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

Dietary Supplements and the Brain

A very important and interesting question is whether supplementation with vitamins or fish oil retards the process of senility which is broadly termed cognitive functioning. Some studies have shown that reduced dietary levels of betacarotene, vitamin C, or docosahexaenoic acid (DHA, an omega-3 fish oil) are associated with more rapid a decline in cognitive function in the elderly whereas other studies have found no differences.

As a physician I see all kinds of seventy-five year olds. Some exercise a lot, eat all the right things, maybe still work or volunteer, and read books or surf the internet. Others, who usually look older, mostly sit on their couches at home. Most people who are active eat a good diet. Many of the couch sitters don’t. That’s why it’s hard to tell if it really is the betacarotene, for instance, in the diet that reduced the decline in brain power or did the study just select out the healthier more active people who took the time to make a spinach salad?

It’s important that AREDS II is testing cognitive functioning. Some people in AREDS II will be randomized to beta-carotene or fish oil whereas other won’t be. The randomization process of five thousand people should result in a pretty good cross section in each group. Then if we find that the people who are getting fish oil keep their brain power, (or not), it may really be due to the fish oil. The AREDS II leadership should be commended for adding cognitive function tests to the follow-up protocol of this study.

References:

Grodstein F, Chen J, Willett WC. High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. The American Journal of Clinical Nutrition 2003; 77(4):975-984. PMID: 12663300

Maksai KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H, Havlik R, White LR. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 2000;54(6):1265-1272. PMID: 10746596

Grodstein F, Kang JH, Glynn RJ, Cook NR, Gaziano JM. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. Archives of Internal Medicine 2007;167(20):2184-90. PMID: 17998490

Dangour AD, Clemens F, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE, Huppert FA, Knight R, Letley L, Richards M, Truesdale A, Vickers M, Uauy R. A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636]. Nutrition Journal 2006;5:20. PMID: 16945130

McNeill G, Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, Milne AC, Ramsay CR, Seymour DG, Stephen AI, Vale LD. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutrition Journal 2007;6:10. PMID: 17474991.

Clear Sailing

Last March (March 1, 2007), I commented on the “Dear Dr.” letter sent from Genentech about the higher risk of stokes in patients receiving 0.5mg Lucentis® compared to those receiving 0.3mg. This risk was found in an interim analysis of the large SAILOR trial which compared the two doses. My general message in that blog was that we should withhold judgment until the one year results are known.

The one-year results have now been announced Dr. David Boyer. The stroke rates at one year in the SAILOR trial were 0.7% for the 0.3mg Lucentis group and 1.2% for the 0.5mg group. There was no significant difference between these two rates.

My blog on January 2, 2008 discussed a recent article that found the annual risk of stroke was about 3.5% in Medicare patients regardless whether they had AMD or not. Thus the stroke risks in the SAILOR trial were much lower than seen in the Medicare population as a whole. Does that mean that Lucentis protects against strokes? Probably not. The reason is probably because the SAILOR trial attracted healthier patients than found in an average Medicare population. This was no conspiracy. Doctors generally don’t offer trials to sick patients and sick patients often don’t want to participate in trials which require monthly follow-up visits and testing. So the SAILOR patients were healthier to being with. The results are still reassuring and show that Lucentis at either dose probably doesn’t increase the risk of stroke.

Reference:

1. Avery RL, Ho AC. Good News for Anti-VEGF Therapy. Retina Today 2008; 3(2):7.