A Very Big Clue to Understanding Dry AMD

Dry AMD with atrophy is still a big cause of vision loss. Vitamin and zinc supplements reduce the rate of vision loss in AMD mainly by decreasing the risk of developing new blood vessels or wet AMD. Non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, or naproxen may decrease the rate of progression to atrophy by decreasing inflammation but they aren’t a cure all.

There was a very interesting article which is scheduled to be published in the October 2, 2008 issue of the New England Journal of Medicine showing an association of variants in the toll-like receptor 3 gene with decreasing the risk of geographic atrophy in people with AMD. This receptor encodes for a viral sensor that is associated with innate immunity-meaning fighting off viral infections.

The scientists put two genetically different toll-like receptors in mice and then injected double stranded RNA into the vitreous; this is analogous to getting a virus. The variant of the receptor that protected against atrophy in people with AMD protected against cell death of the pigment epithelium in mice compared to the normal variant.

How about in layperson’s terms? The idea is that a virus that contains double stranded RNA infects the retinal pigment epithelium. The toll-like receptors are activated to fight the virus. One genetic variant of the receptor perhaps causes more inflammation causing the death of the retinal pigment epithelial cell compared to the other variant. Once again, too much inflammation might be bad.

So how to you decrease atrophy in dry AMD? You can have the genetic variant of toll-like receptor that protects against atrophy. If you don’t have this variant in your genes, perhaps in the future you’ll be able to get the good variant transplanted into your retina. The hooker with this is that usually genes are transplanted via viruses and viruses might be bad especially if you have AMD. Probably a more realistic route would be to decrease the inflammation in the outer retina. We don’t know how to selectively decrease the inflammation started by the toll-like receptor. For now, I would still take 325 mg of aspirin, 200mg of ibuprofen, or 275mg of Naproxen a day.

We need much more information but this recent study is a very impressive start into understanding a complex disease.

References:

1. Yang, Z, Straaton, C, Francis, PJ, et al. Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration. N Engl J Med. 2008;359(14):1456-1463

(reference updated 10-2-2008)

Possible Treatments for Inflammation in AMD

Two weeks ago, I discussed a study that showed inflammation in the neovascular membranes of patients with wet AMD who had been treated with Avastin.® Inflammation promotes neovascularization so it makes sense to try to limit or even eliminate this inflammation. Eliminating inflammation could make the treatment with Avastin® or Lucentis® more effective or at least perhaps decrease the number of injections needed to control the leakage from the new blood vessels.

Inflammation also occurs in dry AMD. Controlling it may reduce the progression of atrophy which is actually a more common cause of visual loss than new blood vessels in this disease.

The problem is that we don’t know the exact type or mechanism of this inflammation so we don’t know what the best way to control it is. Corticosteroids like prednisone work to control a variety of types of inflammation. The problem with oral prednisone is that only a small part of it gets into the eye and it causes osteoporosis, hypertension, and even diabetes especially when used for long periods. Therefore it’s not a good choice especially in older patients.

A corticosteroid called, Kenalog® is often injected into the eye. It is a depot form of medication that is white and therefore causes dense floaters. Usually though, the floaters sink to the bottom of the vitreous and out of the way of the line of sight. The medication lasts three months. It generally will cause a cataract. It will also cause glaucoma in at least 30% of patients that can be severe.

Dr. Calvin Grant presented a poster at the 2008 annual meeting of the Association for Research in Ophthalmology, (ARVO), in Fort Lauderdale. Dr. Grant placed his wet AMD patients on Xibrom® which is non-steroidal anti-inflammatory in an eyedrop form. It is used twice a day. The company that manufactures Xibrom has evidence that it makes its way through the front of the eye back to the retina. Dr. Grant thinks that the concomitant use of this drop with Avastin® or Lucentis® increases the success rate and decreases the need for re-injections. The advantage of this medicine is that it is easy to use as an eyedrop and has few side-effects. The disadvantage is that Medicare hasn’t reimbursed for it since there are cheaper non-steroidal drops that may be just as good. Dr. Grant used it because he thought it may be better at getting back into the retina.

I also counsel AMD patients to take a full 325mg aspirin a day with the approval of their doctor.

Inflammation and AMD

Tatar and colleagues studied 38 neovascular membranes from patients with AMD using histopathology (under the microscope with special stains).(1) The membranes were removed during macular translocation surgery which is seldom done in the US because of the good results using Avastin® or Lucentis®. The interesting part of this study was that 24 patients had received injections of Avastin prior to surgery and 14 had not. The neovascular membranes from the eyes that had received Avastin had much more inflammation than the ones from the eye that had not. This brings up an interesting paradox in that although Avastin works well at preserving or improving vision in wet AMD, it causes increased inflammation in neovascular membranes. Lucentis is a smaller antibody that was manufactured from the Avastin molecule so we would expect similar findings.

There is ample evidence that inflammation plays a role in causing both severe dry AMD with atrophy and choroidal neovascularization. Changes in the complement system that cause increased inflammation are associated with increased AMD. Inflammatory cells have been seen in eyes with AMD that were enucleated after death. It seems then that if inflammation could be reduced, perhaps the progression of AMD could be slowed. The problem is that we really don’t know the exact pathway of inflammation in AMD and therefore we don’t know what drugs or diet modifications would be best to modify it.

References:
1. Tatar O, Yoeruek E, Szurman P, Bartz-Schmidt KU; Tübingen Bevacizumab Study Group, Adam A, Shinoda K, Eckardt C, Boeyden V, Claes C, Pertile G, Scharioth GB,Grisanti S. Effect of bevacizumab on inflammation and proliferation in human choroidal neovascularization. Arch Ophthalmol. 2008 Jun;126(6):782-90. PMID: 18541840

Also see the original blog on this topic: Inflammation and AMD, September 17, 2007