Blepharitis is an inflammatory disease centered on the eyelid margin. It is also called marginal blepharitis. It is one of the most common diseases in ophthalmology, occurring in all age groups and ethnicities. Although it usually does not directly threaten vision, severe cases can lead to corneal epithelial disorders and corneal neovascularization.
Based on anatomical location, it is broadly divided into anterior blepharitis and posterior blepharitis. Anterior blepharitis is inflammation from the eyelash root to the skin side, and is classified by cause into staphylococcal (ulcerative) blepharitis and seborrheic (squamous) blepharitis. Mixed types with both present are not uncommon. Posterior blepharitis primarily involves inflammation of the meibomian glands and is often treated as meibomian gland dysfunction (MGD)3)4).
MGD is defined in the Japanese Ophthalmological Society’s Clinical Practice Guidelines for Meibomian Gland Dysfunction 2023 as “a condition in which the function of the meibomian glands is diffusely abnormal due to various causes, accompanied by chronic ocular discomfort”4). MGD is broadly classified into two types: hyposecretory and hypersecretory, with hyposecretory type accounting for the majority4).
In addition, Demodex blepharitis associated with infestation by Demodex folliculorum and Demodex brevis has been attracting attention as a subtype of blepharitis1). Approximately 30% of patients with chronic blepharitis show Demodex infestation, and in refractory cases, antiparasitic treatment may be effective.
Epidemiology in Japan (MGD Clinical Practice Guidelines 2023)
A population-based study of residents aged 6 to 96 years conducted in Japan showed that the prevalence of MGD clearly increases with age4).
Ages 19 and under: 0%
20s: 11.8%
30s: 5.6%
40s: 21.6%
50s: 32.8%
60s: 41.9%
70s: 48.4%
80s: 63.9%
Multiple reports indicate that blepharitis is more common in males and postmenopausal women4). Risk factors include aging, as well as Asian ethnicity, rural residence, video display terminal work, smoking, soft contact lens wear, and long-term use of glaucoma eye drops4). In a US survey, signs of blepharitis were observed in 37–47% of ophthalmic outpatients, with staphylococcal blepharitis being more common in relatively younger patients (mean age 42) and in women. Demodex-related blepharitis has been reported to affect over 80% of those aged 60 and above, and nearly 100% of those aged 70 and above1).
QHow common are blepharitis and MGD?
A
In a survey of Japanese residents, the prevalence of MGD reaches approximately 11.8% in their 20s, 21.6% in their 40s, 41.9% in their 60s, and 63.9% in their 80s4). It clearly increases with age, and more than half of older adults are estimated to have some form of meibomian gland dysfunction. It is reported to be more common in males and postmenopausal women4).
Slit-lamp photograph of marginal blepharitis. Redness, scales, telangiectasia of the eyelid margin, and meibomian gland abnormalities are visible.
Pyzia J, et al. Demodex Species and Culturable Microorganism Co-Infestations in Patients with Blepharitis. Life (Basel). 2023. Figure 2. PMCID: PMC10533081. License: CC BY.
(A) Meibomian gland dysfunction, keratotic scales, mild blepharitis; (B) Meibomian gland dysfunction, telangiectasia of the eyelid margin, epiphora; (C) Meibomian gland obstruction, telangiectasia of the eyelid margin; (D) Clinical appearance of Demodex blepharitis showing meibomian gland obstruction. This corresponds to “Meibomian gland dysfunction” discussed in the section “2. Main Symptoms and Clinical Findings.”
The main symptoms of chronic blepharitis are a burning sensation, foreign body sensation, and itching of the eyelids. It may also be accompanied by hyperemia, epiphora, discharge, blurred vision, and photophobia. Symptoms tend to worsen in the morning and are characterized by repeated remissions and exacerbations. Staphylococcal blepharitis often presents with acute burning sensation and redness of the eyelid margin. In contrast, seborrheic blepharitis typically begins with a relatively mild chronic burning sensation and foreign body sensation.
MGD is characterized by ocular discomfort, a sensation of pressure, dryness, fatigue, and an abnormal sensation often described as a “sticky feeling”4). Differential diagnosis based solely on subjective symptoms is difficult, and a comprehensive assessment including slit-lamp microscopy findings is necessary4).
Demodex blepharitis is characterized by intense itching from nighttime to early morning, with 80% of patients reporting interference with daily activities, 47% reporting difficulty with nighttime driving, and 34% reporting restrictions on contact lens use or makeup application1).
Observation using a slit-lamp microscope, particularly with a diffuser, is fundamental. The findings by disease type are summarized below.
Anterior Blepharitis
Staphylococcal (ulcerative): Bilateral eyelid margin redness, small papules, small pustules, small ulcers, and crusting occur. Fibrin-derived collarettes surrounding the base of the eyelashes are a characteristic finding. In severe cases, destruction of hair follicles leads to madarosis (loss of eyelashes) and trichiasis, complicated by chronic conjunctivitis and punctate epitheliopathy of the cornea and conjunctiva.
Seborrheic: Redness and edema are milder than in staphylococcal blepharitis, but conjunctival injection around the eyelid margin and greasy, easily removable scales are observed. The characteristic finding is “seborrheic lashes” in which multiple eyelashes become bundled together. Since hair follicles are not destroyed, eyelashes regenerate.
Posterior blepharitis (MGD)
Meibomian gland orifice findings: Obstruction of meibomian gland orifices (plugging, pouting, ridge), disarray of orifice arrangement, anterior or posterior displacement of the mucocutaneous junction, eyelid margin irregularity, and eyelid margin telangiectasia are observed4). Yellow liquid or solidified contents are expressed upon meibomian gland compression.
Associated findings: In seborrheic blepharitis, meibomian foam forms along the lower eyelid margin. Severe cases are accompanied by tarsal thickening and palpebral conjunctival papillary hypertrophy. Reduction of the tear film lipid layer leads to evaporative dry eye, and diffuse superficial keratitis frequently coexists3)4).
Demodex blepharitis
Pathological signs: Cylindrical dandruff at the eyelash base is a highly significant pathological finding and, like collarettes, serves as a diagnostic clue1)2). It is accompanied by conjunctival hyperemia, redness, swelling, telangiectasia of the eyelid margin, and excessive eyelash loss.
Special types: Demodex brevis hides within the meibomian glands and may not be detected by eyelash epilation testing. Cases have been reported in which it can be detected by expressing meibum after cleaning the eyelid margin and observing it directly under a microscope5). Severe keratitis with corneal ulcers and neovascularization has also been reported in pediatric cases, and differentiation of demodicosis is important in treatment-resistant keratitis2).
In Japanese clinical practice, the Shimazaki classification, which evaluates meibum characteristics by applying moderate pressure to the center of the tarsal plate, is widely used.
Grade 0: Clear meibum is easily expressed with light pressure (normal)
Grade 1: Cloudy meibum is expressed with light pressure
Grade 2: Cloudy meibum is expressed with moderate or greater pressure
Grade 3: Meibum cannot be expressed even with firm pressure
Grade 2 or higher is considered abnormal and is used to determine “reduced meibum secretion” in the diagnostic criteria for MGD4).
QWhat are collarettes?
A
Collarettes are scales (dandruff-like deposits) that form around the base of the eyelashes. In staphylococcal blepharitis, fibrin formed in ulcerated areas of the eyelid margin is lifted as the eyelashes grow. In Demodex blepharitis, they are called cylindrical dandruff and serve as a diagnostically significant finding 1)2).
The etiology of blepharitis is multifactorial, and the primary causes differ by disease subtype.
Staphylococcal blepharitis is associated with staphylococcal proliferation on the ocular surface. Cultures are positive for Staphylococcus aureus in 46–51% of patients, which is markedly higher than the 8% observed in healthy individuals. Bacterial exotoxins cause punctate epithelial keratopathy in the adjacent cornea and conjunctival epithelium. Moraxella is an important cause of angular blepharitis.
Seborrheic blepharitis is frequently associated with seborrheic dermatitis, with one report finding seborrheic dermatitis in 95% of patients. Rosacea dermatitis has been reported in 20–42% of all types of blepharitis patients and is recognized as an important cause of blepharitis.
Mechanism of MGD development is summarized in the Japan MGD Clinical Practice Guidelines 2023 as follows4). The main pathophysiology of hyposecretory MGD is hyperkeratinization of the meibomian gland duct epithelium and atrophy of the acini. Acinar atrophy may occur not only secondary to obstruction but also as a primary impairment of gland cells due to aging and other factors.
Demodex (Demodex folliculorum and Demodex brevis) parasitizes sebaceous glands, hair follicles, and meibomian glands, and their excretions and secretions induce follicle obstruction and inflammation1). Inflammatory cytokines such as IL-1β and IL-17, as well as MMP-9, are activated. Demodex also functions as a vector for bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and Streptococcus pneumoniae, and has been reported to potentially promote ocular surface superinfection1).
The association with dry eye is also important. Dry eye is observed in 50% of patients with staphylococcal blepharitis. In MGD, tear lipid layer deficiency leads to increased evaporation, with a dry eye comorbidity rate of 25–40%3). MGD and dry eye have a mutually exacerbating relationship.
QHow are dry eye and blepharitis related?
A
Both conditions are closely related. A qualitative and quantitative decline in the tear film lipid layer due to MGD is a major cause of evaporative dry eye3). Meanwhile, the reduction in lysozyme and immunoglobulins associated with decreased tear fluid promotes the development of staphylococcal blepharitis. Therefore, treatment of blepharitis and treatment of dry eye must be carried out concurrently.
Diagnosis is based primarily on medical history and slit-lamp microscopy. Determine whether the onset is acute or chronic, bilateral or unilateral, and painful or painless. Inquire about systemic diseases (Sjögren’s syndrome, rosacea, diabetes, atopy, thyroid disease, sinusitis), allergy history, use of cosmetics and eye drops, contact lens wear, and smoking history.
Inspection and palpation assess eyelid redness, swelling (diffuse or localized), tenderness, and the presence of eczema. For painful, localized, unilateral swelling, differentiate between hordeolum and acute chalazion; for painful, diffuse, bilateral swelling, differentiate between eyelid abscess and orbital cellulitis.
The diagnosis of hyposecretory MGD is based on all three of the following items being positive4).
Diagnostic item
Positive criterion
Subjective symptoms
Presence of symptoms such as ocular discomfort, foreign body sensation, and feeling of pressure
Findings around the meibomian gland orifice
One or more of: vascular dilation, displacement of the mucocutaneous junction, or irregularity of the eyelid margin
Opening obstruction findings
Obstructive findings such as plugging AND Shimazaki classification grade 2 or higher
These diagnostic criteria proposed by the MGD Working Group in 2010 are widely used, but internationally unified diagnostic criteria do not yet exist4).
Auxiliary Tests (MGD Clinical Practice Guidelines 2023 CQ)
Meibography (infrared): Non-invasively visualizes meibomian gland morphology. Can quantify dropout area, gland shortening, and dilatation, and is recommended for MGD diagnosis4)
Tear Break-Up Time (TBUT): Often shortened in MGD, but not a specific test4)
Slit-lamp observation of meibum: Recommended4)
Fluorescein staining: Most versatile for evaluating corneal and conjunctival epithelial damage4)
Tear osmolarity measurement: Useful for diagnosing concurrent dry eye, reported to have 59% sensitivity and 94% specificity at 316 mOsm/L or higher
Microscopic examination of epilated eyelashes is the basic method. Lee et al. identified adult and larval D. folliculorum under a light microscope by epilating 4 eyelashes from each of the upper and lower lids2). However, D. brevis may not be detected by eyelash epilation because it resides within the meibomian glands. Zhang and Liang detected 15 D. brevis organisms by expressing meibum after antimicrobial treatment of the eyelid margin and examining it under a microscope, reporting that there are cases of Demodex blepharitis where D. brevis exists only within the meibum without external findings5).
For severe recurrent anterior blepharitis or treatment-resistant cases, bacterial culture of the eyelid margin (Staphylococcus, Moraxella) is indicated. For markedly asymmetric, unilateral refractory chalazion-like lesions, eyelid biopsy should be considered to rule out sebaceous gland carcinoma in middle-aged to older patients. Sebaceous gland carcinoma is known to masquerade as refractory blepharitis or chalazion-like lesions.
Differential diagnosis includes chalazion, eyelid abscess, orbital cellulitis, herpetic blepharitis (VZV, HSV), allergic blepharitis, eyelid dermatitis (contact, drug-induced, atopic), eczematous blepharitis, and sebaceous gland carcinoma.
Blepharitis is a chronic condition, and the cornerstone of treatment is controlling symptoms and inflammatory signs. There is no strong evidence for a complete cure, and long-term management is necessary. Treatment strategy is based primarily on the Japanese MGD Clinical Practice Guidelines 20234).
First-Line Treatment: Eyelid Care (Warm Compresses, Lid Hygiene, Meibum Expression)
Warm compresses are described in the MGD Clinical Practice Guidelines 2023 as being strongly recommended for implementation4). By raising the eyelid temperature to the melting point of meibum, it dissolves meibum and promotes secretion, while also improving eyelid blood flow. Patients are instructed to use a commercially available warm eye mask at home at least twice a day for 5 minutes or more. Hot towels are convenient but difficult to temperature-regulate, and in a wet state they cool due to evaporative heat loss, making them a second-line option.
Lid hygiene is described in the same guidelines as being weakly recommended for implementation4). Using a cotton ball moistened with water or a commercially available cleansing agent (such as diluted baby shampoo), properly clean the base of the eyelashes with a cotton swab. Improvements in subjective symptoms, meibomian gland orifice findings, meibum grade, TBUT, and corneal and conjunctival epithelial damage can be expected. Note that adverse events may occur depending on the type of cleansing agent used4).
Meibum expression is effective for obstructive MGD and is weakly recommended4). In outpatient settings, specialized instruments such as the Arita meibomian gland expression forceps (Inami) are used, performed at intervals of approximately 10 days to 1 month. If plugging is extensive, it is removed with forceps or a needle after topical anesthesia.
Topical antibiotics: For staphylococcal blepharitis, bacitracin or erythromycin ophthalmic ointment is applied to the eyelid margin before bedtime, used for 2 to 8 weeks. Azithromycin hydrate ophthalmic solution improves subjective symptoms, orifice findings, and meibum grade in MGD, and is weakly recommended in the guidelines4).
Oral antibiotics: Tetracyclines and macrolides are used for their anti-inflammatory and lipid-regulating effects. Tapering tetracycline from 1,000 mg/day to 250 mg/day, tapering minocycline hydrochloride from 200 mg/day to 100 mg/day, doxycycline 100 mg orally twice daily tapered over 3 to 4 months, and combination with macrolides such as clarithromycin are employed. These are thought to exert their effects by suppressing bacterial enzyme activity and inhibiting biofilm formation.
Topical steroids: When inflammation is severe, 0.1% fluorometholone may be used short-term in combination. The MGD guidelines weakly recommend their use alongside eyelid hygiene and warm compresses to improve subjective symptoms, TBUT, eyelid margin findings, and meibum quality4). In Japan, insurance coverage applies only when blepharitis is also present4).
Artificial tears and adjunctive eye drops: Used adjunctively in cases complicated by evaporative or aqueous-deficient dry eye. Preservative-free formulations should be chosen when used four or more times daily. Diquafosol sodium eye drops are not covered by insurance for MGD alone, and the guidelines weakly recommend against their use for isolated MGD4).
Treatment of Demodex Blepharitis
Tea tree oil (TTO): Its main component, terpinen-4-ol (T4O), exhibits an acetylcholinesterase inhibitory effect, producing a miticidal action1). It is used at concentrations of 5–50%. One report found improvement in all cases after weekly eyelid scrubs with 50% TTO combined with daily scrubs with 0.4% PHMB for six weeks2).
Oral and topical antiparasitic drugs: The combination of ivermectin (which acts on GABA receptors in parasites to induce paralysis) and metronidazole (which causes DNA damage via nitro radicals) is considered the most effective approach1). Both oral and topical routes may be considered.
Mechanical debridement: Combine eyelid margin cleansing with warm compresses and continue daily eyelid care.
Adjuvant therapy: Add artificial tears in cases with concurrent dry eye.
The mechanisms of action of drugs against Demodex are compared below.
Treatment
Mechanism of action
Notes
TTO
AChE inhibition1)
Widely available
Ivermectin
GABA receptor inhibition1)
Enhanced efficacy when combined with metronidazole1)
Angular blepharitis: Administer ophthalmic drops or ointment with high susceptibility to staphylococci.
Herpetic blepharitis (HSV): Start acyclovir ointment (Zovirax ointment) 5 times daily, then reduce frequency as improvement occurs. Use antibiotic ophthalmic drops 3 times daily to prevent mixed infection. In principle, do not use steroids concomitantly.
Herpetic blepharitis (VZV, ophthalmic herpes zoster): Systemic administration of acyclovir or valacyclovir hydrochloride from the early stage of onset can achieve early improvement of lesions.
The MGD guidelines weakly recommend against the use of cyclosporine A eye drops due to limited efficacy4). IPL (Intense Pulsed Light) therapy is strongly recommended based on evidence, but it is not approved as a medical device in Japan and is not covered by insurance, so the recommendation remains weak at this stage4).
QWhat eyelid care can I do at home?
A
The basics consist of three steps: warm compresses, eyelid massage, and eyelid cleansing3)4). First, apply a clean towel or a heated eye mask to the eyelids for at least 5 minutes twice a day. Next, gently massage the upper and lower eyelids in a vertical direction to promote meibomian gland secretion. Finally, carefully clean the eyelash roots with a water-moistened cotton ball or a dedicated cleansing agent. Even after the acute phase has subsided, daily continuation is important.
Staphylococcal blepharitis involves both direct ocular surface irritation by bacterial toxins and enhanced cell-mediated immunity against Staphylococcus aureus. Bacterial exotoxins cause punctate epithelial damage to the adjacent corneal and conjunctival epithelium. Bacterial lipases act on meibomian gland lipids to produce free fatty acids, which trigger inflammation and lead to further gland obstruction, forming a vicious cycle.
The essence of MGD is obstruction of the terminal ducts of the meibomian glands3). The Japanese MGD Clinical Practice Guidelines state that “the main pathophysiology of hyposecretory meibomian gland dysfunction is ductal epithelial hyperkeratinization and acinar atrophy”4). Acinar atrophy may occur not only secondary to meibomian gland obstruction but also as a result of primary damage to acinar cells due to aging, among other causes4). Ductal epithelial hyperkeratinization and increased meibum viscosity lead to progressive obstruction, followed by gland dropout, atrophy, and reduced secretion.
The tear film lipid layer consists of an outer nonpolar layer and an inner polar layer, and it contributes to evaporation prevention and smoothing of the optical surface3). Reduced lipid supply from the meibomian glands leads to evaporative dry eye and increased tear film osmolarity, which in turn induces ocular surface inflammation and epithelial damage3). Alterations in lipid layer composition (increases in ceramides and cholesterol) have been shown to cause disruption and destabilization of the meibomian lipid film3).
In Demodex infestation, the mites’ waste products and secretions cause physical blockage of hair follicles and activate the host’s hypersensitivity reaction1). Inflammatory cytokines such as IL-1β, IL-17, and MMP-9 are induced. Furthermore, D. folliculorum has been reported to act as a vector for bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and Streptococcus pneumoniae, potentially promoting ocular surface superinfection1). D. brevis has been reported to hide within the meibomian glands and present with MGD-like findings, and some cases are difficult to diagnose based on external findings alone5).
The development of novel treatments for Demodex-related blepharitis has been actively progressing in recent years.
Lotilaner Ophthalmic Solution 0.25% (XDEMVY) is an isoxazoline compound that induces spastic paralysis by inhibiting Demodex GABA receptors and glutamate-gated chloride channels1). In a Phase 3 clinical trial (Saturn-2 trial, 412 patients), twice-daily administration for 6 weeks achieved a collarettes resolution rate of 56%, mite eradication rate of 51.8%, and erythema clearance rate of 31.1%1). 90.7% of participants reported good tolerability, with side effects being mild, including burning sensation and mild blurred vision1). It has been approved by the US FDA, with European approval expected around 2027, while the approval timeline in Japan remains undetermined1).
IPL (Intense Pulsed Light) therapy irradiates broadband light, immobilizing and killing Demodex mites through photothermolysis1). In vitro experiments have confirmed that the mite temperature rises to approximately 49°C, resulting in death. After four IPL treatments, significant improvements in OSDI, tear lipid layer, TBUT, meibomian gland secretion, and a reduction in mite count have been reported1). Some reports indicate that improvement at one month was more rapid and pronounced compared to TTO alone. In the Japanese MGD Clinical Practice Guidelines, IPL is strongly recommended based on evidence; however, it remains unapproved as a medical device in Japan and is not covered by insurance, so it is only a weak recommendation4).
BlephEx is a method that uses a rotating microsponge to mechanically remove debris, mites, and collarettes from the eyelid margin1). It is also expected to have a bacterial biofilm disruption effect. Significant improvements in OSDI parameters and mite counts have been reported when used in combination with TTO, but further research is needed to verify long-term efficacy1).
Exploration of natural essential oils is also underway, with reports that sage oil kills mites within 7 minutes and peppermint oil within 11 minutes1). Synergistic effects of castor oil, bergamot oil, and nigella seed oil are also being investigated.
Czepińska-Myszura et al. state that “among new treatments, only Lotilaner ophthalmic solution has demonstrated high efficacy in large-scale clinical trials, while IPL and blepharoexfoliation remain validated only in limited patient populations”1).
Lee et al. analyzed 9 cases of Demodex blepharitis and reported that all cases were D. folliculorum, and that even pediatric cases (ages 5, 13, and 14) presented with severe keratitis involving corneal ulcers and neovascularization2). Demodex infection in children is easily overlooked, and differential diagnosis for Demodex is important in recurrent keratitis2). Additionally, Zhang and Liang reported a case of a 46-year-old man with 15 Demodex brevis organisms found only within the meibum without any external findings, demonstrating that direct meibum observation after lid margin cleansing contributes to diagnosis in refractory cases5).
QCan Lotilaner (XDEMVY) be used in Japan?
A
As of 2025, Lotilaner ophthalmic solution 0.25% (XDEMVY) has been approved by the US FDA, but is not yet approved in Japan or Europe1). Approval in Europe is expected around 2027. The timing of approval in Japan has not been determined, and treatment currently centers on TTO and antiparasitic medications.
Czepińska-Myszura A, Kozioł MM, Rymgayłło-Jankowska B. Pharmacotherapy of Demodex-Associated Blepharitis: Current Trends and Future Perspectives. Pharmacy. 2025;13(5):148.
Lee YI, Seo M, Cho KJ. Demodex Blepharitis: An Analysis of Nine Patients. Korean J Parasitol. 2022;60(6):429-432.
Sabeti S, Kheirkhah A, Yin J, Dana R. Management of Meibomian Gland Dysfunction: a Review. Surv Ophthalmol. 2020;65(2):205-217.
