Cornea
March 2021

by Ellen Stodola
Editorial Co-Director

Demodex mites can cause a number of problems, including ocular issues. Several physicians discussed symptoms, what to look for, and ways to treat an infestation.

According to Vincent de Luise, MD, there are two species of Demodex that cause human disease: Demodex folliculorum and Demodex brevis. These mites are acarids, a type of arachnid, in the phylum Arthropoda, and in the same taxonomic class as spiders, he said.

D. folliculorum is the most common parasite in man, said Henry Perry, MD, adding “the parasite is virtually ubiquitous in our skin by age 45.”

D. folliculorum and D. brevis mites are common on human eyelids and lashes, Dr. de Luise said. He noted that D. folliculorum mites are the larger of the two species and usually inhabit hair follicles, whereas the smaller D. brevis mites are usually found in and around pilosebaceous glands and meibomian glands. “Demodex folliculorum finds its primary habitat at the base of the lash follicle, where it feeds on follicular and glandular epithelial cells, causing direct mechanical damage and microscopic epithelial abrasions that can lead to epithelial hyperplasia and hyperkeratinization.”

Dr. de Luise said it has been estimated that 45% of adults with blepharitis harbor Demodex mites.

Although Demodex occurs more commonly in the older age groups, the most severe cases of Demodex are in children, Dr. Perry said. “The older the patient is, the more likely to find Demodex, but in children who have rosacea, the presence of Demodex is alarming,” he said. It can cause significant ocular issues, including loss of vision or permanent scarring depending on the severity of the rosacea and infestation.

Presentation and symptoms

Dr. de Luise said that Demodex can present with a number of ocular conditions, including anterior blepharitis, posterior blepharitis, meibomian gland dysfunction (MGD), oculocutaneous rosacea, and keratitis. “There is also a correlation between Demodex infestation and acne vulgaris, as well as an association with oculocutaneous rosacea,” he said.

“Because the Demodex mite lives within sebaceous glands and the eyelash follicle is a modified sebaceous gland, the Demodex mite can commonly infest and overgrow within the eyelids,” said Elizabeth Yeu, MD. Demodex blepharitis accounts for approximately 45–50% of blepharitis.

Patient complaints vary, Dr. de Luise said, with symptoms of irritation, discomfort, itching, burning, and foreign body sensation often elicited. Signs of Demodex infestation include collarettes and crusting or matting of eyelashes, tearing, and blurry vision.

When patients come in complaining of itchy, burning eyes, many of these patients have MGD, blepharitis, or dry eyes, Dr. Perry said. “We start trying to look for the factors that are making them worse.”

He said that during examination, one thing to check for is dandruff at the base of the eyelashes. There’s a particular type, called cylindrical dandruff, that’s like a pipe stemming off the eyelashes. It grows in a circular fashion around the eyelashes and usually starts at the base of the eyelash. This cylindrical dandruff is the primary sign of D. folliculorum, Dr. Perry said.

To diagnose, Dr. Perry said he will take an eyelash and examine it under a light microscope. He is often able to see the organism and diagnose this way. He noted that cylindrical dandruff presence on its own is not enough for a definitive diagnosis.

“The clinical finding of the collarette, or cylindrical dandruff at the base of the lash, may be pathognomonic for Demodex blepharitis, according to Gao et al.,”¹ Dr. Yeu said.

Dr. Perry said confocal microscopy may also be helpful, as it can identify Demodex in the follicle without pulling out the lash. But many physicians don’t have this technology available.

Dr. de Luise agreed that in vivo confocal laser scanning microscopy is a more accurate method to confirm a diagnosis. “It allows for a noninvasive magnified view of the affected follicles and is a more sensitive tool compared to slit lamp examination of epilated eyelash samples,” he said.

Dr. de Luise added that Demodex mites cause ocular inflammation by direct mechanism, as well as indirectly. “These mites have no excretory organs; their undigested material is regurgitated and combines with eyelid epithelial cells, keratin, and eggs to form the bulk of the cylindrical lash deposits said to be pathognomonic of Demodex infestation,” he said. “These deposits are clinically observable as collarettes. They contain inflammatory proteases and lipases, which cause symptoms of irritation.”

Demodex can also cause inflammation by an indirect mechanism. “Their hindguts contain bacteria (Bacillus oleronius), which can activate the host’s immune response,” he said. “Even in their death, these mites may elicit an inflammatory response by releasing bacterial antigens that trigger the host’s inflammatory cascade.”

Treatment

When treating, Dr. de Luise said that the overarching goal with Demodex infestation is to reduce eyelid margin mite populations, which in turn reduces ocular surface inflammation. Demodex does not respond to hot compresses or antibiotic-steroid ointment, he said.

Dr. Yeu noted that there is not currently an FDA-approved therapy. She mentioned the use of scrubs, wipes, and other lid hygiene products, particularly those containing tea tree oil but stressed the potential toxicity. Her choice of treatment will vary from patient to patient, and she may choose to be more aggressive for surgical patients.

Dr. de Luise said an over-the-counter strategy for management is OCuSOFT Lid Scrub Plus (OCuSOFT), which contains a 0.5% solution of 1,2-octanediol. When used over a 4-week period, this has been shown to decrease Demodex infestation.

He also mentioned 1% ivermectin and 1% mercury oxide as having acaricidal activity. Hypochlorous acid (Avenova, NovaBay Pharmaceuticals) has minimal activity against Demodex species.²

Recalcitrant cases of Demodex infestation can be offered mechanical debridement using rotary tip devices such as the BlephEx device and a similar technology by Myco Company, Dr. de Luise said.

As more treatment options become available, Dr. Perry said he thinks some may start treating just based on cylindrical dandruff. If you can keep the follicles and lashes clean, the Demodex usually won’t go into the lash follicle, he said. Regular lid hygiene can help with this, including using warm saltwater soaks, BlephEx, and agents like ivermectin.

He noted that tea tree oil is effective. It’s lethal to Demodex, but it can also be toxic, so it’s important to exercise caution when using this option.

“Some practitioners dilute commercially available tea tree oil with macadamia nut or walnut oil to decrease patient discomfort and toxicity to the ocular surface while maintaining efficacy in eradicating the mites,” Dr. de Luise said. “Caution must be taken in those patients with nut allergies.”

Scheffer Tseng, MD, PhD, has done research looking at effectiveness of tea tree oil in treating Demodex but said that tea tree oil alone can be toxic, as noted by the other physicians. He has thus identified the active ingredient of tea tree oil as terpinen-4-ol. Dr. Tseng co-authored a paper discussing Cliradex (Bio-Tissue),³ eyelid cleansing products that contain terpinen-4-ol. He found it to be an effective way to treat Demodex infestations in patients.

Dr. de Luise said direct removal of the mites at the slit lamp can be performed but is time-consuming, and many mites will be burrowed in the glandular tissue and not able to be seen. He also mentioned the use of Cliradex for these patients.

According to Dr. Yeu, recent literature demonstrated that terpinen-4-ol was harmful to human meibomian gland epithelial cells in vitro.⁴ Dr. Yeu said that more research is needed here to assess the potential damage of meibomian glands.

Another option currently in trials is from Tarsus Pharmaceuticals, a late-stage biopharma company that has developed a topical lotilaner 0.25% ophthalmic solution, TP-03. According to Dr. Yeu, it is designed to paralyze and eradicate the mites and other parasites through the inhibition of the parasite-specific GABA chloride channels. So far, the company has completed four Phase 2 clinical trials, and Dr. Yeu noted that the product was well tolerated (“neither comfortable nor uncomfortable,” “comfortable,” or “very comfortable” 87% of the time) and met both primary endpoints (which included collarette cure and mite eradication) in all four Phase 2 studies. In the single-arm open-label trial Io, TP-03 was effective at achieving the primary endpoints of collarette cure in 72% of participants and Demodex mite eradication in 78% of patients at day 42. The randomized, vehicle-controlled Europa study achieved a collarette cure in 80% of participants on TP-03 compared to 16% on vehicle (P<.001) at day 42, and mite eradication was achieved in 73% of participants on TP-03 compared to 21% on vehicle (P=.003) at day 42, Dr. Yeu said.

TP-03 specifically targets the mite nervous system to kill the mites on the GABA chloride channels, treating the underlying cause of disease, Dr. de Luise said.

The company presented that TP-03 has rapid, complete, and durable efficacy with no serious adverse events, Dr. de Luise said. Patients reported that the drop is comfortable with zero study discontinuations due to tolerability.

In September 2020, Tarsus commenced its FDA Phase 2B/3 pivotal registration study, known as Saturn-1, and planned to enroll more than 400 participants in 14 locations, Dr. Yeu said.

The primary objective of the Saturn-1 trial is to assess the safety and efficacy of TP-03 compared to its vehicle from day 1 to day 43 in adult participants with mild to severe Demodex blepharitis, Dr. Yeu said. The primary efficacy endpoints mimic the latter Phase 2 studies and are the collarette cure, defined as the presence of no more than two collarettes on the upper eyelid, and mite eradication rate of zero on the lash of the upper eyelid. The secondary endpoint is a composite score of the collarette cure plus erythema score. Safety will be determined by assessing adverse effects related to the treatment as well as evaluating any changes in visual acuity, intraocular pressure, slit lamp biomicroscopy, and dilated ophthalmoscopy findings.

---

About the physicians

Vincent de Luise, MD
Assistant Clinical Professor of Ophthalmology
Yale University School of Medicine
New Haven, Connecticut

Henry Perry, MD
Chief, Cornea Service
Nassau University Medical Center
East Meadow, New York

Scheffer Tseng, MD, PhD
Chief Technology Officer
TissueTech
Miami, Florida

Elizabeth Yeu, MD
Assistant Professor
Eastern Virginia Medical School
Norfolk, Virginia

References

1. Gao YY, et al. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci. 2005;46:3089–3094.
2. Kabat AG. In vitro democidal activity of commercial lid hygiene products. Clin Ophthalmol. 2019:13:1493–1497.
3. Cheng AM, et al. Recent advances on ocular Demodex infestation. Curr Opin Ophthalmol. 2015;26:295–300.
4. Chen D, et al. Effects of terpinen-4-ol on meibomian gland epithelial cells in vitro. Cornea. 2020;39:1541–1546.

Relevant disclosures

de Luise: None
Perry: Alcon, BlephEx
Tseng: TissueTech
Yeu: Tarsus Pharmaceuticals, TissueTech

Contact

de Luise: vdeluisemd@gmail.com
Perry: hankcornea@gmail.com
Tseng: stseng@ocularsurface.com
Yeu: eyeulin@gmail.com