The Chronic Dry Eye Patient: A Strategy for Achieving and Optimizing Pharmacologic Success. Laura A. Vickers, M.D. and Alan N. Carlson, M.D.
A 45-year-old caucasian woman presented to the Duke Eye Center for a second opinion regarding her 2-year history of severe ocular surface dryness involving both eyes, which was unresponsive to Restasis® (Cyclosporine Ophthalmic Emulsion 0.05%, Allergan, Inc, Irvine, CA). She complained of severe symptoms, including constant foreign body sensation, irritation, “tired eyes” and fluctuating vision throughout the day. She was cosmetically concerned about her persistently red, inflamed eyes. In fact, the patient was so disturbed by these symptoms and by her appearance that she was functionally limited and her quality of life was diminished. She had previously responded poorly to frequent usage of Refresh® artificial tears (Allergan, Inc, Irvine, CA), various oral flax seed and fish oils, and topical Restasis drops used consistently for one year. She also noted that instillation of Restasis caused redness and irritation, which added to her frustration. She was previously employed as a computer analyst and her symptoms worsened after several hours of computer usage, resulting in significant emotional distress.
Her past ocular history was notable for bilateral upper eyelid blepharoplasty with 3 additional follow-up procedures. Upon questioning, she did endorse worse irritation and dryness in the mornings. There were no additional positives on an extensive review of systems, and no relevant past medical or family history.
The patient’s vision fluctuated with blinking during testing, although after instillation of artificial tears her best corrected visual acuity was 20/20 in both eyes. On external examination her eyes were notably red and inflamed. By slit lamp biomicroscopy, the eyelid margins were thickened and inflamed with telangiectasia and significant meibomian gland obstruction. The tear meniscus was deficient and the pre-ocular tear film was notably unstable with a Tear Breakup Time (TBUT) in the right eye of 6 seconds and in the left eye 3.5 seconds. Basic Schirmer Test (BST) in the right eye was 5 mm and in the left was 2 mm at 5 minutes. The cornea was otherwise clear without opacity, and the remainder of the slit lamp and fundus examination were within normal limits. Intraocular pressures were also normal.
LipiView analysis was performed which identified that essentially 100% of her blinking was incomplete or partial. LipiView also identified significant fluctuation in the lipid layer thickness of her tear film between blinks. She was able to forcibly close her eyes but in a relaxed state, we were able to reproduce lagophthalmos.
Discussion and Diagnosis
Our patient was diagnosed with both aqueous and lipid deficient “evaporative” dry eye syndrome exacerbated by incomplete blinking. Additionally, given the severity of her condition and her subjective report of symptoms which were worse upon awakening in the morning, we suspected nocturnal lagophthalmos resulting from the multiple eyelid procedures.
The finding of incomplete blinking on LipiView analysis is common among people who spend hours using the computer as well as those who have undergone previous eyelid surgery. Our patient underwent the 12-minute LipiFlow thermal pulsation treatment. Postoperatively she was instructed to continue the use of topical Restasis twice daily and to keep a diary of her progress. No additional anti-inflammatory medications were used. The application of Soothe® ophthalmic lubricating ointment (Bausch + Lomb, Rochester, N.Y) at night was implemented because of the concern for nocturnal lagophthalmos.
On follow-up evaluation 5 weeks after treatment, she reported a remarkable improvement in ocular redness throughout the day, and was highly satisfied with both comfort and the cosmetic results. Her morning irritation had resolved with the nightly application of ophthalmic ointment. The sensation of “tired eyes” and the previously constant foreign body sensation had almost completely resolved. Restasis no longer caused ocular discomfort and redness upon instillation.
On slit lamp examination, the lid margins were noticeably less inflamed. The pre-ocular tear film was more stable with TBUT of 9.5 seconds in the right eye and 8 seconds in the left. The tear meniscus was much more robust and BST measured 15 mm in the right eye and 5 mm in the left at 5 minutes.
Finally, the patient was optimistic that her improvement in ocular comfort would allow her to return to the workplace and function more normally throughout the day. The emotional burden of her symptoms improved greatly leading to a significant improvement in her quality of life.
“Dry eye” is a very broad term with highly variable clinical presentations. Frequently, there are inconsistencies between the objective signs of dry eye on examination and the patient’s subjective experience and perception of the disease. This can be frustrating for both patient and doctor. This may be due to differences in pain sensitivity as well as lifestyle, emotional and psychological factors.1 While previously considered primarily the consequence of deficient tear production, dry eye is now recognized as a much more complex and prevalent condition where inflammation, poor tear film quality and instability ultimately result in reduced lubrication and subsequent repetitive injury to the ocular surface.23 An unstable tear film reportedly accelerates tear evaporation 4-fold, and produces aqueous deficiency as this is the component of the tear film that readily evaporates.4
The management of this patient’s condition prior to our evaluation demonstrates what may be the most common error in the management of ocular surface dryness: treatment guided exclusively by patient symptoms and expectations. Unfortunately, this approach leads to inconsistency in treatment as it depends on the patient’s subjective perception of their symptoms. The dry eye patient who goes untreated or inadequately treated early in their disease course is at risk for progressing to structural changes of the eyelid margin with gland obstruction, gland atrophy, and ocular surface injury over time making their condition more resistant to pharmacologic management. This leads to a common cycle in the doctor-patient relationship wherein the physician encourages medication compliance while balancing patient expectations for symptomatic improvement as the disease becomes more difficult to treat. Patients often become frustrated as they further limit lifestyle activities due to symptoms and continue to take expensive medications, often unconvinced of their effectiveness.
In such cases, patients may be improperly labeled as Restasis non-responders. While many patients derive benefit from Restasis, a subset may not initially achieve symptomatic relief.5 Presumably, this inability to “get ahead” of the inflammatory cascade in these more challenging patients involves additional inflammatory and structural factors that remain inadequately treated. We observe that the most consistent finding among patients labeled as nonresponsive or poorly responsive to Restasis is the insufficient treatment of meibomian gland and eyelid margin disease. While Restasis has a role in treating the inflammation resulting from a sequel of meibomian gland dysfunction, less responsive patients may require a more aggressive incorporation of adjuvant therapies to maximize their beneficial response to Restasis.4
Our patient underwent LipiView analysis revealing inadequate blink quality along with a deficient and unstable lipid layer in the tear film.6 LipiFlow Thermal Pulsation Therapy was then employed to address her meibomian gland obstruction, reduce eyelid inflammation and improve the tear film quality by enabling a more normal meibomian gland secretion.7 The use of ointment addressed the previously untreated nighttime lagophthalmos. Restasis became more comfortable to use and appears to now be more effective by synergistically improving tear film stability by reducing ocular surface inflammation. 8 This case illustrates that some patients may be labeled as a non-responder to pharmacologic treatments such as Restasis, while the inciting mechanism was an inadequate tear film from increased evaporation resulting from obstruction and hyposecretion of the meibomian glands.
In our practice, we have observed late intervention and inadequate treatment of associated eyelid conditions to be the most prevalent cause of pharmacologic failure in dry eye syndrome, even more so than medication noncompliance. We therefore make the case that a more proactive and comprehensive approach to evaluation and treatment of the dry eye patient is warranted to achieve the subjective and objective pharmacologic benefits of Restasis, especially in patients labeled as Restasis non-responders.
Our patient’s dry eye condition was initially managed inadequately with respect to her meibomian gland dysfunction and lagophthalmos. LipiFlow Thermal Pulsation Therapy and the application of ophthalmic lubricating ointment at night addressed these problems. Initially labeled as a Restasis non-responder after one year of treatment, our patient is now experiencing a very favorable subjective benefit from Restasis. Dry eye is a complex disease state with significant physical and psychological consequences, and patients should thus undergo a comprehensive evaluation and treatment strategy. Restasis non-responders have the potential to respond more successfully after concomitant ocular surface problems are appropriately addressed through synergistic modalities.
1. Vehof J, Kozareva D, Hysi PG, et al. Relationship between dry eye symptoms and pain sensitivity. JAMA ophthalmology 2013;131:1304-8.
2. Shimazaki-Den S, Dogru M, Higa K, Shimazaki J. Symptoms, visual function, and mucin expression of eyes with tear film instability. Cornea 2013;32:1211-8.
3. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface 2007;5:75-92.
4. Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction. Cornea 2012;31:1386-93.