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Nutrition and Behavior as it Applies to Glaucoma

Written by Larry J Alexander OD FAAO Friday, 27 September 2013

Controversy abounds in the arena of the impact of behavior and nutrition related to all disease…including glaucoma. The following is an exercise in science to attempt to bring some organization and sense to the discussion.

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http://www.pillsbury.com/recipes/bacon-cheeseburger-calzones/dd289aa8-a6aa-4528-bb55-1f5057277d83                                     

PROLOGUE

image5Critical review: vegetables and fruit in the prevention of chronic diseases. Boeing H, Bechthold A, Bub A, et al. A critical review on the associations between the intake of vegetables and fruit and the risk of several chronic diseases shows that a high daily intake of these foods promotes health. Therefore, from a scientific point of view, national campaigns to increase vegetable and fruit consumption are justified. The promotion of vegetable and fruit consumption by nutrition and health policies is a preferable strategy to decrease the burden of several chronic diseases in Western societies. (Eur J Nutr. 2012 Sep;51(6):637-63)
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http://www.periodictable.com/Items/026.32/index.html

The association between glaucoma prevalence and supplementation with the oxidants calcium and iron.  Wang SY, Singh K, Lin SC. Results suggest that there may be a threshold intake of iron and calcium above which there is an increased risk of development of glaucoma. Prospective longitudinal studies are needed, to assess whether oxidant intake is a risk factor for development and progression of glaucoma. (Invest Ophthalmol Vis Sci. 2012 Feb 13;53(2):725-31)  

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Oral Glucosamine Supplements as a Possible Ocular Hypertensive Agent. Murphy RK, Ketzler L, Rice RDE, et al.  Study finds that supplementation with glucosamine may increase intraocular pressure in some patients and discontinuation may result in reversal.  This was suggested to be associated with glycosaminoglycans (GAGS) and the effect is similar to corticosteroid response. Monitoring of patients supplementing with glucosamine is in order. (JAMA Ophthalmol. 2013;131(7):955-957.)

INTRODUCTION

Controversy abounds in the arena of the impact of behavior and nutrition related to all disease…including glaucoma.  The following is an exercise in science to attempt to bring some organization and sense to the discussion.

Is There More to Glaucoma Treatment Than Lowering IOP? Maneli Mozaffarieh, MD, and Josef Flammer, MD University Eye Clinic, Basel, Switzerland

Abstract. Classic glaucoma treatment focuses on intraocular pressure (IOP) reduction. Better knowledge of the pathogenesis of the disease has opened up new therapeutical approaches. Whereas most of these new avenues of treatment are still in the experimental phase, others, such as magnesium,

gingko, salt and fludrocortisone, are already used by some physicians. Blood pressure dips can be avoided by intake of salt or fludrocortisone. Vascular regulation can be improved locally by carbonic anhydrase inhibitors, and systemically with magnesium or with low doses of calcium channel blockers.

Experimentally, glaucomatous optic neuropathy can be prevented by inhibition of astrocyte activation, either by blockage of epidermal growth factor receptor or by counteracting endothelin. Glaucomatous optic neuropathy can also be prevented by nitric oxide-2 synthase inhibition. Inhibition of matrix

metalloproteinase-9 inhibits apoptosis of retinal ganglion cells and tissue remodeling. Upregulation of heat shock proteins protects the retinal ganglion cells and the optic nerve head. Reduction of oxidative stress especially at the level of mitochondria also seems to be protective. This can be achieved by

gingko; dark chocolate; polyphenolic flavonoids occurring in tea, coffee, or red wine; anthocyanosides found in bilberries; as well as by ubiquinone and melatonin. (Surv Ophthalmol 52:S174--S179, 2007.  2007 Elsevier Inc. All rights reserved.)

 

To Contrast:

Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. West AL, Oren GA, Moroi SE. The available evidence does support the use of certain vitamins and minerals in patients with certain forms of age-related macular degeneration. For cataracts, the available evidence does not support these supplements to prevent or treat cataracts in healthy individuals. For diabetic retinopathy and glaucoma, the available evidence does not support the use of these supplements. In the category of herbal medicines, the available evidence does not support the use of herbal medicines for any of these ocular diseases. (Am J Ophthalmol. 2006 Jan;141(1):157-66.)

Use of herbal medicines and nutritional supplements in ocular disorders: an evidence-based review. Wilkinson JT, Fraunfelder FW. Current data does not support the use of antioxidants or herbal medications in the prevention or treatment of cataracts, glaucoma or diabetic retinopathy. It is important for providers to be aware of the benefits and the significant potential adverse effects that have been associated with nutritional supplements and herbal medications, and to properly inform their patients when making decisions about supplementation.(Drugs. 2011 Dec 24;71(18):2421-34)

Every approach to the concern about nutrition and disease seems to carve out a very small aspect of the issue, which further complicates the topic.  Curr Eye Res. 2013 Jun 21. [Epub ahead of print] reports that “While greater total consumption of calcium and iron may be associated with increased odds of glaucoma, dietary rather than supplemental consumption of these oxidants was found to be associated with lower odds of glaucoma. Additional research is necessary to elucidate the relationship between glaucoma and oxidant intake from foods versus supplements, and to prospectively evaluate whether oxidant intake is related to glaucoma incidence and progression.”  What they are saying, I suppose is that as long as you do not overdo it on consumption of calcium and iron, you are not really at an increased risk of glaucoma.  This discussion is going to attempt to make some sense of the plethora of reports regarding nutrition, behavior and glaucoma.  There is the added feature that a recent study found that 1 in 9 glaucoma patients use Complementary and Alternative Medicine with 62.5% not reporting it and 40.5% believing that it was helping. (J Glaucoma. 2012 Feb;21(2):79-82) Patients are pursuing alternative medicine with or without our input.

One other concern is the fact that most anti-glaucoma drops contribute to ocular surface disease and that any behavior modification or nutritional supplement will be appreciated by the patients to alleviate dry eye symptoms. (Eur Rev Med Pharmacol Sci. 2013 Apr;17(8):1117-22.) 

Glaucoma is a very complex issue involving the standard association with increased intraocular pressure and subsequent loss of nerve fiber function. However there are multiple issues relating glaucoma to a number of systemic concerns.  Family history is the most associative issue when discussing glaucoma implying genetic relationships.  Having said that there is a proposed relationship of the genetics of glaucoma to the ability of the body to properly absorb, transport and metabolize any nutritional product into the system.  (Mol Vis. 2013;19:231-42. Epub 2013 Feb 3.)  Having said that, there is much more to this discussion than the one-armed approach of nutritional supplementation to overcome geneticsOne pill cannot overcome a lifetime of abuse to the body.

Topics associated with the evolution of the variations of glaucoma include but are not limited to:

REPORTED RISK FACTORS and ASSOCIATIONS WITH GLAUCOMA DEVELOPMENT AND PROGRESSION

Modifiable issues highlighted in blue:

Intraocular pressure
Farsightedness
Nearsightedness
Excessive Caffiene Intake (
J Glaucoma. 2009 Aug;18(6):423-8.)
Playing High Wind Instruments (J Glaucoma. 2009 Aug;18(6):423-8.)

Diabetes
Age
Sex
Trauma
Vascular Disease/Vascular Perfusion
Hyper and Hypotension
Smoking
Obesity
Family History
Dementia
Erectile Dysfunction
Status of the Immune System
History of Ocular Surgery
Pigmentary Dispersion
Pseudoexfoliation
Ethnicity
Sleep Apnea
Low Intracranial Pressure
Hormonal Levels
Hyperhomocysteinemia
Oral, Topical, Inhaled Steroids

Each of the blue topics has behavioral modification implications.  Smoking and Obesity are the most obvious relationships to disease while others are more tangential.  That being said, strangely enough there has never been a definable associative risk between glaucoma and smoking. (J Glaucoma. 2009 Aug;18(6):423-8.)  This discussion will address how behavior modification and nutritional supplements relate to the controlled progression and outcome of glaucoma.

Of particular interest is the behavior of our society in the creation of nutritional deficiencies.  Poverty, side effects of medications, the issues of drug abuse and alcoholism, gastric bypass (bariatric surgery), fad diets, and just ignorance may be opening a door to the genesis of an entirely new set of nutritionally-based diseases and disorders.  The ubiquitous presence and availability of fast (aka FAT FOODS) foods offers the proof of our lunacy related to diet.  Questions that we all must ask in relation to the work-up of any ocular disease patient must include nutritionally-related issues. (Glaucoma Today 2007;5:33) The decreased survival of AREDS participants with AMD and cataract suggests that these conditions may reflect systemic rather than only local processes. (Arch Ophthalmol 2004;122:716)  Vitamin A deficiency, at the least, may become an issue associated with the fat mal-absorption occurring with bariatric surgery (Br J Ophthalmol 2004;88:583) which will then impact directly on the genesis of dysfunctional tear syndrome and retinal health. Vitamin B12 and folate deficiency is also related to mal-absorption and is well known to create ocular side effects with a strong relationship to hyperhomocysteinemia, reported to represent a major cardiovascular threat. (Am J Med 2005;118:1154, Haematologica 2006;911506, Semin Ophthalmol 2002;1729, Am JClin Nutr 2005;82:442)  In spite of a purportedly “healthy diet” in the US 10%-14% of Americans have a vitamin C deficiency, (Am J Public Health 2004;94:870, J Am Coll Nutr 1999;18:582) and up to 15% of adults over 60 years have laboratory evidence of B12 deficiency (Am J Med 2005;118:1154). Treatment of the majority of these readily obtainable nutrients involves basic diet modification or supplementation as well as exercise and general modification of behavior including cessation of smoking and minimizing the use of alcohol.  The thrust of the message in this discussion is that synergism is key rather than an isolated mono-therapy approach in the management of most chronic ,neuro-degenerative, and inflammatory disorders.  Modulation (balance) is the critical watchword in the approach to the management of health in most individuals, while minimizing risk.  Radical behavior or unbalanced therapy can and will create far more harm than good.  Exercise potentiates effects and combinant therapies represent the theme of recent “eurekas.” Remember that exercise is the basis for the mobility of the components of the immune system.  The immune system components circulate by the creation of muscular activity.  A recent study points out that despite eating a diet rich in omega-3 fatty acids, Alaskan Eskimos are developing subclinical atherosclerosis at an early age, likely due in large part to heavy smoking. (The GOCADAN study. Stroke 2008; DOI:10.1161) Regular exercise and consuming long-chain n-3 fatty acids (FAs) from fish or fish oil can independently improve cardiovascular and metabolic health, but combining these lifestyle modifications may be more effective than either treatment alone. (Am J Clin Nutr 2007;85:1267) 

There is neither a magic pill nor a magic nutriceutical, but rather a mental set and lifestyle that set the tone for maximizing health.  While we should expect everyone to modulate their behavior to maximize their health, it just will not happen so we must arm ourselves to become “personal health advisors” to our patients.

Another critical issue regarding supplementation is that the health care provider is often unaware of the patient’s use of non-pharmaceutical products. In a survey conducted in 1999, about 49% of adult Americans were estimated to have used herbal products during the previous year. It has been documented that as many as 31% of the patients who use herbal supplements do so in conjunction with prescribed drugs and about 70% of these patients do not regularly report the use of these products to their health care providers (J of Clin Pharm Ther 2002:27;391). One enlightening report speaks to the use of “complementary medicine use in cancer survivors.  It is reported that prayer and spiritual practice were the most prevalent methods, reported by 61.4% of survivors. The use of spiritual influence was followed by relaxation (44.3%), faith and spiritual healing (42.4%), nutritional supplements and vitamins (40.1%), meditation (15%), religious counseling (11.3%), massage (11.2%), and support groups (9.7%). Hypnosis was least likely to be used (0.4%), and biofeedback therapy (1.0%) and acupuncture/acupressure (1.2%) were used only slightly more often.  (Cancer. 2008;113:1048)

Patients are practicing non-pharmaceutical management of diseases and disorders and the eye care practitioners need to tune into the program and manage the issues accordingly.  The patients are begging for alternatives to expensive medications that virtually always have untoward side effects.

Additionally, there is strong support in the medical literature regarding diet and nutritional support in the management of glaucoma.  Much of the supporting documentation comes from literature considered outside the realm of eye-care, in the areas of vascular and neurological literature.  The manipulation of this aspect of therapy may be particularly applicable to Normal Tension Glaucoma (NTG) with the thought that the cause is actually reported to be vaso-regulative with neurodegenerative issues.  A number of studies support a look outside the paradigm of the current management of glaucoma. (Expert Opin Emerging Drugs 2007;12:195)

Of paramount importance in addressing this topic is that financial restrictions often prevent the “ideal” solution to a problem and those considerations must be put into play.  For example the ideal diet reported in cardiology literature revolves around consumption of fish.  Most fish purchased in the market is well over $10 a pound while a fat-fried fish sandwich at the local fast food store is $2….economic reality.  The most economically challenged, often with the highest incidence of disease just cannot afford to eat well and certainly cannot afford expensive supplementation.  When designing nutritional supplements the same considerations must be taken into account.  A supplement costing over $1 per day would seem excessive to most, especially those who need it most.  Coenzyme Q 10 and alpha-lipoic acid are considered by many to be extremely beneficial, but addition of that to any supplement dramatically increases the cost.  Therefore, when considering any supplement for any disease one must balance potential good with potential cost.  HOW CAN YOU GET THE MOST BANG FOR THE BUCK WHILE USING THE BEST OF INGREDIENTS?  THE LEAST EXPENSIVE APPROACH IS TO FIRST MODIFY BEHAVIOR THAT LENDS TO THE WORSENING OF GLAUCOMA.  THEN DESIGN THE SUPPLEMENT USING WHAT IS ABSOLUTELY INDICATED USING A GOOD MULTIVITAMIN TO COMPLETE THE PACKAGE.

ATTENTION TO BEHAVIOR MODIFICATION and PROPER NUTRITION AS RELATED TO GLAUCOMA

Based on an exhaustive search of the medical literature, the possible positive actions of behavior modification, proper nutrition and exercise in minimizing the risk for the development or progression of ganglion cell and nerve fiber damage in glaucoma include:

  • Minimizing inflammation
  • Normalizing ocular collagen and protecting ocular tissue against the neurotoxicity of glutamate.
    • Address nutrients that exert specific influences on Glycosaminoglycans (GAGs)( Invest Ophthalmol Vis Sci, 1996;37:1360-1367)
  • Increasing ocular antioxidant defenses and scavenging harmful free radical molecules.Increasing the ocular level of glutathione to improve outflow and minimize antioxidant activity
  • Preventing inappropriate release and actions of nitric oxide (NO) and vasoconstrictors from vascular endothelium.
  • Improving ocular blood flow
  • Minimizing inflammation and modulating the immune system
  • Protecting the mitochondria before the process of apoptosis is unstoppableControl excessive glutamate
  • CONSIDER THE GENETICS RELATED TO THE PROBLEM.  NEW DATA INDICATE THAT THERE ARE GENETIC INFLUENCES ON THE ABILITY TO ASSIMILATE AND UTILIZE KEY NUTRITIONAL COMPONENTS.

The primary activity of non-pharmaceutical and traditional medical systems is in modulating the immune system, providing neuroprotection and improving cardiovascular function through action on the mitochondria, the bioenergy center of the cells.  That being said, no supplement is of value without a proper diet and exercise to enhance the effect.  Studies keep accumulating substantiating the importance of exercise on a regular basis.  One of the latest studies points to the fact that increased fitness is associated with 50% to 70% reductions in all-cause mortality. (Circulation 2008;10:1161)  Exercise trumps all issues in reducing inflammation and increasing blood flow. 

THE COMPONENTS OF INFLAMMATION AND GLAUCOMA

GENERAL DISCUSSION

Inflammation is critical to the maintenance of health.  Inflammation is controlled by the immune system and is used to control and ultimately suppress invasion of foreign substances and to facilitate the healing process.  But when inflammation does not shut off, the chronicity creates an imbalance in the system leading to further destruction.  While the relationship of glaucoma to inflammation seems a bit obscure on the surface, there are considerable references in the medical literature relating the two.  Seemingly, unlikely relationships exist and afford the opportunity to intervene with anti-inflammatory drugs, anti-inflammatory diets and anti-inflammatory neutriceuticals.  A brief look at a couple of the studies validates the relationship.

INFLAMMATION and GLAUCOMA

 (Circulation 2005;112:900, J Glaucoma 2005;14:384, Circ Res 2004;95:877, Invest Ophthalmol Vis Sci 2002;43:2704, J Glaucoma 2002;11:259, J Glaucoma 1997;6:83, Br J Ophthalmol 2005;89:60, Invest Ophthalmol Vis Sci 2003;44:2565) 

C-reactive protein (CRP) elevation is also associated with CSVD indicating an inflammatory process, and the elevated CRP levels are also found in NTG patients. The CRP increases endothelin  which has been implicated in the proliferation of astrocytes in the nerve head and changes in the trabecular meshwork and has been found to be elevated in glaucoma and NTG after exposure to cold temperatures.

INFLAMMATION and GLAUCOMA

 (Cell Mol Neurobiol 2001;21:617)

Immune System influences including antibodies generated by B-cells within the rubric of the general inflammatory process lead to cell death in glaucoma.  Protection also occurs through the immune system pointing to the importance of proper modulation of the immune system.

INFLAMMATION and GLAUCOMA

 (Cell Mol Neurobiol 2001;21:617, J Neurosci 2000;20:6421, J Neuroimmunol 2000;106:189, Nat Med 1999;5:49, Am J Ophthalmol 2006;141:1105, Surv Ophthalmol 2001;45:S256, Invest Ophthalmol Vis Sci 2003;44:407, Proc Natl Acad Sci USA 2001;98:3398, Proc Natl Acad Sci USA 2000;97:7446)

Autoimmunity is at the root of most disorders and is defined as an attack on the host cell by activated T cells.  It has actually been shown that survival of RGCs after optic nerve injury is facilitated by the autoimmune response via activated T cells. This response can either be by active immunization with a protein or by transfer of activated T cells. 

INFLAMMATION and GLAUCOMA

 (Mol Med 1997;3:765, Stroke 1994;25:1481, Stroke 1997;28:1233, Invest Ophthalmol Vis Sci 2001;42:1787)

TNF- alpha is a pro-inflammatory cytokine that is present during excitotoxic and ischemic brain injury.  Among other functions, it binds to the death receptor and can induce caspase components of the mitochondrial cell death pathway.   TNF- alpha has been implicated as a mediator in RGC death. 

(Exp Eye Res 2006;83:1335, Exp Eye Res 2006;83:1246)

TNF- α inhibitors (GLC756) are being investigated for the treatment of glaucoma.

WHAT KIND OF BEHAVIOR MODIFICATION AND SUPPLEMENTS MODULATE INFLAMMATION
  • Employ an Anti-Inflammatory Diet
  • Stop smoking
  • Lose Weight
  • Exercise
  • Balance Omega 6 Intake With Omega 3 Supplementation
  • Check Vitamin D Levels and Consider Supplementation
  • Consider the Benefits of a High Quality Vitamin Supplement
  • Consider Curcumin Supplementation and Other Immune System Modulators Like Colostrum

 WHAT KIND OF DIET SUPPORTS ANTI-INFLAMMATION AND NEUROPROTECTION

 The Eye on Fire

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 Modulating The Morbidity of Inflammation 

The topic of non-pharmaceutical management of any disorder always conjures up the image of the “witch doctor’ approach to health care.  Skeptics point to the fact that there is no medically referenced information regarding the benefits of any approach besides pharmaceutical or surgical intervention for any disease or disorder of the human body.  The battle is currently at epic proportions regarding the benefits of omega 3 fish oil supplementation.  The following approach to the introduction of behavioral modification, as it may relate to the management of glaucoma, is medically referenced and relates to all medical disciplines.  The implications of systemic influences on normal tension glaucoma and neurodegeneration (ocular dementia) lend well to the consideration of maintenance of the health of the entire system rather than just the approach of lowering intraocular pressure.  This section is intended to address the topic, stimulate further interest in the relationships, and create an environment where the eye care practitioner will be more comfortable discussing the issues with the patients.  It is hard to ignore the fact that one recent study reports a healthy lifestyle combining 1. not smoking, 2. maintaining a healthy weight, 3. maintaining a healthful diet including moderate alcohol consumption, and 4. performing some daily exercise reduced ischemic strokes by approximately half in both men and women. (Circulation. Published online August 11, 2008)

Cordain contends that our Western diet has evolved in a disparate manner from our basic biological needs. (J Clin Nutr 2005;81:341)  We still have cave-man genes (genotype) requiring the Paleolithic diet that are not being satisfied by our current diet.  This diet then creates an oxidative stress that impacts on the inflammatory reaction as well as the immune system.  Oxidative stress in glaucoma leads to alterations in Retinal Ganglion Cells that precipitate damage and loss of function. (Invest Ophthalmol and Vis Sci 2007; 48: 4580)  Green or black tea (Mol Nutr Food Res 2006;50:229, J Nutr Biochem 2006;17:291, Mol Neurobiol 2005;31:283), coffee (J Nur Biochem 2004;15:722, J Agric Food Chem 2005;53:2658), dark chocolate (J Agric Food Chem 2006;54:4062), and red wine (Ann Neurol 2003;53:825, Adv Food Res Suppl 1969;1:1) contain polyphenolic compounds that act as free radical scavengers.  A recent paper looking at a subset of black women attests to the fact that consuming three or more servings of fruit each day was associated with a 79% decrease in glaucoma risk compared with eating less than one serving per day. (Giaconi et al  at The 18th Annual AGS Meeting, March 2008)  This study was further corroborated in 2012 adding that fruits and vegetables high in vitamins A and C and carotenoids decreased the likelihood of glaucoma in older African-American women. (Am J Ophthalmol. 2012 Oct;154(4):635-44. ) Diet can impact oxidative stress and therefor modulate the inflammatory components of glaucoma.

Additionally a recent study offers the following recommendations for an anti-inflammatory diet to improve the overall health and most specifically the cardiovascular system which has strong implications in both NTG and neurodegenerative diseases.  C-reactive protein levels, among other markers, are a very good indicator of the presence of systemic inflammation.  Any disease with elevated C-reactive proteins could potentially benefit from an anti-inflammatory diet.  This C-reactive protein marker elevation also occurs in diabetes and ARMD. (JAMA Ophthalmol. 2013;():1-8)  After adjusting for known risk factors, increasing quintiles of baseline high-sensitivity C-reactive protein (hsCRP) level may be associated with higher risk of incident CSME and macular hard exudates in the DCCT cohort. Circulating levels of intercellular adhesion molecule 1 (ICAM-1) may also be associated with the development of retinal hard exudates. (JAMA Ophthalmol. 2013;():1-7.)  Overall, these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.  "After matching for age and controlling for cigarette smoking, individuals with baseline hsCRP levels more than 3 mg/L had a 50% increased risk of incident AMD and a nearly 2-fold increased risk of neovascular AMD," the authors write.

THIS ANTI-INFLAMMATORY DIET SHOULD BE CONSIDERED FOR THE PRIMARY AND SECONDARY PREVENTION OF CORONARY ARTERY DISEASE AND DIABETES." (J AM COLL CARDIOL. 2008;51:249)

  • The glycemic index of a food is defined as the incremental increase in the area under the postprandial glucose curve after ingestion of 50 g of a specific amount of food versus that associated with 50 g of oral glucose. Ideal carbohydrates with a low glycemic index include green leafy vegetables such as broccoli and spinach and fruits such as grapefruits and cherries. Select high-fiber carbohydrates with low glycemic index, including vegetables, fruits, whole grains, legumes, and nuts.
  • Excess intake of processed carbohydrates leads to a vicious cycle of transient spikes in blood glucose levels, increased insulin production, and reactive hypoglycemia. Avoid highly processed foods and beverages, particularly those containing sugar, high-fructose corn syrup, white flour, or trans fats.
  • Berries, dark chocolate, red wine, tea, and pomegranates reduce postprandial oxidant stress and inflammation.  Cacao beans contain a subclass of flavonoids which have been reported to augment eNOS and thereby NO.  This improves endothelium-dependent vaso-relaxation. (J Nutr 2000;130:2105S) One study showed that one square of dark chocolate was 6.3 g and represented only 30 kcal per day but previous studies have shown that 100 g of dark chocolate lowers BP by 12/8 mm Hg but with the risk of increased caloric intake. (JAMA. 2007;298:49)

Six Benefits of Dark Chocolate High in Cocoa Bean Concentration (AARP April 2008)

  1. Lower blood pressure by vasodilation
  2. Reduce risk of diabetes by reducing blood sugar and insulin
  3. Activates enzymes that eliminate cancer-causing carcinogens and mutagens
  4. Reduces risk of blood clots and strokes by inhibiting clumping of platelets
  5. Keeps cholesterol levels stable or may improve
  6. Enhances cognitive function by increasing blood flow to brain
  • Bitter is Better and Red Wine is Fine
  • Coffee contains antioxidants and can improve insulin sensitivity. Consumption of black tea reduces platelet activation and plasma levels of C-reactive protein. However, previous research has not demonstrated a consistent reduction in the risk for stroke associated with coffee or tea consumption.  One study suggests that higher levels of coffee and tea consumption can reduce the risk for cerebral infarction among male smokers but not rates of intracranial hemorrhage. (Stroke 2008;39:1681)
  • When paired with a high-glycemic-index meal, cinnamon slows gastric emptying and reduces postprandial glucose excursion.
  • Nuts also slow gastric emptying and can reduce the impact of high-glycemic-index carbohydrates by as much as half. Nuts also reduce postprandial oxidative protein damage, and consumption of nuts at least 5 times weekly can reduced the risks for coronary artery disease and diabetes by 20% to 50%. Eat approximately 1 handful of nuts daily (using a closed fist), consumed with vegetables, grains, berries, or other fruits.
  • Vinegar can reduce postprandial glycemia and promotes satiety. Eat salad daily, consisting of leafy greens with dressing of vinegar and virgin olive oil.
  • Lean protein reduces postprandial glucose excursion and improves satiety. Such protein includes egg whites, game meat, skinless poultry breast meat, and whey protein or other nonfat dairy protein. At all 3 meals, consume lean protein.
  • Drinking 0.5 to 1 alcoholic drink per day for women and 1 to 2 alcoholic drinks per day for men can reduce cardiovascular risk, and 1 to 2 drinks before a meal can reduce postprandial glucose and insulin levels. However, higher levels of drinking can impair glucose metabolism.
  • Exercise acutely lowers glucose and triglyceride levels in a dose-dependent fashion. Perform physical activity for at least 30 minutes or more daily, of at least moderate intensity.
  • Maintain normal weight and avoid being overweight or obesity. Waist circumference should be less than one half of height in inches.

THE EFFECT OF OBESITY AND THE METABOLIC SYNDROME AND INFLAMMATION ON GLAUCOMA AND OTHER OCULAR ISSUES

http://www.eyelessons.com/articles/item/is-there-a-significant-relationship-of-smoking-and-obesity-to-glaucoma

Excessive weight and obesity in concert with an inappropriate diet loom as a constant threat to both systemic and ocular health especially when considering the impact of obesity on inflammation. (Surv Ophthalmol. 2007; 52;180, Harefuah. 2005;144:805, Clin Interv Aging. 2006;1:11) Morbidity and mortality are both affected by diet with a prudent approach being to maintain your weight at a reasonable level while coincidentally consuming health-sustaining nutrients.  There are studies linking obesity to macular degeneration. (Arg Bras Oftalmol. 2005;68:229) In one report overall and abdominal obesity increased the risk for progression to advanced AMD, and more physical activity tended to decrease risk. (Arch Ophthalmol. 2003;121: 785, Br J Ophthalmol. 2005;89: 964)  Ironically there is also increased risk should the patient be too thin. (Arch Ophthalmol 2001;119:1259)  Another recent report suggests that in Latinos cardiovascular risk factors may play a role in advanced AMD. (Am J Ophthalmol. 2008;145:308)  This should be of no surprise since Richer’s original work demonstrated that cardiovascular risk factors including elevated serum iron (Fe) levels contributed to the progression of AMD. (Am J Ther. 2002 ;9:25)   The other risk factors often associated with heart disease such as smoking and altered blood composition are also modifiable in our patient base. (Ophthalmology 2005;112:533, Am J Ophthalmol. 2007;143:473, Arch Ophthalmol. 2007;125:55, Arch Ophthalmol. 1998;116:583, Postepy Hig Med Dose 2007;61:28) Reports also attest to the fact that obesity is actually related to a decrease in macular pigment levels that may be attributable to competition with adipose tissue. (Am J Clin Nutr. 2006;84:1107, Nutr Rev. 2005;63:9, IOVS 2004;45:3840, IOVS 2002;43:47)  Serum levels of lutein and zeaxanthin are the true measures of efficacy and both levels are measured lower with obesity and diabetes. (Am J Clin Nutr. 2006;84:1107) All of these studies still do not absolutely indicate the need for diet control from a scientific standpoint, but all studies point to the necessity for cessation of smoking in minimizing the risk for AMD. (Med J Aust. 2006;184:455)

From the standpoint of cataract development there has been much discussion regarding diet.  While very specific, studies showed a link of metabolic syndrome with the genesis of cataracts. (Medicina (Kaunas). 2006;42:115, Eur J Ophthalmol. 2007;17:605)  It appears that there is a link between oxidative stress and cataract formation with smoking again being implicated. (Expert Opin Investig Drugs. 2004;12:691)  In general it also appears that obesity is a positive marker for the increased likelihood of cataract formation while a bit unpredictable based on the type of cataract. (Eur J Ophthalmol. 2007;17:29, Arch Ophthalmol. 2005;123:1108, Am J Clin Nutr. 1999;69:237)  With a higher Body Mass Index (BMI), abdominal obesity, and diabetes patients develop a higher incidence of cortical and posterior sub-capsular cataracts. (Ophthalmology 1998;105:1244, Am J Clin Nutr. 2003;78:400)

The link to diabetes and obesity (most specifically the metabolic syndrome) is incontrovertible. (J Gen Intern Med. 2006;21:84, Diabetes Care 2002 25:1790, Prim Care Diabetes. 2008;2: 65, Med J Aust. 2007;186:461) Metabolic syndrome denotes a common cluster of naturally connected risk factors including obesity, elevated blood pressure, insulin resistance, dyslipidemia, pro-inflammatory state and pro-thrombotic state.  This scenario has the potential to lead to multiple retinal vascular flow issues within the eye. (Arg Bras Oftalmol. 2008;71:62) The link to diabetic retinopathy is more circumspect but studies have linked retinal microvasculopathy to metabolic syndrome. (Diabetes Care 2002 25:1790, IOVS 2006;47:2341)  Inhibition of inflammatory mediators is likewise implicated in minimizing diabetes risks (Exp Diabetes Res. 2007;2007:95103) and can be achieved by dietary modification.  A diet designed to address the metabolic syndrome seems to be the direction to go to minimize the risk of diabetic retinopathy.  Additionally one must address other situations that may increase oxidative stress and decrease oxygenated blood supply to the eye such as smoking and sleep apnea.

As of 2001, approximately 22% of Americans over age 18 meet the criteria for metabolic syndrome.  (JAMA. 2002;287:356–9.) Patients with either diabetes or hypertension or a combination had an increased hazard of developing open angle glaucoma.  Hyperlipidemia alone did not significantly increase the risk but the combination of hyperlipidemia and hypertension did increase the risk.  (Ophthalmology. 2011 Jul;118(7):1318-26)
General Characteristics of the Metabolic Syndrome
  1. Abdominal obesity
  2. Atherogenic dyslipidemia…Elevated Lipids
  3. Elevated Blood Pressure
  4. High insulin levels
    1. Raises fats into cells
    2. Promotes fat storage
    3. Stimulates arterial smooth muscle cells
    4. Promotes production of bad types of eicosanoid (EC) -intracellular hormones
    5. Series one ECs are good and may be inhibited by too much flaxseed
    6. Series two ECs are bad-glucagon is a strong inhibitor of EC 2 pathway
  5. Promotes retention of fluids by kidneys
    Glucagon is the anti-insulin and is increased by high proteins low carbohydrates
  6. High levels of inflammatory mediators as measured by C-Reactive Protein levels

There also exists an association of weight issues (obesity) to glaucoma and it is likewise estimated that over 60% of Americans are overweight.  It has been demonstrated that a low glycemic index diet is beneficial for both weight loss and lipid profiles. (Cochrane Database Syst Rev. Published online July 18, 2007)  Additionally women in the highest quintile of consumption of a high-fat, low-fiber diet had an increase in the relative risk of developing colon cancer compared with those in the lowest quintile. However, consumption of a high-fiber and healthy protein diet was associated with a trend toward reduced rates of colon cancer. Diet did not significantly affect the risk for rectal cancer. (JAMA. 2007;298:754)

There is certainly a suggestion that there is an association of insulin resistance and the metabolic syndrome to increased intraocular pressure. (Diabetes Metab Res Rev. 2005;21:434)  Body Mass Index appears to have an association with elevated intraocular pressure. (Jpn J Ophthalmol. 2003; 47;191, Int J Epidemiol. 2000;29:661, Clin Experiment Ophthalmol. 2002;30:237, Am J Ophthalmol. 2008;146:69)  Certainly initial reaction to this fact among clinicians would be to point to neck size and positive pressure as a related factor with sleep apnea falling into the picture. (Sleep Med Rev. 2007;11:269, Can J. Ophthalmol. 2007;42;238)  The relationship of cerebrospinal fluid pressure elevation, Idiopathic Intracranial Hypertension, serum cortisol, and sleep apnea also create an interesting scenario for elevated intraocular pressure. (Am J Ophthalmol. 2007;143:635)  While further analysis from a scientific standpoint is critical, it does appear, quite logically, that obesity has a link to glaucoma if from no other standpoint than physical restriction of flow. 

THE EFFECT OF EXERCISE ON INFLAMMATION AND GLAUCOMA

Exercise reduces IOP (Int J Neurosci 2006;116:1207) and the reduction is sustainable.  Exercise also impacts on weight and thus on the inflammatory process.  In another study it was shown that in persons with increased IOP, regular, moderately intense aerobic exercise rather than short-lived intense exercise is more useful in reducing risk. (Int J Neurosci 2006;116:351)  Another study showed that exercise changes Ocular Perfusion Pressure and produces increased tissue blood flow in the retina in the immediate post-exercise period, while blood flow increases more persistently in the choroid-retina. Difference in control of blood flow in these two regions may be related to stronger autoregulatory mechanism of blood flow in the retina. Nitric oxide may play a role in the regulation of blood flow. (Eye 2006;20:796) It is further confirmed the ocular hypotensive effect of strenuous exercise on the IOP and demonstrates that Pulsitile Ocular Blood Flow increases significantly after exercise. (Optom Vis Sci 2003;80:460)

A recent study points to the fact that following a regular exercise routine through middle age can delay biological aging by up to 12 years.  In this study Dr. Shephard states that “Regular exercise substantially reduces the risks of obesity, maturity onset diabetes mellitus, hypertension, myocardial infarction, some forms of stroke, several forms of cancer and osteoporosis, not only in middle age but also during the retirement years.  It is also helpful in rehabilitation following such critical incidents as a myocardial infarction or congestive heart failure. Regular aerobic exercise may have some impact on the likelihood of becoming blind because of a reduced risk of maturity onset diabetes mellitus, and catastrophic falls are less likely if regular aerobic exercise maintains muscle power, balance and coordination.” A decline of 16% per decade in aerobic power is expected in older persons, resulting in greater risk for dependency.  Exercise programs reduce the rate of decline in aerobic capacity and reduce the risk for dependency in elderly subjects. (Brit J Sports Med. Published online April 10, 2008)

Current recommendations call for adults to participate in at least 30 minutes of accumulated moderate-intensity physical activity on 5 or more days per week. However, less than one half of Americans meet this minimal goal. Clinician visits have significant potential to reduce this trend of inactivity because 84% of Americans visit a clinician annually. The average number of clinician visits per individual is 2.1 per year, and clinicians usually spend 1.5 to 3 minutes in health education and counseling during these visits.

The 5 A’s (Assess, Advise, Agree, Assist, Arrange) counseling model can help primary care clinicians deliver brief, individually tailored physical activity messages to patients. “The Centers for Disease Control and Prevention, American College of Sports Medicine, U.S. Surgeon General, and American College of Preventive Medicine recommend that adults participate in at least 30 minutes of accumulated moderate-intensity physical activity (i.e., walking fast [3 to 4 miles per hour] or the equivalent) on five or more days of the week. The following are key principles for physical activity: (1) the more activity the better, (2) accumulated time is more important than intensity, (3) activity can be accumulated in 10-minute increments, and (4) lifestyle activities (e.g., substituting walking or biking for short car rides, using a push rather than a riding lawn mower) are more likely to be sustained than structured activities (e.g., exercising at a gym)."

Specific clinical recommendations for practice are as follows:

$1·         Adults should take part in 30 minutes or more of accumulated moderate-intensity physical activity, such as brisk walking, on at least 5 days per week

$1·         Clinicians should advise their patients to meet recommended levels of physical activity .

$1·         The 5 A's model should be used to counsel patients about physical activity

$1·         Expert advice from professional associations is conflicting with regard to medical clearance before patients with risk factors begin exercise programs .

Specific components of the 5 A's Model for Helping Patients Change Physical Activity Behavior are as follows:

$1·         Assess: The type, frequency, intensity, and duration of current physical activity should be evaluated, as well as contraindications to physical activity, the patient’s degree of readiness for change, specific benefits to the patient, and their social support system and willingness to help others. Self-efficacy (or the patients' level of confidence that they can change their physical activity level) should also be assessed. The authors of the review describe tools that are available for the assessment of physical activity.

$1·         Advise: The clinician should deliver a structured, individually tailored counseling message. Although the national recommendation is for 30 minutes or more of accumulated moderate-intensity physical activity on at least 5 days per week, this amount may be modified based on specific findings from each patient's assessment, as described above.

$1·         Agree: The clinician should lead shared decision making based on the patient's stage of change. When the patient is not ready for change (pre-contemplation stage), the clinician should ask the patient for permission to discuss physical activity in the future. When the patient is thinking about changing (contemplation stage), the next steps should be discussed. In the preparation stage, the patient intends to change soon, so the clinician should assist the patient in planning and in setting a start date. In the action/maintenance stage, the patient is already meeting goals and should be congratulated, encouraged, and asked about his or her readiness to start another healthy behavior.

$1·         Assist: The clinician should give the patient a written prescription for physical activity; printed support materials; a pedometer, calendar, and other self-monitoring tools; and Internet-based resources.

$1·         Arrange: This phase of the model includes scheduling a follow-up visit, using telephone or email reminders, and using Internet-based counseling. Patients who are deconditioned, injured, or have comorbid conditions affecting physical activity, such as arthritis or back pain, should be referred to a dietitian, physical therapist, or other specialists as appropriate. (Am Fam Physician. 2008;77:1029)

THE EFFECT OF SMOKING ON INFLAMMATION AND GLAUCOMA

http://www.eyelessons.com/articles/item/is-there-a-significant-relationship-of-smoking-and-obesity-to-glaucoma

Smoking increases the risk for virtually every human affliction including glaucoma (often defined by increased IOP in studies) because of the interference with the oxygenation of the blood and the increase in oxidative stress. (Arch Ophthalmol 1987;105(8):1066-1071, Surv Ophthalmol 1998;42(6):535-547, Hong Kong Med J 2000;6(2):195-202, J Glaucoma 2003;12(3):209-212, Przegl Lek 2008;65(10):724-727, Przegl Lek 2005;62(10):1167-1170, Chin Med J (ENGL) 2004:117(5):706-710, Public Health 2004;118(4):256-261)   The direct relationship to glaucoma, however, appears to be controversial as studies and reviews fail to establish a firm link between either smoking or environmental smoke and glaucoma development.  Yet the same studies recommend that cessation of smoking is important in the management of glaucoma patients. (Arch Ophthalmol 2003;121(12):1762-1768, J Glaucoma 2008;17(7):558-566, Br J Ophthalmol 2008;92(10):1304-1310)  I would challenge the definitions of glaucoma and methods of quantification that were utilized in all of these studies.  Advances in both structural and functional testing dictate that a well-controlled, well-defined trial is necessary for improving the understanding of the relationship of smoking, environmental smoke, and tobacco products to the progression of glaucoma.

It has been shown that inflammation and apoptosis marker levels increase in the aqueous and plasma of women with POAG. (Mol Vis 2009;15:2953-2959) The issue of smoking is proven to be a risk factor for the presence of glaucoma. (Open Ophthalmol J 2009;3:38-42, J Glaucoma 2009;18(6):423-428)  The most critical risk factors associated with blindness were in high tension glaucoma, however, were elevated initial IOP, fluctuation, poor control, noncompliance and late detection (Clin Ophthalmol 2008;2(4):757-762)  while the for angle-closure the risks include hypertension, family history, shallow anterior chamber and large CD. (Zhonghua Yan Ke Za Zhi 2008;44(6):503-506)  In one large collaborative study it was shown that surgically treated patients with glaucoma had lower IOPs if they were non-smokers. (Ophthalmology 2008;15(6):927-933)  From a functional standpoint, cigarette smoking is associated with reductions in retinal sensitivity.  (Acta Ophthalmol Scand 2004;82(4):432-435) 

In an interesting study on the effects of smoking on normotensive patients it was found that both IOP and BP increased secondary to the nicotine in cigarettes. (Niger J Physiol Sci 2007;22(1-2):33-36)

ANALYSIS OF CONSTITUENTS OF A DIET or SUPPLEMENTATION THAT SUPPORT HEALTHY SYSTEMIC AND OCULAR FUNCTION AS RELATED TO GLAUCOMA

A number of studies directly or indirectly support the nutritional supplementation of patients to minimize the damage associated with the definition of glaucoma.  The applicable supplements will be discussed herein but the intent is purely objective reporting rather than prescriptive reporting.  Recommended allowances change on a regular basis and it is the responsibility of the doctor to monitor the proper prescriptive levels.  The individual eye care practitioner must take the knowledge and deduce his or her particular application of the knowledge.  Clearly exercise and a proper diet is the underpinning of any successful approach to behavioral modification.  Cessation of smoking, excessive use of alcohol and other self-destructive elements must be modified for any plan to be successful.

The issue is a bit complex as illustrated by a recent study that found supplementation with antioxidants decreased intraocular pressure associated with the closed eyelid test when compared to an increase of IOP without the antioxidants. ( Eye (Lond). 2013 Apr;27(4):487-940))  Another recent assessment concluded that a low intake of retinol equivalents and vitamin B1 and a high intake of magnesium appeared to be associated with an increased risk of glaucoma. (Eur J Epidemiol. 2012 May;27(5):385-93)

VITAMIN A – OBTAIN FROM DIET AND AT MINIMAL LEVELS FROM MULTI-VITAMIN

Vitamin A is a generic term referring to related compounds.  It is available in a preformed variation called retinol found in many animal products.  Preformed retinol may be toxic at levels above 10,000 IU.  The other more recognized form is natural beta carotene (carotenoid), which is from fruits and vegetables and is used to form its own vitamin A.  Recent data also point to the fact that this form likewise has potential dangers.

Carotenoids comprise a class of natural fat-soluble pigments, which are found in numerous fruits and vegetables and are attributed with the characteristic of minimizing photo-oxidative damage to tissue. Retinol is an alcohol and retinal is an aldehyde, both referred to as preformed vitamin A.  Retinol, retinal, and retinoic acid are retinoids.  Beta-carotene and other carotenoids that can be converted by the body into retinol are provitamin A variations.  Not all carotenoids sysnthesized by plants are provitamin A carotenoids. 

Retinol reaches the eye through the circulatory system accumulating in the retinal pigment epithelium in the form of a retinyl ester.  The esters may isomerize to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal and transferred to the photoreceptor matrix of the rod where it binds with opsin to form rhodopsin.  Absorption of light catalyzes the 11-cis-retinal to all-trans retinal triggering a cascade leading to the electrical signal that is sent through the retinal nerve fibers.

Vitamin A is responsible for the normal functioning of the immune system (Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:329) especially in the skin and mucosal cells but as previously discussed there is a relationship to glaucoma. (Proceedings of the Nutrition Society. 1999; volume 58: pages 289) The initial protective system from infection in the body is the mucosal system associated with IgA.  Likewise the differentiation of white blood cells is dependant on vitamin A and retinoic acid. (Nutr Rev. 1998;56:S38)  Stem cells are also dependent on retinoids for differentiation into red blood cells. (Nutr Rev. 1997;55:102)  Absence of vitamin A from the diet significantly impacts on tear quality and is responsible for the genesis of Bitot’s spots associated with severe dry eye.  Vitamin A deficiency among children continues to be a leading cause of preventable blindness. (FASEB J. 1996;10:1040) Vitamin A deficiency is considered by some to be a nutritionally acquired immunodeficiency disease (Proc Nutr Soc. 1997;56(1B):459)

One study reports no strong associations between antioxidant consumption and the risk of primary open-angle glaucoma. (Am J Epidemiol. 2003;158:337)  Another report suggests that higher intakes of protein, vitamin A, niacin, thiamin, and riboflavin (i.e. vitamin B-complex) are associated with reduced prevalence of nuclear cataract (Ophthalmology 2000;107:450-6). Intervention trials with large doses of beta-carotene found an adverse effect on the incidence of lung cancer in smokers and workers exposed to asbestos. (Mol Aspects Med. 2005;26:459) The results of the Beta-Carotene And Retinol Efficacy Trial (CARET) suggest that high-dose supplementation of vitamin A and beta-carotene should be avoided in people at high risk of lung cancer. (N Engl J Med. 1996;334(18):1150)

Uses of large dosages of Vitamin A are not without risk and should be approached cautiously.  Utilization in the management of retinitis pigmentosa showed that with common forms of retinitis pigmentosa,  supplementation with 4,500 mcg (15,000 IU)/day of preformed vitamin A (retinol) significantly slowed the loss of retinal function over a period of 4-6 years. (Arch Ophthalmol. 1993;111:761) In contrast, supplementation with 400 IU/day of vitamin E increased the loss of retinal function by a small but significant amount, suggesting that patients with common forms of retinitis pigmentosa may benefit from long-term vitamin A supplementation but should avoid vitamin E supplementation at levels higher than those found in a typical multivitamin.  (Am J Clin Nutr. 1999;69:656)  Both vitamin A serum levels and a fasting lipid profile should be obtained prior to initiation of high levels of Vitamin A therapy.  All of this is related to liver function.

Hypervitaminosis A is caused by over-consumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body. Therefore, toxicity from preformed vitamin A may result acutely from high-dose exposure over a short period of time or chronically from a much lower intake. (Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:305)  Hypervitaminosis A is characterized by dry skin, loss of appetite, headache, cerebral and optic disc edema, and bone and joint pain. In January 2001, the Food and Nutrition Board (FNB) of the Institute of Medicine set the tolerable upper level of vitamin A intake for adults at 3,000 mcg (10,000 IU)/day of preformed vitamin A for persons over age 19 but lower dosages are recommended for children. (Food and Nutrition Board, Institute of Medicine.: National Academy Press; 2001:65)  Results of some studies indicate that vitamin A intake is not associated with detrimental effects on bone mineral density (BMD) or create an increased risk for fracture (Osteoporos Int. 2004;15:872, J Clin Epidemiol. 1990;43:693, J Bone Miner Res. 2001;16(:2306) while other studies report the opposite.  (N Engl J Med. 2003;348:287, J Bone Miner Res. 2002;17:1349)  The use of vitamin A in patients treated for glaucoma with drops will enhance the health of the corneal surface. (Chin J Ophthalmol. 2010;46(2):151–160.)

A safe recommendation would be that the total vitamin A intake is recommended as less than 3000µg per day from retinol. (Nan C, Linda B. Facts about vitamin A (University of Florida, Institute of Food and Agricultural Sciences) Available fr0m: http://edis.ifas.ufl.edu/fy206.)

Excellent Natural Sources:

Beta carotene is less easily absorbed than retinol and must be converted.  The most recent standard for vitamin A is retinol activity equivalents (RAE) which represent vitamin A activity as retinol.  Two mcg of beta carotene in oil can be converted to 1 mcg of retinol at an RAE ratio of 2:1 but 12 mcg of beta carotene from food is required to give 1 mcg of retinol or a 12:1 RAE ratio. (Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington D.C.: National Academy Press; 2001:65)  Based on the old standard, one IU equals 0.3 mcg of retinol.  Retinyl palmitate is a precursor and storage form of retinol.  Retinol typically is available through animal meats and products.  Carotenoids is usually identified as available from fruits and vegetables.  Great sources for retinol based on RAE are cod liver oil, fortified breakfast cereals, eggs, butter, milk, and for carotenoids are sweet potatoes, pumpkin, carrots, cantaloupe, mango, spinach, broccoli, kale, collards,

Recommendation

There is no strong evidence to recommend supplementation of any form of vitamin A beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.  A recent study points to the fact that neither supplementary consumption nor serum levels of vitamins A and E were associated with glaucoma prevalence.  (Eye (Lond). 2013 Apr;27(4):487-940)

LYCOPENE – OBTAIN FROM DIET

Lycopene is a carotenoid in the same family as beta-carotene  Lycopene is gives a tomato, and several other fruits, their deep red color. Lycopene is one of the major carotenoids in the diet of North Americans and accounts for close to 50% of the carotenoid distribution found in blood. One study provides the experimental evidence for protective effects of dietary tomatoes rich in carotenoids on oxidative stress in the retinal pigment epithelium. (Br J Nutr  2006;96:643) Lutein and lycopene, two prevalent carotenoids in the human diet have become increasingly popular ingredients in dietary supplements. A large body of human and animal research suggests that oral forms of these carotenoids may provide benefits in the areas of eye, prostate, skin and cardiovascular health. The evidence of safety is strong at intakes up to 20mg/d for lutein, and 75 mg/d for lycopene. (Regul Toxicol Pharmacol  2006;45:289)

Excellent Natural Sources:

Foods that are commonly consumed which contain lycopene are tomato products, watermelon, pink grapefruit, apricots, papaya, and guava. Cooking and processing of tomato products makes lycopene more readily available to the body, indicating that there may be an added health benefit to eating processed tomato foods like tomato soup, pasta sauce and vegetable juices. In humans, the bioavailability of lycopene is greater from tomato paste than from fresh tomatoes.  (Am J Clin Nutr 1997; 66:116) Ohio State University researchers found that standard daily servings of tomato sauce, tomato soup, and V8 vegetable juice were each effective interventions to significantly increase blood concentrations of lycopene. Lycopene levels increased among study participants by 192% (pasta sauce), 122% (soup) and 92% (vegetable juice) respectively, and plateaued at a new baseline after only 14 days of consumption. The results of one study support the hypothesis that lycopene cis-isomers are highly bioavailable and suggest that special tomato varieties such as tangerine tomatoes can be utilized to increase both the intake and bioavailability of health-beneficial carotenoids. (J Agric Food Chem 2007;55:1597)  No strong evidence suggests that supplementation of Lycopene is as effective as the consumption of processed tomato products in achieving effective serum levels of the antioxidant.

Recommendation

There is no strong evidence to recommend supplementation of any form of Lycopene beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.

LUTEIN AND ZEAXANTHIN - OBTAIN FROM DIET AND MULTI-VITAMINS

There is considerable support in the literature for supplementing with the carotenoids lutein and zeaxanthin in the eye care field.  The primary recommendations revolve around the efficacy in the management of macular degenerative changes.  It has been suggested that “Lutein and zeaxanthin, with its strong antioxidative effects, can represent a viable solution in the complex treatment of glaucoma.”  (Oftalmologia. 2003;59(4):70-5.)  There is also evidence that lutein and zeaxanthin also help protect the optic nerve. The nerve fiber layer of the retina is protected from oxidative damage by lutein. Researchers have found that a lack of lutein in this nerve bundle may be an early sign of glaucoma. (Int Ophthamol 1992;16:251-7.)  There is also the suggestion that the combination may be of benefit in disorders of cognitive function.

Exellent Natural Sources:

Natural sources are kale, spinach, collard, green peas, green beans, and eggs.

Recommendation

There is no strong evidence to recommend supplementation of any form of lutein or zeaxanthin beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.  There is no doubt, however, regarding the benefits of supplementation in cases of retinal degenerative disease.  Anti-oxidants are critical to the maintenance of health.

VITAMIN C – ASCORBIC ACID - OBTAIN FROM DIET AND MULTI-VITAMINS

Recent work has elucidated the fact that normal tension glaucoma patients have lower levels of serum vitamin C (Graefes Arch Clin Exp Ophthalmol. 2010 Feb;248(2):243-8) and that ascorbic acid levels are reduced in the aqueous of patients with glaucoma.  (Eye (Lond). 2009 Aug;23(8):1691-7,Clin Experiment Ophthalmol. 2009 May;37(4):402-6)  It is, however, apparent that genetic tendencies are important when relating vitamin C levels to glaucoma. (Mol Vis 2011;17:2997-3004) Linus Pauling brought Vitamin C to the forefront of healthcare by advocating mega-doses of Vitamin C to fight colds and minimize the risk of cancer.  Vitamin C is a water-soluble antioxidant working in concert with Vitamin E.  Vitamin C must be obtained from the diet with absence creating the disease, scurvy.  Early symptoms of scurvy include fatigue resulting from lowered levels of carnitine and norepinephrine. (J Emerg Med. 2001;21:235) 

Vitamin C (Ascorbic Acid) is required for collagen synthesis, the synthesis of norepinephrine, carnitine and the conversion of cholesterol to bile acids.  The overwhelming fame of Vitamin C is associated with its role as an antioxidant for the protection of molecules from damage by free radicals and reactive oxygen species (ROS) created during metabolism and toxin exposure such as smoking creating oxidative stress.

IOP can be reduced by increasing concentrations of absorbate in the aqueous humor.  This can be done by supplementing with vitamin C (0.5 gm/kg body weight).  It has also been suggested that Intravenous Vitamin C may be of benefit in some cases.  The IOP-lowering actions of vitamin C occur by improving collagen formation, increasing blood osmolarity, improving aqueous outflow, inhibiting lipid peroxidation and raising glutathione levels. (Free Radic Biol Med  1996;21:97, Eye Ear Nose Throat Monthly  1967;46:1502, Oftalmol Zh OG 1989;8:114, Can J Physiol Pharmacol 1997;97:1149, Circulation 1998;97:2222, Acta

Ophthalmol (Copenh) 1969;47:685-689)  Vitamin C is known as a very active antioxidant that also creates an increase in IgA and IgM.  Unfortunately, Vitamin C at high levels induces some side effects such as gastric distress.

There is the suggestion that vitamin supplementation suppresses leukocyte adhesion and thus endothelial dysfunction, associated with increase in iris blood flow perfusion in diabetes. The antioxidant vitamin C may be a therapeutic agent for preventing diabetic retinopathy. (Microvasc Res 2007;74:32) Diabetes mellitus is associated with increased oxidative stress. One study suggests that supplementation with antioxidant vitamins C and E probably plays an important role in improving the constitution of the ocular surface. (Med Sci Monit 2004;10:CR213)  Regarding Vitamin C as a part of an anti-ARM formula, It has been shown that blue light could induce DNA damage to RPE cells but vitamin C could protect the RPE cells from the blue light-induced DNA damage. (Shi Yan Sheng Wu Xue Bao 2003;36:397) Regarding anterior segment, the addition of ascorbic acid to the irrigation solution significantly reduced the amount of endothelial cell loss during phacoemulsification by approximately 70%. (Invest Ophthalmol Vis Sci 2003;44:1866)  Likewise a significantly reduced mean level of ascorbic acid was observed in the aqueous humor of patients with exfoliation syndrome in one study. In view of the fact that ascorbic acid is a major protective factor against free radical action, a role for free radical action is suggested as a possible factor in the genesis of exfoliation syndrome. (Am J Ophthalmol 2002;134:879) 

The utilization of Vitamin C for the prevention of cataract has long been in the literature.  While studies continue to be controversial one study showed the risk for cataract is 60% lower among persons who use multivitamins or any supplement containing vitamin C or E for more than 10 years. However the use of vitamins for shorter duration is not associated with reduced risk for cataract (Arch Ophthalmol 2000;118:1556-63). Another study demonstrated that Vitamin C reduced the risk of cortical cataracts in women aged 60 years or less and carotenoids reduce the risk of posterior subcapsular cataract in women who have never smoked (Am J Clin Nutr 2002;75:540-9). 
Research by the Nutrition and Vision Project (NVP), a cooperative effort of Harvard and Tufts University scientists, has found that women who consume higher-than-recommended doses of vitamin C may lower their risk for more than one type of cataract (Harv Womens Health Watch 2002;9:1).

Vitamin C enhances PGE1 and thus assists in the regulation of T cell function.  Vitamin C increases killer T cell acivity and B cell function.  It also increases glutathione levels.  It is known to protect against viruses by strengthening connective tissue and neutralizing toxins released by phagocytes.  Daily supplementation of vitamin C is recommended at 500 to 1000 mg with consideration for the increased risk for kidney stones.

Potential harms of high-dose antioxidant supplementation must be considered. These may include an increased risk of lung cancer in smokers (beta-carotene), heart failure in people with vascular disease or diabetes (vitamin E) and hospitalization for genitourinary conditions (zinc). (Eye 2008 Apr 18 Epub)

Exellent Natural Sources:

Natural sources are orange and grapefruit, strawberries, tomatoes, sweet red peppers, broccoli and potatoes.

Recommendation

There is evidence to recommend supplementation of vitamin C beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.  It does appear, however, that excessive amounts are not necessary unless the diet is determined to be less than desirable.  Recent work found that vitamin C supplementation was associated with decreased odds of glaucoma but the serum levels did not correlate. (Eye (Lond). 2013 Apr;27(4):487-940)

VITAMIN D3 – OBTAIN FROM DIET BUT IN MANY CASES ADDITIONAL SUPPLEMENTATION IS NECESSARY

Vitamin D is a fat-soluble vitamin essential for promoting calcium absorption in the gut and maintaining adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling. (Am J Clin Nutr. 2004;79(3):362) Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation.  It can also be obtained from the diet, but is fat-soluble.  Sufficient vitamin D prevents rickets in children and osteomalacia in adults and, together with calcium, vitamin D helps protect older adults from osteoporosis. A quantitative meta-analysis recently concluded that at a mean daily dose of vitamin D of 528 IU there was a significant decrease in death (7% to 8%) for those using vitamin D supplement. (Arch Intern Med 2007;167(16):1709-1710) Another recent study found that 40.7% of patients with chronic migraine were deficient in 25-hydroxyvitamin D. The study also showed that the longer individuals had chronic migraine, the more likely they were to be vitamin D deficient. (American Headache Society 50th Annual Scientific Meeting: Abstract S33. Presented June 28, 2008)  The link of Vitamin D3 to glaucoma is associated with vascular perfusion issues as well as neuroprotection.  It has been estimated that 50% to 60% of people do not have satisfactory vitamin-D status, likely related to urbanization, demographic shifts, decreased outdoor activity, air pollution and global dimming, and decreases in the cutaneous production of vitamin D with age. One prospective cohort study demonstrates for the first time that low 25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D levels are associated with increased risk in all-cause and cardiovascular mortality compared with patients with higher serum vitamin-D levels. (Arch Intern Med 2008; 168:1340)

Vitamin D deficiency is widespread among patients being treated for osteoporosis, and such deficiency should be treated aggressively. (American Association of Clinical Endocrinologists 17th Annual Meeting and Clinical Congress: Abstract 520. Presented May 16, 2008)  Bariatric surgery also poses a threat regarding Vitamin D3 deficiency.  Recent reports have increased the awareness of a much broader role for vitamin D.  Vitamin D is involved in differentiation of tissues during development and in proper functioning of the immune system. Over 900 different genes are now known to be able to bind the vitamin D receptor, through which vitamin D mediates its effects. The majority of effects of vitamin D in the body are related to the activity of 1,25(OH)2D including 50 specific genes. 1,25(OH)2D also inhibits proliferation and stimulates differentiation of cells as well as having activity as an immune system modulator.  It is even suggested that 1,25(OH)2D may enhance innate immunity and protect against many autoimmune disorders. (Annu Rev Nutr. 2003;23:117, Cell Mol Biol. 2003;49:277) Evidence also continues to accumulate suggesting a beneficial role for vitamin D in protecting against autoimmune diseases, including multiple sclerosis and type I diabetes, as well as some forms of cancer, particularly colorectal and breast. (Am J Clin Nutr 2007;85:649, J Nutr 2007;137:447,  Am J Clin Nutr 2005;82:281, Neurosci Biobehav Rev 2006;30:696, Am J Clin Nutr 2007;85:931)  Most biological effects of Vitamin D are mediated through a nuclear transcription factor VDR. (J Cell Biochem. 2003;88:296, Mol Endocrinol. 2003;17:777, Nutr Rev. 2003;61:227) A recent review appearing in the FASEB Journal online and in print in April 2008, concludes that there is ample biological evidence to suggest an important role for vitamin D in brain development and function, and that supplementation for groups chronically low in vitamin D is warranted.  Since Calcium is so linked to neurodegeneration, one may hypothesize a link between Vitamin D, the immune system and the negative actions of the calcium ion.

Hypovitaminosis D, especially at levels less than 30 ng/mL, is associated with an increased risk for Myocardial Infarct in men.  Vitamin D is likely to exert its effect on the risk for cardiovascular disease via vascular smooth muscle cell proliferation, inflammation, vascular calcification, the renin-angiotensin system, and blood pressure. (J Clin Invest. 2002;110:229)  The rate of cardiovascular disease–related deaths is greater at higher latitudes, lower at higher altitudes, and higher in the winter months — all associations related to vitamin D deficiency. The vitamin D axis affects vascular smooth muscle cell proliferation, inflammation, vascular calcification, the renin-angiotensin system, and blood pressure, all of which affect cardiovascular disease and MI risk, but evidence linking hypovitaminosis D and MI is sparse. Current recommendations for vitamin D are 200 to 600 IU per day, which may be inadequate to prevent cardiovascular disease. (Arch Intern Med. 2008;168:1174)  Another recent study demonstrated that use of calcitriol in patients with stage III or IV Chronic Kidney Disease with hyperparathyroidism is associated with reduced risk for mortality and long-term dialysis and that the use of calcitriol in patients with stage III or IV CKD with hyperparathyroidism is associated with increased risk for hypercalcemia. CKD affects more than 10% of the US population with disturbances in vitamin D and mineral metabolism. (J Am Soc Nephrol. Published online May 7, 2008)

Vitamin D deficiency has been linked to a poorer outcome in breast cancer. (American Society of Clinical Oncology 2008 Annual Meeting: Abstract 511. Preview presscast, May 15, 2008)  Risk factors for Vitamin D deficiency include: dark skin, sunscreens, increasing age, gastrointestinal disorders associated with fat malabsorption, obesity, bariatric surgery, ill-advised dieting,  and a poor diet. The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women. (J Intern Med. 2006;260:245, Endocr Rev. 2001;22(4):477, JAMA. 2005;293:2257, N Engl J Med. 2006;354:669) but the issue is still very controversial.  Indeed, vitamin D3 (cholecalciferol) is now known to be greater than three times more potent than vitamin D2. (J Clin Endocrinol Metab. 2004;89:5387, Am J Clin Nutr. 2006;84:694)  In order for vitamin D supplementation to be effective in preserving bone health, adequate dietary calcium (1,000 to 1,200 mg/day) should also be consumed.  In general adults should take a supplement that supplies 400IU of vitamin D3 daily and should have 10-15 minutes of sun exposure at least three times a week as close to noon as possible.  Should sunlight exposure be unattainable, 800IU of D3 is advised.  Toxicity-hypercalcemia-can lead to bone loss, kidney stones, and calcification of the heart and kidneys.  Because the consequences of hypervitaminosis D and ensuing hypercalcemia are severe, the Food and Nutrition Board established a very conservative upper limit of 2,000 IU/day (50 mcg/day) for children and adults (National Academies Press; 1999:250) while other reports suggest 10,000IU. (Am J Clin Nutr. 1999;69:842, Am J Clin Nutr. 2006;84:18)

There is even recent work suggesting topical vitamin D3 is of benefit lowering the IOP by increasing drainage in a primate model.  (Arch Biochem Biophys. 2012 Feb 1;518(1):53-60)

Excellent Natural Sources:

Vitamin D is present in only a few foods (e.g. fatty fish), and is also added to fortified milk, but our supply typically comes mostly from exposure to ultraviolet rays (UV) in sunlight. UV from the sun converts a biochemical in the skin to vitamin D, which is then metabolized to calcitriol, its active form and an important hormone. Formation of vitamin D by UV can be 6 times more efficient in light skin than dark skin, which is an important cause of the known widespread vitamin D deficiency among African Americans living in northern latitudes.  The issue of how Vitamin D relates to the general and ocular health of individuals is evolving with research outstripping one’s ability to “keep up.”  A recent AARP magazine presented the following as cited by Michael F. Holick PhD, MD of the VitaminD, Skin and Bone Research Laboratory of Boston University Medical Center.  “To get the vitamin D value of ten minutes’ exposure to sunlight, you’d have to eat… 6 ½ pounds of shitake mushrooms or 150 egg yolks or 3 ¾ pounds of fresh farmed salmon or 30 servings of fortified cereal or 2 1/6 pounds of sardines or 30 cups of fortified orange juice.”  Do the calorie count on that exercise and realize that food sources of vitamin D actually complicate the issue.

Recommendation

There is evidence to recommend supplementation of vitamin D3 beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.  A number of health care providers are assessing vitamin D levels on their patients because of the associative health risks especially cardiovascular.  When in doubt especially in the NTG variation order the test.

VITAMIN E - OBTAIN FROM DIET AND MULTI-VITAMINS

Alpha-tocopherol is the only form of Vitamin E in the human body and is the form recommended for supplementation. Vitamin E is the body’s primary fat-soluble antioxidant and it must be obtained from food or supplements. As an antioxidant Alpha-tocopherol neutralizes free radicals then must be transformed back to Alpha-tocopherol  with the assistance of other antioxidants such as Vitamin C.  Vitamin E travels through the body in low density liporoteins which protect them from from oxidation.  Vitamin E is known to affect the expression and activity of immune and inflammatory cells, to enhance vasodilation and to inhibit the activity of the cell signaling molecule protein kinase C (PKC).  Modulating the PKC pathway may be relevant in glaucoma as PKC inhibitors relax the trabecular meshwork and affect matrix metalloproteinase and PGF2 alpha.  It has been shown that retinal vascular dysfunction due to hyperglycemia was prevented by vitamin E. (Am J Physiol 1995;269:239, Diabetes Res Clin Pract 1999;45:183)  It has also been reported that vitamin E as d-alpha tocopheryl acetate in 300 to 600 mg/day dosages improved blood flow and reduced visual field change in glaucomatous eyes. (Eur J Ophthalmol 2007;17:528)

Alpha-tocopherol at 400 to 800 IU per day is an effective antioxidant with fame in reducing the oxidation of low-density lipoproteins to prevent formation of foam cells and thus atherosclerotic plaques.  Most interest in vitamin E surrounds the cardiovascular issue.  While the studies are variable most point to the fact that vitamin E consumption is associated with some degree of risk reduction in cardiovascular disease. (Am J Epidemiol 1994;139(:1180, N Engl J Med 1993;328:1450, J Am Geriatr Soc 2001;49:651, J Am Coll Cardiol 2001;38:1788, JAMA 2005;294:56, Curr Opin Lipidol 2008;19:30)  Results of trials of intervention with vitamin E in vascular disease have been totally non-definitive. (Lancet 1996;347:781, Lancet 2000;356:1213, N Engl J Med 2000;342:154)

In the framework of diabetes, the studies are likewise inconsistent and contradictory.  (Am J Clin Nutr. 1993;57:650, Am J Clin Nutr. 1994;59:1291, Diabetes Care. 1993;16:1433, J Am Coll Nutr. 1996;15:458)  One study does however state that oral vitamin E treatment appears to be effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short disease duration without inducing a significant change in glycemic control. This suggests that vitamin E supplementation may provide an additional benefit in reducing the risks for developing diabetic retinopathy or nephropathy. (Diabetes Care. 1999;22:124)

Data from the NHANES 1999-2000 indicate that mean dietary intake of alpha-tocopherol is 6.3 mg/day and 7.8 mg/day for women and men, respectively. (Am J Epidemiol. 1999;150:290, Ann N Y Acad Sci. 2004;1031:387)  These intakes are well below the current intake recommendations of 15 mg/day.  It is estimated that more than 90% of Americans do not meet daily dietary recommendations for vitamin E. (J Am Diet Assoc. 2004;104(:567)

Alpha-tocopherol has been shown to enhance the immune system.  Additionally, it works synergistically with Omega 3 FFAs to protect cells from TNF-a induced apoptosis.  Supplementation with Vitamin E has also been shown to increase B cell activity in the aging patient. (JAMA. 2004;292:828, Proc Nutr Soc. 1999;58:697) Vitamin E also works synergistically with Vitamin C to reduce inflammatory prostaglandins and increase T cells, IL-2 and tumor necrosis factor (TNF).

In a prospective observational data from a large cohort of female health professionals, higher dietary intakes of lutein/zeaxanthin and vitamin E from food and supplements were associated with significantly decreased risks of cataract. (Arch Ophthalmol 2008;126:102)  Of interest, a recent study points to the fact that results demonstrated that there was no significant difference between the 600 mg vitamin E and placebo groups in the incidence of cataract when vitamin E was the only intervention. (Ophthalmology. 2008;115:822)  In the realm of ARMD, one study showed evidence that antioxidant (beta-carotene, vitamin C, and vitamin E) and zinc supplementation slowed down the progression to advanced AMD and visual acuity loss in people with signs of the disease, but no evidence that vitamin E or beta-carotene prevented AMD. (Eye. 2008;22:751, Cochrane Database Syst Rev. 2008;(1):CD000253, BMJ. 2007;335:755 ) Health is not a single item but rather a cornucopia of actions and these two contradictory studies point to that.

Upper levels for safety of consumption of vitamin E are established by the Food and Nutrition Board of the Institute of Medicine to minimize hemorrahage for alpha-tocopherol supplements are 1,000 mg/day of alpha-tocopherol in any form (equivalent to 1,500 IU/day of RRR-alpha-tocopherol or 1,100 IU/day of all-rac-alpha-tocopherol).  One meta-analysis reported that to reduce the risk of any disease that 2000 IU/day were necessary to reduce the risk by 6%. (Ann Intern Med. 2005;142:37)  Other studies found no evidence of the decrease of the risk of death with vitamin E supplementation. (J Gen Intern Med. 2004;19:380, Arch Intern Med. 2004;164:1552, Lancet. 2003;361:2017, JAMA. 2007;297:842)

Drug interactions must be taken into account realizing that hemorrhage at excessive dosages is a potential issue.  Any pharmaceutical agents, foods or supplements such as gingko biloba should raise the caution of interaction.

Scientists at the Linus Pauling Institute in Oregon feel there exists credible evidence that taking a supplement of 200 IU (134 mg) of natural source d-alpha-tocopherol (RRR-alpha-tocopherol) daily with a meal may help protect adults from chronic diseases, such as heart disease, stroke, neurodegenerative diseases, and some types of cancer. The amount of alpha-tocopherol required for such beneficial effects appears to be much greater than that which could be achieved through diet alone. ((lpi.oregonstate.edu)  A 2010 report states that in the rat model a vitamin E deficient diet resulted in increase RGC death related to increase levels of lipid peroxidation.  (Curr Eye Res. 2010 Sep;35(9):842-9)

Excellent Natural Sources:

Natural sources of alpha-tocopherol include olive oil, sunflower oil, nuts, whole grains, green leafy vegetables but usually provide less than the RDA of 15 mg/day of RRR-alpha-tocopherol. (National Academy Press; 2000:186) Supplements made from entirely natural sources contain only RRR-alpha-tocopherol (also labeled d-alpha-tocopherol). RRR-alpha-tocopherol is the isomer preferred for use by the body, making it the most bioavailable form of alpha-tocopherol.  Synthetic alpha-tocopherol is less bioavailable and only half as potent.  The formulas for conversion to the RRR form are:

$1·         RRR-alpha-tocopherol (natural or d-alpha-tocopherol):


$1o   IU x 0.67 = mg RRR-alpha-tocopherol

$1·         all-rac-alpha-tocopherol (synthetic or dl-alpha-tocopherol): 


$1o   IU x 0.45 = mg RRR-alpha-tocopherol. 


Recommendation

There is some evidence to recommend supplementation of vitamin E beyond that obtained in the normal diet for minimizing the risk of glaucoma damage but it can be obtained in a good multivitamin.  There are, however, potential risks associated with excessive consumption of vitamin E especially in patients on anti-coagulants.

Hyperhomocysteinemia as a Systemic and Ocular Risk Factor

Hyperhomocysteinemia, Normal Tension Glaucoma, Blood Flow Anomalies and Optic Neuropathy have a lot in common and are often related to supplementation with Vitamins B6, B12 and Folic Acid.  Recent publications have defined a relationship between plasma total homocysteine and POAG but there was no defined relationship to serum folic acid, B12 or B6. (Ophthalmology. 2012 Dec;119(12):2493-9, Curr Eye Res. 2012 Aug;37(8):712-8.) To further complicate the conclusions two years prior to this report there was found to be no association of elevated homocysteine levels in normal tension glaucoma. (J Glaucoma. 2010 Dec;19(9):576-80) Yet other findings demonstrated a relationship of elevated homocysteine only in pseudoexfoliative glaucoma and not normal tension or open angle glaucoma. (Clin Interv Aging. 2010 Apr 26;5:133-9, Graefes Arch Clin Exp Ophthalmol. 2012 Jul;250(7):1067-74, Graefes Arch Clin Exp Ophthalmol. 2011 Mar;249(3):443-8)

VITAMIN B6 – PYRIDOXINE - OBTAIN FROM DIET AND MULTI-VITAMINS

Vitamin B6 is a water-soluble vitamin discovered in 1930 during nutrition studies on rats. It must be obtained from the diet or from supplements because humans cannot synthesize Vitamin B6.  It is critical in the function of many enzymes and the genesis of hemoglobin as well as interacting with gene expression influencing platelet aggregation.  Vitamin B6 is critical in maintenance of the thymus and thus the integrity of the immune system.  Magnesium is a cofactor necessary in the proper absorption of vitamin B6.  More than 100 enzymatic functions depend on the adequate presence of vitamin B6. The Linus Pauling Institute recommends that all adults consume at least 2.0 mg of vitamin B6 daily.

An added note is that coincidental supplementation with folic acid reduces the risk of hyperhomocystenemia and thus cardiovascular disease in prone individuals. (J Nutr. 2000;130:3090)  Most individuals employ two different pathways to metabolize homocysteine. One converts homocysteine back to methionine and is dependent on folic acid and vitamin B12.  The other pathway converts excess homocysteine to the amino acid cysteine, which the kidneys flush from the body. This metabolism requires three B vitamin-dependent enzymes, made up of B6, B12 and folate. It has been suggested that the B vitamin, choline and it's metabolite, betaine, are also players in this sophisticated metabolic process. (Am J Clin Nutr 1991;53:1275, JAMA 1995;274:1049, JAMA 1998;279:359, Circulation 1998;98:204, Circulation 1998;97:437, Circulation 1995;92:2825, Nutrition 2006;22:1146, J Nutr 1994;124:1927)  One study reports reduced oscillatory potentials suggesting microvascular damage to the retina through homocysteine. Decreased photoreceptor function as well as ganglion cell loss as indicated by pathological flash VEPs may reflect a cytotoxic impact of homocysteine on neurons of the visual pathway. (Graefes Arch Clin Exp Ophthalmol. 2005;243:49)

The phosphate ester derivative pyridoxal 5-phosphate (PLP) is the principal coenzyme form of vitamin B6 and has the most importance in human metabolism. (Present Knowledge in Nutrition. Vol. I. Washington, D.C.: International Life Sciences Institute; 2006:269, Handbook of Vitamins. New York: Marcel Decker Inc; 1991:341)  Vitamin B6 deficiency has been associated with impaired immune function, especially in the elderly, because production of immune system white blood cells called lymphocytes, and an anti-inflammatory protein called interleukin-2 (IL-2) are dependent on vitamin B6 intake.

In the brain, the synthesis of the neurotransmitter, serotonin, from the amino acid, tryptophan, is catalyzed by a PLP-dependent enzyme. Other neurotransmitters, such as dopamine, norepinephrine and gamma-aminobutyric acid (GABA), are also synthesized using PLP-dependent enzymes. ( Modern Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413)

Gyrate atrophy of the retina and choroid is a rare autosomal recessive inherited disease, characterized by progressive chorioretinal atrophy that results in progressive deterioration of peripheral and night vision and leading to blindness and is related to hyperornithemia. The exact mechanism of chorioretinal atrophy in hyper-ornithinemia is not known and a small percentage of the affected people respond to Vitamin B6 supplementation. (J Med Case Reports. 2007;1:27)

It is also recognized that Vitamin B6 is an important co-factor in stimulating the neurotransmitters associated with the blink response and the tear production as well as being a major co-factor in both Omega-6 and Omega-3 fatty acid metabolism.  As such, B6 plays a role in maintenance of a healthy tear system.

Vitamin B6 also affects steroid hormones by binding to receptors and inhibiting inappropriate signaling of steroid hormones.  There are suggestions that B6 deficiency may be implicated in breast cancer and prostate cancer. (Mutat Res 2001;475:7)  Recent studies suggest that women who take birth control pills are almost always deficient in vitamin B6. (Am J Clin Nutr 2008;87:1446)

Excellent Natural Sources: 

Baked potato with skin, bananas, salmon, chicken with no skin, spinach, avocado, turkey without skin

Recommendation

There is some evidence to recommend supplementation of vitamin B6 beyond that obtained in the normal diet for minimizing the risk of glaucoma damage but it can be obtained in a good multivitamin.  The relationship is primarily through hyperhomocysteinemia.

FOLIC ACID - OBTAIN FROM DIET AND MULTI-VITAMINS

Folic acid and folate are terms used interchangeably for this water-soluble B complex vitamin but folic acid is the more stable form that occurs only rarely in foods or in the body.  Folate is the form usually found in foods and the human body.  (National Academy Press; 1998:193)  Folate coenzymes mediate the transfer of one-carbon units in a number of reactions critical to the metabolism of nucleic acids and amino acids and play a vital role in DNA metabolism through two different pathways. Those pathways are 1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes. 2) A folate coenzyme is required for the synthesis of methionine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). (J Nutr. 1999;129:779) The synthesis of methionine from homocysteine requires the folate coenzyme as well as a vitamin B12-dependent enzyme.

Folate deficiency can result in decreased synthesis of methionine and a buildup of homocysteine.  Folic Acid is related to homocysteine levels and elevated homocysteine levels and decreased folic acid levels are related to a number of conditions including dementia. Deficiencies may triple the risk of dementia in the elderly. (February 5 2008 Early Release Online Article issue of the Journal of Neurology, Neurosurgery, and Psychiatry)  Vascular disease and elevated homocysteine increase risk for both late-onset depression and Alzheimer's disease and may partly mediate their relationship. (Curr Opin Psychiatry 2006;19:581)  Several investigators have described associations between decreased folate levels and cognitive impairment in the elderly. (Am J Clin Nutr. 2000;71:859, Am J Clin Nutr. 2000;71:993, Arch Neurol. 2007;64:86, Alzheimers Dis. 2006;9:435, Arch Neurol. 2005;62:641)  In a sample of 1,092 men and women without dementia followed for an average of ten years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia ( N Engl J Med. 2002;346:476). Those with plasma homocysteine levels greater than 14 micromoles/liter had nearly twice the risk of developing Alzheimer's disease.

The most well-recognized complication of folate deficiency is neural tube defects-anacephaly or spina bifida-in pregnancy.  Randomized trials demonstrated 60% to 100% reductions in neural tube defects when women consumed folic acid supplements in the periconceptional period.  In 1998 there was even FDA legislation mandating folate fortification of all enriched grain products.  Unfortunately, compliance is less than ideal resulting in a continuation of a preventable disorder. (Am J Clin Nutr. 2000;71:1308S)

Observational studies have found that relatively low folate intake and high alcohol intake are associated with increased incidence of colorectal cancer. (Ann Epidemiol. 2001;11:65, Int J Cancer. 2002;97:864)  While dietary folate may be protective against colorectal cancer, high doses may actually accelerate tumor growth in cancer patients with colorectal adenoma.  (JAMA. 2007;297:2351)  Obviously more research must be performed in this area with better controls for collateral factors. One study reported that women consuming at least one alcoholic drink per day, with folic acid intake of at least 600 mcg daily had about half the risk of breast cancer compared with women who consumed less that 300 mcg of folic acid daily. (JAMA. 1999;281:1632)

Folate deficiency is related to dietary insufficiency, which may be also associated with malabsorption issues.  Drug interactions may also contribute to deficiencies.  NSAIDs in therapeutic dosages may interfere with folate metabolism.  Long term use of anticonvulsants, phenytoin, phenobarbital, and primidone inhibits absorption. (Epilepsy Res. 2001;47:27) Anti-cholesterol agents may also decrease absorption of folate.  (PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001)  Methotrexate is a folic acid antagonist which simulates folate deficiency and there is a report of presumed methotrexate induced optic neuropathy reversed with folate supplementation. (J Neuroophthalmol. 2005;25:109)  Trimethoprim, pyrimetamine, triamterene and sulfasalazine may likewise affect absorption.

The Linus Pauling Institute recommends that adults take a 400 mcg supplement of folic acid daily. A supplement regimen of 400 mcg of folic acid, 2 mg of vitamin B6, and 6 mcg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet is not successful in adequately lowering homocysteine levels. (Circulation 1999;99:178)  Maximum dosages should not exceed 1 mg/day and all folic acid should be consumed with B12 and B6 to maximize effect and minimize toxicity.

Recently the Food and Nutrition Board of the Institute of Medicine set the new dietary recommendation for folate, introducing a new unit, the Dietary Folate Equivalent (DFE). Implementation of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified foods compared to that of naturally occurring food folates. (Nutr Rev. 1998;56(10):294)  For example: 1 microgram (mcg) of food folate provides 1 mcg of DFE, while 1 mcg of folic acid taken with meals or as fortified food provides 1.7 mcg of DFEm and 1 mcg of folic acid (supplement) taken on an empty stomach provides 2 mcg of DFE. 

Excellent Natural Sources:

Natural sources of folate include green leafy vegetables (spinach, asparagus), citrus fruit juices, legumes, fortified cereals and grain products.

Recommendation

There is some evidence to recommend supplementation of folic acid beyond that obtained in the normal diet for minimizing the risk of glaucoma damage but it can be obtained in a good multivitamin.  The relationship is primarily through hyperhomocysteinemia.

VITAMIN B-12 -  COBALAMIN - OBTAIN FROM DIET AND MULTI-VITAMINS

Vitamin B12 is water-soluble and has the most complex chemical structure of all the vitamins. Vitamin B12 contains a metal ion, cobalt and as such cobalamin is the term used to refer to compounds having vitamin B12 activity. (Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999)  The form of cobalamin used in most supplements, cyanocobalamin, is readily converted to 5-deoxyadenosyl and methylcobalamin in the body. In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-CoA mutase   (Modern Nutrition in Health and Disease. Philadelphia: Lippincott Williams & Wilkins; 2006:487) Methylcobalamin is necessary for the function of the folate-dependent enzyme, methionine synthase. This enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine in turn is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA ( Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483)

Vitamin B12 deficiency is estimated to affect 10%-15% of individuals over the age of 60. Associations with vitamin B12 deficiency are: 1) an autoimmune condition known as pernicious anemia and 2) food-bound vitamin B12 malabsorption. Although both causes become more common with increasing age, they are separate conditions. (Ann Rev Nutr 1999;19:357)  Absorption of vitamin B12 from food requires normal function of the stomach, pancreas, and small intestine.  Malabsorption may be associated with issues such as alcoholism and even bariatric surgery. While most address the necessity of avoidance of oral treatment of pernicious, high-dose oral therapy is considered to be as effective as intramuscular injection(Blood 1998;92:1191, JAMA 1991;265:94, JAMA 1991;265:96, Lancet 1998;352:1721)

Although vitamin B12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurological damage in B12 deficiency are not well understood. Individuals with Alzheimer's disease often have low blood levels of vitamin B12. One study found lower vitamin B12 levels in the cerebrospinal fluid of patients with Alzheimer's disease than in patients with other types of dementia, though blood levels of vitamin B12 did not differ. (Am J Clin Nutr 2000;71:643S) Vitamin B12 has demonstrated value in improving retinal function in POAG.  Vitamin B12 exerts protective action on glutamate-induced neurotoxicity at the site of the retinal neurons.  The signs of nitric oxide neurotoxicity are similar to the nerve impairment and symptoms of a vitamin B12 deficiency that include retinal degeneration and visual loss. (Oftalmol Zh 1965;20(6):461-2) (Klin Oczna 1974;44(11):1183-7) (Neurology 1995;45(1):11-6) (Medicine 1991;70(4):229-45) (Blood 1996;88(5):1857-64) (Eur J Pharmacol 1995;281(3):335-40) There are many neurological manifestations of vitamin B(12) deficiency. Optic neuropathy is a rare, but important, manifestation of vitamin B(12) deficiency that should be suspected in patients with risk factors for malnutrition. Vitamin B(12) optic neuropathy is a reversible, treatable cause of vision loss and may be a harbinger for other manifestations of the disease. (Eur J Intern Med 2005;16:447)

Because vitamin B12 mal-absorption and vitamin B12 deficiency are more common in older adults, some respected nutritionists recommend that adults older than 50 years take 100 to 400 mcg/day of supplemental vitamin B12, an amount provided by a number of vitamin B-complex supplements.

Excellent Natural Sources:

Clams, mussels, crab, salmon, rockfish are excellent sources of B12 with beef, chicken, turkey, egg and milk products providing a source as well.

Recommendation

There is some evidence to recommend supplementation of vitamin B12 beyond that obtained in the normal diet for minimizing the risk of glaucoma damage but it can be obtained in a good multivitamin.  The relationship is primarily through hyperhomocysteinemia.

Note on Thiamin (B1).  Thiamin has been found to be deficient in some patient with glaucoma.  (Asregadoo ER. Blood levels of thiamine and ascorbic acid in chronic open-angle glaucoma. Ann Ophthalmol 1979;11:1095-1100.)

MAGNESIUM - OBTAIN FROM DIET AND MULTI-VITAMINS

Magnesium is a mineral and is very short acting. It is considered critical to the maintenance of health but appears to have no direct measurable effect in the management of glaucoma.  The majority of magnesium is within the skeleton, with about ¼ in muscle and it is involved in more than 300 essential reactions within the body. (Am Coll Nutr. 1994;13:479)  Magnesium is involved in glutathione production, cell membrane genesis and chromosome activity.  As related to cellular mechanism, magnesium is critical in ion transport across cell membranes, e.g. in the neurodegeneration model.  Magnesium acts as a smooth muscle relaxant, partially inhibits the effect of endothelin, and is a calcium channel blocker, and as such often acts as a vasodilator and improves peripheral circulation. (Circulation. 2000;102:2353, Graefes Arch Clin Exp Ophthalmol 1998;236:47, Am J Cardiol. 1999;84:152, Ophthalmologica 1995;209:11)  Some studies suggest that magnesium plays a role in hypertension and cardiovascular disease but there is no definitive work to underscore the recommendations for intervention. (Am J Cardiol. 2005;96:1135, Circulation. 1992;86:1475, Am Heart J. 1998;136:480, Hypertension. 1996;27:1065, Ann Epidemiol. 1999;9:159, Epidemiol Rev. 1997;19:258, Arch Biochem Biophys. 2007;458:33, Hypertens. 2006;24:215, Cochrane Database Syst Rev. 2007;(2):CD002755)  Magnesium is very involved in the ATP-synthesizing protein in mitiochondria. (Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:223-247Magnesium seems to have a beneficial effect on the visual field in glaucoma patients with both increased and normal IOP--possibly by alleviating vasospasm at 300 mg/day.  Magnesium also works to activate enzymatic systems. (Ophthalmologica 1995;209(1):11-3) (Surv Ophthalmol 1995;209(1):83-4)  Magnesium does not directly influence immune function but rather is critical in 300 enzymatic functions in the body.  Magnesium deficiency causes an increase in pro-inflammatory cytokines and an excess production of free radicals. 

Magnesium depletion is commonly associated with both insulin dependent (IDDM) and non-insulin dependent (NIDDM) diabetes mellitus. Between 25% and 38% of diabetics have been found to have decreased serum levels of magnesium (hypomagnesemia) perhaps associated with urinary issues. (Arch Intern Med. 1996;156:1143).  It is suggested but not proven that magnesium supplementation may be beneficial in patients with diabetes.  (Diabetes Care. 2003;26:1147, Diabet Med. 2006;23:1050, J Am Coll Nutr. 2004;23:506S)

From a neurological standpoint, persons with recurrent migraines have lower magnesium levels. (Clin Neurosci. 1998;5(1):24)  Supplementation to alleviate the headaches has produced conflicting results and the levels of supplementation result in side effects. (Headache. 2003;43:601, Cephalalgia. 1996;16:436)

Magnesium absorption is impaired by a low protein diet, a high fiber diet, and excesses in zinc consumption, GI disorders, bariatric surgery renal disorders, chronic alcoholism, increasing age. (Am J Clin Nutr. 1973;26:510)  Magnesium can interact with digoxin, anti-malarials, some drugs to treat osteoporosis,, tranquilizers, oral anticoagulants and some antibiotics. In seriously ill patients, the primary care physician should be consulted.

Consumption of magnesium in the US is considered lower than the RDA.  Recommended daily dosage is 420 mg/day for men over 30 and 320 mg/day for women over 30 years of age.  The recommended supplement is 100 mg/day assuming some dietary consumption of magnesium. The tolerable upper level of intake (UL), which is 350 mg/day set by the Food and Nutrition Board.

Excellent Natural Sources:

Natural sources of magnesium are cereals, brown rice, nuts, beans, spinach, chard, okra and bananas.

Recommendation

There is no evidence to recommend supplementation of magnesium beyond that obtained in the normal diet for minimizing the risk of glaucoma damage.

Note on Chromium.  A deficiency of chromium has been implicated in increased IOP in humans and patients with primary open-angle glaucoma. (Lane BC. Evaluation of intraocular pressure with daily, sustained closework stimulus to accommodation, lowered tissue chromium and dietary deficiency of ascorbic acid. Doc Ophthalmol 1980;28:149-155.)

ZINC - OBTAIN FROM DIET AND MULTI-VITAMINS

Zinc is an essential trace element for the proper functioning of a number of human systems.  Zinc is critical for 100 different enzymes relevant to their catalytic role. (National Academy Press; 2001:442)  Zinc is also critical in the structure of proteins and cell membranes. Cell membranes are susceptible to oxidative damage with loss of zinc. (J Nutr. 2000;130:1432S) Zinc also has a role in gene expression acting in the role of transcription factors as well as having responsibilities in cell signaling.  Zinc also plays a role in apoptosis. (J Nutr. 2000;130(5S Suppl):1459S) 

Zinc served the role as the entry point for eye care into the realization of the importance of nutrition in ocular health.  Use in the management of macular degeneration has resulted in mixed reports. (Arch Ophthalmol. 1988;106:192, Am J Epidemiol. 1998;148:204, Ophthalmology. 1999;106:761, Ann Epidemiol. 2001;11:328, Invest Ophthalmol Vis Sci. 1996;37:1225, Arch Ophthalmol. 2001;119:1417, Cochrane Database Syst Rev. 2002;1:CD000254, Cochrane Database Syst Rev. 2006;2:CD000254)  The element is, however, a part of the AREDS recommendation.  When speaking to commercially available vitamin supplements it should be noted that zinc at 80 mg/day resulted in increase genitourinary hospital admissions in the AREDS study. (J Urol 2007;177:639) It has also been found that based on the evidence it is suggest that zinc plays a role in sub-RPE deposit formation in the aging human eye and possibly also in the development and/or progression of AMD. (Exp Eye Res 2007;84:772)

Large quantities of zinc interfere with copper bioavailability by inducing intestinal sysnthesis of metallothionein, which traps copper.  (Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:271-285)  This action may then lead to cupric anemia.  Zinc consumption must be accompanied by copper supplementation.  Iron supplementation and calcium combined with phytic acid (limes) may also decrease the availability of zinc. (Br J Nutr. 2001;85:S181) Zinc is required for the enzyme that converts retinol (vitamin A) to retinal. Zinc deficiency is associated with decreased release of vitamin A from the liver, which may contribute to symptoms of night blindness that are seen with zinc deficiency. (J Nutr. 2000;130:1344S, Am J Clin Nutr. 1998;68:435S)  High doses of zinc also impact negatively in the absorption of magnesium. (J Am Coll Nutr. 1994;13:479)

Zinc is important in the immune system and has gained much press in regard to the prevention of colds and respiratory disease especially as related to children.  (J Pediatr. 1999;135:689, Nutr. 2000;130:1421S, Am J Clin Nutr 1998;68:447S, J Am Geriatr Soc. 1998;46:19) A recent meta-analysis of published randomized controlled trials on the use of zinc gluconate lozenges in colds found that evidence for their effectiveness in reducing the duration of common colds was still lacking. (J Nutr. 2000;130:1512S)  Use of intranasal zinc is also of questionable value. (Clin Infect Dis. 2001;33:1865, Am J Med. 2001;111:103)  There are also implications regarding diarrhea with The World Health Organization and the United Nations Children's Fund currently recommending zinc supplementation as part of the treatment for diarrheal diseases in young children. (The United Nations Children's Fund/World Health Organization. WHO/UNICEF Joint Statement: Clinical Management of Acute Diarrhoea. Geneva; New York; 2004:1-8)

Zinc picolinate has been promoted as a more absorbable form of zinc, but there are few data to support this idea in humans. In order to prevent copper deficiency, the U.S. Food and Nutrition Board set the tolerable upper level of intake (UL) for adults at 40 mg/day, including dietary and supplemental zinc. (National Academy Press; 2001:442-501)  The recommendation for zinc is to take a multivitamin supplement containing 100% of the daily values (DV) of most nutrients will generally provide 15 mg/day of zinc.  Use of zinc may decrease the absorption of tetracyclines and quinolones so an interval of two hours is appropriate. (Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons, 2000:27-51)

Excellent Natural Sources:

Natural sources of zinc include crab, oysters, beef, pork, dark meat chicken and turkey, yogurt, cheese, milk, cashews, almonds, peanuts, and beans. 

Recommendation

There is no evidence to recommend supplementation of zinc beyond that obtained in the normal diet or a good multivitamin for minimizing the risk of glaucoma damage.  There are, however, potential risks associated with excessive consumption of zinc.

SELENIUM - OBTAIN FROM DIET AND MULTI-VITAMINS

Selenium is a trace element that is critical to the maintenance of health but can be toxic, like zinc, at higher levels.  As with zinc, selenium is important in the action of enzymes for the development of proteins and in the actions of the thyroid gland.  (Lancet. 2000;356:233)  Selenium is an effective free radical scavenger that is essential to the production of glutathione peroxidase. (Selenium: Its molecular biology and role in human health. 2nd ed. New York: Springer; 2006:99) Glutathione peroxidase rids the body of environmental toxins. Selenium as gluthathione peroxidase also appears to support the activity of vitamin E (a-tocopherol) in limiting the oxidation of lipids. (J Nutr. 1991;121:258)  Selenium is important in immune function. (Selenium: Its Molecular Biology and Role in Human Health. 2nd ed. New York: Springer; 2006:311)  Deficiency reduces the activity of T cell activity and antibody production.  Selenium supplementation increases IL-2 while reducing inflammatory prostaglandins and leukotrienes. (Biol Trace Elem Res. 1994;41:103, Biol Trace Elem Res. 1994;41:115)  A double-blind, placebo-controlled study of more than 1,300 older adults with a history of non-melanoma skin cancer found that supplementation with 200 mcg/day of selenium-enriched yeast for an average of 7.4 years was associated with a 49% decrease in prostate cancer incidence in men. (BJU Int. 2003;91(7):608) One study indicates that selenium supplementation increased the risk of one type of skin cancer (squamous cell carcinoma) by 25% (J Natl Cancer Inst. 2003;95:1477) but did not significantly decrease the risk of lung cancer. (Cancer Epidemiol Biomarkers Prev. 2002;11:1285)  Selenium supplementation has also been suggested for decreasing the risk of cardiovascular disease by decreasing lipid peroxidation.   Strong clinical support does not, however, exist at this point. (Am J Epidemiol. 1997;145:373)  In regards to diabetes one study in 1,202 men and women participating in the Nutritional Prevention of Cancer trial found that selenium supplementation (200 mcg/day; mean follow-up of 7.7 years) was linked to an increase in prevalence of type 2 diabetes. (Ann Intern Med. 2007 Aug 21;147:217)  Considering HIV, a trial in 174 HIV-1-positive individuals reported that selenium supplementation (200 mcg/day of selenium-enriched yeast) for nine months was associated with increased serum selenium concentrations, increased CD4 T cell counts, and no progression of the HIV-1 viral load. (Arch Intern Med. 2007;167:148)

High dosages of selenium can be very toxic.  Selenosis may occur cumulatively with small doses-hair and nail brittleness and loss.  Supplements may provide selenium but selenate and selinite absorption rates are unpredictable. Selenomethionine that occurs naturally in foods, is about 90% absorbed. (National Academy Press; 2000:284) Recommended dosages are 100-200 mcg/day. Eating a varied diet and taking a daily multivitamin supplement should provide sufficient selenium for most people in the U.S.  The Food and Nutrition Board (FNB) of the Institute of Medicine recently set the tolerable upper intake level (UL) for selenium at 400 mcg/day in adults based on the prevention of hair and nail brittleness and loss and early signs of chronic selenium toxicity.

Excellent Natural Sources:

Food sources of selenium are organ meats, seafood and muscle meats.  Brazil nuts and enriched grains may provide selenium if grown in appropriate soil conditions.

Recommendation

There is no evidence to recommend supplementation of selenium beyond that obtained in the normal diet or a good multivitamin for minimizing the risk of glaucoma damage.  There are, however, potential risks associated with excessive consumption of selenium.

FATTY ACIDS AND GLAUCOMA

Prologue

Ren demonstrated that POAG patients have reduced levels of blood DHA and EPA. (Prostaglandins Leukot Essent Fatty Acids. 2006 Mar;74(3):157-63.)  Acar showed that POAG patients had reduced erythrocyte levels of phosphatidyl-choline carrying docosahexaenoic acid. (Exp Eye Res. 2009 Dec;89(6):840-53)  Nguyen et al demonstrated that an increased consumption of omega-3 fatty acids leads to decreased IOP through an increased aqueous outflow facility. The exact mechanism of the aqueous outflow increase is proposed to be through the actions of prostaglandins (PGs), which are metabolites of omega-3 fatty acids. These prostaglandins are purported to reduce IOP by enhancing uveoscleral and trabecular outflow via direct effects on ciliary muscle relaxation and remodeling of extracellular matrix. (Invest Ophthalmol Vis Sci. 2007;48(2):756–762., FASEB J. 1992;6(8):2530–2536., FASEB J. 1992;6(8):2530–2536.)  Likewise, blood flow issues have been related to glaucoma and fatty acids may impact positively on that issue.  This appears to be the result of decreasing synthesis of very low density lipoprotein, changing red cell deformability and lowering viscosity by altering the protein pattern of the plasma. (Br J Ophthalmol. 1994;78(6):449–453. , Clin Pharm. 1988;7(11):795–807., J Intern Med Suppl. 1989;225(731):129–132.)  Apparently there is also the positive effect on retinal nerve fiber layer architecture. (Graef Arch Clin Exp Ophthalmol. 2009;247(9):1191–1203., Ann Ottalmol Clin Ocul. 1999;125(11-12):329–338., Acta Ophthalmol Scand Suppl. 1999;77(229):54–55.)

While the issue of fatty acids is certainly controversial at this point, research must be addressed relating the consumption of tatty acids and/or supplementation of fatty acids is critical to the any relationship to glaucoma.

Essential Fatty Acids as Related to Health

Alpha-linolenic acid (ALA) an omega-3 fatty acid, and linoleic acid (LA) an omega-6 fatty acid, are considered essential fatty acids because they cannot be synthesized by humans.  They are essential for life and must be consumed.  There is considerable confusion regarding the fatty acids as related to the sustainment of health.  The long-chain omega-6 fatty acid, arachidonic acid (AA) can be synthesized from LA.  The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be synthesized from ALA, but EPA and DHA synthesis may be insufficient under certain conditions as often omega-6 are out of balance with the omega-3s.

Typical Western diets tend to be much higher in omega-6 fatty acids than omega-3 fatty acids, which are polyunsaturated fatty acids, and proper proportions are usually offered as ratios. It is estimated that 83% of Americans are deficient in the balance of Omega 3s.  In contrast Omega 6 essential fatty acids are over-abundant in the diet Omega 3 to Omega 6 being 1:10, with the ideal Omega 3 to Omega 6 ratio being 1:1 or 1:2 largely the result of increased consumption of vegetable oil. (Prostaglandins Leukot Essent Fatty Acids. 2000;63(3):119-121, Circulation. 2002;106(21):2747-2757)  The disproportion set up allows for an imbalance in developmental aspects of tissues as well as fostering the proliferation of more “bad” than “good” prostaglandins in the inflammatory cascade.

Omega-6 and omega-3 polyunsaturated fatty acids are important structural components of cell membranes.  The phospholipids affect cell membrane properties such as fluidity, flexibility, permeability and the activity of membrane bound enzymes. (Chem Phys Lipids. 2003;126(1):1-27)    DHA is found in very high concentrations in the cell membranes of the retina, which conserves and recycles DHA even when omega-3 fatty acid intake is low. (Chem Phys Lipids. 2003;126(1):1-27) Recent research indicates that DHA plays an important role in the regeneration of the visual pigment rhodopsin. (Prog Retin Eye Res. 2005;24(1):87-138) The phospholipids within the gray matter of the brain contain high proportions of DHA and AA, suggesting importance in central nervous system function. (J Pediatr. 2003;143(4 Suppl):S1-8)   Another study showed that eating fish oil (oily fish including mackerel, tuna, salmon, sardines and herring) at least once a week is linked to a reduced risk for neovascular age-related macular degeneration.  This is being further investigated in the ongoing AREDSS2 study. (Am J Clin Nutr 2008 Aug;88(2):398-406)

Most studies point to the importance of balance of essential free fatty acids in ocular and neurological development.  Two new studies have shown that Omega-3 fatty-acid supplementation improves morbidity and mortality in symptomatic heart-failure patients, while statins failed to have any beneficial effect in the same group of patients. (Lancet. 2008 Oct 4;372(9645):1231-9. Epub 2008 Aug 29, Lancet. 2008 Oct 4;372(9645):1195-6. Epub 2008 Aug 29.)

One report indicates that increasing intakes of long-chain omega-3 fatty acids (EPA and DHA) can decrease the risk of cardiovascular disease by 1) preventing arrhythmias that can lead to sudden cardiac death, 2) decreasing the risk of thrombosis that can lead to MI or stroke, 3) decreasing serum triglyceride levels, 4) slowing the growth of atherosclerotic plaque, 5) improving vascular endothelial function, 6) lowering blood pressure slightly and 7) decreasing inflammation. (Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):151-2. Review)

Many reports show men who eat fish at least once weekly have lower mortality from CHD than men who do not eat fish. (N Engl J Med 1985 May 9;312(19):1205-9, Int J Epidemiol. 1995 Apr;24(2):340-5, World Rev Nutr Diet. 1991;66:205-16)  One such study followed 1822 men for 30 years and found that mortality from CHD was 38% lower in men who consumed an average of at least 35 g (1.2 oz) of fish daily than in men who did not eat fish, while mortality from MI was 67% lower. (N Engl J Med. 1997 Apr 10;336(15):1046-53)   In the Nurses’ Health Study, following over 84,000 women for 16 years, CHD mortality was 29-34% lower in women who ate fish at least once a week compared to women who ate fish less than once a month. (JAMA. 2002 Apr 10;287(14):1815-21)  Epidemiological studies suggest that regular fish consumption is inversely associated with the risk of sudden cardiac death. (N Engl J Med. 2002 Apr 11;346(15):1113-8)  Another prospective study that followed more than 45,000 men for 14 years found that the risk of sudden cardiac death was about 40-50% lower in those who consumed an average of at least 250 mg/day of dietary EPA + DHA, the equivalent of 1-2 oily fish meals weekly, than those who consumed less than 250 mg/day. (Circulation. 2005 Jan 18;111(2):157-64)

When referencing the impact on the incidence of stroke, two large prospective studies found that increased fish and omega-3 fatty acid intakes were associated with significantly lower risks of ischemic stroke, but not hemorrhagic stroke. In a study that followed more than 79,000 women for 14 years, those who ate fish at least twice weekly had a risk of thrombotic (ischemic) stroke that was 52% lower than those who ate fish less than once monthly. (JAMA. 2001 Jan 17;285(3):304-12)  Likewise another study that followed more than 43,000 men for 12 years, those who ate fish at least once monthly had a risk of ischemic stroke that was 43% lower than those who ate fish less than once monthly. (JAMA. 2002 Dec 25;288(24):3130-6)

The triglyceride-lowering effects of EPA and DHA increase with dose, but clinically meaningful reductions in serum triglyceride concentrations have been demonstrated at larger doses of 2 g/day of EPA + DHA. (Circulation. 2002 Nov 19;106(21):2747-57, Diabetes Care. 2000 Sep;23(9):1407-15)  Increasing EPA and DHA intake may be beneficial to individuals with diabetes, especially those with elevated serum triglycerides while randomized controlled trials have found that fish oil supplementation decreases joint tenderness and reduces the requirement for anti-inflammatory medication in rheumatoid arthritis patients. (J Clin Epidemiol. 1995 Nov;48(11):1379-90, Am J Clin Nutri  2000 Jan;71(1 Suppl):349S-51S)  The American Diabetes Association recommends that diabetic individuals increase omega-3 fatty acid consumption by consuming two to three 3-oz servings of fish weekly. (Diabetes Care January 2008 vol. 31 no. Supplement 1 S61-S78)

There is also an association with the control of inflammatory bowel disease, ulcerative colitis and Crohn’s disease. (J Intern Med Suppl. 1989;731:225-32, Scand J Gastroenterol. 1996 Aug;31(8):778-85, N Engl J Med. 1996 Jun 13;334(24):1557-60, Am J Gastroenterol 1992 Apr;87(4):432-7, Ann Intern Med. 1992 Apr 15;116(8):609-14, Dig Dis Sci. 1996 Oct;41(10):2087-94)  One recent study also suggests that there may be a beneficial effect of low-dose dietary polyunsaturated free fatty acids on vascular function and disease activity in SLE. (Ann Rheum Dis. 2008 Jun;67(6):841-8) Although limited preliminary data suggests that omega-3 fatty acid supplementation may be beneficial in the therapy of depression, bipolar disorder and schizophrenia, larger controlled clinical trials are needed to determine their efficacy. (Prostaglandins Leukot Essent Fatty Acids. 2005 Mar;72(3):211-8, Am J Psychiatry. 2003 May;160(5):996-8, Am J Psychiatry. 2003 Jan;160(1):167-9)

Omega 3 Fatty acids have many effects including modulation of intracellular calcium ion release. (Cardiovasc Drugs Ther 1992;6:605)  Omega 3 FFAs also increase the production of uncoupling proteins and thereby improve ATP independent heat production, which is most probably impaired in patients with vaso dysregulation. (J Nutr 2001;131:2636, Biochem Biophys Res Commun 1999;259:85)  Omega 3 FFAs can improve vascular regulation as a result of flow-mediated vasodilation properties. (Acta Ophthalmol Scand Suppl 1998;41, Eur J Pharmacol 1992;215:325)     Cacao has the same reported properties. (Nutr Rev 2006;64:109, JAMA 2003;290:1030, J Agric Food Chem 1999;47:4821, Hypertension 2005;46:398)  It should be noted that a regular diet high in n-3 polyunsaturated fat, especially from fish, suggests protection against early and late ARM in an older Australian cohort. (Arch Ophthalmol 2006;124:981)  A meta-analysis suggests that consumption of fish and foods rich in omega-3 fatty acids may be associated with a lower risk for AMD; however, there was insufficient evidence with few prospective studies and no randomized clinical trials to support their routine consumption for the prevention of AMD. (Arch Ophthalmol. 2008;126:826)

One study showed that groups receiving fish oil supplementation had lower triacylglycerol levels, increased high-density lipoprotein (HDL) cholesterol levels, and improved endothelium-dependent arterial vasodilation (P < .05).  Compared with the groups not receiving the exercise intervention, those in the exercise groups had better arterial compliance (P < .05).  Both fish oil and exercise were independently associated with reduced body fat (P < .05).   Fish oil supplements and regular exercise both reduce body fat and improve cardiovascular and metabolic health. Further findings indicate that ncreasing intake of n-3 FAs could be a useful adjunct to exercise programs aimed at improving body composition and decreasing cardiovascular disease risk.  Compliance rate was also increased by taking a biphasic approach. (Am J Clin Nutr. 2007;85:1267)

The review of the studies conclude that "Omega-3 fatty acid supplements can be taken at any time, in full or divided doses, without raising concerns for interactions with any medications.  Omega-3 fatty acids persist in cell membranes for weeks after consumption, and thus intermittent bolus dosing, ie, twice weekly intake of fish or fish oil, provides the same benefits as daily consumption of lower doses." (Mayo Clin Proc. 2008;83:324)  From (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031340)

Excellent Natural Sources:

Omega-6 Fatty Acids

Linoleic Acid: Food sources of LA include vegetable oils, such as soybean, safflower and corn oil, nuts, seeds and some vegetables.  Included are safflower oil, sunflower seeds, pine nuts, sunflower oil, corn oil, soybean oil, pecans, and brazil nuts. Borage seed oil, evening primrose oil and black currant seed oil are rich in gamma-linolenic acid (GLA), and are often marketed as GLA or essential fatty acid (EFA) supplements. Side effects include gastrointestinal distress and may create seizure in patients with undiagnosed temporal lobe epilepsy. (Prostaglandins Med. 1981;6:375)

Omega-3 Fatty Acids

Alpha-Linolenic Acid (ALA): Flaxseeds, walnuts, and their oils are among the richest dietary sources of ALA.  Included are flaxseed oil, walnuts, canola oil, and tofu. Flaxseed oil is available as an ALA supplement as well as a number of fish oils marketed as omega-3 fatty acid supplements. Since EPA and DHA content will vary in fish oil and ethyl ester preparations, it is necessary to read the label to determine the EPA and DHA content of a particular supplement. All omega-3 fatty acid supplements are absorbed more efficiently with meals. Dividing one’s daily dose into two or three smaller doses throughout the day will decrease the risk of gastrointestinal side effects.  Cod liver oil is a rich source of EPA and DHA.  Side effects are characterized by gastrointestinal disorders.

Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA): Oily fish are the major dietary source of EPA and DHA.  Included are herring, salmon, oysters, trout, tuna, and crab.  Cod liver oil is an excellent source of vitamin A, vitamin D and essential EPA and DHA. (Lipids. 2011;46(5):417–423. Int J Ophthalmol. 2011;4(6):648-51)

WHICH FORM OF OMEGA 3 SUPPLEMENT, ETHYL ESTER OR TRIGLYCERIDE BACKBONE OFFERS MORE STABILITY?

The American Heart Association (AHA) recognizes the benefits of Omega 3 fatty acids and recommends: (Arterioscler Thromb Vasc Biol 2003;23;151-152)

1. That all adults eat fish (particularly fatty fish) at least two times a week.

Fish is a good source of protein and is low in saturated fat. Fish, especially oily species like mackerel, lake trout, herring, sardines, albacore tuna, and salmon, provide significant amounts of the two kinds of omega-3 fatty acids shown to be cardioprotective, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The AHA also recommends eating plant-derived omega-3 fatty acids. Tofu and other forms of soybeans; walnuts and flaxseeds and their oils; and canola oil all contain ALA.

2. For patients with documented Coronary Heart Disease (CHD), the AHA recommends 1 g of EPA and DHA (combined) per day. This may be obtained from the consumption of oily fish or from omega-3 fatty acid capsules, although the decision to use the latter should be made in consultation with a physician. The amount of EPA and DHA in fish and fish oil is presented in the recent AHA Scientific Advisory on omega-3 fatty acids and Cardiovascular Disease (CVD).

3. An EPA􏰘DHA supplement may be useful in patients with hypertriglyceridemia. Two to four grams of EPA􏰖DHA per day can lower triglyceride 20% to 40%. Patients taking more than three grams of these fatty acids from supplements should do so only under a physician’s care.

Because of the potential of contamination, fish oil must be distilled, cleaned  (pasteurized) to minimize the risk.  Thus the issue arises regarding the most effective method to render fish oil safe, effective and efficient to the system.  The basis of the distillation process follows:

$11. Crude fish oil (many different variations) is altered with ethanol

$12. This mix is then heat distilled (molecular distillation) under a vacuum to remove contaminants

$13. The result is concentrated (50-70%  ( Lancet 1978;ii:117-119) ) omega 3 molecules in an ethyl ester package

$14. This is then manipulated by different manufacturers to create variations on the theme including addition of other factors or to reattach the molecules to a glyceride backbone (re-esterified Triglyceride) in an attempt to closer simulate the original long-chain omega 3s.

Live fish or fresh fish are probably going to offer the maximum stability for provision of Omega 3s.  All fish oils are particularly susceptible to oxidation.  Vitamin E is often added as a natural anti-oxidant to help delay this oxidation. (Int J Vitam Nutr Res. 2000;70(2):31-42)  Fish oil has an inherent expiration date with 6 months shelf life often anecdotally cited.  The fishy taste is one of the indications of oxidation.  This fishy taste, or eructation (burp-back) may be masked by providing an enteric coating for inferior fish oil.  The most common side effect of the consumption of fish oil is gastrointestinal disturbance that increases with higher levels of supplementation.  (Lancet. 2008 Oct 4;372(9645):1223-30)   A reasonable method of assessing the freshness or levels of oxidation is to actually bite one of the capsules to experience the fishy flavor.  Oxidized fish oil is not pleasant to the taste. 

According to one report DHA in fish oils in the form of ethyl esters are much less stable than those in the natural triglyceride form.  In the study the EE form of DHA was more reactive, and quickly oxidized, demonstrating that EE fish oils are far less stable and more readily produce harmful oxidation products. (Biosci Biotechnol Biochem 2002;66:749-753)   Another study analyzed the stability of DHA in phospholipid, triacylglycerol, and EE form.  Looking at a 10-week oxidation period, the EE DHA oil decayed 33% more rapidly. (Biosci Biotechnol Biochem. 1997;61:2085-2088)  

Summary of Essential Fatty Acids

Essential fatty acids are critical to the maintenance of health.  They must be consumed to create EPA and DHA, which are employed in the balance of the immune system as it relates to inflammation.  Most diets are woefully low in the long-chain omega 3 fatty acids that are most efficient in the provision of EPA and DHA.  A number of issues have been addressed regarding the differences between fish oil supplements.  There is little argument that eating foods rich in omega 3s or supplementing with omega 3s is beneficial to health.  The American Heart Association among other groups readily attest to that fact. 

As a practitioner or consumer, the question is which of the supplements appear to be most beneficial regarding:

$1vSafety and Tolerability?

$1vDelivery of High Concentrations of EPA with Minimal Side Effects?

$1vDelivery of High Concentrations of DHA with Minimal Side Effects?

$1vMaximum bioavailability?

$1vStability?

$1vEconomics Considering Bioavailability?

Safety and tolerability are a minor issue.  There were reports of increased bleed-ability associated with omega 3 consumption, but those issues have been resolved with the assessment by Harris stating that the benefits of triglyceride lowering with omega-3 fatty acids more than outweigh any theoretical risks for increased bleeding. (Am J Cardiol 2007;99[suppl]:44C–46C)   The primary tolerability issues surround the belching and gastrointestinal problems.  This problem seems to occur more frequently with the FFA products and with increased dosing of any of the fish oils.  Gastrointestinal issues are also exacerbated by using expired products.

Delivery of high concentrations of both EPA and DHA appear to occur more efficiently with the triglyceride variations and even better with re-esterified TG.  Apparently the bioavailability between EE and TG variations is somewhat related to absorption time differences.  Also it appears that consumption of high fat meals improves the bioavailability of all variants but of course that creates other issues of risk. 

Stability is an issue for all supplements, but the data seems to indicate that EE variations are more easily oxidizable than the rTG variants.  Care must be exercised in looking at the expiration dates to assure maximum bioavailability without the complications of putting more oxidants in the system.

Recommendation

There is some evidence to recommend supplementation of fatty acids beyond that obtained in the normal diet for minimizing the risk of glaucoma damage especially related to the immune system.  Triglyceride backbone appears to offer the maximal bioavailability without side effects.

CURCUMIN/TURMERIC-OBTAIN FROM DIET BUT STRONGLY CONSIDER SUPPLEMENTATION

Curcumin is a component of turmeric, the yellow spice in curry.  It has been shown to be a potent immune-modulatory agent that modulates activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells.  It also down-regulates various pro-inflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12 and chemokines while concurrently enhancing the antibody responses. (J Clin Immunol 2007;27:19, Exp Brain Res 2005;167:641)  It is a phytophenolic compound with proven antioxidant, anti-inflammatory, anti-infectious and anticancer activitiy and is potentially applicable to the treatment of malignancies, diabetes, allergies, arthritis, Alzheimer’s, Crohn’s disease, inflammatory bowel disease, psoriasis, idiopathic inflammatory orbital pseudotumors, chronic anterior uveitis, pterygia, COPD, experimental abdominal aortic aneurysms and other chronic diseases. (Adv Exp Med Biol 2007;595:1, Ann NY Acad Sci 2005;1056:206, Ann Vasc Surg 2006;20:360, Dig Dis Sci 2005;50:2191, Phytother Res 2000;14:443, J Huazhong Univ Sci Technolog Med Sci 2007;27:339, Phytother Res 1999;13:443, Nutr Clin Pract 2008;23:49, Int J Chron Obstruct Pulmon Dis 2006;1:15, Expert Opin Investig Drugs 2007;16:1921)  There is even one report suggesting that Curcumin may be beneficial in the prevention of posterior capsular opacification. (Zhonghua Yan Ke Za Zhi 2006;42:649)  One of the more obvious applications is to the management of dysfunctional tear syndrome which is known to have immune-related inflammatory response.  In this application, the effect is to mediate the transcription factor NF-dappa B which has the ability to block the inflammatory and apoptotic effect of TNF-a. (IOVS 2008;49:565)  Its activity is thought to occur by inhibition of prostaglandin E (2). (J Pharmacol Exp Ther 2005;315:788)  The effects of Curcumin are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes.  It Inhibits such mediators of inflammation as NFkappaB, cyclo-oxygenase-2 COX 2, lipooxygenase-OOX, and inducible nitric oxide synthase. (JPEN J Parenter Enteral Nutr 2006;30:45)  Curcumin has at least ten known neuroprotective actions and targets multiple AD pathogenic cascades, making it a strong candidate for use in the prevention or treatment of major disabling age-related neurodegenerative diseases like AD, Parkinson’s and stroke. (Adv Exp Med Biol 2007;595:197)  Curcumin affects many aspects of angiogenesis, downregulating such proangiogenic proteins as VEGF and BFGF and inhibiting signal transduction pathways. (Adv Exp Med Biol 2007;595:185)

The suggested daily dosage is 500 to 1000 mg.  Toxicities were not experienced at levels of 3600 to 8000 mg/day for four months with the exception of nausea and diarrhea. (Adv Exp Med Biol 2007;595:471)  There are, however, issues with bioavailability and methods to enhance this are under investigation. (Mol Pharm 2007;4:807)

Excellent Natural Sources:

The yellow spice in curry powder.

Recommendation

There is some evidence to recommend supplementation of curcumin beyond that obtained in the normal diet for minimizing the risk of glaucoma damage especially related to the immune system. 

NUTRITION WITH MITOCHONDRIAL IMPACT

Mitochondria can be impaired either genetically (as in Leber's) or through acquired insults (such as nutritional or toxic factors). Either may challenge energy production in all cells of the body. While this challenge may be met through certain compensatory mechanisms (such as in the size, shape, or number of the mitochondria), there exists in neurons a threshold, which once passed, leads to catastrophic changes. This threshold may be that point at which mitochondrial derangement leads to such ATP depletion that axonal transport is compromised, and decreased mitochondrial transport results in even further ATP depletion. Neurons are singularly dependent on the axonal transport of mitochondria.” (Trans Am Ophthalmol Soc. 1998;96:881)  More recent studies report that IOP elevation may directly damage mitochondria in the ONH axons by promoting reduction of COX, mitochondrial fission and cristae depletion, alterations of OPA1 and Dnm1 expression, and induction of OPA1 release. Thus, interventions to preserve mitochondria may be useful for protecting ON degeneration in glaucoma. (Invest Ophthalmol Vis Sci. 2008 May 9. [Epub ahead of print])

Mitochondrial decay is likely to be a major contributor to aging. (Proc. Natl. Acad. Sci. USA 1993; 90:7915,  Proc. Natl. Acad. Sci. USA 1994;91:10771, Biochim. Biophys. Acta. 1995;1271:165, Methods Enzymol 1996; 264:442, Proc. Natl. Acad. Sci. USA 1997;94:306,  J. Alz. Dis. (2004;6:117)  Four areas of mitochondrial metabolism decline with age: (FASEB J 1997;12:1183, Gene 1998; 209:23, Proc. Natl. Acad. Sci. USA 1997; 94:3064) (a) oxidant by-products increase with a concomitant increase in ascorbate, protein, lipid, and nucleic acid oxidation; (b) cardiolipin decreases in mitochondrial membranes; (c) membrane potential decreases; and (d) oxygen utilization decreases.  It has been shown in animal studies that the combination of acetyl carnitine and lipoic acid, improves mitochondrial function in the liver and brain and increases activity levels and scores on cognition tests. (Proc. Natl. Acad. Sci. USA 2002;99:2356, Proc. Natl. Acad. Sci. USA 2002;99:1870, Proc. Natl. Acad. Sci. USA 2002;99:1876). Recent studies on dogs show that the combination also improves cognition in old beagle dogs. (J. Neurochem 2002; 82:375). A recent double blind clinical trial on aged humans shows a decrease in hypertension. (J Clin Hypertens (2007; 9:249) Lipoic acid has also been shown to protect retinal pigment epithelial cells from oxidation, a model for macular degeneration. (Invest. Ophthalmol Vis Sci 2005;46:4302, Invest. Ophthalmol Vis Sci 2007;48:339)

Bruce Ames, the undisputed leader in the field of micronutrient impact on mitochondria, posits a new theory about homeostasis during micronutrient shortage, which, if confirmed, will radically change thinking about requirements for micronutrients and public health. His triage hypothesis offers that the risk of degenerative diseases associated with aging, including cancer, cognitive decline, and immune dysfunction, can be decreased by ensuring adequate intake of micronutrients (the 40 essential vitamins, minerals, amino acids, and fatty acids) earlier in life, a simple and inexpensive solution to a potentially large public health problem. The triage hypothesis predicts that insidious changes may indeed be occurring, providing a unifying rationale for diverse observations in the literature that suggest links between micronutrient availability, aging, and the diseases of aging. (Proc Natl Acad Sciences USA 2006;103:17589)

ALPHA-LIPOIC (LIPOIC ACID) ACID- OBTAIN FROM DIET BUT STRONGLY CONSIDER SUPPLEMENTATION

In a Russian controlled trial of lipoic acid, 45 patients with stage I and II glaucoma were supplemented with either 75 mg (n=26) or 150 mg (n=19) for two months. A control group of glaucoma patients (n=31) were given only local hypotensive medication. Improvement in visual function was seen in approximately 45 percent of subjects supplemented with lipoic acid. (Filina AA, Davydova NG, Endrikhovskii SN, Shamshinova AM. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 1995;111:6-8.)

Alpha-lipoic acid is an antioxidant that is both fat and water-soluble.  Alpha-lipoic acid deactivates a broad range of free radicals, crosses the blood-brain barrier and mimics other less powerful antioxidants.  Alpha-lipoic acid is the only antioxidant that raises levels of the important ocular antioxidant glutathione in red blood cells and lacrimal fluid. (Oftalmol 1992;108:13-15, Vestn Oftalmol  1993;109:5) It also regenerates antioxidant nutrients such as vitamins C and E that have been converted into free radicals after they quench other free radicals, all the while protecting neurons from glutamate toxicity.  Alpha-lipoic Acid also acts to remove the strong oxidant, iron, and has a beneficial action on ocular tissue and hydrodynamic parameters. (Vestn Oftalmol 1991;107:19,, J Klin Monatsbl Augenheilkd 1980;177:577-83) (In: Rokan (Ginkgo Biloba) Recent results in pharmacology and clinic. Fungeld (ed) Springer Verlager , New York, 1988) (In: Ginkgo Biloba (V:Ginkgo-1) A textbook of Natural Medicine Bastyr College Publications, Seattle, WA,. 1993)

Other studies point to the fact that Alpha-alpha-lipoic acid protects and rescues the retinal neurons under stress (PLoS One. 2013 Jun 5;8(6):e65389., J Neurosci 2010,30: 5644–5652, Neuropharmacology 2002;43:1015, Neuroscience 2007;145:1120) even when challenged by toxins in cigarette smoke. (Invest Ophthalmol Vis Sci 2007;48:339)  Work by Ames et al in numerous studies point to the fact that alpha-lipoic acid  and acetyl-carnitine supplements ameliorate the mitochondrial decay of aging. (Dr. Bruce N. Ames Awarded the First Annual American Society for Nutrition/CRN an excerpt from his nomination) Mitochondrial affectation is one of the cornerstones of neurodegeneration. It has been shown in animal studies that the combination of acetyl carnitine and lipoic acid, improves mitochondrial function in the liver and brain and increases activity levels and scores on cognition tests. (Proc. Natl. Acad. Sci. USA 2002;99:2356, Proc. Natl. Acad. Sci. USA 2002;99:1870, Proc. Natl. Acad. Sci. USA 2002;99:1876). Recent studies on dogs show that the combination also improves cognition in old beagle dogs. (J. Neurochem 2002; 82:375). Lipoic acid has also been shown to protect retinal pigment epithelial cells from oxidation, a model for macular degeneration. (Invest. Ophthalmol Vis Sci 2005;46:4302, Invest. Ophthalmol Vis Sci 2007;48:339) It has been demonstrated that antioxidant treatment can slow disease progression and improve disease outcomes in many clinical ways.  (Treatments in Endocrinology 2004, 3: 173–189)

Excellent Natural Sources:

Good food sources of alpha-lipoic acid include spinach, broccoli, spinach, beef, yeast (particularly Brewer's yeast), and certain organ meats (such as the kidney and heart). (J Appl Nutr 1997;49:3)

Recommendation

There is some evidence to recommend supplementation of alpha lipoic acid beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as it crosses the blood brain barrier and positively affects mitochondrial health. 

ACETYL-L-CARNITINE-USUALLY SYNTHESIZED BY THE BODY IN HEALTHY INDIVIDUALS.

Acetyl-L-carnitine (ALC) is a natural molecule widely distributed in vertebrate and invertebrate nervous system. ALC is a nutrient responsible for the transport (carnitine shuttle) of long-chain fatty acids into the energy-producing centers of the cells (known as the mitochondria). In other words, carnitine helps the body convert fatty acids into energy and assists in elimination of fat build up.  ALC maximizes mitochondrial function, which serves as the bioenergy locus of the cell.  The body produces carnitine in the liver and kidneys and stores it in the skeletal muscles, heart, brain, and sperm.  ALC is known to have significant effects on neuronal activity playing a role as neuroprotective and anti-nociceptive agent, as well as neuromodulatory factor. (Neuroscience 2006; 142:931) ALC is also known to have potential in inhibiting acute and delayed cell death following exposure to NMDA an excitotoxic glutamate antagonist (Ann NY Acad Sci 2005;1053:153), thus the relationship to neuroprotection.  A recent work reports that carnitine reduces the lipoperoxidative damage after cell stress in experimental glaucoma.  (Cell Death Dis. 2010 Aug 5;1:e62. doi: 10.1038/cddis.2010.40.) A deficiency of carnitine is known to have major deleterious effects on the CNS. (Ann NY Acad Sci 2005;1053:183) Oxidative mitochondrial decay is a major contributor to aging. (Ann NY Acad Sci 2004;1033:108)

Supplementation in animal studies reduces age-associated changes in lipid metabolism. (Journal of Lipid Research 2004;45:729)  It has been reported that an appropriate combination of compounds including ALC, coenzyme Q10, and Omega 3 FFAs, which positively affect mitochondrial lipid metabolism, may improve and subsequently stabilize visual functions, and it may also improve fundus alterations in patients affected by early AMD. (Ophthalmologica 2005;219:154, Ophthalmologica 2003;217:351, Orv Hetil 2007;148:2259)  L-Carnitine is capable of protecting the RPE cells from H2O2-induced oxidative damage, implying that micronutrients can have a positive effect and can play an important role in the treatment of oxidation-induced ocular disorders. Further studies are needed to understand the mechanism of LC-induced protection to the RPE cells. (Curr Eye Res. 2007;32:575)  The most exciting aspect of this compound is its ability as a secondary antioxidant to reduce or block neuronal death in Alzheimer’s disease (Expert Opin Investig Drugs 2007;16:1921) which could then lead to investigation in the management of glaucoma.  When used in combination one study demonstrated that administration of a combination of vitamin E (which prevents de novo membrane oxidative damage), folate (which maintains levels of the endogenous antioxidant glutathione), and acetyl-L-carnitine (which prevents Abeta-induced mitochondrial damage and ATP depletion) provides superior protection in Alzheimer’s disease to that derived from each agent alone. (Brain Res 2005;1061:114)  ALC has also been recommended in chronic pain neuropathies (e.g. diabetes, fibromyalgia) for its analgesic effect. (CNS Drugs 2007;21 Suppl 1:31, Clin Exp Rheumatol 2007;25:182) Another recent study demonstrates that administering ALC may reduce both physical and mental fatigue in elderly and improves both the cognitive status and physical functions. (Arch Gerontol Geriatr 2008;46:181)

Excellent Natural Sources:

Acetyl-L-carnitine is synthesized by the body.  Good food sources of Acetyl-L-carnitine are red meat, especially mutton.

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Recommendation

There is some evidence to recommend supplementation of acetyl-L-carnitine beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as it positively affects mitochondrial health. 

GINKGO BILOBA-CONSIDER SUPPLEMENTATION WITH CARE

Gingko biloba is a botanical antioxidant.  Gingko has several properties which may lend well to management of glaucoma including: enhancing central and peripheral blood flow, minimizing vasospasm, inhibition of platelet activating factor, lowering serum viscosity, antioxidant activity, and inhibition of apoptosis and excitotoxicity.  Oxidative stress at the level of the mitochondria may be positively affected by Ginkgo biloba. (Pharmacopsychiatry 2003;36:S15, Ann NY Acad Sci 2005;1056:474) Utilization of antioxidants to scavenge the free radicals created under oxidative stress has been recommended as a possible method of management of neurodegenerative issues in glaucoma. (Acta Ophthalmol Scand Suppl 1998;227:41)  Gingko biloba is a potent antioxidant and has demonstrated survival of RGC in experimental glaucoma by interfering with the NMDA receptors. (J Neurotrauma 2002;19:369, Ophthalmologica 1998;212:268)

The target of oxidative stress relevant in the development of glaucomatous optic neuropathy are mitochondria but only molecules reaching the inner membrane of the mitochondria can be of potential use. (Invest Ophthalmol Vis Sci 2006;47:2533)  Ginkgo has free radical scavenging properties but actually enters the mitochondria to create the effect of protecting the retinal ganglion cells. (Med Hypotheses 2000;54:221, Cur Opin Ophthalmol 2000;11:78, Curr Eye Res 2004;28:153, Phamacopsychiatry 2003;36:S15, Ann NY Acad Sci 2005;1056:474, Curr Opin Ophthalmol 2000;54:221, Arch Ophthalmol 2005;123:458)  One study demonstrated that Ginkgo biloba at 120 mg/day improved visual fields in glaucoma patients with safety reports suggesting this dosage acceptable. (Ophthalmology 2003;110:359, Public Health Nutr 2000;3:495)

Ginkgo biloba improves circulation by inhibiting platelet aggregation, dilating blood vessels, and promoting the integrity of vascular linings.  Ginkgo biloba exerts its vascular actions through effects on the vascular endothelium and adrenergic vasoregulatory system. Ginkgo biloba has produced improvements in visual field disturbances in patients with severe degenerative retino-choroidal circulatory disturbances, glaucomatous visual field defects, and chronic cerebral and retinal insufficiency. (J Klin Monatsbl Augenheilkd 1980;177:577, In: Rokan (GinkgoBiloba) Recent results in pharmacology and clinic. Fungeld (ed) Springer Verlager , New York, 1988) (A textbook of Natural Medicine Bastyr College Publications, Seattle, WA,. 1993, Klin Monatsbl Augenheilkd 1981;178:386-389)  More recent studies point to the importance of antioxidants like Gingko biloba, resveratrol and quercitin in reduction of oxidative stress issues. (Invest Ophthalmol Vis Sci. 2007;48:4580)  Use of Gingko biloba must be tempered by the blood thinning side effects, especially if combined with Vitamin E.

Excellent Natural Sources:

Gingko Biloba is used in many Asian dishes but only derived from the Gingko plant.

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Recommendation

There is some evidence to recommend supplementation of gingko biloba for minimizing the risk of glaucoma damage as it positively affects mitochondrial health.  But, there are potential side effects of excessive use.

COENZYME Q10-UBIQUINONE-OBTAIN FROM DIET AND STRONGLY CONSIDER SUPPLEMENTATION ESPECIALLY IN HEART PATIENTS

Coenzyme Q10 (CoQ10) is a powerful fat-soluble antioxidant that buffers the potential adverse consequences of free radicals produced during oxidative phosphorylation in the inner mitochondrial membrane. CoQ10 works synergistically with Vitamin E.  Within the framework of mitochondrial function, Coenzyme Q10 is critical in the energy production by way of the electron transport chain.  As such CoQ10 does have potential in the realm of neuroprotection. (J Biol Chem 2003;278:28220, Int Rev Neurobiol 2007;82:397)  CoQ10 is concentrated in the myocardium. Its role in the heart makes sense: the heart, one of the body's most energetic organs, beats approximately 100,000 times a day and 36 million times a year, and depends on CoQ10 for "bioenergetics."  In a well-controlled study, 19 patients who were expected to die from heart failure rebounded with an "extraordinary clinical improvement," with CoQ10 supplementation. (Proceedings of the National Academy of Sciences of the USA 1985;82:4240).  Numerous case studies demonstrated the dramatic effect of CoQ10 in cardiovascular diseases. (Biochemical and Biophysical Research Communications 1993;182:247, Wochenschrift 1988;66:583, Clinical Investigator 1993;71S:145, Clinical Investigator 1993;71S:134)  Reviews suggest a role for CoQ10 in the management of cardiovascular disease (Mitochondrion 2007;7 Suppl:S154) with the coincident effect of lowering both systolic and diastolic blood pressure. (J Hum Hypertens 2007;21:297)  CoQ10 levels appear to have a direct relationship to thyroid hormone levels, with decreases in hyperthyroidism. (Biofactors 2005;25:201)  There are numerous studies addressing the relationship of CoQ10 to statin-induced myopathy but the results are conflicting and any general statement regarding that issue is a bit premature. (Arch Neurol 2005;62:1709, Fundam Cin Pharmacol 2007;21 Suppl 2:35)

CoQ10 is best documented in the treatment of heart failure but there is also evidence suggesting benefit in certain types of cancer (Biochemical and Biophysical Research Communications1993;192:241, Biochemical and Biophysical Research Communications 1994;199:1504, Basic Clin Pharmacol Toxicol 2007;100:387) and may assist tamoxifen when used in combination with riboflavin and niacin in reducing recurrence and metastases of breast cancer. (Biol Pharm Bull 2007;30:367)  There is also the suggestion that low levels of CoQ10 are an independent prognostic factor in the risk for melanoma progression. (J Am Acad Dermatol 2006;54:234)  Neurodegenerative conditions such as amyotrophic lateral sclerosis. (Free Radic Res 2008;42:221, J Neurol Sci 2008;267:66), Friedrich’s ataxia (Mitochondrion 2007;7 Suppl:S127), Parkinson’s (Nervenarzt 2007;7:1378, J Neural Transm Suppl 2006;71:113, Neurology 2007;68:20), Oculomotor apraxia (Neurology 2007;68:295), and Huntington’s disease (Neurochem Res 2006;31:1103) may also benefit from supplementation.  Because of the action of CoQ10 on mitochondrial metabolism there is the suggestion that it may be effective in the prophylaxis of migraine (effects on inhibition of excess glutamate). (Current Treat Options Neurol 2008;10:20, Headache 2008;47:73)  Other neurological connections include studies A recent animal study regarding the effects of excitotoxicity in the development of retinal ganglion cell damage demonstrated that CoQ10 minimized glutamate increases affording neuroprotection to the eye. The study suggests that oxidative stress and energy failure might be implicated in the mechanism of RGC death and that CoQ10 may be of benefit in ocular neuroprotection. (Int Rev Neurobiol 2007;82:397)

There are also reports that CoQ10 supplementation could extend the lifespan of patients with acquired immune deficiency syndrome (AIDS).  (Biochemical and Biophysical Research Communications 1988;153:888). There is also a relationship of CoQ10 deficiency and Cystic Fibrosis-Fat Malabsorption- (J Pediatr Gastroenterol Nutr 2006;43:646) as well as cerebellar ataxias. (Orphanet J Rare Dis 2006;1:47)  There is the suggestion that any disorder related to mitochondrial dysfunction, encephalopathy, lactic acidosis, stroke-like episodes (MELAS), chronic progressive external ophthalmoplegia, and Kearns-Sayre syndrome may benefit from CoQ10 therapy. (Muscle Nerve 2007;35:235, Curr Opin Rheumaol 2006;18:636)

Co Q10 is a coenzyme for the inner mitochondrial enzyme complexes that has demonstrated prevention of lipid peroxidation and DNA damage induced by oxidative stress. (In Vivo 2005;19:1005, Biochem Biophys Res Commun 1990;169:851) Co Q10 is involved in energy production within the cell with strong antioxidant properties. (FASEB J 2001;15:1425)  When combined with acetyl-L-carnitine and omega 3 FFAs, there is evidence that the combination is very effective in altering the progression of ocular disease such as AMD.  Studies also suggest that acute and chronic supplementation of CoQ10 may affect acute and/or chronic responses to various types of exercise and increase time to exhaustion. (J Int Soc Sports Nutr 2008;4:5, Nutrition 2008;24:293)  A recent report demonstrated that CoQ10 was effective in the management of experimental glaucoma. (Invest Ophthalmol Vis Sci 2007;48:E-Abstract 4369)  See Cross-Talk for more information on CoQ10.                                                                          

Therapeutic dosages of CoQ10 for serious diseases range from 200-400 mg. daily, while a common preventive dose ranges from 10-30 mg daily.  Available data suggests that CoQ10 is relatively safe and tolerated over a range of 300 to 2,400 mg/day. (CNS Spectr 2007;12:62)  CoQ10 does suffer from issues of bioavailability because of its hydrophobicity and large molecular weight.  Work is continuing regarding that issue (J Med Food 2007;10:731, Mitochondrion 2007;7 Suppl:S78, Eur J Pharm Biopharm 2007; 67:361) with one study suggesting that CoQ10 absorption is enhanced with food intake. (Yakugaku Zasshi 2007;127:1251)  It should also be noted that alterations of CoQ10 and alpha tocopherol occur throughout the menstrual cycle further implicating hormonal influence in levels of all fat-bound supplements. (Am J Obstet Gynecol 2006;194:e35)

One study demonstrated that supplementation with Coenzyme Q10 was effective in preventing negative cardiac effects associated with the use of Timolol.  (J Cardiovasc Pharmacol, 1989;14:462-468.)

Excellent Natural Sources:

Sources of coenzyme Q 10 include fish, organ meats and the germ portion of whole grains.

Recommendation

There is some evidence to recommend supplementation of coenzyme Q10 beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as positively effects mitochondrial health especially in patients with cardiovascular compromise. 

MELATONIN-OBTAIN FROM DIET AND ONLY SUPPLEMENT WITH GREAT CARE AS MELATONIN IS A HORMONE

Melatonin (N-acetyl-5-methoxytryptamine) (MT) is a hormone that acts as an antioxidant. It is produced by the pineal gland, in the gastrointestinal tract, within the immune system and within the retina and its release is blocked by light entering the eye. (Physiol Pharmacol 2007;58 Suppl 6:115, Acta Ophthalmol 2008 May 20. [Epub ahead of print])  The relationship to the gastrointestinal tract has implications in the management of GI disorders. (J Phys Pharm 2006;57( Suppl 5): 51)  It has also been shown that specific melatonin receptors have been located in the cornea, ciliary body, lens, choroid and sclera, which suggests that cells in these tissues may be targets for melatonin action. (Pharmacol Ther 2007;113:507, Exp Eye Res  2003;77:219) and that there is even a relationship to dry eye syndrome (Ocul Surf 2004;2:92) and the management of glaucoma (Exp Eye Res 2007;84:1021) but moderate and severe glaucoma does not appear to be associated with abnormal melatonin concentrations in aqueous humor. (Am J Ophthalmol 2006;142:325) Light is the major synchronizer of circadian rhythms to the 24-hour solar day and this activity is related to Melatonin. (Neurosci Lett  2008. [Epub ahead of print, FASEB J  2007;21:3866) It has been reported that patients with circadian rhythm sleep disorders, including some blind patients with no light-induced suppression of melatonin, benefit from melatonin treatment. (Eye  2007;21:901) Does Melatonin assist in sleep?  Studies have shown that exogenous melatonin administration possesses circadian-phase-dependent hypnotic properties, allowing for improved sleep. (Sleep 2006;29:609) Current evidence suggests that melatonin may act as a protective agent in ocular conditions such as photo-keratitis, cataract, glaucoma, retinopathy of prematurity and ischemia/reperfusion injury. (J Pineal Res  2006;40:101)  Melatonin is shown to scavenge free radicals and stimulate anti-oxidative enzymes. (J Pineal Res 2006;41:116, Endocrine 2005;27:119)  One study demonstrated that in pseudophakic patients with ARMD more Melatonin is produced during the day compared to pseudophakic subjects without ARMD. It is suggested that this be caused by the reduced visual acuity in patients with ARMD, whereby less light reaches the photoreceptors, allowing Melatonin secretion to continue during the day. Because Melatonin also acts as an antioxidant and daytime levels are higher in patients with ARMD, these results might be interpreted as a rescue factor. (Acta Ophthalmol  2008 May 20. [Epub ahead of print)  In another report associated with ARMD it was demonstrated that the daily use of 3 mg melatonin seems to protect the retina and to delay macular degeneration. (Ann N Y Acad Sci  2005;1057:384)  Although there are numerous reports describing the effects of Ultraviolet A (UVA) on cells of the skin and eye, no studies have described the anti-oxidative properties of Melatonin in relation to UVA-irradiated cells but intracellular levels may positively effect the ocular tissues in UV exposure. (Postepy Hig Med Dosw (Online). 2008 Jan 22;62:23) One report addresses the fact that that elevated intraocular pressure and large cup-to-disk ratios were independently associated with earlier melatonin timing. (J Circadian Rhythms  2005;3:13) Melatonin is reported to have a strong anti-apoptotic signaling function, an effect that it exerts even during ischemia. It has been reported that Melatonin cyto-protective properties may have practical implications in the treatment of ocular diseases, like glaucoma and age-related macular degeneration.  (Vis Neurosci  2006;23:853, Neurotox Res 2003;5(5):323)  Another study points to the fact that in animal research Melatonin therapy could increase the survival rate of the RGCs and could rescue and restore the injured RGCs. (J Huazhong Univ Sci Technolog Med Sci  2006;26:235)  There is a particular circadian rhythm within the eye and the impact on the genesis of ocular disorders is evolving. (Prog Retin Eye Res  2008;27:137)  It is suggested that this circadian rhythm association has an effect on the management of glaucoma.  (Invest Ophthalmol Vis Sci 1985;26:1315-1319.)  One report suggested that artificial supplementation of Melatonin and zinc should be considered as an adjunctive therapy to classic treatment of Toxoplasma retinochoroiditis especially in immunosuppressed and elderly patients if our data are confirmed in a clinical setting.  This suggestion was based on animal data. (Ophthalmologica  2007;221:421)  Another animal based study suggested that Melatonin effectively reduced the vascular permeability in the retina of hypoxic rats that its administration may be of potential benefit in the management of retinal edema associated with retinal hypoxia. (J Pathol  2007;212:429)

Of additional interest is the fact that melatonin levels in the retina are naturally decreased with age and lenticular opacification and “normal” levels may be restored with lens replacement. (Ophthalmic Physiol Opt 2003;23:181)

A relationship of melatonin to estrogen levels exists and as such there is a natural relationship to cancer. Melatonin levels in cancer patients have been correlated with tumor behavior. (Med Hypotheses 2002;59:302, Med Sci Monitor 2002;8:CR457) There is an association of estrogen-receptor-positive breast cancer with low plasma melatonin levels. (New Eng J Med  1997;336:186)  Another report demonstrates that melatonin inhibits human breast cancer cell growth (Histology & Histopathology 2000;15:637) and reduces tumor growth. (Cancer Research 1998;58:4383)

Melatonin does not bind to the estrogen receptor or interfere with the binding of estradiol to its receptor as do drugs like tamoxifen (Endocr Relat Cancer 2003;10:153) and may actually increase the therapeutic efficacy of tamoxifen. (Br J Cancer 1995;71:854) 

Melatonin is a hormone. Studies in humans have shown melatonin toxicity to be remarkably low with no serious negative side effects even at high doses (3 to 6.6 g) administered over a period of 35 days. (Jama1972;221:88, J Pineal Res. 2000;29:193)  None-the-less, reactions to melatonin supplementation such as sleepiness, vivid dreams, headache, abdominal pain, and nausea have been reported. (Neuroendocrinol Lett. 2002;23:118)  The National Institutes of Health has issued warnings of the potential severe side effects of Melatonin supplementation including female infertility, decreased male sex drive, interaction with hormone replacement therapy, damage to the retina of the eye, and hypothermia. 

It is recommended that those who are pregnant, breast-feeding, those suffering from depression or schizophrenia, and those with autoimmune diseases such as lupus should avoid melatonin until more long-term studies are completed.

High cortisol levels are common with increased stress levels.  High cortisol levels at night suppress melatonin, which opens the door for immune system disorders.  High cortisol levels are reflected in poor sleep patterns.  5HTP may assist sleep issues (balances the thyroid) as well as melatonin.

Melatonin is recommended at 1 mg to 6 mg at 1 hour before sleep but other recommended levels may be prescribed for specific conditions.

Excellent Natural Sources:

Melatonin occurs in many foods including olive oil, wine, beer, tomatoes, grape skin, tart cherries, and walnuts. 

Recommendation

There is some evidence to recommend supplementation of melatonin beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as positively effects mitochondrial health and potentially influences diurnal variations. Melatonin does, however, have some potential side effects as it is a hormone.  

TAURINE-SYNTHESIZED BY THE HEALTHY BODY AND OBTAINED THROUGH DIET.  MAY CONSIDER SUPPLEMENTATION WITH POOR DIET.

Taurine is an amino acid (small sulfonic acid) essential for retinal function and is concentrated in the RPE and is about 50% of the free amino acid content of the retina (J Neurochem 1974 22: 887–891.).  Taurine functions, as well, as a very potent water-soluble antioxidant and is produced by the body in adults.  It counterbalances excessive levels of excitatory neurotransmitters (glutamate) and protects ocular tissue against ischemia and oxidative stress. (J Biomed 2010, Sci 17 Suppl 1S1, Amino Acids 2008 34: 321–328, Adv Exp Med Biol 526: 421–431, Prog Brain Res 2008, 173: 495–510.).  Taurine protects the eye against neurotoxins including excessive levels of glutamate that may be responsible for the loss of ganglion cells and optic nerve damage.  Another important property of taurine is its osmotic regulative effect achieved by modulating normal endothelial function. The combination of taurine and timolol maleate lowered intraocular pressure and improved ocular hemodynamics of patients with POAG.  The fluid discharge efficacy almost doubled, and the Becker's coefficient was nomalized in 68.6 percent of patients. (Vestn Oftalmol 1990;106(4):9-11, Vestn Oftalmol 1978;(1):22-5, Vision Res  1988;28(10):1071-6, Neuroscience 1991;45(2):451-9, J Neurochem 1990;55(2):714-7, Adv Exp Med Biol  1996;257:507-17)

Taurine has also been demonstrated to function to enhance retinal ganglion cell survival in the animal model by means of neuroprotection as well as altering mitochondrial function. (PLoS One. 2012;7(10):e42017. doi: 10.1371/journal.pone.0042017. Epub 2012 Oct 24)   In the rat model taurine is protective of ganglion cells in hypoxia induced apoptosis by positively altering mitochondrial dysfunction. (Brain Res. 2009 Jul 7;1279:131-8.)

There is no specified RDA but often it is taken at 2 grams t.i.d.

Excellent Natural Sources:

Taurine is produced by the body in adults and occurs in many foods including beef, lamb, fish, eggs, dairy products and brewer’s yeast.

Recommendation

There is some strong evidence to recommend supplementation of taurine beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as positively effects mitochondrial health.  It is available in a good diet and is synthesized by the healthy body.

N-ACETYL CYSTEINE

N-acetyl cysteine is a derivative of amino acid cysteine that is ultimately converted into glutathione by endothelial cells.  Cysteine is often called the rate-limiting factor in the production of glutathione, a key component in the free radical protection system of the eye.  N-acetylcysteine protects the eye against the cytoxicity of nitric oxide, minimizes oxidant injury and helps prevent the development of aberrant circulation.  N-acetyl cysteine also assists in the regeneration of Vitamins E and C.  (Biochem Pharmacol 1991;78:13, J Inherit Metab Dis 1989;112:120, Circulation 1988;78:202, Eur J Pharmacol 1997;321:87, J Biol Chem 1997;272:18411, Hepatology 1998;272:689)  N-Acetyl-Cysteine acts as a chelating agent and as such increases the excretion of zinc and other essential minerals when taken over an extended period. It is therefore necessary to supplement zinc, copper and other trace minerals when taking N-Acetyl Cysteine.  Likewise when taking N-acetyl cysteine it is also recommended that two to three times as much Vitamin C be taken at the same time. Failure to do so may result in more harm than good from taking this product because of the prolonged presence of the oxidized form of L-Cysteine. Vitamin C also helps keep the glutathione that is produced from the Cysteine in its reduced form so that it can continue acting as an antioxidant. N-Acetyl Cysteine is also believed to reduce mucous secretions in the lung.

Typical dosage recommendations are in the range of 250-1500mg of NAC daily for the majority of therapeutic benefits.

Excellent Natural Sources:

N-acetyl cysteine is not found naturally in foods.  Cysteine is however found in many plant and animal sources.

Recommendation

There is some evidence to recommend supplementation of N-acetyl cysteine for minimizing the risk of glaucoma damage as positively effects mitochondrial health.  However potential side effects and must supplement with extra vitamin C, copper and zinc when taking.

If you are not receiving enough cysteine in your diet, consult your medical-care provider before taking NAC supplements. Too much cysteine or methionine can cause health problems, as well. A 2009 study by Temple University found that diets high in methionine can contribute to the development of Alzheimer ’s disease in mice. According to the University of Maryland Medical Center, NAC may also raise another amino acid associated with heart disease. Possible side effects of NAC can occur at any dose and include nausea, vomiting, and diarrhea. Oral administration of NAC may cause a severe allergic reaction that swells the soft tissue below the skin of the face, lips and eyes and can develop to a life-threatening condition..

Read more: http://www.livestrong.com/article/531520-food-sources-of-n-acetyl-cysteine/#ixzz2d6FsHCLX

RESVERATROL-OBTAIN FROM DIET AND CONSIDER SUPPLEMENTATION

Resveratrol is a naturally occurring substance that is found in the vines, roots, seeds, skins and stalks of grapes, peanuts, mulberries, the Japanese knotweed plant and several other plants. Resveratrol, along with other polyphenols including quercetin, catechins, gallocatechins, procyanidins and prodelphidins are extracted from grape seeds and skins and found in red wine. The most powerful polyphenolic antioxidant in red wine is resveratrol which activates the sirtuin enzyme system.  Resveratrol increased the lifespan in several animal models by activating sirtuin-2 an enzyme linked to the benefits of caloric restriction which then extends the lifespan. (Nature Rev Drug Disc 2006;8:493)  A single infusion of resveratrol can elicit neuroprotective effects on cerebral ischemia-induced neuron damage through free radical scavenging and cerebral blood elevation due to nitric oxide release. (J Agric Food Chem 2006;54:3126)  Its anti-apoptotic activity suggests that resveratrol may minimize oxidative injury in immune-perturbed states and human chronic degenerative disease. (Eur J Clin Invest 2003;33:818) Resveratrol inhibits the oxidation of low-density lipoprotein (LDL) cholesterol, inhibits smooth muscle cell proliferation and inhibits platelet aggregation. Resveratrol also reduces the synthesis of lipids in the liver and inhibits the production of pro-atherogenic eicosanoids by human platelets and neutrophils. (Nature 2004;430:686, Int J Mol Med. 2002;9:77, Eur J Clin Nutr. 2006; 60:4, Brain Res Brain Res Rev. 2006;52:316,, Nutr Clin Care. 2000; 3:76, Eur J Pharmacol. 2007;554:196, Coron Artery Dis. 1997;8:645, Cardiovascular Res. 2000; 47:549)

Since resveratrol is known to inhibit platelet aggregation and blood clot formation, individuals with bleeding disorders or taking anti-coagulant medications should consult their physician before using resveratrol supplements.  Likewise resveratrol is a natural supplier of estrogen and should be used with caution.

The maximum recommended dosage is 40 mg per day with no RDA established.

It takes approximately 41 glasses of red wine to equal the resveratrol in one 20 mg. capsule.

Excellent Natural Sources:

Red grape juice, red wines, peanuts, red grapes.

Recommendation

There is some evidence to recommend supplementation of resveratrol beyond that obtained in the normal diet for minimizing the risk of glaucoma damage as positively effects mitochondrial health.  Watch Carefully in clotting disorders.

MIRTOGENOL

This link will take you to the full article.  http://www.eyelessons.com/articles/item/mirtogenol-is-it-the-real-deal 

Mirtogenol™ is a combination of two phenolic extracts extracted from bilberry, (Mirtoselect®) (standardized to 36% anthocyanins; USP 31) and French maritime pine bark (Pycnogenol® ) (standardized to 70% procyanidins; USP 31).  A phenolic extract is any of a class of organic compounds with a hydroxyl group attached to a carbon atom in a ring of an aromatic compoundMirtoselect® is reported to be a powerful antioxidant and to promote benefits for retinal capillaries. Pycnogenol® is likewise an antioxidant but is reported to have the effect of improving blood viscosity by reducing plasma endothelin-1 and enhancing the activity of nitric oxide. http://www.online-eye-info.com/mirtogenol.html 

Previous work in the area of mechanism of action of Pycnogenol® was in the control of capillary leakage in diabetic retinopathy. Pycnogenol® has been tested for treatment and prevention of retinopathy in five clinical trials with a total number of 1289 patients since the late 1960's.  In a review it was reported that all of these studies unequivocally showed that Pycnogenol® retains progression of retinopathy and partly recovers visual acuity. It was also concluded that Pycnogenol®  was shown to improve capillary resistance and reduce leakages into the retina. (Int Ophthal. 2001;24:161–171) Other studies illustrated control of capillary leakage and decreased retinal bleeding associated with Pycnogenol® . (Ann Ottalmol Clin Ocul. 1987;113:1173–1190.

Ann Ottalmoll Clin Ocul.1987;113:357–361)  Pycnogenol®  has also been reported to improve endothelial function which is altered in POAG. (Graefes Arch Clin Exp Ophthalmol. 2009;247:583–591.Hypertens Res 2007;30:775–780) Mirtoselect® is reported to counteract the hyperpermeability of ciliary capillaries…acting on aqueous secretion. (Boll Ocul. 1986;65:789–795)

While not universally accepted as standard of care in the management of glaucoma, research has been conducted on the effects and benefits of the utilization of Mirtogenol™.  In a 2008 controlled study, Steigerwalt et al analyzed 38 asymptomatic subjects with intraocular hypertension of 22 mm Hg to 26 mm Hg.  After 2 months of supplementation of 20 patients with Mirtogenol™(80 mg Pycnogenol®  and 160 mg Mirtoselect) , they reported that IOP was significantly lowered compared to that of untreated controls.  In the treated group the IOP baseline was 25.2+/-3.1 mm Hg and the control was 24.6+/-2.8 mm Hg.

At two months the treated group IOP dropped to 22.2+/-2.1 mm Hg or an 11.9% decline compared to the untreated group with an IOP drop to 24.0+/-2.6 mm Hg or a 2.4% drop.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447819/

The group also reported no side effects and also reported improvement in systolic and diastolic blood flow in the central retinal, ophthalmic and posterior ciliary arteries.  The table below reflects the percentage increase in blood flow velocity from baseline in the CENTRAL RETINAL ARTERY (CRA), the OPHTHALMIC ARTERY (OPH) and the POSTERIOR CILIARY ARTERY (PCA).  All vessels measured demonstrated an increase in velocity from 13% for systolic CRA to 39% for diastolic CRA.  It is noteworthy that the maximum effect occurred between months two and three.  

The second clinical study conducted by Steigerwalt et al in 2010 assessed the effect of a reduced dosage of Mirtogenol™ on seventy-nine asymptomatic ocular hypertensive patients in three groups receiving the supplement, latanoprost, or both.  The baseline IOP values were 37.7+/-2.0 mm Hg in the latanoprost group, 38.1+/-2.0 mm Hg in the Mirtogenol™ group and 38.0+/-3.1 mm Hg in the combined group. Most patients had previously used latanoprost but had discontinued use in the past.  Mirtogenol™(40 mg Pycnogenol®  and 80 mg Mirtoselect) was dosed to the patients in the selected groups.  The results on the effect on IOP are shown below.  Latanoprost quickly lowered the IOP 29% within 4 weeks to stability with Mirtogenol™ alone taking up to 20 weeks plus to achieve a similar effect of 20%.  The combination of both, however was even more effective at lowering IOP by 42% at 20 weeks.

The diastolic and systolic blood flow velocity was also measured in the cohort.  The diastolic flow is reported below. At the end of 24 weeks the report demonstrates an increase from baseline of 140% on Mirtogenol alone, an increase of  38% on Latanoprost alone and an increase of 192% with a Combination for diastolic blood flow. The systolic flow is reported below. At the end of 24 weeks the report demonstrates an increase from baseline of 17% on Mirtogenol alone, an increase of  24% on Latanoprost alone and an increase of 39% with a Combination for diastolic blood flow.

A summary of the study would include that the additive effects of Latanoprost and Mirtogenol™ for lowering IOP and increasing blood flow velocity appear to really start to occur at about weeks 4 to 6.  The combination of the effects is more dynamic than the individual effects alone. In the discussion the authors conclude “The improved ocular blood flow shown in this study supports the assumption that the dietary supplement may exert an action on lowering IOP by decreasing humor inflow. Yet, it will remain difficult to identify whether the supplement affects outflow pathways, or aqueous humor inflow, or both.”  They also report “We speculate that the effect of the combination of Mirtoselect and Pycnogenol predominantly affects vascular responses involved in ocular hypertension by normalizing capillary filtration of the ciliary body.”  (Clinical Ophthalmology 2010; 4: 471–476)

OVERALL TAKE HOME MESSAGE REGARDING BEHAVIOR MODIFICATION AND NUTRITIONAL SUPPLEMENTATION

Maintenance of health does not occur in a vacuum.  Each medical discipline seems to have a knowledge base in refereed journals regarding the importance of nutrition to cellular thus organ health.  However each of these disciplines appears to be working in that very vacuum and not coordinating activities and advice to maximize patient health. 

Unfortunately, the health care team does not concentrate on advice regarding total lifestyle modification.  Diet is important relating to both obesity and proper consumption of nutrients.  Likewise exercise is critical.  De-stressing is very important in the overall management of disease with the American Institute of Stress saying that “90% of all health problems are related to stress.”  Laughter, humor, exercise, breathing exercises, contemplation, relaxation strategies, are all issues for de-stressing that will contribute positively to the maintenance of the immune system.

IN SUMMARY:

SUPPRESS INFLAMMATION

FACILITATE NEUROPROTECTION

INCREASE VASCULAR FLOW

What is the overall recommendation for patients with glaucoma?

$1   Do Not Smoke

$1   Maintain the Ideal Weight (BMI)

$1   Exercise Daily

$1   Control Hypertension and Cholesterol

$1   Control Diabetes

$1   Eliminate Stress

$1   Control Inflammation

$1   Maintain an Anti-Inflammatory Diet

$1   Maintain a Healthy Diet

$1   Consider Use of Nutritional Supplementation Especially in Consideration of Existing Systemic Disease and/or a Known Poor Diet or Malabsorption Issues (Conservative)

TABLE OF SUPPLEMENTATION TO SUPPORT THE GLAUCOMA PATIENT.  ALL CONSIDERATIONS OF FORMULAE MUST BE SENSITIVE TO PRODUCT COST

Desirable Minimal Supplements in a Daily Multivitamin

Beneficial Action

Recommended Dosage

High Quality Multivitamin with 400 mcg Folic Acid, 2 mg B6 6 mcg B12.

Anti-Oxidation, Balance and Control of Homocysteine

q.d. or b.i.d. based on brand.  Folic acid competes with methotrexate.

Vit E, based on AHA recommendations.

Anti-Oxidation

200 IU/day

Vit C

Anti-Oxidation, Immune System Modulation

500 to 1000mg/day

Vit A

Immune System Modulation

Under 3000 micro grams/day

Zinc

Immune System Modulation

15 mg/day

Selenium

Assists in Glutathione Production

100-200 mcg/day

Magnesium

Assists in Glutathione Production

420 mg/day men  320 mg/day women

Lutein and Zeaxanthin

Anti-Oxidation

Lutein 10 mg/day and Zeaxanthin 2 mg/ day

Desirable Extra Minimal Supplements

Beneficial Action

Recommended Dosage

Triglyceride Backbone Omega 3

Immune System Modulation

1000 mg b.i.d. but no recommended RDA

Vitamin D3

Neuroprotection, Immune System Modulation

500 IU b.i.d. with RDA in flux as measurement of blood levels becoming more important

Mirtogenol

Reduces IOP, Increases Vascular Flow

Mirtogenol™(40 mg Pycnogenol®  and 80 mg Mirtoselect) q.d.

Desirable Potential Optional Supplements For Mitochondrial Protection

Beneficial Action

Recommended Dosage

Alpha Lipoic Acid , Acetyl L Carnitine

Anti-Oxidant Crossing Blood Brain Barrier, Raises Glutathione.  Together Maximize Lipid Metabolism. 

500 mg Alpha Lipoic q.d. to b.i.d. but there is no established RDA.  400 mg Acetyl L Carnitine

Curcumin

Neuroprotection, Immune System Modulation

500 mg q.d. but there is no established RDA

Ginkgo biloba

Anti-Oxidant, Facilitates Blood Flow. 

60 mg q.d. to b.i.d. with caution as it can thin blood

CoEnzyme Q10

Anti-Oxidation

100 mg q.d. but more needed if on Statins or Red Yeast Rice. There is no established RDA

Melatonin

Hormone Anti-Oxidant

1 mg to 6 mg. Take care as side effects. Typically 1 hour before bed.

Taurine

Amino Acid That Acts as an Anti-Oxidant and Neuroprotectant

2 to 6 grams per day

N-acetyl cysteine

Anti-Oxidant and Neuroprotectant

Potential Issues…Avoid other than obtained in diet via cysteine

Resveratrol

Anti-Oxidant and Neuroprotectant,

Inhibits clotting.  Also facilitates estrogen

40 mg per day with caution


THE GLAUCOMA FORMULA BASED ON SYNERGISTIC USE OF THE MULTIVITAMIN WITHOUT INTRODUCING POTENTIAL SIDE EFFECTS

VITAMIN C (ASCORBIC ACID)…500 MG

Ω 3…1000 MG TRIGLYCERIDE BACKBONE

VITAMIN E (D-ALPHA TOCOPHERYL SUCCINATE)…200 IU

MIRTOSELECT…80 MG

PYCNOGENOL…40 MG

CURCUMIN…500 MG

LIPOIC ACID…500 MG

ACETYL-L-CARNITINE…400 MG

CO-ENZYME Q10…100 MG

TAURINE…2 GRAMS 

CRITICAL COMPONENTS OF THE MULTIVITAMIN FOR SYNERGISM WITH THE GLAUCOMA FORMULA ARE HIGHLIGHTED

VITAMIN A…2500IU

VITAMIN C…90 MG

VITAMIN D…500 IU

VITAMIN E…50 IU

VITAMIN K…30 MCG

THIAMIN…1.5 MG

RIBOFLAVIN…1.7 MG

NIACIN…20 MG

VITAMIN B6…3 MG

FOLIC ACID…500 MCG

VITAMIN B12…25 MCG

BIOTIN…30 MCG

CALCIUM…220 MG

PHOSPHORUS…110 MG

IODINE…150 MCG

MAGNESIUM…50 MG

ZINC…11 MG

SELENIUM…55 MCG

COPPER…0.9 MG

MANGANESE…2.3 MG

CHROMIUM…45 MCG

MOLYBDENUM…45 MCG

CHLORIDE…72 MG

POTASSIUM…80 MG

LYCOPENE…300 MCG

LUTEIN…250 MCG

BORON…150 MCG

VANADIUM…10 MCG

NICKEL…5 MCG

 

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About the Author(s)

Larry J Alexander OD FAAO

Larry J Alexander OD FAAO

Dr. Alexander (1948-2016) was a 1971 graduate of Indiana University School of Optometry. He served in the US Navy then served as a Professor at the University of Alabama Birmingham School of Optometry. Larry contributed to a number of chapters in textbooks and has published three editions of Primary Care of the Posterior Segment, as well as contributed to the professional literature. He also lectured extensively in the area of ocular and systemic disease. His areas of special interest included dysfunctional tear syndrome, glaucoma and macular degeneration.  His lessons are the basis for this site and he will be dearly missed. 

Comments (2)

  • Jerrold Russell

    22 February 2015 at 21:14 | #

    The most comprehensive, organized and well documented discussion on the subject that I have ever read.

    reply

    • Larry Alexander

      23 February 2015 at 18:51 | #

      Jerrold thank you for the kind words.

      Larry

      reply

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