The trifecta of contact lens comfort has always existed in the interaction among the lens, the care solutions, and the ocular surface. Over the last two decades, our knowledge of lens comfort has shifted as an industry. Led by incredible researchers and our industry partners, the two of us have personally observed this evolution. We have brought about new knowledge and insight into how we can improve our patients’ lens-wearing experience. Throughout our professional careers, we have observed a surge of new lenses become developed, including silicone hydrogels. Discussions concerning the amount of oxygen permeability and the way that we incorporate silicone into a lens revealed incredible insights that have enhanced the way that contact lenses are currently being produced.
We have seen the influence of contact lens care solution and appropriate wettability on our patients’ long-term comfort for those patients wearing frequent replacement lenses. During this period, we also realized the influence of compliance on the safety and comfort of our lens wearers’ experience. We saw the growth of daily disposable lenses during this period as well, as manufacturing processes became streamlined and lens material designs advanced.
Just as we have been practicing in an era of remarkable advances in contact lens technologies, our understanding of the ocular surface and how it functions has also advanced. We are still learning what makes a healthy individual’s tear film function appropriately, and ultimately what dysfunction causes an abnormal tear film. Additionally, the traditional symptoms that we associated with dry eye do not necessarily always hold true. More than a decade ago, we were taught that if the eye burns, then it is dry, and if it itches, then it is allergies. We’ve now come to terms with the fact that oftentimes, this over-simplification of symptoms is frequently incorrect. In fact, many individuals who have early signs of dry eye may not experience the classic “burning eye” symptoms; instead, they experience other symptoms such as fluctuating vision, uncomfortable eyes, and periodic discomfort, depending on their environment.
As our knowledge of dry eye and the ocular surface has advanced, so have the diagnostic tools and therapeutics that we have available to identify, monitor, and treat those individuals suffering from dry eye. At one time, we treated solely to reduce symptoms by placing artificial tears on the eye.
Our treatment paradigms have shifted significantly to start treating at the first signs of the disease. The goal is to not only to simply reduce symptoms, but also to promote the long-term health and wellness of the ocular surface. With newer diagnostics, we can now detect ocular surface changes sooner than we ever could before.
This is so fundamentally critical to comfortable contact lens wear, as it is a healthy ocular surface that helps support the contact lens technology that is on the eye. As such, it has become incumbent for eyecare practitioners to pay particularly close attention to the ocular surface and to appropriately treat the eye to optimize and promote its health.
But, with the advent of new diagnostics and therapeutics, we have been inundated with options that oftentimes makes it difficult to select the one that is appropriate for our patients. In this review, we will simplify the process of managing dry eye by appropriately diagnosing it along with selecting the best treatment options for your patients.
A number of diagnostic tools are available to help us understand how the ocular surface functions. But, just as with any condition, the information that we acquire about the ocular surface must be weighed with all of the other information we have about our patients to customize the appropriate treatment for them. Additionally, some of the information about the eye that we acquire from diagnostic testing will show us what the sequelae of dry eye is, while others will share information about the underlying cause. It is important to understand the information acquired, as this will help us to most appropriately treat these patients.
Slit Lamp Evaluation There are specific things to be cognizant of identifying during the slit lamp evaluation that will guide clinicians toward the appropriate treatment regimen. Misdirected lashes, including trichiasis and madarosis, indicate the sequelae of eyelid inflammation that is frequently seen in blepharitis1 (Figure 1). Additionally, assessing the lashes for signs of deposits and collarettes is critical, as the elimination of these are important for symptom control in those patients.
Assessing the lid margin is also critical. Specifically, look for visible inflammation. Additionally, all patients should be assessed for meibomian glands yielding liquid secretions (MGYLS). This can be done by placing pressure on the upper and lower lid margin while assessing the presence of visible meibum coming out of the glands. A decrease in MGYLS has been shown to be associated with symptoms of dry eye.2
Meibomian gland expressors allow you to perform this test in a controlled way by applying a given force to the anterior eyelid surface and creating consistency of the pressure applied, which is similar to the force on the glands during a blink. It is important to note that this is critical to perform on patients to identify those individuals who may have non-obvious meibomian gland dysfunction (NOMGD). By definition, NOMGD is non-obvious, thus a slit lamp evaluation would reveal a normal-appearing lid margin. Only upon attempted expression of the lid margin will abnormal secretions and reduced MGYLS be noted.3
Fluorescein Stain This one vital dye provides us with much information about the integrity of the ocular surface. It is a hydrophilic dye that diffuses into the tear film. Tear film breakup time (TBUT) is often an initial diagnostic marker. We expect a normal tear film to have a TBUT of greater than 10 seconds, and anything less likely indicates a compromise to how the tears cover the ocular surface.
Additionally, fluorescein can expose a number of other things. When viewed with a cobalt blue light and a Wratten filter (which optimizes its visualization), you can see the presence of corneal and conjunctival staining. Additionally, the line of Marx, which is the junction between the mucocutaneous tissue of the palpebral conjunctiva and the keratinized epithelium of the anterior lid margin, can also be visualized after instillation of fluorescein. In patients who have chronic dry eye, an anterior migration of the line of Marx can occur. This can also be observed with lissamine green stain as well.
In addition, there is a small area of tissue on the posterior margin of the upper eyelid referred to as the lid wiper area. Excessive friction between the upper lid and the ocular surface—or the contact lens in lens wearers—can cause staining to occur in this area, creating what is referred to as lid wiper epitheliopathy (LWE). LWE will absorb fluorescein and will be visible upon upper lid eversion.4
All of the findings that we see with fluorescein are considered sequelae of dry eye and are important to follow over time as treatment is initiated.
Lissamine Green Stain Lissamine green can also stain the conjunctiva and cornea in dry eye patients. Additionally, the line of Marx and LWE can be observed with this dye. Keep in mind that lissamine green should be viewed with a standard white light slit lamp evaluation. Using a diffuser or lowering the intensity of the slit lamp light will optimize the visualization of the dye on the ocular surface if staining is, in fact, present. Lissamine green staining is the sequelae of dry eye and needs to be monitored as treatment is undertaken.
Meibomian Gland Evaluation Appropriate meibomian gland structure is critical, and having glands that are either shortened or dropped out will ultimately affect the way that meibum is produced by the gland. There are a number of ways that meibomian gland structure can be assessed.
A gross view of the meibomian glands present on the lower lid can be observed by simply having the patient look up while the lower lids are pulled down. Under normal room illumination, you will be able to see the glands in most individuals. Depending on the pigmentation and the room lighting, it may be difficult to view the meibomian glands in some individuals.
Eyelid transillumination also allows the visualization of the meibomian glands at the slit lamp (Figure 2). To perform this, the lights at the slit lamp are turned off, with the only light source being that from the transilluminator. The transilluminator is used to evert the lower lid, and the light that is shone through the lid will cause the meibomian glands to appear darker compared to the surrounding tissue; the meibum and the glands are more difficult for the light to shine through. This is an easily performed examination technique at the slit lamp. However, the test is limited because it is difficult to perform on the upper eyelid.
Advanced meibomian gland imaging has been developed that allows visualization of the meibomian glands in the upper and lower eyelid. The technology utilizes infrared imaging to allow visualization and photodocumentation of the meibomian glands.
Blink Pattern Assessment The blink pattern is critical. Blinks are important because they are the impetus for the riolan muscle to contract and ultimately squeeze meibum onto the ocular surface from the meibomian gland orifice. But, only under a complete blink does this occur.
With the increasing utilization of digital devices and computer screens, our eyes tend to undergo less frequent blinks and are more likely to undergo incomplete blinks as well.5 Not only does this expose the ocular surface to the environment, but the riolan muscle has less opportunity to activate with less blinking. This is believed to fundamentally change the effectiveness of the riolan muscle over time. New technologies allow a thorough analysis of a patient’s blink.
Tear Film Technologies We have discussed the use of fluorescein to assess TBUT. There are also advanced technologies that allow a potentially more reliable way to perform this test. At least one corneal topographer has functionality that allows a truly objective way to metricize TBUT. Additionally, another instrument takes this one step further by allowing the visualization of the lipid layer. Using these images, it can measure absolute tear thickness of the tear film lipid layer. Meibomian gland dysfunction (MGD) increases the risk of a reduction in the lipid layer thickness, the outer-most layer of the tear film.
Point-of-Care Testing Point-of-care testing has changed the way we monitor the ocular surface in dry eye. Tear osmolarity testing can now be performed in-office by acquiring a small microliter sample of the tears at the tear meniscus and allowing the sample to be measured for osmolarity. Tear film osmolarity tends to be higher in dry eye patients than in normals. Osmolarity values provide clinicians a metric for monitoring patients over time as treatment is initiated.
Additionally, there is a point-of-care test that measures whether matrix metalloproteinase-9 (MMP-9) levels are above 40ng/mL on the ocular surface by taking a sample of the tears from the lower palpebral conjunctiva.6 Interestingly, if the test is positive, the signal strength of the line is proportional to the concentration of MMP-9 on the ocular surface.
We have proposed a grading scale on signal strength that we presented at the 2016 Global Specialty Lens Symposium.7 Grading the signal strength helps to determine the influence that treatment has had on the level of inflammation present on the ocular surface. Interestingly, inflammation may be the sequelae and also the underlying cause of dry eye. Special care should be used to manage inflammation on the ocular surface in a dry eye patient.
With our ever-advancing knowledge of the ocular surface, we have reviewed a relatively quick evolution of the way we view and treat dry eye. But, this has made the decision process somewhat more difficult regarding how to treat patients and what recommendations to make because of the number of options available. We are proposing a new paradigm that simplifies the process through appropriately utilizing the technologies available. The paradigm will also help explain the condition to patients along with the goals of treatment.
There are a number of options for treatment. So how do we simplify the process and formulate a logical path toward improving the function of the ocular surface? We feel that it is a combination of two things that are performed simultaneously—improving function through both physical and chemical means. We will first discuss improving function through physical means.
1. Physical Several procedures can be performed in the office, and in a number of practices, these are performed on a daily basis. However, it requires a much more active examination process to deduce the underlying cause of the ocular surface disease and most appropriate treatment course.
For example, consider a patient actively complaining about ocular comfort issues who has significant deposits at the base of the lashes, with or without the presence of other findings. You might conclude that his blepharitis needs to be managed, as this condition left untreated could ultimately lead to more chronic dry eye.8 Although we traditionally relied heavily on topical antibiotics or combination agents containing antibiotics and steroids, or on patients performing lid hygiene on a daily basis, we now have technologies that allow us to manage this more actively in the practice.
Eyelid cleaning devices are now commercially available that help us actively manage these patients. Just a few years ago, the only option that we had available was a cotton tip applicator to mechanically rid the eye of the deposits at the lid margin. This often allowed only partial removal of the debris at the base of the lashes.
Today, one product has a sponge end oscillating at high speeds that allows in-office removal of much of the scurf and collarettes that occur at the base of the lashes. Newer technologies have allowed more active management of this commonly seen condition. Other products are also available that assist clinicians with keeping the eyelid margins clean.
Lid debridement is another procedure that has been embraced by a number of practitioners. Research has shown that individuals who have MGD often have obstructed glands due to keratinized tissue that lines the eyelid margin. Debriding the lid margin along the line of Marx helps the flow of meibum from the glands by actively removing the tissue that is believed to obstruct the gland orifice9 (Figure 3). Additionally, visibly capped glands can also be debrided relatively easily.
Golf spud debriders have been available for years, which has given us the ability to perform this procedure in the office. The challenge with the golf spuds is the small contact between the lid margin and the golf spud. Recently, one debrider was introduced that provides a long curved surface that is easily moved along the lid margin. The larger surface of the debrider can make it easier to perform the procedure.
For patients who have demonstrated incomplete blinking patterns, optimizing the blink is critical. Improving a patient’s blink will more actively spread the tear film over the ocular surface. Simple blink exercises can be performed to optimize this response. This can be accomplished by educating individuals to consciously blink for 10 seconds 10 times per day.
Punctal occlusion is also a treatment strategy that should be considered in the dry eye regimen. Traditional thoughts were to reduce inflammation and then retain the tears that the eye is producing through occlusion of the puncta. Interestingly, this philosophy was embraced prior to the advent of point-of-care tests available to measure inflammation on the ocular surface. So clinically, we were making judgements on inflammation reduction based on the appearance of the eye.
But clinicians can now measure for the presence of inflammation. We can measure MMP-9 levels in the tear film and more strategically position punctal occlusion for our patients. Once the inflammation has decreased to negligible levels, it is an opportune time to consider punctal occlusion.
Fortunately, we have several options for punctal occlusion. For initial testing to determine whether someone would benefit from the treatment, collagen plugs work remarkably well. They last about 10 to 14 days before they dissolve. If they improve symptoms, a silicone plug, which is more permanent, can be used. For patients who may be aware of the top of the plug from contact with the bulbar conjunctiva, intracanalicular plugs that last for approximately six months work very well. With these plugs, it is important to follow up with patients in approximately six months, as they will likely need to have new plugs inserted at that time.
Our knowledge of MGD has advanced tremendously over the past decade. It is estimated that MGD contributes to dry eye approximately 86% of the time.10 It is important to understand that MGD is subdivided into two main subtypes: 1) obvious and 2) nonobvious.
Obvious MGD, as its name implies, is obvious. During the slit lamp evaluation, visible inflammation is present at the lid margin and around the orifices of the meibomian glands. Additionally, tylotic lid margins and visible capping are common signs that accompany obvious MGD. NOMGD, as discussed earlier, is a form of MGD that is not obvious. The lid margins appear normal, but upon attempted expression, the glands express either no meibum or thickened secretions.3
Applying moist heat against the eyelids is a mainstay of treatment for MGD. Homeopathic means, such as a warm washcloth applied to the eye, often fall short of their intended goal because of their inability to retain, and ultimately transfer, heat sufficiently for the necessary time required to provide therapeutic effects.
A number of commercially available warm compresses are designed to provide sustained heat to the eyelids. These treatments have been shown to increase non-invasive TBUT and lipid layer thickness.11 They are required to be used on a regular basis for patients to both decrease the viscosity and maintain the fluidity of the meibum.
Recent advancements with in-office therapeutics for dry eye have truly changed the paradigm in treating the underlying cause of dry eye. One product delivers thermal pulsation to the palpebral surface of the eyelid. As the heat is applied, a pulsating pressure is simultaneously applied to the front of the eyelid, which actively evacuates the meibomian glands.12 When that treatment was compared to warm compresses, improvements in symptoms, meibomian gland secretion, and TBUT were observed.13
With another in-office treatment, heat is delivered to the eyelid through the front of the eye and has to be actively applied by the practitioner or a trained assistant. This is different from the other product mentioned above in which, after the device has been set on the eye, the instrument performs the treatment on its own while being only monitored by the eyecare practitioner or an assistant.
New to the arena of physical optimization of the ocular surface is TrueTear (Allergan), an intranasal tear neurostimulator that has been shown to improve a number of signs associated with dry eye.14 It is a medical device that is placed within the nostrils and delivers a small electric current. Clinical experience with this technology will help us better position it for the most appropriate patients.
Physically optimizing the ocular surface through the strategies discussed is really 50% of the battle in managing dry eye patients. As can be seen with all of the examples discussed, the physical treatment depends on the underlying cause of the dry eye and the technology that you have available in your practice. Optimizing the function of the ocular surface through appropriate chemical modification is the other half of the battle.
2. Chemical Optimization Optimization of the tear film and ocular surface health through chemical modification is just as critical as physically optimizing it. There are a number of ways that we can do this.
We discussed blepharitis management through physically removing scurf and collarettes from the base of the lashes, but helping maintain appropriate lid margin health in these individuals is critical. This is usually accomplished with temporary use of either a topical antibiotic or an antibiotic/steroid combination before or after the previously discussed in-office cleaning regimen is performed. Additionally, some type of lid hygiene maintenance over time is critical for these individuals.
A number of over-the-counter foams and lid wipes are available for patients to utilize. A purified form of hypochlorous acid is also available as a prescription product.15 It is important to note that if Demodex overpopulation is suspected to be the cause of the blepharitis, tea tree oil has been well established as the standard to eradicate the Demodex overpopulation.16
Another way to chemically alter the ocular surface is through appropriate nutrition. High levels of omega-3 essential fatty acids have been shown to improve dry eye symptoms, promote neuroprotection, and improve signs of dry eye including decreasing inflammation on the surface of the eyes.16,17 Omega-6 essential fatty acids have also been shown to improve both signs and symptoms of dry eye patients.16,18 Additionally a number of other compounds including vitamin A (retinyl palmitate),19 vitamin D,20,21 tumeric extract,22,23 green tea extract,24,25 and mixed tocotrienols/tocopherols have been known to decrease inflammation related to ocular surface inflammation.26
As the evidence grows regarding the importance of nutrition on the health of the ocular surface, it will become increasingly important to recommend appropriate oral nutrition to support the health of the eye. Keep this in mind and recommend appropriate nutrition and supplements when appropriate.
Controlling inflammation topically has become a mainstay in managing dry eye patients. Topical corticosteroids are known to decrease inflammatory markers quickly on the ocular surface along with improving patient symptoms.27,28 But, topical corticosteroids are most frequently utilized on a short-term basis because of the side effect profile, which includes a risk for increased intraocular pressure and cataract development; it also decreases the immune response, which theoretically makes the eye less resilient to defend against pathogens.
In 2003, cyclosporine 0.005% was approved to use 1gt b.i.d. OD and OS. Available commercially, many clinicians who were most successful with this treatment realized that patient education about the chronicity of dry eye and the effects of the medication was needed to optimize treatment efficacy. The key to success was having patients continue therapy. Depending on several factors—including age, severity of signs and symptoms, and environmental factors—we’ve seen individuals respond successfully to therapy by demonstrating benefits anywhere from one to six months after beginning therapy.
Some practitioners may start patients concurrently on topical corticosteroids and cyclosporine to help alleviate inflammation more quickly initially, then discontinue steroids while continuing with the cyclosporine b.i.d. OD and OS.29 Recently, cyclosporine has been packaged in a multi-dose bottle that is preservative-free and provides patients with a more convenient option compared to unit-dose vials.
Lifitegrast 5%, introduced last year and commercially available, is a lymphocyte function-associated antigen antagonist (LFA).30 This is the novel mechanism of action believed to help control inflammation31 and to translate into both its clinical efficacy and its U.S. Food and Drug Administration (FDA) approval for both the signs and symptoms of dry eye. In pivotal clinical trials, patients randomized to lifitegrast showed improvements in symptoms compared to patients taking placebo in as little as two weeks after treatment was started.32
Oral antibiotics have also been shown to improve ocular surface health by decreasing the presence of inflammatory markers including MMP-9 on the surface of the eye.33 Doxycycline provides therapy through a non-specific anti-inflammatory mechanism. We have found that the people who would benefit most from this therapy are those individuals who are suspected to have ocular rosacea.34
It is important to keep in mind that these chemical optimization strategies for the ocular surface are not necessarily mutually exclusive. Because many of these therapies have unique mechanisms of action, we have often found that patients utilizing one of these treatments will have additive benefits when a second therapy is added, assuming their mechanisms of action are different.
WHAT ABOUT ARTIFICIAL TEARS?
The goal with our dry eye patients is to improve the way that the ocular surface functions to adequately produce tears that provide appropriate function and comfort. We have outlined a new strategic approach that many have likely already incorporated into how they are managing dry eye patients. We feel that a thorough analysis of the ocular surface and how it functions is critical to appropriately understand its current status and also to monitor treatment. Additionally, when treatment is started, we think that the most appropriate strategy includes both physical and chemical optimization of the ocular surface. So where do artificial tears enter into the treatment paradigm?
Artificial tears used to be the mainstay treatment for dry eye patients. As our understanding of dry eye has evolved, we realize that artificial tears do several things for the ocular surface including improving symptoms temporarily and improving some of the signs that we see with dry eye. But, they do not improve the way that the ocular surface functions and produces tears. As such, artificial tears can provide temporary relief as the function of the ocular surface is being rehabilitated to better produce its own tears.
We will often compare artificial tears for dry eye as having a similar role that acetaminophen has for someone who has minor back pain. Just as the acetaminophen will not necessarily improve the way the back functions, it will temporarily relieve pain and improve comfort. Artificial tears function in a similar manner for dry eye patients. Artificial tears can provide temporary relief, but the long-term goal should be to improve the eyes’ ability to produce more healthy tears.
If your patients need more than four to six drops of artificial tears per day to stay comfortable, one consideration may be hydroxypropyl cellulose inserts that can be placed in the lower fornix. These are available by prescription. Patients place one in the lower fornix using an applicator once a day, and the insert slowly dissolves over a 24-hour time period.
As our knowledge of dry eye has increased over the last decade, so have our options for diagnostics and treatments. Consider the approach that we have described by optimizing the way that the ocular surface functions both through physical and chemical optimization of the ocular surface. CLS
- Bernardes TF, Bonfioli AA. Blepharitis. Semin Ophthalmol. 2010 May;25:79-83.
- Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye symptoms and gland location. Cornea. 2008 Dec;27:1142-1147.
- Blackie CA, Korb DR, Knop E, Bedi R, Knop N, Holland EJ. Nonobvious obstructive meibomian gland dysfunction. Cornea. 2010 Dec;29:1333-1345.
- Efron N, Brennan NA, Morgan PB, Wilson T. Lid wiper epitheliopathy. Prog Retin Eye Res. 2016 Jul;53:140-174.
- Argilés M, Cardona G, Pérez-Cabré E, Rodríguez M. Blink Rate and Incomplete Blinks in Six Different Controlled Hard-Copy and Electronic Reading Conditions. Invest Ophthalmol Vis Sci. 2015 Oct;56:6679-6685.
- Messmer EM, von Lindenfels V, Garbe A, Kampik A. Matrix Metalloproteinase 9 Testing in Dry Eye Disease Using a Commercially Available Point-of-Care Immunoassay. Ophthalmology. 2016 Nov;123:2300-2308.
- Brujic M, Kading D. Making Matrix Metalloproteinase-9 Levels Meanigful. Poster presented at the 2016 Global Specialty Lens Symposium, Las Vegas.
- Rynerson JM, Perry HD. DEBS - a unification theory for dry eye and blepharitis. Clin Ophthalmol. 2016 Dec 9;10:2455-2467.
- Korb DR, Blackie CA. Debridement-scaling: a new procedure that increases Meibomian gland function and reduces dry eye symptoms. Cornea. 2013 Dec;32:1554-1557.
- Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of Aqueous-Deficient and Evaporative Dry Eye in a Clinic-Based Patient Cohort: A Retrospective Study. Cornea. 2012 May;31:472-478.
- Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of Self-applied Heat Therapy for Meibomian Gland Dysfunction. Optom Vis Sci. 2015 Sep;92:e321-e326.
- Friedland BR, Fleming CP, Blackie CA, Korb DR. A novel thermodynamic treatment for meibomian gland dysfunction. Curr Eye Res. 2011 Feb;36:79-87.
- Lane SS, DuBiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. 2012 Apr;31:396-404.
- Friedman NJ, Butron K, Robledo N, et al. A nonrandomized, open-label study to evaluate the effect of nasal stimulation on tear production in subjects with dry eye disease. Clin Ophthalmol. 2016 May 4;10:795-804.
- Stroman DW, Mintun K, Epstein AB, et al. Reduction in bacterial load using hypochlorous acid hygiene solution on ocular skin. Clin Ophthalmol. 2017 Apr 13;11:707-714.
- Koo H, Kim TH, Kim KW, et al. Ocular surface discomfort and Demodex: effect of tea tree oil eyelid scrub in Demodex blepharitis. J Korean Med Sci. 2012 Dec;27:1574-1579.
- Molina-Leyva I, Molina-Leyva A, Bueno-Cavanillas A. Efficacy of nutritional supplementation with omega-3 and omega-6 fatty acids in dry eye syndrome: a systematic review of randomized clinical trials. Acta Ophthalmol. 2017 Mar 30. [Epub ahead of print]
- Aragona P, Bucolo C, Spinella R, et al. Systemic omega-6 essential fatty acid treatment and pge1 tear content in Sjögren’s syndrome patients. Invest Ophthalmol Vis Sci. 2005 Dec;46:4474-4479.
- Sherwin JC, Reacher MH, Dean WH, Ngondi J. Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations. Trans R Soc Trop Med Hyg. 2012 Apr;106:205-214.
- Jin KW, Ro JW, Shin YJ, et al. Correlation of vitamin D levels with tear film stability and secretion in patients with dry eye syndrome. Acta Ophthalmol. 2017 May;95:e230-e235.
- Bae SH, Shin YJ, Kim HK, et al. Vitamin D Supplementation for Patients with Dry Eye Syndrome Refractory to Conventional Treatment. Sci Rep. 2016 Oct 4;6:33083.
- Pescosolido N, Giannotti R, Plateroti AM, et al. Curcumin: therapeutical potential in ophthalmology. Planta Med. 2014 Mar;80:249-254.
- Liu XF, Hao JL, Xie T, et al. Curcumin, A Potential Therapeutic Candidate for Anterior Segment Eye Diseases: A Review. Front Pharmacol. 2017 Feb 14;8:66.
- Nejabat M, Reza SA, Zadmehr M, et al. Efficacy of Green Tea Extract for Treatment of Dry Eye and Meibomian Gland Dysfunction; A Double-blind Randomized Controlled Clinical Trial Study. J Clin Diagn Res. 2017 Feb;11:NC05-NC08.
- Hsu SD, Dickinson DP, Qin H, et al. Green tea polyphenols reduce autoimmune symptoms in a murine model for human Sjögren’s syndrome and protect human salivary acinar cells from TNF-alpha-induced cytotoxicity. Autoimmunity. 2007 Mar;40:138-147.
- Ribeiro A, Sandez-Macho I, Casas M, et al. Poloxamine micellar solubilization of α-tocopherol for topical ocular treatment. Colloids Surf B Biointerfaces. 2013 Mar 1;103:550-557.
- Pinto-Fraga J, López-Miguel A, González-García MJ, et al. Topical Fluorometholone Protects the Ocular Surface of Dry Eye Patients from Desiccating Stress: A Randomized Controlled Clinical Trial. Ophthalmology. 2016 Jan;123:141-153.
- Lee JH, Min K, Kim SK, et al. Inflammatory cytokine and osmolarity changes in the tears of dry eye patients treated with topical 1% methylprednisolone. Yonsei Med J. 2014 Jan;55:203-208.
- Sheppard JD, Scoper SV, Samudre S. Topical loteprednol pretreatment reduces cyclosporine stinging in chronic dry eye disease. J Ocul Pharmacol Ther. 2011 Feb;27:23-27.
- Perez VL, Pflugfelder SC, Zhang S, et al. Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease. Ocul Surf. 2016 Apr;14:207-215.
- Paton DM. Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease. Drugs Today. 2016 Sep;52:485-493.
- Holland EJ, Whitley WO, Sall K, et al. Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. Curr Med Res Opin. 2016 Jul 22:1-7. [Epub ahead of print]
- Beardsley RM, De Paiva CS, Power DF, Pflugfelder SC. Desiccating stress decreases apical corneal epithelial cell size--modulation by the metalloproteinase inhibitor doxycycline. Cornea. 2008 Sep;27:935-940.
- López-Valverde G, Garcia-Martin E, Larrosa-Povés JM, et al. Therapeutical Management for Ocular Rosacea. Case Rep Ophthalmol. 2016 May 2;7:237-242.