Blepharitis is a common condition encountered by eyecare providers, with over 2 million cases reported annually in the US.1-4 Typically, the condition is caused by bacterial overgrowth or allergies and responds well to routinely used treatments, such as antibiotics. However, in some cases, patients do not respond to standard treatments leading to persistent irritation and ocular symptoms.
In such cases, other potential causes should be explored, and one of the top suspects should be the parasitic mite—Demodex. Demodex are ectoparasitic mites that live on human skin and are found in hair follicles and sebaceous glands as part of the skin’s natural microflora.5,6 However, when the mites overpopulate, their presence can lead to Demodex blepharitis (DB) as well as several other ocular maladies including meibomian gland dysfunction (MGD), conjunctivitis, keratitis, and eyelash disruptions.5,7-13
“This makes properly identifying an overgrowth of Demodex and appropriately treating the condition vital to successfully managing stubborn cases of ocular surface disease.”
Though blepharitis is common, Demodex as a causative organism is often overlooked. While traditionally about half of cases of blepharitis (equaling nearly 9 million) have been recognized as DB1-4, this may be a gross underestimate as recent studies have found that about 58% of all patients presenting to eye clinics for any reason show signs of DB, which pushes the number of estimated cases in the US to roughly 25 million.14-16
When the total patient population displaying signs of DB was broken down into specific groups, it was found that 1.2 million were dry eye patients currently using a prescription medication to treat their condition, 2.3 million were contact lens intolerant patients, and 2.2 million patients had cataracts.14-16 These numbers are particularly important considering these are groups where ocular surface health is crucial, whether they are suffering from chronic ocular surface irritation, desiring but unable to wear contact lenses, or about to undergo cataract surgery and a healthy ocular surface is critical to obtaining reliable preoperative measurements to ensure the best post-operative refractive outcome.
Additionally, DB can have a significant effect on quality of life with nearly 80% of DB patients reporting negative consequences of the condition.17 The majority of patients suffering from DB reported ocular irritation for over 4 years.18 In addition to discomfort, patients reported cosmetic concerns, such as redness and challenges wearing makeup, and functional issues, like difficulty with nighttime driving.17
Despite all the negative effects of Demodex infestation on ocular surface health and function, DB still remains underdiagnosed as a recent study showed that 58% of patients presenting with signs and symptoms of Demodex never received a diagnosis of DB.18 This underscores the need for all eyecare providers (ECPs) to carefully look for this condition in our patients to prevent cases of DB from going unresolved.
Who is at risk for Demodex blepharitis?
Demodex are a normal part of our skin’s microflora so everyone, at some point in their lives, will exhibit Demodex.5,6,19 There are conflicting data regarding whether Demodex are more common in males or females with differing studies finding the mite to be more prevalent in females,20-22 more prevalent in males,23-25 or finding no difference between sexes.26,27 Demodex are observed in all races.26
However, the density of Demodex is highly correlated to age, as Demodex are present in 84% of the population by age 60 and 100% of the population at 70 and older.19 As Demodex increase with age, they are less common in the pediatric population with most pediatric cases involving immunocompromised individuals, although, rarely, Demodex can occur in healthy pediatric patients as well.28
Similarly, Demodex tend to be found in immunocompromised individuals in general including those with condition such as cancer or HIV or individuals undergoing immunosuppressive therapy.7,29 Other factors that increase risk for Demodex infestation include rosacea, fair skin complexion, diet (consumption of spicy foods, alcohol, and hot beverages), emotional state (stress), environmental conditions (sunlight exposure, sudden temperature changes), and smoking.5,30,31
Interestingly, many of these risk factors are also triggers for rosacea, which has a high correlation with Demodex infestation, with Demodex overpopulation even being proposed as the underlying etiology of rosacea.9,32-36
It is important to note, however, that the presence of Demodex does not necessarily mean an individual will experience any ocular symptoms. In fact, many individuals displaying signs of Demodex are asymptomatic.37,38
Additionally, it has been debated whether the presence of Demodex is beneficial or detrimental.8 It has been proposed that Demodex may be helpful by blocking overgrowth of other more harmful microbes such as certain bacteria and other mites.11 However, it is thought that when the density of Demodex becomes too great, this overpopulation upsets the natural homeostatic balance of the environment of the lids and lashes leading to an infestation of Demodex referred to as demodicosis.5,7-13
Once demodicosis has occurred, patients are at risk for negative ocular manifestations such as DB, MGD, conjunctivitis, keratitis, and eyelash disruptions. The exact tipping point between normal Demodex presence and overpopulation is not known, so standard criteria for what constitutes demodicosis has not been explicitly established.7,8 However, it has been shown that 100% of patients displaying cylindrical dandruff or collarettes at the base of the eyelashes have DB, to the extent that lash collarettes are considered pathognomonic for the condition.11,16,39
While this finding does not determine the exact extent of Demodex infestation or if a patient is symptomatic, it can be a useful sign for identifying a patient at risk of having or developing symptomatic DB.
As seen in Figure 1, Demodex blepharitis is caused by an overpopulation of Demodex mites resulting in a disruption of the lids, lashes, and ocular surface.
Figure 1: Photo by author
What are Demodex?
Demodex are ectoparasitic mites that live on human skin and are part of our natural microflora.5,6 They are arthropods with three body segments and have a cigar-like shape with four pairs of legs with clawed ends and pincer-like mouth pieces40,41 that make the mites adept at gripping cylindrical structures, such as eye lashes, and burrowing into glands and follicles.10,11
“Humans are host to two species of Demodex: Demodex folliculorum and Demodex brevis.”
While there are many species of Demodex found across mammals, these are the only two found in humans and are the only ones that affect the eye.7 The two mites also occupy separate niches, with D. folliculorum (the larger species at 0.3-0.4 mm in length) found on the lashes and lash follicles, and D. brevis (the smaller species at 0.2-0.3 mm in length) inhabiting sebaceous glands.5,13,42-45
Although they occupy different areas, D. folliculorum and D. brevis are often found together.23,24,46 The mites can also be found on the skin of the cheeks, nose, forehead, and in the eyebrows as well.5,19,47,48 The mites feed on epithelial cells and sebum found where they reside,5,10,11,40 however they lack a fully formed digestive system so they must regurgitate all undigested material with this physiology leading to a relatively short life span.40,49
Demodex mate in the openings of hair follicles and lay their eggs in either hair follicles or sebaceous glands, where it takes about 2 weeks for the eggs to develop into a larval stage.5,40,45 The adult mites then live an additional week giving Demodex a typical lifespan of about 3 weeks.5,45
Figure 2 illustrates Demodex folliculorum (0.3-0.4 mm in length).104
Figure 2: Photo credit-K.V. Santosh
Figure 3 illustrates Demodex brevis (0.2-0.3 mm in length).105
Figure 3: Photo credit-Austin Whittal
How do Demodex cause Demodex blepharitis?
The ocular manifestations of Demodex are a result of the mites’ physiology and ecological niches which contribute to mechanical damage, inflammation, and chronic hypersensitivity.8 D. folliculorum feeds upon the epithelial cells of hair and lash follicles, with the mite physically biting the cells resulting in microabrasions. Over time this microtrauma results in hyperplasia and hyperkeratinization which can cause lid margin thickening and disruption of the lashes including lash loss and misdirection.5,13,16,50
D. brevis burrow into the meibomian glands, which are modified sebaceous glands, where the feed upon meibum.5,10,11,42,40 This burrowing physically obstructs the gland orifices leading to meibomian gland hyperplasia and dysfunction, with blockage further exacerbated by the accumulation of the mites’ waste.8,10,13 D. folliculorum and brevis lay their eggs in lash follicles and meibomian glands, respectively, which also leads to obstruction of both structures.39,40 In addition to the mechanical damage caused by physical biting and obstruction, the mites also elicit an inflammatory response.
Because Demodex lack a fully developed excretory system, they must regurgitate all undigested material.49 This excreta contains proinflammatory digestive enzymes that can cause irritation to the lid margin and disrupt the tear film and ocular surface.11,39
Furthermore, when this waste mixes with other debris and Demodex eggs, it forms a waxy, cylindrical coating that wraps around the base of the lashes which is referred to as cylindrical dandruff or lash collarettes.7,11,12,39,50 These collarettes, which are the hallmark sign of DB, act as a significant source of inflammation and can disrupt both the lashes and lid margin.
Additionally, the exoskeleton of Demodex is made of chitin, which is thought to elicit a foreign body response which stimulates the formation of a granuloma around the mite. This granulomatous response can lead to chalazion development, especially in cases of D. brevis as they are found inside the meibomian glands.5,7,39,51
In Figure 4, Demodex folliculorum inhabit lash follicles and produce waste and eggs that mix to produce a buildup of waxy debris, known as cylindrical dandruff or collarettes, which forms at the base of the lashes. In the above image a heavy accumulation of collarettes can be observed.
Figure 4: Photo by author
Demodex may also indirectly provoke an inflammatory response by acting as a vector for bacteria. Streptococcal and Staphylococcal species have been shown to live on the surface of Demodex mites, while Bacillus oleronius resides inside their abdomen.52-54 Each of these bacterial species can cause inflammation that results in blepharitis, so Demodex may be acting as a bacterial reservoir in addition to the direct damage they inflict.
Finally, it has been proposed that Demodex promote a Type IV hypersensitivity reaction. It is thought proteins contained inside the mites and their waste stimulate a delayed, cell-mediated response that can lead to chronic inflammation.53,55
It has also been noted that Demodex can still cause disruption even after their demise, as proinflammatory proteins and bacteria are released from their bodies upon death.5,8 Each of these mechanisms ultimately elicits an inflammatory response resulting in blepharitis, MGD, and eyelash disruption that can further develop into conjunctivitis and keratitis if this inflammation spills over to the conjunctiva and cornea.
Figure 5 demonstrates Demodex brevis being found in sebaceous glands including the meibomian glands, which are modified sebaceous glands. This leads to a physical obstruction of the gland orifices which can cause MGD as is displayed by the blocked and inspissated meibomian glands pictured above.
Figure 5: Photo by author
What are the signs and symptoms of Demodex blepharitis?
The signs and symptoms of DB are a direct result of the mechanical and inflammatory damage they inflict upon the lid margin and lashes. Physical biting, use of digestive enzymes, obstruction of follicular and meibomian glands, and the presence of proinflammatory collarettes all result in ocular surface irritation and dysfunction, with the most common symptoms of DB presenting as foreign body sensation, burning, stinging, epiphora, transiently blurred vision, and general irritation.7,50
The signs of DB are easily recognizable in the form of characteristic waxy, cylindrical collarettes wrapping around the bases of the lashes signifying the presence of D. folliculorum,7,50 in addition to meibomian gland hyperplasia and obstruction, indicating D. brevis infestation.8,13 Obstruction and inflammation of the glands may also lead to recurrent hordeola and chalazia.39,51
Other signs include lid margin erythema and telangiectasia (which is also indicative of ocular rosacea which is commonly associated with demodicosis)32,56 as well as lid notching or scalloping due to chronic inflammation, especially if the condition is left untreated.8 D. folliculorum will often cause disruption to the eyelashes themselves in the form of madarosis, trichiasis, and distichiasis.5,7,50
While many of the signs and symptoms of Demodex blepharitis are nonspecific, the presence of sleeve-like collarettes around the lash base, as seen in Figure 6, are pathognomonic for Demodex blepharitis.
Figure 6: Photo by author
Demodex blepharoconjunctivitis and blepharokeratitis occur when inflammation from DB is so great it spills over onto the conjunctiva and cornea. D. brevis are more likely to cause blepharoconjunctivitis and blepharokeratitis due to their closer proximity to the conjunctiva and cornea.5,9,12 Demodex blepharoconjunctivitis presents with all the signs and symptoms of DB in addition to conjunctival injection and possible chemosis.
Demodex blepharokeratitis is notable for the fact that the degree of inflammation present is often significant, to the point where it is commonly misidentified as herpetic keratitis.7-9 Demodex blepharokeratitis typically occurs bilaterally and can display superficial punctate keratitis (SPK), peripheral neovascularization, marginal corneal infiltrates, central stromal infiltrates, corneal scars or opacities, nodules or phlyctenular lesions, limbitis, and rarely perforation.7-9 Though rare, other important noted associations for demodicosis are basal and sebaceous gland carcinomas.5,57-59
As seen in Figure 7, mites found inside the meibomian glands and hair follicles can elicit a granulomatous response that results in hordeolum or chalazion development.
Figure 7: Photo by author
What conditions are associated with Demodex blepharitis?
There are several common comorbidities and conditions related to demodicosis and DB. These include other ocular surface conditions such as dry eye and ocular rosacea. As previously noted, demodicosis can cause MGD and chalazion or hordeolum development in addition to blepharitis, so these conditions are not always separate entities.
This may also be the case for dry eye and ocular rosacea as well. MGD is involved in about 80% of cases of dry eye60, so MGD secondary to demodicosis can ultimately result in dry eye.39 Additionally, demodicosis as an underlying cause of ocular rosacea is widely supported.9,32-36 So, even these ostensibly independent comorbid conditions may be caused by an underlying mite infestation as well.
Regardless of the ultimate origin of these related disorders, they should be included on the list of differential diagnoses for DB and treated accordingly if found to coexist alongside DB.
Demodex and keratitis
Keratitis, specifically herpetic keratitis, warrants a special mention in terms of differential diagnosis as the literature notes that Demodex blepharokeratitis can closely mimic herpes keratitis and is a common misdiagnosis.7,8 For this reason, it is recommended that Demodex be included as a potential diagnosis in cases of keratitis, especially if they are nonresponsive to antiviral therapy.5,7,8 This same philosophy has been suggested to be extended to all forms of ocular surface disease (blepharitis, MGD, dry eye, conjunctivitis, etc.) that do not improve with standard therapy.
In such cases, the recalcitrant nature of these usually readily treated conditions is often due to demodicosis acting as the root cause, and until the mites are addressed the condition will not resolve.7,8
Ocular rosacea, which is characterized by marked lid and ocular surface telangiectasia, like that illustrated in Figure 8, is commonly associated with Demodex blepharitis. In fact, it is even thought that Demodex may be the underlying cause of the condition.
Figure 8: Photo by author
How is Demodex blepharitis diagnosed?
Demodicosis and DB are typically diagnosed clinically based on signs and symptoms, with the diagnosis confirmed by microscopic analysis of lash sampling.7,8 However, as previously discussed DB presents with several nonspecific signs and symptoms such as ocular irritation, redness, and tearing that can also be attributed to other ocular surface conditions, like dry eye and ocular rosacea which are also common comorbidities of DB.
So, from a symptomatic standpoint it can be very easy to overlook DB or misattribute the patient’s condition to one of these other ocular surface diseases. This places greater emphasis on the unique signs of DB, which are fortunately easily identifiable. The presence of collarettes at the base of the lashes is pathognomonic for DB, with the literature reporting that 100% of patients displaying collarettes have DB.11,16,39
Although the presence of collarettes make the diagnosis of DB relatively straightforward, subtle collarettes can be easily missed when a patient is in primary gaze. For this reason, it is recommended that ECPs have patients look down during slit lamp examination to bring the base of the lashes and any collarettes into plain view, making evaluation of the lashes and lid margin quick and efficient. It is worth noting the presence of collarettes is technically only indicative of D. folliculorum, however patients will likely have D. brevis as well, especially if signs of MGD, such as gland hyperplasia or obstructed gland orifices, are also present.
Another major indicator that aids in the diagnosis of DB is ocular surface disease that is refractory to standard treatments.7,8 For instance, cases of blepharitis, conjunctivitis, or keratitis that do not respond to traditional antibiotic, antiviral, or steroidal therapies strongly suggests Demodex as the underlying cause as the mites are resistant to all these forms of treatment.7-9,47,61 So, cases of nonresponsive ocular surface disease can be indicative of demodicosis and are confirmed by the presence of lash collarettes.
While the diagnosis of Demodex blepharitis can be made clinically based upon the presence of lash collarettes, the diagnosis is confirmed by lash sampling, as seen in Figure 9. The process traditionally involves epilating several lashes from each lid and viewing the samples under a microscope to quantify the number of Demodex present.
Figure 9: Photo by author
While the presence of collarettes and meibomian gland dysfunction are sufficient for a clinical diagnosis of DB, the diagnosis is traditionally confirmed through lash sampling.7,8 The Coston Method of lash sampling involves epilation of four random, nonadjacent lashes per lid and then mounting them on a slide by applying a drop of oil and coverslip followed by viewing with a confocal microscope and a count of the mites being made.50,62
However, it is strongly recommended that lashes with collarettes be epilated rather than random lashes as sampling random lashes tends to underestimate the extent of the infestation.5,8,63
Alternative methods of assessing the density of Demodex involve using sodium fluorescein, peanut oil, or 75% alcohol to free embedded mites from debris when analyzing lash samples.8 A noninvasive method includes the Mastrota Twirling Technique, which involves using forceps to rotate the lash without epilation as this motion coaxes the mites out of lash follicles and allows for direct viewing behind a slit lamp.50
Another method makes use of in vivo confocal laser scanning microscopy (CLSM) for noninvasive viewing of the mites which appear round or cone-like in appearance.12,64
One caveat to note when diagnosing demodicosis or DB, whether through clinical observation of collarettes, lash sampling, or viewing with a slit lamp or in vivo CLSM, is that there is no exact established mite count that constitutes an overpopulation that moves the presence of Demodex from a normal density to an infestation warranting a diagnosis of demodicosis.7,8 Therefore, there is still a degree of clinical judgment required when making the diagnosis, which usually comes down to a patient experiencing ocular symptoms in the presence of lash collarettes.
How is Demodex blepharitis treated?
Demodex are highly resistant to most forms of treatment. As they are parasitic arthropods, they will not respond to antibacterial, antiviral, or antifungal treatment, and they are surprisingly resistant to other broad antimicrobial agents such as 75% alcohol and 10% povidone-iodine.47
Xdemvy (lotilaner ophthalmic solution 0.25%)
Although anti-inflammatory agents may reduce the inflammation caused by Demodex, they do not address the root cause, which is the mites themselves. For this reason, treatment with antiparasitic agents with acaricidal properties is required. Traditionally, this involved using hygiene-based treatments such as tea tree oil (TTO). However, while these cleansers can be beneficial in managing DB, they are imperfect treatments. As will be discussed in more detail in the following section describing the use of TTO in DB, TTO is a relatively harsh compound and can cause ocular irritation. This is especially true of the higher concentrations that are often recommended for more effective mite eradication, which typically exceed the commonly used 2-5% formulations. Additionally, there is no established standard dosing when treating DB with TTO, and a systematic literature review of the use of TTO for short-term DB treatment could not definitively establish its efficacy for this purpose despite its widespread use.76 All these factors create a degree of clinical uncertainty that is less than desirable when attempting to treat DB.
However, the FDA-approval of Xdemvy (lotilaner ophthalmic solution 0.25%, Tarsus Pharmaceuticals) represents a shift in DB management and offers a new primary treatment for DB. Xdemvy is an antiparasitic agent that eradicates Demodex by inhibiting parasite-specific GABA-Cl channels, which causes paralysis of the mites, resulting in death.77,78,106 Xdemvy is also highly lipophilic, which allows it to be readily absorbed into the eyelash follicles and meibomian glands where the mites reside and can be directly targeted by the medication.107 In two Phase 3 studies, Xdemvy was shown to significantly improve DB through mite eradication (60% of patients achieved complete mite eradication defined as 0 mites per lash), collarette reduction (50% of patients achieved complete collarette cure defined as ≤2 collarettes on the upper lid, while clinically meaningful collarette cure defined as ≤10 collarettes was observed in 85% of patients), and improvement of eyelid erythema (25% of patients displayed erythema cure defined as grade 0 or no lid margin erythema on a 0-3 scale corresponding to no erythema, mild, moderate, and severe erythema, respectively) when dosed BID x 6 weeks, which corresponds to roughly two life cycles of the mites.108-110 However, benefits for some patients were shown as early as two weeks of use.108-111 Additionally, Xdemvy was well-tolerated, with 90% of patients reporting the drop to be neutral to very comfortable, with the most common side-effect being stinging and burning upon instillation in 10% of patients, which was typically mild and transient.108-110 Therefore, given its status as the first and only FDA-approved treatment specifically indicated for the management of DB, its high degree of clinical efficacy, and its safety and tolerability profile, Xdemvy represents a new, definitive first-line treatment for DB.112
However, this also signals a major shift in the DB treatment paradigm. While lid hygiene-based treatments used to be the primary therapies for DB, they will now likely take on a more fitting role as secondary, supportive therapies rather than first-line treatment. For instance, TTO or okra-based cleansers will likely now be used as routine maintenance treatments after and between courses of Xdemvy as an adjunct therapy while Xdemvy will function as the primary therapeutic agent. Additionally, Xdemvy may lessen the treatment burden on patients. Whereas the use of lid hygiene has no definitive dosing duration and is therefore sometimes used indefinitely, Xdemvy’s 6-week course provides a rather concrete endpoint for treatment. While we have yet to see how frequently patients may need to undergo a repeat course of Xdemvy, and although the use of lid hygiene treatments will likely still be beneficial, if a patient is able to discontinue the use of some of the other cleansers, even temporarily, this could provide a significant benefit. The reason for this is that the spectrum of ocular surface disease is often multifactorial, therefore the majority of patients will need to be on multiple, often long-term, treatments to address each contributing element. Therefore, reducing the number of required treatments, even by one, can improve a patient’s quality of life (QoL) by reducing their treatment burden.
Although Xdemvy fundamentally changes how DB has been traditionally managed, this will likely allow ECPs to possibly achieve enhanced treatment outcomes for DB than we have previously been able to obtain through lid hygiene alone.
Tea Tree Oil
Before the advent of Xdemvy, tea tree oil (TTO), which comes from the tea tree (Melaleuca alternifolia) for which it receives its name, was the most commonly used primary treatment for DB.65,66
The active ingredient in TTO is terpinen-4-ol (also referred to as 4-terpineol) which is broadly antimicrobial and antiseptic with antibacterial, antiviral, antifungal, anti-inflammatory, and most importantly, demodicidal properties.65-69 Terpinen-4-ol is an acetylcholinesterase inhibitor, which kills the mites, and the presence of TTO forces the mites to evacuate the follicles and sebaceous glands they inhabit.16,47,66 The mites are then left exposed on the surface of the skin and prevented from laying eggs in follicular and sebaceous glands, making them vulnerable to eradication.70
Additionally, TTO effectively removes collarettes and cleanses the lashes.47 TTO successfully can be used at varying concentrations, however it is worth noting the same properties that make TTO an effective antimicrobial agent also make it a relatively harsh treatment with side effects that can include ocular irritation, contact dermatitis, and an allergic response,71 with the risks of these side effects increasing with higher concentrations. These side effects help shape the most routinely utilized dosing regimens used in TTO therapy. Typically, the concentrations of TTO used range from 2-50%.8,47,66
The most widely used at-home treatments are 2% and 5% TTO dosed BID, with 50% treatments usually reserved for once weekly administration in-office due to a higher side effect profile.8,48,71TTO comes in numerous forms including foam cleansers, scrubs, and wipes, all of which can be effective, so the choice is primarily dependent on ECP and patient preference.
Some commonly used lower concentration at-home options:
- EyeEco’s Advanced Formula 2% Tea Tree Eyelid & Facial Cleanser foam (EyeEco)
- Cliradex Light Foam and Towelettes (Bio-Tissue)
- Optase TTO Eye Lid Gel and TTO Lid Wipes (SCOPE)
- Oust Demodex Cleanser foam and Oust Demodex Cleanser Pre-Moistened Pads (OCuSoft)
- HylaWipe Eyelid Wipes (TearRestore)
For high concentration, in-office treatment Oust Demodex Swabstix (tea tree oil 50%, OCuSoft) can be used.
There is no established standard duration of treatment, as treatment can range from weeks to an indefinite period. However, it is recommended that treatment last a minimum of 6 weeks as this corresponds to two life cycles of the mites.12
As previously mentioned, a systematic literature review of short-term treatment of DB with TTO could not conclusively determine its efficacy.76 Additionally, it is crucial to mention that the goal of treatment with TTO is not complete eradication of the mites, as that goal is generally considered unobtainable with most traditional treatments but rather a reduction in mite density.8,18,65 This is also an appropriate clinical goal as Demodex are part of our normal microflora, so as long as their population is held to an appropriate level, patients should be asymptomatic.
However, to keep the Demodex population in check prophylactic treatment, usually at less frequent dosing, beyond the initial 6 weeks of treatment is often required. Application of the preferred form of treatment should involve thorough scrubbing of the lids and lashes, especially at the base of the lashes and the lid margin where the mites reside, to ensure the environment is rendered uninhabitable and the mites are eliminated.
Additionally, TTO should be applied to the eyebrows, cheeks, nose, and forehead as Demodex can also be found in these areas and act as a reservoir for ocular reinfestation if left untreated.47,48 It is important to stress to patients that the TTO treatment is meant for the lids and lashes and not the eyes themselves, as TTO can cause transient, but intense, irritation if it gets onto the surface of the eye proper.
A typical treatment regimen involves using 2-5% TTO BID for 6 weeks followed by QD or every other day use for prophylaxis. The duration of prophylactic treatment can vary from patient to patient as DB is a chronic condition, and in-turn requires chronic treatment. However, the dosing and treatment pattern used will largely depend on patient symptoms and side effect tolerability. If a patient is asymptomatic after completion of 6 weeks of treatment but tends to react poorly to TTO, then the patient can be treated on an as needed basis and resume TTO use if symptoms return.
Conversely, if a patient tolerates TTO well but symptoms quickly return upon discontinuation of therapy, they can be kept on treatment indefinitely. If in-office treatment with 50% TTO is performed, patients should receive one treatment weekly for 6 weeks with the patient also performing an at-home 2-5% TTO treatment QD-BID. The aim of this treatment regimen is to use the 50% concentration to force the mites out of the lash follicles and meibomian glands and on to the surface where they are exposed and vulnerable to eradication by lower strength 2-5% at-home TTO treatments.8,65,72
As a reminder, the use of 2-5% TTO QD-BID will now likely act as an adjunct maintenance therapy between courses of Xdemvy and, therefore, function in a supportive rather than primary role when managing DB.
Patients are also advised to discard any makeup used prior to treatment and to routinely launder their towels and bedding to prevent these items from serving as potential sources of reinoculation.8
Other treatments for DB
Other potential treatments for DB include hypochlorous acid, such as HyClear (hypochlorous acid 0.01%, Contamac), Avenova (hypochlorous acid 0.01%, NovaBay Pharmaceuticals), and Optase Protect (hypochlorous acid 0.015%, SCOPE). Hypochlorous acid (HOCl) is produced by leukocytes of the immune system as a natural antiseptic agent.73 However, while some studies have suggested that hypochlorous acid may reduce the number of Demodex present, whether the compound is truly demodicidal remains controversial.8,74
Even if hypochlorous acid is not demodicidal it may be helpful in the management of DB, as it has broad antiseptic activity that can reduce the number of Streptococcal and Staphylococcal bacteria present on the lids and lashes, as these bacteria are found on the surface of Demodex mites, and can themselves contribute to chronic bacterial conjunctivitis, which can be a related comorbidity to DB.52-54,73
For this reason, after the initial 6-week period of treatment with TTO, patients can use TTO and hypochlorous acid in tandem, with one used in the morning and the other before bed, to provide two separate mechanisms of lid hygiene that address both the Demodex and bacterial components of blepharitis.Additionally, hypochlorous acid can be a useful alternative in cases where patients are unable to use TTO due to an allergic reaction or intolerance, even if hypochlorous acid cannot reduce Demodex to the same extent as TTO.
Another potential alternative includes okra-based cleansers, such as ZocuFoam Eyelid Cleanser and Moisturizer and ZocuWipes (Zocular) which have also shown capability in eradicating Demodex.75 Though it has traditionally been used to treat blepharitis, the use of baby shampoo should be avoided as not only does it fail to eradicate Demodex, but it can have a detrimental effect on the tear film as well.8,65
As illustrated in Figure 10, it can be challenging to achieve the complete elimination of Demodex. The goal of treatment is to reduce the number of mites and proinflammatory collarettes to an asymptomatic level.
Figure 10: Photo by author
Alternative treatments for Demodex blepharitis
Aside from topical therapies, there are other treatments that can be helpful in managing DB.
In-office debridement
Debridement of the lid margin and lashes using microblepharoexfoliation can be an excellent adjunct treatment to TTO use.48 Demodicosis causes a buildup of debris on the lid margin and lashes due to an accumulation of waste, proteins, Demodex eggs, and collarettes.7,11,12,39,50 This can lead to thickening of the lid margin and physical obstruction of the lash follicles and meibomian glands resulting in MGD and chalazion and hordeolum development, as well as lid margin changes such as notching due to the inflammatory nature of this debris.5,7,8,10,13,39,51
Additionally, the Staphylococcal, Streptococcal, and Bacillus bacteria present on the surface and inside of the mites can add a bacterial component to DB which results in the development of proinflammatory biofilm on the lid margin as well.8,52-54 Microblepharoexfoliation performed in-office, with a device such as NuLids PRO (NuLids) or BlephEx (Blephex), or with an at-home device like NuLids (NuLids) can greatly improve DB by debriding the lids and lashes of inflammatory debris and collarettes, while also reducing the number of Demodex mites and bacteria present.48,79,80
Zocular Eyelid System Treatment
Another alternative exfoliative treatment for DB is ZEST (Zocular Eyelid System Treatment; ZocuKit, Zocular), which involves using an okra-based cleansing gel in conjunction with manual debridement of the lids and lashes.75
Thermal pulsation
Thermal pulsation treatments with in-office procedures like LipiFlow (Johnson & Johnson), iLux (Alcon), or TearCare (Sight Sciences) as well as at-home use of warm compresses can be helpful in managing the MGD observed in DB by melting any clogged meibum and then expressing the obstructed glands.81,82
However, these treatments alone will not address the root cause of the problem in cases of Demodex-associated MGD, as D. brevis are ultimately responsible for the obstruction of the meibomian glands. Therefore, it is necessary to address any demodicosis associated with MGD by using TTO treatment in conjunction with thermal pulsation therapies to achieve maximum benefit.
Tear film stabilizers and neurostimulatory agents
Again, although tear film instability caused by Demodex-induced MGD must ultimately be addressed by a treatment that targets the mites directly, other therapies that can help stabilize the tear film may be beneficial. Miebo (100% perfluorohexyloctane ophthalmic solution, Bausch + Lomb) can help stabilize the tear film by forming a protective monolayer over the surface of the tear film that mimics the function of the lipid layer and aids in preventing premature evaporation,113-115 whereas Tyrvaya (varenicline solution nasal spray 0.03mg, Viatris) increases natural tear production through neurostimulation of the parasympathetic pathway via the trigeminal nerve.116,117
Intense pulsed light therapy
In my professional opinion, another excellent treatment option in cases of DB is intense pulsed light (IPL) therapy. IPL functions through the delivery of high intensity polychromatic light (400-1200 nm) to the target tissue.83,84 IPL is an ideal treatment option for DB because it addresses several components of the condition in a single treatment modality. IPL has been shown to be demodicidal as the chitinous exoskeletons of Demodex contain chromophores that absorb the energy delivered by the pulsed light that leads to a rapid heating of the mite, resulting in death via coagulative necrosis.85,86
Additionally, IPL treatment decreases the number of bacteria present and decreases inflammation via photobiomodulation.86-88 The procedure also has been shown to improve the signs and symptoms of MGD86,89 and can lead to the regression of proinflammatory telangiectatic blood vessels associated with ocular rosacea.86,90 Again, this makes IPL an excellent treatment option for DB as both MGD and ocular rosacea are routinely observed alongside the condition.
The use of IPL for the treatment of MGD and dry is widely supported as the OptiLight IPL device is FDA-approved for these indications.91,92 A typical IPL treatment protocol for DB would be 4 total treatments spaced 3-4 weeks apart.93,94
Omega-3 supplements
Additional treatments to consider are adjunct therapies that address any concomitant ocular surface diseases such as dry eye. Omega-3 fatty acid supplementation is encouraged as it has been shown to improve the signs and symptoms of MGD as well as reduce inflammation.95-99 A high-quality re-esterified, triglyceride-based supplement containing a 3:1 EPA to DHA ratio and at least 2 grams of combined EPA and DHA, such as PRN De3 (PRN Physician Recommended Nutriceuticals), is highly recommended as this formulation has demonstrated efficacy in improving MGD.100
Immunomodulators
Prescription anti-inflammatory medications, such as Xiidra (lifitegrast 5% ophthalmic solution, Novartis), Cequa (cyclosporine 0.09% ophthalmic solution, Sun Pharmaceuticals), Vevye (0.1% cyclosporine Ophthalmic Solution, Harrow), and Restasis (cyclosporine 0.05% ophthalmic emulsion, Allergan) can be helpful in managing long-term inflammation associated with DB.
A patient displaying signs of ocular rosacea, such as pronounced lid margin telangiectasia, may need additional treatment like low-dose oral doxycycline.101,102 Cosmetic redness is another common concern for patients affected by DB. A vasoconstrictive agent such as Lumify (brimonidine tartrate 0.025% ophthalmic solution, Bausch + Lomb), is a treatment of choice as it provides redness reduction without inducing any rebound redness once its effects wear off.103
Again, it should be noted that these treatments should be used in conjunction with a demodicidal agent such as TTO in cases of DB, as the resolution of the condition will only occur if the underlying Demodex infestation is addressed.
Demodicosis can result in several different ocular disorders, including blepharitis, MGD, and chalazion development, all of which can be observed in Figure 11. However, unless the underlying Demodex infestation is treated, these conditions will often remain unresponsive to traditional therapies. Therefore, it is critical to address any mite overpopulation when managing ocular surface conditions in the presence of Demodex.
Figure 11: Photo by author
Educating patients about Demodex blepharitis
Like all ocular surface conditions, patient education is key. This is especially true for DB, as many patients may be unaware that their symptoms of itching, dryness, and redness are not due to allergies or traditional dry eye, but an overabundance of parasitic mites. Therefore, in addition to explaining the condition in a clear and understandable manner (example script for ECPs given below), photographs or the use of models can be powerful tools in helping the patient understand the condition.
When a patient hears that they have mites on their lids and then sees a picture of a mite and collarettes, either their own through slit lamp photography or through an example picture, patients tend to react quite strongly and often respond that they will do whatever they need to get rid of the Demodex. Additionally, it is important to explain that the goal of treatment does not have to be the complete elimination of the mites, as we normally have some level of Demodex on our skin. So, as long as we can keep the number of Demodex at a low enough level that they do not cause ocular symptoms, then they should not experience any issues.
This also sets expectations for treatment and creates an understanding that maintenance therapy in the form of routine lid hygiene with TTO or future retreatment with a prescription medication like Xdemvy may be needed if the Demodex population increases to a problematic level once again. This also helps patients understand exactly what is occurring in DB. This understanding often improves compliance with treatment and ultimately improves outcomes.
Example patient education script for Demodex blepharitis
“Demodex are small mites that live on our skin, specifically in our hair follicles and oil glands. It is completely normal for these mites to be there, as we will all have them at some point in our lives, and, normally, they do not cause any issues. However, in some cases, the number of mites present gets too high, which leads to a buildup of their waste on our eyelids and eyelashes causing irritation and redness. They can also clog up our oil glands which can cause chalazia to form.
Because these mites are not a bacterium or virus, they cannot be treated with antibiotic or antiviral medication. Subsequently, this makes them a little more difficult to get rid of.
Traditionally, we treated the mites with eyelid cleansers like tea tree oil, a compound derived from the tea tree plant which can be applied to the lids and lashes, especially near the lid margin because that is where the mites live. But, one potential issue with these TTO cleansers is the oil is very strong so it can be irritating to the eyes when you use it, especially if it gets in the eye itself because it will cause a stinging or burning sensation.
However, we also now have a prescription option for the treatment of Demodex blepharitis referred to as Xdemvy. The drop is FDA-approved and it is able to effectively reduce the number of mites, eyelash collarettes, and amount of eyelid redness present when used twice a day for 6 weeks. I typically like to start with this treatment and use a lid hygiene cleanser for maintenance afterwards, but if the mites return to infestation levels, we can do another course of Xdemvy.”
Models and photos of Demodex mites, as seen in Figure 12, can be an excellent way to educate patients and help them visually understand their condition. The use of these educational resources can improve compliance and result in better treatment outcomes.
Figure 12: Photo by author
Summary
“Blepharitis is one of the most common conditions ECPs routinely encounter.”
There can be several causes for the condition; however, one often overlooked cause is an overgrowth of Demodex mites. The two mites that affect the eye, D. folliculorum and brevis, reside in the lash follicles and meibomian glands, respectively, which can lead to blepharitis, MGD, lash disruption, conjunctivitis, and even keratitis. Therefore, if a patient develops blepharitis or one of these other ocular surface conditions and does not respond to normal treatments, such as antibiotics or antivirals, demodicosis should be suspected, and if collarettes are present at the base of the lashes, this is pathognomonic for Demodex blepharitis.
As ECPs, it is crucial to properly identify and diagnose Demodex blepharitis, especially now that there exists the first FDA-approved treatment in the form of Xdemvy in addition to traditional therapies such as TTO. By doing so, we can treat the underlying cause of several ocular surface disorders triggered by mite infestation and ultimately potentially improve patients’ ocular surface health and QoL.
