Multiple Sclerosis: Using the Eye as a ‘Window Into the Brain’

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Posted on 1st November 2012 by Pacific ClearVision Institute in General

An inexpensive, five-minute eye scan can accurately assess the amount of brain damage in people with the debilitating autoimmune disorder multiple sclerosis (MS), and offer clues about how quickly the disease is progressing, according to results of two Johns Hopkins studies.

“The eye is the window into the brain and by measuring how healthy the eye is, we can determine how healthy the rest of the brain is,” says Peter A. Calabresi, M.D., a professor of neurology at the Johns Hopkins University School of Medicine, and leader of the studies described in recent issues of The Lancet Neurology and the Archives of Neurology. “Eye scans are not that expensive, are really safe, and are widely used in ophthalmology, and now that we have evidence of their predictive value in MS, we think they are ready for prime time. We should be using this new quantitative tool to learn more about disease progression, including nerve damage and brain atrophy.”

Calabresi and his colleagues used optical coherence tomography (OCT) to scan nerves deep in the back of the eye, applying special software they co-developed that is capable of assessing previously immeasurable layers of the light-sensitive retinal tissue. The scan uses no harmful radiation and is one-tenth the cost of an MRI. The software will soon be widely available commercially.

In the Lancet paper, Calabresi and his team reported measuring thickness or swelling of the inner nuclear layer of the retina in 164 patients with MS and 60 healthy controls, following changes in these tissues over four years. At the same time, they also used brain MRI to measure inflammation spots directly, and performed clinical tests to determine disability levels.

The more inflammation and swelling the researchers found in the retinas of the MS patients, the more inflammation showed up in their brain MRIs. The correlation, they said, affirmed the value of the retinal scans as a stand-alone surrogate for brain damage. Having such information so easily available could allow physicians to accurately tell how far the disease has progressed, and to better advise patients about how they should proceed with their care.

The researchers also found microcystic macular edema in the central part of the retinas of 10 of the MS patients, tiny pockets of fluid typically found in older, usually diabetic people. While Calabresi cautions that eye scans do not as yet have primary diagnostic value for MS, he says finding a cyst like this on the eye of a young, healthy person might be reason to have her evaluated for the disorder.

In the United States, there are roughly 400,000 people living with MS. The disorder typically strikes between the ages of 20 and 50 and affects two-to-three times as many women as men.

In the paper published in the Archives of Neurology, Calabresi and colleagues looked at eye and brain scans of 84 MS patients and 24 healthy controls. This time, they focused on two other deep retinal layers, the ganglion cell layer + inner plexiform layer (GCL+IPL), and the peripapillary retinal nerve fiber layer (pRFNL). Greater cell wasting in those areas was strongly correlated with more atrophy in the gray matter of the brain, signifying more nerve damage from MS. Gray matter consists of the part of the brain where nerve cells live, and plays a role similar to a computer’s hard drive, in contrast to white matter that is more like the wiring that sends information out from the brain to the spinal cord and the rest of the body’s nerves.

Calabresi, director of the Johns Hopkins Multiple Sclerosis Center, says this finding is particularly important because neurodegeneration is so difficult to accurately gauge. In a young person with MS, the brain may be atrophying but may cause no symptoms because the brain is able to compensate for what is being lost. Ultimately, though, the loss of brain cells becomes apparent and is irreversible. Calabresi says that if he saw the kind of thickness on an eye scan indicating severe atrophy, he would consider a patient’s prognosis less encouraging than someone with a healthy retina, and this information may guide physicians to treat more aggressively. For example, he says he would likely redouble efforts to enter a patient into a clinical trial for an experimental medication before too much permanent damage takes place.

Calabresi says his findings could also shift how researchers approach MS, long believed to be caused by an immune system that wrongly attacks the fatty protein called myelin that insulates nerves and helps them send electrical signals that control movement, speech and other functions. The usefulness of the scans raises the possibility that there could be something else going on, as there is no myelin deep in the retina of the eye. If the immune system is going after something else along with myelin, it could help researchers find new medications to target the incapacitating symptoms of MS, such as blurred vision, numbness and weakness.

“It is really important to know what the immune system is attacking,” he says. “The treatments we have right now are only moderately effective, so maybe we’re not blocking the right kinds of cells.”

Study Suggests Caution and Further Studies On Drugs Used to Treat Macular Degeneration

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Posted on 1st November 2012 by Pacific ClearVision Institute in General |Retina

Millions of people with “wet” macular degeneration are prescribed a class of medication known as anti-VEGF drugs. But now scientists at The Scripps Research Institute (TSRI) have found that a drastic reduction of VEGF activity may do more harm than good.

In the new study, the researchers deleted the gene for the blood-vessel growth factor VEGF, which has been implicated in stimulating abnormal blood vessel growth in a range of cancers and eye diseases, from cells in the retinas of adult mice. The results showed that without VEGF a large subset of light-sensing cells lost their main blood supply and shut down, causing severe vision loss.

“It’s becoming clear that VEGF has a critical function in maintaining the health of the retina, and we need to preserve that critical function when we treat VEGF-related conditions,” said TSRI Professor Martin Friedlander, MD, PhD, senior author of the new study, which appears in the November 2012 issue of the Journal of Clinical Investigation.

Major Target for Drug Developers

VEGF (vascular endothelial growth factor) has long been a major target for drug developers. Tumors often overproduce VEGF to stimulate local blood vessel growth and thus keep their fast-dividing cells well supplied with oxygen and nutrients. Low-oxygen conditions in the eyes of elderly or diabetic individuals also can trigger the overproduction of VEGF, resulting in a vision-destroying bloom of abnormal, leaky retinal blood vessels.

Several anti-VEGF drugs (such as Lucentis® (ranibizumab), Macugen (pegaptanib), Eylea® (aflibercept) and Avastin® (bevacizumab)) are already in use, and dozens more are in clinical trials against cancers and common eye disorders such as wet macular degeneration.

However, to date there have not been extensive studies on the effects of such drugs on the normal role of VEGF, in part because it is hard to generate adult animals that lack the VEGF gene. When the gene is removed from the embryos of mice, in a standard “knockout” experiment, the mice fail to develop normally and die before birth.

New Insights

In the new study, Friedlander laboratory postdoctoral fellows Toshihide Kurihara, MD, PhD, and Peter D. Westenskow, PhD, found a way to delete the major VEGF gene from mice after the animals had grown to adulthood. To determine VEGF’s role in the retina, they confined the gene deletion to the animals’ retinal pigment epithelial cells, which nourish and repair the retina and are a major retinal source of VEGF. The result suggests that VEGF does have a crucial function in the adult retina.

“Only three days after we knocked down the gene, we observed the complete deterioration of the choriocapillaris, a layer of capillaries that is a major supplier of nutrients to the outer retina, the location of the rod and cone photoreceptors,” said Kurihara.

Nearby light-sensing cone cells, which are specialized for detecting color and fine detail in visual images, also rapidly lost their function, causing pronounced vision loss in the mice. Seven months after the knockdown of the VEGF gene, the retinal damage and vision loss were still evident. “The deterioration seems irreversible if VEGF is not present,” said Westenskow.

Rod cells, which support low-light and peripheral vision, were not affected by the VEGF-gene deletion. The researchers note that cone cells may be more vulnerable because they are unusually active metabolically and may be unable to withstand a significant decrease in blood supply. Cone cells also bear receptors for VEGF molecules and thus may require direct VEGF stimulation to remain healthy. In any case, even if only cone cells died and rod cells were spared, a patient would experience severe vision loss. “You’d be defeating your purpose if you dried up the abnormal blood vessel growth but at the same time killed off the cone cells,” said Friedlander.

Paths for Future Research

Whether such side effects are happening with existing anti-VEGF treatments is unclear. While these assessments are possible, but they have been considered prohibitively expensive and invasive.

Friedlander, however, now believes such studies are necessary and plans to conduct such assessments in eye-disorder patients — who typically receive direct injections of anti-VEGF drugs to their eyes — to determine whether the drugs are causing these adverse side effects. He notes that the evaluations may be particularly necessary for a new class of anti-VEGF drugs recently approved for use in the treatment of age-related macular degeneration — drugs that are much more potent and persistent than previous anti-VEGF agents.

Fortunately, anti-VEGF drugs are not the only possible strategy for treating pathological blood vessel growth, as the new study makes clear. VEGF-related tumors and eye conditions also involve the overproduction of low-oxygen signaling proteins known as HIFs. The team found that deleting the genes for these HIFs in retinal cells largely prevents blood vessel overgrowth in a standard mouse model — without affecting the normal-level production of retinal VEGF or causing eye damage.

“In light of the present findings, other strategies for treating these eye conditions could be a possibility,” Friedlander said. “Conceivably, an anti-HIF treatment could also be combined with an anti-VEGF treatment, allowing the dose of the latter to be lowered significantly.”

The Friedlander lab, in collaboration with the laboratories of David Cheresh, PhD, and Michael Sailor, PhD, of the University of California, San Diego, has also been exploring the potential utility of inhibiting microRNAs that regulate angiogenic genes further upstream to VEGF. This work is being supported by a $10 million grant from the National Eye Institute and could lead to the development of antagonists that avoid the off-target effects of VEGF inhibitors.

In addition to Friedlander, Kurihara and Westenskow, other contributors to the study, “Targeted deletion of Vegfa in adult mice induces vision loss,” were Stephen Bravo and Edith Aguilar, both of TSRI.

Smoking May Lead to Cataracts in Aging Population

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Posted on 1st November 2012 by Pacific ClearVision Institute in Cataracts |General

Cigarette smoking is a well-known risk factor for a wide-range of diseases. Now, scientists have evidence that smoking may also increase the risk of age-related cataract, the leading cause of blindness and vision loss in the world.

Reported in Investigative Ophthalmology & Visual Science, the new findings are the result of a meta-analysis conducted by a team of researchers from China.

“Although cataracts can be removed surgically to restore sight, many people remain blind from cataracts due to inadequate surgical services and high surgery expenses,” said author Juan Ye, MD, PhD, of the Institute of Ophthalmology, Zhejiang University in China. “Identifying modifiable risk factors for cataracts may help establish preventive measures and reduce the financial as well as clinical burden caused by the disease.”

The team performed the analysis using 12 cohorts and eight case-control studies from Africa, Asia, Australia, Europe and North America, to compare the prevalence of age-related cataract in individuals who ever smoked cigarettes to those who have never smoked. Further subgroup analyses were performed based on the subjects’ status as a past or current smoker and the three subtypes of age-related cataract.

The results showed that every individual that ever smoked cigarettes was associated with an increased risk of age-related cataract, with a higher risk of incidence in current smokers. In the subgroup analysis, former and current smokers showed a positive association with two of the subtypes: nuclear cataract, when the clouding is in the central nucleus of the eye, and subscapular cataract, when the clouding is in the rear of the lens capsule. The analysis found no association between smoking and cortical cataract, in which the cloudiness affects the cortex of the lens.

While the overall analysis suggests that smoking cigarettes may increase the risk of age-related cataracts, the researchers point out that further effort should be made to clarify the underlying mechanisms.

“We think our analysis may inspire more high-quality epidemiological studies” said Ye. “Our analysis shows that association between smoking and the risk of age-related cataract differ by subtypes, suggesting that pathophysiologic processes may differ in the different cataract types.”

Antioxidant May Prevent, Even Cure, Cataracts and Other Degenerative Eye Disorders

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Posted on 1st November 2012 by Pacific ClearVision Institute in Cataracts |General

Researchers at Missouri University of Science and Technology are working with an antioxidant that could prevent or cure cataracts, macular degeneration and other degenerative eye disorders.

The research group, headed by Dr. Nuran Ercal, the Richard K. Vitek/Foundation for Chemical Research Endowed Chair in Biochemistry at Missouri S&T, is studying eye drops prepared with the antioxidant N-acetylcysteine amide (NACA) as a treatment for these eye conditions.

Ercal says NACA is an improvement over another experimental treatment, the antioxidant N-acetylcysteine (NAC), because it passes more easily across cell membranes, allowing the medication to be used in lower doses.

“NACA’s characteristics as a drug were improved over NAC by neutralizing the carboxylic group of NAC, which makes the NACA pass cellular membranes easily,” says Ercal. “And because NACA can be administered at a lower dose, the drug has a greater therapeutic index and lowers the risk of side effects traditionally associated with NAC.

“NACA is also an excellent source of glutathione, a cell’s main antioxidant power, which is diminished during degenerative eye disorders,” she adds.

Vision loss from age-related eye disorders affects more than 30 million people in the United States and is expected to double in the coming decades, Ercal says.

In addition, more than $9 billion is spent annually in the U.S. on cataract surgery alone. The total annual cost of all services related to vision problems exceeds $20 billion, she says.

“NACA eye drops could drastically reduce these costs and represent an alternative to costly surgery, while greatly improving the quality of life for those afflicted,” says Ercal.

Ercal and her team have been testing NACA on HIV-related problems, lead poisoning and other toxicities for 10 years. About four years ago they began testing it on eye disorders.

Ercal recently received a $378,000 three-year research grant from the National Eye Institute of the National Institutes of Health. The preliminary data submitted for the funding was based on research by her former Ph.D. student, Joshua Carey.

Carey’s dissertation involved preliminary studies of the effects of NACA to slow down cataract growth on rats that had been given L-buthionine-S,R-sulfoximine (BSO), a solution that causes cataracts to form. “The NACA solution prevented cataracts from forming,” says Ercal. “Our research will build on Josh’s research, to see if NACA can actually reverse the degeneration as well.”

Ercal, who is also an M.D., says further testing will help establish appropriate dosage and frequency, as well as possible side effects and other factors. She says successful results using animal subjects may eventually support the viability of human usage.

Ercal works closely with Dr. Shakila Tobwala, a post-doctoral fellow in Missouri S&T’s chemistry department. Others in the research group include the grant’s co-investigator, Dr. Humeyra Karacal from the ophthalmology department at Washington University in St. Louis, and Missouri S&T graduate and undergraduate students.

Specialty Contact Lenses May One Day Help Halt the Progression of Nearsightedness in Children

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Posted on 1st November 2012 by Pacific ClearVision Institute in General |Retina

Nearsightedness, or myopia, affects more than 40 percent of people in the U.S. and up to 90 percent of children in some parts of Asia. The problem begins in childhood and often progresses with age. Standard prescription lenses can correct the defocus but do not cure nearsightedness, and do not slow progression rates as children grow. But recent experimental work by biomedical scientist David Troilo and colleagues at the State University of New York (SUNY) College of Optometry in New York City supports the development of a potential cure for myopia by using specialty contact lenses that coax the eye to grow in a way that can correct nearsighted vision while reducing myopia progression.

Troilo will describe his findings at the Optical Society’s (OSA) Annual Meeting, Frontiers in Optics (FiO) 2012, taking place Oct. 14 in Rochester, N.Y.

Myopia develops when the eye is too long, making it difficult to focus light from distant objects on the retina. Glasses or contact lenses that correct the defocus on the main visual axis can create a slight degree of farsightedness in the peripheral retina, Troilo says. The peripheral farsightedness may worsen myopia because as children grow, the eye grows to move the retina to where the light is focused, naturally lengthening the eye even further.

Troilo has shown that specially designed contact lenses that alter how light is focused in the peripheral retina can induce changes in growth that help reshape the eye in the desired way. The experimental lenses use different focal powers within a single lens: either alternating focal powers across the lens, or confined to the outer edge. Experiments with the new lenses found that they changed eye growth and refractive state, or focus, in a predictable way. The lenses successfully reduced the elongation of the eye that causes myopia progression.

Several contact lens designs may soon be available to help eye doctors manage the progression of myopia in children, Troilo says. Presentation FW1C.1 “Optical Approaches for Controlling Myopia Progression: Evidence from Experimental Models” takes place Wednesday, Oct. 17 at 8 a.m. EDT at the Rochester Riverside Convention Center.