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The ocular surface is an integrated functional unit containing eight interdependent entities: the tears, the eyelids, the naso-lacrimal drainage apparatus, the lacrimal functional unit producing tears, the cornea epithelium, the conjunctival epithelium, the fifth cranial nerve and the seventh cranial nerve.¹ Malfunction or disease in any of these components may adversely affect visual performance and patient comfort. Blepharitis is a broad term describing inflammation of the eyelid, which is a complex appendage comprised of eight major components, starting anteriorly and dissecting posteriorly: the skin, orbicularis oculi, lash follicles, lashes, the grey line, the tarsal plate, the meibomian glands and the tarsal conjunctival epithelium (see Figure 1). Each tissue is subject to specific afflictions, where inflammation in one component can adversely affect every other adjacent tissue. We will explore how each tissue is affected by blepharitis.

Cutaneous Layer

Blepharitis is often simplistically parsed into anterior: skin, lashes, and muscle; and posterior: tarsus, meibomian glands and conjunctiva. Although useful, more specific identification of the primary pathology better serves treatment success.

The lid skin may reflect diffuse dermatologic diseases including eczema, psoriasis, contact dermatitis, and several viral diseases including verrucae, molluscum contagiosum, herpes simplex, and herpes zoster.² Collaboration with a dermatologist is fruitful because degenerative cutaneous diseases including xanthalasma, seborrheic keratoses, erythroderma, synringomas, hydrocystomas and acrochordons often demand oculo-plastic expertise.

Careful attention to excipients in dermatologic preparations should avoid ocular surface irritation. Preservative-free topical loteprednol ointment (Lotemax, Bausch + Lomb) as well as topical calcineurin inhibitors—such as pimecrolimus (Elidel, Bausch + Lomb) and tacrolimus (Protopic, Astellas)—are also useful for recalcitrant cases of seborrheic and atopic dermatitis.³

Orbicularis Oculi

The facial nerve, cranial nerve VII, innervates the orbicularis oculi. A variety of neurogenic disorders affect orbicularis function including myasthenia gravis, benign essential blepharospasm, ocular myokymia, psychogenic ptosis and Bell’s palsy and facial nerve paralysis from surgical trauma, injury or neoplasia. Orbicularis inflammation may occur in thyroid ophthalmopathy, orbital pseudotumor, pre-septal or orbital cellulitis, sarcoidosis and IgG4 related disease.⁴ The orbital septum interdigitates with the orbicularis posteriorly, providing a barrier to infection. The levator palpebrae superioris slides posterior to the orbicularis and Mullers muscle elevates the eye lid and tarsus.⁵

Lash Follicles

Two of 65 known Demodex species, Demodex folliculorum and Demodex brevis are human ectoparasites that commonly infest eyelash follicles, becoming more prevalent with each decade of life.⁶ Demodex blepharitis causes redness, itching, swelling, crusting, discomfort, cosmetic disadvantage and, classically, collarettes at the cilia base. Commonly associated dermatopathology includes rosacea, demodicosis and seborrheic dermatitis.⁷ There is no available cure. Treatment strategies include topical tea tree oil or its active ingredient terpinen-4-ol. Both are commercially available (Cliradex, BioTissue) with favorable clinical outcomes. Alternative treatments include lid hygiene, hypochlorous acid, metronidazole, selenium sulfide, microblepharoexfoliation and topical or oral ivermectin.⁸ Novel, now FDA-approved targeted anti-parasitic therapy with BID topical lotilaner ophthalmic solution 0.25% (Xdemvy, Tarsus Pharmaceuticals) for 6 weeks was safe and well tolerated. It met the primary end point and all secondary end points for the treatment of Demodex blepharitis compared with vehicle control in a phase 3 trial.⁹

Lashes

Trichiasis or misdirected lashes results from trauma, inflammation or tarsal scarring, and can create damage to the ocular surface. Lash loss or madarosis¹⁰ may result from chronic tarsitis, alopecia universalis, alopecia areata, psoriasis, atopic dermatitis, hypothyroidism, chemotherapy, herpetic blepharitis, trauma, trichotillomania, lupus and scleroderma.

Grey Line

Lid-wiper region, at the juncture of conjunctival mucosal and cutaneous epithelium, is composed of a thin layer of stratified squamous epithelium that overlies a dense layer of connective tissue.¹¹ This area is responsible for distributing the tear film evenly across the ocular surface. Any damage can lead to poor tear film quality and stability, resulting in a range of ocular symptoms, including foreign body sensation, burning and redness. Diagnosis is accomplished by fluorescein staining and lid eversion. Treatment includes topical anti-inflammatories, tear replacement strategies and contact lens optimization or discontinuation.

Tarsal Plate

The inferior tarsal plate is readily observed by lower lid retraction with a finger or cotton tip applicator. The superior tarsal plate is best seen with eversion, which is readily accomplished with a cooperative patient in relaxed downgaze. Younger and less willing patients respond better to topical anesthesia. A wealth of information can be gleaned and documented from the superior tarsus, including acute inflammation with papillae, edema and vasodilation; as well as chronic inflammation with follicles, concretions, sub-epithelial scarring and vessel dropout or complete loss of normal vascular structures.¹² Tarsal examination is essential to evaluation of recalcitrant conjunctivitis, superior limbic keratoconjunctivitis, trachoma, chronic ocular pain, ptosis, floppy eyelid syndrome, giant fornix syndrome, ocular surface neoplasia and dry eye.

Meibomian Glands

Meibomian gland disease (MGD) is highly prevalent and responsible for 86% of dry eye disease cases, especially as we age.¹³ Classic symptoms of burning, redness, itching and epiphora overlap with other blepharitis etiologies. Slitlamp observation of the meibomian orifices and the sphincter of Riolan; expression, compression, and qualitative characterization of meibomian content; and meibography readily identify MGD. Local treatment recommendations include warm compresses, lid massage, medicated lid wipes, hypochlorous acid spray,¹⁴ tea tree oil¹⁵ or home expression devices such as NuLids. Office interventions include thermal pulsation (LipiFlow, Johnson & Johnson), heat with expression (TearCare, Sight Sciences), LED heating (Systane iLux, Alcon), blepharoexfoliation (BlephEx) and intense pulsed light, which is especially effective for patients with rosacea.¹⁶ Oral antibiotic therapy with appropriate precautions and concomitant probiotics using low dose doxycycline 20 to 50 mg per day or azithromycin 250 mg per day is also productive for selected individuals.¹⁷

Conjunctival Epithelium

The conjunctiva consists of a non-keratinized epithelial layer, three to five cells thick, composed of stratified squamous and stratified columnar epithelium, interspersed goblet cells, immune cells, accessory lacrimal glands and an underlying substantia propria.¹⁸ The conjunctival ocular surface epithelium has 17 times the surface area of the cornea, reflecting off the bulbar surface into the fornices then overlying the superior and inferior tarsus. Conjunctivitis may be classified into bacterial, viral, parasitic, allergic, toxic, chemical and keratoblepharoconjunctivitis, depending upon its primary etiology. Most cases of blepharitis spill over into the conjunctival epithelium, and therapeutic interventions cross over as well. Conjunctival scarring is an important indicator of significant antecedent chronic or acute inflammation, with inferior cicatrix following severe adenovirus infection, alkaline chemical burns or pemphigoid, while superior tarsal disease reflects atopic, autoimmune, trachomatous, superior limbic keratitis or contact lens-induced inflammation.¹²

Diagnosis

Blepharitis is a clinical diagnosis. A detailed history and careful examination of the lids, meibomian expression contents, adnexa, face, pre-auricular lymph nodes, the ocular surface with slitlamp evaluation of vital stains and everted superior tarsus will focus a differential diagnosis.

Prevention

Avoidance of local irritating agents, unnecessary medications, cheap makeup, solutions with preservatives and allergens can reduce medication requirements and clinic visits. The advisory committee on immunization practices strongly recommends two doses of recombinant zoster vaccine (RZV, Shingrix, GlaxoSmithKline) for all patients 50 and above,¹⁹ as well as selected immunodeficient patients above the age of 19 with HIV infection, autoimmune disease or malignancy.²⁰

Prognosis

Most blepharitis patients improve with targeted therapy, preventive measures and individualized environmental management. Some forms persist for decades, and cures are rare. Relapses and remissions are best controlled by an educated, motivated, self-aware patient.

References

1. Friend J, Thoft RA. Functional competence of regenerating ocular surface epithelium. Invest Ophthalmol Vis Sci. 1978 Feb;17(2):134-139.
2. Chang P, Moreno-Coutiño G. Periocular dermatoses. Int J Womens Dermatol. 2017 Sep;3(4):206-218. doi:10.1016/j.ijwd.2017.08.001
3. Tzu JH, Utine CA, Stern ME, Akpek EK. Topical calcineurin inhibitors in the treatment of steroid-dependent atopic keratoconjunctivitis. Cornea. 2012 Jun;31(6):649-654. doi:10.1097/ICO.0b013e31822481c2
4. Lee MJ, Planck SR, Choi D, et al. Non-specific orbital inflammation: current understanding and unmet needs. Prog Retin Eye Res. 2021 Mar;81:100885. doi:10.1016/j.preteyeres.2020.100885
5. Tong J, Lopez MJ, Fakoya AO, Patel BC. Anatomy, head and neck: orbicularis oculi muscle. [Updated 2024 May 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441907/
6. Chioveanu FG, Niculet E, Torlac C, Busila C, Tatu AL. Beyond the surface: understanding Demodex and its link to blepharitis and facial dermatoses. Clin Ophthalmol. 2024 Jun;18:1801-1810. doi:10.2147/OPTH.S440199
7. Ayres BD, Donnenfeld E, Farid M, et al. Clinical diagnosis and management of Demodex blepharitis: the Demodex Expert Panel on Treatment and Eyelid Health (DEPTH). Eye (Lond). 2023 Oct;37(15):3249-3255. doi:10.1038/s41433-023-02500-4
8. Shah PP, Stein RL, Perry HD. Update on the management of Demodex blepharitis. Cornea. 2022 Aug;41(8):934-939. doi:10.1097/ICO.0000000000002911
9. Gaddie IB, Donnenfeld ED, Karpecki P, et al. Lotilaner ophthalmic solution 0.25% for Demodex blepharitis: randomized, vehicle-controlled, multicenter, phase 3 trial (Saturn-2). Ophthalmology. 2023 Oct;130(10):1015-1023. doi:10.1016/j.ophtha.2023.05.030
10. Aumond S, Bitton E. The eyelash follicle features and anomalies: a review. J Optom. 2018 Oct-Dec;11(4):211-222. doi:10.1016/j.optom.2018.05.003
11. Korb DR, Herman JP, Blackie CA, et al. Prevalence of lid wiper epitheliopathy in subjects with dry eye signs and symptoms. Cornea. 2010 Apr;29(4):377-383. doi:10.1097/ICO.0b013e3181ba0cb2
12. Solomon AW, Kello AB, Bangert M, et al. The simplified trachoma grading system, amended. Bull World Health Organ. 2020 Oct;98(10):698-705. doi:10.2471/BLT.19.248708
13. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012 May;31(5):472-478. doi:10.1097/ICO.0b013e318225415a
14. Akl MM. Hypochlorous acid has emerged as a potential alternative to conventional antibiotics due to its broad-spectrum antimicrobial activity. Int J Clin Microbiol Biochem Technol. 2023;6:001-004. doi:10.29328/journal.ijcmbt.1001026
15. Tighe S, Gao YY, Tseng SCG. Terpinen-4-ol is the most active ingredient of tea tree oil to kill Demodex mites. Transl Visi Sci Technol. 2013 Nov;2(7):2., doi:10.1167/tvst.2.7.2
16. Zhang W, Cao X, Yang L, Duan Y, Zhang W. Analysis of treatment efficacy of intense pulsed light (M22) for meibomian gland dysfunction with Demodex mites. Clin Cosmet Investig Dermatol. 2023 Dec;16:3743-3751. doi:10.2147/CCID.S435723.
17. Onghanseng N, Ng SM, Halim MS, Nguyen QD. Oral antibiotics for chronic blepharitis. Cochrane Database Syst Rev. 2021 Jun;6(6):CD013697.
18. Takahashi Y, Watanabe A, Matsuda H, et al. Anatomy of secretory glands in the eyelid and conjunctiva: a photographic review. Ophthalmic Plast Reconstr Surg. 2013 May-Jun;29(3):215-219. doi:10.1097/IOP.0b013e3182833dee.
19. CDC. Shingles (herpes zoster). Accessed November 21, 2024. https://www.cdc.gov/shingles
20. Lu PJ, Hung M-C, Srivastav A, Williams WW, Dooling KL. Shingles vaccination of U.S. adults aged 50-59 years and ≥60 years before recommendations for use of recombinant zoster vaccine. Am J Prev Med. 2020 Jul;59(1):21-31. doi:10.1016/j.amepre.2020.01.017
    
    
    

    

    John D. Sheppard, MD is a board-certified ophthalmologist and fellowship-trained corneal eye surgeon in Norfolk, Virginia.