Natural History, Diagnosis and Treatment
By Jeffrey P. Gilbard, M.D., N. Andover, Mass.
Our understanding of dry eye disorders has improved dramatically in the past several years. This increased understanding has enhanced our ability to diagnose and treat patients who have these traditionally challenging conditions.
Here, we'll look at the natural history, diagnosis, and treatment of dry eye disorders. But first, let's talk about the mechanisms underlying them.
Classifying dry-eye disorders
Central to virtually all dry eye disorders is a loss of water from the tear film that increases its osmolarity (concentration) above the normal limit of 311 mOsm/L. Tear film osmolarity increases when water is lost from the tear film, while solutes, such as sodium and potassium, are not. This loss of water and increase in osmolarity may result from any condition that either decreases tear production or increases tear evaporation (see Figure 1 below).
Increased tear osmolarity is the link between changes in the lacrimal glands and lids, and disease of the ocular surface. Studies of preclinical models of lacrimal gland disease and meibomian gland dysfunction show that the ocular surface changes of dry eye disease are dependent upon and proportional to increases in tear film osmolarity. Clinical studies corroborate these findings.
Decreased tear secretion may result from any condition that damages the lacrimal gland or its excretory ducts. Autoimmune disease with inflammation of the tear gland is the most common cause. Less common causes include cicatricial ocular surface conditions. Tear secretion also may be decreased by any condition that decreases corneal sensation, including diabetes, herpes zoster, long-term contact lens wear and surgery that involves corneal incisions or ablates corneal nerves.
Increased tear evaporation may occur in one of two ways:
1. Long-standing posterior blepharitis causing meibomian gland dysfunction. When these glands function properly, they produce an oil layer that coats the tear film and retards evaporation.
2. A large palpebral fissure width, occurring either naturally, secondary to cosmetic surgery or with thyroid eye disease, places evaporative stress on the tear film. Evaporation is proportional to the palpebral-fissure surface area. Increased evaporation also explains why symptoms become worse with exposure to air conditioning, dry heat, low humidity or wind.
Aging tends to result in a gradual decline in tear secretion secondary to the associated decline in corneal sensation and meibomian gland function. In most patients, physiologic reserve, along with a bit of ptosis (drooping of the lids), is adequate to prevent the development of symptoms and disease.
While studies of human disease have shown the ocular surface changes that occur with dry eye, the study of preclinical models of keratoconjunctivitis sicca (KCS) helps us delineate the natural history of these changes. We now know that dry eye disease evolves through a sequence of four milestones:
Let’s have a closer look at the natural history. In dry eye, decreased tear production or increased tear evaporation is rapidly reflected by an increase in tear osmolarity, and soon thereafter by a decrease in goblet cell density (Figure 2). The loss of goblet cells is significant because they produce mucus, the major lubricant in the tear film, and serve in the defense of the ocular surface—mucus fired from goblet cells helps trap foreign matter and expel it from the eye.
The increase in the osmotic gradient between the tear film and the ocular surface, in addition to decreasing goblet cells, pulls water between conjunctival epithelial cells. This action breaks the delicate attachments between these cells and increases conjunctival cell desquamation. In unison with the decrease in goblet cells is a decrease in corneal glycogen. This loss of glycogen is clinically important because glycogen is the energy source for the sliding step of corneal wound healing.
But the cornea doesn't stay 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. The result is an increase in corneal desquamation with a resultant decrease in corneal barrier function. Even later in the natural history of the disease, changes in the corneal epithelial cell surface become severe, resulting in a loss of corneal surface glycoproteins and destabilization of the cornea-tear interface (the attachment between the cornea and the tears.
Understanding the natural history of the disease is crucial for interpreting and evaluating diagnostic tests and appreciating treatment advances. For more information, see "Four Milestones of Dry-Eye Disease" below.
In most cases the diagnosis of dry eye can be made based upon the patient history. The purpose of the examination is to determine why the patient has dry eye.
Patients with dry eye, either from decreased tear production or increased evaporation, most frequently complain of chronic sandy-gritty irritation in their eyes that gets worse as the day goes on. This is because eye closure during sleep forms a watertight seal over the tear film and gives the ocular surface a chance to recover. When the eyes open, evaporation begins, which increases tear-film osmolarity as the day goes on. It's difficult to overstate the usefulness of this history in diagnosing dry eye. If there are symptoms for more than 3 months and if the onset was gradual, the patient has dry eye until proven otherwise.
Keep in mind that patients with meibomitis (known also as posterior blepharitis) also complain of chronic sandy-gritty eye irritation. But in these patients, the irritation is worse upon awakening. This is because tear production decreases during sleep, and eye closure brings the inflamed lids right up against the eye where the release of inflammatory mediators act on the cornea all night. When these patients awaken, tear flow increases, the lids pull away from the cornea, and their symptoms improve as the day goes on.
Eventually the chronic meibomian gland inflammation leads to meibomian gland dysfunction. When that happens, these patients develop a second peak in symptoms from dryness toward the end of the day. Finally, when the meibomian gland inflammation and secondary healing obliterate the meibomian glands, the morning symptoms resolve and patients are left with symptoms from dryness alone, with sandy-gritty irritation that gets worse as the day goes on.
The most sensitive and specific test for dry eye is osmolarity measurement of nanoliter tear samples collected from the inferior marginal tear strip. This is consistent with expectations given that loss of water from the tear film defines the disease. The effort of performing measurements is the only limiting factor to this test’s usefulness. But engineering advances promise to remove this limitation soon, and when this occurs, this test will be the first step in the examination of the patient with chronic eye irritation where dry eye is a consideration.
You are now ready to begin the examination. Look first for facial telangiectasias that may presage meibomitis or meibomian gland dysfunction associated with rosacea. Because evaporation is proportional to surface area, measure palpebral fissure width. Palpebral fissure widths greater than 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 (Figure 3).
Next, touch a wet fluorescein strip to the patient's inferior tarsal conjunctiva and examine the tear film. Lack of spontaneous fluorescence indicates decreased tear volume. In patients with more markedly decreased tear volume, you'll see debris in the tear film and possibly dehydrated mucus that has precipitated in the inferior fornix.
The appearance of the tear film of patients with meibomian gland dysfunction has a watery quality. The tears tend to "splash" around more because meibomian oils, in addition to decreasing tear evaporation, also lower the surface tension of the tear film, which holds the tear film "tight" to the eye.
There is a common misconception that dry-eye patients can experience “tearing.” In fact, patients with dry eye from meibomian gland dysfunction may report that it “feels like” their eyes are tearing. This sensation results from their tears “splashing around” more and because the oil barrier created by the secretion of oil onto the lid margin is missing. As a result, tear fluid can touch the cutaneous portion of the muco-cutaneous junction, making it feel as if the eyes are tearing. It is important to note that these patients won’t have tear overflow. Patients who have tear overflow (frank epiphora) have nasolacrimal drainage obstruction until proven otherwise.
Two methods for clinically evaluating the conjunctival changes that occur relatively early in disease are impression cytology and rose bengal staining. Impression cytology requires setting up a small laboratory and takes a serious commitment; we won't examine it here. In contrast, rose bengal staining is clinically practical. Another dye called lissamine green appears to stain the ocular surface equivalently to rose bengal, but with fewer irritating side effects. In light of the natural history of dry eye, either rose bengal or lissamine green stain the conjunctiva sometime after tear osmolarity increases and once goblet cell loss has become quite significant. Recent evidence suggests that staining occurs when surface cell glycoproteins are altered to an extent that cells have less capacity to retain mucus.
The pattern of rose bengal staining is more useful than merely the presence or absence of stain or even the amount of stain. With dry eye, the nasal conjunctiva stains more than the temporal conjunctiva, and the resilient cornea stains less than the conjunctiva and later in the disease process. Corneal staining likely begins with the loss of corneal cell surface glycoproteins -- the last of the four milestones in the natural history of dry eye disease.
The rapid development of randomly located dark spots in the precorneal tear film (evident after the instillation of fluorescein dye) reflects tear film instability. This finding has been used diagnostically as the tear film breakup time measurement. Yet, as many as half of patients with dry eye will have normal tear film stability. We now understand that this is because dry spots are a result of, not a cause for, dry eye disease. The corneal epithelial changes required to cause tear film instability -- loss of corneal cell surface glycoproteins -- occur late in the natural history of dry eye disease. Although not a sensitive test (it's not highly positive in the presence of disease), breakup time is probably highly specific in that it's negative when disease is absent.
Early treatments for dry eye disorders targeted the late milestones in dry eye disease. In part, this is because the late milestones are easier to spot. For example, dry spot formation is more obvious than increased tear osmolarity and loss of conjunctival goblet cells. But as our knowledge and understanding of dry eye have improved, treatment has begun to target earlier milestones in the disease progression.
Many years ago, demulcents (polymers) were added to artificial tear solutions to improve their lubricant properties and change their viscosity. In 1975, a classic study demonstrated that artificial tear solutions (all containing a preservative at the time) transiently increased tear film stability in normal subjects. These solutions, whether of high or low viscosities, act by temporarily mimicking cell-surface glycoproteins, which are lost late in the disease. Solutions of higher viscosity remain in the eye longer. Whatever releif preserved artificial tear solutions provide hinges on their ability to temporarily stabilize the cornea-tear interface.
The next treatment advance -- preservative-free artificial tear solutions -- occurred about 15 years ago, shortly after researchers recognized that preservatives increase corneal desquamation. A recent study showed that traditional preservative-free artificial tear solutions improve but don't normalize corneal barrier function in dry eye patients. Improved corneal barrier function reflects decreased corneal epithelial desquamation and improved corneal cell junctions. Treatment with a preserved artificial tear solution, while briefly increasing tear film stability, actually diminished corneal barrier function. Preservative-free solutions, by eliminating corneal "peeling" due to artificial tear solutions, established a new benchmark in artificial tear solution treatment, yet still did not address the desquamation caused by dry eye itself.
Since then, researchers have tried to improve the effect of these preservative-free solutions on corneal barrier function by adding various ions. The electrolyte balances of these preservative-free solutions were the best that could be designed while focusing only on issues related to corneal morphology. From the natural history of dry eye disease, we know that decreases in conjunctival goblet-cell density and corneal glycogen are much more sensitive indicators of ocular surface health than changes in corneal morphology.
Knowing what we know now about the mechanism and natural history of dry eye, we would expect that the next advance in treatment would address decreased conjunctival goblet cells, decreased corneal glycogen and elevated tear-film osmolarity. TheraTears is the first eye drop shown in preclinical studies to restore conjunctival goblet-cell density and corneal glycogen with q.i.d. dosing for 12 weeks (Figure 2). TheraTears was developed through a goal-based research program sponsored by the National Eye Institute.
First, given the importance of lowering elevated tear film osmolarity, studies were performed to determine how hypotonic an eye drop needed to be to lower tear film osmolarity in dry eye patients. These studies showed that neither the isotonic eye drops nor the hypotonic eye drops that existed at the time effectively lowered osmolarity. Eye drops needed to be more hypotonic than existing solutions. Based on these findings, the tonicity of TheraTears was set to lower osmolarity from a level of about 330 mOsm/L before eye drop instillation to about 280 mOsm/L after instillation. As a result of this effect, TheraTears reverses the osmotic gradient between the tear film and the ocular surface, and moves fluid onto the surface of the eye rehydrating the dehydrated tissues. As a result of this fluid movement, continued treatment results in rehydration of the tear film-ocular surface system reflected by a progressive, significant and sustained lowering of elevated tear osmolarity.
The second mechanism of action results from an improved understanding of why the eye needs a tear film. The living cells that comprise the surface of the eye don't have a blood supply. Instead they depend on the tear supply for two crucial life requirements: Oxygen and electrolytes. The tear film receives oxygen by direct absorption from the air, and electrolytes through active secretion by the lacrimal glands. In clinical studies, we measured the electrolyte composition of the normal tear film, and in preclinical studies, we demonstrated that this electrolyte balance was crucial for maintaining conjunctival goblet cells. 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 lubricating the ocular surface, also defend the ocular surface. They fire in response to pain, changes in temperature and change in electrolyte balance from that which is native in the tear film. Mucus fired from goblet cells helps trap foreign matter and expel it from the eye. TheraTears provides an electrolyte balance that the ocular surface and the goblet cells cannot distinguish from native normal tear fluid. .
Confirming a pre-clinical study, a recent clinical study found that TheraTears helps restore conjunctival goblet cells in the dry-eye condition that often occurs after laser-assisted in-situ keratomileusis (LASIK) surgery. In the study, one group of patients received TheraTears at least four times a day and one drop of Celluvisc® (1% carboxymethylcellulose) at night. Patients in a control group received a preservative-free balanced salt solution. At 1 week and 1 month after surgery, respectively, 87.5% and 100% of dry-eye patients who received TheraTears were free of dry-eye symptoms, while only 12.5% and 20% of patients in the control group were symptom-free. Plus, goblet-cell density measured by impression cytology 1 month after treatment showed that TheraTears significantly restored conjunctival goblet cell density, whereas the control treatment didn’t. Two subsequent studies have found that patients who start using TheraTears about 1 week before LASIK surgery see better faster and feel more comfortable than patients who don’t receive such treatment. A 1% carboxymethylcellulose version of TheraTears is now available in a liquid gel format.
Punctal occlusion also helps lower elevated tear film osmolarity, reduce rose bengal staining and improve symptoms. But controlled studies indicate that punctal occlusion doesn't have any effect on goblet-cell density. Why? In our studies of keratoconjunctivitis sicca patients with lacrimal gland disease, we found an increase in tear osmolarity and all measured tear electrolytes. There was, however, a significantly disproportionate increase in tear sodium levels in these patients. Disproportionately high sodium levels deplete conjunctival goblet-cell density. So, while punctal occlusion can add water to the tear film, it can't correct the disproportionate increase in tear sodium seen in keratoconjunctivitis sicca that depletes goblet cells.
Until now our approach to dry eye has been a topical one, and by lowering elevated tear film osmolarity and providing an electrolyte-matched tear solution we have achieved effective treatment. Now we are seeing a new approach to dry eye treatment, a revolutionary change, with TheraTears Nutrition for dry eyes, an omega-3 dietary supplement containing a blend of flaxseed oil, fish oil and vitamin E. TheraTears Nutrition will be taking a major role in the treatment of dry eyes and, as we shall see, meibomitis as well, addressing the conditions that lead to increases in tear film osmolarity.
New research, presented for the first time at the 2003 Annual meeting of the Association for Research in Vision and Ophthalmology has found that high dietary intake of omega-3 essential fatty acids decrease the risk of dry eye. Using the Women’s Health Database at the Harvard School of Public Health, the investigators examined the dietary intake of essential fatty acids in 32,470 female health professionals. They found that the higher the dietary ratio of omega-3 to omega-6 essential fatty acids, the lower the likelihood of dry eye, and the higher the dietary omega-3 intake, the lower the likelihood of dry eye. Conversely, they found that the lower the ratio of omega-3s to omega-6s the higher the likelihood of dry eye.
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. They are known to have a multitude of health benefits, yet, as a population, Americans are omega-3 deficient—Americans have among the lowest dietary intake of omega-3s in the world (Figure 4).
Omega-6s are another group of essential fatty acids. Americans obtain an excess of omega-6’s through their consumption of beef, dairy and vegetable shortening and cooking oils (i.e. hamburgers, cheese burgers, pizza, ice cream, potato chips etc.). Unfortunately, while the recommended ratio of omega-3s to omega-6s is 1:2.3, the existing ratio of omega-3s to omega-6s consumption has been estimated to be as low as 1:10.
Omega-3s decrease inflammation
Omega-3s in the diet, once consumed, are elongated by enzymes to produce anti-inflammatory prostaglandin E3 (PGE3) and anti-inflammatory leukotriene B5 (LTB5) (Figure 5). Even more importantly, eicosapentaenoic acid (EPA), a long-chain omega-3 provided directly by fish oils, blocks the gene expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-a), interleukin-1 a (IL-1a), interleukin-1b (IL-1b), proteoglycan degrading enzymes (aggrecanases) and cyclooxygenase (COX-2) (Figure 6).
These anti-inflammatory effects go a long way to explain why omega-3s have been useful in treating patients with posterior blepharitis or meibomitis. The results are so positive that it is displacing my use of systemic tetracyclines as treatment for the eye irritation that my meibomitis patients experience upon awakening in the morning. But the effects of omega-3s only begin with their effects on meibomitis.
Omega-3s decrease apoptosis
Suppressing TNF-a is also important because in Sjögren’s syndrome and in lacrimal gland-based dry eye, increased TNF-a in the lacrimal glands increases lacrimal gland apoptosis (programmed cell death). Increased apoptosis contributes to the decrease in tear production, and increase in tear film osmolarity that drives dry-eye ocular surface disease.
In addition TNF-a induces apopotosis on the ocular surface in dry eye. Specifically, Luo and co-workers found that increasing tear film osmolarity in animal models increases the expression of TNF-a and the associated cell regulators that increase apoptosis on the ocular surface. There has been a lot of interest recently in ocular surface inflammation in dry eye. This important study shows that it is elevated tear film osmolarity that induces the increased expression of pro-inflammatory cytokines in dry eye, just as elevated tear film osmolarity has been shown to produce all the morphological ocular surface changes described in dry eye.
Restasis, a very expensive drug administered topically because it is so toxic systemically, also inhibits TNF-a production by monocytes. Applied topically it achieves good concentrations in the eye surface but is not thought to reach the orbital lacrimal gland in humans. TheraTears Nutrition, taken by mouth, reaches the lacrimal gland by the blood supply, and, as we shall see later, the ocular surface via meibum. Restasis and TheraTears Nutrition both appear to inhibit pro-inflammatory cytokines, but differ in their ability to reach relevant target tissues.
While EPA decreases the gene expression of TNF-a, DHA, another long-chain omega-3 provided directly by fish oils, protects cells from TNF-a –induced apoptosis. Yano and co-workers have demonstrated that vitamin E works synergistically with DHA to protect cells from TNF-a –induced apoptosis. So EPA and DHA work together to protect the lacrimal gland and ocular surface from apoptosis.
Omega-3’s stimulate tear secretion
The effects of suppressing pro-inflammatory cytokines don’t stop here. We now know that the pro-inflammatory cytokines TNF-a, IL-1a, and IL-1b, 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 is probably the main mechanism by which tear secretion decreases in dry eye.
The profound importance of this has been illustrated in recent work that shows that when TNF-a gene expression is blocked by gene therapy in an animal model, autoimmune lacrimal gland disease can be reversed, and tear secretion restored. The relevance of this animal model is supported by the epidemiological data cited above, as well as an additional study that finds that Sjögren’s patients have a lower dietary intake of omega-3s, including EPA and DHA, than age-matched controls.
While EPA is central in blocking the gene expression of pro-inflammatory cytokines, DHA may help in a complementary way. Neural synapses contain among the highest concentration of DHA in the body and research has shown that dietary supplementation with DHA restores neural DHA levels and improves age-related declines in synapse function. DHA may reduce the ability of pro-inflammatory cytokines in the lacrimal gland to inhibit signal transduction at the synapse. Lending credence to this hypothesis is the finding that severity of dry eye in Sjögren’s patients has been found to be inversely proportional to membrane and serum levels of DHA.
Omega-3s affect the lacrimal gland in another way. EPA and DHA and alpha-linolenic acid (ALA) from flaxseed oil competitively inhibit the conversion of omega-6s to arachidonic acid (AA) thereby promoting the conversion of DGLA to prostaglandin E1 (PGE1) (Figure 5 ). PGE1 also has anti-inflammatory properties and, in addition, acts on the E-prostanoid receptors EP2 and EP4 to activate adenylate cyclase, increasing cyclic AMP (cAMP). PGE1 and cAMP have been shown to stimulate aqueous tear secretion.
Omega 3’s, the meibomian gland oils
Meibomian glands use essential fatty acids to synthesize oil (meibum). Dietary intake of omega-3s in general, and EPA and DHA in particular, have recently been shown to affect the polar lipid profiles of meibum as observed by HPLC. Indeed, Boerner has observed the clearing and thinning of meibomian gland secretions with omega-3 supplementation. Further studies are needed to determine whether these effects are sufficient to bolster the oil layer and retard evaporation.
With these findings and
insights, we can approach patients who have chronic eye irritation in a
more systematic and effective way. Follow this approach:
As we've seen here, understanding the natural history of dry eye disease improves our ability to diagnose the condition and to appreciate the meaning of our examination and testing. With this information, we can better differentiate between various treatments at our disposal and offer patients the best care possible.
Dr. Gilbard practices with Tallman Eye Associates in North Andover, Mass (978-794-8118). He is founder and CEO of Advanced Vision Research, which markets TheraTears and where he maintains an active research and teaching program.
Abdel-Khalek LMR, Williamson
J, Lee WR: Morphologic changes in the human conjunctival epithelium. II.
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Mathers WD: Ocular
evaporation in meibomian gland dysfunction and dry eye. Ophthalmology
100(3): 347-51, 1993.
and the eye
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