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Corneal Physician

Article

Blepharitis: Know When Demodex is the Culprit

Identify these ectoparasites, as they are a common cause of ocular surface disease

By: Elizabeth Yeu, MD
Corneal Physician April 1, 2021 Vol 25, Issue April 2021 Page(s): 26, 27

Extrapolating incidence and population data, as many as 20 million U.S. adults may have blepharitis. Additionally, the literature indicates the prevalence of ocular Demodex infestation is significantly correlated with blepharitis. Specifically, a meta-analysis study reported that the rate of Demodex infestation in blepharitis subjects is 44.5%, compared to 16.7% in normal controls.1-3 So, how do we know when Demodex is the cause of blepharitis?

Here, I answer this question by providing an overview on Demodex and describing its symptoms and signs. Additionally, I discuss the current treatment of this common cause of ocular surface disease.

Overview

There are two types of Demodex, Demodex folliculorum, which burrow into eyelash follicles, and Demodex brevis, which inhabit the sebaceous and meibomian glands.4,5 Demodex blepharitis is seen in upwards of 69% of dry eye disease (DED) patients.6

Demodex folliculorum infestation is highly prevalent (83.7%) in patients who have posterior lid margin disease.7 Although Demodex mites are common, it is their overpopulation, or infestation, that is associated with ocular surface inflammatory conditions, such as chalazia, blepharokeratoconjunctivitis, ocular rosacea and phlyctenular keratitis.8

Demodex infestation of the eyelids increases with age,3,8-10 which is unsurprising since nearly 100% of individuals older than age 70 incidentally have Demodex as part of their facial skin flora.10 Anecdotally, the architectural changes associated with aging, such as the sagging of upper eyelids seen in dermatochalasis, with its resultant dark, wet environment, likely provide a perfect host environment for Demodex overgrowth. Also, recent studies demonstrate that greater skin Demodex folliculorum mite infestation is seen in metabolic syndromes, such as hyperglycemia.11

Demodex mites contribute to blepharitis inflammation through mechanical damage as they burrow and lay eggs. Chemical irritation from their digestive enzymes, the waste products released upon mite death and bacterial contamination with Propionibacterium acnes, as well as gram-positive cocci, like staphylococcus, cluster and overgrow using Demodex as the vector.5

As the mites feed on eyelid skin and hair follicular epithelial cells, and proceed through their life cycle, the partially digested epithelial cells, waste, and eggs form collarettes at the base of the lashes. This cylindrical dandruff, seen at the base of the lash follicles are pathognomonic for Demodex blepharitis.12,13

Symptoms and Signs

The symptoms of Demodex blepharitis are itching, foreign body sensation, a gumminess of the lids, gunk build-up in the morning, and fluctuating vision. Its signs are redness, edema, missing and misdirected lashes, and the presence of collarettes, particularly on the upper lid margin. Demodex infestation within the lash follicle causes the mite excretion, exoskeleton, and regurgitated waste to fill and push out of the lash follicle, which is then observed as the lash-cuffing collarette that can be seen more along the anterior lid margin of the upper eyelid, in particular, when looking down the base of the lash.

Two or three collarettes across the lid margin are a reason to treat, in my opinion. Collarettes are often sectoral; they cluster, and will likely progress to more diffuse lash involvement, with longer and thicker collarettes. (Figures 1A-C)

 

FIGURES 1A-C: Collarettes are often sectoral; they cluster, and will likely progress to more diffuse lash involvement, with longer and thicker collarettes.
FIGURES 1A-C: Collarettes are often sectoral; they cluster, and will likely progress to more diffuse lash involvement, with longer and thicker collarettes.

 

Treatment

There are no FDA-approved treatments for Demodex blepharitis. The American Academy of Ophthalmology Preferred Practice Pattern (PPP) suggests a combination of antibiotics, topical anti-inflammatory agents, and daily lid hygiene.1 The mainstay lid hygiene approach involves the use of scrubs, wipes, and gels containing tea tree oil (TTO) or its major acaricidal component, terpinen-4-ol (T4O). It’s efficacy is mixed, and it can also be uncomfortable, as it stings upon application.14-19

My treatment of Demodex blepharitis depends on how symptomatic the patient is and why he or she is in my chair. For pre-surgical patients, I am particularly aggressive, as I do not want to take any chances with suboptimal outcomes or potential infection. I have patients start some form of a TTO-based wipe or foam for at least 4 weeks.

After 1 or 2 weeks, they return, and I perform an exfoliation treatment. By removing the collarette debris, topical treatments can better penetrate into the lash follicle. If the patient also has significant meibomian gland dysfunction, I add thermal pulsation therapy in addition to the exfoliation treatment. Other commercially available treatments include topical hypochlorous acid solutions and intense pulsed light (IPL) therapy. (See “New Drop on the Horizon,” right.)

Identify Demodex Blepharitis

Ocular surface disease encompasses many etiologies, with blepharitis being one of the most common. For many eye care specialists who care for an older patient population, Demodex is “hiding in plain sight.” I have found that the condition has been underappreciated partly because the available treatment options are only somewhat effective and have tolerability issues. I now recognize that many of my patients who have recalcitrant DED or greater symptomatology after cataract surgery had Demodex blepharitis. Let’s actively identify these ectoparasites. CP

NEW DROP ON THE HORIZON

TP-03 is a novel therapeutic based on the drug lotilaner that is being developed by Tarsus Pharmaceuticals, Inc. The drop is designed to paralyze and eradicate mites and other parasites through the inhibition of parasite-specific GABA-Cl channels.

The company has completed four Phase 2 clinical trials.20-22 The Phase 2 trials Mars and Jupiter have shown TP-03 is well tolerated and effective at reducing collarettes and Demodex density with 28 days of treatment, and maintaining results through 90 days.20,21 Specifically, the trials evaluated 75 patients and showed statistically significant decreases in collarettes and Demodex density at day 14 of treatment. No treatment-related adverse events were observed, and patients reported the drop to be comfortable.

In the Phase 2a, single-arm open-label trial Io, TP-03 was effective at achieving the primary and secondary endpoints, respectively, of collarette cure in 72% of participants, and Demodex mite eradication in 78% of patients at day 42.22 In the randomized vehicle-controlled Europa study, made up of 54 patients, 80% of participants on TP-03, compared to 16% on vehicle (P < .001), achieved statistically significant results for the primary endpoint of collarette cure at day 42, and the secondary endpoint of mite eradication was seen in 73% of participants on TP-03 compared to 21% on vehicle (P = .003) at day 42.22

TP-03 was well tolerated, and there were no reports of serious adverse events or treatment discontinuations due to adverse events in either study. Further, participants in Europa rated the eye drops as “neither comfortable nor uncomfortable,” “comfortable,” or “very comfortable” 87% of the time.

The company is now evaluating TP-03 in two pivotal registration trials, Saturn-1 and Saturn-2, the former of which is underway. It expects the data will support the potential submission of an New Drug Application for TP-03 for the treatment of Demodex blepharitis.

References:

  1. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidelines. Blepharitis. San Francisco, CA: American Academy of Ophthalmology; 2018. 
  2. Zhao YE, Wu LP, Hu L, Xu JR. Association of blepharitis with Demodex: A meta-analysis. Ophthalmic Epidemiol. 2012;19(2):95-102. 
  3. Biernat MM, Rusiecka-Ziólkowska J, Piatkowska E, Helemejko I, Biernat P, Gosciniak G.Occurrence of Demodex species in patients with blepharitis and in healthy individuals: a 10-year observational study. Jpn J Ophthalmol. 2018;62(6):628-633. 
  4. Cheng AM, Sheha H, Tseng SCG. Recent advances on ocular Demodex infestation. Curr Opin Ophthalmol. 2015;26(4):295-300.
  5. Fromstein SR, Harthan JS, Patel J, Opitz DL.Demodexblepharitis: Clinical perspectives. Clin Optom (Auckl). 2018;10:57-63.
  6. Cheng AM, Hwang J, Dermer H, Galor A. Prevalence of Ocular Demodicosis in an Older Population and Its Association With Symptoms and Signs of Dry Eye. Cornea. 2020 Sep 21. doi: 10.1097/ICO.0000000000002542. Online ahead of print.
  7. López-Ponce D, Zuazo F, Cartes C, Salinas-Toro D, et al. High prevalence of Demodex spp. infestation among patients with posterior blepharitis: correlation with age and cylindrical dandruff. Arch Soc Esp Oftalmol. 2017;92(9):412-418. 
  8. Luo X, Li J, Chen C, Tseng S, Liang L. Ocular Demodicosis as a Potential Cause of Ocular Surface Inflammation.Cornea.2017;36(Supp 1):S9-S14.
  9. Post CF, Juhlin E. Demodex folliculorum and blepharitis. Arch Dermatol. 1963;88:298-302. 
  10. Liu J, Sheha H, Tseng SCG. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol.2010;10(5):505-510.
  11. Toka Özer T, Akyürek Ö, Durmaz S. Association between Demodex folliculorum and Metabolic Syndrome. J Cosmet Dermatol. 2020;19(11):3145-3149. doi: 10.1111/jocd.13721. Epub 2020 Oct 5. PMID: 33017081.
  12. Zhong J, Tan Y, Li S, et al.The prevalence of Demodex folliculorumand Demodex brevisin Cylindrical Dandruff Patients. J Ophthalmol. 2019:8949683. 
  13. Gao YY, Di Pascuale MA, Li W, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci.2005;46(9):3089-3094. 
  14. Arrúa M, Samudio M, Fariña N, et al. Comparative study of the efficacy of different treatment options in patients with chronic blepharitis. Arch Soc Esp Oftalmol.2015;90(3):112-118. 
  15. Murphy O, O'Dwyer V, Lloyd-McKernan A. The efficacy of tea tree face wash, 1,2-octanediol and microblepharoexfoliation in treating Demodex folliculorum blepharitis. Cont Lens Anterior Eye. 2018;41(1):77-82.
  16. Gao YY. In vitro and in vivo killing of ocular Demodex by tea tree oil. Br J Ophthalmol. 2005;89(11):1468-1473. 
  17. Karakurt Y, Zeytun E. Evaluation of the Efficacy of Tea Tree Oil On the Density of Demodex Mites (Acari: Demodicidae) and Ocular Symptoms in Patients With Demodectic Blepharitis. J Parasitol. 2018;104(5):473-478.
  18. Messaoud R, El Fekih L, Mahmoud A, et al.Improvement in ocular symptoms and signs in patients with Demodexanterior blepharitis using a novel terpinen-4-ol (2.5%) and hyaluronic acid (0.2%) cleansing wipe. Clin Ophthalmol. 2019;13:1043-1054.
  19. Savla K, Le JT, Pucker AD. Tea tree oil for Demodex blepharitis. Cochrane Database Syst Rev.2020;6(6):CD013333.
  20. Gonzalez-Salinas R, Ramos-Betancourt N, Corredor-Ortega C, et al. Pilot study to evaluate the safety and efficacy of TP-03 for the treatment of blepharitis due to Demodex infestation (Mars Study). Paper 2984-80042 presented at: Association for Research in Vision and Ophthalmology 2020. 
  21. Hom MH, Ceballos JC, Massaro-Corredor M, et al. Randomized controlled trial to evaluate the safety and efficacy of TP-03 for the treatment of blepharitis due to Demodex infestation (Jupiter Study). Poster presented at: Optometry's meeting 2020.
  22. Cision PR Newswire. Tarsus Releases Data from lo and Europa Trials for TP-03 to Treat Demodex Blepharitis and Begins Enrollment and Treatment in Phase 2b/3 Saturn-1 Trial. https://www.prnewswire.com/news-releases/tarsus-releases-data-from-io-and-europa-trials-for-tp-03-to-treat-demodex-blepharitis-and-begins-enrollment-and-treatment-in-phase-2b3-saturn-1-trial-301146578.html. (Accessed Feb. 21, 2020.)

 

DR. YEU is a cataract, corneal and refractive surgeon at Virginia Eye Consultants in Norfolk, Va. She is a consultant for Alcon, Allergan, Bausch + Lomb, BlephEx, CorneaGen, Dompé, Johnson & Johnson Vision, Kala Pharmaceuticals, Novartis, Ocular Science, Ocular Therapeutix, OCuSoft, Regener-Eyes, ScienceBased Health, Sight Sciences, Surface Pharmaceuticals, Tarsus, Théa, TearLab, and Tissue Tech.

 

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