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Dry Eye Intervention

Here’s one thing we have learned for sure: achieving clinical control of keratoconjunctivitis sicca makes reaching target IOP in glaucoma patients seem relatively simple.

Here’s another thing we know: Dry eye syndrome continues to be the most common medically treatable eye disease seen in our practices.

The pathophysiologies of glaucoma and dry eye disease are far from elucidated. Hopefully, as research continues to reveal the nuances of these diseases, more therapies can be developed to combat them.

While a rational algorithm can be fashioned for IOP reduction, dry eye management is too complex and variable to permit a clinically valid algorithm. There are numerous approaches to patients so afflicted: artificial tears, punctal plugs, anti-inflammatory drugs, oral doxycycline, and oral omega-3 fatty acid supplementation. Deciding which approach(es) will best serve the needs of each individual patient is often reduced to logical, methodical trial and error.

Artificial Tears
These simple and time-honored eyedrops might actually work if patients would use them as directed. Between the two of us, we might have a handful of patients who do so. The vast majority woefully underutilize their artificial tears. Compliance with glaucoma medications is far less of a problem. This is a real paradox, as one would think a symptomatic disease like dry eye would command greater eyedrop compliance than would an asymptomatic disease like glaucoma. Once you and your patient have decided on a trial of artificial tears, you must then decide on low, medium, or high viscosity; preserved, non-preserved, or transiently preserved; solution, emulsion, gel or ointment; bottled tears versus unit-dose. What a mess! Whichever of these you choose, what frequency of instillation is optimum for your patient? The complexity in dry eye management overshadows glaucoma drug selection, and we’re only on artificial tears!

Punctal Plugs
Punctal plugs do seem to be helpful for many patients. For those patients with moderate tear volume, plugs can offer significant symptomatic relief. However, if the tear volume is scant, the main benefit that plugs may offer is prolonging the residence time of artificial tear supplementation. Patients with scant lacrimal lakes must use the recommended artificial tear frequently (at least every 4 hours); otherwise, tear film stagnation caused by the punctal plugs may concentrate pro-inflammatory cytokines in the tear film and actually exacerbate signs and symptoms of dry eye. It may be that in such cases pulse dosing with Lotemax q.i.d. for 2 weeks, then b.i.d. for 2 weeks, along with frequent instillation of artificial tears should be accomplished prior to plugging the inferior puncta.

Since plug extrusion is a common problem, we always attempt to insert the largest size plug that can reasonably and practically be fitted. To maximize this goal, we use punctal gauge devices to determine the optimal size. Use of such devices has helped us decrease our extrusion and loss rate significantly.

Whether to plug one punctum initially (in the more symptomatic eye), similar to a monocular therapeutic trial, or to plug both lower puncta is a matter of choice. Either way, have the patient return in a month to assess efficacy.

Anti-inflammatory Therapy
Photophobic, painful and injected eyes are inflamed. These eyes almost invariably respond to pulse dosing with Lotemax or FML q.i.d. for two to four weeks, along with frequent use of artificial tears. While most patients with ocular surface drying do not overtly manifest inflammation, they may still benefit significantly from immunosuppressive intervention. This can be augmented with topical loteprednol 0.5%, cyclosporine, or perhaps better with a several months’ course of orally-administered doxycycline or omega-3 essential fatty acid supplementation.

Biomedical research has confirmed that inflammation plays a clinically significant role in many eyes with precorneal tear film dysfunction. The challenge in this morass is to know which patients will benefit from anti-inflammatory therapy and which ones will not. Generally speaking, the greater the signs and symptoms, the more success we have had with topical inflammation therapy. Note that concurrent use of artificial tears is always implemented.

If you have decided upon a therapeutic trial with an anti-inflammatory medication, there are two ways to proceed: topical corticosteroids or topical cyclosporine. Since corticosteroids such as Lotemax or FML have an onset of action much faster than Restasis (cyclosporine), initiate anti-inflammatory therapy q.i.d. with one of the steroids. (We usually use Lotemax). When the patient returns in a month, the clinical response (or lack thereof) will evidence whether this patient’s dry eye is characterized by clinically significant inflammation.

If the steroid trial was significantly beneficial, two choices are available: either continue the Lotemax b.i.d. for 1 month then taper to once-daily for a month or two (along with artificial tears), or continue the Lotemax b.i.d. for a month along with Restasis b.i.d. Since it usually takes Restasis at least a month to render a meaningful effect (and in many patients, two to four months), front-loading with the steroid quantitatively diminishes the expression of inflammation and seems to potentiate the therapeutic effect of the Restasis. Bear in mind that steroids reign supreme in the treatment of inflammation, and neither Restasis nor any NSAID comes close to matching their anti-inflammatory action. (See “Loteprednol or Cyclosporine” below.)

As with glaucoma management, cost can be a major factor in a patient’s ability to “purchase and persist” with therapy. Just keep two points in mind for those dry eye patients who benefited from anti-inflammatory suppression yet do not have a drug plan and may not be able to afford Restasis: Lotemax is markedly less expensive than Restasis. While steroids have the potential to increase IOP and/or cause posterior subcapsular cataracts, the potential for such adverse events are exceedingly reduced with loteprednol. A drop or two a day for two to four months should be completely safe in virtually all patients. Along these lines, a very enlightening study describes the efficacy and safety of using 0.2% loteprednol (Alrex).1 This study clearly confirmed the long-term, safe use of this ester-based corticosteroid.

Furthermore, many patients with chronic iritis, stromal herpes keratitis, and/or corneal transplants have safely used once-daily prednisolone drops for months and even years. Without debate, long-term use of Restasis carries less risk for side effects than any steroid, but the risks with Lotemax q.d. or b.i.d. are low. Fortunately, most patients we encounter have a drug plan, making Restasis relatively affordable.

The larger issue is how long do we need to keep patients on any anti-inflammatory therapy in the setting of dry eye. Such is not yet definitively established. Our best hunch is 6 to 12 months. Keep in mind that concomitant efforts with artificial tears, punctal plugs, and meibomian gland functional enhancement should reduce ocular surface inflammation to a clinically insignificant level in a few to several months. Once the patient has achieved good control (or resolution) of his or her signs and symptoms, it should be relatively easy to maintain the patient without anti-inflammatory interventions.

Our experience has shown that some patients do well for months, then become acutely symptomatic. Pulsing with Lotemax q.i.d. for 1 week, then b.i.d. for a week or two can regain control for many more months. Since Restasis is a slow-onset drug, it is not suitable for pulse dosing. If the time period between acute symptomatic exacerbation becomes too short, then either continue the Lotemax at b.i.d tapered to q.d. after a week or two, or Restasis at b.i.d. for several months
After patients with dry eye syndrome are on Restasis or once-daily Lotemax for several months, periodically stop the medicine to assess how the patient does without it. Always attempt to use the least amount of medicine to care for the patient.

Loteprednol or Cyclosporin Obviously, lower concentration steroids have less risk for side effects than those of higher concentration. So why not use Alrex instead of Lotemax? Our general philosophy is to be aggressive with inflammation. When we encounter inflammatory dry eye (or what we presume to be so), we want to aggressively achieve control, then taper the steroid dosage, or transfer the patient to Restasis. Simply put, Lotemax will control the inflammation more efficiently than Alrex. It could be argued that, once control is achieved and once-daily Lotemax is maintaining the patient’s symptoms adequately, the patient could be switched to Alrex once a day. This possibility is being explored; however, if the inflammatory expression is presumably so mild that Alrex once-daily works, then perhaps no anti-inflammatory intervention is needed at all. These are thoughts to ponder, as a definitive answer regarding this issue is not known. After a few months of good control with Restasis, can it be reduced to once-daily use, and still maintain control? This, also, is being explored. There is only one way to find out—try it! Only when we have thousands of O.D.s treating thousands of patients over a year or two with various modalities, will we be able to gain meaningful understanding of which approaches to dry eye syndrome will best serve our patients. Like so many other aspects of medical care, there are many intricacies of treatment that are still unknown.

Meibomian Gland Enhancement
“Evaporative” dry eye results when meibomian gland function is compromised. Both oral doxycycline and oral omega-3 fatty acids can enhance meibomian gland function and result in a more stable, well-functioning tear film. The question arises as to which of these two oral treatments best enables the meibomian gland to function optimally. Once again, scientific clinical studies are, to our knowledge, inconclusive on this specific issue.

We offer the following observations: meibomian glands are modified sebaceous glands. Dysfunction of facial sebaceous glands can cause acne. Dermatologists commonly prescribe an oral tetracycline to treat facial acne. In a landmark major review of meibomian gland dysfunction, published in 1996, researchers exhaustively discussed every nuance of meibomian gland function and recommended oral tetracycline’s use for several months in patients with posterior blepharitis. We generally prescribe doxycycline at 50mg, 2 tabs b.i.d. for two weeks, then 50mg q.d. for six months. We may have the patient stay on the doxycycline even longer if they are happy and are tolerating it well.

The tetracyclines (tetracycline, doxycycline and minocycline) are antibiotics with multiple other pharmacologic actions. They are safe and well-tolerated as evidenced by their intense, widespread, and protracted use by dermatologists to help treat a variety of skin conditions. Many patients are safely kept on these antibiotics for years. This class is also generic and inexpensive.

The tetracyclines are pregnancy rated Category D, which means they are contraindicated for pregnant women. (They interfere with dental enamelization.) For this same reason, the tetracyclines are contraindicated in nursing mothers and children under 8 years of age.

Side effects in adults are nil, save occasional, bothersome, vaginal yeast infections. Some patients are bothered by photosensitivity and appropriate precautions may be advised, such as use sunscreen or minimization of UV exposure. Whether to continue with doxycycline and treat the yeast infection will depend on the degree of benefit being derived relative to the aggravation of the yeast overgrowth. This is largely the patient’s call. We are just now beginning to transfer successfully treated doxycycline patients to omega-3 supplements to see if these continue to keep the patients asymptomatic.

Like doxycycline, omega-3 essential fatty acids (derived from flaxseed, evening primrose, or fish oils) are slow-onset in their action, and usually take three to four months for the patient to notice an effect. The common dosage is 2,000mg of flaxseed oil per day. Our preferred way to obtain omega-3 is with TheraTears Nutrition supplementation; however, any equivalent source would be fine. The recommended dosage is 4 capsules taken in the morning. These capsules contain half flaxseed oil and half fish oils. For patients preferring a liquid formulation, Cynacon/OcuSoft makes Hydrate Essential; a combination of flaxseed oil, evening primrose oil, and bilberry extract. Some people occasionally develop some GI upset, so at least mention this possibility to your patients.

The question now arises as to which approach to meibomian gland enhancement is more therapeutically effective. Most of the experts with whom we have spoken feel that doxycycline packs considerably more punch, and we generally prefer it as an initial therapeutic trial. However, some patients simply prefer an “alternative medicine” approach, and this is certainly fine. We have had excellent success with both approaches, and often ask our patients which they would prefer.

In  summary, we now have an armamentarium capable of eliminating the signs and symptoms of ocular surface disease in most patients. What we do not know is which approach(es) are optimum for each individual patient. For now, at least, we must simply determine the most effective course of treatment by enlightened trial-and-error. We hope that the information set forth in this chapter will enable the reader to more effectively formulate a plan to help patients who are plagued with this widespread disease.

1. Ilyas H, Slonim CB, Braswell GR, et al. Long-term safety of loteprednol etabonate 0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Eye Contact Lens 2004 Jan;30(1):10-3.
2. Driver PJ, Lemp MA. Meibomian gland dysfunction. Surv Ophthalmol 1996 Mar-Apr;40(5):343-67.