Article

Do You Know Demodex?

These mites, an overlooked cause of ocular inflammation, can be the root cause of your tougher blepharitis cases

Do You Know Demodex?

These mites, an overlooked cause of ocular inflammation, can be the root cause of your tougher blepharitis cases.

By Jingbo Liu, MD, PhD, and Scheffer C. G. Tseng, MD, PhD

Given the multitude of factors that can contribute to blepharitis, precise diagnosis and targeted therapy are often elusive. However, more cases than you may realize can be directly linked to Demodex, the most common microscopic ectoparasite found in the human skin, due to the eye's general inaccessibility by daily facial hygiene.1

Compounding the problem, ocular inflammation caused by this parasite has not been well recognized by ophthalmologists. As a result, this potential cause is often overlooked in differential diagnosis of corneal and external diseases, let alone the consideration of therapeutic options. In this article, we will discuss the pathogenic potential of Demodex in causing ocular surface inflammation, as well as tips for diagnosis and treatment.

Microscopic Features of Demodex Mites

Two distinct species have been detected on human skin: Demodex folliculorum and Demodex brevis (Figure 1). The adult D. folliculorum is 0.35 to 0.4 mm long with four pairs of well-developed legs and a stumpy body. It is prone to cluster at the root of eyelashes, leading to anterior blepharitis. D. brevis is 0.15 to 0.2 mm long with an evenly distributed head-body ratio. It usually burrows deep in the sebaceous gland and Meibomian gland, causing posterior blepharitis and ocular inflammation.3

Figure 1. Demodex mites at 400x magnification: (A) D. folliculorum adult, (B) larva, and (C) D. brevis.

Life Cycle and Risk Factors

The life-span of the Demodex mite is very short, about 14 to 18 days from the egg to the larval stage followed by five days in the adult stage. Females may live an additional five days after oviposition.4 Because of the limited life-span of the adult mites, mating plays an important role in perpetuating Demodex infestation. For transmission of mites, direct contact is required. The rate of Demodex infestation increases with age, being observed in 84% of the population at age 60 and in 100% of those older than 70 years.2

A number of risk factors have been described for Demodex infestation. Rosacea predisposes patients to blepharitis mainly by creating an environment on the skin that congests all the oil-producing glands necessary for a healthy dermis and epidermis. Other factors may change the environment to encourage mite proliferation, such as skin phototype, sunlight exposure, alcohol intake, smoking, stress, hot beverages, spicy food and abrupt changes in temperature.5

Once Demodex infestation establishes in the face, it is likely to spread and flourish in the eye, leading to blepharitis and ocular inflammation. Again, this is because the eye is generally inaccessible by daily facial hygiene.2

Pathogenesis

Demodex mites consume epithelial cells at the hair follicle and mechanically block the orifices of meibomian glands, causing disorders of the eyelashes6,7 and lipid tear deficiency.8 In addition, Demodex mites can serve as the vector of bacteria. Streptococci and Staphylococci have been found on the surface of their skin, while Bacillus oleronius has recently been detected inside Demodex mites.9 Both mites and the proteins they release may trigger a cascade of host immune responses resulting in severe ocular inflammation.7 Recently, a strong correlation has been found among positive serum immunoreactivity to two bacillus proteins, ocular Demodex infestation, blepharitis and facial rosacea.10

Symptoms and Signs of Ocular Infestation

Itching, burning, foreign body sensation, dryness, redness, light sensitivity, pain and blurry vision can be the patient's complaints once ocular Demodex infestation occurs. Since these findings are also quite common in many other ocular surface disorders, corroborating evidence is necessary if one is to isolate Demodex as the cause. Clinical signs include cylindrical dandruff surrounding the lashes and other disorders of the eyelashes, lid margin inflammation, Meibomian gland dysfunction, blepharo-conjunctivitis and blepharo-keratitis. Here's some elaboration:

Cylindrical dandruff (CD) at the root of eyelashes (Figure 2A), a common finding in some patients with blepharitis, has been shown to be pathognomonic for ocular Demodex infestation using the modified lash sampling and counting method.6 As such, it is the single best indicator of Demodex involvement in the pathogenesis of lid disease for the patient being evaluated.

Disorders of eyelashes such as mal-alignment, trichiasis or madarosis are more common in Demodex blepharitis than in other forms of the disease. Trichiasis may induce secondary trauma to the corneal epithelium, causing punctate epithelial erosions followed by corneal ulceration and pannus formation in severe longstanding cases.

Meibomian gland dysfunction. Blockage of the Meibomian gland orifice by D. brevis may lead to filling, swelling and much enlarged glands (a cyst) or even infection. Such pathogenic change may contribute to the insufficiency of lipid and unstable tear film. Furthermore, granulomatous responses in Meibomian glands may lead to a recurrent hordeolum or chalazion that is refractory to conventional treatments.

Lid margin inflammation. The mechanical blockage and the delayed host immune response can result in the severe lid margin inflammation, including variable injection, neovascularization, thickening and keratinization.

Conjunctival inflammation. In severe and long-standing cases, lid margin inflammation may spread to the conjunctiva, causing blepharo-conjunctivitis. Patients may have notable conjunctivitis as evidenced by redness involving the bulbar conjunctiva and papillary follicular reaction involving the tarsal conjunctiva (Figure 2B). This misdiagnosed Demodex-related conjunctivitis, usually resistant to conventional drugs, provides a challenge for ophthalmologists.

Recently, we reported successful treatment of ocular demodicosis resolves blepharo-conjunctivitis refractory to conventional treatments both in adults8,11 and in pediatric patients (Liang et al, Cornea, 2010, in press). These results suggest that demodicosis may be an overlooked cause of refractory conjunctival inflammation.

Figure 2. The clinical features of Demodex blepharitis include: (A) cylindrical dandruff at the root of the lashes (yellow arrow) and inflamed eyelid, (B) conjunctival inflammation, and (C) a corneal lesion (yellow arrow).

Corneal manifestation. Inflammation derived from the lid margin, especially the meibomian glands, may also spread to the cornea, depending on its severity. Demodex infestation may cause various sight-threatening corneal lesions (Figure 2C), including superficial corneal vascularization, marginal infiltration, superficial opacity and nodular scar.8,11

Our Method of Diagnosis

Besides CD, which is specific for this mite infestation, all symptoms and most signs can be found in other external eye diseases. Therefore, the physician may like to increase the index of suspicion of mite infestation as a potential cause when the above clinical abnormalities cannot be resolved by conventional treatments.

To confirm the diagnosis, we advise using our modified lash sampling and counting method to verify the presence and amount of mite infestation. Here is our protocol:

Supplies:

► Epilation forceps
► Glass slides and cover slips
► 0.25% fluorescein drops
► Light microscope

Lash Epilation and Microscopic Examination (Figure 3):

  1. Under a slit lamp, identify lashes with CD.
  2. Use fine forceps to epilate two lashes from each eyelid after wiggling the lashes to loosen the CD to increase the likelihood of detecting mites.
  3. Place both lashes from each eyelid together inside a circle on a glass slide.
  4. Apply one drop of fluorescein to the center of each circle of each slide.
  5. Put a cover slip over each slide and examine under light microscope.

Differential Diagnosis:

► Conjunctivitis (bacterial, viral and allergic)
► Keratitis (bacterial, fungal and herpetic)
► Keratoconjunctivitis (atopic, epidemic, sicca and superior limbic)
► Dry eye syndrome
► Limbal stem cell deficiency

Managing Ocular Demodex Infestation

Your treatment strategy should be targeted to eradicate the mites, prevent mating and avoid reinfestation. Previously, we found that adult D. folliculorum can dose-dependently be killed by tea tree oil (TTO).12 Moreover, 50% TTO lid scrubs may also attract mites to come out of the lash follicles while the 5% TTO ointment prevents mating and re-infestation from the skin around the eye.

As a result, daily lid scrub with 50% TTO and lid massage with 5% TTO ointment is recommended for eradicating ocular Demodex infestation, as evidenced by bringing the Demodex count down to zero in four weeks in a majority of patients.8,11 We recommend the following precautions to ensure the Demodex does not come back:

  • Discard used facial make-up.
  • Wash hair, face, nostrils, the external ear and the neck with soap daily.
  • Wash bedding and pillow cases in hot water and dry in a heated dryer immediately before beginning a lid scrub regimen, and once a week thereafter.
  • Keep pets away from sleeping surfaces.
  • Avoid direct transmission from family members.

Figure 3. Procedure of lash sampling and fluorescent staining.

Take-Away Points

In summary, Demodex mites may play an important role in the occurrence of ocular inflammation that is refractory to conventional treatments and may be overlooked by ophthalmologists. The modified eyelash sampling and counting method makes it easier and more accurate to diagnose Demodex infestation. As for remedies, tea tree oil shows promising potential to treat Demodex-related ocular inflammation by reducing Demodex counts with additional antibacterial, antifungal and anti-inflammatory actions. OM

References

1. Kamoun B, Fourati M, Feki J, Mlik M, Karray F, Trigui A, Ellouze S, Hammami B, Chaabouni M, Ayadi A. Blepharitis due to Demodex: myth or reality? J Fr Ophtalmol 1999;22:525-527.
2. Post CF, Juhlin E. Demodex folliculorum and blepharitis. Arch Dermatol 1963;88:298-302.
3. Basta-Juzbasic A, Subic JS, Ljubojevic S. Demodex folliculorum in development of dermatitis rosaceiformis steroidica and rosacea-related diseases. Clin Dermatol 2002;20:135-140.
4. Rufli T, Mumcuoglu Y. The hair follicle mites Demodex folliculorum and Demodex brevis: biology and medical importance. A review. Dermatologica 1981;162:1-11.
5. Bernstein JE. Rosacea flushing. Int J Dermatol 1982;21:24.
6. Gao Y-Y, Di Pascuale MA, Li W, Liu D, Baradaran-Rafii A, Elizondo A, Kuo IC, Kawakita T, Raju VK, Tseng SCG. High prevalence of ocular demodex in lashes with cylindrical dandruffs. Invest Ophthalmol Vis Sci 2005;46:3089-3094.
7. Bevins CL, Liu FT. Rosacea: skin innate immunity gone awry? Nat Med 2007;13:904-906.
8. Gao YY, Di Pascuale MA, Elizondo A, Tseng SC. Clinical treatment of ocular demodecosis by lid scrub with tea tree oil. Cornea 2007;26:136-143.
9. Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea 1. Br J Dermatol 2007;157:474-481.
10. Li J, O'Reilly N, Sheha H, Katz R, Raju VK, Kavanagh K, Tseng SC. Correlation between ocular Demodex infestation and serum immunoreactivity to Bacillus proteins in patients with Facial rosacea. Ophthalmology 2010;117:870-877.
11. Kheirkhah A, Casas V, Li W, Raju VK, Tseng SC. Corneal manifestations of ocular demodex infestation. Am J Ophthalmol 2007;143:743-749.
12. Gao Y-Y, Di Pascuale MA, Li W, Baradaran-Rafii A, Elizondo A, Raju VK, Tseng SCG. In vitro and in vivo killing of ocular demodex by tea tree oil. Br J Ophthalmol 2005;89:1468-1473.

Dr. Liu is a clinical fellow at the Ocular Surface Center in Miami and practices at the Eye Hospital, Wenzhou Medical College, China. Dr. Tseng is the medical director of the Ocular Surface Center and research director of the Ocular Surface Foundation in Miami. Contact him via e-mail: stseng@ocularsurface.com

The Latest in Blepharitis Research

By Rene Luthe, Senior Associate Editor

Four recent studies from Cornea show investigators making strides in finding new and effective treatments.

A study in the August 2010 issue looked at the effect of four weeks of treatment with azithromycin ophthalmic solution 1% (AzaSite) on signs and symptoms of blepharitis, eyelid bacterial load and tear cytokines. Twenty-six subjects mild to severe cases were treated for 28 days in the multisite, open-label study. Dosage was BID on days 1 and 2, and QD on days 3 through 28; no warm compresses or eyelid scrubs were administered. Blepharitis signs and symptoms were evaluated at baseline and compared with end of treatment, on day 29, and with follow-up visits at two weeks and four weeks post-treatment. The researchers also performed tear collection and eyelid margin bacterial cultures at baseline and end of treatment; tear cytokines were measured by a multiplex immunobead assay.
The researchers reported that four-week azithromycin therapy showed “significant decreases” from baseline for Meibomian gland plugging (P < 0.001),="" eyelid="" margin="" redness="">P < 0.001),="" palpebral="" conjunctival="" redness="">P < 0.001)="" and="" ocular="" discharge="">P < 0.002)="" at="" day="" 29.="" these="" improvements="" persisted="" at="" 4="" weeks="">
As for lid margin bacterial load, significant decreases from baseline were found for coagulse-negative Staphylococci and Corynebacterium xerosis (P = 0.037 and < 0.001,="" respectively).="" additionally,="" subject-reported="" symptoms="" including="" eyelid="" itching,="" foreign="" body="" sensation,="" ocular="" dryness,="" ocular="" burning/pain="" and="" swollen="" eyelids="" demonstrated="" improvement="" from="" baseline.="" changes="" in="" the="" concentration="" of="" cytokines="" in="" subjects'="" tears="" were="" not="" observed="" after="" treatment="" with="">
Haque RM, Torkildsen GL, Brubaker K, et al. Multicenter Open-label study evaluating the efficacy of azithromycin ophthalmic solution 1% on the signs and symptoms of subjects with blepharitis. Cornea. Aug. 2010. 8:871-877.

A prospective, observational open-label clinical trial examined the effect of topical azithromycin ophthalmic solution on both clinical signs and symptoms of Meibomian gland dysfunction (MGD), and spectroscopic behavior of the Meibomian gland lipids. Twenty-two subjects diagnosed with symptomatic MGD who were unresponsive to lid massage after application of a hot compress to the eyelids were recruited. Signs of MGD were evaluated with a slit lamp, and symptoms were measured by subjects' responses to a questionnaire. Approximately 1 mg of Meibum lipid was obtained from each subject for direct spectroscopic study. All subjects were dosed 1% topical azithromycin ophthalmic solution BID for two days, then QD for the duration of the four-week study. All subjects reported relief or absence of symptoms at four weeks of therapy. According to the investigators, “All signs of eyelid margin disease improved at four weeks, including the number of obstructed glands, the amount of lid margin erythema, the ease of expression of the meibomian glands and the character of meibomian gland secretion.” Additionally, improvement in TBUT was statistically significant at four weeks (P < 0.001).="" the="" study="" appears="" in="" the="" july="" 2010="" issue="" of="">Cornea.
Foulks GN, Borchman D, Yappert M, Kim SH, McKay JW. Topical azithromycin therapy for meibomian gland dysfunction: Clinical response and lipid alterations. Cornea. July 2010. 7: 781-788.

A novel thermodynamic treatment device to address obstructive MGD associated with dry eye succeeded in restoring Meibomian gland functionality in a subject with severe evaporative dry eye, according to a report in the August issue of Cornea. The device applies controlled heat directly to the upper and lower palpebral conjunctival surfaces and eyelid margins via direct contact with a resistive heater. Meanwhile, pulsating pressure is simultaneously applied to the outer eyelids using an inflatable air bladder (TearScience). The subject was diagnosed with MGD; none of the approximately 24 Meibomian glands of the right lower eyelid and one gland of the left lower eyelid were functional. Prior to insertion of the treatment device, the patient received two drops of topical anesthetic. Each treatment lasted for 12 minutes. The treatment restored the functionality of eight glands in each eye, the investigators report, doubled fluorescein break-up time and decreased symptom scores by 80%.
Follow-up visits occurred at 1 week, 1 month and 3 months post-treatment. While there was a significant decrease in symptoms at 1 week, the most significant drop was seen at one month; this reduction was maintained at 3 months, the investigators report. Additionally, there was no change in the patient's IOP or in ocular surface staining following treatment.
Korb DR, Blackie CA. Restoration of Meibomian gland functionality with novel thermodynamic treatment device: A case report. Cornea. Aug. 2010. 8:930-933

Investigators examined 55 eyes of 55 subjects with perennial allergic conjunctivitis (AC) and 47 control eyes to observe morphologic changes of Meibomian glands and to assess the relation between morphologic changes of the meibomian glands of both eyelids and tear film parameters. Subjects underwent slit lamp examination, measurement of tear film break-up time, grading of meibomian gland morphologic changes assessed with a noncontact meibography, Meibomian gland duct distortion in meibography, tear production by the Schirmer I test, and grading of meibum expression. The investigators found that the frequency of Meibomian gland duct distortion was 45% greater in patients with AC than in controls (8.5%; P < 0.0001).="" additonally,="" the="" meibum="">P = 0.049) and superficial punctate keratopathy scores (P = 0.0076) were “significantly higher” in AC subjects than in controls. Investigators found no significant difference, however, in meibography score, TFBUT or Schirmer value between the AC and control subjects. Finally, the Meibomian expression score was significantly higher in subjects with AC with meibomian gland duct distortion than in AC subjects AC without Meibomian gland duct distortion (P = 0.0012).
Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, Amano S. Meibomian gland duct distortion in patients with perennial allergic conjunctivitis. Cornea. Aug. 2010. 8:858-860.