To the Editor:
Dr. Richard Bone and colleagues recently published an article  [Targeting AMD with a Critical Carotenoid, March 2011] that claims benefits of meso-zeaxanthin, the non-dietary component of the macular pigment. Bone and Landrum discovered that meso-zeaxanthin was a constituent of the macular pigment in 1993. Meso-zeaxanthin (MZ) is not found in substances consumed in a typical diet. In a study published in 1986, Maoka et al. identified MZ in turtle fat, shrimp carapace and fish skin and did not detect MZ in foods that contain high concentrations of zeaxanthin such as corn and egg yolks.4 However, the extraction procedure used in this study may have in fact generated MZ as subsequent studies have failed to reproduce the Maoka results (EJ Johnson, Tufts/USDA, personal communication).

Currently, there are only three published human clinical trials and one conference abstract in which subjects were supplemented with MZ.1-3,5 These trials also included lutein and zeaxanthin in the treatment regimen as the synthesis of MZ produces a mixture of the three xanthophylls. The source, amount and ratio of these three xanthophylls varied in each of the four studies. Bone et al. state that “the L to MZ conversion can be augmented by supplementing the diet directly with MZ.” There is no published evidence that supports this statement. Three of the four trials evaluated macular pigment optical density (MPOD) as an endpoint, but any increase in MPOD cannot be attributed to MZ as any potential beneficial effect of MZ cannot be isolated from those conferred by lutein or dietary zeaxanthin. Additionally, as MPOD is a measurement of the total level of xanthophylls in the macula, there is no way to determine whether increases in MPOD were due to an increase in the conversion of lutein to MZ or enhanced deposition of MZ in the macula.

Finally, the available evidence suggests supplementation with MZ may actually hinder the uptake of lutein and zeaxanthin. All three published studies showed a decreased absorption rate of lutein and zeaxanthin into the blood stream, compared with results from other studies that supplemented subjects with lutein and/or zeaxanthin alone at comparable levels, suggesting that MZ might actually impair the body’s ability to absorb lutein and zeaxanthin. For example, one study showed that MZ was less bioavailable than dietary zeaxanthin since dietary zeaxanthin was 2.6 times better absorbed than MZ.5 Epidemiology studies from 1993 on have supported a role for lutein and dietary zeaxanthin in eye health. This led to the NEI launching the AREDS-2 trial with just these two pigments. The safety of lutein and dietary zeaxanthin has been reviewed numerous times by the FDA in response to, e.g., New Dietary Ingredient notifications and Generally Recognized as Safe notifications from various manufacturers seeking to use these ingredients in dietary supplements and conventional foods. In contrast, the public record reflects no such safety submissions and FDA response for meso-zeaxanthin.

Eye-care professionals should proceed with caution when considering whether to recommend a supplement containing meso-zeaxanthin. As MZ is not consumed in the diet and is the result of a biotransformation of lutein in the macula, there is no evidence that the body either needs or deposits exogenous sources of MZ. The human clinical literature is limited and does not provide competent and reliable scientific evidence that supports a benefit of MZ for eye health.

Diane E. Alexander, PhD

Des Moines, Iowa
Dennis Gierhart, PhD
Chesterfield, Mo.

Dr. Alexander is the technical service manager at Kemin Health, L.C., a lutein manufacturer, and Dr. Gierhart is chairman and CSO of ZeaVision, LLC, a company that sells eye supplements and optical measuring devices, and holds patents on dietary zeaxanthin.

1. Bone RA. Macular pigment response to a supplement containing meso-zeaxanthin, lutein and zeaxanthin. Nutrition & Metabolism 2007:4.
2. Connolly EE, Beatty S, Loughman J, and Nolan JM. Meso-Zeaxanthin Ocular Supplementation Trial: MOST (Abstract). Invest Ophthalmol Vis Sci 51: E-Abstract 514, 2010.
3. Connolly EE, Beatty S, Thurnham DI, Loughman J, Howard AN, Stack J, and Nolan JM. Augmentation of macular pigment following supplementation with all three macular carotenoids: An exploratory study. Curr Eye Res 2010:35:335-351.
4. Maoka T, Arai A, Shimizu M, and Matsuno T. The first isolation of enantiomeric and meso-zeaxanthin in nature. Comp Biochem Physiol B 1986:83;121-124.
5. Thurnham DI, Tremel A, and Howard AN. A supplementation study in human subjects with a combination of meso-zeaxanthin, (3R,3’R)-zeaxanthin and (3R,3’R,6’R)-lutein. Br J Nutr 2008: 100;1307-1314.

Authors’ response:
Dr. Alexander and Dr. Gierhart have commented on our article “Targeting AMD with a Critical Carotenoid” on a number of specific points.

1) Drs. Alexander and Gierhart suggest that Moaka’s study (reference 18, our article) on the occurrence of meso-zeaxanthin in marine animals was flawed and that the extraction process may have catalyzed the formation of the meso-zeaxanthin. They have cited an unpublished study that failed to replicate Moaka’s result but do not present positive data that lutein in such samples would have been converted into meso-zeaxanthin by the process. This is not a scientifically credible argument. Scheidt et al. (see refs. 18-21) have, in fact, replicated Maoka’s method with salmon and rainbow trout. Both of these fish have been demonstrated to contain meso-zeaxanthin, principally in skin but also in the flesh of the rainbow trout. Evidence supports a conclusion that it is formed via a reductive pathway from astaxanthin.

Furthermore, in their investigation, Maoka et al. applied their extraction procedure to six higher plants as well as seven marine animals with the result that, in each of these cases, only the R,R form of zeaxanthin was found to be present. If the extraction process were able to catalyze conversion of lutein to meso-zeaxanthin, as argued by Alexander and Gierhart, then they would certainly have observed meso-zeaxanthin in the plant extracts which are rich in lutein.

Because formulation of a carotenoid supplement can dramatically alter its bioavailability, comparing the lutein and zeaxanthin uptake between different studies... is not meaningful. 
2) As we noted in our paper, the supplementation studies involving meso-zeaxanthin (references 33 and 34, our article), used supplements that also contained lutein and a small amount of zeaxanthin. Drs. Alexander’s and Gierhart’s statement that increases in macular pigment could not be attributed solely to meso-zeaxanthin is valid. We agree. It is, however, difficult to explain the magnitude of the macular pigment increases observed solely on the basis of the lutein and R, R-zeaxanthin content of the supplement.

3) Because formulation of a carotenoid supplement can dramatically alter its bioavailability, comparing the lutein and zeaxanthin uptake between different studies as suggested by Alexander and Gierhart is not meaningful, and differences cannot be attributed to the presence of meso-zeaxanthin in one formulation.
Richard A. Bone, PhD
John T. Landrum, PhD

 Stephen Beatty, MD 
John Nolan, PhD  

To the Editor:
Conjunctival chalasis (conjunctivochalasis) seems to mean different things to different people. I apply this term to a condition where there is an excess of conjunctiva. The conjunctiva may vary from a slight elevation with wrinkling to a cystic elevation the size of a grape. The conjunctival elevation may be caused by an irritation from dry eye, a spastic entropian, etc. Fluid is secreted into the subconjunctival area, which elevates the conjunctiva. Patients may want elevated conjunctiva released due to discomfort or for cosmetic reasons.

I suggest an easy way to release both the elevated conjunctiva and the subconjunctival fluid. May I call it the “EARL” or EAsy ReLease procedure?

One simply places the warm tip of a hand-held, disposable cautery on the surface of the conjuctival chalasis. The warm tip will produce a hole in the conjunctiva. The fluid under the conjunctiva will run out through the hole, and the chalasis will collapse. The heat produces a coagulum around the conjunctival hole that sticks the conjunctiva to the subconjunctival tissues.

I explain the procedure to the patient and provide him with an antibiotic drop to use for a few days prior to the procedure. One needs to place a topical anesthetic in the eye and then insert a strong eye speculum. Turn the cautery on and then turn it off and wait a few seconds so the tip will be warm but not very hot. If the tip is too hot the patient will feel the heat and jump.

I have not had to repeat the procedure but I’m sure that one may repeat it if necessary. I understand some surgeons excise conjunctiva and may place an amniotic membrane graft. I have not found this necessary. Please contact me if you desire.

Earl Braunlin, MD 
717 W. Jefferson Blvd. 
Fort Wayne, Ind. 46802 
(260) 426-3494