Dry eye is one of the most common complaints seen by by csgirla

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									Continuing Professional Development                     .
                                               Jeffrey P Gilbard MD




                                               Nutrition and the eye
                                               Dry eye and the role of nutrition
                                                        ry eye is one of the most common complaints seen by


       ABDO has awarded this article
           2 CET credits (GD).
                                               D        optometrists. Epidemiological studies have found a prevalence
                                                        of about 15% in patients over the age of 50, with this
                                                        prevalence increasing with age1-3. As a result, with the
                                                changing demographics of Western civilisations, we are seeing
                                                increasing numbers of dry eye patients in our practices.

                                               Our understanding of dry eye disorders has         which either decreases tear production or
                                               improved dramatically in the past several          increases tear evaporation (Figure 1).
                                               years. This increased understanding has                Increased tear osmolarity is the link
                                               enhanced our ability to diagnose and treat         between changes in the lacrimal glands and
                                               patients who have these traditionally              lids, and disease of the ocular surface.
   The Association of Optometrists Ireland     challenging conditions. This article looks at      Studies of pre-clinical models of lacrimal
          has awarded 1 CET credit.            the natural history, diagnosis, and                gland disease and meibomian gland
                                               treatment of dry eye disorders – beginning         dysfunction show that the ocular surface
                                               with the underlying mechanisms.                    changes of dry eye disease are dependent
                                                                                                  upon and proportional to increases in tear
                                               Classifying dry eye disorders                      film osmolarity5-10. Clinical studies
                                               Central to virtually all dry eye disorders is a    corroborate these findings11,12.
                                               loss of water from the tear film, which                Decreased tear secretion may result from
                                               increases its osmolarity (concentration)           any condition which damages the lacrimal
                                               above the normal limit of 311mOsm/L4.              gland or its excretory ducts. Autoimmune
                                               Tear film osmolarity increases when water          disease with inflammation of the tear gland
      The College of Optometrists has          is lost from the tear film, while solutes,         is the most common cause. Less common
     awarded this article 2 CET credits.       such as sodium and potassium, are not.             causes include cicatricial ocular surface
          There are 12 MCQs with               This loss of water and increase in                 conditions. Tear secretion also may be
           a pass mark of 60%.                 osmolarity may result from any condition           decreased by any condition that decreases

                                                                                                                                           Figure 1
            Sponsored by

    a
                                                        Decreased tear secretion or increased tear film evaporation increase tear film osmolarity,
                                                                      causing the progressive ocular surface changes observed in dry eye disease
                                                                  (modified from W.B. Saunders Company, Philadelphia, In Albert DM, Jakobiec FA eds:
                                                                                            Principles and Practice of Ophthalmology, 1994; 257-76).
    SPECIALISTS IN EYECARE
                                                       Lacrimal gland disease
                                                                                        Decreased secretion
                                                 Decreased corneal sensation
                                                                                                                   Increased tear osmolarity
                                                   Increased palpebral fissure
                                                                                      Increased evaporation
                 Module 6 Part 6                 Meibomian gland dysfunction
    Nutrition and the Eye series
                                                                                                                                             Table 1
                                                                                                              Four milestones of dry eye disease
                                                      The natural history of dry eye disease dictates the sensitivity of diagnostic tests
                                                       and the efficacy of treatment. The most efficacious treatment now addresses
                                                                            all four milestones of dry eye disease.
                                                Milestones                           Diagnostic tests         Eye drop type
                                                1. Increased tear                    Patient history          Sufficiently/optimally
                                                   osmolarity                        Tear osmolarity          hypotonic

                                                2. Decreased goblet cell density Conjunctival staining        Tear-matched electrolyte balance
                        About the author           Decreased corneal glycogen Impression cytology
           Dr Jeffrey P. Gilbard is Clinical
                     Assistant Professor of     3. Increased corneal                 Corneal staining         Preservative-free lubricants of
               Ophthalmology at Harvard            epithelial desquamation                                    various viscosities
          Medical School and the Founder,
               Chief Executive Officer and      4. Decreased corneal cell            Tear film break-up       Preserved lubricants of
                   Chief Scientific Officer        surface glycoproteins             time                     various viscosities
             of Advanced Vision Research.



   34 | June 4 | 2004 OT
                                                                                       Continuing Professional Development




corneal sensation13, including diabetes,         wound healing.                                       Understanding the natural history of the
herpes zoster, long-term contact lens wear          However, the cornea does not stay              disease is crucial for interpreting and
and surgery which involves corneal               unaffected forever. Much later in the             evaluating diagnostic tests and appreciating
incisions or ablates corneal nerves.             natural history of the disease, after resisting   treatment advances (Table 1).
   Increased tear evaporation may occur in       changes in the tear film, the attachments
one of two ways:                                 between corneal cells finally loosen. The         Why dry eye?
1. Long-standing posterior blepharitis           result is an increase in corneal                  In most cases, the diagnosis of dry eye can
   causing meibomian gland dysfunction.          desquamation with a resultant decrease in         be made based upon the patient history.
   When these glands function properly,          corneal barrier function. Even later in the       The purpose of the examination is to
   they produce an oil layer which coats         natural history of the disease, changes in        determine why the patient has dry eye.
   the tear film and retards evaporation.        the corneal epithelial cell surface become           Patients with dry eye, either from
2. A large palpebral fissure width,              severe, resulting in a loss of corneal surface    decreased tear production or increased
   occurring either naturally, secondary to      glycoproteins and destabilisation of the          evaporation, most frequently complain of
   cosmetic surgery or with thyroid eye          cornea-tear interface (the attachment             chronic sandy-gritty irritation or dryness in
   disease14, places evaporative stress on the   between the cornea and the tears).                their eyes which gets worse as the day goes
   tear film. Evaporation is proportional to
                                                                                                                                          Table 2
   the palpebral-fissure surface area.
                                                                                                             What causes chronic eye irritation?
   Increased evaporation also explains why
   symptoms become worse with exposure            Causes other than dry eye and meibomitis may explain a patient’s chronic eye
   to air conditioning, dry heat, low             irritation. Consider these other possible causes and their symptoms.
   humidity or wind.                              Anterior blepharitis
                                                  Patients have crusting and irritation at the base of lashes without diurnal variation. Onset
Ageing tends to result in a gradual decline       is insidious.
in tear secretion secondary to the associated
                                                  Medicamentosa
decline in corneal sensation and
                                                  Patients complain of burning and irritation without diurnal variation. Symptoms are
meibomian gland function15. In most
                                                  equivalent throughout the day because overuse of topical medications promotes damage.
patients, physiologic reserve, along with a
                                                  You should suspect this condition in all patients who use traditional artificial tears more
bit of ptosis, is adequate to prevent the
                                                  than four times a day. Patients generally have a history of escalating tear use.
development of symptoms and disease.
                                                  Lacrimal drainage obstruction
Milestones of dry eye                             Patients often have symptoms of tearing with actual and demonstrable tear overflow.
While studies of human disease have               Patients with meibomian gland dysfunction may feel like their eyes are tearing, but these
shown the ocular surface changes which            patients have frank epiphora.
occur with dry eye, the study of pre-clinical     Allergic conjunctivitis
models of keratoconjunctivitis sicca (KCS)        The primary symptom for this condition is itchy eyes. Patients’ eyes may also exhibit
helps us delineate the natural history of         increased mucus production. Onset of this condition is commonly seasonal, and it may be
these changes. We now know that dry eye           associated with hay fever, asthma and eczema.
disease evolves through a sequence of four        Nocturnal lagophthalmos
milestones:                                       Patients’ eyes may burn upon awakening. Patients frequently have a history of lid surgery
• Loss of water from the tear film with an        or thyroid eye disease.
   increase in tear osmolarity
• Decreased conjunctival globlet-cell             Superior limbic keratoconjunctivitis
   density and decreased corneal glycogen         Symptoms include burning and irritation without diurnal variation. Abrupt onset and
• Increased corneal epithelial                    remissions characterise this condition. Patients often have a history of thyroid dysfunction.
   desquamation                                   Superficial punctate keratitis (Thygenson’s)
• Destabilisation of the cornea-tear              Patients with this condition experience insidious onset of photophobia, eye irritation and
   interface                                      decreased vision. The condition is episodic and recurring.
                                                  Dry eyelid skin
Decreased tear production or increased tear       Patients complain of ‘dry eyes’. This condition underscores the importance of accurate
evaporation is rapidly reflected by an            localisation of symptoms.
increase in tear osmolarity, and soon
                                                  Tarsal foreign body
thereafter by a decrease in goblet cell
                                                  Patients experience a chronic sensation of having a foreign body in their eye. This
density. The loss of goblet cells is
                                                  sensation results from exogenous material or an exposed meibomian gland-derived
significant because they produce mucus, the
                                                  conjunctival concretion.
major lubricant in the tear film, and serve
in the defence of the ocular surface (mucus       Mucus fishing syndrome
fired from goblet cells helps trap foreign        Symptoms include chronic eye irritation and increased mucus production. Patients who
matter and expel it from the eye).                reach into their conjunctival cul-de-sac to remove mucus strands caused by conjunctival
    The increase in the osmotic gradient          trauma initiate the condition. A vicious cycle can develop.
between the tear film and the ocular              Blepharospasm
surface, in addition to decreasing goblet         Patients may complain that their eyes feel ‘tired’. Careful questioning reveals that patients
cells, pulls water between conjunctival           are experiencing an involuntary closure of the eyes, rather than eye irritation. Driving,
epithelial cells. This action breaks the          reading and exposure to sunlight worsen symptoms.
delicate attachments between these cells          Non-specific ocular irritation
and increases conjunctival cell                   Normal eyes, abnormal environment. Eye irritation in response to smoke would be a
desquamation. In unison with the decrease         typical example.
in goblet cells is a decrease in corneal
                                                  Normal eyes with hypochondriasis
glycogen. This loss of glycogen is clinically
                                                  This condition is uncommon. A careful history which fails to mesh with the examination
important because glycogen is the energy
                                                  can provide the first clue to its presence.
source for the sliding step of corneal


                                                                                                                       35 | June 4 | 2004 OT
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                                                                                                                             Jeffrey P Gilbard MD
                                                                                                                                                                                                                 SPECIALISTS IN EYECARE




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                                                                                                                                                                                                                    Figure 2
                                                                                                                                                              Natural history of meibomitis. Meibomian gland inflammation
                                                                                                                                                    leads first to stenosis and then closure of the meibomian gland orifice
                                                                                                                                                         (by courtesy of International Ophthalmology Clinics 1994; 34: 27-36)

                                                                                                                             on16. This is because eye closure during          telangiectasias, which may presage
                                                                                       Select 01- or 02- for optometrist     sleep forms a watertight seal over the tear       meibomitis or meibomian gland
                                                                                       D- for dispensing optician            film and gives the ocular surface a chance        dysfunction associated with rosacea.
                                                                                       Irish- for Irish board registration   to recover. When the eyes open,                   Because evaporation is proportional to
                                                                                                                             evaporation begins, which increases tear          surface area, measure palpebral fissure
                                                                                                                             film osmolarity as the day goes on11. It is       width. Palpebral fissure widths greater than
                                                                                                                             difficult to overstate the usefulness of this     10mm place significant evaporative stress
                                                                                                                             history in diagnosing dry eye. If there are       on the tear film. Study the meibomian
                                                                                                                             symptoms for more than three months and           gland orifices with a slit lamp. As the
                                                                                                                             if the onset was gradual, the patient has dry     natural history of meibomitis advances, the
                                                                                                                             eye until proven otherwise.                       meibomian gland orifices progress from
                                                                                                                                 Keep in mind that patients with active        open to stenosed to closed (Figure 2).
                                                                                                                             meibomitis (also known as posterior                   Next, touch a wet fluorescein strip to the
                                                                                                                             blepharitis) also complain of chronic             patient’s inferior tarsal conjunctiva and
                                                                                       Select the examination you want       sandy-gritty eye irritation. But in these         examine the tear film. Lack of spontaneous
                                                                                       to enter from those available. It     patients, the irritation is worse upon            fluorescence indicates decreased tear
                                                                                       is important that you choose the      awakening. This is because tear production        volume. In patients with more markedly
                                                                                       right one and do not enter your       decreases during sleep, and eye closure           decreased tear volume, debris will be
                                                                                       answers into any other available      brings the inflamed lids right up against         visible in the tear film as well as, possibly,
                                                                                       examinations running at the same      the eye where the release of inflammatory         dehydrated mucus which has precipitated
                                                                                       time as you will not be able to go    mediators act on the cornea all night.            in the inferior fornix.
                                                                                       back to try again. Any errors         When these patients awaken, tear flow                 The appearance of the tear film of
                                                                                       made by participants cannot be        increases, the lids pull away from the            patients with meibomian gland
                                                                                       recalled.                             cornea, and their symptoms improve as the         dysfunction has a watery quality. The tears
                                                                                                                             day goes on.                                      tend to ‘splash’ around more because
                                                                                                                                 Eventually, the chronic meibomian             meibomian oils, in addition to decreasing
                                                                                                                             gland inflammation leads to meibomian             tear evaporation, also lower the surface
                                                                                                                             gland dysfunction. When that happens,             tension of the tear film, which holds the
                                                                                                                             these patients develop a second peak in           tear film ‘tight’ to the eye.
                                                                                                                             symptoms from dryness toward the end of               There is a common misconception that
                                                                                                                             the day. Finally, when the meibomian              dry eye patients can experience ‘tearing’. In
                                                                                                                             gland inflammation and secondary healing          fact, patients with dry eye from meibomian
                                                                                                                             obliterate the meibomian glands, the              gland dysfunction may report that it “feels
                                                                                                                             morning symptoms resolve and patients             like” their eyes are tearing. This sensation
                                                                                                                             are left with symptoms from dryness alone,        results from their tears ‘splashing’ around
                                                                                                                             with sandy-gritty irritation and dryness          more, and because the oil barrier created by
                                                                                                                             which gets worse as the day goes on.              the secretion of oil onto the lid margin is
                                                                                       Enter your answers, and an                Eye irritation has many other causes,         missing. As a result, tear fluid can touch the
                                                                                       optional email address if you want    which should be considered when                   cutaneous portion of the muco-cutaneous
                                                                                       email notification of your results.   approaching a patient with chronic                junction, making it feel as if the eyes are
                                                                                       Check your name is correct and        symptoms (Table 2).                               tearing. It is important to note that these
                                                                                       press the ‘send answers’ button.          The most sensitive and specific test for      patients will not have tear overflow.
                                                                                       The next screen will show your        dry eye is osmolarity measurement of              Patients who have tear overflow (frank
                                                                                       percentage and any credits            nanolitre tear samples collected from the         epiphora) have nasolacrimal drainage
                                                                                       gained.                               inferior marginal tear strip. This is             obstruction until proven otherwise.
                                                                                                                             consistent with expectations, given that loss
                                                                                          The results page should be         of water from the tear film defines the           Evaluation options
                                                                                       printed out or emailed to you if      disease. The effort of performing                 The two methods for clinically evaluating
                                                                                       you entered your email address        measurements is the only limiting factor to       the conjunctival changes which occur
                                                                                        earlier. You will need to keep       this test’s usefulness. Unfortunately, at the     relatively early in disease are impression
                                                                                       this for your records and future      current time, there is no way to do this test     cytology and rose bengal staining.
                                                                                               self-certification.           in the clinical setting.                          Impression cytology requires setting up a
                                                                                                                                 On examination, look first for facial         small laboratory. This takes serious


                        36 | June 4 | 2004 OT
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commitment and will not be covered in              Targeted treatment                                 film osmolarity, while its tear-matched
this article. In contrast, rose bengal staining    Early treatments for dry eye disorders             electrolyte balance permits the restoration
is clinically practical. Another dye, called       targeted the late milestones in dry eye            of mucus-containing conjunctival goblet
lissamine green (not available in the UK           disease. In part, this was because the late        cells and corneal glycogen23.
yet), appears to stain the ocular surface          milestones were easier to spot. For example,           Punctal occlusion also helps to lower
equivalently to rose bengal, but with fewer        dry spot formation was more obvious than           elevated tear film osmolarity, reduce rose
irritating side effects. In light of the natural   increased tear osmolarity and loss of              bengal staining and improve symptoms24.
history of dry eye, either rose bengal or          conjunctival goblet cells. But as our              However, controlled studies indicate that
lissamine green stain the conjunctiva some         knowledge and understanding of dry eye             punctal occlusion does not have any effect
time after tear osmolarity increases and           have improved, treatment has begun to              on goblet-cell density25. Why? In our
once goblet cell loss has become quite             target earlier milestones in the disease           studies of KCS patients with lacrimal gland
significant. Recent evidence suggests that         progression.                                       disease, we found an increase in tear
staining occurs when surface cell                      Many years ago, demulcents (polymers)          osmolarity and all measured tear
glycoproteins are altered to an extent that        were added to artificial tear solutions to         electrolytes. There was, however, a
cells have less capacity to retain mucus17,18.     improve their lubricant properties and             significantly disproportionate increase in
    The pattern of rose bengal staining is         change their viscosity. In 1975, a classic         tear sodium levels in these patients15.
more useful than merely the presence or            study demonstrated that artificial tear            Disproportionately high sodium levels
absence of stain or even the amount of             solutions (all containing a preservative at        deplete conjunctival goblet-cell density26.
stain. With dry eye, the nasal conjunctiva         the time) transiently increased tear film          So, while punctal occlusion can add water
stains more than the temporal conjunctiva,         stability in normal subjects19. These              to the tear film, it cannot correct the
and the resilient cornea stains less than the      solutions, whether of high or low                  disproportionate increase in tear sodium
conjunctiva and later in the disease               viscosities, act by temporarily mimicking          seen in KCS which depletes goblet cells.
process. Corneal staining usually begins           cell surface glycoproteins, which are lost
with the loss of corneal cell surface              late in the disease. Solutions of higher           Nutrition and dry eyes
glycoproteins – the last of the four               viscosity remain in the eye longer.                Until now the approach to dry eye has
milestones in the natural history of dry eye       Whatever relief preserved artificial tear          been a topical one, and by lowering
disease (Table 1).                                 solutions provide hinges on their ability to       elevated tear film osmolarity and providing
    The rapid development of randomly              temporarily stabilise the cornea-tear              a tear-matched electrolyte-balanced tear
located dark spots in the pre-corneal tear         interface.                                         solution, effective treatment has been
film (evident after the instillation of                The next treatment advance –                   achieved. Now we are seeing a new
fluorescein dye) reflects tear film                preservative-free artificial tear solutions –      approach to dry eye treatment, a
instability. This finding has been used            occurred about 15 years ago, shortly after         revolutionary change, with the introduction
diagnostically as the tear film break-up           researchers recognised that preservatives          of oral treatments.
time measurement, yet as many as half of           increased corneal desquamation20. A recent             Oral supplementation for dry eye began
patients with dry eye will have normal tear        study showed that traditional preservative-        with the introduction of a product call
film stability. We now understand that this        free artificial tear solutions improved, but       HydroEye. The problem with this
is because dry spots are a result of, not a        did not normalise, corneal barrier function        supplement, however, is that it adds to the
cause of, dry eye disease. The corneal             in dry eye patients. Improved corneal              already excessive amount of omega-6s in
epithelial changes required to cause tear          barrier function reflects decreased corneal        the average Western diet. Omega-6s
film instability – loss of corneal cell surface    epithelial desquamation and improved               increase serum levels of arachidonic acid
glycoproteins – occur late in the natural          corneal cell junctions. Treatment with a           (AA) and promote heart disease, stroke and
history of dry eye disease. Although not a         preserved artificial tear solution, while          other degenerative diseases.
sensitive test (it is not highly positive in       briefly increasing tear film stability, actually       New research, presented for the first
the presence of disease), break-up time is         diminished corneal barrier function21.             time at the 2003 annual meeting of the
probably highly specific in that it is             Preservative-free solutions, by eliminating        Association for Research in Vision and
negative when disease is absent.                   corneal ‘peeling’ due to preserved artificial      Ophthalmology, has found that high
    Given that decreased tear production or        tear solutions, established a new                  dietary intake of omega-3 essential fatty
increased evaporation can cause dry eye, it        benchmark in artificial tear solution              acids decrease the risk of dry eye27. Using
is understandable why, in controlled               treatment, yet still did not address the           the Women’s Health Database at the
studies, the value obtained through the            desquamation caused by dry eye itself.             Harvard School of Public Health, the
Schirmer test is not the best means of                 Since then, researchers have tried to          investigators examined the dietary intake of
diagnosis. This poor sensitivity, specificity      improve the effect of these preservative-free      essential fatty acids in 32,470 female health
and predictive value pertains whether or           solutions on corneal barrier function by           professionals. They found that the higher
not dry eye patients are selected based on         adding various ions. The electrolyte               the dietary ratio of omega-3 to omega-6
symptoms, increased osmolarity or ocular           balances of these preservative-free solutions      essential fatty acids, the lower the
surface disease. In other words, no matter         were the best which could be designed,             likelihood of dry eye, and the higher the
how you diagnose dry eye, whether by               while focusing only on issues related to           dietary omega-3 intake, the lower the
history, increased osmolarity, or rose             corneal morphology22. From the natural             likelihood of dry eye. Conversely, they
bengal staining, the Schirmer test has poor        history of dry eye disease, we know that           found that the lower the ratio of omega-3s
sensitivity, specificity and predictive value.     decreases in conjunctival goblet-cell density      to omega-6s, the higher the likelihood of
    While lacrimal gland disease decreases         and corneal glycogen are much more                 dry eye.
Schirmer measurements, meibomian gland             sensitive indicators of ocular surface health          Omega-3s are essential fatty acids.
dysfunction increases these measurements.          than changes in corneal morphology.                ‘Essential’ means that, because they cannot
With decreased oil on the lid margin, the              Knowing what we know now about the             be produced by the body, their inclusion in
Schirmer strip wets more easily. Indeed, in        mechanism and natural history of dry eye,          the diet is essential for good health. The
a rabbit model of dry eye with meibomian           we would expect that the next advance in           two best sources of omega-3s are dark, oily,
dysfunction, elevated tear film osmolarity,        treatment would address decreased                  cold water fish, and flaxseed. They are
decreased conjunctival goblet-cell density,        conjunctival goblet cells, decreased corneal       known to have a multitude of health
decreased corneal glycogen, and rose               glycogen and elevated tear film osmolarity.        benefits yet, as a population, Westerners are
bengal staining, Schirmer test strips wet          A recently introduced artificial tear is           omega-3 deficient (Figure 3).
more than those used in control eyes8.             sufficiently hypotonic to lower elevated tear          Omega-6s are another group of essential


                                                                                                                         37 | June 4 | 2004 OT
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                                                     Jeffrey P Gilbard MD
                                                                                                                                                              SPECIALISTS IN EYECARE




                                                                                                                        of TNF-α, DHA, another long-chain omega-
                       Contribution of fish to human diet                                                               3 provided directly by fish oils, protects
                                                   Fish as a percentage of                                              cells from TNF-α –induced apoptosis. Yano
                                                   total animal protein intake                                          and co-workers have demonstrated that
                                                                                                                        vitamin E works synergistically with DHA
                                                   0 5    10 15 20 25 30
                                                                                                                        to protect cells from TNF-α-induced
                                            Asia                             26.2                                       apoptosis29. So EPA and DHA work together
                                          Africa                   17.4                                                 to protect the lacrimal gland and ocular
                                                                                                                        surface from apoptosis.
                                         Europe            9.2
                                   Former USSR            9.0                                                           Omega-3s stimulate tear secretion
                                        Oceania            8.8                                                          The effects of suppressing
                       North & Central America           7.4                                                            pro-inflammatory cytokines do not stop
                                  South America          7.2                                                            here. It is known that the pro-
                                        LIFDCs*                           21.8                                          inflammatory cytokines, TNF-α, IL-1α, and
                                        WORLD                     16.4                                                  IL-1β, impair tear secretion in lacrimal
                                                                                                                        gland disease-based dry eye by inhibiting
                        * including China
                                                                                                                        the release of neurotransmitters from
                                                                             Figure 3                                   neural synapses, and interfering with the
                                  Westerners, in general are omega-3 deficient                                          secretory response of lacrimal gland acinar
                                                                                                                        cells to stimulation30,31. This is probably the
  fatty acids. Omega-6s are consumed in              increase in tear film osmolarity which                             main mechanism by which tear secretion
  beef, dairy and vegetable shortening and           drives dry eye ocular surface disease.                             decreases in dry eye.
  cooking oils (i.e. hamburgers, cheese                 In addition, TNF-α induces apopotosis                               The profound importance of this has
  burgers, pizza, ice-cream, potato chips etc).      on the ocular surface in dry eye.                                  been illustrated in recent work which
  Unfortunately, while the recommended               Specifically, Luo and co-workers found that                        shows that when TNF-α gene expression is
  ratio of omega-3s to omega-6s is 1:2.3, the        increasing tear film osmolarity in animal                          blocked by gene therapy in an animal
  existing ratio of omega-3s to omega-6s             models increases the expression of TNF-α                           model, autoimmune lacrimal gland disease
  consumption has been estimated to be as            and the associated cell regulators that                            can be reversed, and tear secretion
  low as 1:1028.                                     increase apoptosis on the ocular surface10.                        restored32. The relevance of this animal
      This, and other research, contributed to       There has been a lot of interest recently in                       model is supported by the epidemiological
  a switch to using omega-3s, with flaxseed          ocular surface inflammation in dry eye.                            data cited above, as well as an additional
  oil, fish oil and vitamin E, in supplements.       This important study shows that it is                              study which reported that Sjögren’s patients
  Such formulations address both                     elevated tear film osmolarity which induces                        had a lower dietary intake of omega-3s,
  meibomitis and the underlying causes of            the increased expression of pro-                                   including EPA and DHA, than age-matched
  dry eye.                                           inflammatory cytokines in dry eye, just as                         controls33.
                                                     elevated tear film osmolarity has been                                 While EPA is central in blocking the
  Omega-3s decrease inflammation                     shown to produce all the morphological                             gene expression of pro-inflammatory
  Omega-3s in the diet, once consumed, are           ocular surface changes described in dry eye.                       cytokines, DHA may help in a
  elongated by enzymes to produce anti-                 While EPA decreases the gene expression                         complementary way. Neural synapses
  inflammatory prostaglandin E3 (PGE3) and
  anti-inflammatory leukotriene B5 (LTB5)
  (Figure 4). Even more importantly,
  eicosapentaenoic acid (EPA), a long-chain                                           Metabolic pathways of essential fatty acids
  omega-3 provided directly by fish oils,
  blocks the gene expression of the                                                   Omega-6                                                   Omega-3
  pro-inflammatory cytokines tumour                                                  fatty acids                                               fatty acids
  necrosis factor alpha (TNF-α), interleukin-
  1α (IL-1α), interleukin-1b (IL-1β),                                               Linoleic acid                                    Alpha-linolenic acid
  proteoglycan degrading enzymes                                                                                                        (flaxseed oil)
  (aggrecanases) and cyclooxygenase
  (COX-2) (Figure 5).
                                                                            Gamma-linolenic acid (GLA)
      These anti-inflammatory effects go a
                                                                              e.g. evening primrose,                                      Steridonic acid
  long way to explain why omega-3s have
                                                                                blackcurrent seed
  been useful in treating patients with
  posterior blepharitis or meibomitis. The
  results are so positive that it may result in                                                                                      Elcosatraenoic acid
                                                                             Dihomo-gamma-linolenic
  the displacement of systemic tetracyclines
                                                                                  acid (DGLA)                                             AA
  as treatment for the early morning eye                                                                                        DGLA to
                                                                                                                conversion of              EPA (fish oils)
  irritation suffered by meibomitis patients.                                                         EPA block                                                         DHA
  However, the effects of omega-3s only                              PGE1                                                           E2
                                                                                                                            (AA), PG )
  begin with their effects on meibomitis.                                                                         onic acid        tory
                                                             (anti-inflammatory)                           Arachid (pro-inflamma
                                                                                                                  α2
                                                                                 EP2, EP4 receptors       LTB4 TX
  Omega-3s decrease apoptosis                                                                                     PGE3 (anti-inflammatory)
  Suppressing TNF-α is also important                               cAMP
  because in Sjögren’s syndrome and in                                                                                                            LTB5 (anti-inflammatory)
  lacrimal gland-based dry eye, increased                  Aqueous tear secretion
  TNF-α in the lacrimal glands increases
  lacrimal gland apoptosis (programmed cell                                                                                                                          Figure 4
  death). Increased apoptosis contributes to                Flaxseed and fish oils to generate anti-inflammatory PGE3 and LTB5 and suppress blepharitis,
  the decrease in tear production, and                                        while increasing PGE1 to promote tear secretion (see text for other effects)


   38 | June 4 | 2004 OT
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                                                                                                  Figure 5    development of xerophthalmia
                                             EPA supplied by fish oils, blocks the gene expression on TNF-α   – a condition characterised by squamous
                                                                      and other pro-inflammatory cytokines    metaplasia of the ocular surface, with
                                                                                                              increased keratinisation and loss of
  Critical role of eicosapentaenoic acid (EPA)                                                                conjunctival goblet cells. Experimental
                                                                                                              studies have found that deficiencies of
                 LTA4 hydrolase          5-lipoxygenase         cyclooxygenase                                vitamin A and zinc can reduce corneal and
                                                                                              PGE2            conjunctival microvilli and conjunctival
               LTB4               LTA4                     AA                    PGH2                         goblet cells, and increase ocular surface
                                                                                              TXα2
                                                                                                              keratinisation. It has also been shown that
                                                                                                              supplementation with these antioxidants
                                                                                                              can reverse these changes40.
                                                          EPA                                                     In one study, antioxidant
                                                                                                              supplementation has been tried as a
        Omega 6s                   DGLA                                                                       therapy in patients with mild dry eye, and
                                                                                                              shown to increase conjunctival goblet cell
                                                                                                              density and non-invasive tear film break-up
                                                                                                              time. These changes were not associated
                                           transcription                     TNF-α                            with an alteration in tear production or an
                                                                          IL-1α, IL-1β                        improvement in patient symptoms41. It can
                           DNA                                           Aggrecanases                         be hypothesised, therefore, that while the
                                                  amino acids                COX-2                            antioxidant supplementation promoted
                                                                                                              normal ocular surface differentiation, it did
                                                                                                              not address the underlying elevation in tear
                                                                                                              film osmolarity which is responsible for
                                                                                                              patient symptoms.
contain among the highest concentration of                  EP4 to activate adenylate cyclase, increasing
DHA in the body and research has shown                      cyclic AMP (cAMP). PGE1 and cAMP have
that dietary supplementation with DHA                       been shown to stimulate aqueous tear
restores neural DHA levels and improves                     secretion36,37.                                   Conclusion
age-related declines in synapse function34.                                                                   With these findings and insights, it is
DHA may reduce the ability of                               Omega 3s, the meibomian gland oils                possible to approach patients who have
pro-inflammatory cytokines in the lacrimal                  Meibomian glands use essential fatty acids        chronic eye irritation in a more systematic
gland to inhibit signal transduction at the                 to synthesise oil (meibum). Dietary intake        and effective way. Understanding the
synapse. Lending credence to this                           of omega-3s in general, and EPA and DHA           natural history of dry eye disease improves
hypothesis is the finding that severity of dry              in particular, has recently been shown to         our ability to diagnose the condition and
eye in Sjögren’s patients has been found to                 affect the polar lipid profiles of meibum as      to appreciate the meaning of our
be inversely proportional to membrane and                   observed by HPLC38. Indeed, Boerner has           examination and testing. With this
serum levels of DHA35.                                      observed the clearing and thinning of             information, we can better differentiate
   Omega-3s affect the lacrimal gland in                    meibomian gland secretions with omega-3           between various treatments at our disposal
another way. EPA and DHA and alpha-                         supplementation along with an                     and offer patients the best care possible.
linolenic acid (ALA) from flaxseed oil                      improvement of patient symptoms39.
competitively inhibit the conversion of                     Further studies are needed to determine
omega-6s to arachidonic acid (AA) thereby                   whether these effects are sufficient to           References
promoting the conversion of dihomo-                         bolster the oil layer and retard evaporation.     For a full set of references, email
gamma-linolenic (DGLA) to prostaglandin                                                                       nicky@optometry.co.uk or visit
E1 (PGE1) (Figure 4). PGE1 also has anti-                   Oral antioxidants                                 http://www.dryeyeinfo.org/
inflammatory properties and, in addition,                   In areas of the world where nutrition is          Dry_Eye_In_Depth.htm#Nutrition_and_the
acts on the E-prostanoid receptors EP2 and                  poor, vitamin A deficiency leads to the           _eye.



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                                                                                                                                  39 | June 4 | 2004 OT
                                                                                                                       a
                                                                                                              Sponsored by
Continuing Professional Development                               .
                                                         Jeffrey P Gilbard
                                                                                                                                               SPECIALISTS IN EYECARE




                                                                                                                                                    MCQs
  Module 6 Part 6 of the Nutrition and the Eye series
  Dry eye and the role of nutrition
  Please note there is only ONE correct answer
  1. Which one of the following does NOT                 5. Which one of the following                           a. They reduce the risk of stroke
     decrease tear production?                              statements best describes patients                   b. They add to the excess of omega-6 in
  a. Autoimmune lacrimal gland disease                      with active meibomitis?                                 the American diet
  b. Herpes zoster                                       a. They are most symptomatic when they                  c. They reduce the risk of heart disease
  c. Small palpebral fissure                                first wake up                                        d. They decrease arachidonic acid levels
  d. Long-term contact lens wear                         b. They never develop two symptom
                                                            peaks                                                9. Punctal occlusion does all of the
  2. Which one of the following is NOT a                 c. They have no diurnal variation and                      following except which one?
     milestone in the natural history of dry                have equal symptoms all day long                     a. Lower elevated tear film osmolarity
     eye surface disease?                                d. Their symptoms typically become                      b. Improves symptoms
  a. Increased tear film osmolarity                         worse as the day goes on                             c. Reduces rose bengal staining
  b. Increased corneal glycogen                                                                                  d. Restores conjunctival goblet cells
  c. Decreased goblet cell density                       6. Which one of the following is
  d. Increased corneal epithelial                           INCORRECT about rose bengal                          10. Which one of the following does not
     desquamation                                           staining?                                                need to be addressed by a dry eye
                                                         a. It is clinically practical                               treatment?
  3. Which one of the following statements               b. It can help evaluate conjunctival                    a. Decreased conjunctival goblet cells
     about goblet cells is INCORRECT?                       changes which occur early in disease                 b. Decreased corneal glycogen
  a. They decrease in the presence of                    c. The pattern of rose bengal staining                  c. Elevated tear film osmolarity
     increased tear osmolarity                              offers valuable clues about a patient’s              d. The blood supply of the living cells
  b. They help lubricate the ocular surface                 condition                                                that comprise the ocular surface
  c. Simultaneously with the decrease in                 d. Rose bengal stains the conjunctiva
     goblet cells, corneal glycogen levels                  some time before tear osmolarity                     11. EPA, available directly from fish oils,
     increase                                               increases and goblet cell loss has                       does all of the following except
  d. They produce mucus                                     become significant                                       which one?
                                                                                                                 a. Blocks the gene expression of TNF-α
  4. Which one of the following statements               7. Up to what percentage of patients                    b. Competitively inhibits the conversion
     describes patients with dry eye?                       with dry eye have normal tear                            of omega-6s to arachidonic acid
  a. They are most symptomatic in the                       break-up time?                                       c. Promotes the conversion of DGLA
     morning                                             a. 20%                                                      acid to PGE1
  b. They have two symptom peaks: one in                 b. 50%                                                  d. Improves age-related declines in
     the morning upon awakening, and                     c. 15%                                                      synapse function
     again later in the day                              d. 75%
  c. They have no diurnal variation and                                                                          12. Increased dietary intake of omega-3s
     have symptoms all day long                          8. Which one of the following is                            does all of the following except
  d. They typically become more                             CORRECT about omega-6                                    which one?
     symptomatic as the day goes on                         supplements?                                         a. Reduces the risk of dry eye
                                                                                                                 b. Has been observed to reserved to
                                                                                                                     result in a thinning and clearing of
   An answer return form is included in this issue. It should be completed and returned to: CPD initiatives          meibomian gland oils
   (c4750f), OT, Victoria House, 178-180 Fleet Road, Fleet, Hampshire, GU51 4DA by July 2, 2004.                 c. Addresses both meibomitis and the
   Under no circumstances will forms received after this date be marked – the answers to the module will             underlying causes of dry eye
   have appeared in our July 4 issue and scores sent electronically to the accrediting bodies.                   d. Increases the risk of sudden death
                                                                                                                     from heart disease and stroke


                                                                                                                                                Answers
  Nutrition and the eye: Nutrition and glaucoma: Do supplements reduce IOP?
   Here are the correct answers to Module 6, Part 5, which appeared in our May 7, 2004 issue.
  1. The proportion of glaucoma in the                   2. The proportion of POAG at the age of                 3. In 1996, according to the RNIB,
     total population over the age of 40                    80 years is highest in which one of                     glaucoma accounted for
     years is:                                              the following populations?                              approximately how many people
  a. 0.1-0.2%                                            a. Scandinavians                                           registered as blind and partially
  b. 1-2%                                                b. Caucasians                                              sighted?
  c. 3-4%                                                c. Asian races                                          a. One in 10
  d. 5-6%                                                d. Afro Caribbean races                                 b. One in 20
                                                                                                                 c. One in 30
                                                                                                                 d. One in five
  b is correct                                           d is correct
  The overall incidence of glaucoma is 1-2%              Around 1% of Caucasians have POAG at                    a is correct
  of the total population over the age of 40             the age of 50 years1, rising to around 4% at            According to the Royal National Institute of
  years, with approximately 25% of these                 the age of 80 years. Estimates for                      the Blind, glaucoma is the primary cause
  cases going undiagnosed in the                         Afro-Caribbeans are 3% and 13% at the                   for 11.7% of those registered as blind or
  community.                                             equivalent ages.                                        partially sighted.



   40 | June 4 | 2004 OT
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                                                                                                                        Answers

  4. Which one of the following types of         7. Which one of the following foods           10. Which one of the following is
     glaucoma is the most common in the             give a definite causal link to                 correct regarding ginkgo biloba?
     UK?                                            glaucoma?                                  a. Blood flow in NTG is enhanced
  a. Chronic angle-closure                       a. Bilberry extract                           b. The trabecular meshwork opens
  b. Acute angle-closure                         b. Vitamin C                                  c. The trabecular meshwork closes
  c. Primary open-angle                          c. Vitamin A                                  d. The action of prostaglandin
  d. Low tension                                 d. No food stuffs or vitamins                     analogues is enhanced

  c is correct                                   d is correct                                  a is correct
  Primary open-angle glaucoma (POAG) is          No studies have proved conclusively a         The nutritional extract of ginkgo biloba
  the most common form of glaucoma in            connection between specific foods and         enhances blood flow and appears to
  the UK, where it accounts for over 60% of      glaucoma.                                     improve pre-existing visual field damage
  diagnosed cases.                                                                             in some patients with NTG.
                                                 8. Which one of the following is
  5.   A safe level of IOP for glaucoma is:         correct regarding ReVision Formula?        11. Which one of the following is
  a.   15mmHg                                    a. It contains vitamin A                          correct regarding large doses of
  b.   25mmHg                                    b. It contains gingko biloba                      vitamin C?
  c.   19mmHg                                    c. It is an eye drop                          a. The oxidative stress in the eye is
  d.   none of the above                         d. It is best taken at midday                     increased
                                                                                               b. It causes bowel intolerance
  d is correct                                   b is correct                                  c. It causes constipation
  The ‘safe’ level is very patient dependent     ReVision Formula includes bupleurem,          d. It interacts with beta-blocking
  and is reliant on factors such as age,         dong guai, white peony, poria,                    agents
  presenting IOP, visual fields, corneal         atractylodes and licorice, plus additional
  thickness and optic nerve damage and           herbs tree peony, ginger, gardenia, coleus,   b is correct
  analysis. Different optimal IOP levels need    gingko biloba, milk thistle, dandelion,       Alternative medical practitioners often
  to be set for each case and there is no one,   eyebright, bilberry and hoelen.               suggest that people with glaucoma take
  single optimal IOP which can be                                                              enough vitamin C to cause loose stools,
  prescribed for all.                            9. Which one of the following is              and then reduce this amount slightly, to
                                                    correct regarding the effect of            an amount termed ‘bowel tolerance’.
  6. The current mainstay of first-line             marijuana?
     current glaucoma treatment is:              a. IOP increases                              12. Salvia miltiorrhiza is:
  a. YAG laser treatment                         b. IOP decreases                              a. a fungus
  b. 5FU trabeculectomy                          c. The anterior chamber angle opens           b. a bacteria
  c. Laser trabeculoplasty                       d. The anterior chamber angle closes          c. a botanical used in Chinese
  d. Beta-blockers and/or prostaglandin                                                            medicine
     analogue medication                         b is correct                                  d. found in the retinal ganglion cells
                                                 Although it is well known that smoking
  d is correct                                   marijuana can reduce pressure within the      c is correct
  Topical beta-blockers and prostaglandin        eye, the drug may also reduce the blood       Salvia miltiorrhiza is a common
  analogues are first-line treatments.           supply to the optic nerve head.               botanical used in Chinese medicine.




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