key literature and our research experience regarding the pathogenic potential of Demodex mitesin causing ocular surface inflammation with a special emphasis on blepharitis.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptLife of Demodex mites in human
Two distinct species have been identified in human: Demodex folliculorum and D. brevis (Fig.1). In the eyelids, D. folliculorum can be found in the lash follicle, whereas D. brevis burrowsdeep into sebaceous glands and meibomian glands looking for sebum which is thought to betheir main food source. It has also been proposed that these mites might feed on follicular andglandular epithelial cells leading to direct damage of the lid margin. The life cycle of theDemodex mite is approximately 14–18 days from the egg to the larval stage followed by 5 daysin the adult stage. Females may live an additional 5 days after oviposition [12]. Because of thelimited life span of the adult mites, mating plays an important role in perpetuating Demodexinfestation. Furthermore, Demodex’s life span is limited outside the living body, thus, directcontact is required for transmission of mites. Accordingly, it is important to prevent mating ofmites and avoid direct transmission as an indispensable treatment strategy.
Risk factors of Demodex blepharitis
Recently, we have demonstrated a close correlation between the severity of rosacea and
Demodex blepharitis [13••]. Rosacea predisposes patients to blepharitis mainly by creating anenvironment on the skin that congests all the oil-producing glands necessary for a healthydermis and epidermis. Other factors may change the environment to encourage mites’
proliferation, such as the skin phototype, sunlight exposure, alcohol intake, smoking, stress,hot beverages, spicy food, and abrupt changes in temperature [14,15]. Because of the anatomicfeature of the face, eyelids are not accessible to routine cleansing hygiene providing a favorableenvironment for Demodex mites to spread and flourish. Infestation of Demodex mites is proneto develop in patients whose local or systemic immune status is compromised by topical orsystemic administration of steroids or other immunosuppressive agents or by diseases such asleukemia and HIV [16].
Pathogenesis
Demodex blepharitis can be divided anatomically into anterior and posterior blepharitis. Theformer refers to infestation of eyelashes and follicles by D. folliculorum, clustering to the rootof the lashes, whereas the latter involves infestation of the meibomian gland preferentially byD. brevis. The following action mechanisms have been proposed to explain the pathogenic roleof Demodex in blepharitis.
Direct damage
Demodex mites, especially folliculorum, consume epithelial cells at the hair follicle resultingin follicular distention, which may contribute to formation of loose or misdirected lashes.Micro-abrasions caused by the mite’s claws can induce epithelial hyperplasia and reactivehyperkeratinization around the base of the lashes, forming cylindrical dandruff [17,18]. On theother hand, D. brevis can mechanically block the orifices of meibomian glands, giving rise tomeibomian gland dysfunction with lipid tear deficiency [19]. D. brevis usually burrows deepinto the meibomian glands and its chitinous exoskeleton may act as a foreign body causinggranulomatous reaction. D. brevis has been observed in the center of meibomian granulomas,surrounded by epithelioid cells, histocytes fibroblasts, lymphocytes, and plasma cells [20,21].Thus, Demodex mites may be a potential cause of recurrent and refractory chalazia.
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Vector for bacteria
Demodex mite can cause blepharitis by carrying bacteria on its surface including
Streptococci and Staphylococci. Superantigens produced by these bacteria are also implicatedin the induction of rosacea [22]. In addition, bacterium inside Demodex mites has been foundimportant to trigger the host immune reaction. Bacillus oleronius, which was recently detectedinside Demodex mites, can stimulate proliferation of peripheral blood mononuclear cells inpatients with rosacea [23]. Our collaborative and prospective study further disclosed a strongcorrelation among positive serum immunoreactivity to the 83-kDa and 62-kDa bacillusproteins, ocular Demodex infestation, facial rosacea, and blepharitis [13••]. Even the dyingmites in the follicles or glands may increase the release of these two bacterial antigens loadingto a critical level to trigger a cascade of host inflammatory responses [18].
Hypersensitivity reaction
The protein inside the Demodex mites as mentioned above, and their debris or wastes may elicithost’s inflammatory responses via a delayed hypersensitivity or an innate immune response[18]. By studying 92 consecutive cases of papulopustular rosacea and 92 age- and sex-matchedcontrols, Georgala et al. [5] found that hair follicle infestation was associated with intenseperifollicular infiltrate of predominantly (90–95%) CD4 helper or inducer T cells. An increasednumber of macrophages and Langerhans cells were observed only in those subjects with apositive D. folliculorum finding.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptClinical manifestation
The main symptoms are itching, burning, foreign body sensation, crusting and redness of thelid margin, and blurry vision. Signs include cylindrical dandruff, disorders of eyelashes, lidmargin inflammation, meibomian gland dysfunction, blepharoconjunctivitis, andblepharokeratitis.
Disorders of eyelashes
In addition to cylindrical dandruff found in Demodex blepharitis (Fig. 2a), persistent infestationof the lash follicles may lead to malalignment, trichiasis or madarosis (Fig. 2b). Trichiasis mayinduce trauma to the corneal epithelium causing punctate epithelial erosions followed bycorneal ulceration and pannus formation in severe longstanding cases.
Meibomian gland dysfunction
Blockage of the meibomian gland orifice may lead to filling, swelling, and much enlargedglands (a cyst) or even infection which prevents the spread of the lipid over the tear film [19](Fig. 2c). Furthermore, granulomatous responses in meibomian glands may lead to hordeolumor chalazion. In order to detect the changes in the time and pattern of lipid spread and stabilityof resultant lipid thickness, DR1 that detects the tear interference images can be used in patientswith meibomian gland dysfunction. Our previous study showed that vertical streaking wasobvious in eyes with lipid tear deficiency dry eye, where the lipid layer is much thinner andthe spreading time is delayed [19,24].
Lid margin inflammation
The mechanical blockage and the delayed host immune hypersensitive reaction can result inthe severe lid margin inflammation. Our previous study [13••] has already shown that there isa close correlation between facial rosacea and lid margin inflammation. Therefore, infraredphotography can be used to proportionally correlate the skin temperature with the severity ofinflammation caused by Demodex infestation, demonstrating ‘fire-red’ Demodex face [19].
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Conjunctival inflammation
Without proper hygiene, lid margin inflammation (Fig. 2d) may spread over to the conjunctivaproducing a condition known as blepharoconjunctivitis (Fig. 2e). This misdiagnosedDemodex-related conjunctivitis is usually refractory to conventional medications.
Ourclinical experience reveals that successful treatment of ocular demodicosis resolvesblepharoconjunctivitis in adults when traditional therapies have failed [19,25]. AlthoughDemodex has been implicated as a potential cause of blepharoconjunctivitis in adults [8,10,11,19,25,26], its role in children remains unclear. Recently, we reported ocular demodicosisin 12 healthy pediatric patients with a history of recurrent blepharoconjunctivitis refractory toconventional treatments. All patients had notable conjunctivitis as evidenced by redness
involving bulbar conjunctiva and papillary follicular reaction involving the tarsal conjunctiva[27]. Using the lid scrubs or massage to eradicate mites, all patients showed dramatic resolutionof ocular irritation and inflammation but Demodex counts dropped. These results suggest thatdemodicosis may be an over-looked cause of refractory pediatric blepharoconjunctivitis.
Corneal manifestation
Inflammation derived from the lid margin, especially meibomian glands, may also spread tothe cornea, depending on its severity. Demodex infestation may cause various sight threateningcorneal lesions including superficial corneal vascularization, marginal infiltration, a
phlyctenule-like lesion, superficial opacity, and nodular scar [19,25] (Fig. 2f). Interestingly,D. brevis is more often associated with such corneal manifestation although the chance ofdetecting D. brevis, normally thought to reside singly in the sebaceous and meibomian glands,in epilated lashes is rather rare in the general patient population. Future studies are needed todetermine whether such an unusually high infestation rate of D. brevis may play a causativerole in inducing these corneal manifestations.
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptDiagnosis
The potential criteria for diagnosis of Demodex blepharitis are summarized below:
1.
Clinical history: high index of suspicion when blepharitis, conjunctivitis or keratitisin adult patients or blepharoconjunctivitis or recurrent chalazia in young patients arerefractory to conventional treatments, or when there is madarosis or recurrenttrichiasis.
Slit-lamp examination: typical cylindrical dandruff at the root of eyelashes.Microscopic confirmation: detection and counting of Demodex eggs, lavae and adultmites in epilated lashes.
2.3.
Previously, there had been argument regarding whether cylindrical dandruff in eyelashes, acommon finding in some patients with blepharitis, is pathognomonic of Demodex infestationor not. Our previous study has provided strong evidence to support that prior controversy hasresulted from random lash epilation and miscounting. Using a modified sampling and countingmethod, we show that eyelashes with cylindrical dandruff indeed have significantly higherDemodex infestation [17].
In brief, under a slit-lamp microscope at a magnification of ×25, two lashes, one from eachhalf of each lid, are removed by fine forceps and placed separately on each end of glass slides.A coverslip is mounted onto each lash before slowly pipetting 20 μl of saline to the edge ofthe coverslip to surround the lash. This maneuver results in preservation of the Demodex thathas a loose contact with the lash at the tip. Under the microscope, the number of Demodex iscounted in a conventional manner. If a compacted cylindrical dandruff is preserved, 20 μl of
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Liu et al.Page 5
100% alcohol or 0.25% fluorescein drops is pipetted into the edge of the coverslip, and thecounting time is prolonged up to 20 min to allow the embedded Demodex to migrate from thecylindrical dandruff (Fig. 3) [28].
NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptTreatment regimen
Various treatments have been used to control Demodex mites such as mercury oxide 1%ointment, pilocarpine gel, sulfur ointment, and camphorated oil. Most of them involve
spreading an ointment at the base of the eyelashes at night to trap mites as they emerge fromtheir burrow and/or move from one follicle to another. However, using an in-vitro microscopicobservation for a period of 150 min, we found that adult D. folliculorum is resistant to a widerange of common antiseptic solutions including 75% alcohol and 10% povidone–iodine, andsuch antimicrobials as erythromycin and metronidazole but can dose-dependently be killed bytea tree oil (TTO) [29]. Unlike Baby shampoo, lid scrub with TTO not only cleanses cylindricaldandruff from the lash root but also stimulates embedded mites to migrate out to the skin. Asa result, daily lid scrub with 50% TTO and lid massage with 5% TTO ointment are effectivein eradicating ocular Demodex infestation in vivo, as evidenced by bringing the Demodex countdown to zero in 4 weeks in a majority of patients [19,25,30] (Fig. 4). The two treatments wereequally effective in eradicating mites although we presume they may act differently. The 50%TTO has direct killing effect on the mites, whereas the 5% may interrupt their life cycle bypreventing mating. Apart from Demodex eradication, TTO treatments resulted in dramaticalleviation of symptoms and marked resolution of inflammation in the lid margin, conjunctiva,and cornea [19]. Because TTO also may exert antibacterial [25,31,32] antifungal [33-37], andanti-inflammatory actions [38,39], we cannot attribute its therapeutic benefit in treating theabove eye diseases solely to its effect of killing mites. As the Demodex also serves as the vectorof the skin organisms, the comorbidity based on a symbiotic relationship of B. oleronius inDemodex mites also justifies the consideration of a therapeutic strategy directed to killing thesymbiotic bacterium via oral antibiotics such as tetracycline.
Conclusion
Demodex mite plays an important role in the occurrence of a series of ocular surface diseasessuch as Demodex blepharitis, meibomian gland dysfunction, conjunctival inflammation, andcorneal lesions. Ocular infestation has a close relationship with the systemic infestation. Furtherstudies are needed for developing easy and sensitive diagnostic methods and more effectiveand specific treating regimens.
Acknowledgments
A part of the studies described in this article is supported by a research grant 1R43 EY019586-01 from NationalInstitutes of Health, National Eye Institute. The content is solely the responsibility of the authors and does notnecessarily represent the official views of the National Institutes of Health.
References and recommended reading
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•••
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NIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1. Microscopic photograph of Demodex mites
Demodex folliculorum (a), Demodex brevis (b), Demodex larva with three pairs of poorlydeveloped legs (c) and Demodex egg (d).
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NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptCurr Opin Allergy Clin Immunol. Author manuscript; available in PMC 2010 October 1.
Figure 2. Ocular manifestations of Demodex infestation
Photographs demonstrating the typical cylindrical dundraff at the root of the eyelashes (a, redarrow); misdirected lashes (b, blue arrow); meibomian gland dysfunction (c, green arrow); lidmargin inflammation (d, black arrow); bulbar conjunctiva inflammation (e); corneal infiltrationand pannus (f, yellow arrow).
Liu et al.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptPage 10
Figure 3. Microscopic examination of lashes
Obscured Demodex mites in a compact dandruff (a, green arrows) were easily detected afteradding 0.25% fluorescein solution (b, blue arrows). Reproduced from [28].
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Figure 4. Photographs before and after TTO treatments
Cylindrical dandruff (a), lid margin inflammation and bulbar conjunctival injection (b) andmarginal corneal vascularization (c; yellow arrows) were resolved with TTO regimen (d–f),respectively. Reproduced from [25].
Curr Opin Allergy Clin Immunol. Author manuscript; available in PMC 2010 October 1.
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