CE Credit Article. Dry Eye: Mechanisms, Natural History, Diagnosis, and Treatment Jeffrey P. Gilbard, MD

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1 CE Credit Article Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Jeffrey P. Gilbard entitled Dry Eye: Mechanisms, Natural History, Diagnosis, and Treatment. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 22 for complete instructions. Dry Eye: Mechanisms, Natural History, Diagnosis, and Treatment Jeffrey P. Gilbard, MD ABSTRACT Virtually all dry-eye conditions share an increase in tear-film osmolarity. Tear-film osmolarity increases due to either decreased tear production or increased tear film evaporation. This increase in tear-film osmolarity drives the ocular surface changes that occur over time. These progressive, time-dependent changes in the tear-film ocular surface system can be divided into four patho-physiological milestones: 1) loss of water from the tear film, 2) decreased goblet cell density and decreased corneal glycogen, 3) increased corneal desquamation, and 4) loss of corneal cell surface glycoproteins. The natural history of dry-eye disease determines the sensitivity of diagnostic tests and the efficacy of treatment. Currently, patient history is the most sensitive diagnostic test for dry eye. In preclinical studies, TheraTears (Advanced Vision Research) restored goblet cells, restored corneal glycogen, and promoted healing by lowering elevated tear-film osmolarity and by providing a tear-matched electrolyte balance to the ocular surface. Recently, this agent has been shown to speed resolution of symptoms and restore conjunctival goblet cells in the dry-eye condition seen after LASIK vision correction surgery. J.P. Gilbard Clinical Assistant Professor, Harvard Medical School, Boston, MA; Director, Dry Eye and Ocular Surface Disease Clinic, New England Eye Center, Boston, MA; Founder, CEO & Chief Scientific Officer, Advanced Vision Research, Inc., Woburn, MA Correspondence to: Dr. Jeffrey Gilbard, Advanced Vision Research, 660 Main St., 1st Floor, Woburn, MA Dr. Gilbard is the inventor of TheraTears and founder, CEO and Chief Scientific Officer of Advanced Vision Research, which distributes TheraTears. INTRODUCTION In the scientific literature, there has been much progress in our understanding of dry-eye disease, including its mechanisms as well as its natural history. Knowledge of this progress improves and informs the clinical diagnostic approach to the patient as well as the selection of treatment. CLASSIFICATION OF DRY-EYE DISORDERS Central to virtually all dry-eye disorders is a loss of water from the tear film sufficient to increase tear-film osmolarity when water is lost from the tear film, but solutes are not, tear osmolarity increases. This loss of water and increase in osmolarity may result from any condition that either decreases tear production or increases tear evaporation (Fig. 1). It is now evident that increased tear osmolarity is the link between changes in the lacrimal glands and lids, and the irritation and disease of the ocular surface. The most convincing data come from studies of preclinical models of lacrimal gland disease and meibomian gland dysfunction. In these studies the ocular surface changes in dry-eye disease have been shown to be consistent with, dependent upon, and proportional to increases in tear-film osmolarity. 1-5 Other clinical studies have provided still further corroboration. 6 Tear secretion may be decreased by any process that damages the lacrimal gland or its excretory ducts. Most commonly encountered would be autoimmune disease; less common causes include cicatricial ocular surface conditions. Tear secretion may also be decreased by any condition that decreases corneal sensation, including such common entities as herpes zoster, long-term contact lens wear, and surgery that involves corneal incisions or that ablates corneal nerves (i.e., laser in situ keratomileusis [LASIK]). 7,8 Increased tear evaporation may occur in one of two ways. First, since the meibomian glands in the lids produce an oil layer that coats the tear film and retards evaporation, meibomian gland dysfunction, resulting from long-standing blepharitis, can increase tear-film evaporation. Second, large palpebral fissure width, either occurring naturally or in association with thyroid eye disease, places evaporative stress on the tear film 9 12 Clinical & Refractive Optometry 18:1, 2007

2 Increased Tear-Film Osmolarity: The Final Common Pathway for Dry-Eye Disease Lacrimal Gland Disease Decreased Corneal Sensation Large Papebral Fissure Width Meibomian Gland Dysfunction Decreased Secretion Increased Evaporation Increased Tear Osmolarity Fig. 1 Mechanisms for increased tear osmolarity. Increased tear osmolarity causes the progressive ocular surface changes observed in dry-eye disease. (Modified from: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology, Philadelphia: W.B Saunders, 1994: ) evaporation is proportional to surface area. Increased evaporation also explains the exacerbation of symptoms that occurs with exposure to air conditioning, dry heat, low humidity, or wind. Aging tends to result in a gradual decline in tear function secondary to the associated decline in corneal sensation and meibomian gland function. 10 In most patients, physiologic reserve, along with a little bit of age-related ptosis, is adequate to prevent the development of dry-eye symptoms or disease. NATURAL HISTORY OF DRY-EYE DISORDERS While studies have reported on ocular surface changes in patients with dry eye, the study of preclinical models of keratoconjunctivitis sicca (KCS) has enabled us to delineate the natural history of these surface changes. 1-5 We now know that dry-eye disease evolves cumulatively over time through a sequence of four milestones: 1) decreased tear production or increased tear evaporation with an increase in tear osmolarity, 2) decreased conjunctiva goblet-cell density and corneal glycogen, 3) increased corneal epithelial desquamation, and 4) destabilization of the cornea-tear interface (Table I). Decreased tear production or increased tear-film evaporation is rapidly reflected by an increase in tear osmolarity and, soon thereafter, by a decrease in gobletcell density. Loss of goblet cells is important because they produce mucus, the major lubricant in the tear film. The cornea initially remains morphologically untouched. There is however, coincident with the decrease in goblet cells, a decrease in corneal glycogen levels. Loss of glycogen is important because glycogen is the energy source for the sliding step of corneal wound healing. The increase in the osmotic gradient between the tear film and ocular surface allows water to be pulled between conjunctival epithelial cells, breaking the delicate attachments between these cells and increasing conjunctival cell desquamation. Unlike the conjunctival epithelium, the corneal epithelium is held together by tight junctions. As a result, the corneal epithelium is morphologically more resilient than the conjunctival epithelium to the increase in tear osmolarity, and corneal morphology initially remains normal while the disease affects the conjunctiva. The cornea does not remain unaffected forever. Much later in the natural history of the disease, after resisting changes in the tear film, the attachments between corneal cells finally loosen, and there is a decrease in the corneal barrier function and ultimately an increase in corneal desquamation. Once changes in the corneal epithelial cell surface become severe, still later in the natural history of the disease, there is a loss of corneal surface glycoproteins and destabilization of the cornea-tear interface results. As we shall see, understanding the natural history of dry eye is crucial in interpreting and evaluating diagnostic tests, and understanding advances in treatment modalities. DIAGNOSIS OF DRY-EYE DISORDERS Patients with dry eye from either decreased tear production or increased tear evaporation complain of chronic sandy-gritty irritation in their eyes. Eye closure at night forms a watertight seal over the tear film and this gives the ocular surface a chance to recover. Once the eyes open, evaporation begins and, as a result, tear-film osmolarity increases as the day goes on. 14 This is why patients with dry eye typically note that their symptoms get worse as the day goes on. It is difficult to overstate the usefulness of this history in diagnosing dry eye. Given the appearance of these symptoms upon initiation of surface disease, they are a highly sensitive indicator of dry-eye disease (Table I). It is important to recognize that patients with meibomitis (also known as posterior blepharitis) also complain of chronic sandy-gritty irritation. In these patients the irritation is worse upon awakening in the morning. This is because the inflammation is in the eyelids. At night tear production decreases, 15 eye closure brings the lids right up against the eye, and the inflammatory mediators released have all night to irritate the cornea. Once these patients awaken, tear flow increases, the lids pull away from the cornea, and their symptoms quickly improve. Eventually the chronic meibomian gland inflammation leads to meibomian gland dysfunction, and these patients develop a second peak in symptoms from dryness toward the end of the day. Finally, once the meibomian gland inflammation and secondary healing obliterate the meibomian glands, the Dry Eye Gilbard 13

3 Table I Physiological milestones, diagnostic tests, and treatment of dry-eye disease Physiological Milestones Diagnostic Tests Treatment Loss of water History Sufficiently/optimally hypotonic eye drops from the tear film Tear osmolarity (Preservative-free TheraTears, TheraTears in a bottle, TheraTears Liquid Gel [Advanced Vision Research]) Decreased goblet Conjunctival staining Tear-matched electrolyte balance eye drops cell density / Decreased Impression cytology (Preservative-free TheraTears, TheraTears in a bottle, corneal glycogen TheraTears Liquid Gel [Advanced Vision Research]) Increased corneal Corneal staining Preservative-free lubricants of various viscosities desquamation (Refresh Plus [Allergan], Bion Tears [Alcon], Tears Natural Free [Alcon], GenTeal [Novartis], GenTeal Gel [Novartis], etc.) Loss of cell Tear film break-up time Preserved lubricants of various viscosities surface glycoproteins (Refresh Tears [Allergan], Tears Natural II [Alcon], etc.) Table II Causes, other than dry eye and meibomitis, of chronic eye irritation Diagnosis Anterior blepharitis Medicamentosa Lacrimal drainage obstruction Allergic conjunctivitis Nocturnal lagophthalmos Superior limbic keratoconjunctivitis Superficial punctate keratitis (Thygenson s) Dry eyelid skin Tarsal foreign body Mucus fishing syndrome Blepharospasm Nonspecific ocular irritation Normal eyes with hypochondriasis Symptoms, Features Crusting, irritation at base of lashes. No diurnal variation. Onset insidious. Suspect in all patients using traditional artificial tears more than four times a day. Generally a history of escalating tear use. No diurnal variation symptoms are equivalent throughout the day because damage is promoted by continued overuse of topical medications. Symptoms of tearing with actual and demonstrable tear overflow. Patients with meibomian gland dysfunction may feel like their eyes are tearing, but these patients have frank epiphora. Symptoms of itching. May also have increased mucus production by the eye. Onset commonly seasonal. May be associated with hay fever, asthma, eczema. Symptoms of burning in the eyes upon awakening. Frequently previous history of lid surgery or thyroid eye disease. Burning and irritation without diurnal variation. Abrupt onset and remissions. Common history of thyroid dysfunction. Insidious onset of photophobia, irritation, and decreased vision. Episodic and recurring. Underscores the importance of accurate localization of symptoms. Chronic foreign body sensation. Exogenous material or an exposed meibomian-gland derived conjunctival concretion. Chronic eye irritation and increased mucus production. Caused by patients reaching into their conjunctival cul-de-sac to remove mucus strands caused by conjunctival trauma. A vicious cycle develops. Patients may complain of a tired feeling. On careful questioning there is no eye irritation but rather an involuntary closure of the eyes. Symptoms are made worse by driving, reading, and exposure to sunlight. Normal eyes, abnormal environment. Uncommon. A careful history that fails to mesh with the examination can provide the first clue. 14 Clinical & Refractive Optometry 18:1, 2007

4 Fig. 2 Natural history of meibomitis. Meibomian gland inflammation leads first to stenosis and then closure of the meibomian gland orifice. (Published courtesy of: Gilbard JP. Human tear film electrolyte concentrations in health and dry-eye disease. Int Ophthalmol Clin 1994; 34: ) morning symptoms resolve, and these patients are left with symptoms from dryness alone, with sandy-gritty irritation that gets worse as the day goes on. There are many other causes of ocular irritation that need to be considered when assessing and treating patients with chronic symptoms. These are summarized in Table II. Osmolarity measurement of nanoliter tear samples collected from the inferior marginal tear strip has been shown to be the most sensitive and specific diagnostic test for dry eye, no doubt because loss of water from the tear film defines the disease. 16,17 The usefulness of tearosmolarity measurement is limited only by the effort required to perform measurements. Engineering advances promise to eliminate this limitation soon. After taking the history, the next step in assessing patients with chronic ocular surface irritation is the examination. Ask about central facial flushing and look first for facial telangiectasias that may presage meibomitis and/or meibomian gland dysfunction associated with rosacea. Since evaporation is proportional to surface area, measure the palpebral fissure width. Palpebral fissure widths greater than 9 or 10 mm place significant evaporative stress on the tear film. Study the meibomian gland orifices with the slit lamp. As the natural history of meibomitis advances, the meibomian gland orifices progress from open to stenosed to closed (Fig. 2). Next, touch a wetted fluorescein strip to the inferior tarsal conjunctiva. Lack of spontaneous fluorescence indicates decreased tear volume. The tear film of patients with meibomian gland dysfunction has a watery quality; the tears tend to splash around more. This is because meibomian oils, in addition to decreasing tear evaporation, also lower the surface tension of the tear film, thereby holding the tear film tight to the eye. In patients with decreased tear volume, debris may be visible in the tear film and, as the eyes become drier, precipitated mucus may be found in the inferior fornix. Patients with dry eye caused by meibomian-gland dysfunction may report that they feel like their eyes are tearing. This is because they are deficient in the oil layer and their tears splash around more, and because they are missing the oil barrier created by the secretion of oil onto the lid margin. As a result, tear fluid can touch the cutaneous portion of the muco-cutaneous junction, and it will feel as if the eyes are tearing. Important to note is that the patient will not have tear overflow. Patients who have tear overflow frank epiphora have nasolacrimal drainage obstruction until proven otherwise. Given that decreased tear production or increased evaporation can cause dry eye, it becomes more understandable why the Schirmer test, in controlled studies, continues to fare poorly as a diagnostic test. This poor sensitivity, specificity, and predictive value pertains whether or not dry-eye patients are selected based on symptoms, 18 increased osmolarity, 19 or ocular surface disease. 20 While lacrimal gland disease would be expected to decrease Schirmer measurements, meibomian gland dysfunction would be expected to initially increase these measurements. With decreased oil on the lid margin the Schirmer strip would be expected to wet more easily. Indeed, in a preclinical model of meibomian gland dysfunction Schirmer test strips wet more than in control eyes early in the natural history of the disease. 3 There are two methods of clinically testing for the conjunctival changes that occur relatively early in the disease process: rose bengal staining and impression cytology. Once again impression cytology takes a serious commitment. 21 Rose bengal staining is useful and clinically practical. Lissamine green appears to stain the ocular surface equivalently, but with fewer irritating side effects. In light of our knowledge of the natural history of dry eye, we know that either rose bengal or lissamine green stains the conjunctiva sometime after tear osmolarity increases, once goblet cell loss becomes quite significant. Recent evidence suggests that staining results when surface cell glycoproteins are altered to the extent that cells have a decreased capacity to retain mucus. 22 In diagnosing dry eye, the pattern of rose bengal staining is more useful than merely the presence or absence of stain: the nasal conjunctiva stains more than the temporal conjunctiva, and the resilient cornea stains less than the conjunctiva and later in the disease process. It s probable that corneal staining begins with the development of the late morphological changes in the corneal epithelium (Table I). 23 The rapid development of randomly located dark spots in the precorneal tear film after the instillation of fluorescein dye reflects tear-film instability, and tear-film break-up time measurement has been used as a diagnostic test. As many as 50% of dry-eye patients have normal tear-film stability. 24 We now understand that this is because the corneal epithelial changes required loss of Dry Eye Gilbard 15

5 solutions, (all containing a preservative at the time) increased tear-film stability in normal subjects. 25 We now understand that these solutions, whether they are of high or low viscosities, act by temporarily mimicking cell surface glycoproteins lost late in the disease. Solutions of higher viscosity remain in the eye longer. The effectiveness of these preserved demulcent solutions is limited to their ability to transiently modify a very late change in dry-eye disease: destabilization of the cornea-tear interface (Table I). Fig. 3 Flat-mount preparation of conjunctiva in keratoconjunctivitis sicca (upper right) shows decreased goblet cells relative to normal conjunctiva (upper left). Twelve weeks of q.i.d. treatment with TheraTears produces a significant (p < 0.01) restoration of goblet cells (lower left). Treatment with control preserved eye drop decreases goblet cells (lower right). (Modified from: Gilbard JP, Rossi SR. An electrolyte-based solution that increases corneal glycogen and conjunctival goblet-cell density in a rabbit model for keratoconjunctivitis sicca. Ophthalmology 1992; 99: ) corneal cell surface glycoproteins occur late in the natural history of dry-eye disease (Table I). While not a sensitive test (highly positive in the presence of disease), tear-film break-up time is probably highly specific (negative in the absence of disease). TREATMENT OF DRY-EYE DISEASE The late events in the natural history of dry-eye disease have been more obvious than the early events. Dry-spot formation, for example, is more obvious than increased tear osmolarity and loss of conjunctival goblet cells. Early on, treatments were designed to treat what was obvious the late changes in dry-eye disease. As our knowledge and understanding have improved, treatment has been directed at earlier and more important milestones in the natural history of dry-eye surface disease. Demulcents Demulcents are polymers added to artificial tear solutions to improve their lubricant properties and change their viscosity. In 1975, a classic study demonstrated that demulcent solutions, otherwise known as artificial tear Preservative-Free Artificial Tear Solutions The next advance in the solutions recommended to dryeye patients occurred about ten years ago, shortly after it was recognized that preservatives increase corneal desquamation. 26 This advance was the introduction of preservative-free artificial tear solutions. In a recent study, it was shown that the elimination of preservatives from traditional artificial tear solutions permitted these solutions to improve corneal barrier function in dry eye patients, reflecting a decrease in corneal epithelial desquamation and an improvement of corneal cell junctions. Treatment with a preserved artificial tear solution, while no doubt briefly increasing tear-film stability, actually diminishes corneal barrier function. 27 Preservative-free solutions thus established a new benchmark in artificial tear solution treatment. Subsequently, there have been some attempts to incrementally improve the effect of these preservativefree solutions on corneal barrier function by adding various ions to the solution. The electrolyte balances of these preservative-free solutions were the best that could be designed while focusing only on issues related to corneal morphology As we know from the study of the natural history of dry-eye disease, decreases in conjunctival goblet-cell density and corneal glycogen are much more sensitive indicators of ocular surface health than changes in corneal morphology. TheraTears TheraTears (Advanced Vision Research) is the first eye drop shown in preclinical studies to restore conjunctival goblet-cell density and corneal glycogen in dry eye with q.i.d. dosing for 12 weeks (Fig. 3). 31 This demulcent solution accomplishes this biologic effect through two mechanisms of action. First, loss of water from the tear film with elevation of tear-film osmolarity is what drives the development and progression of the ocular surface changes seen in dry eye. Given the importance of lowering elevated osmolarity, clinical studies were performed to determine how hypotonic an eye drop needed to be to lower elevated tear osmolarity in dry-eye patients. 32 These studies demonstrated that neither isotonic eye drops nor existing hypotonic eye drops continued on page Clinical & Refractive Optometry 18:1, 2007

6 Gilbard continued from page 16 A 120% B P<0.01 % Patients Symptom-Free 100% 80% 60% 40% 20% TheraTears PF Control 100% 80% 60% 40% 20% % Normal Goblet Cell Density 0% 1 day 1 week 1 month (Lenton L, Albietz J, 1999) 0% PF Control TheraTears (Lenton L, Albietz J, 1999) Fig. 4 Treatment of LASIK patients with TheraTears (A) eliminated dry-eye symptoms while (B) restoring conjunctival goblet cells. (Modified from: Lenton LM, Albietz JM. Effect of carmellose-based artificial tears on the ocular surface in eyes after laser in situ keratomileusis. J Refract Surg 1999; 15: S227-S231.) were effective in lowering elevated osmolarity. Eye drops needed not only to be hypotonic but to be more hypotonic than existing solutions. Based on these studies the tonicity of TheraTears was set to fully lower osmolarity from a level of about 330 mosm/l before eye drop instillation to about 280 mosm/l after eye drop instillation (normal tear osmolarity is below 311 mosm/l). By fully lowering osmolarity, TheraTears reverses the osmotic gradient between the tear film and the ocular surface, and moves fluid into the surface of the eye, rehydrating the dehydrated tissues. With continued treatment, as a result of this fluid movement, there is rehydration of the tear-film ocular surface system reflected by a progressive, significant and sustained lowering of elevated tear osmolarity. 31 However, it was determined that lowering elevated tear-film osmolarity alone is not sufficient to restore conjunctival goblet cells and corneal glycogen. The second mechanism of action is based on an improved understanding of why the eye needs a tear film. The living cells that make up the surface of the eye have no blood supply. Because of the blood-tear barrier they depend upon the tear supply for two crucial life requirements: oxygen and electrolytes. Oxygen is provided to the tear film by direct absorption from the air, while electrolytes are actively secreted by the lacrimal glands. In clinical studies we were able to measure the electrolyte composition of the normal human tear film in tear microvolumes, 10 and in preclinical studies we were able to demonstrate that this electrolyte balance was crucial for the maintenance of conjunctival goblet cells. 33 If sodium levels were too high, or if bicarbonate levels were too low, for example, mucus-containing goblet cells were lost. It turns out that goblet cells, in addition to providing lubrication for the ocular surface, also defend the ocular surface, firing in response to pain, change in temperature, and changes in the electrolyte balance from that which is native in the tear film. The mucus fired by goblet cells helps trap foreign matter and expel it from the eye. When goblet cells function in this way they act as the anti-aircraft missiles of the eye surface, loaded with a mucus warhead, and firing their mucus in response to, among other things, foreign electrolyte balances. In preclinical studies, TheraTears restored goblet cells, restored corneal glycogen, and promoted healing by lowering elevated tear-film osmolarity and by providing the electrolyte balance to the ocular surface that is needed for growth, maintenance, and repair. Recently, TheraTears has been shown to restore conjunctival goblet cells in the dry-eye condition seen after LASIK vision correction surgery. 34 In this study, patients were treated with TheraTears at least four times a day, and at night one drop of Celluvisc was applied. Controls were treated with a preservative-free balanced salt solution. At one week and one month respectively, 87.5% and 100% of TheraTears-treated patients were free of dry-eye symptoms, while only 12.5% and 20% of control-treated patients were symptom-free (Fig. 4A). When the authors of the study looked at goblet cell density by impression cytology after one month of treatment, TheraTears was shown to significantly restore conjunctival goblet cell density while treatment with a preservative-free control did not (Fig. 4B). Shortly after this study was published, several doctors wondered whether beginning TheraTears treatment before LASIK would improve postoperative results. Wellish, 35 and in a separate study, Smith, Krasnow and 18 Clinical & Refractive Optometry 18:1, 2007

7 Richlin, 36 found that by starting TheraTears about one week before LASIK surgery, patients saw better faster, and felt more comfortable than patients not receiving such treatment. Punctal Occlusion Punctal occlusion also has been shown to lower elevated tear-film osmolarity, reduce rose bengal staining, and improve symptoms. 37 However, unlike TheraTears in controlled studies, punctal occlusion has been shown to have no effect on decreased goblet cell density. 38 Why? In our studies of tear osmolarity and electrolytes in patients with lacrimal gland disease we found there was an increase in tear osmolarity and an increase in all measured tear electrolytes. 10 There was, however, a significantly disproportionate increase in tear sodium levels in these patients. In earlier studies we had demonstrated that disproportionately high sodium levels depleted mucus-containing conjunctival goblet cell density. 33 While punctal occlusion can add water to the tear film, it cannot correct the goblet-cell depleting disproportionate increase in tear sodium seen in keratoconjunctivitis sicca. This explains why punctal occlusion does not restore conjunctival goblet cells. Flaxseed Oil, Fish Oil and Omega-3 Supplementation Omega-3s are essential fatty acids. Essential means that, because they cannot be produced by the body, their inclusion in the diet is essential for good health. The two best sources of omega-3s are dark, oily, cold-water fish, and flaxseed. Each of these provides a different type of omega-3. Cold-water fish provide long-chain omega-3s while flaxseed provides short-chain omega-3s. Once consumed, long-chain omega-3s are directly elongated by enzymes to produce anti-inflammatory prostaglandin E3 (PGE3) and anti-inflammatory leukotriene B5 (LTB5) that suppress inflammation. 39,40 Short-chain omega-3s require several additional elongation steps, and this explains why even high-dose flaxseed oil supplementation has not been shown to suppress inflammation. 41 In addition, eicosapentaenoic acid (EPA), one of the long-chain omega-3s from fish oil, blocks the gene expression of the dry-eye relevant pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), and interleukin-1 beta (IL-1β). We now know that these pro-inflammatory cytokines impair tear secretion in lacrimal gland disease-based dry eye by inhibiting the release of neurotransmitters from neural synapses, and interfering with the secretory response of lacrimal gland acinar cells to stimulation. This leads to the decrease in tear secretion seen in these patients. 42,43 Unlike the long-chain omega-3s in fish oil, the shortchain omega-3s from flaxseed oil do not suppress inflammation. Flaxseed oil, instead, has a significant effect on the tear film oil layer. Boerner has observed the clearing and thinning of meibomian gland secretions with flaxseed oil supplementation, 44 and Chan and Boxer Wachler have quantified the thickening of the tear film oil layer with flaxseed oil supplementation. 45 To date, the long-chain omega-3s from fish oil have not been shown to have these same effects on the oil layer. Besides having these separate and distinct effects, the short- and long-chain omega-3s from flaxseed oil and fish oil, respectively, work together synergistically to competitively inhibit the conversion of omega-6s to arachidonic acid (AA), with flaxseed blocking the elongation of shortchain omega-6s, and fish oil blocking the elongation of long-chain omega-6s. As a result, omega-6 metabolism is forced to take a detour and convert medium chain length omega-6s to prostaglandin E1 (PGE1). PGEI acts on E-prostanoid receptors to increase cyclic AMP (camp) 46 and stimulate aqueous tear production, and, as we shall see, saliva production. It is known that lacrimal and salivary gland secretion can be stimulated in similar ways. Recently, Papas and colleagues, in a prospective, randomized, double-masked, placebo-controlled clinical trial in Sjögren s patients, demonstrated that TheraTears Nutrition, a nutritional supplement providing a flaxseed and fish oil blend, significantly increased salivary secretion, virtually doubling basal rates of salivary gland secretion (p=0.029), while helping both dry-eye and dry-mouth symptoms. 50 Flaxseed oil and fish oil each help dry eye in different ways. Together they work synergistically to decrease inflammation, and augment both the oil and water layers of the tear film. OUR CURRENT APPROACH TO PATIENTS WITH CHRONIC EYE IRRITATION Based on the findings and insights reported in this paper, we can now approach patients with chronic eye irritation in a systematic and effective way. At the time of the initial visit, the cause of chronic eye irritation is determined (Table II). Patients with dry eye are started on preservativefree TheraTears four times a day, with an instruction to use saturation dosing using the entire contents of a single vial in both eyes within a 5-minute period. While the published studies 31,33 were not done with saturation dosing, the purpose of saturation dosing is to accelerate rehydration of the tear-film ocular surface system. Only so much water can be moved into the ocular surface with one drop, and for this reason I developed the technique of saturation dosing to maximize movement of water back into the osmotically dehydrated ocular surface. Patients Dry Eye Gilbard 19

8 who need supplemental topical treatment upon initiation of treatment are instructed to follow saturation dosing with a single drop of TheraTears Liquid Gel. This provides a liquid bandage until the next saturation dosing of TheraTears. At the same time, I start all of my dry-eye patients on TheraTears Nutrition. I have seen other practitioners recommend withholding omega-3 supplementation until later in the treatment plan, but given the benefits for these patients, the fact that both flaxseed oil and fish oil are known to have a multitude of health benefits, and that, as a population, Americans are omega-3 deficient, 39,40 I begin this treatment at the first visit. In general, with the exception of those with severe disease, patients are followed up in about eight weeks, at which time they are divided into one of two groups: improved and happy, or improved but still unhappy. Patients who are improved and happy are continued on TheraTears and TheraTears Nutrition and are followed up between two and three months. With this treatment regimen the symptoms of sandy-gritty irritation late in the day abate. Once patients reach their comfort zone I graduate them from q.i.d. saturation dosing with preservative-free TheraTears to TheraTears in a bottle using one or two drops as needed. Patients who are improved but still unhappy or who need dosing more frequently than four times a day, continue TheraTears and TheraTears Nutrition, and receive lower silicone punctal plugs. These patients are generally followed up in one to three months, at which time a decision is made regarding the addition of superior silicone punctal plugs. Patients with mild to moderate meibomitis are started on TheraTears Nutrition. For those with moderate to severe meibomitis I add minocycline 50 mg a day. An exception is made for obese patients who, because minocycline is a fat-soluble medication, are started on 100 mg a day. In addition, patients with meibomitis are instructed to perform lid hygiene, and to use hot compresses and lid massage twice a day. These patients have bacterial overgrowth on their lids. 51 This overgrowth has been hypothesized to contribute to the symptoms of meibomitis by the production of bacterial lipases and esterases that hydrolyze the wax and sterol esters in meibum, creating free fatty acids that are irritating to ocular tissue and may effect tear-film stability. 52 In addition, these fatty acids may promote eyelid and ocular surface inflammation. 53 I have these patients perform lid hygiene using SteriLid Eyelid Cleanser, a linalool-based foam cleanser that has been shown to be bactericidal for the most common gram positive and negative eyelid organisms (minocycline and SteriLid are available in a prescription kit called Cleeravue-M). This is followed by hot compresses and lid massage. I instruct patients to close their eyes and gently massage their eyelids, paying special attention to the lower lids. The heat increases blood flow to the lids, decreasing inflammation, while the massage helps reduce stasis of oil within the meibomian glands. This stasis of oil within the meibomian glands is believed to help stimulate the inflammatory response. These patients are followed up in two months, and by that time they will notice a reduction in morning symptoms. Data now associates long-term tetracycline use, and longterm antibiotic use in general, to an increase in the risk of breast cancer in women 54,55,56 so I now aim to limit treatment with minocycline for between 4 and 8 weeks. I continue these patients indefinitely on TheraTears Nutrition, SteriLid lid hygiene, hot compresses and lid massage, tapering lid hygiene and hot compresses as permitted by the symptoms. 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