Eyeworld

MAR 2012

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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70 EW CORNEA March 2012 Expanding "dry eye" definitions Pharmaceutical focus by Michelle Dalton EyeWorld Contributing Editor Recognizing that ocular surface diseases encompass more than just dry eye may help tailor treatments accordingly W hat used to be thought of as simply "dry eye" is now rec- ognized to be several different diseases that all negatively affect the ocular sur- face in some way, and it's becoming a big(ger) part of ophthalmic diag- noses. "Dysfunction in the ocular sur- face unit can lead to ocular surface disease; one of those symptoms and signs is the disease 'dry eye.' But it is important to remember that dry eye is much more complex than just aqueous phase deficiency of tears," said Vincent P. de Luise, M.D., as- sistant clinical professor of ophthal- mology, Yale University School of Medicine, New Haven, Conn. Dr. de Luise said the ocular sur- face is "a complex biological and physiological unit of tissues com- prising the corneal epithelium, lim- bal stem cells, bulbar and tarsal conjunctiva, the main lacrimal gland, and several crucial structures within the lid margin, specifically the meibomian glands, the accessory lacrimal glands of Krause and Wolfring, and the glands of Zeiss and Moll." Ocular surface disease is a dys- function of the ocular surface unit— usually the various lacrimal glands, conjunctival surface, and lid margin, he said. Damage can occur to the Distinguishing continued from page 68 In neurotrophic epitheliopathy, the pseudodendrite is often in the interpalpebral region of the cornea. "The patient has already undergone treatment with either oral or topical antivirals," Dr. Chan explained. "Suspect if the infectious keratitis lasts more than 2 weeks." Acanthamoeba may be to blame if a patient has a history of im- proper contact lens wear and hy- giene, and uses contacts while swimming or in hot tubs. "Symptoms can range from for- eign body sensation to pain out of corneal and conjunctival surface as a result of genetics or inflammation, and "these increase tear osmolarity and exacerbate inflammation, caus- ing irritation in the process and structural damage at the end stages," he said. The role of inflammation in oc- ular surface diseases "is not clearly understood," said Michael A. Lemp, M.D., clinical professor of ophthal- mology, Georgetown University and George Washington University, Washington, D.C., and chief medical officer, TearLab Corp., San Diego. With the increased emphasis on dry eye and the meibomian gland (after reports on both topics were published), "we now have the capac- ity to tailor or target our therapy based on the actual problem," Dr. de Luise said. For instance, if the issue is aqueous-based, physicians should consider non-preserved artifi- cial tears, he said. The role of preservatives in topi- cal treatments is being strongly eval- uated now in glaucoma medications, Dr. Lemp said. "We're at a point now where a lot of ophthalmologists recognize that ocular surface diseases impact a patient's quality of life, including, most importantly, the quality of vi- sion," he said. Physicians may sometimes opt for a short course of topical steroids (such as loteprednol) to quickly im- prove the surface if the patient is ex- pected to undergo surgery, Dr. de Luise said. Similarly, the patient may benefit from oral tetracycline deriva- tives (doxycycline, minocycline) or topical azithromycin for the treat- ment of meibomian gland dysfunc- tion. He recommended considering topical cyclosporine 0.05% suspen- sion, but holding off on placing punctal plugs until the inflamma- tory aspects of the surface have been addressed. Placing the plugs while the inflammatory aspects of ocular surface disease are active can para- doxically worsen a patient's symp- toms as the "inflamed tears" are still in the tear film. "However, topical cyclosporine 0.05% can take months to really be effective," he said. "T-cells have a half life of 110 days, and topical cyclosporine only works on newly born T-cells." Coming down the pike Several companies are developing pharmaceutical candidates that will address one or more ocular surface diseases. Some target a specific path- way; others are being revamped to eliminate preservatives; still others are being developed to work with or against a particular gene. For in- stance, Dr. Lemp said several compa- nies are developing compounds that "look at better biomarkers for the study end points." Additionally, he likes matrix metalloproteinase (MMP-9) as a potential biomarker, even though it's not specific for dry eye. "Measuring MMP-9 is an inter- esting test because it will probably give the physician useful informa- tion about the amount of inflamma- tion in the eye," Dr. Lemp said. While MMP-9 may not be the best marker in a clinical trial, it may lead researchers to discover the role of in- flammation in surface diseases, he said. Biomolecules based on blocking interleukin (namely, IL-1) are also showing potential. "Schepens Eye Research Insti- tute (Boston) researchers are evaluat- ing mucin levels and finding when we think we're getting staining, it's really a breakdown in the mucin coating of the cells," Dr. Lemp said. "Changes in the MUC-16 profile associated with dry eye in general may lead us to a better understand- ing of the disease overall." Dr. de Luise explained: "The conjunctival goblet cells elaborate the various mucins, some of which are soluble mucins and others of which are membrane-bound mucins. These latter membrane- bound mucins bind to the glycoca- lyx on the surface of the cornea, which adsorb the hydrophilic aque- ous phase of tears to the hydropho- bic cornea, and also serve to lower surface tension and help to spread the tear film." Among the more promising pharmaceutical candidates for ocular surface disease are below. Anti-inflammatory drugs CF-101, in 0.1 and 1.0 mg doses (Can-Fite BioPharma, Petah-Tikva, Israel): An adenosine receptor ago- nist in Phase III studies for the treat- ment of aqueous-deficient dry eye (including Sjogren's syndrome). The company estimated enrollment of 240 patients, randomized to one of three interventions (CF101 0.1 mg, CF101 1.0 mg, or placebo). Outcome measures include complete clearing of corneal staining by fluorescein staining. The study is expected to close in August. proportion to the clinical appear- ance," Dr. Chan said. "Isolated ep- ithelial pseudodendrites can appear as granular, cystic-appearing epithe- lium with little or no stromal in- flammation." If a patient has a history of corneal abrasion, no prior history of herpes simplex, and no ulceration upon exam, the pseudodendrite is likely due to a healing epithelial de- fect. However, if the patient's af- fected eye was recently cut or injured, consider recurrent erosion syndrome. "[Patients have] classic clinical history of awaking at night or upon first awakening sudden pain, 'like my eye lid is ripping the skin off my eye,'" Dr. Chan explained. "Always check the fellow eye to determine if there are any signs of epithelial basement membrane degeneration." In rare cases, pseudodendrites can be caused by tyrosinemia type 2. Those patients will have associ- ated findings of mental retardation and hyperkeratosis of the hands and feet. EW Reference Holland EJ and Schwartz GS. Classification of herpes simplex virus keratitis. Cornea 1999; 18:144-154. Editors' note: The doctors mentioned have no financial interests related to this article. Contact information Chan: clara.chan@gmail.com Mannis: mjmannis@ucdavis.edu

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