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The Dry Eye Battle: Part One

2T in Australia | 1G in New Zealand | 1 February 2019

Note: The printed version of The Dry Eye Battle Part 1 in mivision issue 142 contained incorrect references to figures. These errors have been corrected online.

 

By Mark Koszek

Dry eye disease is a chronic disease that worsens with age and is more prevalent in women. It has been shown that the impact of severe dry eye disease on quality of life is similar to the impact of moderate to severe angina.1,2 Yet this debilitating disease is often not taken seriously enough.
In the first part of a two part article, optometrist Mark Koszek explores the tests used to diagnose dry eye disease and quantify its severity. He also describes the role of medications in its treatment. 

 LEARNING OBJECTIVES

  1. Understand common tests used in dry eye diagnosis
  2. Be able to quantify the severity of dry eye
  3. Understand the role of inflammation and osmolarity in the pathophysiology of dry eye
  4. Appreciate the role of anti-inflammatory medications in the treatment of dry eye
  5. Understand the role of topical and oral medications in the treatment of meibomian gland dysfunction
  6. Appreciate the various treatment levels.

 

It’s often forgotten by many people that Neville Chamberlain was the British prime minister at the start of World War II. In 1939, when the Germans moved into what was then known as Czechoslovakia, he prepared Britain for war. It was Chamberlain who spoke on the radio, informing the British people that war had begun. He became famous for the quote “In war, whichever side may call itself the victor, there are no winners, but all are losers”.

Eight months into the war, Chamberlain resigned and was replaced by Sir Winston Churchill.

Dry eye also feels like a war where there are no winners, only a lot of misery. To manage this chronic disease, we need to bunker down for a long protracted battle and be prepared to attack on many fronts. In our armoury we have lubricants, steroids, immune-suppressants, antibiotics, drops made out of our own blood, honey, vitamins, punctal plugs, and contact lenses, to name a few. Hopefully, after reading this article you’ll have some idea of how to wage war on dry eye.

Know Your Enemy

The first rule of war is to know your enemy. Dry eye is both an ageist and sexist condition, since it worsens with age and is more prevalent in women. The 2013 National Health and Wellness Survey found that of the 75,000 participants, 18.6 per cent of people aged 75 or over demonstrated dry eye disease (DED) compared to 2.7 per cent of people aged 18–34.3 In the same study, women were approximately twice as likely to suffer with DED (8.8 per cent of women compared to 4.5 per cent of men). LASIK, contact lenses, and systemic medications such as anti-depressants can all cause dry eye as can many systemic and autoimmune diseases such as rosacea, Sjögrens syndrome, rheumatoid arthritis, and lupus. Dry eye is a stealthy disease. It is often more severe than we give it credit for and patients may suffer with dryness without showing overt signs, which brings me to my second rule of dry eye – your patients’ dryness is generally going to be worse than you think.

How do we make sure we’re not under-estimating our patients’ level of dry eye disease? The answer is to use a dry eye questionnaire. I use the Ocular Surface Disease Index (OSDI) questionnaire. The 12 questions of the OSDI are graded on a scale of zero to four, where zero indicates none of the time; one indicates some of the time; two – half of the time;  three – most of the time; and four – all of the time. The OSDI is scored on a scale of zero to 100, with higher scores representing greater disability. If you don’t have time to perform a questionnaire, simply ask the patient to grade their dryness on a scale of zero to 10.

By way of illustrating the points made in this article, we will refer to Kelly, a 37 year old female, who entered my practice complaining of dry, burning eyes. Kelly had suffered with dry eye for some time, which she generally self-medicated with lubricants. The only noteworthy aspect of her history was she had been taking anti-depressants for post-natal depression for five years.

The next challenge with dry eye is to determine the type of dry eye we’re dealing with and to ascertain if there are any underlying factors. We know dry eye can be sub-divided into aqueous deficient dry eye (ADDE) and evaporative dry eye (EDE) due to meibomian gland dysfunction. What a lot of practitioners may not realise is that the two conditions are interrelated – a patient may start out with EDE but subsequently develop ADDE and vice versa. A 2017 study4 on a Norwegian cohort of patients with primary Sjögrens syndrome found these patients also had a higher degree of meibomian gland loss and a higher degree of lid abnormality. The DEWS2 group proposed that ADDE and EDE exist as a continuum5 – you may start out with one type of dry eye but end up with both.

Is there a difference between dry eye and dry eye disease (DED) and how do we determine the difference? It’s quite normal for many of us over the course of our lives to intermittently experience dry eye symptoms, yet for patients with DED the symptoms tend to be more debilitating and chronic. The recent DEWS2 report suggests that in order for a patient to be classified as having DED they need to demonstrate one of the following:

  • OSDI score ≥13
  • Tear film break up time (TFBUT) <10 seconds
  • Osmolarity ≥ 308 mOsm/L
  • > five corneal staining spots/dots
  • > nine conjunctival staining spots/dots
  • Staining of the lid margin ≥ in 2mm length and ≥ 25 per cent of the lid margin width.

The list of tests above is an excellent starting point for your dry eye battery.

Staining allows us to detect devitalised cells on the ocular surface. Fluorescein is used to check for corneal staining and lissamine for conjunctival staining. Fluorescein stains damaged tissue or tissue in which cell to cell junctions are compromised whereas lissamine stains tissue that has lost its protective mucin coating such as devitalised goblet cells on the conjunctiva. If time is at a premium you can mix the two dyes together rather than applying each separately. Conjunctival staining is one of the most under used dry eye tests. The conjunctiva provides a lot of information about the health of the ocular surface. Significant conjunctival staining can indicate goblet cell dysfunction. Goblet cells have the important role of creating mucins, which improve the adhesion and spreadability of the tear film to the ocular surface. Conjunctival staining will often precede and be more severe than corneal staining.6 My patient Kelly demonstrated no signs of fluorescein corneal staining but moderate conjunctival lissamine staining and lid wiper epitheliopathy (Figure 1a and b).

Figure 1a

Figure 1b


Gary Foulks, one of the fathers of modern dry eye research, suggests that in aqueous deficient dry eye, nasal conjunctival staining will often be greater than temporal staining.7 Florid conjunctival staining can also be an indicator of an autoimmune disease, so we should start questioning the patient about other possible autoimmune symptoms such as dry mouth and joint pain. Sjögrens syndrome is an autoimmune disease that mainly affects the eyes and salivary glands, which are similar types of exocrine glands that are both stimulated by the facial nerve. The hallmark sign of Sjögrens syndrome is a dry mouth, making this an important question to ask all your dry eye patients. Mouth dryness can be so bad for some patients that they need to drink liquids to help them swallow food.

The next test in our battery is tear film break up time (TFBUT), which can be measured by observing fluorescein break up in vivo or non-invasively with a keratograph. TFBUT is a measure of tear volume and tear evaporation, and is the time required for dry spots to appear on the corneal surface after blinking. As the tear film evaporates the tear film thickness decreases, which is observed by a decrease in fluorescence intensity. Normal TFBUT is 14.39 seconds in males and 12.55 seconds in females, whereas the TFBUT of dry eye patients was found to be 5.39 seconds in males and 5.25 seconds in females.8

Kelly’s TFBUT was almost immediate, in the range of one to two seconds (Figure 2).

Figure 2


In dry eye diagnosis it’s absolutely imperative that we try to measure aqueous production, which allows us to determine the type of dry eye a patient has while also quantifying its severity. Tear meniscus height is an indirect measure of aqueous production, reflecting the amount of tears present where the bulbar conjunctiva and lower eyelid margin meet. A figure less than 0.2mm is indicative of aqueous deficiency according to DEWS2 (Figure 3).

Figure 3 (Click on image to see enlarged version)

 

Unfortunately, we don’t all have access to keratographs, so how else do we determine whether a patient has ADDE or EDE?

We could perform either a Schirmer or phenol red test. The phenol red test has the advantage of taking 15 seconds versus five minutes for the Schirmer and has been shown to be equally as sensitive in detecting dry eye.9 I perform the Schirmer and during the five minutes the test takes to perform, I perform the OSDI questionnaire. The point I’d like to stress here, is that if you don’t perform a test of aqueous function then you have little way of classifying the patient’s dry eye disease and you have no conclusive way of knowing whether the patient has aqueous deficiency or evaporative dry eye.

Kelly had a Schirmer score of RE 3mm,
L 2mm after five minutes.

I use the Colorbar Schirmer test, which has a blue dye impregnated in the 5mm line on the strip. The tears drip down the Schirmer strip and once they reach the 5mm line, the colour starts leaching down the paper so you can more easily record tear production.

Unfortunately Kelly’s tears didn’t make it to the 5mm line, so I had to determine her tear production by looking at how far the wetness of the paper had travelled (Figure 4).

Figure 4

 

A normal Schirmer is greater than 15mm after five minutes. Lemp and Sullivan10 classified aqueous deficiency as occurring when a patient has a Schirmer values less than 7mm. The Schirmer test is one of the criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification of Primary Sjögrens syndrome. If a patient has a Schirmer result less than 5mm after five minutes they are given one point towards their overall score. A diagnosis is made if a patient scores four or greater based on the guidelines (see the classification criteria in table 1).

Table 1

 

So, for Kelly there is a chance she may have Sjögrens syndrome or possibly another type of autoimmune condition. The alarming aspect of Kelly’s case is that she didn’t demonstrate any signs of corneal staining.

The point I’d like to make is, if fluorescein staining is the primary way in which you assess for dry eye, then you’re going to grossly under diagnose both the number of patients with dry eye and the severity of dry eye. I encourage all practitioners to perform a questionnaire, a test of aqueous function and to utilise lissamine staining of the conjunctiva and lid wiper. The lid wiper is the leading zone (one to 1.5mm) of the palpebral conjunctiva, being proximal from Marx’s line which represents the muco-cutaneous junction, i.e. the transition zone from skin to conjunctiva. Healthy lid wiper cells contain goblet cells that produce mucins that lubricate the ocular surface during a blink.11 Increased friction on the lid wiper region causes decreased production of mucins. Korb et al12 demonstrated that lid wiper epitheliopathy (LWE) was more likely to occur in symptomatic patients vs. un-symptomatic patients (88 per cent vs. 16 per cent). As a result, LWE may be the cause of dry eye symptoms in the absence of corneal signs since the lid wiper is thought to be the natural site of frictional contact between the eyelid margin and the surfaces of the bulbar conjunctiva and cornea.13

If aqueous deficiency is best determined by performing a tear function test, then evaporative dry eye is determined by assessing the meibomian glands and eyelid margin. The meibomian glands are delicate structures that produce a clear lipid which has the role in the tear film of preventing evaporation of the aqueous. Using a painting analogy, if the aqueous and mucin layers are the undercoat of the tear film then the lipid layer is the sealant. Meibomian gland dysfunction (MGD) is characterised by obstruction of the meibomian glands by solidified meibum and keratin.

I love the biochemistry of dry eye – let me try to explain what happens to meibum on a chemical level. Meibum is composed of a complex mixture of cholesterol and wax esters, triglycerides and fatty acids. Bacteria, such as staphylococcus aureus secrete lipases and esterases that break down the triglycerides, cholesterol and wax esters. In MGD unsaturated lipids that possess double bonds are converted into saturated lipids, which have no double bonds. The double bond in a molecule causes it to kink, and when we remove the double bond the molecule assumes a more linear shape, which allows molecules to compact closer together. In MGD, the conversion of unsaturated lipids to saturated lipids allows the molecules to be compacted closer together, which increases the melting point, causing the meibum to solidify, which we can see clinically as plugs of solidified meibum in the meibomian gland orifices. Blockage of the meibomian glands will not always be obvious – it’s important that practitioners try to express the glands to assess the quality of the meibum, which can be rated on its consistency and colour. Ideally, the meibum should be clear oil, yet in advanced MGD it will appear as an opaque paste.

One of the other by-products of the cleavage of triglycerides, cholesterol and wax esters are free fatty acids. These are extremely potent and irritating substances because they have a caustic carboxylic tail, which can have a direct toxic effect on the ocular surface causing staining. Free fatty acids also activate neutrophils, which heighten the inflammatory reaction. Inflammation is at the heart of dry eye disease, being responsible for what we call the vicious cycle.

Inflammation causes dysfunction of the meibomian glands and the lacrimal functional unit. This causes decreased aqueous and meibum production, which causes the release of further inflammatory mediators such as matrix metalloproteases and cytokines, causing further declines in aqueous and oil production. Once the dry eye train starts, it is hard to get off.

MGD, and ocular rosacea patients in particular, will demonstrate obvious inflammation of the lid margin. This is characterised by a chronic reddish hue and telangiectasia, which is the abnormal dilation of the small blood vessels on the eyelid margin. Rosacea is an inflammatory skin condition that affects the central face, with women being more affected than men.14 Symptoms include persistent erythema (redness) of the face due to repeated vasodilation, then telangiectasia and skin inflammation in the form of papules and pustules. It is believed that microbes that are part of the normal skin flora, including demodex mites and staphylococcus epidermidis, may be triggers of rosacea.15,16 The incidence of ocular involvement varies between 6 to 72 per cent.17,18

In MGD, inflammation and ductal obstruction causes degenerative gland dilation and atrophy, which can be observed as meibomian gland dropout upon which a notch appears on the lid margin. Hyperkeratinisation of the orifice epithelium19 is believed to be an important event in the atrophy of meibomian glands, meaning the glands become more skin like and are no longer capable of producing meibum. Free fatty acids, formed from the breakdown of normal meibum by bacteria on the eyelids, has been proposed as a cause of hyperkeratinisation.20,21 Meibography has become a valuable tool to demonstrate to patients the severity of their meibomian gland disease (Figure 5).

Figure 5

On examination, Kelly demonstrated significant lid margin redness and telangiectasia. On expression, her meibum was predominantly solid and had an opaque colour. Approximately half of her meibomian glands on the lower lid did not eject meibum on expression. Kelly also demonstrated signs of facial rosacea, characterised by redness of her cheeks and nose.

Kelly presented a complex challenge; she had severe aqueous deficiency, perhaps in part due to her anti-depressant medication, but she also demonstrated signs of ocular rosacea and MGD. I could see that Kelly’s dry eye was going to be a hard war to win, and a battle to be waged on two fronts.

Treatment

In treating dry eye, I believe we’re trying to do one of five things, with the end goal being to restore lacrimal, meibomian and goblet cell function:

  1. Replenish the aqueous,
  2. Stabilise the lipid layer,
  3. Improve meibum quality and output,
  4. Control microbial overgrowth, and
  5. Control ocular surface inflammation.

 

Replenish Aqueous

Lubricants continue to be the mainstay of dry eye treatment. A hundred years ago people used collyriums or lotions to wash out their eyes. Being composed of things like rosewater, they were sold by travelling salesmen as a salve for conditions of the eyes. It wasn’t until the 1980s that there was any significant advancement in topical lubricants. This next generation integrated natural polymers (e.g. methylcellulose derivatives) and synthetic polymers (e.g. polyethylene glycol, polyvinyl alcohol, and HP guar) into artificial tear formulations, which increased the viscosity of the drops and ocular retention times but could also blur patients’ vision. Ocular retention has long been the bugbear of lubricant companies – many products struggle to eke out retention times longer than 30 minutes.

Over the last decade a number of novel preparations have hit the dry eye market, one of the best being Hyloforte containing hyaluronic acid. Hyaluronic acid (HA) is a mucopolysaccharide occurring naturally in all living organisms including our synovial joints and vitreous. Its function in the body is to bind water and to lubricate movable body parts. Hyaluronic acid is one of the most hydrophilic (water-loving) molecules in the natural world, its viscoelastic nature and biocompatibility has led to its use in many clinical fields.22,23 Physiologically, Hyaluronic acid behaves like a salt and as such, is known as sodium hyaluronate. It’s quite an amazing molecule – it assumes a coil structure that is able to trap approximately 1,000 times its weight in water,24 making it quite viscous like jelly. When placed under pressure, it is elastic and moves easily, making it an ideal choice as a lubricant, since its shear dependent viscosity reduces blur. A 2014 study demonstrated that 0.3 per cent sodium hyaluronate (SH) had significantly longer retention times than both CMC and HPMC25 (Figure 6).

Figure 6

Mochizuki et al26 found that it took 57.6 minutes before 99 per cent of HA cleared from the pre-corneal tear film when conjugated with a fluorescein tracer. The prolonged residence time of HA may be due to its known ability to bind with fibronectin and CD44, a cell surface adhesion molecule on corneal epithelial cells.27

Stabilise the Lipid Layer

Hyaluronate helps tackle the moisture problem, but what about tear film evaporation and the aberrant lipid layer due to MGD? A relatively new product known as Novatears offers great promise. Novatears contains perfluorohexyloctane, a non-water based semi-fluorinated alkane which has strong spreading properties due to its low surface tension.28 Surface tension is the energy required to increase the surface area of a liquid. Water for example has a surface tension of 72mNm whereas perfluorohexyloctane has a surface tension of only 19.65mNm, meaning it more easily spreads across a surface. This is important in dry eye, as it effectively seals the tear film preventing evaporation. A simple exercise you can perform is to place a drop of perfluorohexyloctane on a mirror. Most drops will bead up with a high wetting angle; in contrast Novatears will spread across the mirror, appearing almost invisible. So, if we extend our paint analogy to topical lubricants, if Hyloforte is the undercoat, then Novatears is the sealant.

Tear film stability is greatly improved with Novatears. In my practice, I use the Medmont E300’s tear film analyser, which non-invasively examines changes in tear film stability by analysing the structure of the reflected placido disc image. The colours on the tear film maps represent TFBUT, not corneal curvature. Greater tear film instability is represented by warmer colours such as yellow and red. The software calculates the tear film surface quality (TFSQ) index. A TFSQ of 0.3 or greater corresponds to visible distortion in the placido ring pattern and from this the TFSQ area is calculated, which is the percentage of the tear film area with a TFSQ index greater than 0.3. Figure 7 and 8 were taken fifteen seconds after the patient was instructed not to blink. Figure 7 is before the installation of Novatears, while Figure 8 is post installation. The difference between the plots is quite remarkable. Before installation and 15 seconds after the blink, 55 per cent of the patient’s cornea demonstrated significant tear film evaporation. In contrast, only 10 per cent of the cornea had significant tear film break up post-Novatears. Again, Figure 8 is 15 seconds after the blink.

Figure 7

Figure 8

 

Perfluorohexyloctane has proven so effective at increasing tear film stability and corneal residence time that it has been proposed as a potential drug vehicle delivery system. A 2018 study29 by Agarwal et al demonstrated that semi-fluorinated alkanes such as perfluorohexyloctane were able to increase corneal residence time and corneal penetration of poorly soluble drugs such as cyclosporine (Restasis). The study demonstrated an eight fold increase in corneal penetration and a two to 11 fold increase in the pre-corneal residence time of cyclosporine when used with a semifluorinated alkane compared to cyclosporine alone.

Improve Meibum Quality and Output

The question arises, is Novatears simply like other lipid layer stabilisers, like anionic phospholipids? The answer is no. Perfluorohexyloctane has a known ability to dissolve lipids,30,31 meaning it may be able to dissolve plugs of solidified meibum in meibomian gland orifices, which has the potential to improve meibomian gland expressibility. Does the evidence support the claim? A 2017 study by Steven et al32 analysed 72 patients with MGD and associated dry eye. Clinical assessment included TFBUT, anterior and posterior blepharitis assessment, number of expressible meibomian glands, meibum quality and quantity, ocular surface fluorescein staining, lid margin, and symptom assessment using the OSDI. Patients received one drop of perfluorohexyloctane four times daily over a six to eight week period. At the completion of the study, TFBUT, corneal and conjunctival fluorescein staining, number of expressible meibomian glands, and severity of anterior and posterior blepharitis significantly improved. In addition, symptoms improved as demonstrated by a significant decrease in OSDI values.

Hot compresses and lid massage have also been a mainstay of dry eye treatment. The melting point of meibomian lipids is between 28 and 32°C. In patients with MGD, the melting point rises to 35°C.33 Applying heat to the lid margins softens the solidified meibum, much like melting candle wax, while massage helps express the blocked secretions and restore normal meibum flow. There are a number of ways to apply heat to the eyelids, from wheat packs and bead masks to heating devices such as Blephasteam and Lipiflow. Olson et al34 reported that five minutes of treatment with warm towel compresses (40?C) applied to the skin of closed eyelids increased lipid layer thickness (LLT) by more than 80 per cent in patients with obstructive MGD, whilst Paugh et al2 reported that lid scrubs and massage increased TFBUT. As mentioned previously, the meibomian glands can also become obstructed by keratinised cells. Lid margin debridement with a golf club spud or micro-exfoliation of the lid margin with a device such as the Blephex can help remove the keratinised material occluding the orifices.

In the second part of this CPD article on dry eye, we will continue to discuss the case of our patient Kelly. In the process, we will explore microbial overgrowth, ocular surface inflammation and other forms of dry eye disease treatment.

   

Mark Koszek B.Optom, M.Optom, Grad Cert Oc.Ther graduated from the University of New South Wales in 1996, completed his Master of Optometry in 2002 and his Graduate Certificate of Ocular Therapeutics in 2012. Mark is a founding partner and the Professional Education Officer of EyeQ Optometrists who have 25 practices Australia wide. Mark is a former councillor for the Optometry Association of Australia (NSW division) and is on the board of the Cornea and Contact Lens Society of New South Wales. Mark was a fourth year clinic supervisor between 2002 and 2015. Mark has lectured extensively throughout Australia, New Zealand and Asia on contact lenses, dry eye and ocular diseases. Mark has a special interest in contact lenses, orthokeratology, dry eye, ocular diseases and behavioural optometry.


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' “Dry eye is both an ageist and sexist condition, since it worsens with age and is more prevalent in women” '