Dry Eye for the busy practitioner

This case study is provided by our SCC Online Series partner Good Optical.

Dry Eye, do I have time to investigate, discuss management, and then review? Is my hard work going to make any difference for the patient? Is it financially viable?

The above are questions I commonly get asked when meeting with colleagues around Australia and in some cases, the answer can be no! However, the aim of this article is to engage you to help your Dry Eye patients with minimal chair time and to also learn when to put up the white flag and refer the patient to crazy people like myself who spend hours trying to improve the quality of life for the more severe dry eye patients.

DEWS 2 has reminded us just how complex and multifactorial Dry Eye is. I have seen the interest in Dry Eye explode in recent years and I have heard a lot of opinions on how to best diagnose and manage the condition. While I am excited about the enthusiasm of Optometrists to tackle the condition, I think it is important that we constantly review the literature to ensure our advice and methods remain current. This is where the DEWS 2 report is so important for any practitioner serious about making a difference for Dry Eye patients. The report allows us to look at our opinions and our current practice protocols to see if they correlate with what the evidence suggests is best practice.

Treatment timeline

It is important to remember that Dry Eye is a chronic condition and that treatments generally take a long time for maximum effect. Because of this, we as practitioners need to be confident in our advice and methods knowing that at first, the patient may see little improvement. If we don’t stay strong and stand behind our advice, compliance will waiver or treatments will be changed unnecessarily, and ultimately, we will mismanage the patient’s condition. Donald Korb suggested that a review at three months will ensure you assess treatments at their maximum effect. [5]

Diagnosis

An accurate diagnosis of the type and severity of Dry Eye Disease affecting your patient is critical to successful management and does not need to be an expensive process or consume considerable chair time. To aid us, DEWS 2 has done all of the hard work. [Fig 5]

 

From the above diagram, the critical tests are an accurate symptom assessment and vital stains. I recommend using NaFl stain and Lissamine Green stain to assess tear stability, quantity, and surface staining. If time permits, expression of the Meibomian glands with gentle pressure is also a valuable test. The above should take less than five minutes and is inexpensive. Key points:

·        NaFl good to assess Tear Meniscus height and FBUT (<6.5 sec abnormal) [380]

·        Lissamine Green best to assess cell health, conjunctival stain often precedes corneal

·        Number of glands expressing, and the quality of the expression can help tailor treatment

Treatment

For every Dry Eye patient attending my clinic, they all leave with similar basic advice prior to returning for more advanced treatments. Part of the initial consultation is to educate the patient about their Dry Eye disease, set expectations and discuss all management options. For many, the cheaper more labour intensive is their first preference, and this is what I will discuss next.

I discuss four key elements with every Dry Eye patient. Drops, Lid Hygiene, Hot Compresses and Omega-3 intake.

These four elements appear in Steps 1 and 2 of the DEWS II recommendations.

 

 

Now I will admit here that Dry Eye consultations are never easy, the long case history can mean your coffee break evaporates and by the end of the consultation you are tempted to have a quick nip of the Christmas Scotch hiding in your top draw! Before getting to the main elements of Step 1 treatments I will spend a moment on one aspect of environmental modification which I do spend time discussing with every Dry Eye patient.

Blink rate. This is an environmental aspect which can be easily overlooked, yet can cause a patient dry eye symptoms even when their tear film is perfect. Our world has changed since the launch of the iPhone and the way we embrace screen-based technology has meant that the blink rate of our patients is now significantly less. Simply discussing with patients, the need to take conscious blinks and/or follow blink exercises can go a long way to promoting a healthier tear film. [483]

Lid Hygiene

Apart from treating Anterior Blepharitis, Lid Hygiene is an important element of managing Dry Eye disease as obstruction of the Meibomian Glands can be due to hyperkeratinisation of the eyelid margin. [477] Accumulated debris and keratinised cells on the lid margin need to be removed to promote better Meibomian Gland function. This can be done initially with a stainless-steel golf spud which has been shown in one study to improve patient symptoms in 22% and MG function in 46% of subjects. [478] In addition to this, dedicated eye lid cleansers should be utilised. DEWS 2 quotes a recent study where the efficacy of diluted baby shampoo was compared to a lid cleanser. The commercial lid cleanser was better tolerated, improved lipid layer quality and reduced inflammatory markers while the baby shampoo was also found to have a negative effect on goblet cell function. [388]

In discussing lid hygiene, I must also mention the need to be mindful of Demodex. While it has not been shown to directly cause MGD, its role in Anterior Blepharitis and symptomatic dry eye patients has been documented. [389] Tea Tree Oil is toxic to Demodex. [417] Pure Tea Tree Oil can be toxic to the eye so diluted commercial preparations are advised. [418,419] The key to success is treatment duration. The papers assessed in DEWS 2 suggest 4-8 weeks of twice daily treatment. [Table 6] What was also mentioned is that compliance is often poor with a suggestion that only 55% of patients were compliant after six weeks, hence  periodical review is important with these patients. [390]

My go-to products are Oust Demodex or Occusoft Plus Platinum. The addition of Hypochloric Acid in Platinum plus ensures excellent results in even advanced cases of Anterior Blepharitis.

Warm Compresses

This is an area where I see a lot of sub-therapeutic techniques and a lot of non-compliance due to a lack of education. There is strong evidence on the efficacy of warm compresses, but, in reality a lack of sufficient heat, sufficient time or sufficient longevity of treatment hinders results. [389,390,429-432] So, let’s move forward and upgrade to a newer better version of hot compresses! DEWS 2 evidence shows that a warm compress can soften and liquify Meibum but what is not definitive is the temperature and time required to be successful. [434,435,437-439] The more obstructed the glands, the higher the melting point of the Meibum. [434,437,440] Evidence suggests that heating the Meibomian glands to at least 40oC is required for optimal results. [433,437,441] Further to this, application of the device for at least 5 minutes twice a day is required for a treatment period of between 2-4 weeks. [442] Of note is the statement that a hot washer is only effective when used multiple times from a bundle of hot washers. [433]

The time involved to make the hot washer therapeutic invariably leads to non-compliance so even if you think you are helping by saving the patient money, ultimately the result will be suboptimal. I would strongly suggest that if you are going to discuss warm compresses with your patient that you recommend one of the commercial heat packs. There are a number on the market now and a small study found that they were all more effective than a hot washer in achieving 40oC for at least five minutes. [444] 

The Eye Doctor mask is an excellent choice and was shown to have the most stable heat over the 9-minute testing protocol. It can also be used cold which is an excellent adjunct therapy for your patients suffering ocular allergy.

Lid expression has been advocated in MGD by multiple papers and while effective, the limiting factor to success is either the patient’s pain threshold or the practitioner’s confidence level. [460-464] A recent study investigated the outcome of four in-office expressions a week apart and found significant improvement in gland secretion, lipid layer thickness and the number of expressible glands. The patient’s symptoms also improved. [461] While in-office I use a paddle style forceps, it is important to mention here a caution for patients attempting expression at home. DEWS 2 mentions that the Cornea can rise in temperature from 36 to 39.4oC after 8 minutes of a warm compress. If rubbing of the Cornea then occurs or advice to massage the Meibomian glands against the Cornea is actioned, there is a risk of corneal deformation and visual blur. [448-450] As such, my advice and something that I demonstrate, is after the heating device is removed, with clean hands, pull the eyelid away from the eye in a pinch like fashion and squeeze for a count of three. Repeat this for each eyelid. This technique ensures that no pressure is exerted on the Cornea immediately after the warm compress.

Dietary modifications

For those who are still unsure of the role of nutritional supplementation and Dry Eye I would suggest you peruse the considerable evidence nicely tabled on page 609 of the DEWS 2 report. [Table 13] Apart from discussing general hydration with our patients [819-821], the evidence suggests that we should also be discussing essential fatty acids (EFAs) [822]. Humans must source EFAs through food. Important in DED are long chain Omega3 EFAs which exist as EPA and DHA. These are found in high concentrations in oily fish such as Salmon, Tuna, Mackerel, Trout and Sardines. [823] Within the body Omega3 and Omega6 EFA’s compete for enzymes and ultimately regulate systemic inflammation. The ratio of consumed Omega3 to Omega6 is important in balancing inflammatory cytokines. [824] Our current Western diet has an elevated Omega6 intake and so to restore the balance, nutritional intervention in the form of Omega3 supplements is required. [827] We could reduce our Omega6 intake but who wants to tell their patients to order a Big Mac without the bun or side of fries! Go there if you dare.

Want more evidence? The Woman’s Health Study involving over 32,000 subjects reported a 30% reduction in the risk of DED for every additional gram of Omega3 consumed/day. [846]

So, the common question asked is how much and for how long?

Based on the summarised DEWS 2 papers, most researchers assess performance at 3 months. Most used samples of over 1000mg of Omega3 up to 2240mmg. [Table 13] A recent pilot study also suggested that 1500mg of Omega3/day can have a central corneal neuroprotective effect. [860] This is exciting!

Two important things to note when suggesting Dietary modification. Firstly, the capsule size does not reflect the actual Omega3 content and close examination of the nutritional label is important to ensure a therapeutic dose is being taken. Often the patient chosen, may I say it “cheaper” option, is invariably full of other ingredients. Think fillers, stimulants, grass clippings etc Sounds like a good night out on the Gold Coast!!

Second, high-dose Omega3 supplements can have systemic side effects so best practice is always to advise the patient’s GP of the dosage you are recommending. Be aware of patients with liver disease, bleeding disorders and atrial fibrillation. [862]

Role of Anti-inflammatory therapy

Before we move on to artificial tears, let’s discuss the other drops which many Dry Eye patients require. We know from DEWS that Dry eye is a self-perpetuating inflammatory cycle. We also know that there is a cascade of events starting with an unstable tear film, leading to hyperosmolarity which then promotes inflammation which can lead to cell damage. Because of the above, many of our dry eye patients will require anti-inflammatory therapy as part of their treatment.

DEWS II also identified that inflammation can cause changes to the neurobiology of the ocular surface and this helps explain those patients who still report discomfort/irritation despite their ocular surface appearing normal. [539]

Studies have found that topical corticosteroids are effective in breaking the cyclical immune response in Dry Eye Disease. [541,542] In my experience this is one area of management of Dry Eye Disease where many of us either avoid, manage at a sub-therapeutic level or fail to ensure adequate compliance over the required time period. Remember that a 5ml bottle of eyedrops used four times a day in both eyes is likely to last two weeks, so, if you set a review in a month because that patient required corticosteroids for a month, you will not be optimally managing their condition as their drops will run out before their review. To minimise potential complications of topical corticosteroids, repeated short term pulse therapy has been found to be effective. One paper looked at this [559] and found that after an initial pulse of two weeks, if disease-free, the drops were tapered, and the patient remained in a disease-free state for 57 weeks. In this cohort, 21% had a return of their dry eye disease and underwent a second pulse treatment. After the second course, all bar 1.9% of patients were disease-free for a period of 72 weeks. No complications were encountered during the entire study period.

DEWS II tables clinical studies reporting benefits following the use of topical corticosteroids including improved symptoms, reduced staining, improved goblet cell appearance, reduced inflammatory cells, improved Schirmer score, increased tear film breakup time and reduced conjunctival hyperaemia. [547-557] Some points to note to guide practitioners are the most common available agent used was FML 0.1%, dosage was four times a day over one month. Other findings were that topical corticosteroids were more effective than topical NSAID (flurbiprofen) [549], more effective than HA drops alone [551] and more effective than CsA 0.5% [556].

Artificial tear substitutes

For those of you still reading, we are now on the home straight. Recharge your hot beverage and settle in for the final chapter.

While historically tear replacement, products have been the common solution for patients with Dry Eye, these generally over-the-counter products, were never intended to treat the underlying condition. [16] The number of available treatment options, as discussed above, will ensure we can help our patients better than ever before, however, we still need to manage our patient’s symptoms. As mentioned before, many of the Dry Eye treatment options take time to be effective so it is imperative to also give attention to the best artificial tear supplement to keep our patients happy while we wait for the results.

Traditionally we have focused on aqueous supplements and indeed the market has many for us to choose from. Given however that we now know that approximately 85% of our Dry Eye patients have an element of Evaporative Dry Eye [139,140], I would suspect that the use of Lipid containing tear supplements should rise.

Aqueous supplements generally work by enhancing the natural tear volume and viscosity. Many agents exist including, but not limited to, carbomer, carboxymethyl cellulose (CMC), hyaluronic acid (HA), HP-Guar, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA) and polyethylene glycol. To help you navigate through all the reported benefits to ultimately make the right selection for the individual patient, DEWS 2 highlighted a few points.

CMC based products have been shown to bind to corneal epithelial cells and promote healing. [22,23] HPMC is found in a wide range of products and has been shown to be a safe and effective lubricant. [16] HA has also been found to be able to bind to ocular surface cells and aid healing. [28-33] One advantage HA and HP-Guar have over Cellulose derivatives is that they exhibit Non-Newtonian properties. This exciting property means that the viscosity of the lubricant will vary depending on the shear forces occurring, so in the real world this means that the lubricant will thin while the patient is blinking and then thicken once the blink is finished. [34] This ultimately helps ocular retention which has been a challenge for cellulose products where they have needed to rely on increased viscosity to aid ocular retention, however, if too viscous, will cause blurred vision.

Hylofresh and Hyloforte (0.1%) and (0.2%) respectively are pure HA products which are dispensed from the very clever COMED bottle which enables sterile preservative multi-dose instillations from a multidose bottle.

Like a good Shiraz and Eye Fillet, some things work better together. This is the case with HA and CMC. A study involving 305 subjects found that symptoms and signs improved more in the group using a CMC+HA product compared with the group using a CMC product alone. [44] I have also found combining Hylo products with Novatears a synergistic solution for more holistic tear film supplementation.

And now for the top-shelf products, the Lipid supplements. Despite only being discussed for a single page in DEWS 2, I really feel this is where we need, and will see, future innovation. Multiple studies have already shown that lipid-based eyedrops and liposomal sprays improve the symptoms and in some cases signs of Dry Eye disease. [65,141,142,177-182] Lipid-based eyedrops are formed as emulsions. They are more difficult to formulate than aqueous supplements [143]. Emulsions can be categorised based on the droplet size. Products such as Systane Balance (Alcon) and Optive Advanced (Allergan) are macroemulsions with droplet sizes larger than 100 nm.

Systane Balance incorporates the LipiTech molecule which is mineral oil surrounded by anionic phospholipids. It has been suggested that anionic polar phospholipids have a greater ability to increase the lipid layer thickness [46,173]. The mechanism suggested is that they form a stable lipid film by binding to the non-polar lipids at the surface of the aqueous layer [174]. Optive Advanced utilises Polysorbate 80 which is a non-ionic surfactant and oil in water emulsifier. The drop is biphasic and when applied to the salty tear film divides into Polysorbate 80 to complement the Lipid layer and CMC and Glycerin to complement the aqueous layer.

Other options to complement the Lipid layer are Liposomal Sprays and the semifluorinated alkane, Nova Tears. While both these products work well on the lipid layer, best results can be achieved when these products are used as “chasers” after the preferred aqueous supplement is instilled. Like the Tequila tastes better after the salt and lemon! The sprays contain phospholipid liposomes which are microscopic droplets of oil with an aqueous core. Nova tears is a water free wetting agent with a very low surface tension. It is a nanoemulsion with the droplet size being between 10-100nm. The very small droplet size allows rapid spreading across the ocular surface and avoids the light scatter and initial blur which can occur with macroemulsions.

So, when do you decide to refer patients on? For busy practitioners, if you have allowed three months for a good management plan including lid hygiene, Omega-3 advice, warm compresses with expression and appropriate topical therapy to work and the patient returns unhappy, that is the point where I would suggest phoning a dedicated Dry Eye clinic. For some patients you may decide to review them after each month to ensure compliance and potentially change your topical therapy, but ultimately for some Dry Eye patients, relief may require more invasive procedures including IPL, LipiFlow and RexonEye

 

 

References

 

[1] Management and therapy of dry eye disease: report of the management and

therapy subcommittee of the international dry eye WorkShop. Ocul Surf

2007;2007(5):163e78.

[2] Nelson JD, Shimazaki J, Benitez-del-Castillo JM, Craig JP, McCulley JP, Den S,

et al. The international workshop on meibomian gland dysfunction: report of

the definition and classification subcommittee. Invest Ophthalmol Vis Sci

2011;52(4):1930e7.

[3] Craig JP, Nichols KK, Akpek E, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II

definition and classification report. Ocul Surf 2017;15. XX-XX.

[4] Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Cornea 2012;31(5):

472e8.

[5] Korb, DR, Blackie, CA, Finnemore VM, Douglass T. Effect of Using a combination of Lid Wipes,

 Eye Drops and Omega 3 Supplements on Meibomian Gland Functionality in Patients with Lipid

 Deficient/Evaporative Dry Eye. Cornea Vol 34, No. 4, April 2015

[6] Lemp, M et al. The definition and classification of dry eye disease, The Ocular Surface, 5(2):2007, 75-92

[16] Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) artificial tear drops for

dry eye syndrome. Cochrane Database Syst Rev 2016;2:CD009729.

[17] Downie LE, Keller PR. A pragmatic approach to dry eye diagnosis: evidence

into practice. Optom Vis Sci 2015;92(12):1189e97.

[18] Wegener AR, Meyer LM, Sch€onfeld CL. Effect of viscous agents on corneal

density in dry eye disease. J Ocul Pharmacol Ther 2015;31(8):504e8.

[19] Yu F, Liu X, Zhong Y, Guo X, Li M, Mao Z, et al. Sodium hyaluronate decreases

ocular surface toxicity induced by benzalkonium chloride-preserved latanoprost:

an in vivo study. Invest Ophthalmol Vis Sci 2013;54:3385e93.

[20] Doughty MJ, Glavin S. Efficacy of different dry eye treatments with artificial

tears or ocular lubricants: a systematic review. Ophthalmic Physiol Opt

2009;29(6):573e83.

[21] Kamel S, Ali N, Jahangir K, Shah SM, El-Gendy AA. Pharmaceutical significance

of cellulose: a review. Express Polym Lett 2008;2(11):758e78.

[22] Garrett Q, Simmons PA, Xu S, Vehige J, Zhao Z, Ehrmann K, et al. Carboxymethylcellulose

binds to human corneal epithelial cells and is a modulator of

corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2007;48(4):

1559e67.

[23] Garrett Q, Xu S, Simmons PA, Vehige J, Xie RZ, Kumar A, et al. Carboxymethyl

cellulose stimulates rabbit corneal epithelial wound healing. Curr Eye Res

2008;33(7):567e73.

[24] Bruix A, Adan A, Casaroli-Marano RP. Efficacy of sodium carboxymethylcellulose

in the treatment of dry eye syndrome. Arch Soc Esp Oftalmol 2006;81:

85e92.

[25] Noecker RJ. Comparison of initial treatment response to two enhanced-viscosity

artificial tears. Eye Contact Lens 2006;32(3):148e52.

[26] Lee JH, Ahn HS, Kim EK, Kim TI. Efficacy of sodium hyaluronate and

carboxymethylcellulose in treating mild to moderate dry eye disease. Cornea

2011;30(2):175e9.

[27] Rah MJ. A review of hyaluronan and its ophthalmic applications. Optometry

2011;82(1):38e43.

[28] Inoue M, Katakami C. The effect of hyaluronic acid on corneal epithelial cell

proliferation. Invest Ophthalmol Vis Sci 1993;34(7):2313e5.

[29] Stiebel-Kalish H, Gaton DD, Weinberger D, Loya N, Schwartz-Ventik M,

Solomon A. A comparison of the effect of hyaluronic acid versus gentamicin

on corneal epithelial healing. Eye (Lond) 1998;12(5):829e33.

[30] Gomes JA, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate

(hyaluronic acid) promotes migration of human corneal epithelial cells in

vitro. Br J Ophthalmol 2004;88(6):821e5.

[31] Camillieri G, Bucolo C, Rossi S, Drago F. Hyaluronan-induced stimulation of

corneal wound healing is a pure pharmacological effect. J Ocul Pharmacol

Ther 2004;20(6):548e53.

[32] Yang G, Espandar L, Mamalis N, Prestwich GD. A cross-linked hyaluronan gel

accelerates healing of corneal epithelial abrasion and alkali burn injuries in

rabbits. Vet Ophthalmol 2010;13(3):144e50.

[33] Ho WT, Chiang TH, Chang SW, Chen YH, Hu FR, Wang IJ. Enhanced corneal

wound healing with hyaluronic acid and high-potassium artificial tears. Clin

Exp Optom 2013;96(6):536e41.

[34] Pis_ar_cik M, Bako_s D, _Ceppan M. Non-Newtonian properties of hyaluronic acid

aqueous solution. Colloids Surf A 1995;97:197e202.

[35] Johnson ME, Murphy PJ, Boulton M. Carbomer and sodium hyaluronate

eyedrops for moderate dry eye treatment. Optom Vis Sci 2008;85(8):750e7.

[36] Lekhanont K, Chuckpaiwong V, Vongthongsri A, Sangiampornpanit T. Effects

of sodium hyaluronate on wavefront aberrations in dry eye patients. Optom

Vis Sci 2014;91(1):39e46.

[37] Kinoshita S, Oshiden K, Awamura S, Suzuki H, Nakamichi N, Yokoi N,

Rebamipide Ophthalmic Suspension Phase 3 Study Group. A randomized,

multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1%

sodium hyaluronate in the treatment of dry eye. Ophthalmology

2013;120(6):1158e65.

[38] Takamura Etsuko, Tsubota Kazuo, Watanabe Hitoshi, Ohashi Yuichi. A

randomised, double-masked comparison study of diquafosol versus sodium

hyaluronate ophthalmic solutions in dry eye patients. Br J Ophthalmol

2012;96(10):1310e5.

[39] Cheema A, Aziz T, Mirza SA, Siddiqi A, Maheshwary N, Khan MA. Sodium

hyaluronate eye drops in the treatment of dry eye disease: an open label,

uncontrolled, multi-centre trial. J Ayub Med Coll Abbottabad 2012 Jul-

Dec;24(3e4):14e6.

[40] Baudouin C, Cochener B, Pisella PJ, Girard B, Pouliquen P, Cooper H, et al.

Randomized, phase III study comparing osmoprotective carboxymethylcellulose

with sodium hyaluronate in dry eye disease. Eur J Ophthalmol 2012

Sep-Oct;22(5):751e61.

[41] Pinto-Fraga J, Lopez-de la Rosa A, Blazquez Arauzo F, Urbano Rodriguez R,

Gonzalez-Garcia MJ. Efficacy and safety of 0.2% hyaluronic acid in the

management of dry eye disease. Eye Contact Lens 2017;43:57e63.

[42] Park Y, Song JS, Choi CY, Yoon KC, Lee HK, Kim HS. A randomized multicenter

Study comparing 0.1%, 0.15%, and 0.3% sodium hyaluronate with 0.05%

cyclosporine in the treatment of dry eye. J Ocul Pharmacol Ther 2017;33(2):

66e72.

[43] She Y, Li J, Xiao B, Lu H, Liu H, Simmons PA, et al. Evaluation of a novel

artificial tear in the prevention and treatment of dry eye in an animal model.

J Ocul Pharmacol Ther 2015;31(9):525e30.

[44] Simmons PA, Liu H, Carlisle-Wilcox C, Vehige JG. Efficacy and safety of two

new formulations of artificial tears in subjects with dry eye disease: a 3-

month, multicenter, active-controlled, randomized trial. Clin Ophthalmol

2015;9:665e75.

[45] Springs C. Novel ocular lubricant containing an intelligent delivery system:

details of its mechanism of action. Dev Ophthalmol 2010;45:139e47.

[46] Benelli U. Systane lubricant eye drops in the management of ocular dryness.

Clin Ophthalmol 2011;5:783e90.

[47] Christensen MT. Corneal staining reductions observed after treatment with

Systane lubricant eye drops. Adv Ther 2008;25(11):1191e9.

[48] Ousler GW, Michaelson C, Christensen MT. An evaluation of tear film

breakup time extension and ocular protection index scores among three

marketed lubricant eye drops. Cornea 2007;26(8):949e52.

[49] Cervan-Lopez I, Saenz-Frances-San-Baldomero F, Benitez-Del-Castillo JM,

Garcia-Sanchez J. Reduction of corneal permeability in patients treated with

HP-guar: a fluorophotometric study. Arch Soc Esp Oftalmol 2006;81:327e32.

[50] Moon SW, Hwang JH, Chung SH, Nam KH. The impact of artificial tears

containing hydroxypropyl guar on mucous layer. Cornea 2010;29(12):

1430e5.

[51] Uchiyama E, Di Pascuale MA, Butovich IA, McCulley JP. Impact on ocular

surface evaporation of an artificial tear solution containing hydroxypropyl

guar. Eye Contact Lens 2008;34(6):331e4.

[52] S_anchez MA, Arriola-Villalobos P, Torralbo-Jim_enez P, Gir_on N, de la Heras B,

Herrero Vanrell R, et al. The effect of preservative-free HP-Guar on dry eye

after phacoemulsification: a flow cytometric study. Eye (Lond) 2010;24(8):

1331e7.

[53] Gifford P, Evans BJ, Morris J. A clinical evaluation of Systane. Cont Lens Anter

Eye 2006;29(1):31e40.

[54] Rangarajan R, Kraybill B, Ogundele A, Ketelson HA. Effects of a hyaluronic

acid/hydroxypropyl guar artificial tear solution on protection, recovery, and

lubricity in models of corneal epithelium. J Ocul Pharmacol Ther 2015;31(8):

491e7.

[55] Werblin TP, Rheinstrom SD, Kaufman HE. The use of slow-release artificial

tears in the long-term management of keratitis sicca. Ophthalmology

1981;88(1):78e81.

[56] McDonald M, D’Aversa G, Perry HD, Wittpenn JR, Donnenfeld ED,

Nelinson DS. Hydroxypropyl cellulose ophthalmic inserts (lacrisert) reduce

the signs and symptoms of dry eye syndrome and improve patient quality of

life. Trans Am Ophthalmol Soc 2009;107:214e21.

[57] The definition and classification of dry eye disease: report of the definition

and classification subcommittee of the international dry eye WorkShop. Ocul

Surf 2007;2007(5):75e92.

[58] Gilbard JP, Rossi SR, Heyda KG. Ophthalmic solutions, the ocular surface, and

a unique therapeutic artificial tear formulation. Am J Ophthalmol

1989;107(4):348e55.

[59] Gilbard JP, Rossi SR. An electrolyte-based solution that increases corneal

glycogen and conjunctival goblet-cell density in a rabbit model for keratoconjunctivitis

sicca. Ophthalmology 1992;99(4):600e4.

[60] Gilbard JP. Dry eye: pharmacological approaches, effects, and progress. CLAO

J 1996;22(2):141e5.

[61] Troiano P, Monaco G. Effect of hypotonic 0.4% hyaluronic acid drops in dry

eye patients: a cross-over study. Cornea 2008;27(10):1126e30.

[62] Baeyens V, Bron A, Baudouin C, Vismed/Hylovis Study Group. Efficacy of

0.18% hypotonic sodium hyaluronate ophthalmic solution in the treatment

of signs and symptoms of dry eye disease. J Fr Ophtalmol 2012;35(6):412e9.

[63] Sullivan BD, Crews LA, S€onmez B, de la Paz MF, Comert E, Charoenrook V,

et al. Clinical utility of objective tests for dry eye disease: variability over

time and implications for clinical trials and disease management. Cornea

2012;31(9):1000e8.

[64] Scuderi G, Contestabile MT, Gagliano C, Iacovello D, Scuderi L, Avitabile T.

Effects of phytoestrogen supplementation in postmenopausal women with

dry eye syndrome: a randomized clinical trial. Can J Ophthalmol 2012;47(6):

489e92.

[65] Tomlinson A, Madden LC, Simmons PA. Effectiveness of dry eye therapy

under conditions of environmental stress. Curr Eye Res 2013;38(2):229e36.

[66] Versura P, Profazio V, Giannaccare G, Fresina M, Campos EC. Discomfort

symptoms reduction and ocular surface parameters recovery with Artelac

Rebalance treatment in mild-moderate dry eye. Eur J Ophthalmol 2013 Jul-

Aug;23(4):488e95.

[67] Montani G. Intrasubject tear osmolarity changes with two different types of

eyedrops. Optom Vis Sci 2013;90(4):372e7.

[68] Lee JE, Kim NM, Yang JW, Kim SJ, Lee JS, Lee JE. A randomised controlled trial

comparing a thermal massager with artificial teardrops for the treatment of

dry eye. Br J Ophthalmol 2014;98(1):46e51.

[69] Aslan Bayhan S, Bayhan HA, Muhafız E, Bekdemir S¸ , Gürdal C. Effects of

osmoprotective eye drops on tear osmolarity in contact lens wearers. Can J

Ophthalmol 2015;50(4):283e9.

[70] Miserocchi E, Iuliano L, Berchicci L, Bandello F, Modorati G. Tear film osmolarity

in ocular mucous membrane pemphigoid. Cornea 2014;33(7):

668e72.

[71] Gilbard JP, Huang AJ, Belldegrun R, Lee JS, Rossi SR, Gray KL. Open-label

crossover study of vitamin A ointment as a treatment for keratoconjunctivitis

sicca. Ophthalmology 1989;96(2):244e6.

[72] Finis D, Hayajneh J, K€onig C, Borrelli M, Schrader S, Geerling G. Evaluation of

an automated thermodynamic treatment (LipiFlow®) system for meibomian

gland dysfunction: a prospective, randomized, observer-masked trial. Ocul

Surf 2014;12(2):146e54.

[73] Mathers WD, Shields WJ, Sachdev MS, Petroll WM, Jester JV. Meibomian

gland morphology and tear osmolarity: changes with Accutane therapy.

Cornea 1991;10(4):286e90.

[74] Labb_e A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in

patients treated for glaucoma or ocular hypertension. Cornea 2012;31(9):

994e9.

[75] Lee JH, Min K, Kim SK, Kim EK, Kim TI. Inflammatory cytokine and osmolarity

changes in the tears of dry eye patients treated with topical 1% methylprednisolone.

Yonsei Med J 2014;55(1):203e8.

[76] Jadidi K, Panahi Y, Ebrahimi A, Mafi M, Nejat F, Sahebkar A. Topical cyclosporine

a for treatment of dry eye due to chronic mustard gas injury. J

Ophthalmic Vis Res 2014 Oct-Dec;9(4):417e22.

[77] Hamada S, Moore TC, Moore JE, Al-Dreihi MG, Anbari A, Shah S. Assessment

of the effect of cyclosporine-A 0.05% emulsion on the ocular surface and

corneal sensation following cataract surgery. Cont Lens Anter Eye

2016;39(1):15e9.

[78] Nelson JD, Farris RL. Sodium hyaluronate and polyvinyl alcohol artificial tear

preparations. A comparison in patients with keratoconjunctivitis sicca. Arch

Ophthalmol 1988;106(4):484e7.

[79] Iester M, Orsoni GJ, Gamba G, Taffara M, Mangiafico P, Giuffrida S, et al.

Improvement of the ocular surface using hypotonic 0.4% hyaluronic acid

drops in keratoconjunctivitis sicca. Eye (Lond) 2000;14(Pt 6):892e8.

[80] Benelli U, Nardi M, Posarelli C, Albert TG. Tear osmolarity measurement

using the TearLab Osmolarity System in the assessment of dry eye treatment

effectiveness. Cont Lens Anter Eye 2010;33(2):61e7.

[81] C€omez AT, Tufan HA, Kocabıyık O, Gencer B. Effects of lubricating agents with

different osmolalities on tear osmolarity and other tear function tests in

patients with dry eye. Curr Eye Res 2013;38(11):1095e103.

[82] Garrett Q, Xu S, Simmons PA, Vehige J, Flanagan JL, Willcox MD. Expression

and localization of carnitine/organic cation transporter OCTN1 and OCTN2 in

ocular epithelium. Invest Ophthalmol Vis Sci 2008;49(11):4844e9.

[83] Xu S, Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. Transport of

L-carnitine in human corneal and conjunctival epithelial cells. Mol Vis

2010;16:1823e31.

[84] Khandekar N, Willcox MD, Shih S, Simmons P, Vehige J, Garrett Q. Decrease

in hyperosmotic stress-induced corneal epithelial cell apoptosis by L-carnitine.

Mol Vis 2013;19:1945e56.

[85] Garrett Q, Khandekar N, Shih S, Flanagan JL, Simmons P, Vehige J, et al.

Betaine stabilizes cell volume and protects against apoptosis in human

corneal epithelial cells under hyperosmotic stress. Exp Eye Res 2013;108:

33e41.

[86] Corrales RM, Luo L, Chang EY, Pflugfelder SC. Effects of osmoprotectants on

hyperosmolar stress in cultured human corneal epithelial cells. Cornea

2008;27(5):574e9.

[87] Hua X, Su Z, Deng R, Lin J, Li DQ, Pflugfelder SC. Effects of L-carnitine,

erythritol and betaine on pro-inflammatory markers in primary human

corneal epithelial cells exposed to hyperosmotic stress. Curr Eye Res

2015;40(7):657e67.

[88] Chen W, Zhang X, Li J, Wang Y, Chen Q, Hou C, et al. Efficacy of osmoprotectants

on prevention and treatment of murine dry eye. Invest Ophthalmol

Vis Sci 2013;54(9):6287e97.

[89] Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG,

et al. Role of hyperosmolarity in the pathogenesis and management of dry

eye disease: proceedings of the OCEAN group meeting. Ocul Surf 2013;11(4):

246e58.

[90] Chen W, Zhang X, Liu M, Zhang J, Ye Y, Lin Y, et al. Trehalose protects against

ocular surface disorders in experimental murine dry eye through suppression

of apoptosis. Exp Eye Res 2009;89(3):311e8.

[91] Hovakimyan M, Ramoth T, L€obler M, Schmitz KP, Witt M, Guthoff R, et al.

Evaluation of protective effects of trehalose on desiccation of epithelial cells

in three dimensional reconstructed human corneal epithelium. Curr Eye Res

2012;37(11):982e9.

[92] Li J, Roubeix C, Wang Y, Shi S, Liu G, Baudouin C, et al. Therapeutic efficacy of

trehalose eye drops for treatment of murine dry eye induced by an intelligently

controlled environmental system. Mol Vis 2012;18:317e29.

[93] Iturriaga G, Su_arez R, Nova-Franco B. Trehalose metabolism: from osmoprotection

to signaling. Int J Mol Sci 2009;10(9):3793e810.

[94] Luyckx J, Baudouin C. Trehalose: an intriguing disaccharide with potential for

medical application in ophthalmology. Clin Ophthalmol 2011;5:577e81.

[95] Matsuo T. Trehalose protects corneal epithelial cells from death by drying. Br

J Ophthalmol 2001;85(5):610e2.

[96] Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a

novel mTOR-independent autophagy enhancer, accelerates the clearance of

mutant huntingtin and alpha-synuclein. J Biol Chem 2007;282(8):5641e52.

[97] Cejkov_a J, Cejka C, Luyckx J. Trehalose treatment accelerates the healing of

UVB-irradiated corneas. Comparative immunohistochemical studies on

corneal cryostat sections and corneal impression cytology. Histol Histopathol

2012;27(8):1029e40.

[98] Baudouin C, Labb_e A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in

eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010;29(4):

312e34.

[99] Augustin AJ, Spitznas M, Kaviani N, Meller D, Koch FH, Grus F, et al. Oxidative

reactions in the tear fluid of patients suffering from dry eyes. Graefes Arch

Clin Exp Ophthalmol 1995;233(11):694e8.

[100] Hongyok T, Chae JJ, Shin YJ, Na D, Li L, Chuck RS. Effect of chitosan-N-acetylcysteine

conjugate in a mouse model of botulinum toxin B-induced dry

eye. Arch Ophthalmol 2009;127(4):525e32.

[101] Kim EC, Choi JS, Joo CK. A comparison of vitamin a and cyclosporine a 0.05%

eye drops for treatment of dry eye syndrome. Am J Ophthalmol 2009;147(2):

206e13. e3.

[102] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J,

et al. TFOS DEWS ii iatrogenic dry eye report. Ocul Surf 2017;15. XX-XX.

[103] Stoddard AR, Koetje LR, Mitchell AK, Schotanus MP, Ubels JL. Bioavailability

of antioxidants applied to stratified human corneal epithelial cells. J Ocul

Pharmacol Ther 2013;29(7):681e7.

[104] Brzheskiy VV, Efimova EL, Vorontsova TN, Alekseev VN, Gusarevich OG,

Shaidurova KN, , et alRyabtseva AA, Andryukhina OM, Kamenskikh TG,

Sumarokova ES, Miljudin ES, Egorov EA, Lebedev OI, Surov AV, Korol AR,

Nasinnyk IO, Bezditko PA, Muzhychuk OP, Vygodin VA, Yani EV,

Savchenko AY, Karger EM, Fedorkin ON, Mironov AN, Ostapenko V,

Popeko NA, Skulachev VP, Skulachev MV. Results of a multicenter, randomized,

double-masked, placebo-controlled clinical study of the efficacy

and safety of Visomitin eye drops in patients with dry eye syndrome. Adv

Ther 2015;32(12):1263e79.

[105] Mostert V. Selenoprotein P: properties, functions, and regulation. Arch Biochem

Biophys 2000;376(2):433e8.

[106] Higuchi A, Takahashi K, Hirashima M, Kawakita T, Tsubota K. Selenoprotein P

controls oxidative stress in cornea. PLoS One 2010;5:e9911.

[107] Baudouin C. The pathology of dry eye. Surv Ophthalmol 2001;45(Suppl 2):

S211e20.

[108] Noecker R. Effects of common ophthalmic preservatives on ocular health.

Adv Ther 2001 Sep-Oct;18(5):205e15.

[109] Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with

ocular hypertension and glaucoma. Curr Eye Res 2011;36(5):391e8.

[110] Mantelli F, Tranchina L, Lambiase A, Bonini S. Ocular surface damage by

ophthalmic compounds. Curr Opin Allergy Clin Immunol 2011;11(5):

464e70.

[111] Stalmans I, Sunaric M_egevand G, Cordeiro MF, Hommer A, Rossetti L, Go~ni F,

et al. Preservative-free treatment in glaucoma: who, when, and why. Eur J

Ophthalmol 2013 Jul-Aug;23(4):518e25.

[112] Anwar Z, Wellik SR, Galor A. Glaucoma therapy and ocular surface disease:

current literature and recommendations. Curr Opin Ophthalmol 2013;24(2):

136e43.

[113] Pinheiro R, Panfil C, Schrage N, Dutescu RM. The impact of glaucoma medications

on corneal wound healing. J Glaucoma 2016;25(1):122e7.

[114] Chen W, Zhang Z, Hu J, Xie H, Pan J, Dong N, et al. Changes in rabbit corneal

innervation induced by the topical application of benzalkonium chloride.

Cornea 2013;32(12):1599e606.

[115] Lin Z, He H, Zhou T, Liu X, Wang Y, He H, et al. A mouse model of limbal stem

cell deficiency induced by topical medication with the preservative benzalkonium

chloride. Invest Ophthalmol Vis Sci 2013;54(9):6314e25.

[116] Kaercher T, H€onig D, Barth W. How the most common preservative affects

the Meibomian lipid layer. Orbit 1999;18(2):89e97.

[117] Schrage N, Frentz M, Spoeler F. The Ex Vivo Eye Irritation Test (EVEIT) in

evaluation of artificial tears: Purite-preserved versus unpreserved eye drops.

Graefes Arch Clin Exp Ophthalmol 2012;250(9):1333e40.

[118] Jee D, Park SH, Kim MS, Kim EC. Antioxidant and inflammatory cytokine in

tears of patients with dry eye syndrome treated with preservative-free

versus preserved eye drops. Invest Ophthalmol Vis Sci 2014;55(8):5081e9.

[119] Bernauer W, Thiel MA, Kurrer M, Heiligenhaus A, Rentsch KM, Schmitt A,

et al. Corneal calcification following intensified treatment with sodium

hyaluronate artificial tears. Br J Ophthalmol 2006;90(3):285e8.

[120] Imayasu M, Hori Y, Cavanagh HD. Effects of multipurpose contact lens care

solutions and their ingredients on membrane-associated mucins of human

corneal epithelial cells. Eye Contact Lens 2010;36(6):361e6.

[121] Lehmann DM, Cavet ME, Richardson ME. Nonclinical safety evaluation of

boric acid and a novel borate-buffered contact lens multi-purpose solution,

Biotrue multi-purpose solution. Cont Lens Anter Eye 2010;33(Suppl 1):

S24e32.

[122] Pelton R, Hu Z, Ketelson H, Meadows D. Reversible flocculation with

hydroxypropyl guar-borate, a labile anionic polyelectrolyte. Langmuir

2009;25(1):192e5.

[123] Khanal A, Cui Y, Zhang L, Pelton R, Ren Y, Ketelson H, et al. Cationic liposome

colloidal stability in the presence of guar derivatives suggests depletion interactions

may be operative in artificial tears. Biomacromolecules

2010;11(9):2460e4.

[124] Saarinen-Savolainen P, J€arvinen T, Araki-Sasaki K, Watanabe H, Urtti A.

Evaluation of cytotoxicity of various ophthalmic drugs, eye drop excipients

and cyclodextrins in an immortalized human corneal epithelial cell line.

Pharm Res 1998;15(8):1275e80.

[125] Viaud-Quentric K, Lefranc-Jullien S, Feraille L, Elena PP. Long-term tolerance

of preservative-free eye drops containing macrogol hydroxystearate as an

excipient. J Fr Ophtalmol 2016;39(2):156e63.

[126] Smedowski A, Paterno JJ, Toropainen E, Sinha D, Wylegala E, Kaarniranta K.

Excipients of preservative-free latanoprost induced inflammatory response

and cytotoxicity in immortalized human HCE-2 corneal epithelial cells. J

Biochem Pharmacol Res 2014;2:175e84.

[127] Gensheimer WG, Kleinman DM, Gonzalez MO, Sobti D, Cooper ER, Smits G,

et al. Novel formulation of glycerin 1% artificial tears extends tear film breakup

time compared with Systane lubricant eye drops. J Ocul Pharmacol Ther

2012;28(5):473e8.

[128] Willcox MDP, Argüeso P, Georgiev G, Holopainen J, Laurie G, Millar T, et al.

TFOS DEWS ii tear film report. Ocul Surf 2017;15. XX-XX.

[129] Tiffany JM. Tears in health and disease. Eye (Lond) 2003;17(8):923e6.

[130] Stahl U, Willcox M, Stapleton F. Osmolality and tear film dynamics. Clin Exp

Optom 2012;95(1):3e11.

[131] Schotanus MP, Koetje LR, Van Dyken RE, Ubels JL. Stratified corneal limbal

epithelial cells are protected from UVB-induced apoptosis by elevated

extracellular K⁺. Exp Eye Res 2011;93(5):735e40.

[132] Ubels JL, Schotanus MP, Bardolph SL, Haarsma LD, Koetje LR, Louters JR.

Inhibition of UV-B induced apoptosis in corneal epithelial cells by potassium

channel modulators. Exp Eye Res 2010;90(2):216e22.

[133] Green K, MacKeen DL, Slagle T, Cheeks L. Tear potassium contributes to

maintenance of corneal thickness. Ophthalmic Res 1992;24(2):99e102.

[134] Bachman WG, Wilson G. Essential ions for maintenance of the corneal

epithelial surface. Invest Ophthalmol Vis Sci 1985;26(11):1484e8.

[135] Smolin G, Foster CS, Azar DT, Dohlman CH. Smolin and Thoft’s The Cornea:

Scientific Foundations and Clinical Practice. 4thLippincott Williams & Wilkins

ed. Lippincott Williams & Wilkins; 2005.

[136] Lopez Bernal D, Ubels JL. Artificial tear composition and promotion of recovery

of the damaged corneal epithelium. Cornea 1993;12(2):115e20.

[137] Ubels JL, McCartney MD, Lantz WK, Beaird J, Dayalan A, Edelhauser HF. Effects

of preservative-free artificial tear solutions on corneal epithelial

structure and function. Arch Ophthalmol 1995;113(3):371e8.

[138] Craig JP, Tomlinson A. Importance of the lipid layer in human tear film

stability and evaporation. Optom Vis Sci 1997;74(1):8e13.

[139] Lee SY, Tong L. Lipid-containing lubricants for dry eye: a systematic review.

Optom Vis Sci 2012;89(11):1654e61.

[140] Moshirfar M, Pierson K, Hanamaikai K, Santiago-Caban L, Muthappan V,

Passi SF. Artificial tears potpourri: a literature review. Clin Ophthalmol

2014;8:1419e33.

[141] Korb DR, Scaffidi RC, Greiner JV, Kenyon KR, Herman JP, Blackie CA, et al. The

effect of two novel lubricant eye drops on tear film lipid layer thickness in

subjects with dry eye symptoms. Optom Vis Sci 2005;82(7):594e601.

[142] Scaffidi RC, Korb DR. Comparison of the efficacy of two lipid emulsion

eyedrops in increasing tear film lipid layer thickness. Eye Contact Lens

2007;33(1):38e44.

[143] Mason TG, Wilking JN, Meleson K, Chang CB, Graves SM. Nanoemulsions:

formation, structure, and physical properties. J Phys Condens Matter

2006;18:R635.

[144] Royle L, Matthews E, Corfield A, Berry M, Rudd PM, Dwek RA, et al. Glycan

structures of ocular surface mucins in man, rabbit and dog display species

differences. Glycoconj J 2008;25(8):763e73.

[145] Daull P, Lallemand F, Garrigue JS. Benefits of cetalkonium chloride cationic

oil-in-water nanoemulsions for topical ophthalmic drug delivery. J Pharm

Pharmacol 2014;66(4):531e41.

[146] Amrane M, Creuzot-Garcher C, Robert PY, Ismail D, Garrigue JS, Pisella PJ,

et al. Ocular tolerability and efficacy of a cationic emulsion in patients with

mild to moderate dry eye disease – a randomised comparative study. J Fr

Ophtalmol 2014;37(8):589e98.

[147] Zhang W, Wang Y, Lee BT, Liu C, Wei G, Lu W. A novel nanoscale-dispersed

eye ointment for the treatment of dry eye disease. Nanotechnology

2014;25(12):125101.

[148] Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. Successfully improving

ocular drug delivery using the cationic nanoemulsion, novasorb. J Drug Deliv

2012;2012:604204.

[149] Kinnunen K, Kauppinen A, Piippo N, Koistinen A, Toropainen E,

Kaarniranta K. Cationorm shows good tolerability on human HCE-2 corneal

epithelial cell cultures. Exp Eye Res 2014;120:82e9.

[150] Pinheiro R, Panfil C, Schrage N, Dutescu RM. Comparison of the lubricant

eyedrops Optive®, Vismed Multi®, and Cationorm® on the corneal healing

process in an ex vivo model. Eur J Ophthalmol 2015 Sep-Oct;25(5):379e84.

[151] Yoncheva K, Vandervoort J, Ludwig A. Development of mucoadhesive poly(

lactide-co-glycolide) nanoparticles for ocular application. Pharm Dev

Technol 2011;16(1):29e35.

[152] Paolicelli P, de la Fuente M, S_anchez A, Seijo B, Alonso MJ. Chitosan nanoparticles

for drug delivery to the eye. Expert Opin Drug Deliv 2009;6(3):

239e53.

[153] De Campos AM, S_anchez A, Alonso MJ. Chitosan nanoparticles: a new vehicle

for the improvement of the delivery of drugs to the ocular surface. Application

to cyclosporin A. Int J Pharm 2001;224(1e2):159e68.

[154] Rieger G. Lipid-containing eye drops: a step closer to natural tears. Ophthalmologica

1990;201(4):206e12.

[155] Choi JH, Kim JH, Li Z, Oh HJ, Ahn KY, Yoon KC. Efficacy of the mineral oil and

hyaluronic acid mixture eye drops in murine dry eye. Korean J Ophthalmol

2015;29(2):131e7.

[156] Katzer T, Chaves P, Bernardi A, Pohlmann AR, Guterres SS, Beck RC. Castor oil

and mineral oil nanoemulsion: development and compatibility with a soft

contact lens. Pharm Dev Technol 2014;19(2):232e7.

[157] Maïssa C, Guillon M, Simmons P, Vehige J. Effect of castor oil emulsion

eyedrops on tear film composition and stability. Cont Lens Anter Eye

2010;33(2):76e82.

[158] Moscovici BK, Holzchuh R, Chiacchio BB, Santo RM, Shimazaki J, Hida RY.

Clinical treatment of dry eye using 0.03% tacrolimus eye drops. Cornea

2012;31(8):945e9.

[159] Rantam€aki AH, Javanainen M, Vattulainen I, Holopainen JM. Do lipids retard

the evaporation of the tear fluid? Invest Ophthalmol Vis Sci 2012;53(10):

6442e7.

[160] Parrilha LR, Nai GA, Giuffrida R, Barbero RC, Padovani LD, Pereira RH, et al.

Comparison of 1% cyclosporine eye drops in olive oil and in linseed oil to

treat experimentally-induced keratoconjunctivitis sicca in rabbits. Arq Bras

Oftalmol 2015 Sep-Oct;78(5):295e9.

[161] Radomska-Soukharev A, Wojciechowska J. Microemulsions as potential

ocular drug delivery systems: phase diagrams and physical properties

depending on ingredients. Acta Pol Pharm 2005 Nov-Dec;62(6):465e71.

[162] Greiner JV, Glonek T, Korb DR, Booth R, Leahy CD. Phospholipids in meibomian

gland secretion. Ophthalmic Res 1996;28(1):44e9.

[163] Dean AW, Glasgow BJ. Mass spectrometric identification of phospholipids in

human tears and tear lipocalin. Invest Ophthalmol Vis Sci 2012;53(4):

1773e82.

[164] Ham BM, Cole RB, Jacob JT. Identification and comparison of the polar

phospholipids in normal and dry eye rabbit tears by MALDI-TOF mass

spectrometry. Invest Ophthalmol Vis Sci 2006;47(8):3330e8.

[165] Shine WE, McCulley JP. Keratoconjunctivitis sicca associated with

meibomian secretion polar lipid abnormality. Arch Ophthalmol 1998;116(7):

849e52.

[166] Chen J, Green-Church KB, Nichols KK. Shotgun lipidomic analysis of human

meibomian gland secretions with electrospray ionization tandem mass

spectrometry. Invest Ophthalmol Vis Sci 2010;51(12):6220e31.

[167] Butovich IA, Uchiyama E, Di Pascuale MA, McCulley JP. Liquid chromatography-

mass spectrometric analysis of lipids present in human meibomian

gland secretions. Lipids 2007;42(8):765e76.

[168] Butovich IA, Wojtowicz JC, Molai M. Human tear film and meibum. Very long

chain wax esters and (O-acyl)-omega-hydroxy fatty acids of meibum. J Lipid

Res 2009;50(12):2471e85.

[169] Ham Bryan M, Jacob Jean T, Cole Richard B. MALDI-TOF MS of phosphorylated

lipids in biological fluids using immobilized metal affinity chromatography

and a solid ionic crystal matrix. Anal Chem 2005;77(14):4439e47.

[170] Saville JT, Zhao Z, Willcox MD, Ariyavidana MA, Blanksby SJ, Mitchell TW.

Identification of phospholipids in human meibum by nano-electrospray

ionisation tandem mass spectrometry. Exp Eye Res 2011;92(3):238e40.

[171] Ham BM, Jacob JT, Keese MM, Cole RB. Identification, quantification and

comparison of major non-polar lipids in normal and dry eye tear lipidomes

by electrospray tandem mass spectrometry. J Mass Spectrom 2004;39(11):

1321e36.

[172] Pucker AD, Haworth KM. The presence and significance of polar meibum and

tear lipids. Ocul Surf 2015;13(1):26e42.

[173] Korb DR, Greiner JV, Glonek T. The effects of anionic and zwitterionic

phospholipids on the tear film lipid layer. Adv Exp Med Biol 2002;506(Pt A):

495e9.

[174] Korb D, Stone R. Are phospholipids the critical ingredient? Rev Cornea

Contact Lens 2012;149:38e41.

[380] Green-Church KB, Butovich I, Willcox M, Borchman D, Paulsen F, Barabino S,

et al. The international workshop on meibomian gland dysfunction: report of

the subcommittee on tear film lipids and lipid-protein interactions in health

and disease. Invest Ophthalmol Vis Sci 2011;52(4):1979e93.

[381] McCulley JP, Dougherty JM, Deneau DG. Classification of chronic blepharitis.

Ophthalmology 1982;89(10):1173e80.

[382] McCulley JP, Shine WE. Changing concepts in the diagnosis and management

of blepharitis. Cornea 2000;19(5):650e8.

[383] Nichols KK. The international workshop on meibomian gland dysfunction:

introduction. Invest Ophthalmol Vis Sci 2011;52(4):1917e21.

[384] Nichols KK, Foulks GN, Bron AJ, Glasgow BJ, Dogru M, Tsubota K, et al. The

international workshop on meibomian gland dysfunction: executive summary.

Invest Ophthalmol Vis Sci 2011;52(4):1922e9.

[385] Smith RE, Flowers Jr CW. Chronic blepharitis: a review. CLAO J 1995;21(3):

200e7.

[386] Key JE. A comparative study of eyelid cleaning regimens in chronic blepharitis.

CLAO J 1996;22(3):209e12.

[387] Romero JM, Biser SA, Perry HD, Levinson DH, Doshi SJ, Terraciano A, et al.

Conservative treatment of meibomian gland dysfunction. Eye Contact Lens

2004;30(1):14e9.

[388] Craig JP, Sung J, Wang MT, Cheung I, Sherwin T, Ismail S. Commercial lid

cleanser outperforms baby shampoo for management of blepharitis in randomized,

double-masked clinical trial. Invest Ophthalmol Vis Sci 2017;58. Eabstract

2247eB0014.

[389] Geerling G, Tauber J, Baudouin C, Goto E, Matsumoto Y, O’Brien T, et al. The

international workshop on meibomian gland dysfunction: report of the

subcommittee on management and treatment of meibomian gland

dysfunction. Invest Ophthalmol Vis Sci 2011;52(4):2050e64.

[390] Alghamdi YA, Camp A, Feuer W, Karp CL, Wellik S, Galor A. Compliance and

Subjective Patient Responses to Eyelid Hygiene. Eye Contact Lens 2017. In

press.

[391] Coroneo MT, Rosenberg ML, Cheung LM. Ocular effects of cosmetic products

and procedures. Ocul Surf 2006;4(2):94e102.

[392] Goto T, Zheng X, Gibbon L, Ohashi Y. Cosmetic product migration onto the

ocular surface: exacerbation of migration after eyedrop instillation. Cornea

2010;29(4):400e3.

[393] Ng A, Evans K, North RV, Purslow C. Migration of Cosmetic Products into the

Tear Film. Eye Contact Lens 2015;41(5):304e9.

[394] Paugh JR, Knapp LL, Martinson JR, Hom MM. Meibomian therapy in problematic

contact lens wear. Optom Vis Sci 1990;67(11):803e6.

[395] Guillon M, Maissa C, Wong S. Eyelid margin modification associated with

eyelid hygiene in anterior blepharitis and meibomian gland dysfunction. Eye

Contact Lens 2012;38(5):319e25.

[396] Guillon M, Maissa C, Wong S. Symptomatic relief associated with eyelid

hygiene in anterior blepharitis and MGD. Eye Contact Lens 2012;38(5):

306e12.

[397] Doan S. Tolerability and acceptability of Blephagel: a novel eyelid hygiene

aqueous gel. Clin Ophthalmol 2012;6:71e7.

[398] Khaireddin R, Hueber A. Eyelid hygiene for contact lens wearers with blepharitis.

Comparative investigation of treatment with baby shampoo versus

phospholipid solution. Ophthalmologe 2013;110:146e53.

[399] Arrúa M, Samudio M, Fari~na N, Cibils D, Laspina F, Sanabria R, et al.

Comparative study of the efficacy of different treatment options in patients

with chronic blepharitis. Arch Soc Esp Oftalmol 2015;90(3):112e8.

[400] Ngo William, Srinivasan Sruthi, Houtman Diane, Jones Lyndon. The relief of

dry eye signs and symptoms using a combination of lubricants, lid hygiene

and ocular nutraceuticals. J Optom 2017;10(1):26e33.

[401] Benitez-Del-Castillo JM. How to promote and preserve eyelid health. Clin

Ophthalmol 2012;6:1689e98.

[402] Needle JJ, Petchey R, Lawrenson JG. A survey of the scope of therapeutic

practice by UK optometrists and their attitudes to an extended prescribing

role. Ophthalmic Physiol Opt 2008;28(3):193e203.

[403] Jackson WB. Management of dysfunctional tear syndrome: a Canadian

consensus. Can J Ophthalmol 2009;44(4):385e94.

[404] Zhao YE, Wu LP, Hu L, Xu JR. Association of blepharitis with Demodex: a

meta-analysis. Ophthalmic Epidemiol 2012;19(2):95e102.

[405] Junk AK, Lukacs A, Kampik A. Topical administration of metronidazole gel as

an effective therapy alternative in chronic Demodex blepharitisea case

report. Klin Monbl Augenheilkd 1998;213:48e50.

[406] Czepita D, Kuzna-Grygiel W, Czepita M, Grobelny A. Demodex folliculorum

and Demodex brevis as a cause of chronic marginal blepharitis. Ann Acad

Med Stetin 2007;53:63e7. discussion 7.

[407] Fulk GW, Clifford C. A case report of demodicosis. J Am Optom Assoc

1990;61(8):637e9.

[408] Fulk GW, Murphy B, Robins MD. Pilocarpine gel for the treatment of

demodicosis-a case series. Optom Vis Sci 1996;73(12):742e5.

[409] Kheirkhah A, Casas V, Li W, Raju VK, Tseng SC. Corneal manifestations of

ocular demodex infestation. Am J Ophthalmol 2007;143(5):743e9.

[410] Gao YY, Di Pascuale MA, Elizondo A, Tseng SC. Clinical treatment of ocular

demodecosis by lid scrub with tea tree oil. Cornea 2007;26(2):136e43.

[411] Holzchuh FG, Hida RY, Moscovici BK, Villa Albers MB, Santo RM, Kara-Jos_e N,

et al. Clinical treatment of ocular Demodex folliculorum by systemic ivermectin.

Am J Ophthalmol 2011;151(6):1030e4. e1.

[412] Filho PA, Hazarbassanov RM, Grisolia AB, Pazos HB, Kaiserman I, Gomes J_A.

The efficacy of oral ivermectin for the treatment of chronic blepharitis in

patients tested positive for Demodex spp. Br J Ophthalmol 2011;95(6):

893e5.

[413] Koo H, Kim TH, Kim KW, Wee SW, Chun YS, Kim JC. Ocular surface

discomfort and Demodex: effect of tea tree oil eyelid scrub in Demodex

blepharitis. J Korean Med Sci 2012;27(12):1574e9.

[414] Gao YY, Xu DL, Huang lJ, Wang R, Tseng SC. Treatment of ocular itching

associated with ocular demodicosis by 5% tea tree oil ointment. Cornea

2012;31(1):14e7.

[415] Salem DA, El-Shazly A, Nabih N, El-Bayoumy Y, Saleh S. Evaluation of the

efficacy of oral ivermectin in comparison with ivermectin-metronidazole

combined therapy in the treatment of ocular and skin lesions of Demodex

folliculorum. Int J Infect Dis 2013;17(5):e343e7.

[416] Carson CF, Hammer KA, Riley TV. Melaleuca alternifolia (Tea Tree) oil: a

review of antimicrobial and other medicinal properties. Clin Microbiol Rev

2006;19(1):50e62.

[417] Gao YY, Di Pascuale MA, Li W, Baradaran-Rafii A, Elizondo A, Kuo CL, et al. In

vitro and in vivo killing of ocular Demodex by tea tree oil. Br J Ophthalmol

2005;89(11):1468e73.

[418] Tighe S, Gao YY, Tseng SC. Terpinen-4-ol is the Most Active Ingredient of Tea

Tree Oil to Kill Demodex Mites. Transl Vis Sci Technol 2013;2(7):2.

[419] Cheng AM, Sheha H, Tseng SC. Recent advances on ocular Demodex infestation.

Curr Opin Ophthalmol 2015;26(4):295e300.

[420] Nicholls SG, Oakley CL, Tan A, Vote BJ. Demodex treatment in external ocular

disease: the outcomes of a Tasmanian case series. Int Ophthalmol

2016;36(5):691e6.

[421] Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis

with oral ivermectin and topical permethrin cream. J Am Acad Dermatol

1999;41(5 Pt 1):775e7.

[422] McCann LC, Tomlinson A, Pearce EI, Papa V. Effectiveness of artificial tears in

the management of evaporative dry eye. Cornea 2012;31(1):1e5.

[423] Sindt CW, Foulks GN. Efficacy of an artificial tear emulsion in patients with

dry eye associated with meibomian gland dysfunction. Clin Ophthalmol

2013;7:1713e22.

[424] Aguilar AJ, Marquez MI, Albera PA, Tredicce JL, Berra A. Effects of Systane(®)

Balance on noninvasive tear film break-up time in patients with lipid-deficient

dry eye. Clin Ophthalmol 2014;8:2365e72.

[425] Kaercher T, Thelen U, Brief G, Morgan-Warren RJ, Leaback R. A prospective,

multicenter, noninterventional study of Optive Plus(®) in the treatment of

patients with dry eye: the prolipid study. Clin Ophthalmol 2014;8:1147e55.

[426] Guthrie SE, Jones L, Blackie CA, Korb DR. A Comparative Study Between an

Oil-in-Water Emulsion and Nonlipid Eye Drops Used for Rewetting Contact

Lenses. Eye Contact Lens 2015;41(6):373e7.

[427] Ousler 3rd G, Devries DK, Karpecki PM, Ciolino JB. An evaluation of Retaine™

ophthalmic emulsion in the management of tear film stability and ocular

surface staining in patients diagnosed with dry eye. Clin Ophthalmol 2015;9:

235e43.

[428] Gan L, Wang J, Jiang M, Bartlett H, Ouyang D, Eperjesi F, et al. Recent advances

in topical ophthalmic drug delivery with lipid-based nanocarriers.

Drug Discov Today 2013;18(5e6):290e7.

[429] Sim HS, Petznick A, Barbier S, Tan JH, Acharya UR, Yeo S, et al. A Randomized,

Controlled Treatment Trial of Eyelid-Warming Therapies in Meibomian

Gland Dysfunction. Ophthalmol Ther 2014;3(1e2):37e48.

[430] Villani Edoardo, Garoli Elena, Canton Veronica, Pichi Francesco, Nucci Paolo,

Ratiglia Roberto. Evaluation of a novel eyelid-warming device in meibomian

gland dysfunction unresponsive to traditional warm compress treatment: an

in vivo confocal study. Int Ophthalmol 2015;35(3):319e23.

[431] Lacroix Z, L_eger S, Bitton E. Ex vivo heat retention of different eyelid

warming masks. Cont Lens Anter Eye 2015;38(3):152e6.

[432] Bitton E, Lacroix Z, L_eger S. In-vivo heat retention comparison of eyelid

warming masks. Cont Lens Anter Eye 2016;39(4):311e5.

[433] Murakami DK, Blackie CA, Korb DR. All Warm Compresses Are Not Equally

Efficacious. Optom Vis Sci 2015;92(9):e327e33.

[434] Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul

Surf 2004;2(2):149e65.

[435] Nichols KK, Ham BM, Nichols JJ, Ziegler C, Green-Church KB. Identification of

fatty acids and fatty acid amides in human meibomian gland secretions.

Invest Ophthalmol Vis Sci 2007;48(1):34e9.

[436] Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness

following treatment with warm compresses in patients with meibomian

gland dysfunction. Eye Contact Lens 2003;29(2):96e9.

[437] Blackie CA, Korb DR, Knop E, Bedi R, Knop N, Holland EJ. Nonobvious

obstructive meibomian gland dysfunction. Cornea 2010;29(12):1333e45.

[438] Goto E, Endo K, Suzuki A, Fujikura Y, Tsubota K. Improvement of tear stability

following warm compression in patients with meibomian gland dysfunction.

Adv Exp Med Biol 2002;506(Pt B):1149e52.

[439] Tiffany JM. The lipid secretion of the meibomian glands. Adv Lipid Res

1987;22:1e62.

[440] Ong BL, Larke JR. Meibomian gland dysfunction: some clinical, biochemical

and physical observations. Ophthalmic Physiol Opt 1990;10(2):144e8.

[441] Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation

with dry eye symptoms and gland location. Cornea 2008;27(10):1142e7.

[442] Arita R, Morishige N, Shirakawa R, Sato Y, Amano S. Effects of Eyelid

Warming Devices on Tear Film Parameters in Normal Subjects and Patients

with Meibomian Gland Dysfunction. Ocul Surf 2015;13(4):321e30.

[443] Blackie CA, Solomon JD, Greiner JV, Holmes M, Korb DR. Inner eyelid surface

temperature as a function of warm compress methodology. Optom Vis Sci

2008;85(8):675e83.

[444] Chang CM, Chu HT, Wei YH, Chen FP, Wang S, Wu PC, et al. The Core Pattern

Analysis on Chinese Herbal Medicine for Sj€ogren’s syndrome: A Nationwide

Population-Based Study. Sci Rep 2015;5:9541.

[445] Despa F, Orgill DP, Neuwalder J, Lee RC. The relative thermal stability of

tissue macromolecules and cellular structure in burn injury. Burns

2005;31(5):568e77.

[446] Moritz AR, Henriques FC. Studies of Thermal Injury: II. The Relative Importance

of Time and Surface Temperature in the Causation of Cutaneous Burns.

Am J Pathol 1947;23(5):695e720.

[447] Plaghki L, Decruynaere C, Van Dooren P, Le Bars D. The fine tuning of pain

thresholds: a sophisticated double alarm system. PLoS One 2010;5:e10269.

[448] Blackie CA, McMonnies CW, Korb DR. Warm compresses and the risks of

elevated corneal temperature with massage. Cornea 2013;32(7):e146e9.

[449] Solomon JD, Case CL, Greiner JV, Blackie CA, Herman JP, Korb DR. Warm

compress induced visual degradation and Fischer-Schweitzer polygonal reflex.

Optom Vis Sci 2007;84(7):580e7.

[450] McMonnies CW, Korb DR, Blackie CA. The role of heat in rubbing and massage-

related corneal deformation. Cont Lens Anter Eye 2012;35(4):148e54.

[451] Man Lam S, Tong L, Duan X, Acharya UR, Tan JH, Petznick A, , et alWenk MR,

Shui G. J Lipid Res 2014;55(9):1959e69.

[452] Pearce EI, Archer CV, McWilliams MA, Tomlinson A, Fuller JR. Effects of novel

eye warming goggles on the tear film. Invest Ophthalmol Vis Sci 2006;47:

5601.

[453] Pult H, Riede-Pult BH, Purslow C. A comparison of an eyelid-warming device

to traditional compress therapy. Optom Vis Sci 2012;89(7):E1035e41.

[454] Doan S, Chiambaretta F, Baudouin C, ESPOIR study group. Evaluation of an

eyelid warming device (Blephasteam) for the management of ocular surface

diseases in France: the ESPOIR study. J Fr Ophtalmol 2014;37(10):763e72.

[455] Wang MT, Gokul A, Craig JP. Temperature profiles of patient-applied eyelid

warming therapies. Cont Lens Anter Eye 2015;38(6):430e4.

[456] Bilkhu PS, Naroo SA, Wolffsohn JS. Randomised masked clinical trial of the

MGDRx EyeBag for the treatment of meibomian gland dysfunction-related

evaporative dry eye. Br J Ophthalmol 2014;98(12):1707e11.

[457] Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of Self-applied Heat

Therapy for Meibomian Gland Dysfunction. Optom Vis Sci 2015;92(9):

e321e6.

[458] Goto E, Monden Y, Takano Y, Mori A, Shimmura S, Shimazaki J, et al.

Treatment of non-inflamed obstructive meibomian gland dysfunction by an

infrared warm compression device. Br J Ophthalmol 2002;86(12):1403e7

[459] Lane SS, DuBiner HB, Epstein RJ, Ernest PH, Greiner JV, Hardten DR, et al. A

new system, the LipiFlow, for the treatment of meibomian gland dysfunction.

Cornea 2012;31(4):396e404.

[460] Hom MM, Silverman MW. Displacement technique and meibomian gland

expression. J Am Optom Assoc 1987;58(3):223e6.

[461] Korb DR, Greiner JV. Increase in tear film lipid layer thickness following

treatment of meibomian gland dysfunction. Adv Exp Med Biol 1994;350:

293e8.

[462] McCulley JP, Sciallis GF. Meibomian keratoconjunctivitis. Am J Ophthalmol

1977;84(6):788e93.

[463] Korb DR, Henriquez AS. Meibomian gland dysfunction and contact lens

intolerance. J Am Optom Assoc 1980;51(3):243e51.

[464] Korb DR, Blackie CA. Meibomian gland therapeutic expression: quantifying

the applied pressure and the limitation of resulting pain. Eye Contact Lens

2011;37(5):298e301.

[465] Blackie CA, Carlson AN, Korb DR. Treatment for meibomian gland dysfunction

and dry eye symptoms with a single-dose vectored thermal pulsation: a

review. Curr Opin Ophthalmol 2015;26(4):306e13.

[466] Finis D, K€onig C, Hayajneh J, Borrelli M, Schrader S, Geerling G. Six-month

effects of a thermodynamic treatment for MGD and implications of meibomian

gland atrophy. Cornea 2014;33(12):1265e70.

[467] Blackie CA, Coleman CA, Holland EJ. The sustained effect (12 months) of a

single-dose vectored thermal pulsation procedure for meibomian gland

dysfunction and evaporative dry eye. Clin Ophthalmol 2016;10:1385e96.

[468] Greiner JV. Long-Term (3 Year) Effects of a Single Thermal Pulsation System

Treatment on Meibomian Gland Function and Dry Eye Symptoms. Eye

Contact Lens 2016;42(2):99e107.

[469] Goldberg DJ. Current trends in intense pulsed light. J Clin Aesthet Dermatol

2012;5(6):45e53.

[470] Craig JP, Chen YH, Turnbull PR. Prospective trial of intense pulsed light for

the treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci

2015;56(3):1965e70.

[471] Vegunta S, Patel D, Shen JF. Combination Therapy of Intense Pulsed Light

Therapy and Meibomian Gland Expression (IPL/MGX) Can Improve Dry Eye

Symptoms and Meibomian Gland Function in Patients With Refractory Dry

Eye: A Retrospective Analysis. Cornea 2016;35(3):318e22.

[472] Gupta PK, Vora GK, Matossian C, Kim M, Stinnett S. Outcomes of intense

pulsed light therapy for treatment of evaporative dry eye disease. Can J

Ophthalmol 2016;51(4):249e53.

[473] Maskin SL. Intraductal meibomian gland probing relieves symptoms of

obstructive meibomian gland dysfunction. Cornea 2010;29(10):1145e52.

[474] Fermon S, Hindi Zaga I, Alvarez Melloni D. Intraductal meibomian gland

probing for the treatment of blepharitis. Arch Soc Esp Oftalmol 2015;90(2):

76e80.

[475] Nakayama N, Kawashima M, Kaido M, Arita R, Tsubota K. Analysis of Meibum

Before and After Intraductal Meibomian Gland Probing in Eyes With

Obstructive Meibomian Gland Dysfunction. Cornea 2015;34(10):1206e8.

[476] Wladis EJ. Intraductal meibomian gland probing in the management of

ocular rosacea. Ophthal Plast Reconstr Surg 2012 Nov-Dec;28(6):416e8.

[477] Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop

on meibomian gland dysfunction: report of the subcommittee on anatomy,

physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol

Vis Sci 2011;52(4):1938e78.

[478] Korb DR, Blackie CA. Debridement-scaling: a new procedure that increases

Meibomian gland function and reduces dry eye symptoms. Cornea

2013;32(12):1554e7.

[479] Ngo W, Caffery B, Srinivasan S, Jones LW. Effect of Lid Debridement-Scaling

in Sj€ogren Syndrome Dry Eye. Optom Vis Sci 2015;92(9):e316e20.

[480] McMonnies CW. Incomplete blinking: exposure keratopathy, lid wiper epitheliopathy,

dry eye, refractive surgery, and dry contact lenses. Cont Lens

Anter Eye 2007;30(1):37e51.

[481] Pereira MV, Gl_oria AL. Semin Ophthalmol 2010;25(3):72e8.

[482] Zeev MS, Miller DD, Latkany R. Diagnosis of dry eye disease and emerging

technologies. Clin Ophthalmol 2014;8:581e90.

[483] Bron AJ, de Paiva CS, Chauhan S, Bonini S, Gabison EE, Jain S, et al. TFOS

DEWS II Pathophysiology Report. Ocul Surf 2017;15. XX-XX.

[484] Katz J, Kaufman HE. Corneal exposure during sleep (nocturnal lagophthalmos).

Arch Ophthalmol 1977;95(3):449e53.

[485] Sohrab M, Abugo U, Grant M, Merbs S. Management of the eye in facial

paralysis. Facial Plast Surg 2015;31(2):140e4.

[486] V_asquez LM, Medel R. Lagophthalmos after facial palsy: current therapeutic

options. Ophthalmic Res 2014;52(4):165e9.

[487] Latkany RL, Lock B, Speaker M. Nocturnal lagophthalmos: an overview and

classification. Ocul Surf 2006;4(1):44e53.

[488] So HM, Lee CC, Leung AK, Lim JM, Chan CS, Yan WW. Comparing the effectiveness

of polyethylene covers (Gladwrap) with lanolin (Duratears) eye

ointment to prevent corneal abrasions in critically ill patients: a randomized

controlled study. Int J Nurs Stud 2008;45(11):1565e71.

[489] Koroloff N, Boots R, Lipman J, Thomas P, Rickard C, Coyer F. A randomised

controlled study of the efficacy of hypromellose and Lacri-Lube combination

versus polyethylene/Cling wrap to prevent corneal epithelial breakdown in

the semiconscious intensive care patient. Intensive Care Med 2004;30(6):

1122e6.

[490] Kartush JM, Linstrom CJ, McCann PM, Graham MD. Early gold weight eyelid

implantation for facial paralysis. Otolaryngol Head Neck Surg 1990;103(6):

1016e23.

[491] Linder T, Linstrom C, Robert Y. Rehabilitation of the eye in patients with

facial paralyses: indications and results of gold weight implantation. Klin

Monbl Augenheilkd 1997;210:293e5.

[492] Lucena A, Akaishi PM, Rodrigues Mde L, Cruz AA. Upper eyelid entropion and

dry eye in cicatricial trachoma without trichiasis. Arq Bras Oftalmol 2012

Nov-Dec;75(6):420e2.

[493] Geerling G, Borrelli M. Adnexal surgery for severe ocular surface disease.

Semin Ophthalmol 2005 Apr-Jun;20(2):101e12.

[494] Hintschich C. Correction of entropion and ectropion. Dev Ophthalmol

2008;41:85e102.

[495] Ross AH, Cannon PS, Selva D, Malhotra R. Management of upper eyelid

cicatricial entropion. Clin Exp Ophthalmol 2011;39(6):526e36.

[496] Al-Amry MA. Ocular manifestation of Ichthyosis. Saudi J Ophthalmol 2016

Jan-Mar;30(1):39e43.

[497] Damasceno RW, Avgitidou G, Belfort Jr R, Dantas PE, Holbach LM, Heindl LM.

Eyelid aging: pathophysiology and clinical management. Arq Bras Oftalmol

2015 Sep-Oct;78(5):328e31.

[498] Monga P, Gupta VP, Dhaliwal U. Clinical evaluation of changes in cornea and

tear film after surgery for trachomatous upper lid entropion. Eye (Lond)

2008;22(7):912e7.

[499] Cosar CB, Cohen EJ, Rapuano CJ, Maus M, Penne RP, Flanagan JC, et al. Tarsorrhaphy:

clinical experience from a cornea practice. Cornea 2001;20(8):

787e91.

[500] Papas EB, Ciolino JB, Jacobs D, Miller WL, Miller WS, Pult H, et al. The TFOS

International Workshop on Contact Lens Discomfort: report of the management

and therapy subcommittee. Invest Ophthalmol Vis Sci 2013;54(11):

TFOS183e203.

[501] Koh Shizuka, Maeda Naoyuki, Soma Takeshi, Hori Yuichi,

Tsujikawa Motokazu, Watanabe Hitoshi, et al. Development of Methicillin-

Resistant Staphylococcus aureus Keratitis in a Dry Eye Patient With a

Therapeutic Contact Lens. Eye Contact Lens Sci Clin Pract 2012;38(3):200e2.

[502] Henry CR, Flynn Jr HW, Miller D, Forster RK, Alfonso EC. Infectious keratitis

progressing to endophthalmitis: a 15-year study of microbiology, associated

factors, and clinical outcomes. Ophthalmology 2012;119(12):2443e9.

[503] Stapleton F, Keay L, Edwards K, Naduvilath T, Dart JK, Brian G, et al. The

incidence of contact lens-related microbial keratitis in Australia. Ophthalmology

2008;115(10):1655e62.

[504] Dart JK, Radford CF, Minassian D, Verma S, Stapleton F. Ophthalmology

2008;115(10):1647e54. 1654e1-3.

[505] Schein OD, Glynn RJ, Poggio EC, Seddon JM, Kenyon KR. The relative risk of

ulcerative keratitis among users of daily-wear and extended-wear soft

contact lenses. A case-control study. Microbial Keratitis Study Group. N Engl

J Med 1989;321(12):773e8.

[506] Stapleton F, Dart JK, Minassian D. Risk factors with contact lens related

suppurative keratitis. CLAO J 1993;19(4):204e10.

[507] Foulks GN, Harvey T, Raj CV. Therapeutic contact lenses: the role of high-Dk

lenses. Ophthalmol Clin North Am 2003;16(3):455e61.

[508] Ahad MA, Anandan M, Tah V, Dhingra S, Leyland M. Randomized Controlled

Study of Ocular Lubrication Versus Bandage Contact Lens in the Primary

Treatment of Recurrent Corneal Erosion Syndrome. Cornea 2013;32(10):

1311e4.

[509] Wipperman JL, Dorsch JN. Evaluation and management of corneal abrasions.

Am Fam Physician 2013;87(2):114e20.

[510] Siu GD, Young AL, Jhanji V. Alternatives to corneal transplantation for the

management of bullous keratopathy. Curr Opin Ophthalmol 2014;25(4):

347e52.

[511] Grentzelos MA, Plainis S, Astyrakakis NI, Diakonis VF, Kymionis GD,

Kallinikos P, et al. Efficacy of 2 types of silicone hydrogel bandage contact

lenses after photorefractive keratectomy. J Cataract Refract Surg

2009;35(12):2103e8.

[512] Chen D, Lian Y, Li J, Ma Y, Shen M, Lu F. Monitor corneal epithelial healing

under bandage contact lens using ultrahigh-resolution optical coherence

tomography after pterygium surgery. Eye Contact Lens 2014;40(3):175e80.

[513] Daglioglu MC, Coskun M, Ilhan N, Tuzcu EA, Ilhan O, Keskin U, et al. The

effects of soft contact lens use on cornea and patient’s recovery after autograft

pterygium surgery. Cont Lens Anter Eye 2014;37(3):175e7.

[514] Mohammadpour M, Amouzegar A, Hashemi H, Jabbarvand M, Kordbacheh H,

Rahimi F, et al. Comparison of Lotrafilcon B and Balafilcon A silicone hydrogel

bandage contact lenses in reducing pain and discomfort after photorefractive

keratectomy: A contralateral eye study. Cont Lens Anter Eye 2015;38(3):

211e4.

[515] Russo PA, Bouchard CS, Galasso JM. Extended-wear silicone hydrogel soft

contact lenses in the management of moderate to severe dry eye signs and

symptoms secondary to graft-versus-host disease. Eye Contact Lens

2007;33(3):144e7.

[516] Goyal S, Hamrah P. Understanding Neuropathic Corneal PaineGaps and

Current Therapeutic Approaches. Semin Ophthalmol 2016;31:59e70.

[517] Galor A, Levitt RC, Felix ER, Martin ER, Sarantopoulos CD. Neuropathic ocular

pain: an important yet underevaluated feature of dry eye. Eye (Lond)

2015;29(3):301e12.

[518] Smiddy WE, Hamburg TR, Kracher GP, Gottsch JD, Stark WJ. Therapeutic

contact lenses. Ophthalmology 1990;97(3):291e5.

[519] Lim L, Tan DT, Chan WK. Therapeutic use of Bausch & Lomb PureVision

contact lenses. CLAO J 2001;27(4):179e85

[520] Jacobs DS, Rosenthal P. Boston scleral lens prosthetic device for treatment of

severe dry eye in chronic graft-versus-host disease. Cornea 2007;26(10):

1195e9.

[521] Schornack MM, Baratz KH, Patel SV, Maguire LJ. Jupiter scleral lenses in the

management of chronic graft versus host disease. Eye Contact Lens

2008;34(6):302e5.

[522] Takahide K, Parker PM, Wu M, Hwang WY, Carpenter PA, Moravec C, et al.

Use of fluid-ventilated, gas-permeable scleral lens for management of severe

keratoconjunctivitis sicca secondary to chronic graft-versus-host disease.

Biol Blood Marrow Transpl 2007;13(9):1016e21.

[52

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