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The Dry Eye Battle: Part Two

2T CPD in Australia | 1CD in New Zealand | 1 April 2019

By Mark Koszek       

In the final part of a two part article, optometrist Mark Koszek describes the escalating case of a patient referred to as Kelly. He explores the challenges that can arise when managing severe dry eye disease, and strategies for treatment including steroids, supplements, intense pulsed light, and platelet rich growth factors. The first part of this article was published in mivision issue 142, February 2019.

LEARNING OBJECTIVES

  1. Understand the role of inflammation and osmolarity in the pathophysiology of dry eye,
  2. Appreciate the role of anti-inflammatory medications in
  3. the treatment of dry eye,
  4. Understand the role of topical and oral medications in the treatment of meibomian gland dysfunction, and
  5. Appreciate the various treatment levels.

 

Controlling Microbial Overgrowth

Patients with meibomian gland dysfunction (MGD) commonly have bacterial overgrowth on their eyelids. In anterior blepharitis, the bacterial overgrowth causes inflammation at the base of the lashes. In posterior blepharitis, bacterial overgrowth causes an inflammatory process centred around the meibomian glands. Albietz and Lenton1 demonstrated changes in the microbial populations in patients with MGD compared to normal eyes, specifically an increase in the populations of staphylococcus aureus, coagulase negative staphylococci, and cornyebacterium.

Manuka honey is my most prescribed topical treatment for MGD. Honey has been used for thousands of years to treat infections, and Manuka honey in particular, has a number of mechanisms of activity. The antibacterial effects of Manuka come from its Methylglyoxal (MGO)2,3 concentration from the nectar of the Manuka bush flower (leptospermum scoparium). The concentration of MGO in Manuka honey is up to 100-fold higher than in other honeys. Manuka and MGO can have different effects on different bacteria, for example with staphylococcus aureus it disrupts bacterial cell division by inhibiting murein hydrolase,4 whereas with pseudomonas aeruginosa it inhibits flagellum production, which decreases the motility of the bacteria.5 Albietz and Lenton’s aforementioned study demonstrated significant decreases in the populations of bacteria on the lids and conjunctiva, with patients using honey for three months. Apart from its effect on the ocular microflora, the phenolic content of Manuka honey also affords it anti-inflammatory effects. Phenols are a class of compound known to inhibit the production of the inflammatory cytokine TNF-α.6

A 2017 study by Albietz and Schmid,7 using both Manuka honey drops and gel, demonstrated improvements in tear film break up time (TFBUT), staining, tear osmolarity, meibum quality and bulbar, limbal and lid margin redness. Staphylococcus epidermidis and overall bacterial colony units also decreased with the use of Manuka honey.

I prescribed Kelly Optimel Manuka honey gel bid.

Inflammation Control

Osmolarity is the canary in the coal mine for dry eye. Osmolarity is simply a measure of solid particles in a solution; hyperosmolarity therefore means an increased number of particles in the solution. In regards to tears, hyperosmolarity refers to less water and more salt than typical tears. The tears become saltier due to evaporation of water from the tear film.

Osmolarity increases when tear film thinning and break up occurs.8 Exposure of corneal epithelial cells to hyperosmolarity causes an increase of cytokines (e.g. IL-6, IL-8) into the tears. Cytokines recruit immune cells into the cornea and conjunctiva, stimulate the nerve endings that mediate pain and itching, and promote innate immune defences such as vasodilation of blood vessels. Osmolarity has been found to have 75% sensitivity in diagnosing mild/moderate disease and 95% sensitivity in severe disease.8 Mean tear film osmolarity values in normal participants range from 270 to 315 mOsm/L,9,10 with an overall average of 300 mOsm/L.11 Osmolarity values above 308 mOsm/L12 are indicative of dry eye disease, which can be measured with devices such as the TearLab and the I-Pen.

Kelly’s osmolarity readings were in the normal range, RE 290 LE 284 mOsm/L.

How do we treat ocular surface inflammation?

Hypo-osmolar drops can decrease the osmolarity of the tear film, which will hopefully prevent the upregulation of cytokines.

Table 1

Table 1 lists the osmolarity of some of the commonly prescribed lubricants in Australia.13

For our patient Kelly, topical steroids and cyclosporine were both potential options.

Topical corticosteroids suppress the inflammatory response associated with dry eye and have been shown to reduce ocular surface staining and dry eye symptoms,14,15,16 as well as improving TFBUT and tear secretion.17 I’m always impressed by studies that show an improvement in lacrimal function, it’s a sign that the battle has turned. A long term study by Jung et al18 followed two groups of 133 Sjögrens patients for up to two years. The patients used either loteprednol etabonate 0.5% (Group A) or fluorometholone 0.1% (Group B). The drops were instilled twice per day and patients were followed bimonthly. Additionally, patients were given 0.1% sodium hyaluronate. The Schirmer score in Group A was 4.38±1.04mm at baseline and 5.90±1.08mm at 24 months. The Schirmer score in Group B was 4.36±1.50mm at baseline and 5.48±1.30mm at 24 months (Figure 1).

Figure 1

As Figure 1 indicates, the Schirmer scores gradually increased at each review period in both groups. The study highlights the importance of prolonged steroid intervention with severe aqueous deficient dry eye.

What about the risk of increasing intraocular pressure (IOP)? 

Fluorometholone (FML) 0.1% is equivalent to FML. Of the 67 patients in Group B, only nine (13.4% of participants) had an IOP elevation greater than 2mmHg. Of the 66 loteprednol patients in Group A, only four (6.1%) had an IOP increase greater than 2mmHg. Loteprednol patients had lower mean IOPs than the FML patients (15mmHg vs. 16.5mmHg). Loteprednol is what we call a soft steroid, since it has minimal effect on IOP, although it is nearly as potent as prednisolone. In the last column of Table 2, the relative in vitro potency of loteprednol is 550 vs. 600 for prednisolone. Loteprednol is structurally similar to prednisolone, but rapidly undergoes hydrolysis in the anterior chamber to become an inactive derivative.19 Therefore it has less impact on IOP.

Table 2. Anti-inflammatory Potency of Topical Ophthalmic Solutions
Sources: Sendrowski DP et al. Anti-inflammatory drugs. In Bartlett JD, Jeanurs SO. Eds. Clinical Ocular Pharmacology, 5th ed. St Louis: Butterworth-Heinemann, 2008:222-244: Samudre SS et al. J Ocul Pharmacol Ther. 2004:20(6):533-547. 
Abbreviations: GCR, glucocorticoid receptor: NA, information not available.


The study described in Figure 2 reiterates the need to use steroids chronically for moderate to severe dry eye patients. Thankfully, soft steroids are quite safe to be used long term, but regular monitoring is imperative. Loteprednol has recently been added to optometrists’ schedule of medicines.

Figure 2

 

Cyclosporine is an immune suppressant that reduces T-cell activity. Chronic inflammation associated with autoimmune conditions such as Sjögrens syndrome is characterised by the presence of lymphocytes, which consist of T cells (CD4+ and CD8+) and B cells,20,21 infiltrating the lacrimal gland, releasing pro-inflammatory cytokines, and tumour necrosis factor. These mediators decrease the activity of the lacrimal gland, eventually leading to cellular destruction. Cyclosporine has been shown in some aqueous deficient dry eye (ADDE) patients to increase tear production and tear meniscus heights.22,33,24

I referred Kelly to an ophthalmology clinic that specialises in dry eye. She was subsequently prescribed non-preserved cyclosporine 0.05% bid.

Omega 3 fish oils and flaxseed oil also help reduce the inflammatory signs of dry eye. Omega 3s are found naturally in foods such as oily fish, nuts, and seeds yet unfortunately many people are deficient in omega 3 since the typical diet now often consists of foods high in omega 6s such as breads, cereals, and vegetable oils. Omega 6 fatty acids can be precursors to pro-inflammatory mediators whereas omega 3 fatty acids inhibit the production of pro-inflammatory mediators. The ideal ratio of omega 6 to omega 3 in our diet should be four to one, but in today’s western diet is more like 18 to one.25 Omega 3 supplements have been shown to increase tear production and tear volume26 and decrease apoptosis of the secretory epithelial cells in the lacrimal gland.27

It has long been known that vitamin A has an important role in dry eye since vitamin A deficiency causes severe dry eye (Xerophthalmia). Vitamin A contains retinol palmitate, which regulates the proliferation and differentiation of corneal epithelial cells and preserves conjunctival goblet cells.28 Sources of vitamin A can be found in foods such as dairy products, including milk, butter, and egg yolks. Vit A Pos is a sterile preservative free ointment containing retinol palmitate equivalent to 250IU/g of vitamin A. Studies have shown improvements in dry eye symptoms, visual acuity, corneal staining scores, Schirmer test,29 TFBUT, and goblet cell density after the use of topical vitamin A ointment.30

I prescribed Kelly Lacritec omega 3 supplements.

What about systemic treatments for MGD and ocular rosacea? The oral antibiotics, doxycycline and azithromycin, can be effective treatments for rosacea. Doxycycline is an antibiotic from the tetracycline family that has both anti-bacterial and anti-inflammatory activity. It is believed that the clinical effectiveness of doxycycline is likely due to its anti-inflammatory properties rather than its anti-microbial effect.31 Doxycycline has been shown to improve TFBUT, Schirmer test results and the number of symptoms reported.32 Doxycycline is the safest drug in the tetracycline family as it is excreted primarily into the faeces in an inactive form rather than via the kidneys. It should still be used with caution since it can cause nausea, constipation, diarrhoea, permanent tooth discolouration, and skin photosensitivity, although to a lesser extent than tetracycline. Azithromycin is a macrolide antibiotic from the same class as erythromycin. Like the tetracyclines, it has antibacterial and anti-inflammatory effects. Azithromycin is lipid soluble, with its tissue concentration being over 50 times higher than its plasma concentration,33 which improves its efficacy in the ocular tissues. It also has an extremely long half-life, allowing it to work for several days, possibly even weeks after cessation of treatment. Doxycycline and azithromycin are taken in oral form and are excreted predominantly in the faeces,34 which makes them both useful treatments for patients with irritable bowel symptoms.

What is the link between rosacea and irritable bowel syndrome? Many people do not realise that there are 100 trillion bacteria present in the human gastrointestinal tract and 1,000 different species colonising the intestines.35,36 The gut microbiome has an important function in the immune system. Dysbiosis or bacterial overgrowth of the gastrointestinal (GI) tract has been implicated in rosacea, which has also been shown to be significantly correlated with irritable bowel syndrome including Crohn’s disease and ulcerative colitis.37 The question then becomes, by restoring homeostasis to the GI tract, are we able to arrest the signs of rosacea?

Firstly, what do we mean by homeostasis? Of the 1,000 species of bacteria in our intestines, some will be helpful to the host while others are harmful. The goal of any treatment would be to increase the helpful bacteria while reducing the population of harmful bacteria. As mentioned previously, oral antibiotics such as doxycycline and azithromycin are a possible treatment for rosacea. But what do these agents do to the bacterial flora? Do they nuke both good and bad bacteria – and what about antibiotic resistance? Assessments of a wide variety of systemic antibiotics such as amoxicillin, amoxicillin/clavulanate, ciprofloxacin, and clindamycin showed a definite tendency toward rapid and marked changes in GI flora within days, with a return to baseline state within a few months.38 Unfortunately this return to baseline can often be partial or incomplete. The second problem is the development of antibiotic resistant bacteria. Oral azithromycin for example, has been shown to markedly increase the proportion of macrolide-resistant streptococci as compared to placebo.39 A study investigating the resistance to doxycycline found that after antibiotic treatment for up to 14 days, the number of Escherichia coli (E.coli) isolates resistant to doxycycline increased from 28% to 58%.40 Sub-antimicrobial doses of doxycycline have been used to treat rosacea, which involves prescribing the patient 20mg, twice daily. The aim of such treatment is to give the patient the anti-inflammatory benefits of the drug without affecting the microbial flora.

Kelly was subsequently prescribed oral doxycycline by the ophthalmology clinic, 50mg, twice per day.

So, are there any softer approaches to rosacea? Probiotics are supplements that contain live bacterial cultures such as lactobacillus and/or bifidobacterium. Probiotics have been shown to improve the barrier function of the colonic mucosa.41 A 2016 study,42 using oral supplements containing Escherichia coli Nissle (EcN) on patients with acne, rosacea, and seborrheic dermatitis found that 89% of patients improved or recovered completely. Most strains of E.coli are non-pathogenic yet some can be associated with food poisoning. In 1917, Alfred Nissle discovered that the gram-negative strain EcN prevented the growth of salmonella in culture. EcN is the active component of the microbial drug Mutaflor used in many GI disorders including diarrhoea, uncomplicated diverticular disease, and ulcerative colitis. In the aforementioned study EcN caused pathogenic flora to decrease from 73% to 14% while there was no significant change in the control arm. There was a shift towards a protective microbiota with predominance of lactobacteria and bifidobacteria. Stool consistency, colour and smell normalised. Understanding this association between the gut microbiome and rosacea, optometrists are in a position to delve a little deeper into their patients’ histories. We could be asking them questions such as: do you have any irritable bowel symptoms? Do you suffer with bloating, trapped gas, constipation, or diarrhoea?

Kelly denied any irritable bowel symptoms.

Intense Pulsed Light (IPL) has grown in popularity recently as a non-medication treatment for ocular rosacea. IPL involves the use of a hand held Xenon flashgun to deliver an intense, broad spectrum pulse of light, generally in the visible spectral range of 400 to 1200nm. IPL works on the same principles as lasers, in that light energy is absorbed into particular target cells, namely chromophores in the skin. The light energy is converted to heat energy, which causes damage to the specific target area. IPL therapy is considered a non-ablative resurfacing technique, which means it targets the lower layers of the skin (dermis) without affecting the top layers of the skin (epidermis). The mechanism of action of IPL is, at this stage, not conclusive. Heating of the meibomian glands makes logical sense. Associate Professor Jennifer Craig and her team at Auckland University have demonstrated improvements in lipid layer thickness and non-invasive break up time (NIBUT) after treatment.43 Light in the 500nm range has been proposed to be absorbed by blood cells in the abnormal telangiectatic vessels of MGD patients, which causes them to coagulate and then finally close. Sealing of the blood vessels decreases the release of inflammatory mediators,44 which creates further improvement in skin appearance. In the treatment of rosacea, Mark et al45 demonstrated a decrease in blood flow (30%), a decrease in surface area of telangiectasias (29%), and a decrease in the intensity of erythema (21%). Another possible mode of action of IPL is eradicating demodex. Demodex folliculorum mites are a type of ectoparasite that normally burrow deep into sebaceous and meibomian glands to feed on their sebum/meibum secretions.46 Demodex ingest the bacterium bacillus oleronius47 and upon their own death, release the bacterium onto the eyelids, triggering a cascade of events that may cause the chronic inflammatory signs of MGD. It has been proposed that the pigmented exoskeleton of demodex contains a chromophore that absorbs IPL energy, which induces coagulation and necrosis.48

The evidence is mounting that IPL is an effective treatment for the signs of ocular rosacea but what about the underlying cause? It’s important to stop and ask ourselves and our patients whether dysbiosis of the gut microbiome could be the causative factor of their rosacea and whether referral to a gastro-intestinal specialist or naturopath may be a better starting point.

What Does Kelly’s Case Teach Us?

Firstly, we need to be aggressive in our treatment – don’t under treat or under dose.

When deciding what treatment to choose, we want to make sure it will give us:

  • Maximal efficacy,
  • Least amount of side effects,
  • Lowest effective concentration,
  • Lowest dosage frequency, and
  • Most convenient delivery system.

In Kelly’s case I prescribed Hyloforte, Novatears, Optimel Manuka gel, and Lacritec Omega 3s. The ophthalmologist added cyclosporine and doxycycline.

Hyloforte, with its high water binding capacity replenishes the aqueous. Additionally, its biocompatibility and preservative free preparation helps reduce any toxic ocular reactions. The thing to remember is, that as a patient’s tear film decreases in volume, any preservative applied to the surface will have a higher effective concentration since it’s not diluted by a thick tear film. Any patient with aqueous deficiency (i.e. Schirmer < 7mm after five minutes) warrants a preservative free formulation.

I recommended that Kelly instil Novatears 30–60 seconds after Hyloforte, because it acts as a sealant, preventing aqueous evaporation while improving lipid layer thickness and TFBUT. It also helps restore natural meibum production by dissolving solidified meibum plugs.

I prefer agents which have multimodal action, and Optimel Manuka gel is one of the best. It controls the ocular surface microbiome, improves meibum quality, and reduces ocular surface inflammation. Omega 3s also reduce the inflammatory signs of dry eye. Cyclosporine reduces the T-cell response and the production of inflammatory mediators. Doxycycline helps control the gut microbiome and improves rosacea due to its anti-inflammatory action.

Have we ticked all the boxes? Yes.

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

It’s also essential that there are clear referral pathways. A local GP isn’t always the best person to refer to because they may not trust an optometrist’s diagnosis or fully understand its significance. Referral to an ophthalmologist or clinic that specialises in dry eye is a better avenue in my opinion.

Patient Review

Possibly the most important aspect of management is structuring the treatment. Our patients need to understand two things, firstly that dry eye is chronic and rarely defeated, and secondly that if our treatment doesn’t work then we need to ramp it up. Treatment is a ladder, and as optometrists it’s critical that we make sure we start our patients on the right rung by using questionnaires, aqueous production tests, and lissamine staining to better quantify the severity of their disease. Table 3 summarises my treatment strategies.

Table 3

 

Being a chronic disease, it is also critical that we review our management strategy to ascertain whether it has worked. As a general rule, it will often take at least two weeks for patients to respond to treatment. My advice is to review at one month, and two weeks if the patient is using a topical steroid.

If Kelly’s dry eye gets worse, Platelet Rich in Growth Factors (PRGF) will become an option.

PRGF are a new generation of autologous eye drops for severe dry eye, that are made from a patient’s own platelets. Many people do not realise they are a source of proteins and growth factors, which is why our tissue heals after an injury. A 2017 study49 of 297 aqueous deficient and evaporative dry eye patients, involving six weeks of monotherapy with autologous PRGF reported that dry eye symptoms improved in 87.5% of cases, corneal staining decreased in 76.1% of patients, and 28.8% of patients improved at least one line of BCVA.

If Kelly’s dry eye worsens further, we could also consider punctal plugs, bandage contact lenses, and minisclerals.

At the time of writing this article, Kelly was continuing to take omega 3s, Hyloforte, Novatears, Optimel, cyclosporine, and oral doxycycline. She was subsequently referred to an immunologist but was not diagnosed with an autoimmune condition; she is trying to wean herself off her anti-depressant medication.

Since the beginning of treatment she has noticed improvements in both her eyes and skin, however it’s a long road.

Dry eye is a battle we rarely win. We have peace for a while before we have to go into battle again. This disease is possibly the most common war that eye health professionals fight and optometrists are the foot soldiers at the battlefront.

   

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. Mr Koszek is a founding partner and the Professional Education Officer of EyeQ Optometrists which has 25 practices Australia wide. Mark Koszek is a former councilor for the Optometry Association of Australia (NSW division) and is on the board of the Cornea and Contact Lens Society of New South Wales. He was a fourth year clinic supervisor between 2002 and 2015 and has lectured extensively throughout Australia, New Zealand and Asia on contact lenses, dry eye and ocular diseases. Mark Koszek has a special interest in contact lenses, orthokeratology, dry eye, ocular diseases and behavioural optometry.

 
 
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' PRGF are a new generation of autologous eye drops for severe dry eye, that are made from a patient’s own platelets '