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Chronic Dry Eye: Demodex ‘Mite’ be Found Guilty

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Dry eye disease (DED) is a mystifying condition that a clinician frequently encounters, not always enthusiastically. Patients become progressively more miserable with subsequent visits if conventional treatment regimens are ineffective. The traditional definition of a “lack of tears” does not begin to scratch the surface when considering the multifactorial nature of DED. Could the tiny Demodex mites be partly responsible for our chronic dry eye epidemic? 

Who can we hold accountable?

Demodex folliculorum and Demodex brevis are two parasitic mites that live on and around the base of human hair follicles. Demodex folliculorum (0.3-0.4 mm) has a long body and can be found clustered around the base of the eyelash. In contrast, brevis mites are smaller (0.2-0.3 mm) and inhabit the sebaceous glands.1,2 Most of the time these mites are harmless, but in a weakened immune system or in large quantities they can cause irritation. Changes of the anterior and posterior lid margin occur with Demodex infestation, which causes blepharitis, meibomian gland dysfunction, and dry eye.3 Rabenstiener et al. found the Demodex parasite was associated with 40.2% of patients who experienced dry eye symptoms.3 This is a significant correlation, but the overlap with co-existing anterior segment conditions leads to underdiagnosis and incorrect management.2 

What incriminating evidence do we have?

Conventionally, clinical diagnosis for Demodex has involved examination of the epilated lash with slit lamp biomicroscopy or a laboratory microscope, but this is not always convenient. Apart from the obvious resulting patient discomfort with this method, a clinical study has now proven it may not fully diagnose the extent of the manifestation.4 It confirmed that eyelash manipulation rather than epilation can more accurately determine infestation numbers4. The researchers used sterile forceps to remove dandruff from the base of the lash and then lateral tension was applied to the lash, which caused the tails of the Demodex to be exposed and viewed with high magnification on the slit lamp. They then epilated the same lash and compared the quantity found on the lash with those seen after manipulation. The two techniques identified similar numbers of mites, but the lash manipulation consistently found higher numbers and was a more acceptable method for patients.4 

Innocent until proven guilty

The fact that the Demodex is a normal part of our lid flora is well known, and in some people they remain asymptomatic, with a healthy ecosystem where the mites clean away bacteria from the lashes and work as immune regulators.5 It is when the fine balance is tipped and the mites proliferate that the patient becomes symptomatic. Demodex prevalence increases with age and has been shown to be present in 100% of the general population over 70 years of age.6 In a recent study by Ayyildiz et al., Schirmer test scores and patient comfort scores were found to be similar in patients with Demodex colonization compared with those who had a DED diagnosis.7 Demodex should be on every differential diagnosis list for symptomatic anterior segment disease in the aging population.

Demodex folliculorum feed on the epithelium at the base of the lash follicle, causing mechanical damage, and their eggs can clump together and lead to lash misdirection. Undigested material, epithelial cells, and eggs form the lash deposits that are pathognomonic for Demodex presence, resulting in lash and eyelid margin irritation. The toxins found on the surface of the mites activate inflammatory cascades, causing irritation and inflammation.6 Even when the mite has died it triggers an inflammatory host response to the bacterial antigens released.2 This leads to the classic presentation of anterior blepharitis.

In meibomian gland dysfunction, Demodex brevis blocks the outlet of the gland and its excretions elicit an inflammatory reaction. A strong correlation between the prevalence of D. brevis and chalazion has also been documented.8

With the lid margin inflammation there can be associated conjunctival inflammation which will not respond effectively to antibiotic, antiviral, or lubricant treatments. In some chronic cases the cornea can also be affected; superficial punctate keratopathy, infiltration, opacities, limbitis, and corneal neovascularization have all been associated with Demodex.2,9 

How do we eradicate the guilty mites?

The mites cannot completely be eradicated as they play a role in the normal flora of our lid margins. Treatment is targeted at mite population reduction to provide a healthier environment for the ocular surface. 

Demodex mites are resistant to many agents, including alcohol, povidine-iodine, baby shampoo, and erythromycin.2 Currently the most effective treatment is tea tree oil derived from the leaves and terminal branches of a tree known as the Australian Melaleuca alternifolia.10 Tighe et al. have proven that Terpinen-4-ol is the active ingredient that is most potent in tea tree oil. It has acetylcholinesterase-inhibiting effects, leading the mite to migrate away from the follicle and onto the skin surface before it mates.11 Terpinen-4-ol at 1% concentration reduces the Demodex infestation effectively over 4 weeks.11 The bacteria that Demodex mites carry can also promote blepharitis so the antibacterial effects of TTO (increased membrane permeability) may enhance the therapeutic action.10 Tea tree oil also exhibits anti-inflammatory properties which will promote resolution of blepharitis symptoms. So TTO has many properties that work together to very effectively reduce the infestation and inflammation from Demodex. As with all good things, there is a disadvantage; tea tree oil can cause skin irritations and allergies so at high concentrations it should be administered in the office. A recommended practice is to treat with up to 50% concentration in the office once per week, and the patient is then to use tea tree oil in a low concentration cleanser twice daily to remove the migrating Demodex from the skin.11 

In our practice we dilute TTO with almond oil to 50 % concentration. We apply the oil in the office to the upper and lower eyelid margins with a cotton bud. The patient is then to sit with their eyes closed for 10 minutes. We repeat the treatment three times using local anesthetic before each application. We then irrigate with sterile saline and wipe the lids clean. The patient is sent home with cleansing wipes to use for 2 weeks twice daily and then we repeat the treatment. Three treatments are performed over 6 weeks. Cliradex wipes contain terpinen-4-ol and are a good option for patients to use at home. 

The Cochrane Library is currently conducting a systematic review investigating the treatment of Demodex infestation with tea tree oil. Although use of TTO is clinically accepted, evidence is not well documented for treatment success and adverse side effects.12

The future: Could honey “bee” the sticky remedy for a Demodex infestation?

Clinical research at the Ocular Surface Laboratory, Auckland University, New Zealand conducted by Dr. Jennifer Craig has proven that honey can reduce the symptoms of blepharitis. Honey is known for its natural antimicrobial properties and has been applied directly to cuts and scrapes for years. Craig et al. found that honey derived from the New Zealand manuka or tea tree–Leptospermum scoparium–demonstrates superior antibacterial properties to other honeys due to the 100-fold higher concentration of methylglyoxal (MGO).13 Manuka honey (MH) is commercially available as FDA-approved Medihoney for wound healing and skin ulcers. Optimel is an ophthalmic product with reported benefits in meibomian gland dysfunction and dry eye.14 For the past decade at Auckland University, Dr. Craig and colleagues have been conducting trials with a topical formulation of MH in a micoremulsion (MHME). The human trial on 25 healthy individuals found there was no ocular surface discomfort or compromise. Concurrently they showed in an ex vivo study that MHME has the potential to be effective against Demodex. MHME was observed to perform with equivalent acaricidal efficacy to 50% tea tree oil.15 More recently in a masked trial to look at the efficacy of MHME in treating blepharitis there was improvement in symptoms, tear film stability, lipid layer thickness, and degree of lid margin staining. But perhaps most importantly there was a significant reduction in the Demodex population.15 Given the tolerability and clinical efficacy of MHME, it is emerging as a promising alternative treatment for Demodex that may be available for clinical use in the near future. 

Research has determined that the Demodex mite is a significant culprit in DED. Demodex should always be considered in the differential diagnosis for symptomatic anterior segment disease. A lash manipulation at the slit lamp will quickly determine the prevalence and magnitude of mite infestation and then appropriate treatment can be initiated. 

References

1. Navel V, Mulliez A, Benoist d’Azy C, et al. Efficacy of treatments for Demodex blepharitis: A systematic review and meta-analysis. The Ocular Surface. doi:  10.1016/j.jtos.2019.06.004.

2. Fromstein SR, Harthan JS,  Patel J Opitz DLDemodex blepharitis: clinical perspectives. Clin Optom. 2018;10:57-63. doi:10.2147/OPTO.S142708.

3. Rabensteiner DF, Boldin I, Nitsche-Resch M, Berisha B, Schwantzer G, Horwath-Winter, J. Demodex mite infestation and its associations with tear film and ocular surface parameters in patients with ocular discomfort. Am J of Ophthal. 2019;204:7–12.  doi:10.1016/j.ajo.2019.03.007.

4. Murphy O, O’Dwyer V, Lloyd-McKernan A. The clinical use of eyelash manipulation in the diagnosis of demodex folliculorum blepharitis. Eye Contact Lens. 2019.

5. Nicholls SG, Oakley CL, Tan A, Vote BJ. Demodex species in human ocular disease: new clinicopathological aspects. Int Ophthalmol. 2017;37(1):303–312.

6. Liu J, Sheha H, Tseng SC. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10(5):505–510.

7. Ayyildiz T, Sezgin FM. The effect of ocular Demodex colonization on Schirmer test and OSDI scores in newly diagnosed dry eye patients. Eye Contact Lens. 2019.

8. Liang L, Ding X, Tseng SC. High prevalence of Demodex brevis infestation in chalazia. Am J Ophthalmol. 2014;157(2):342–348.

9. Kheirkhah A, Casas V, Li W, Raju VK, Tseng SC. Corneal manifestations of ocular demodex infestation. Am J Ophthalmol. 2007;143(5):743–749.

10. Lam NS, Long XX, Griffin RC, Chen MK, Doery JC. Can the tea tree oil (Australian native plant: Melaleuca alternifolia Cheel) be an alternative treatment for human demodicosis on skin? Parasitology. 2018;145(12):1510‐1520.

11. 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;2:2.

12. Salva K, Le JT, Pucker AD. Tea tree oil for Demodex blepharitis. Cochrane Database of Systematic Reviews. 2019. doi:  10.1002/14651858.CD013333.

13. Craig JP, Rupenthal I, Seyfoddin A, et al. Preclinical development of MGO Manuka Honey microemulsion for blepharitis management. BMJ Open Ophthalmol. 2017;1(1). doi:  10.1136/bmjophth-2016-000065.

14. Albietz JM, Lenton LM. Effect of antibacterial honey on the ocular flora in tear deficiency and meibomian gland disease. Cornea. 2006;25(9):1012-1019.

15. Craig JP, Wang MT, Ganesalingam K, et al. Randomised masked trial of the clinical safety and tolerability of MGO Manuka Honey eye cream for the management of blepharitis. BMJ Open Ophthalmol. 2017;1(1). doi: 10.1136/bmjophth-2016-000066.

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