Insights advance current diagnosis, treatment of dry eye

In 2007, the International Dry Eye WorkShop, sponsored by the Tear Film and Ocular Surface Society, provided the ophthalmic and scientific communities with a new definition of dry eye:

“Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”

The definition summarized the conclusions of a critical review of all current knowledge on dry eye disease by an international panel of experts that worked on the issue for more than 3 years.

Image: Gupta N

“We have now a clear classification of the different types of dry eye,” Noopur Gupta, MS, DNB, said. “We know it can be primary, commonly referred to as keratoconjunctivitis sicca. It might be secondary to systemic disorders, such as Sjögren’s syndrome and autoimmune diseases like rheumatoid arthritis or lupus, or secondary to local disorders such as blepharitis, conjunctivitis or meibomian gland dysfunction. It might be a secondary effect of specific drugs, such as antihistamines, antidepressants, beta-blockers or anti-hypertensive drugs. It might be hormone-related, and finally, it might be influenced by a variety of environmental factors, from computer use to dry, dusty climates.”

Prevalence

Literature-reported prevalence of dry eye varies greatly, from 0.46% to 34%, due to lack of standardization in the type of subjects enrolled and in the questionnaires and clinical tests employed, Gupta said. With her group at Lady Hardinge Medical College, New Delhi, she has performed studies on the epidemiology and environmental correlations of dry eye in the Indian population.

“We have found a positive correlation with high altitude in Himalayan groups of population, and we are currently investigating the prevalence of dry eye in rural India,” she said.

Preliminary results of a population-based study seem to indicate a prevalence of around 20% to 25% in the hot, dusty climate of rural regions, while in the sunny, windy, cold and dry environmental conditions prevailing at high altitudes, an incidence of 36% was previously found.

As a clinician, there are two well-defined groups of patients that Gupta encounters.

“One is about 50 to 60 years of age working in the outside environment, and the other is very young patients with allergic eye disease or using contact lenses or working on computers in an air-conditioned environment,” she explained.

Meibomian gland dysfunction (MGD) is involved in up to 50% to 60% of cases, especially in older people, she said.

On the whole, dry eye is a common condition that deserves more attention.

“It is a neglected disease with a high impact on patients’ quality of life,” Gupta said. “We need to increase awareness of dry eye and do more population-based studies to understand the epidemiology of this common ocular condition.”

Increase in disease

The Asia-Pacific region has the highest prevalence of dry eye worldwide, according to published data. However, dry eye is becoming more common in the Western world.

“The aging of the population, but also environmental and lifestyle-related factors like the prolonged exposure to light from computer monitors or TV, air conditioning, pollution and possibly a high-calorie diet, may all be correlated with increased risk of dry eye,” Pierre-Jean Pisella, MD, said.

In France, 25% of general practitioners’ consultations are for some form of ocular surface disease, he said.

The aggressive actions of contact lens wear, corneal refractive surgery and toxic eye drop components such as preservatives also play a role. So do intense sport activities, which are a less well-known but frequent cause of dry eye from contamination of the tear film by intense perspiration, according to Piergiorgio Neri, MD, PhD.

Other potential risk factors, such as cigarette smoke, alcohol, contraceptive pills and botulin toxin, have not been proven but are likely to have a contributing role, he said.

Women are reported to have a significantly higher prevalence of dry eye. This difference is thought to result from hormonal effects on the lacrimal functional unit and goblet cell density, Gupta explained.

Some patients may present with a combination of causative factors. One such case could be a patient with seborrheic dermatitis who lives in an unfavorable environment, Neri explained.

“Individual etiologies often cause dry eye by several interacting mechanisms, but whatever the cause, the process that is eventually triggered is always what we call the vicious circle of dry eye,” he said.

Self-perpetuating condition

The key point of the Dry Eye WorkShop definition was the recognition that ocular surface inflammation is always present in dry eye.

“It was a paradigm shift, as dry eye ceased to be just a lack of water and became a complex disease involving inflammation,” Pisella said.

Tear film hyperosmolarity, which may arise from either insufficient tear secretion or excessive evaporation, was also recognized as a core mechanism of dry eye, correlated to inflammation in a bidirectional vicious circle: A dysfunctional tear film triggers a cascade of inflammatory events, but on the other hand, a dysfunctional tear film can be the result of an acute or chronic state of inflammation.

Within this circle, inflammation tends to self-perpetuate and self-maintain, which explains why dry eye has an inherent tendency to become chronic.

High tear osmolarity and inflammation adversely affect the corneal epithelium, Stephen C. Pflugfelder, MD, said.

“High osmolarity stresses the epithelium and causes the epithelial cells to produce inflammatory mediators such as MMP-9, a proteolytic enzyme that degrades the tight junctions between cells,” he said.

“Increased MMP-9 activity accelerates detachment of apical corneal epithelium, exposing less mature subapical epithelial cells and nociceptors that signal discomfort from the ocular surface. It also allows inflammatory mediators and T-cells to percolate down through the epithelium,” he said.

T-cells that infiltrate the conjunctival and corneal stroma and epithelium produce two types of cytokines: interferon gamma and interleukin-17 (IL-17), Pflugfelder explained.

Interferon gamma promotes cell apoptosis of the epithelium and causes the cells to produce a cornified envelope, a component of the skin’s epidermis that is impervious to water.

“This cell envelope doesn’t belong to the natural structure of healthy corneal epithelial cells, but interferon gamma promotes the cells in the eye to start producing cornified envelope precursors,” Pflugfelder said. “That’s why in very severe dry eye conditions, like Stevens-Johnson syndrome, the surface of the eye might start showing a skin-like appearance.”

“IL-17 has been reported to upregulate the expression of MMP-9, which accelerates detachment of ocular surface epithelial cells, leading to barrier disruption and influx of inflammatory cells and mediators from the tears. We are well inside the vicious cycle,” Pflugfelder said.

Tear film instability profoundly affects visual quality.

“The air-tear interface is the principal refracting surface on the eye, accounting for approximately 65% of its optical power. A stable tear layer is essential to maintain a smooth surface and high-quality vision,” he explained. “When there is dry eye or an unstable tear film, or the corneal epithelium is irregular and doesn’t hold the overlying tears, then that optical surface becomes irregular and starts affecting quality of vision.”

Patients with dry eye typically have diminished visual acuity in low-contrast conditions.

“They also present severe symptoms of ocular irritation and discomfort that can significantly impact quality of life and productivity,” Pflugfelder said.

A study by Schiffman and colleagues, presented at the American Academy of Ophthalmology meeting in 2001 and published in Ophthalmology in 2003, showed by utility assessment questionnaires that the impact of the most severe forms of dry eye on quality of life is equivalent to unstable angina.

Diagnostic tools

Current means to diagnose dry eye include slit lamp examination, corneal staining with fluorescein, conjunctival staining with lissamine green, Schirmer’s test and evaluation of tear breakup time. New diagnostic methods involve digital imaging of the ocular surface, identification of inflammatory markers and measurement of tear osmolarity, a key marker of dry eye.

According to Pisella, Schirmer’s test, which has been largely abandoned since the introduction of vital dyes, remains a fundamental tool in diagnosing aqueous-deficient dry eye.

“It is the only test that gives true information about the production of water by the lacrimal glands,” he said.

In a clinical setting, tests should always progress from the least invasive method to the most invasive, according to Gupta.

“History, questionnaires, ocular surface examination, Schirmer’s and tear film breakup time are the most reliable and feasible means to diagnose dry eye,” she said.

For research purposes, impression cytology and confocal microscopy are additional useful tools. Community-based screenings should be based on questionnaires, Schirmer’s test and tear breakup time.

More advanced tools include the Keeler Tearscope, which evaluates the appearance, volume and stability of the tear film, and the TearLab Osmolarity System, which measures tear film osmolarity.

The latter, Neri said, is an important new frontier in dry eye disease management because osmolarity plays a crucial role in the pathogenesis of the condition.

“The TearLab analyzes the composition of a tear fluid sample and converts it into numeric data that help understanding disease level and monitoring the patient’s response to treatment,” he said.

However, cost issues limit the use of the technology for routine testing.

“I have it in my office, but only use it for clinical trials. The cost of the test is around 20, and there is no reimbursement for it,” Pisella said.

The RPS InflammaDry Detector is designed to test for matrix metalloproteinase-9 (MMP-9), the inflammatory marker that has been shown to be elevated in the tears of patients with dry eye disease.

Another effective way of evaluating the presence of inflammation is impression cytology, Neri said.

If a rheumatic disease is suspected, specific tests for anti-SSA and SSB antibodies, which are found in the circulation of patients with Sjögren’s syndrome, should be performed, he said.

“And never forget the eyelids, which are critical to detect dermatological comorbidities,” Neri said.

Dry eye treatment

Dry eye management hinges on patients’ understanding of the multifaceted and chronic nature of the disease and their compliance to a regimen of strict surveillance and long-term treatment.

Physicians, on the other hand, need to establish personalized strategies that account for individual etiologies and response to treatment.

“In our setup, poor compliance and a tendency toward do-it-yourself management of the symptoms strongly influence our therapeutic choices,” Gupta said.

Tear substitutes have been the mainstay in the treatment of dry eye symptoms for many years. Although no longer considered as a standalone therapy, they nevertheless remain an important component in a more complex treatment strategy.

Recent advances in the understanding of tear film physiology and pathology have allowed the formulation of a variety of tear substitutes capable of addressing specific deficiencies of tear components.

“In the old days, substitutes were only meant to mimic the volume of human tears. In the early ’80s, we used sodium chloride, and not much more was available,” Neri explained. “A few years later, and up to 2000, mucomimetic polymers were introduced, aiming at re-establishing not only the quantity but also the quality of tears. Substitutes containing hyaluronic acid, polyvinyl alcohol, carbomer-based lipids and [tamarind seed polysaccharide] were developed. But the true revolution was after 2000, when the outermost oil layer of the tears, which was thought to be irreplaceable, was recreated by novel tear substitutes.”

The choice of artificial tears is made according to the clinical signs and etiology of dry eye, Pisella said.

Tear film instability and hyper-evaporation associated with MGD require gel-form tear substitutes to replace the mucin layers, while aqueous-deficient dry eye needs to be treated by preservative-free, water-based tear substitutes.

“In patients with associated Sjögren’s syndrome and MGD, and therefore suffering from both lack of water production and hyper-evaporation, a combination of tear substitutes, as well as warm compresses, should be applied,” Pisella said.

Compounds containing transiently preserved cellulose ethers (hydroxypropyl methylcellulose and carboxymethylcellulose) and HP-Guar with glycols in its various formulations are mainstream therapy for primary dry eye conditions in Gupta’s eye department. For secondary cases, treating and controlling the underlying cause are important.

“This is as much as we can do in quite a few of our cases because steroids are often improperly used when we prescribe them and cyclosporine is too expensive for a large proportion of our patients,” she said.

For those who can afford it, cyclosporine is a good option to address the inflammatory component of the disease, she said. In India, it is available on the market as Restasis (cyclosporine ophthalmic emulsion, Allergan), but concentrations higher than 0.05% are often required in severe and chronic cases such as Stevens-Johnson syndrome and are prepared by the hospital pharmacy.

“Typically, the people who can afford cyclosporine are educated people who understand and comply well [with] the long-term requirements of the therapy and come back regularly to follow-up visits,” Gupta said.

In most cases, topical steroids are not prescribed and not discussed.

“The risk of side effects due to steroid overuse is too great here. If patients experience the efficacy of steroids, they keep using them, also because they can buy them off the counter. If prescribed, especially in those with severe inflammation or immune-mediated dry eye, it is only for a short duration, and a warning and counseling about the potential harmful effects like glaucoma, corneal thinning and infection are emphasized at the outset,” Gupta said. – by Michela Cimberle and Matt Hasson

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Brignole-Baudouin F, Baudouin C, Aragona P, et al. A multicentre, double-masked, randomized, controlled trial assessing the effect of oral supplementation of omega-3 and omega-6 fatty acids on a conjunctival inflammatory marker in dry eye patients. Acta Ophthalmol. 2011;89(7):591-597.

The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.

De Paiva CS, Schwartz CE, Gjörstrup P, Pflugfelder SC. Resolvin E1 (RX-10001) reduces corneal epithelial barrier disruption and protects against goblet cell loss in a murine model of dry eye [published online ahead of print Jan. 17, 2012]. Cornea. doi:10.1097/ICO.0b013e31823f789e.

De Paiva CS, Volpe EA, Gandhi NB, et al. Disruption of TGF- signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca. PLoS One. 2011;6(12):e29017.

Gupta N, Prasad I, Himashree G, D’Souza P. Prevalence of dry eye at high altitude: a case controlled comparative study. High Alt Med Biol. 2008;9(4):327-334.

Gupta N, Prasad I, Jain R, D’Souza P. Estimating the prevalence of dry eye among Indian patients attending a tertiary ophthalmology clinic. Ann Trop Med Parasitol. 2010;104(3):247-255.

Jacobi C, Jacobi A, Kruse FE, Cursiefen C. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea. 2011;30(12):1289-1292.

Kamao TK, Yamaguchi M, Kawasaki S, Mizoue S, Shiraishi A, Ohashi Y. Screening for dry eye with newly developed ocular surface thermographer. Am J Ophthalmol. 2011;151(5):782-791.

Khanal S, Tomlinson A, McFadyen A, Diaper C, Ramaesh K. Dry eye diagnosis. Invest Ophthalmol Vis Sci. 2008;49(4):1407-1414.

Lane SS, DuBiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. 2012;31(4):396-404.

Narayanan S, Corrales RM, Farley W, McDermott AM, Pflugfelder SC. Interleukin-1 receptor-1-deficient mice show attenuated production of ocular surface inflammatory cytokines in experimental dry eye. Cornea. 2008;27(7):811-817.

Pflugfelder SC. Tear dysfunction and the cornea: LXVIII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;152(6):900-909.

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Su MY, Perry HD, Barsam A, et al. The effect of decreasing the dosage of cyclosporine A 0.05% on dry eye disease after 1 year of twice-daily therapy. Cornea. 2011;30(10):1098-1104.

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For more information:

Noopur Gupta, MS, DNB, can be reached at Department of Community Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences (AIIMS), New Delhi 110 029, India; +91-9868449673; email: noopurgupta@hotmail.com.

Piergiorgio Neri, MD, PhD, can be reached at The Ocular Immunology Service, Clinica Oculistica, Università Politecnica delle Marche, Via conca 71, Ancona, Italy; +39-071-5965385; email: p.neri@univpm.it.

Stephen C. Pflugfelder, MD, can be reached at Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin St., NC 205, Houston, TX 77030, U.S.A.; +1-713-798-4944; email: stevenp@bcm.tmc.edu.

Pierre-Jean Pisella, MD, can be reached at Université François Rabelais, 10 Boulevard Tonnellé, 37032 Tours Cedex, France; email: pisella@med.univ-tours.fr.

Disclosures: Dr. Gupta has no relevant financial disclosures. Dr. Neri is a consultant for Bausch + Lomb. Dr. Pflugfelder is a consultant for Alcon, Allergan, Bausch + Lomb, GlaxoSmithKline and Mimetogen. He does research for Allergan and Mimetogen. Dr. Pisella has no relevant financial disclosures.

 

 

Do you perform corneal refractive surgery in patients with dry eye?

Dry eye not a contraindication for LASIK

I treat most patients with dry eye syndrome, and I treat them with LASIK. Of course, I exclude patients who present epithelial complications or chronic forms of keratitis due to incomplete lid closure after cosmetic surgery. However, when dry eye is controlled with a simple treatment or with a punctum plug, I never refuse to perform a corneal refractive procedure.

I have worked several years in Dubai, a region of the world where many patients have dry eyes, and I have operated on a great number of them.

I never perform PRK in dry eye cases. I do LASIK with thin flaps, adapting the diameter to the treatment and cutting the flaps with the femtosecond laser.

Patients in a series treated at the Magrabi eye center in Dubai were systematically implanted with an absorbable punctum plug at the end of the LASIK procedure. The postoperative course was significantly more comfortable in these patients.

As a postoperative treatment, I prescribe artificial tears and nutritional supplements containing choline, which seems to accelerate flap re-innervation. I have had good results with the same supplements in corneal grafting as well. Omega-3 and vitamin B6 are also beneficial. I prescribe cyclosporine only for complicated cases of keratitis.

I had corneal refractive surgery myself, and I had dry eyes. Eleven years after the procedure, I am still doing very well.

 

Alain Telandro, MD, is an OSN Europe Edition Board Member based in Cannes, France. Disclosure: Dr. Telandro has no relevant financial disclosures.

PRK an ideal option in mild to moderate dry eye

I perform corneal refractive surgery in patients with mild to moderate dry eye. I have a decade of experience with both LASIK and PRK, but I definitely prefer PRK in these cases. LASIK severs the corneal nerves, leading in some cases to untreatable dry eye symptoms. Surface ablation is less likely to cause dry eye, and haze is better dealt with.

I have recently adopted the TransPRK option of the Schwind Amaris laser. The laser applies energy to ablate the epithelium, and then the required correction is performed in a single step, without the need to use alcohol or touch the cornea with any instrument.

I put my dry eye patients on mild steroids, such as loteprednol etabonate, for 1 week just before the procedure, along with artificial tears.

After the treatment, I apply mitomycin, cooled balanced salt solution and a bandage contact lens.

All my PRK patients receive antibiotic-steroid combination eye drops to instill twice hourly on day 1 and four times a day for a week, as well as oral and topical painkillers. For long-term control of inflammation, I always prescribe artificial tears for 2 months and topical steroids, such as fluorometholone, three times daily for 15 days. In dry eye patients, I add cyclosporine twice a day for 2 months. I monitor dry eye patients closely after surgery to see how the cornea and tear film respond to surgery. I also advise them to take nutritional supplements containing omega-3 fatty acids.

 

Cyres K. Mehta, MS, FASCRS, is an OSN APAO Edition Board Member based in Mumbai, India. Disclosure: Dr. Mehta has no relevant financial disclosures.