Optometric Management

Dry Eye
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.

Central to virtually all dry-eye disorders is a loss of water from the tear film that increases its osmolarity above the normal limit of 311 mOsm/L. Tear film osmolarity increases when water is lost from the tear film but solutes 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).

Figure 1: 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).

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. Increased tear-film osmolarity is the link between changes in the lacrimal glands and lids, and ocular surface disease. Clinical studies corroborate these findings.

Decreased tear secretion may result from any condition that damages the lacrimal gland or its excretory ducts. Autoimmune disease 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 herpes zoster, long-term contact lens wear and surgery that involves corneal incisions or ablates corneal nerves.

1. Long-standing posterior blepharitis may cause dysfunction of the meibomian glands. 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 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 often are 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, is adequate to prevent the development of symptoms and disease.

Although 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:

Here's how a patient's condition progresses through each milestone. 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. Despite the loss of goblet cells, the cornea initially remains morphologically untouched. However, simultaneous with the decrease in goblet cells, corneal glycogen levels decrease. Glycogen is the energy source for corneal wound healing; so its loss is important.

The increase in the osmotic gradient between the tear film and the ocular surface pulls water between conjunctival epithelial cells. This action breaks the delicate attachments between these cells and increases conjunctival cell desquamation. Unlike the conjunctival epithelium, the corneal epithelium is held together by tight junctions. Thus, the corneal epithelium is more resilient to increased tear-film osmolarity than the conjunctival epithelium. Consequently, the disease first affects the conjunctival morphology while the corneal morphology initially remains normal.

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.

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" on page 4.

In most cases, you can diagnose dry eye from a patient's history. Your examination will determine why a 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. Also, patients with dry eye typically note that their symptoms get 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 a patient has these symptoms for more than 3 months and if the onset was gradual, the patient has dry eye until you prove 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 because the inflammation is in the eyelids. During sleep, tear production decreases, eye closure brings the inflamed lids right up against the eye, and the released inflammatory mediators act on the cornea all night, creating a symptom peak upon eye opening. When these patients awake, 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.

Eye irritation has many other causes, which we need to consider when approaching a patient with chronic symptoms. See "What Causes Chronic Eye Irritation?" for more information on these other causes.

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 because 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).

Figure 3. Natural history of meibomitis. Meibomian gland inflammation
leads first to stenosis and then closure of the meibomian gland orifice.
Published courtesy of International Ophthalmology Clinics. (1994; 34:27-36).

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 precipitated mucus 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.

Clinicians commonly report that patients with dry eye may complain of "tearing." Indeed, 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 mucocutaneous junction, making it feel as if the eyes are tearing. It's important to note that the patient 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 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.

Where the Schirmer Test Falls Short

Given that decreased tear production or increased evaporation can cause dry eye, it's understandable why, in controlled studies, the value obtained through the Schirmer test isn't the best means of diagnosis. This poor sensitivity, specificity and predictive value pertain whether or not dry-eye patients are selected based on symptoms, increased osmolarity or ocular surface disease. In other words, no matter how you diagnose dry eye, whether by history, increased osmolarity, or rose bengal staining, the Schirmer test has poor sensitivity, specificity and predictive value.

While lacrimal gland disease decreases Schirmer measurements, meibomian gland dysfunction increases these measurements. With decreased oil on the lid margin, the Schirmer strip wets more easily. Indeed, in a rabbit model of dry eye with meibomian dysfunction, elevated tear film osmolarity, decreased conjunctival goblet-cell density, decreased corneal glycogen, and rose bengal staining, Schirmer test strips wet more than those used in control eyes.

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 demulcent 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. The effectiveness of preserved demulcent solutions hinges on their ability to temporarily stabilize the cornea-tear interface.

The next treatment advance -- preservative-free demulcent solutions -- occurred about 15 years ago, shortly after researchers recognized that preservatives increase corneal desquamation. A recent study showed that traditional preservative-free demulcent 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 demulcent solution, while briefly increasing tear-film stability, actually diminished corneal barrier function. Preservative-free solutions established a new benchmark in artificial tear solution treatment.

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 can anticipate 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). A preservative-free demulcent solution, the product accomplishes this effect through two mechanisms.

First, given the importance of lowering elevated tear-film osmolarity, studies were performed to determine how hypotonic an eye drop must 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.

Another study suggests that TheraTears helps restore conjunctival goblet cells in the dry-eye condition that often occurs after LASIK surgery, when decreased corneal sensation decreases tear production and increases tear-film osmolarity. In the study, one group of patients received TheraTears at least four times a day and one drop of Celluvisc 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.

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 KCS 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 KCS that depletes goblet cells.

With these findings and insights, we can approach patients who have chronic eye irritation in a systematic and effective way. Follow this approach:

2. Start patients who have dry eye on preservative-free TheraTears four times a day. Instruct them to use "saturation dosing," which means splitting the entire contents of a single vial between both eyes within a 5-minute period. Although patients in the studies didn't use saturation dosing, this technique helps accelerate rehydration of the tear film-ocular surface system. One drop can move only so much water into the ocular surface. Saturation dosing helps maximize water movement into the dehydrated ocular surface.

3. See dry-eye patients again in 4 to 8 weeks, at which time, you can categorize them as either improved and happy or improved but still unhappy. (If a patient is not improved, re-evaluate your diagnosis.)

Patients who are improved and happy should continue using TheraTears and visit you again in 2 to 3 months. With continued treatment, the sandy-gritty irritation that patients experience late in the day should abate. When a patient reaches his "comfort zone," switch him from saturation dosing with the preservative-free unit dose to maintenance treatment using one or two drops at a time of TheraTears in a bottle. TheraTears in a bottle contains the perborate preservative system, which converts to oxygen and water through the action of enzymes on the ocular surface.

Patients who are improved but still unhappy or who require more than four doses a day should have lower silicone punctal plugs inserted. See these patients again in 1 to 3 months, when you can decide whether to add superior silicone punctal plugs.

4. Start patients who have meibomitis on 50 mg a day of doxycycline. Start obese patients on 100 mg a day because doxycycline is a fat-soluble medication. Also, advise patients to apply warm compresses to their lids and to perform lid massages twice a day. Teach patients to heat and massage their lids by closing their eyes and using a warm washcloth to gently massage the eyelids for about 5 seconds, paying special attention to the lower lids. The heat increases blood flow to the lids, decreasing inflammation. The massage helps reduce stasis of oil within the meibomian glands. This stasis of oil within the meibomian glands is believed to stimulate the inflammatory response.

See these patients again in 3 months. By that time, they'll notice a reduction in morning symptoms. Once morning symptoms have abated, reduce the doxycycline dose by half, and taper it every 3 months until the patient is off the medication or, more typically, on the lowest possible maintenance dose. Patients who work outdoors or who are exposed to lots of sun may take minocycline instead of doxycycline (50 mg of doxycycline is equivalent to 100 mg of minocycline).

Reserve lid scrubs or lid hygiene for patients who have anterior blepharitis or a dandruff-like process at the base of the lashes. These patients should switch to a dandruff shampoo and use the suds from their hair to wash their eyelashes with their eyes closed.

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. He is founder and CEO of Advanced Vision Research, which markets TheraTears and where he maintains an active research and teaching program.

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 Drops
1 Increased tear osmolarity	Patient history Tear osmolarity	Sufficiently/optimally hypotonic (Preservative-free TheraTears, Thera Tears in a bottle)
2 Decreased goblet cell density Decreased corneal glycogen	Conjunctival staining Impression cytology	Tear-matched electrolyte balance (Preservative-free TheraTears, Thera Tears in a bottle)
3 Increased corneal desquamation	Corneal staining	Preservative-free lubricants of various viscosities (Refresh Plus, Bion Tears, Celluvisc, GenTeal, GenTeal Gel
4 Decreased corneal cell surface glycoproteins	Tear film breakup time	Preserved lubricants of various viscosities (Refresh Tears, Tears Naturale II)

What Causes Chronic Eye Irritation?

Causes other than dry eye and meibomitis may explain a patient's chronic eye irritation. Consider these other possible causes and their symptoms.

Anterior blepharitis
Patients have crusting and irritation at the base of lashes without diurnal variation. Onset is insidious.

Medicamentosa
Patients complain of burning and irritation without diurnal variation. Symptoms are equivalent throughout the day because overuse of topical medications promotes damage. You should suspect this condition in all patients who use traditional artificial tears more than four times a day. Patients generally have a history of escalating tear use.

Lacrimal drainage obstruction
Patients often have 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.

Allergic conjunctivitis
The primary symptom for this condition is itchy eyes. Patients' eyes may also exhibit increased mucus production. Onset of this condition is commonly seasonal, and it may be associated with hay fever, asthma and eczema.

Nocturnal lagophthalmos
Patients' eyes may burn upon awakening. Patients frequently have a history of lid surgery or thyroid eye disease.

Superior limbic keratoconjunctivitis
Symptoms include burning and irritation without diurnal variation. Abrupt onset and remissions characterize this condition. Patients often have a history of thyroid dysfunction.

Superficial punctate keratitis (Thygenson's)
Patients with this condition experience insidious onset of photophobia, eye irritation and decreased vision. The condition is episodic and recurring.

Dry eyelid skin
Patients complain of "dry eyes." This condition underscores the importance of accurate localization of symptoms.

Tarsal foreign body
Patients experience a chronic sensation of having a foreign body in their eye. This sensation results from exogenous material or an exposed meibomian-gland derived conjunctival concretion.

Mucus fishing syndrome
Symptoms include chronic eye irritation and increased mucus production. Patients who reach into their conjunctival cul-de-sac to remove mucus strands caused by conjunctival trauma initiate the condition. A vicious cycle can develop.

Blepharospasm
Patients may complain that their eyes feel "tired." Careful questioning reveals that patients are experiencing an involuntary closure of the eyes, rather than eye irritation. Driving, reading and exposure to sunlight worsen symptoms.

Non-specific ocular irritation
Normal eyes, abnormal environment. Eye irritation in response to smoke would be a typical example.

Normal eyes with hypochondriasis
This condition is uncommon. A careful history that fails to mesh with the examination can provide the first clue to its presence.

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