Blepharitis is a general term describing inflammation of the eyelids, whereas marginal blepharitis is inflammation of the eyelid margin, which can be subdivided into anterior and posterior blepharitis.
Anterior blepharitis involves inflammation of the lid margin anterior to the gray line and concentrated around the eyelashes and hair follicles. It may be accompanied by squamous debris, scurfs, and collarettes around the lashes. Posterior blepharitis involves inflammation posterior to the gray line, which may have various causes, including meibomian gland dysfunction (MGD) and conjunctivitis.
MGD is defined as a chronic, diffuse abnormality of the MGs, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in glandular secretion. It may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
Key Features
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Chronic burning, irritation, foreign body sensation, epiphora.
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Inflammatory changes of the eyelid including thickening, erythema, hyperkeratinization, vascularization, telangiectasia, or notching.
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Presence of scurf, collarettes, and sleeves along lashes.
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Minimal meibomian gland secretion with pressure or abnormal meibum, which is turbid, foamy, or granular in appearance.
Introduction
Blepharitis , first described by Elschnig in 1908, poses a significant challenge for the clinician because of its chronic nature and availability of diverse treatment options but minimal scientific evidence for their efficacy.
Nonetheless, given the prevalence of blepharitis, its association with dry eye disease (DED), and its effect on quality of life, better understanding and management of this condition is essential for reducing ocular discomfort and improving the patient’s quality of life.
Epidemiology
MGD is one of the most common disorders encountered by eyecare providers. MGD is now considered the leading cause of evaporative dry eye.
The prevalence of MGD varies considerably in published studies, from 3.5% to almost 70%.
This striking difference is partly attributed to inconsistent diagnostic criteria among countries and to varying age distribution between study groups. The prevalence of MGD is affected by age, with older patients at increased risk of developing MGD.
Pathogenesis
The pathophysiology of blepharitis involves a complex interaction of various factors, including abnormal lid-margin secretions, lid-margin organisms, and a dysfunctional precorneal tear film. Several classification systems exist for blepharitis. It can be anatomically subdivided into anterior blepharitis ( Fig. 4.4.1 ) and posterior blepharitis. Alternatively, blepharitis can be classified according to the presenting clinical features into staphylococcal, seborrheic, mixed staphylococcal and seborrheic, and MGD ( Fig. 4.4.2 ).
The lid inflammation characteristic of blepharitis is most often caused by a combination of anterior and posterior factors of varying degrees. In most types of blepharitis, some MG involvement occurs. MGs are tubuloacinar, holocrine glands that produce and secrete meibum, an oily substance that produces the lipid layer of the preocular tear film. Embedded in the tarsal plates, normally 30–40 MGs occur in the upper lid and 20–30 glands in the lower lid. Each MG consists of a main duct surrounded by grape-like acinar clusters. These ducts open into the lid margin just anterior to the mucocutaneous junction, delivering meibum to the tear film. MGD is defined as a chronic, diffuse abnormality of MGs, commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. Alterations in the composition of the meibomian secretions occur in patients with chronic blepharitis. Alteration in nonpolar lipids raises the melting point of the meibum, leading to thickening of the meibum and stagnation. Decreased amounts of polar lipids result in uneven spreading of tears, likely leading to instability of the tear film and hyperosmolarity, increased bacterial growth, evaporative dry eye, and ocular surface inflammation, including keratinization, scarring, and retraction of the gland orifices, thus further exacerbating MGD. Several factors can aggravate MGD, such as increasing age, contact lens wear, and hormonal imbalance.
Several bacteria, fungi ( Pitysporum ), and parasites ( Demodex ) also have been implicated. The most common organisms isolated from patients with chronic blepharitis include Staphylococcus epidermidis , Propionibacterium acnes , corynebacteria, and Staphylococcus aureus . S. epidermidis and S. aureus produce lipolytic enzymes, such as triglyceride lipase, cholesterol esterase, and wax esterase, which hydrolyze wax and sterol esters with the release of highly irritating free fatty acids, resulting in the disruption of the tear film integrity. In seborrheic blepharitis, the increased amount of low viscosity meibum favors the growth of bacteria and leads to inflammation of the lids. Acne rosacea is a relatively common chronic skin disease characterized by persistent erythema, telangiectasis, papules, pustules, and sebaceous gland hypertrophy, predominantly affecting the forehead, cheeks, and nose. Although the pathogenesis is still unclear, studies suggest that it is primarily caused by an altered innate immune response in those with a genetic predisposition. Certain reactive oxygen species and infectious agents, such as Demodex folliculorum and Helicobacter pylori also have been implicated.
Ocular Manifestations
Typical symptoms of blepharitis include redness, itching, burning, crusting along the lid margin, loss of lashes, stickiness of lashes, and tearing. Furthermore, as MGD has been suggested to be the leading cause of DED, presenting symptoms, such as dryness, ocular irritation, and fluctuating vision, may indicate the need for the clinician to examine the lid margin. These symptoms are chronic, usually waxing and waning, and may be exacerbated by some environmental factors, such as wind, smoke, dust, cosmetic products, and so on. Symptoms usually are bilateral but may be asymmetrical. The presence of predominantly unilateral symptomatology should alert the clinician to consider other diagnoses, such as sebaceous cell carcinoma, which may masquerade as chronic unilateral blepharitis.
External examination using slit-lamp biomicroscopy is essential in establishing diagnosis and determining the type of blepharitis. Staphylococcal anterior blepharitis is more common in the younger population and has a female preponderance. Findings include vascularization and erythema of the lid margin, telangiectasia, eyelid edema, loss or misdirection of lashes, collarettes around the base of the lashes, and crusting or hyperkeratosis. Chronic findings of ulceration, punctal misdirection, and scar formation may be seen. There can be signs of corneal involvement in severe cases, presenting with phlyctenulosis, corneal neovascularization, thinning, or marginal ulceration. Seborrheic blepharitis is more common in the older age group. It presents with scurfs , which is a term used to refer to the scales, oily debris, and greasy material that collects along the lash shaft as a result of hypersecretion from MGs. In blepharitis associated with Demodex sp. infestation, the most commonly seen finding is coating of the lash with cylindrical dandruff-like material (sleeves).
Clinical signs of MGD may include rounding, thickening, and irregularity of the eyelid margin; changes in the lid vascularity and presence of telangiectasia; pouting, plugging, and narrowing of the gland orifices; reduction in volume and number of glands secreting liquid; and changes in gland secretion quality, clarity, and viscosity with greater pressure required to express secretions. “Non-obvious MGD” is a common form of obstructive MGD that shows no obvious signs of inflammation, hypersecretion, or purulent secretion of the glands but may become more apparent with pressure on the lid as the meibum orifices are examined. In chronic MGD, there may be cicatricial changes along the lid margin, and the mucocutaneous junction may migrate anterior to the MG line. Subtle signs, such as the frothy quality of the tear meniscus, and decreased Schirmer’s scores and tear breakup time (TBUT), may be found. Other ocular conditions, such as recurrent chalazia, trichiasis, and keratoconjunctivitis sicca, may be seen. External examination of the face and skin may reveal associated dermatological problems, such as seborrheic dermatitis, atopy, herpes zoster ophthalmicus, and acne rosacea. In ocular rosacea, dilated and telangiectatic vessels at the lid margin and interpalpebral hyperemia may be seen.
Diagnosis and Ancillary Testing
Blepharitis is mainly a clinical diagnosis. However, ancillary testing may be considered in those who have chronic disease or are unresponsive to therapy, to monitor treatment effect, and for research purposes.
Culture samples taken from the eyelid margins may grow the typical bacteria associated with blepharitis, as well as viruses, such as herpes simplex, herpes zoster, and molluscum contagiosum. Microscopic examination of the epilated lashes may show Demodex eggs, and adult mites.
MG secretion can be analyzed by its quality and expressibility. This can be done by digital pressure or with the use of a device that applies a standard pressure that is equivalent to the pressure exerted on the lids during a normal blink. This device targets a standard area of one third of the total number of glands (8–10 glands). Expressibility is graded according to the number of glands that express fluid; decreased expressibility indicates disease. Although it sounds simple, marked variability exists among individuals, and hence a definite cutoff between normal and abnormal cannot be defined. Moreover, the location of the glands along the lid margin influences their expressibility. It was found that nasal glands tend to express most actively, followed by central glands, and then temporal glands. The quality of glandular secretion can be evaluated in terms of appearance. It can be classified as clear, cloudy opaque, viscous, or toothpaste-like by using various grading schemes.
More recently, interferometry has been developed to measure the lipid layer of tears. The patient’s eye is illuminated with light directed at the corneal surface; light passes through the tear film and is reflected into a camera, forming an interference pattern called an interferogram . The interferometer measures the lipid layer thickness of a defined area of tear film and captures the blink profile during a designated time interval. A positive correlation between tear film lipid layer thickness and expressible MGs suggests that a low lipid layer thickness indicates a high probability of MGD.
Changes in MG morphology and gland dropout can be assessed using meiboscopy. This is done with transillumination through the skin and observing the glandular silhouette through the everted mucosal side. Photodocumentation of the same is called meibography . The disadvantage of the transillumination method is that it may be tedious and time consuming. Noncontact meibography applies the same principle but is easier and more rapid than transillumination. It uses an infrared transmitting filter attached to a slit lamp and video camera. Photographs are taken, and MG morphology and dropout are then analyzed. Recent advancements to the technology now include mobile, handheld, pen-shaped systems with an infrared light-emitting diode fixed to the camera, which enables capturing of videos and images that are comparable in quality with previous meibography systems. It is convenient and applicable for examination of MGs in patients of all ages.
Keratography permits visual assessment of the topography of the corneal surface, allowing for an analysis of tear film stability by comparing the irregularities in recorded images. In addition to evaluating TBUT, keratography can examine MGs, tear meniscus height, and lipid layer.
In vivo laser scanning confocal microscopy is a contact technique can be used to examine the microstructure of MG acinar units and measure their size.
Treatment
The goal of all the treatments of MGD is to improve the flow of meibomian gland secretions, thus achieving normal tear film stability.
Treatment strategies aiming at improving the quality of the meibum include a combination of lid hygiene, management of MGD, reducing bacterial colonization of the lids, suppression of inflammation, and restoring tear quality. It is crucial to educate patients about the chronic, recurrent nature of the disease and the need for long-term intervention. Despite the availability of diverse treatment options, very few treatments have been extensively evaluated for safety and efficacy in randomized controlled trials, and most are typically not approved by the U.S. Food and Drug Administration (FDA) for use in blepharitis specifically. Treatment recommendations are largely dependent on clinical experience and published case reports.
Lid hygiene, the mainstay of treatment for blepharitis, consists of warm compresses, lid massage, lid scrubs, and avoidance of excessive eye makeup. Treatment with warm compresses involves the placement of a warm washcloth on closed lids daily for 5–10 minutes. The goals of heat therapy are to soften and loosen encrustations, liquefy the solidified and stagnant secretions, and to dilate ducts. This is followed by lid massage. The eyelid is held taut at the outer corner with one hand while the index finger of the other hand sweeps from the inner corner of the lid toward the ear while applying pressure. This is repeated several times to express the MG contents, which have melted during the warm compresses step. Cleansing with lid scrubs is usually done once or twice daily initially. Commercially available scrubs or a cotton-tipped applicator soaked with a weak solution of baby shampoo can be used to rub along the lid margin to remove deposits and the abnormal oily secretions from the lids. Patients should be instructed to avoid excessive scrubbing and massage because these actions can lead to ocular irritation.
Besides self-care, therapeutic MG expression as an in-office procedure performed by the clinician can help relieve MGD by using probes and/or mechanical pressure to open and express meibum. Intraductal MG probing is a relatively nontraumatic method that utilizes small stainless steel probes to open the MG orifices, and this may mechanically open and dilate the natural orifices and ducts of the MGs.
Participants currently are being recruited for a randomized, double-blind trial investigating the efficacy of intraductal MG probing compared with a sham procedure in patients with refractory MGD. However, therapeutic expression may be painful to the patient. The BlephEx device, a less invasive method of microexfoliation of the lid margins, utilizes a rapidly rotating microsponge to remove lid debris and microbial biofilm from the lid margins. Recently, a new thermopulsation device has been developed, and it allows heat to be applied to the palpebral surfaces of the lids directly over the MGs while simultaneously applying graded pulsatile pressure to the outer eyelid surfaces, thereby gently expressing MGs during heating. The automated treatment device has two main components: a lid warmer and an eye cup. The lid warmer resembles a large oval scleral lens designed to rest on the bulbar conjunctiva and vault the cornea. The eye cup contains an inflatable air bladder that massages the eyelids to express MGs in the upper and lower eyelids simultaneously.
Topical antibiotics are added when underlying bacterial infection is suspected. Bacitracin and erythromycin ophthalmic ointments are effective agents for anterior blepharitis. Generally, ointments are applied directly to the lid margins to avoid toxicity to the ocular surface. Fluoroquinolone eyedrops have minimal ocular toxicity and have a wide coverage of organisms. Topical fusidic acid has shown efficacy in patients with ocular rosacea blepharitis. Although not yet approved by the FDA, topical metronidazole gel 0.75%–1% also may be effective when used on the lid margin for treatment of ocular rosacea. Systemic antibiotics, such as cloxacillin, may be added for treatment of persistent or recurrent staphylococcal blepharitis. Oral tetracyclines are commonly used in the management of rosacea and MGD. They are mainly used for their anti-inflammatory and lipid-regulating properties, rather than for their antimicrobial effects. They decrease the production of bacterial lipases, thus reducing the concentration of free fatty acids and their deleterious effects on lipid composition. They exert anti-inflammatory effects resulting from inhibition of matrix metalloproteinases, cytokines, lymphocyte and neutrophil activation, and chemotaxis. They also have antiangiogenic and antiapoptotic properties. They usually are used in doses ranging from 250 mg once to four times a day (tetracycline and oxytetracycline) to 50–100 mg once or twice a day (doxycycline and minocycline). Low doses of doxycycline 20 mg may be used when long-term therapy is required. A 40 mg/day slow-release dose of doxycycline is approved for treatment of rosacea and is used by some clinicians. Tetracycline use is limited by its common side effects, which include sun sensitivity and gastrointestinal upset and known contraindications for use in pregnant women and children. Oral macrolide antibiotics, such as erythromycin and azithromycin, are safer and also have immunomodulatory and anti-inflammatory effects similar to those of tetracyclines. Recently, the use of a topical azithromycin (1%) was suggested as an effective treatment of posterior blepharitis, with a significant improvement in MG secretion quality, eyelid redness, tear quality, and overall symptomatic relief, but results from studies regarding efficacy are mixed.
In cases with more severe lid margin inflammation, a short-term course of topical corticosteroids or antibiotic–corticosteroid combinations may be utilized. Long-term use of corticosteroids is limited by serious side effects, such as cataracts, glaucoma, and infection. Topical immunomodulators, such as cyclosporine A 0.05%, a calcineurin inhibitor, have been shown to be beneficial in the treatment of MGD in conjunction with rosacea and/or DED, with a significant improvement in lid margin inflammation and signs of DED. Nearly all suggested treatments have not received FDA approval for use in lid disease.
As change in tear composition and tear film stability may be a key contributor to lid margin inflammation, supplementation of the tear film may improve both MGD and DED. Treatment options include tears, gels, ointments, environmental control, and moisture goggles. A newer class of tear substitutes involving the use of lipid-containing eyedrops, liposomal sprays, emulsion-type eyedrops, and ointments that may be more effective than saline-based artificial tears in DED associated with MGD. Dietary supplementation with omega-3 fatty acids has been shown to be effective in improving signs and symptoms of DED and MGD by reducing ocular surface inflammation and improving the lipid composition of meibum.
Several additional methods of treatment exist that have been found to be helpful when used in conjunction with the core interventions mentioned above. Antiseborrheic shampoos, such as those containing selenium sulfide or tar, may be helpful when seborrheic dermatitis is significant. Weekly lid scrubs with 50% tea tree oil and daily lid scrubs with tea tree shampoo are effective in eradicating Demodex infestation of the lids but can be irritating to the ocular surface. As MGD may be related to androgen deficiency or receptor dysfunction, topical androgens are being evaluated as a possible therapeutic option for patients with MGD.
A growing interest exists in the role of blepharitis, especially MGD, in understanding and treating ocular surface disease, especially DED. However, to date, there is still limited understanding of what findings are clinically pathological and associated with signs and symptoms of ocular disease and what treatments would most benefit patients. Current research is addressing environmental, dietary, pharmacological, and surgical interventions to better understand blepharitis and to optimize the treatment of this chronic ocular condition.
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