DRY EYE: EMERGING OPHTHALMIC PROBLEM

DR. M. R. JAIN M.S, FICS ( USA), FACLP ( London ) FAMS
MEDICAL DIRECTOR
M. R. J INSTITUTE AND JAIN EYE HOSPITAL, JAIPUR

Dry eye is the most frequent disorder in Ophthalmology. Fortunately, only infrequently it becomes the most severe. Although the condition was recognized as a clinical disorder in the year 1920 and described clinically in the early 1930’s, the greatest amount of information both from an epidemiological and pathogenetic perspective has accrued during the last ten years.

What is dry eye?

Dry eye is a disorder of the preocular tearfilm that results in damage to the ocular surface and is associated with symptoms of ocular discomfort. Dry eye is characterized by instability of the tearfilm that can be due to insufficient amount of tear production or due to poor quality of tearfilm, which results in increased evaporation of the tears.
Dry eye therefore can be divided in two groups, namely
1. Aqueous production deficient
2. Evaporative

Prevalence of dry eye.

No authentic prevalence survey has been conducted in India but it is noted that out of the patients above the age of 30 years attending the outdoor, one out of every five has a complaint pertaining to dry eye. A recent survey conducted in year 2002, based upon a well – characterized population of adult men and women in the USA, identified a prevalence of 6.7 percent in women over the age of 50 and 2.3 % in men over the age of 55.These rates extrapolate to potentially 9.1 million dry eye patients in USA alone.
In women at the age of 50-52 when menopause usually sets in, an imbalance occurs between the oestrogen and androgen hormone due to decrease of androgens after the menopause. Decrease in androgen levels, excites inflammation in lacrimal gland and ocular surface, disrupting the normal homeostatic maintenance of the lacrimal gland and ocular surface.
The factors which has increased the incidence of dry eye can be narrated as under
a. increasing longitivity of the population
b.increased consumption of medication, both systemically and topically which have adverse effect on the production of high quality of tears
c. increased computer use
d. increased contact lens use and cosmetic surgery of LASIK/ LASEK
e better understanding and diagnosis of dry eye.
f possibly, adulteration in the food?

Pathogenesis of Dry Eye

It is an established fact that any lacrimal gland damage would result in decreased tear flow. This leads to decreased washout of the tear surface debris and bacterias as well as increased presence of inflammatory cytokines and decreased growth factors to maintain ocular surface integrity.
Almost all tear flow is due to a reflex mechanism due to stimuli from cornea sending impulses to the brain and to the lacrimal gland. Any thing which disturbs corneal sensations like hormonal imbalance, contact lenses, LASIK surgery or any other trauma to the eye, may it be surgical or accidental.

The aqueous deficient dry eye (keratoconjunctivitis sicca) is a disturbance of the neuro-humoral interaction of the ocular surface which interrupt secretomotor nerve impulses to the lacrimal gland that results in inflammatory suppression of aqueous secretion, a necessary component of the tearfilm, with subsequent damage to the ocular surface, producing symptoms of ocular irritation and discomfort. The evaporative dry eye is a disturbance of the stability of the tearfilm, which is usually due to abnormalities of Meibomian gland secretion or abnormal eyelid position and movement. Both types of dry eye results in damage to the ocular surface and symptoms of ocular discomfort and impaired visual function.

Tear Film
It comprises of three layers
Outer Lipid layer
It is formed by the oily secretion of Meibomian glands. It acts as a lubricant and prevent evaporation of tears.
Middle Aqueous Layer
It is the main tear fluid liberated from lacrimal gland and Accessory glands. It contains proteins, immunoglobulins, lysozyme, lactoferin and betalycin. It provides moisture to the eye, nutrition to the cornea and antibacterial activity. It provides the epithelial cells with glucose, oxygen and growth factors. It flushes out the debris and organisms from the corneal surface and drains into nasolacrimal canal.
Inner Mucous Layer
The innermost mucous layer of the tear film forms a highly hydrophilic wetting surface over the hydrophobic epithelial surface of the cornea and conjunctiva. The mucous also reduces the surface tension between the lipid layer of the tear film and the water layer, thus contributing to the stability of the tear film.

Classification Based On Etiology

1. Age Related. Lacrimal secretion begins to decrease after the age of 30 years. At the age of 6o, we reach the borderline between the production and need. At the age of 90, almost all persons have dry eye.
2. Hormonal. At the age of menopause almost every women develops dry eye either mild or moderate. Recent research has shown that it is due to lowering of androgen levels produced by the ovaries. Men develop dry eye related to hormones with less frequency and intensity than women.
3. Pharmacological. There is adverse effect on production of tears due to preservatives in teardrops used for long period. Glaucoma patients are more prone to this problem due to prolonged therapy.
Systemic drugs like antidepressants, antihypertensives, antihistaminics, anticholinergics, antipsychotics, angiolytics, antiparkinsonians, diuretics and hormones too can cause dry eye.

4. Immunological: This is related to autoimmune reaction in exocrine glands affecting outside body secretion like secretion of tears, saliva, sweat and vaginal secretions. The Sjogren’s syndromes are those in which patient’s immunological system attacks its own exocrine glands. Rheumatism, cicatricial pemphigoid and erythema multiform can lead to Sjogren’s syndrome.
5. Infection. Chronic infection of conjunctiva can affect mucous secretion leading to mucin deficiency and infection of lacrimal glands can affect aqueous secretion. Inflammation of lids may affect oily secretion. Any of the component if affected, tearfilm is disturbed.
6. Hypo nutrition. Avitaminosis A, and alcoholism that leads to poor intestinal absorption may give rise to dry eye.
7. Traumatic: Any trauma to the eye may it be accidental or surgical, can precipitate dry eye. Major surgeries like removal of tumour etc has more chances to cause dry eye. Cataract or glaucoma surgery too can be responsible especially in older persons.
8. Neurological.
a. Post LASIK. Lasik leads to the development of temporary dry eye in about 4 percent of patients. The Lasik induced dry eye tends to resolve approximately within 6 months.

b. Contact lens wear. Contact lenses when worn for prolonged period, affect corneal sensations and hence decrease tear secretion.
9. Defective glands. Responsible for aqueous, mucin and lipid secretions.
10. Inability to utilize tears. There is normal production of tears but cornea is unable to use them due to:
a. Epitheliopathy or corneal dystrophy, which decreases corneal, wet ability.
b. Due to lipid defect the lids are unable to circulate the tears over the entire ocular surface (lid paralysis, ectropion, lagophthalmos)
Symptoms
Dry eye patient can present any one of them or multiple symptoms:
Itching, burning, irritation, pain, discomfort. There may be pain and photophobia and blurred vision that improves with blinking. There is usually stringy ropy mucous discharge, which can increase in the afternoon. The discomfort in the eye usually increases while reading, watching T.V or working on the computer. At times there may be excess of watering, specially during breeze.
All these symptoms are exaggerated during dry and windy conditions.
Some of the patients give a typical history of desire to frequently sprinkle water into the eyes.
Signs

Tear Lake. Normally at the lower lid margin there is there is concave tear meniscus of 0.3 to 0.5 mm, which is called Tear Lake. In dry eye it is usually less than 0.1mm.
Debris. There is increased debris in the decreased tear lake. Mucous threads may be seen.
Other Signs. Redundant conjunctiva, injection of the conjunctival vessels, and sometimes mild chemosis may be present. In advanced cases, the conjunctival and corneal dryness may be very evident.
Staining.

1. Fluorescein stain. Fluorescein may stain any denuded area of corneal epithelium. The reduced tear lake could easily be appreciated with fluorescein.
2. Rose Bengal Stain. Rose Bengal (solution 1 % or strip) stains the damaged devitalized epithelial cells of the conjunctiva and cornea. It can detect even mild cases of Keratoconjunctivis Sicca (KCS) by staining the palpabral conjunctiva in the form of two triangles with their base towards limbus..
Tear Film Break Up Time. (TBUT)
It is a quantative measurement of tear film stability. A mucous deficiency results in beading of the aqueous tear around the small amount of available mucous on the epithelial surface and reduction of TBUT.
Diagnosis.

Diagnosis is most often based on the complaint of the patient without any evident cause in the eye. Quite often, persistent fishing for ropy mucous discharge is very classical and so is the importance of the complaint of increased discomfort in dry and windy environment.
Diagnostic tests mostly employed are as under
a. Shirmer Test. The test is used to quantitatively measure the tear secretions by the lacrimal gland, and should be done before any other examination as the manipulation of the eyelid and eye can alter the results of the test.
Shirmer I Test. Is used to measure tear secretion rate without anesthesia.
Shirmer II Test is done similar to Shirmer one but after instillation of anesthetic drops.
Other employed tests are :
a. Tear Function Index (TFI)
b. Fluophotometery.
c. Tear Osmolarity.
Treatment

Conservative
1. Patient Information. Patient must be educated and fully informed about the disease as well as he must be explained the limitations of medical management. This maintains the patient’s confidence in your line of treatment.
2. Controlling the surroundings. Special stress must be put to control the surroundings to minimize the severity of the condition.
a. Still Air. Patient must avoid sitting facing direct flow of air from air conditioners, ventilators, windows or fans. It is better that patient avoid sitting in front of door in a room. While driving car, the car window must be closed and the patient should use glasses. Car A.C. wind should not blow directly on the face.
b. Humid Air. Even if there is no refractive error, patient must wear glasses. Just by wearing spectacles, the humidity between the eyes and the spectacles rises by 2 %. Spectacles with side panels and moist chamber may be reserved for more severe cases. Humidifiers must be used in the rooms. There are air-conditioners available with attached humidifiers.
Special glasses with moist inserts ameliorate severe dry eye symptoms. The moist inserts on the side panels increase the ambient humidity, resulting in a decrease in the tear evaporation from the ocular surface. Another type of moist chamber is obtained more easily and less expensively by using swimming goggles. The most favorable range of relative humidity for minimizing tear evaporation is reported to be 40% to 50 %. Wet gauze mask is an alternative treatment modality.
c. Pure Air. Polluted air is very harmful for dry eye patients. Palpabral aperture must remain open as little as possible. Closed window in the car, helmet with a shield while driving scooter and covering your eyes with goggles while driving bicycle gives some relief. While reading books, the book should be kept as close to chest as possible so as to have minimum palpabral aperture. While looking down, ocular surface exposed to the air is just 1 square centimeter, whereas while looking straight, 2.0 sq. cm. and while looking up, 3,0 sq. cm.
Computer Vision Syndrome. While looking at the monitor, the eyes have the tendency to stare at the screen thereby reducing the blink to about 6-7 blinks a minute. If the computer is at a higher level than the eye, there is further increased evaporation of tears. To avoid computer vision syndrome, one must keep the computer at the lower level than the eyes and a habit must be formed to blink about 10-12 times per minute. When working for long period, one must close the eyes for some time or use some artificial teardrops.

Medical Management

Tear Substitutes.

Tear substitutes are the mainstay in the medical management of dry eye. Variety of tear substitutes is available. Hypotonic non-viscous solutions counteract the hyper tonicity in dry eye syndrome and can last up to two hours. Viscous solution contains cellulose as their base and thus last longer. Preservatives are added to increase the shelf life and the stability of the solution. The commonly used preservatives include benzalkonium chloride, thimerosal, and chlorhexidine. In spite of their low concentration, they can produce toxic effect on the cornea and conjunctiva and adversely affect the dry eye condition.

THE use of unpreserved collyria, and more recently preservatives that are transient or which rapidly oxidize to non-toxic compounds upon exposure to air and the ocular surface, has become routine for those patients requiring more than three or four lubricant drops per day. The tear supplements have focused on maintaining a hypotonic collyrium with normalization of electrolyte concentration to combat the damaging effects of hyper tonicity.

In India, preservative free tear substitutes used are :

Refresh Tear Drops (Allergan),
Gen Teal drops (Novartis) ,
Eye Mist Drops (Avesta) ,
Tear Drops (Milmet)
Celluvisc 1 % (Allergan)
Refresh Liquigel (Allergan)
Tear substitutes are instilled in the eyes 3- 6 times a day
depending on the severity of the condition. If necessary, Refresh
Liquigel or Celluvisc is instilled at bedtime.
Androgens

Role of androgen as a therapy is yet not well established though it is known that in females, lack of Androgens play important role in its etiology.
Topically, androgenic supplementation of artificial tears, appears to lower the Osmolarity of patient’s tears either by retarding evaporation or possibly stimulating tear secretion.

Tear Stimulants
Tear stimulants have as yet not proved very useful.
Recent trials with purinergic P2Y2 agonist has reached phase three trial in USA. The medication designated diquafosol tetrasodium (Inspire Pharmaceuticals, USA) has been extremely well tolerated and increases tear film volume and mucin content. The pharmacological action is to increase fluid transport across the conjunctiva and stimulate mucin release from goblet cells.

Cyclosporine A

Looking to the immunological aspect of the disease, cyclosporin A in the form of topical drops (0.005 %) is being used in moderate to severe form of DES to treat inflammation of the ocular surface and lacrimal gland. The drops are instilled twice a day and the beneficial results are observed within four to six months. The drug may have to be used for whole life. Cyclomune is an immunomodulator. It selectively suppresses lymphocytic functions involved in a disease without actually suppressing the entire immune system. It inhibits T helper cells that are known to cause inflammation of the ocular surface and lacrimal glands in patients with dry eye. The main indication for the use of Cyclomune is surface staining of the cornea. Instillation of drops is associated with stinging sensations, which gradually decrease.
Cyclosporine drops are marketed by Allergan as Restasis in USA and by Avesta in India as Cyclomune

Meibomitis.
A recent study in USA has shown that about 38 % patients with dry eye has concurrent Meibomian gland involvement. Hot wet compresses, betadain scrub, eyelid massage and oral tetracycline or doxycycline, may treat Meibomian inflammation.

Topical Steroids (Soft steroids)

Topical steroids are being tried in some of the resistant or advanced cases of dry eye or in patients who have severe itching. Lodeprednol etabonate 0.2 % is a good choice for long-term use. It is soft steroid that is activated by enzymes as it passes through the cornea. It seems to have very little effect on IOP. It is marketed as Alrex by Bausch & Lomb
Mucolytics.
Topical 5 percent Acetylcysteine drops are recommended for instillation four times a day. It is effective in eyes with excessive mucous.
Future Therapies.
Apart from tear substitutes, anti-inflammatory therapy, androgen hormone replacement, and tear stimulant diquafosol tetrasodium may form main therapeutic measures. Herbal supplements such as oil of primrose and flax seed oil are reported to be help in relieving symptoms of dry eye and Meibomitis. Essential fatty acids of omega 3 and specially omega 6 category as food supplements are showing some promising results.
Surgical Management

A. Canalicular Obstruction by Punctal Plugs
It is a simple procedure that decreases the tear drainage markedly and improves the qualitative and quantitative component of tears. A decrease in osmolarity of the tears is noted. Improvement can be seen by Schirmer and TBUT test.
B. Punctal Patch Technique This is most efficacious surgical technique for long lasting occlusion of the lacrimal drainage system. In this technique a raw area is created surrounding upper and lower puncta. A piece of bulbar conjunctiva is taken and transplanted to the punctal wound with its raw surface in contact with the lid and sutured to it with four 9. 0 stitches.
Summary

Dry eye disease appears to be on increase due to multiple factors. Inspite of great advance in understanding and diagnosing the disease, the disease remains a challenge to medical profession. Preservative free drops have significantly improved the quality of life of dry eye patients. Anti-inflammatory therapy, androgen hormones and tear stimulant, namely, diquafosol tetrasodium and probably some herbal drugs hold great hope for a DES patient.

The procedure ‘LASIK’ for correction of refractive errors has now become very familiar. This laser correction of vision has changed the lives of millions for the better.
For more than a century, spectacles have provided good vision for people with almost all kinds of refractive errors. Spectacles are still the first option to start with. Many individuals have even used them in distinctly different styles and shapes and made them a part of their identity.
For those who were looking for alternatives, contact lenses provided the break, to show off their faces without spectacles.
More and more people are on the lookout for a ‘permanent’ solution for their refractive errors. LASIK is being offered as a magic cure by some commercial outfits. A lowdown on the pros and cons of this refractive surgery procedure shall help one to make an informed decision, whether to go for it or not.
Refractive surgery for vision correction has made tremendous advances since its start as radial keratotomy, or RK. The concept was first used in the early 1960s by Sato in Japan. The original procedure, however, didn’t work for most people.
RK is the earliest form of vision correction surgery. It was perfected in the 1970s by the Russian ophthalmologist Fyodorov and was first performed in the United States in 1978.
Today, several different options exist to help the majority of people who wear glasses or contact lenses reduce their dependence on their corrective lenses. In almost all cases, refractive surgery is elective and cosmetic.
Vision correction surgery can benefit people with myopia (nearsightedness), hyperopia (farsightedness), and astigmatism (vision distortion due to variation in corneal surface in different meridians).
[Vision correction surgery will usually not benefit people with presbyopia (defective near vision). This condition affects all people older than 40-45 years. In presbyopia, the lens loses its ability to change shape and thus focus the eye for near vision. A further refinement to LASIK, called multifocal LASIK, is undergoing clinical trials and may be available very soon]
Not every person requesting laser vision correction is a candidate for the surgery. Factors, such as very high refractive errors, certain ocular diseases, and certain medical diseases, may prevent a person from being a candidate for refractive surgery.

Minimum criteria for LASIK could be:
Age 18 years or older for myopia or hyperopia
Age 21 years or older for astigmatism
Stable refraction for at least 1 year
There are three main steps to the procedure:
1) Creation of a corneal flap, using a microkeratome
2) Corneal stromal ablation, using excimer laser
3) Replacing the corneal flap

The Risks
As with any surgical procedure, complications may occur. In laser vision corrections, complications may occur during the procedure (intraoperatively) or during the healing period following the procedure (postoperatively).
Complications during the procedure mainly occur during the creation of the flap with the microkeratome. These include incomplete flaps, irregular or small flaps, buttonholes, decentered flaps, or free flaps. When these complications occur during surgery, the procedure is stopped, and the flap is put back in place. The flap is then allowed to heal for 3-6 months. After this healing period, the procedure may be repeated and the flap may be recut.
Early complications after the procedure include dislodged flaps and flap folds. Folds can be described as macrofolds and microfolds, which can cause visual distortion. Dislodged flaps and macrofolds require that the flap be lifted and repositioned, thus eliminating the folds.
Other complications include interface debris (debris between the flap and the lasered cornea), epithelial downgrowth into the flap, epithelial defects, or corneal abrasions.
Infection of the cornea (infectious keratitis) and inflammation can also occur. Infections are rare but very serious if they do occur.
Refractive complications include undercorrections or overcorrections, which may require additional laser correction (an enhancement procedure) and decentered laser ablation, which may require retreatment or the use of a hard contact lens.
Laser vision correction could also induce astigmatism. Halos and glare, especially at night, may occur after the procedure. They are common after the procedure but usually get better gradually.
Regression of the procedure may occur and would require additional laser treatment or the use of glasses or contact lenses.
After the surgery, dry eye symptoms are the most common complaint. Dry eyes following LASIK may occur due to a decrease in corneal sensation because the microkeratome cuts through the superficial corneal nerves. This may result in a decreased blink rate and, thus, a decrease in rewetting of the eye. Improvement occurs with the use of artificial tear lubrication and with time.

Every person who is considering LASIK must undergo a complete eye examination prior to surgery.
During this examination, the corneal thickness will be measured with a device called a pachymeter. Adequate corneal tissue remaining after the procedure is extremely important. If the cornea is too thin, LASIK may not be able to treat the refractive error without thinning the cornea too far, inducing a complication.
A map of the corneal surface, called topography, is performed to rule out any corneal problems that may lead to a poor result with the surgery, such as keratoconus. The size of the pupils in light and dark will be measured. People with large pupil diameters in a dimly lit room may not be good candidates for the LASIK procedure.
The refractive error will be checked prior to dilation of the pupils and again after dilation. This helps ensure that the refractive error is stable. A glaucoma test and a thorough retinal examination are also performed at this visit.
During the Procedure
The procedure is performed on an out-patient basis. It takes about 10 minutes to perform for each eye. Both eyes are usually done during the same procedure, although there may be times when the patient or the surgeon prefers to have each eye done at different times.
Prior to the procedure, most people will be given medication for relaxation. The eyes are anesthetized with topical anaesthetic drops prior to the procedure. The eyes are cleansed, and drapes are applied to the eyelids to cover the eyelashes so they cannot interfere with the procedure. The eyelids are held open with an eyelid retractor.
An instrument called a microkeratome is used to create the LASIK flap. Initially, a small mark is placed on the cornea to help realign the flap at the completion of the procedure. A suction ring is applied to the eye, which may cause a pressure sensation. The microkeratome creates a flap in the anterior cornea at about 20-25% of its depth. The flap is then retracted back, exposing the corneal stroma or inner layer of the cornea.
Next, the laser is used to resculpt the corneal surface. The laser portion of the surgery can take several seconds to several minutes to complete. During this time, the patient has to look continuosly at a target, such as a flashing red light or a flashing green light. The laser itself is invisible, although ne can hear a loud tapping sound when the laser is firing.
In myopic corrections, the laser works to flatten the central cornea. This allows light rays to focus onto the retina, reducing myopia.
In hyperopic corrections, the laser is used in the peripheral cornea, causing a steepening of the central cornea, which allows better focusing of light rays onto the cornea.
Once the laser portion of the procedure is completed, the flap is returned to its original position on the cornea. Through the natural characteristics of the cornea, the flap will seal itself in place after a few minutes. Usually, the flap is allowed to dry for approximately 3 minutes prior to removing the lid retractor. At the end of the procedure, antibiotic and anti-inflammatory drops are put into the eyes.

After the Procedure
As with any surgery, some discomfort is expected following LASIK too.
Immediately following the procedure, antibiotic drops and steroid drops will be placed into the eyes. The flap will be checked under magnification (using slit-lamp) to be sure it is smooth and wrinkle-free with no debris under it. Finally, protective eyewear, such as goggles or shields, will be placed on the eyes to protect them. With the goggles in place, one will be less likely to rub the eyes, which may cause dislocation of the flap.
The hours following the procedure can be more uncomfortable than the procedure itself.
Immediately after surgery, one may experience just a small amount of scratchiness of the eyes, or tears and burning sensation. These symptoms usually go away in about 6 hours. Your surgeon may encourage you to take a nap after the procedure. Taking a nap will help you through the most uncomfortable part of the healing with minimal discomfort.
Immediately after the surgery, most people will notice an improvement in their uncorrected visual acuity. The vision may appear rather smoky, as if one is looking through a smoke-filled room. The vision will stabilize in about 1 week.
The Good News
Almost all of the complications of LASIK are due to the complexity of the first step [unpredictable results during use of the microkeratome (the ‘blade’) and variations in surgeons’ skills].
The arrival of the Femtosecond laser has automated this step completely, without the need for a microkeratome.
The results are wonderfully better and more and more centres are beginning to offer this new procedure to their patients.
This type of LASIK is now marketed as All Laser LASIK or iLASIK (meaning intraLASIK, from a manufacturers name for femtosecond laser) or Blade-Free LASIK.
The flip side though, is the very high cost of this new technique, which is expected to come down in due course.

Diabetes and the Eye
A sweet disease of bitter company

Facts that every Diabetic should know

1. Diabetics are a higher risk of developing eye problems – some of which can lead to irreversible blindness

2. The longer the duration of Diabetes and worse the control – more are the chances of developing eye problems – Repeated Testing and Adequate control over long period of time is the best way

3. Eye Problems can go totally un-noticed unless Vision is tested under standard conditions and retina seen by qualified eye specialist

4. Diabetics are at a higher risk of developing
o Cataract (Safed Motia)
o Glaucoma (Kala Motia)
o Diabetic Retinopathy (Spots on the Retina)

5. Cataract is curable with Surgery and IOL Implant and Glaucoma leads to progressive blindness-which is irreversible.

6. Early Diabetic Retinopathy can be best detected by Fundus Fluroscien Angiography FFA (where a dye is injected into the vein of the hand and Retinal Photographs taken using special light and instruments)

7. Diabetics should have complete eye check up by an Eye Specialist as per guidelines of American Academy of Ophthalmologists recommendations:
o All Diabetics at the time of first diagnoses & of more than 5 years duration of disease – at-least once a year if no retinopathy
o All Diabetics with diagnosed retinopathy, on insulin or unstable control – once every 6 months.

8. Laser and other Forms of Treatment prevent the rapid progress of disease and in some cases can reverse early changes and slow down the onset of irreversible blindness.


Contributed by

Dr.Sanjay Dhawan
M.B.B.S., D.O., M.S.(Ophthal)
Senior Eye Specialist (Gold Medallist)
Mob: 9810635968

Dr.Sanjay Dhawan is Senior Consultant at the Department of Ophthalmology at Maharaja Agarsen Hospital and Max Hospital Pitampura and has a practice at A-52. Meera Bagh. Paschim Vihar. He joins this hospital after a 12 year stint abroad working with various international eye care NGO’s – Sight Savers International of UK and ORBIS International of USA. Can be contacted on Mobile: 9810635968

ANTIOXIDANTS IN OPHTHALMOLOGY
EVOLVING CONCEPTS

Prof Dr M R Jain, FAMS



ABSTRACT
As one ophthalmologist had mentioned way back a decade ago: ‘advocating antioxidants is like shooting in the dark’. It is no more now. Today the pathophysiology of free radical mediated eye degenerative diseases like age-related macular degeneration and cataract are well established, and so is the definite role of antioxidants, particularly carotenoids. As far as eye is concerned, lutein and zeaxanthin have a vital role to play, and these two carotenoids are a must for the eye to be well protected form developing macular degeneration as well as cataract. In addition, lycopene, another carotenoids has a special place in eye defense since it is the best quencher of singlet oxygen - a reactive oxygen species which causes havoc particularly in the eye.


INTRODUCTION
Free radical chemistry began in 1900s when they were determined as cause for fat spoilage. Importance of free radicals in human diseases pathophysiology was first recognized in 1969 when McCord & Fridovich isolated the first antioxidant enzyme superoxide dismutase.

The controversy as regards the use of antioxidants, particularly carotenoids, in ophthalmic diseases seems to be resolving due to advances made in measuring their levels in foods and tissues. There is consistent experimental and epidemiological evidence to substantiate the role of particularly lutein and zeaxanthin in prevention and, to a certain extent, cure of early age-related macular degeneration (ARMD) and cataract formation. Also clinical observations depending upon the recommended dietary modification and therapeutic supplementation presently are encouraging.



FREE RADICALS
DEFINITION
A free radical is defined as any species capable of independent existence and contains one or more unpaired electrons.



HOW FREE RADICALS ARE FORMED?
The various tissues in the human body are formed by innumerable molecules. Each molecule consists of two or more atoms joined together by chemical bonds. An atom, the smallest particle of an element, consists of a core which contains positively charged protons (or positrons) as well as neutral neutrons. In the orbit of each atom (referred to as orbital) are present the electrons (or negatrons). Each orbital can accommodate a maximum of two electrons both of which spin in opposite directions.

Most molecules are non-radical since they contain a paired set of electrons. But oxygen is always electronegative. As a consequence, it pulls electrons away from other atoms (including oxygen itself) and renders these as free radicals.
Oxygen-derived free radicals have a lifespan of only a few microseconds. Their concentration at any single site is miniscule. However the danger lies in their ability to combine with another nonradical to render the latter as free radical. Normally, bonds don’t split in a way that leaves a molecule with an odd, unpaired electron. But when weak bonds split, free radicals are formed. Free radicals are very unstable and react quickly with other compounds, trying to capture the needed electron to gain stability.

Fig: Serial formation of free radicals.



Generally, free radicals attack the nearest stable molecule, thereby "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself. This leads to a process of chain reaction. Once such a process has started, it can cascade, finally resulting in the disruption of a living cell.

Radicals can react with other molecules in a number of ways. If two radicals meet, they can combine their unpaired electrons symbolized by.) and join to form a covalent bond (a shared pair of electrons). The hydrogen atom, with one unpaired electron, is a radical and two atoms of hydrogen easily combine to form the diatomic hydrogen molecule:
H. + H.

Radicals react with nonradicals in several ways. A radical may donate its unpaired electron to a non-radical (a reducing radical) or it might take an electron from another molecule in order to form a pair (an oxidizing radical). A radical may also join onto a nonradical. Whichever of these three types of reaction occurs, the nonradical species becomes a radical. A feature of the reactions of free radicals with nonradicals is that they tend to proceed as chain reactions, where one radical begets another.



SOURCES OF FREE RADICALS
Some free radicals arise normally during metabolism. Sometimes the body’s cells or its immune system purposefully create them to neutralize viruses and bacteria. However, environmental factors such as pollution, radiation, cigarette smoke and herbicides can also generate free radicals. Free radicals causing structural damage (to proteins) resulting in aging changes such as cataract and ARMD.

An adult utilizes 3.5 ml oxygen per kg body weight per minute. Assuming a body weight of 70 kgs, this works out to 352.8 liters per day. Even if 1% of oxygen is converted to free radicals, this amounts to 1.72 kg of free oxygen radicals per year!



EXAMPLES SOURCES OF FREE RADICALS
Some free radicals well studied free radicals are:
• SUPEROXIDE ANION (O2.)
• HYDROXYL RADICAL (OH.)
It is important to note that free radicals such as hydroxyl radical differ from hydroxyl ions in their content of electrons.



REACTIVE OXYGEN SPECIES
These are partially reduced oxygen species which do not contain any unpaired electron. Examples of reactive oxygen species are:

• HYDROGEN PEROXIDE (H2O2)
• HYDROPEROXY RADICAL (HOO-)
• HYPOCHLOROUS ACID RADICAL (HOCl)

Under certain conditions reactive oxygen species have potential to enter free radical reactions to form the more toxic free radicals. Another reactive oxygen species, which is not a free radical, is singlet oxygen (O). In this, a rearrangement of electrons has occurred which allows it to react faster with biological molecules - as compared to ‘normal’ oxygen.



ANTIOXIDANTS
DEFINITION
Antioxidants can be defined as substances whose presence in relatively low concentrations significantly inhibits the rate of oxidation of the targets.



HOW ANTIOXIDANTS WORK?
Antioxidants serve as natural protectors in the body, mopping up free radicals and reactive oxygen species, which are potentially damaging. Antioxidants protect the tissues in 4 ways:

• Physically separating the free radicals / reactive oxygen species from the susceptible molecules of the human body.
• Providing molecules which effectively compete for oxygen.
• Rapidly repair the damage caused by free radicals / reactive oxygen species.
• Lyse the free radicals / reactive oxygen species and rapidly remove these.



CLASSIFICATION OF ANTIOXIDANTS
• ANTIOXIDANT ENZYMES
• Superoxide dismutase
• Catalase
• Glutathione peroxidase
• PREVENTIVE ANTIOXIDANTS
• Ceruloplasmin
• Transferrin
• Albumin
• CHAIN-BREAKING ANTIOXIDANTS
• Water-soluble*
• Uric acid (200-400 mmol/L)
• Ascorbate (25-100 mmol/L)
• Thiols (400-500 mmol/L)
• Bilirubin (10-20 mmol/L)
• Flavanoids
• Fat-soluble*
• Tocopherols (20-30 mmol/L)
• Ubiquinol-10 (<2 mmol/L)
• Beta-carotene (1-2 mmol/L)
• Estrogens
* optimal blood level given in brackets


The most important antioxidants are three vitamins and three minerals.

• ANTIOXIDANT VITAMINS
• CAROTENOIDS
• VITAMIN E
• VITAMIN C
• ANTIOXIDANT MINERALS
• SELENIUM
• ZINC
• MANGANESE
• COPPER




CAROTENOIDS
Carotenoids circulate in lipoproteins; 53% of beta carotene occurs in low density lipoproteins. Besides the well known beta carotene, the other carotenoids of human importance are:

• Lutein
• Zeaxanthin
• Lycopene
• Alpha carotene
• Beta cryptoxanthin

As far as the eye is concerned, Lutein and zeaxanthin are exclusively concentrated in the macula, lens and iris. The retina and choroids additionally contain lycopene, alpha- and beta carotene. In the ciliary body, all the carotenoids taken in foodstuff or as dietary supplement get accumulated.



VITAMIN E
Being a fat soluble vitamin, alpha tocopherol is abundant in all cell membranes as well as in lipoproteins. In the eye, vitamin E is present in retina and choroids, and balance in iris and ciliary body. It is important in protection of rods and cones in retina, and also for preventing free radical damage to lens. Vitamin E acts synergistically with vitamin C, beta carotene and selenium for better functioning of glutathione.



VITAMIN C
Vitamin C is protective for the cytoplasm & is also most important for plasma defense. It also occurs in certain cells like muscle, adrenals and eye. Vitamin C has the capacity to regenerate vitamin E. It is more significant in combating free radicals formed due to pollution and cigarette smoke. Vitamin C especially concentrates in ocular tissues and is the first antioxidant to tackle free radicals.



ZINC, MANGANESE & COPPER
Zinc (Zn), manganese (Mn) and copper (Cu) are constituents of superoxide dismutase (SOD) antioxidant enzyme. SOD is widely distributed in tissues as well as fluid compartments. CuZnSOD is present in cytoplasm and nucleus, MnSOD in operates mitochondria whilst CuSOD is most distributed in plasma. SOD attacks free radicals like hydroxyl radical to convert these into hydrogen peroxide.

Besides, Zn serves an important structural role, whilst Cu is necessary for functioning of another antioxidant enzyme called as catalases. Hydrogen peroxide is converted by catalases into harmless water and molecular oxygen.

In the retina, SOD plays an important role by scavenging free radicals to prevent the oxidative damage which plays a role in the development of drusen, an early sign of ARMD. Catalases, on the other hand, are vital for lens protection.


SELENIUM
Selenium (Se) is the most important dictator of glutathione peroxidase activity. Glutathione peroxidase is concentrated in various tissues, besides blood and synovial fluid. In tisues, it operates in the cytoplasm and mitochondria principally. Like catalases, glutathione peroxidase breaks down hydrogen peroxide, besides reducing lipid peroxidation like vitamin E and beta carotene.

Glutathione peroxidase and related enzymes in the retina, plus the precursor amino acids (N-acetylcysteine, L-glycine, and glutamine and selenium) are protective against damage to human retinal pigment epithelium cells. Glutathione peroxidase prevents free radical-induced apoptosis (cell suicide) and helps prevent or treat ARMD.



CAROTENOIDS
DEFINITION
More than 500 distinct compounds are today identified as naturally occurring carotenoids. They include cyclic hydrocarbon-carotenoids (carotenes), acyclic hydrocarbon carotenoids (lycopene), and oxygenated hydrocarbon carotenoids (xanthophylls like lutein and zeaxanthin).

Handelman and associates noted carotenoids concentration in the macula to be 5-fold higher compared to peripheral retina and 500 times more than the concentration in other tissues. Lutein is the major carotenoid in the peripheral retina, whereas zeaxanthin becomes more and more dominant as the foveal centre is approached. The proportion of lutein to zeaxanthin in macula is 1:2 and the proportion is reversed in the peripheral retina. The distribution of xanthophyll carotenoids suggests a possible role of lutein in protecting the rods and for zeaxanthin in protecting the cones that are concentrated in the central retina. The human lens carotenoids content is 10-20 ng/gm of wet tissue, and the ratio is 1.6:2.2 for Lutein and zeaxanthin.

Another most important dietary antioxidant of ocular significance is lycopene, which is however, conspicuous by its absence in macula. Due to its presence in high concentration in circulating blood in the eye, lycopene plays a prominent role in prevention of macular degeneration mainly by its very potent singlet oxygen quenching capacity.





FOCUS ON CAROTENOIDS IN ARMD
ARMD - INTRODUCTION
In developed countries, ARMD is the leading cause of blindness amongst the elderly (more than 60 years) with a prevalence ranging between 2 to 7% for severe (wet) form and a range of 12 to 30% for the dry form. The disease has caused irreversible visual impairment in an estimated 1.7 million Americans over the age of 65 years. The number of cases of ARMD has been predicted to increase from 2.7 million in 1970 to 7.5 million by the year 2030.

In India, the incidence of ARMD affects approximately 4-5 per cent of the population over the age of 50 years and may be affecting 19-20 per cent of people above 70 years of age. Early disease is characterized by yellowish-colored subretinal drusen. Late disease, which may be ‘dry’ or ‘wet’, may lead to significant loss of central vision. Wet form occurs only in 10 percent of population.



ARMD - PATHOPHYSIOLOGY
The light must pass the macular pigment, which contains abundance of zeaxanthin and lutein before striking the photoreceptors. If any damage to the rods and cones is to be prevented the short wave length of light rays (<500 nm range) must be filtered. This is accomplished as follows:

• 5-286 nm wavelength (ultraviolet C rays): filtered by the earth’s ozone layer.
• 286-320 nm wavelength (ultraviolet B rays): filtered by cornea.
• 320-400 nm wavelength (ultraviolet C rays): filtered by lens.
• 400-500 nm wavelength (visible blue light): filtered by lutein / zeaxanthin in macula.

The light entering the retina is between the wavelengths of 400 to 700 nm. The eye would be in perfect focus for daylight only at 560 nm, and even at night 500 nm wavelength of light is optimal for functioning of rods. Hence, filtering out 400-500 nm wavelength of light prevents damage to macula without affecting vision.
Thus macular pigments represent a significant filtering element and hence protect against the light–initiated cumulative oxidative damage. The macular pigment also removes much of the blurry, short wave blue and blue-green light that results from the eye’s chromatic aberration. Apart from this the earth’s atmosphere through which we view objects almost always contain small-suspended particles, which scatters short wave length light more than other wavelengths and results in a bluish veiling luminance.
The eye and skin are the only structures which have dual exposure to oxygen and light. In presence of blue light (400-500 nm wavelength) the oxygen will be split into singlet oxygen which is one of the most deadly reactive oxygen species as far as the eye is concerned. The blue light has potential to split molecular oxygen due to the high energy contained in it.

The singlet oxygen and other free radicals formed inside the eye initiate lipid peroxidation of photoreceptors. The polyunsaturated fatty acids in the outer membrane of rods and cones are attacked by free radicals and singlet oxygen species to result in damage of these photoreceptors. As a consequence, there is accumulation of lipofuscin by retinal pigment epithelium which then contributes in druse formation.



ARMD - MEDICAL MANAGEMENT
The damage to macula and formation of drusen can be prevented by filtering out the damaging blue light of the visible spectrum. This is possible by the macula, if its content of lutein and zeaxanthin are adequate. The additional available of lycopene in adequate amounts is of paramount importance in tackling the singlet oxygen single this carotenoids is the best antioxidant known for quenching this reactive oxygen species. In addition, glutathione peroxidase and SOD too have been shown to have preventive benefit in ARMD.



FOCUS OF CAROTENOIDS IN CATARACT
CATARACT - INTRODUCTION
Cataract is a multifactorial disease. Oxidative stress together with weakened antioxidant defense mechanism is attributed to the changes observed in human diabetic cataract. Oxidative damage to the lens has been recognized as a primary event in the pathogenesis of many forms of cataract. Consistent with this view, epidemiological reports have identified factors related to oxidative process that both increase (eg smoking and light exposure) and decrease (eg antioxidant intake) cataract risk.

Epidemiological studies provide evidence that nutritional antioxidants slow down the progression of cataract.



CATARACT - PATHOPHYSIOLOGY
Oxidative stress is high in the eye due to ultraviolet rays which promote liberation of free radicals and singlet oxygen. The epidemiological evidence to support the possibility that lutein and zeaxanthin have an important role in reducing the risk of cataract is somewhat consistent, and justifies the belief in free radical & reactive oxygen species mediated damage to the lens.

Few of the recent studies have stressed the significance of vitamin C, E and selenium in the etiology of cataract. Role of vitamin E has been more specifically stressed by several workers. Low blood levels of vitamin E are associated with approximately twice the risk of both cortical and nuclear cataracts, compared to median or high levels. Smokers are 2.6 times likely to develop posterior subcapsular cataracts more than nonsmokers. Patients with senile cataracts were found to have significantly lower blood and intraocular levels of the mineral selenium than control.



CATARACT - MEDICAL MANAGEMENT
Lower prevalence of nuclear cataract in women or men was associated with intake of lutein and zeaxanthin in high doses. Furthermore, in prospective cohort studies it was noted that people who consumed diet rich in lutein and zeaxanthin, had 20-25 percent lower risk of cataract extraction and 70 percent lower risk of cataract extraction under the age of 65 years.

Experimental study in human lens epithelial cells (HLEC) in culture was evaluated and it was concluded that addition of lycopene had a protective effect to prevent vacuolization of epithelial cells. It was observed that there was as positive effect of retardation of lens opacities due to lutein and zeaxanthin in the aging lenses.

In an 8 year prospective cohort study, Hankinson et al reported that an elevated intake of spinach, which is high in lutein and zeaxanthin (but low in beta carotene content) was most consistently associated with a lower risk of cataract extraction, whereas high beta carotene and vitamin E intakes alone had no beneficial effects against cataract prevention.

This study corroborated data from Jaques et al 1988 who demonstrated that persons with slightly elevated levels of plasma total carotenoids had a 25% lower risk for any type of cataract.



ANTIOXIDANTS IN RETINITS PIGMENTOSA
There is possibility that lutein may slow degeneration of vision in retinitis pigmentosa, a heterogeneous group of slow retinal degenerations. However, only preliminary data in a very small number of patients has been published in which lutein slowed vision loss associated with retinitis pigmentosa in one.






ANTIOXIDANTS IN DIABETIC RETINOPATHY
Several studies are in progress as regards role of antioxidants in diabetic retinopathy and glaucoma but as yet none is conclusive.



CONCLUSION
The overwhelming body of evidence points to significant beneficial effects of nutritional supplementation for most degenerative eye conditions. Important to remember is that most of the above studies used blood levels and food intakes associated with a normal diet. Taking supplements, specifically containing zeaxanthin, lutein and lycopene in adequate doses, which are theorized to provide protection to macula and lens with adequate doses, may have a much more protective effect than dietary levels alone. With so little risk, and the other potential health benefits from taking nutritional supplements, it would certainly seem prudent to try them, especially for macular degeneration where there are no real options.

Once the damage is done it cannot be reversed (except to a small degree), so prevention and early intervention is essential, especially if we have a family history of the disease. Of course, it's important to slow further progression at any stage of development. Prevention of lens and macula from the ultraviolet rays and hazard of smoking, however, needs to be over stressed.



























ANTIOXIDANTS IN OPHTHALMOLOGY
EVOLVING CONCEPTS

Prof Dr M R Jain, FAMS



ABSTRACT
As one ophthalmologist had mentioned way back a decade ago: ‘advocating antioxidants is like shooting in the dark’. It is no more now. Today the pathophysiology of free radical mediated eye degenerative diseases like age-related macular degeneration and cataract are well established, and so is the definite role of antioxidants, particularly carotenoids. As far as eye is concerned, lutein and zeaxanthin have a vital role to play, and these two carotenoids are a must for the eye to be well protected form developing macular degeneration as well as cataract. In addition, lycopene, another carotenoids has a special place in eye defense since it is the best quencher of singlet oxygen - a reactive oxygen species which causes havoc particularly in the eye.


INTRODUCTION
Free radical chemistry began in 1900s when they were determined as cause for fat spoilage. Importance of free radicals in human diseases pathophysiology was first recognized in 1969 when McCord & Fridovich isolated the first antioxidant enzyme superoxide dismutase.

The controversy as regards the use of antioxidants, particularly carotenoids, in ophthalmic diseases seems to be resolving due to advances made in measuring their levels in foods and tissues. There is consistent experimental and epidemiological evidence to substantiate the role of particularly lutein and zeaxanthin in prevention and, to a certain extent, cure of early age-related macular degeneration (ARMD) and cataract formation. Also clinical observations depending upon the recommended dietary modification and therapeutic supplementation presently are encouraging.



FREE RADICALS
DEFINITION
A free radical is defined as any species capable of independent existence and contains one or more unpaired electrons.



HOW FREE RADICALS ARE FORMED?
The various tissues in the human body are formed by innumerable molecules. Each molecule consists of two or more atoms joined together by chemical bonds. An atom, the smallest particle of an element, consists of a core which contains positively charged protons (or positrons) as well as neutral neutrons. In the orbit of each atom (referred to as orbital) are present the electrons (or negatrons). Each orbital can accommodate a maximum of two electrons both of which spin in opposite directions.

Most molecules are non-radical since they contain a paired set of electrons. But oxygen is always electronegative. As a consequence, it pulls electrons away from other atoms (including oxygen itself) and renders these as free radicals.
Oxygen-derived free radicals have a lifespan of only a few microseconds. Their concentration at any single site is miniscule. However the danger lies in their ability to combine with another nonradical to render the latter as free radical. Normally, bonds don’t split in a way that leaves a molecule with an odd, unpaired electron. But when weak bonds split, free radicals are formed. Free radicals are very unstable and react quickly with other compounds, trying to capture the needed electron to gain stability.

Fig: Serial formation of free radicals.



Generally, free radicals attack the nearest stable molecule, thereby "stealing" its electron. When the "attacked" molecule loses its electron, it becomes a free radical itself. This leads to a process of chain reaction. Once such a process has started, it can cascade, finally resulting in the disruption of a living cell.

Radicals can react with other molecules in a number of ways. If two radicals meet, they can combine their unpaired electrons symbolized by.) and join to form a covalent bond (a shared pair of electrons). The hydrogen atom, with one unpaired electron, is a radical and two atoms of hydrogen easily combine to form the diatomic hydrogen molecule:
H. + H.

Radicals react with nonradicals in several ways. A radical may donate its unpaired electron to a non-radical (a reducing radical) or it might take an electron from another molecule in order to form a pair (an oxidizing radical). A radical may also join onto a nonradical. Whichever of these three types of reaction occurs, the nonradical species becomes a radical. A feature of the reactions of free radicals with nonradicals is that they tend to proceed as chain reactions, where one radical begets another.



SOURCES OF FREE RADICALS
Some free radicals arise normally during metabolism. Sometimes the body’s cells or its immune system purposefully create them to neutralize viruses and bacteria. However, environmental factors such as pollution, radiation, cigarette smoke and herbicides can also generate free radicals. Free radicals causing structural damage (to proteins) resulting in aging changes such as cataract and ARMD.

An adult utilizes 3.5 ml oxygen per kg body weight per minute. Assuming a body weight of 70 kgs, this works out to 352.8 liters per day. Even if 1% of oxygen is converted to free radicals, this amounts to 1.72 kg of free oxygen radicals per year!



EXAMPLES SOURCES OF FREE RADICALS
Some free radicals well studied free radicals are:
• SUPEROXIDE ANION (O2.)
• HYDROXYL RADICAL (OH.)
It is important to note that free radicals such as hydroxyl radical differ from hydroxyl ions in their content of electrons.



REACTIVE OXYGEN SPECIES
These are partially reduced oxygen species which do not contain any unpaired electron. Examples of reactive oxygen species are:

• HYDROGEN PEROXIDE (H2O2)
• HYDROPEROXY RADICAL (HOO-)
• HYPOCHLOROUS ACID RADICAL (HOCl)

Under certain conditions reactive oxygen species have potential to enter free radical reactions to form the more toxic free radicals. Another reactive oxygen species, which is not a free radical, is singlet oxygen (O). In this, a rearrangement of electrons has occurred which allows it to react faster with biological molecules - as compared to ‘normal’ oxygen.



ANTIOXIDANTS
DEFINITION
Antioxidants can be defined as substances whose presence in relatively low concentrations significantly inhibits the rate of oxidation of the targets.



HOW ANTIOXIDANTS WORK?
Antioxidants serve as natural protectors in the body, mopping up free radicals and reactive oxygen species, which are potentially damaging. Antioxidants protect the tissues in 4 ways:

• Physically separating the free radicals / reactive oxygen species from the susceptible molecules of the human body.
• Providing molecules which effectively compete for oxygen.
• Rapidly repair the damage caused by free radicals / reactive oxygen species.
• Lyse the free radicals / reactive oxygen species and rapidly remove these.



CLASSIFICATION OF ANTIOXIDANTS
• ANTIOXIDANT ENZYMES
• Superoxide dismutase
• Catalase
• Glutathione peroxidase
• PREVENTIVE ANTIOXIDANTS
• Ceruloplasmin
• Transferrin
• Albumin
• CHAIN-BREAKING ANTIOXIDANTS
• Water-soluble*
• Uric acid (200-400 mmol/L)
• Ascorbate (25-100 mmol/L)
• Thiols (400-500 mmol/L)
• Bilirubin (10-20 mmol/L)
• Flavanoids
• Fat-soluble*
• Tocopherols (20-30 mmol/L)
• Ubiquinol-10 (<2 mmol/L)
• Beta-carotene (1-2 mmol/L)
• Estrogens
* optimal blood level given in brackets


The most important antioxidants are three vitamins and three minerals.

• ANTIOXIDANT VITAMINS
• CAROTENOIDS
• VITAMIN E
• VITAMIN C
• ANTIOXIDANT MINERALS
• SELENIUM
• ZINC
• MANGANESE
• COPPER




CAROTENOIDS
Carotenoids circulate in lipoproteins; 53% of beta carotene occurs in low density lipoproteins. Besides the well known beta carotene, the other carotenoids of human importance are:

• Lutein
• Zeaxanthin
• Lycopene
• Alpha carotene
• Beta cryptoxanthin

As far as the eye is concerned, Lutein and zeaxanthin are exclusively concentrated in the macula, lens and iris. The retina and choroids additionally contain lycopene, alpha- and beta carotene. In the ciliary body, all the carotenoids taken in foodstuff or as dietary supplement get accumulated.



VITAMIN E
Being a fat soluble vitamin, alpha tocopherol is abundant in all cell membranes as well as in lipoproteins. In the eye, vitamin E is present in retina and choroids, and balance in iris and ciliary body. It is important in protection of rods and cones in retina, and also for preventing free radical damage to lens. Vitamin E acts synergistically with vitamin C, beta carotene and selenium for better functioning of glutathione.



VITAMIN C
Vitamin C is protective for the cytoplasm & is also most important for plasma defense. It also occurs in certain cells like muscle, adrenals and eye. Vitamin C has the capacity to regenerate vitamin E. It is more significant in combating free radicals formed due to pollution and cigarette smoke. Vitamin C especially concentrates in ocular tissues and is the first antioxidant to tackle free radicals.



ZINC, MANGANESE & COPPER
Zinc (Zn), manganese (Mn) and copper (Cu) are constituents of superoxide dismutase (SOD) antioxidant enzyme. SOD is widely distributed in tissues as well as fluid compartments. CuZnSOD is present in cytoplasm and nucleus, MnSOD in operates mitochondria whilst CuSOD is most distributed in plasma. SOD attacks free radicals like hydroxyl radical to convert these into hydrogen peroxide.

Besides, Zn serves an important structural role, whilst Cu is necessary for functioning of another antioxidant enzyme called as catalases. Hydrogen peroxide is converted by catalases into harmless water and molecular oxygen.

In the retina, SOD plays an important role by scavenging free radicals to prevent the oxidative damage which plays a role in the development of drusen, an early sign of ARMD. Catalases, on the other hand, are vital for lens protection.


SELENIUM
Selenium (Se) is the most important dictator of glutathione peroxidase activity. Glutathione peroxidase is concentrated in various tissues, besides blood and synovial fluid. In tisues, it operates in the cytoplasm and mitochondria principally. Like catalases, glutathione peroxidase breaks down hydrogen peroxide, besides reducing lipid peroxidation like vitamin E and beta carotene.

Glutathione peroxidase and related enzymes in the retina, plus the precursor amino acids (N-acetylcysteine, L-glycine, and glutamine and selenium) are protective against damage to human retinal pigment epithelium cells. Glutathione peroxidase prevents free radical-induced apoptosis (cell suicide) and helps prevent or treat ARMD.



CAROTENOIDS
DEFINITION
More than 500 distinct compounds are today identified as naturally occurring carotenoids. They include cyclic hydrocarbon-carotenoids (carotenes), acyclic hydrocarbon carotenoids (lycopene), and oxygenated hydrocarbon carotenoids (xanthophylls like lutein and zeaxanthin).

Handelman and associates noted carotenoids concentration in the macula to be 5-fold higher compared to peripheral retina and 500 times more than the concentration in other tissues. Lutein is the major carotenoid in the peripheral retina, whereas zeaxanthin becomes more and more dominant as the foveal centre is approached. The proportion of lutein to zeaxanthin in macula is 1:2 and the proportion is reversed in the peripheral retina. The distribution of xanthophyll carotenoids suggests a possible role of lutein in protecting the rods and for zeaxanthin in protecting the cones that are concentrated in the central retina. The human lens carotenoids content is 10-20 ng/gm of wet tissue, and the ratio is 1.6:2.2 for Lutein and zeaxanthin.

Another most important dietary antioxidant of ocular significance is lycopene, which is however, conspicuous by its absence in macula. Due to its presence in high concentration in circulating blood in the eye, lycopene plays a prominent role in prevention of macular degeneration mainly by its very potent singlet oxygen quenching capacity.





FOCUS ON CAROTENOIDS IN ARMD
ARMD - INTRODUCTION
In developed countries, ARMD is the leading cause of blindness amongst the elderly (more than 60 years) with a prevalence ranging between 2 to 7% for severe (wet) form and a range of 12 to 30% for the dry form. The disease has caused irreversible visual impairment in an estimated 1.7 million Americans over the age of 65 years. The number of cases of ARMD has been predicted to increase from 2.7 million in 1970 to 7.5 million by the year 2030.

In India, the incidence of ARMD affects approximately 4-5 per cent of the population over the age of 50 years and may be affecting 19-20 per cent of people above 70 years of age. Early disease is characterized by yellowish-colored subretinal drusen. Late disease, which may be ‘dry’ or ‘wet’, may lead to significant loss of central vision. Wet form occurs only in 10 percent of population.



ARMD - PATHOPHYSIOLOGY
The light must pass the macular pigment, which contains abundance of zeaxanthin and lutein before striking the photoreceptors. If any damage to the rods and cones is to be prevented the short wave length of light rays (<500 nm range) must be filtered. This is accomplished as follows:

• 5-286 nm wavelength (ultraviolet C rays): filtered by the earth’s ozone layer.
• 286-320 nm wavelength (ultraviolet B rays): filtered by cornea.
• 320-400 nm wavelength (ultraviolet C rays): filtered by lens.
• 400-500 nm wavelength (visible blue light): filtered by lutein / zeaxanthin in macula.

The light entering the retina is between the wavelengths of 400 to 700 nm. The eye would be in perfect focus for daylight only at 560 nm, and even at night 500 nm wavelength of light is optimal for functioning of rods. Hence, filtering out 400-500 nm wavelength of light prevents damage to macula without affecting vision.
Thus macular pigments represent a significant filtering element and hence protect against the light–initiated cumulative oxidative damage. The macular pigment also removes much of the blurry, short wave blue and blue-green light that results from the eye’s chromatic aberration. Apart from this the earth’s atmosphere through which we view objects almost always contain small-suspended particles, which scatters short wave length light more than other wavelengths and results in a bluish veiling luminance.
The eye and skin are the only structures which have dual exposure to oxygen and light. In presence of blue light (400-500 nm wavelength) the oxygen will be split into singlet oxygen which is one of the most deadly reactive oxygen species as far as the eye is concerned. The blue light has potential to split molecular oxygen due to the high energy contained in it.

The singlet oxygen and other free radicals formed inside the eye initiate lipid peroxidation of photoreceptors. The polyunsaturated fatty acids in the outer membrane of rods and cones are attacked by free radicals and singlet oxygen species to result in damage of these photoreceptors. As a consequence, there is accumulation of lipofuscin by retinal pigment epithelium which then contributes in druse formation.



ARMD - MEDICAL MANAGEMENT
The damage to macula and formation of drusen can be prevented by filtering out the damaging blue light of the visible spectrum. This is possible by the macula, if its content of lutein and zeaxanthin are adequate. The additional available of lycopene in adequate amounts is of paramount importance in tackling the singlet oxygen single this carotenoids is the best antioxidant known for quenching this reactive oxygen species. In addition, glutathione peroxidase and SOD too have been shown to have preventive benefit in ARMD.



FOCUS OF CAROTENOIDS IN CATARACT
CATARACT - INTRODUCTION
Cataract is a multifactorial disease. Oxidative stress together with weakened antioxidant defense mechanism is attributed to the changes observed in human diabetic cataract. Oxidative damage to the lens has been recognized as a primary event in the pathogenesis of many forms of cataract. Consistent with this view, epidemiological reports have identified factors related to oxidative process that both increase (eg smoking and light exposure) and decrease (eg antioxidant intake) cataract risk.

Epidemiological studies provide evidence that nutritional antioxidants slow down the progression of cataract.



CATARACT - PATHOPHYSIOLOGY
Oxidative stress is high in the eye due to ultraviolet rays which promote liberation of free radicals and singlet oxygen. The epidemiological evidence to support the possibility that lutein and zeaxanthin have an important role in reducing the risk of cataract is somewhat consistent, and justifies the belief in free radical & reactive oxygen species mediated damage to the lens.

Few of the recent studies have stressed the significance of vitamin C, E and selenium in the etiology of cataract. Role of vitamin E has been more specifically stressed by several workers. Low blood levels of vitamin E are associated with approximately twice the risk of both cortical and nuclear cataracts, compared to median or high levels. Smokers are 2.6 times likely to develop posterior subcapsular cataracts more than nonsmokers. Patients with senile cataracts were found to have significantly lower blood and intraocular levels of the mineral selenium than control.



CATARACT - MEDICAL MANAGEMENT
Lower prevalence of nuclear cataract in women or men was associated with intake of lutein and zeaxanthin in high doses. Furthermore, in prospective cohort studies it was noted that people who consumed diet rich in lutein and zeaxanthin, had 20-25 percent lower risk of cataract extraction and 70 percent lower risk of cataract extraction under the age of 65 years.

Experimental study in human lens epithelial cells (HLEC) in culture was evaluated and it was concluded that addition of lycopene had a protective effect to prevent vacuolization of epithelial cells. It was observed that there was as positive effect of retardation of lens opacities due to lutein and zeaxanthin in the aging lenses.

In an 8 year prospective cohort study, Hankinson et al reported that an elevated intake of spinach, which is high in lutein and zeaxanthin (but low in beta carotene content) was most consistently associated with a lower risk of cataract extraction, whereas high beta carotene and vitamin E intakes alone had no beneficial effects against cataract prevention.

This study corroborated data from Jaques et al 1988 who demonstrated that persons with slightly elevated levels of plasma total carotenoids had a 25% lower risk for any type of cataract.



ANTIOXIDANTS IN RETINITS PIGMENTOSA
There is possibility that lutein may slow degeneration of vision in retinitis pigmentosa, a heterogeneous group of slow retinal degenerations. However, only preliminary data in a very small number of patients has been published in which lutein slowed vision loss associated with retinitis pigmentosa in one.






ANTIOXIDANTS IN DIABETIC RETINOPATHY
Several studies are in progress as regards role of antioxidants in diabetic retinopathy and glaucoma but as yet none is conclusive.



CONCLUSION
The overwhelming body of evidence points to significant beneficial effects of nutritional supplementation for most degenerative eye conditions. Important to remember is that most of the above studies used blood levels and food intakes associated with a normal diet. Taking supplements, specifically containing zeaxanthin, lutein and lycopene in adequate doses, which are theorized to provide protection to macula and lens with adequate doses, may have a much more protective effect than dietary levels alone. With so little risk, and the other potential health benefits from taking nutritional supplements, it would certainly seem prudent to try them, especially for macular degeneration where there are no real options.

Once the damage is done it cannot be reversed (except to a small degree), so prevention and early intervention is essential, especially if we have a family history of the disease. Of course, it's important to slow further progression at any stage of development. Prevention of lens and macula from the ultraviolet rays and hazard of smoking, however, needs to be over stressed.