheral findings on ultrawide angle angiography. These findings ranged from excellent peripheral perfusion to extreme nonperfusion. The cases with extensive nonperfusion seemed (in my clinical observation) to respond more favorably to intravitreal Avastin (bevacizumab). This association has been described by others (primarily Steve Schwartz, MD and his colleagues at UCLA) with access to the Optos system.

This is an exciting time to practice retina. Improvements such as anti-VEGF therapy and small gauge surgery have made retina a great area to specialize in. These new technologies in retinal imaging will continue to add to this excitement and will help our understanding of various retinal conditions. This understanding will lead to better treatments and outcomes.

References
1. Machemer, R., et al. Pseudofluorescence--a problem in interpretation of fluorescein angiograms. Am J Ophthalmol. 1970: 70(1); 1-10.
2. von Ruckmann, A., F.W. Fitzke, and A.C. Bird. Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 1995: 79(5); 407-412.
3. Delori, F.C., et al. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci. 1995. 36(3): 718-729.
4. Spaide, R.F. Fundus autofluorescence and age-related macular degeneration. Ophthalmology. 2003. 110(2): 392-399.
5. Feeney-Burns, L., E.R. Berman, and H. Rothman. Lipofuscin of human retinal pigment epithelium. Am J Ophthalmol. 1980. 90(6): 783-791.
6. Jarc-Vidmar, M., A. Kraut, and M. Hawlina. Fundus autofluorescence imaging in Best's vitelliform dystrophy. Klin Monatsbl Augenheilkd. 2003. 220(12): 861-867.
7. Lois, N., et al. Fundus autofluorescence in Stargardt macular dystrophy-fundus flavimaculatus. Am J Ophthalmol. 2004. 138(1): 55-63.
8. Framme, C., et al., Fundus autofluorescence in acute and chronic-recurrent central serous chorioretinopathy. Acta Ophthalmol Scand. 2005. 83(2): 161-167.
9. Schmitz-Valckenberg, S., et al. Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci, 2006. 47(6): 2648-2654.
10. Heimes, B., et al., Foveal RPE autofluorescence as a prognostic factor for anti-VEGF therapy in exudative AMD. Graefes Arch Clin Exp Ophthalmol. 2008. 246(9): 1229-1234.
11. Novotny, H.R. and D.L. Alvis, A method of photographing fluorescence in circulating blood in the human retina. Circulation. 1961. 24: 82-86.

Implantable Telescope for End-Stage Age-related Macular Degeneration: Long-term Visual Acuity and Safety Outcomes

R. Doyle Stultingb, Jeffrey S. Heierc, Stephen S. Laned, David F. Change, Lawrence J. Singermanf, Cynthia A. Bradfordg, Robert E. Leonardg, IMT002 Study Group

Purpose
To evaluate long-term safety and best-corrected visual acuity (BCVA) results of a telescope prosthesis in patients with end-stage age-related macular degeneration (AMD).

Design
Prospective, open-label clinical trial with fellow-eye controls.

Methods
Patients with end-stage AMD (bilateral geographic atrophy or disciform scars; BCVA, 20/80 to 20/800) received the telescope prosthesis at 28 centers. Methods were similar to those described in the one-year results, with follow-up visits continuing at 18 and 24 months. Main outcome measures included BCVA change from baseline, endothelial cell density (ECD) and morphometry, and incidence of complications.

Results
At two years, data from 174 (92.6%) of 188 available patients were analyzed. Overall, 103 (59.5%) of 173 telescope-implanted eyes gained three lines or more (doubling of visual angle) of BCVA compared with 18 (10.3%) of 174 fellow control eyes (P < .0001). Mean BCVA improved 3.6 lines (standard deviation [SD], 1.9 lines) and 2.8 lines (SD, 2.3 lines) from baseline in eyes with the 3X and 2.2X device models, respectively. Mean ECD stabilized through two years, with 2.4% mean cell loss occurring from one to two years. There was no significant change in coefficient of variation or percentage of hexagonal endothelial cells from within six months to two years after surgery. The most common complication was inflammatory deposits.

Conclusions
Long-term results of this telescope prosthesis show the substantial BCVA improvement at one year is maintained at two years. Key indicators of corneal health demonstrate ECD change that reflects remodeling of the endothelium associated with the implantation procedure. ECD stabilizes over time, and there is no evidence of any ongoing endothelial trauma.

Brain Reorganizes To Adjust For Loss Of Vision

ScienceDaily (Nov. 21, 2008) — A new study from Georgia Tech shows that when patients with macular degeneration focus on using another part of their retina to compensate for their loss of central vision, their brain seems to compensate by reorganizing its neural connections. Age–related macular degeneration is the leading cause of blindness in the elderly. The study appears in the December edition of the journal Restorative Neurology and Neuroscience.

“Our results show that the patient’s behavior may be critical to get the brain to reorganize in response to disease,” said Eric Schumacher, assistant professor in Georgia Tech’s School of Psychology. “It’s not enough to lose input to a brain region for that region to reorganize; the change in the patient’s behavior also matters.”

In this case, that change of behavior comes when patients with macular degeneration, a disease in which damage to the retina causes patients to lose their vision in the center of their visual field, make up for this loss by focusing with other parts of their visual field.

Previous research in this area showed conflicting results. Some studies suggested that the primary visual cortex, the first part of the cortex to receive visual information from the eyes, reorganizes itself, but other studies suggested that this didn’t occur. Schumacher and his graduate student, Keith Main, worked with researchers from the Georgia Tech/Emory Wallace H. Coulter Department of Biomedical Engineering and the Emory Eye Center. They tested whether the patients’ use of other areas outside their central visual field, known as preferred retinal locations, to compensate for their damaged retinas drives, or is related to, this reorganization in the visual cortex.

The researchers presented 13 volunteers with a series of tests designed to visually stimulate their peripheral regions and measure brain activity with functional magnetic resonance imaging. They found that when patients visually stimulated the preferred retinal locations, they increased brain activity in the same parts of the visual cortex that are normally activated when healthy patients focused on objects in their central visual field. They concluded that the brain had reorganized itself.

The parts of the visual cortex that process information from the central visual field in patients with normal vision were reprogrammed to process information from other parts of the eye, parts that macular degeneration patients use instead of their central visual areas.

While there is evidence with other tasks that suggests that the brain can reorganize itself, this is the first study to directly show that this reorganization in patients with retinal disease is related to patient behavior.

The research group is currently studying how long this reorganization takes and whether it can be fostered through low-vision training.

The research was funded in part by a seed grant from the Georgia Tech/Emory Health Systems Institute.

Study Shows Lutein and Zeaxanthin Protect Against Age-Related Macular Degeneration

(NaturalNews) Researchers from Ohio State University may have discovered a mechanism by which proteins known as xanthophylls help prevent against age-related vision loss, they reported in a study published in the Journal of Lipid Research.

"Our research to understand this mechanism might provide a greater appreciation for how one could intervene to possibly slow macular degeneration," said senior study author Earl Harrison.

Age-related macular degeneration is one of the most common causes of age-related vision loss and affects approximately 10 million people in the United States. The deterioration of the macula, a tissue located in the center of the retina, causes vision in the center of the eye to blur, which lead to functional blindness. The condition cannot be reversed once it develops; it can only be slowed.

Prior research has suggested that the xanthophyll proteins lutein and zeaxanthin may protect against the eight-related macular degeneration by filtering out potentially harmful light from the blue end of the spectrum and also protecting the eye against damage from oxidation. The two proteins have been observed to concentrate in the macula, forming a yellow spot.

In the current study, researchers tested the hypothesis that the xanthophylls are transported to the macula by proteins known as scavenger receptor class B, type 1 (SR-B1). They treated pigment cells from the lining of the human retina with lutein, zeaxanthin and the related compounds beta-carotene, finding that the cells absorbed more xanthophylls than they did beta-carotene.

The researchers then blocked the action of SR-B1 by one of two methods. Both of the methods led to a decrease in xanthophyll of distortion of 41 to 87 percent.

Lutein and zeaxanthin cannot be synthesized by the body, but must be consumed in foods such as green, leafy vegetables, peas, summer squash, or yellow and orange fruits and vegetables (including carrots, papaya and peaches).