Aspirin and AMD

by Dan Roberts
Updated 12/19/12
This is an attempt to shed some light on the issue of aspirin and macular degeneration.
In the spring of 2005, a large study introduced some interesting new information about aspirin. The study was done using 39,876 women over a 10-year period in order to clarify the suspected differences between men and women in the way that aspirin affects the system.
To translate and summarize the conclusions of the study, 100 mg of aspirin every other day . . .

  • lowers the risk of stroke in women, but not in men
  • reduces the risk of cardiovascular problems in men, but not in women, EXCEPT women age 65 and older. (Information about men was not derived from this study, but from 5 other studies referenced)
  • has a greater benefit for people who don’t smoke
  • increases the risk of gastrointestinal hemorrhages (i.e. gastrointestinal bleeding and peptic ulcer) in women age 65 and older

The authors conclude by saying, “…any decision about the use of aspirin in primary prevention … must ultimately be made after [consulting a] physician or health care provider, so that the net absolute benefits and risks for the individual patient can be ascertained.” Here is the study, for those who wish to learn more:
Ridker, P.M., et al. “Low-dose aspirin in the primary prevention of cardiovascular disease in women.” (The New England Journal of Medicine. Vol 352 (March 31) Pgs 1293-1304. 2005. Read the original paper.
An earlier study that shed light on aspirin use in connection with AMD concluded that “therapy with … aspirin is associated with decreased rates of CNV [choroidal neovascularization] among AMD patients.” That study is:
“Statin and aspirin therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration.” (Wilson HL, Schwartz DM, Bhatt HR, McCulloch CE, Duncan JL. Department of Ophthalmology, UCSF School of Medicine, San Francisco, CA 94143, USA.)
This connection is made, because AMD has been shown to have causes in common with cardiovascular disease. In other words, treat the cardiovascular problem with aspirin, and you might also be helping to prevent AMD. Here is that study:
“Do age-related macular degeneration and cardiovascular disease share common antecedents?” (KK Snow, JM Seddon – Ophthalmic Epidemiology, 1999 – taylorandfrancis.metapress.com)
Inflammation is now thought to be one of those commonalities, and we all know that aspirin is a good anti-inflammatory.
That having been said, here is a more recent conflicting study (Ref: AAO Annual Meeting: Abstract 1620, May 3, 2010) that suggests aspirin might actually be somehow associated with progression of the disease.
4691 patients 65 years and older were asked about their use of aspirin and about other possible risk factors for aging macula disorders. The results showed that odds ratios for all grades of early aging macula disorder rose with increasing aspirin intake frequency for subjects who reported daily use.
These researchers, therefore, concluded that frequent aspirin use seems to be harmful for aging macula disorder in older populations. Study leader Dr. Paulus de Jong said, however, that patients with cardiovascular disease should not stop taking aspirin. “But if they are taking it as a pain killer, there are other medications they can use.”
A 2012 report, “Long-term Use of Aspirin and Age-Related Macular Degeneration” by Barbara E. K. Klein, MD et al (JAMA. 2012;308(23):2469-2478. doi:10.1001/jama.2012.65406) concluded that “Among an adult cohort, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.” These results were derived from a 14.8 year followup of subjects in the Beaver Dam Eye Study.
It was reported here in November 2012 that Emily Chew, M.D. (deputy director, Division of Epidemiology and Clinical Applications, National Eye Institute) reported to Retina 2012 that evidence suggests there is no major harmful effect of aspirin use by AMD patients. Furthermore, she supported the opinion that aspirin may actually offer significant protection from the development of the disease.
The findings of the recent research by Dr. Klein et al, however, suggest that the mechanisms underlying the association of aspirin with late AMD may be different from its blood thinning properties. It might even be found to enhance new blood vessel growth, since it has been found in lab studies to increase vascular density. Dr. Chew based her comments on the blood thinning issue, but the recent findings suggest there may be more to to consider.
Dr. Chew recommends that, in light of aspirin’s benefit to the cardiovascular system, the best course of action for AMD patients is to consult with their physicians and take aspirin when it is clinically indicated. Until the results of this new research are substantiated by more studies, that is still good advice.

Degenerative Myopia

by Dan Roberts
(Updated November 2015)

Overview
Myopia is a condition whereby images come into focus in front of the eye, resulting in a blurred image on the retina. The more severe the nearsightedness, the farther the image is from the retina, which results in more blurry vision in the distance.
Myopia causes light rays to focus on the front of the retina. As a result, close objects are seen clearly, while distant objects appear blurred. Near vision, however, can deteriorate to a level where reading even close to the face can become difficult.

There are three ways for an eye to become myopic:
1. The front surface of the eye (the cornea) is too curved and, therefore, too powerful.
2. The eyeball itself is too long.
3. A combination of both of the above.

In many cases, myopia will stabilize when the growth process has been completed, and glasses can offer normal vision. Higher levels of myopia, however, tend to be hereditary, meaning that if there is a moderately or highly nearsighted parent, the odds are higher for one of the children to be myopic.

Myopia that develops in childhood is often called juvenile onset myopia, which almost always increases in severity with the progression into adulthood.

In the more severe chronic cases (“degenerative” or “pathological” myopia), there is the possibility of sight loss. The deformation of the eye creates stress on the retina, which can become damaged or detached, and this can then provoke additional changes. This is especially true in degenerative myopia, which can lead to macula problems (not to be confused with age-related macular degeneration).

There are at least four other clinical types of myopia: simple, nocturnal, pseudo, and induced. For the purposes of this article, degenerative myopia is described here.

Degenerative Myopia
Degenerative myopia is the seventh leading cause of legal blindness, occurring in about 2% of the U.S. population. It is most often seen in people of Chinese, Japanese, Middle Eastern and Jewish descent. This condition can start at birth, but most often starts during the pre-teen years. It is believed to be hereditary.
Degenerative myopia is more severe than other forms of myopia and is associated with retina changes, potentially causing severe vision loss. It progresses rapidly, and visual outcome depends largely on the extent of fundus and lenticular changes. The diagnosis of degenerative myopia is accompanied by characteristic chorioretinal degenerations. Pathologic myopes, particularly those with higher refractive errors, are at risk for retinal detachment and macular changes.

Patients with degenerative myopia typically complain of decreased vision, headaches, and sensitivity to light. If retinal degeneration or detachment is present, patients may also report light flashes and floaters, which are associated with retina changes. Those with degenerative myopia have an increased incidence of cataract formation (nuclear cataracts are most typical).

Some of the most typical features of degenerative myopia are:

  • Vitreous liquefaction and posterior vitreous detachment
  • Peripapillary atrophy appearing as temporal choroidal or scleral crescents or rings around the optic disc
  • Lattice degeneration in the peripheral retina
  • Tilting or malinsertion of the optic disc, usually associated with myopic conus
  • Thinning of the retinal pigment epithelium with resulting atrophic appearance of the fundus
  • Ectasia of the sclera posteriorly (posterior staphyloma)
  • Breaks in Bruch’s membrane and choriocapillaris, resulting in lines across the fundus called “lacquer cracks”
  • Fuch’s spot in the macular area

Myopic degeneration is similar to age-related macular degeneration AMD) in that it causes loss of central vision due to degeneration of the photoreceptor cells. This is caused by separation of the retina as a result of abnormal elongation of the eyeball. This usually happens because the back of the eye is larger than normal when the eye is very nearsighted. Marked thinning and stretching may lead to break down of the macula, surrounding retina and it’s underlying tissue. This will cause a varying amount of blurred vision.

Even after the eyeball has fully grown (by adulthood), weakness in the sclera (the white outer shell) can lead to development of a posterior staphyloma. This is a distention of the sclera at the back of the globe where the optic disc and macula are located. Breaks in Bruch’s membrane and atrophy of the choroid layer of the retina (where the blood vessels are) can create lesions known as lacquer cracks. Blood vessels may protrude through the cracks and leak into the subretinal space beneath the photoreceptor cells. Known as “choroidal neovascularization,” this hemorrhaging can lead to scarring, retinal separation, and profound sight loss in the central field. If this occurs, immediate treatment is needed, which may be in the form of photodynamic therapy, antiangiogenic drug treatment or both.

(Source: www.revoptom.com)

Treatment for Prevention of Degenerative Myopia

Four treatments are showing promise. One is scleral buckling, which can be read about in the article, Degenerative Myopia: a Review of its Nature and its Treatment.

A second treatment is early systemic treatment with 7-methylxanthine, which has been shown to normalize the abnormal growth pattern of myopic eyes in children aged 8-13. In the abstract, “Effect of 7-methylxanthine on eye growth in myopic children” (Ophthalmic and Physiological Optics, Vol. 26, Suppl. 1, August 2006), researchers Klaus Trier and Soren Munk Ribel-Madsen reported that “axial growth in the 7-methylxanthine group was reduced by 22% in the low axial growth stratification layer and by 8% in the high axial growth layer compared with placebo. The myopia progression in the two layers was reduced by 21% and 12%.” This study was based upon the success of earlier research, in which 7-methylxanthine increased the content of collagen and proteoglycans (connective tissue components of the sclera) as well as the diameter of collagen fibrils in rabbits. Excessive eye elongation is related to abnormal organization and reduced content of these components.

Contact lenses are being looked at as a possible means of slowing axial lengthening in children. Soft multifocal contact lenses have been shown to reduce myopia progression in children by as much as 50% (Walline, Jeffrey J. et al. “Multifocal Contact Lens Myopia Control.” Optometry and Vision Science 90.11 (2013):1207-1214.) Clinical trials are underway.

Finally, off-label use of atropine eye drops in a trial at Singapore National Eye Centre appeared to reduce the progression of myopia in children. Low-dose atropine trials have been scheduled for children in Japan and the U.K. In Singapore, nearly 1,000 children have been in enrolled in 0.01% treatment programs for further research. The updated trial results will be published in Ophthalmology in February 2016. (Source: Tan D, et al “Five-year clinical trial on atropine for the treatment of myopia2: myopia control with atropine 0.01% eyedrops” AAO 2015.)

Drusen Lasering

by Dan Roberts
(Updated 11/4/06)
Drusen are thought to be fatty waste products from the photoreceptor cells. They often appear on the macula (the center of the retina) in the early stages of Macular Degeneration, and they can cause gradual loss of central vision. “Hard” drusen are common in aging eyes, and do not necessarily lead to MD. Irregular and ill-defined “soft” drusen,” however, often indicate problems in the near future.
In 1999, ophthalmologists took an interest in using the laser to destroy drusen, based upon the theory that ridding the retina of these deposits may slow the development of MD, or even stop the progression from the “dry” form to the “wet” form. Studies were conducted at the University of Michigan School of Medicine and the University of Pittsburgh, and continued until 2005. Called “Complications of AMD Prevention Trial” (CAPT) and Prophylactic Treatment of AMD” (PTAMD), they used low-intensity lasers on human volunteers in the early stages of MD.
A grid pattern was lasered around the macula of patients with high-risk large drusen in both eyes. One treatment (funded by the National Eye Institute) used a low-intensity argon laser, and the other used an infrared diode laser. After two years, researchers using the latter procedure reported a significant reduction in the number of and area occupied by drusen and significant improvement in the subjects’ visual acuity. (Olk RJ, Friberg TR, Stickney KL, et al. “Therapeutic benefits of infrared (810-nm) diode laser macular grid photocoagulation in prophylactic treatment of nonexudative age-related macular degeneration.” Ophthalmology. 1999;106:2082-2090.
Later, however, in a presentation to the 2002 ARVO convention (“Prophylactic Treatment of Age-Related Macular Degneration (PTAMD): Update on the Clinical Trial”), researchers reported that prophylactic subthreshold laser treatment of a patient already having AMD in one eye showed no beneficial effect in preventing choroidal neovascularization (CNV), and the procedure may actually promote CNV events and vision loss, at least in the short term. At the same time, it was determined that patients who had drusen in both eyes, but no occurences of CNV may or may not benefit from prophylactic subthreshold laser treatment.
Finally, in April 2006, Friberg et al reported that laser treatment “to an eye with multiple large drusen in a patient whose fellow eye has already suffered a neovascular event places the treated eye at higher risk of developing choroidal neovascularization.” They concluded by advising against using prophylactic subthreshold diode laser treatment in these eyes.
For the full report, see “Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen.” (Friberg TR, Musch DC, Lim JI, Morse L, Freeman W, Sinclair S; PTAMD Study Group, Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.)
A few months later, on November 1, 2006, the National Eye Institute announced that their CAPT studies have been small, and the results inconsistent. No difference in vision or in progression to advanced AMD between treated and untreated eyes were observed, so doctors are advised to reconsider drusen lasering as a treatment for AMD.

Gene Therapy Studies Successful in Slowing Neovascularization

by Dan Roberts
January 2002
(Updated February 2006)
Researchers at Johns Hopkins’ Wilmer Eye Institute have been able to successfully slow blood vessel growth in laboratory mice in two different experiments involving injection of genes, and human trials have begun.
In one study (Mori, K., et al., “Inhibition of Choroidal Neovascularization by Intravenous Injection of Adenoviral Vectors Expressing Secretable Endostatin,” American Journal of Pathology, 159: 313-320.), a gene was injected which causes the body to produce endostatin, a substance which has been reported to inhibit abnormal blood vessel growth in tumors. The endostatin reduced retinal neovascularization in the mice by about 50%, and the more endostatin in the bloodstream, the lower the amount of neovascularization. More study is needed to determine if any organs are adversely affected by the procedure.
In the second study (Mori, K., et al., “Pigment Epithelium-Derived Factor Inhibits Retinal and Choroidal Neovascularization,” Journal of Cellular Physiology, 188: 253-263.), viral vectors were injected which contained the gene for pigment epithelium-derived factor (PEDF). This is a protein in the eye which promotes survival of retinal and other nerve cells.
In this study, the viral carrier was injected directly into the eye, which eliminated possible damage from the high levels of PEDF to the rest of the body. The mice with induced macular degeneration showed a reduction of blood vessel growth by as much as 65%. Mice with induced diabetic retinopathy showed a reduction of 90%.
These results are highly significant, and they raise hopes that gene therapy may someday be an effective treatment for stopping or preventing neovascularization in people with the wet form of macular degeneration and similar diseases.
The endostatin study was supported by the U.S. Public Health Service, the National Eye Institute, the Juvenile Diabetes Foundation, Research to Prevent Blindness and CIBA Vision Inc., a division of Novartis Ltd. Pharmaceuticals. The PEDF study was sponsored in part by the Juvenile Diabetes Foundation and the National Eye Institute.
UPDATES:
Results of a phase I trial to evaluate the safety and feasibility of intravitreous AdPEDF in humans was published as a poster presentation at the 2004 ARVO meeting. The title was *AdPEDF Therapy for Subfoveal Choroidal Neovascularization (CNV): Preliminary Phase I Results*. (Authors: P.Campochiaro, M.Klein, E.Holz, A.Gupta, D.Saperstein, S.Bressler1, L.L. Wei, A.Ray, R.N. Frank, T.Stout.)
After a single intravitreous injection of AdPEDF in a small sample population and one-year follow-up, researchers have concluded that the viral vector is proving to be well-tolerated and safe for human application. The trial is ongoing, with additional subjects being enrolled.
February 7, 2006: GenVec announced that “a prolonged therapeutic effect may be achieved after a single injection of AdPEDF.” This came as a result of finding that “subjects in the phase I trials who received higher doses of AdPEDF showed no increase in the size of retinal lesions at six and twelve months post-injection, compared to patients in the lower dose group whose lesions increased over time. Visual acuity in patients in the higher dose group was stable for the entire twelve months of the study, while those treated in the lower dose group appeared to show deterioration at six and twelve months.”

Gene Therapy Successful in Halting CNV

by Dan Roberts
Researchers have been able to halt (at least temporarily) choroidal neovascularization (CNV) with gene replacement therapy. This was done by single injections into the eyeballs of patients during a phase I clinical trial. Here is more detail, as reported on January 17, 2006 by Genetic Engineering News (www.genengnews.com):
Clinical Trial on Gene Therapy for Macular Degeneration Published in Human Gene Therapy
An adenoviral-based vector containing the gene for human pigment epithelium-derived factor (PEDF) showed evidence of being able to stop disease progression when injected directly into the eyes of patients with neovascular age-related macular degeneration, according to the results of a phase I clinical trial to be published in the February 2006 issue (Volume 17, Number 2) of Human Gene Therapy.
These promising results suggest that adenoviral vector-mediated ocular gene transfer represents a viable approach to treating ocular disorders such as age-related macular degeneration (AMD), which is one of the most common causes of severe vision loss.
Peter Campochiaro, M.D., Professor of Ophthalmology and Neuroscience, and Co-director of Vitreoretinal Surgery at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine (Baltimore, MD), and colleagues report on the use of a single intravitreous gene therapy injection in 28 patients with advanced neovascular AMD in a paper entitled, “Adenoviral Vector-Delivered Pigment Epithelium-Derived Factor for Neovascular Age-Related Macular Degeneration: Results of a Phase I Clinical Trial.”
AMD is a complex disorder characterized by the death of photoreceptors and retinal pigmented epithelial cells, caused in part by the growth of new blood vessels (angiogenesis) in the eye and the resulting leakage of plasma that form pockets of fluid around the retina. Visual loss is still reversible at this stage of disease if the angiogenic process can be stopped and fluid resorption takes place.
Injections of low and high doses of the adenoviral-PEDF vector caused no serious adverse effects in these patients. Although the therapy yielded no improvement (decrease) in the median lesion size from baseline, in the group that received high-dose gene therapy the lesions showed no increase in size at 6 and 12 months post-injection, compared to a median increase in lesion size of 0.5 and 1.0 disc area, respectively, in the low-dose group. This suggests that therapy was able to at least temporarily halt the natural progression of angiogenesis in neovascular AMD.
“It is encouraging that evidence of a sustained therapeutic effect was seen…after one intravitreal injection,” writes Jean Bennett, M.D., Ph.D., Professor of Ophthalmology, Cell and Developmental Biology, at the University of Pennsylvania School of Medicine (Philadelphia), in an accompanying Commentary in the February issue of the Journal. “The results from the Campochiaro et al. study are extremely encouraging as there were no serious adverse events or dose-limiting toxicities through the highest dose.”