Strategies to Diagnose and Treat Lid Margin Disease

Deciphering the various symptoms of LMD is key to prescribing the appropriate treatments.

By Kelly Nichols, O.D., M.P.H., Ph.D., F.A.A.O.

The diagnosis and treatment of lid margin disease (LMD) can be especially challenging for the clinician. Diagnosis is difficult because LMD and ocular surface conditions often coexist, with overlapping signs and symptoms. Treatment is complicated because LMD typically is a chronic condition requiring long-term management. Furthermore, no comprehensive, universally accepted treatment approach exists.

However, progress is being made. Interest in the best ways to diagnose and treat LMD is increasing. We've gained new insights into the interactions of eyelid microflora, meibomian gland function, tear film function and the inflammatory mediators responsible for the clinical manifestations of LMD. As a result, new therapies have improved our ability to treat LMD, and significant additional advances appear to be on the horizon. This article follows current thinking to summarize the steps clinicians can take to improve the care of patients with LMD.

Symptom Assessment

LMD can be classified as either anterior blepharitis (staphylococcal or seborrheic) or posterior blepharitis (meibomian gland disease or meibomian seborrhea). Patients' descriptions of symptoms tend to be similar for all types of LMD. They may report burning, itching, sensitivity to light, and a gritty, foreign body sensation that may worsen upon waking. These symptoms also are common in dry eye, ocular allergy, conjunctivitis and hypersensitivity reactions. Therefore, delving deeper into complaints from patients is necessary for gaining additional insight into their cause(s). For example, it can be useful to ask patients about the timing and duration of their symptoms and if they've experienced symptom improvement with past therapies.

Thorough examination of the eyelids and lashes should be performed to detect the clinical manifestations most likely to be associated with LMD. Anterior blepharitis predominantly affects the lids around the lashes and is characterized by inflammation due to excessive bacterial colonization in the area. Scaling, flaky debris and lid crusting, which may appear greasy, are usually present. Removal of crusting may leave small lid margin ulcers that ooze or bleed. Loss of lashes, eyelid thickening, or abnormal lash growth also may be seen, especially in chronic cases. Sties may be present and patients also may have seborrheic dermatitis.

Patients with posterior blepharitis present with redness around the gland orifice and inflammation of the lid margin fine vasculature.

Patients with meibomian gland disease (MGD) also present with inflammation and a thickening of the posterior lid margin. They may have coexisting seborrheic dermatitis or rosacea. In addition, they may have chalazia, which unlike sties, are most prominent on the inside of the eyelid. Detection of posterior blepharitis hinges on close examination of the meibomian glands. No meibomian gland grading scheme is widely accepted; however, evaluating and grading lid margin redness, gland secretions and gland dropout are useful for diagnosis, as well as for monitoring the effects of treatment. The more severe the clinical signs in these areas, the more likely LMD is involved or responsible for symptoms.

Redness around the gland orifice, pouting of the gland orifice and inflammation of the lid margin fine vasculature can be graded from zero (clear/none) to 4 (extreme). The glands can be expressed and the quantity and quality (color of secretions) can be graded from zero (expresses easily and is clear) to 4 (expresses with significant force and is opaque). Expressing the glands involves encouraging lipid secretion by applying pressure to the lid with a finger or cotton-tipped applicator for 5 to 10 seconds, while moving the finger or applicator along the lid margin using an upward rolling pressure toward the lashes. Normal lipid secretion typically is instantaneous or rapid, but it's important to note that not every gland is actively secreting all of the time. If glands are blocked, lipid expression could take longer or not occur at all.

Meibography by transillumination of the eyelid is useful for evaluating meibomian gland morphology and density.¹ A common technique is to visualize the central 10 glands on each lower lid, counting how many are present and how many have "dropped out," meaning they aren't visible and aren't functioning. The more glands that have dropped out, the less able the lid is to secrete lipids adequately enough to maintain tear film stability. As such, meibomian gland disease is a frequent cause of evaporative dry eye.

The close connection between dry eye and posterior blepharitis dictates that clinicians must distinguish between the aqueous deficient and evaporative forms of dry eye. When dry eye is due to meibomian gland disease, treatments targeting the aqueous deficient form, such as artificial tears and punctal plugs, won't resolve symptoms. Using the Schirmer or phenol red thread test to measure baseline tear production volume is useful for differentiating between evaporative and aqueous deficient dry eye. Also, when corneal dyes are used as part of the ocular surface exam, staining usually appears inferiorly when LMD is present.

Updated Approach to Therapy

According to the 2007 Report of the Dry Eye WorkShop (DEWS²), meibomian gland disease may cause or contribute to dry eye, but dry eye also may exist independently of the condition. Therefore, the best clinical approach is to treat LMD early for 6 to 12 weeks and repeat the ocular surface examination to determine whether dry eye remains after the lid disease is resolved. Often, signs and symptoms of dry eye resolve following treatment of anterior and posterior blepharitis. However, if tear production volume remains low after LMD treatment, therapies aimed at aqueous deficient dry eye can be initiated or supplemented.

Infrared meibography is useful for evaluating meibomian gland morphology. The same effect can be achieved using a transilluminator to invert and back-light the lower lid.

The mainstay of therapy for both anterior and posterior blepharitis is lid hygiene (lid scrubs) and lid hyperthermia (warm compresses). Lid hygiene is necessary for controlling symptoms and preventing complications. Lid scrubs are a more important factor for anterior blepharitis because a key goal of therapy is to remove the flakes and crustiness (which are a haven for bacteria) from the lashes and lids. Several types of lid scrub products are available including liquids that are applied to sterile pads and premoistened pads and foams. Some clinicians recommend cleaning the lids and lashes by dipping a Q-tip in water-diluted baby shampoo, but this "home remedy" may be too harsh for some patients. Certain types of gentle facial cleansers may be an acceptable option.

While lid scrubs are key for good hygiene in cases of anterior blepharitis, they also may be helpful in posterior blepharitis or in mixed cases. Along with warm compresses, lid scrubs may stimulate meibomian gland secretions while simultaneously and gently cleaning the lid margin. It's still unclear if bacteria play a primary role in meibomian gland disease, or a secondary role in contributing to the inflammatory condition. When in doubt, therapy should address a potential bacterial component. Warm compresses are particularly important in posterior blepharitis, because they heat the meibum, softening it so it's more easily secreted.

Several strategies on how to apply warm compresses can be recommended, but no consensus exists on which is most effective. Furthermore, effectiveness depends on how often the patient uses the compresses, and the technique that's used. The hotter the compress and the longer it's applied, the better the results. Frequently recommended methods include heating a cloth with warm tap water, wetting a cloth and heating it in the microwave, or filling a clean sock with uncooked rice and heating it in the microwave. In addition, patients can use commercially available gel-filled eye masks. The clinician must gauge the level of compliance the patient is likely to sustain when selecting the type of compress therapy to recommend.

Medical Therapy

Mild cases of anterior or posterior blepharitis may respond to lid scrubs and warm compresses, but more severe cases may require medical therapy — topical or oral antibiotics and perhaps topical steroids — to control the infectious component and inflammation.

When considering the use of medical therapy, clinicians should keep in mind the following factors:

• Severity of the condition. Given the lack of specific grading and classification schemes for LMD, severity is a clinical judgment call. Clinicians can rely on the patient's complaints and perception of symptom severity, backed by the clinical findings when determining whether medical therapy is needed.

• Effectiveness of the agent. Oral tetracycline-type of antibiotics, particularly doxycycline and minocycline, often are prescribed for patients with LMD. These antibiotics have been shown to be effective,^3–7 but the dosing regimens vary. When LMD is chronic, as is often the case, long-term therapy may be required. In these cases, lower-dose doxycycline has been effective.⁸ Often, erythromycin ointment also is prescribed. It's a safe option, but it may have limited effectiveness.⁹ In some cases, the addition of a topical steroid/antibiotic combination ointment or a topical steroid alone may produce better results than an antibiotic alone. In general, patients are prescribed a short course of steroids, which is then tapered. Chronic use of steroids isn't recommended because of potential side effects, such as increased IOP, cataract development, delayed wound healing and potential alterations to the bacterial flora. While steroids may be appropriate for acute cases of anterior blepharitis, other alternatives should be used for MGD.

• Potential for toxicity reactions, allergic reactions and unwanted side effects. All medications have the potential to cause toxic or allergic reactions; therefore, LMD patients undergoing treatment should be monitored for these effects. Some oral and topical medications are more likely than others to cause such reactions. For example, some topical antibiotics (drops and ointments) can create hypersensitivity reactions (staining) on the ocular surface and eyelids, such as redness, irritation and swelling.

In addition, oral tetracyclines have known side effects, including gastrointestinal upset and sun sensitivity. They also may reduce the effectiveness of other medications, such as birth control pills.

Evolving Treatment Protocols

Given the potential systemic side effects of oral medications and the challenges of patient compliance — especially with long-term therapy — safe, effective, less frequently-dosed topical treatments for LMD are an attractive option. A recent addition to the antibiotic market, azithromycin ophthalmic solution 1% (Azasite, Inspire Pharmaceuticals), may be useful. Azithromycin is a macrolide antibiotic indicated for the treatment of bacterial conjunctivitis caused by CDC coryneform group G, Staphylococcus aureus, Streptococcus mitis, Streptococcus pneumoniae and Haemophilus influenzae. In addition to their antibacterial properties, macrolides have known anti-inflammatory characteristics.¹⁰

This topical formulation of azithromycin provides prolonged drug concentration in eyelid and conjunctival tissue^11,12 and has been well-tolerated. Azithromycin remains on the ocular surface longer than conventional drops.^13,14 This may be due to the gel-forming characteristics of its drop formulation and because it's a lipophilic molecule. Furthermore, it has a simpler dosing schedule — one drop once or twice a day — than other currently available ocular anti-infective drops.^15–17 These characteristics may allow for less frequent, individually tailored dosing regimens when this medication is used off-label, which in turn could improve patient compliance.

Azithromycin has changed the LMD treatment regimen for anterior and posterior blepharitis at our clinic and others. It's given us the ability to employ an effective topical treatment instead of beginning medical therapy with a systemic medication that has associated side effects and compliance challenges. We recommend that patients follow their nighttime lid hygiene routine with one drop of azithromycin instilled in the eyes. Because of the viscosity of the drop, it will disperse easily to the lids and lashes. It may be rubbed on the eyelids, using a clean fingertip. We have patients follow this routine for a minimum of 2 weeks to a month, and we closely monitor their results.

Another recent shift in the treatment of LMD is the use of omega fatty acids to help control inflammation and provide a potential alternative to long-term use of oral antibiotics.^18–20 Omega fatty acids are increasingly being prescribed by a variety of practitioners, based on theory and early evidence that reducing the overall inflammatory status of the body may benefit patients with a wide range of conditions. The entire mechanism by which this occurs is unclear, but it's thought to be related to the arachidonic acid pathway and inhibition of inflammatory mediators that are the end result of that pathway.

Clinical trial research is limited regarding the efficacy of oral supplements for ocular surface disease and LMD, but a growing body of evidence is linking natural dietary intake of fatty acids with benefits in dry eye conditions. There's no consensus on the amount that should be recommended for patients with dry eye and LMD, but most clinicians suggest 2 or 3 grams a day. This is based on the premise that people on average consume approximately 1 gram a day as part of their usual dietary intake. An off-label 4-gram a day prescription of omega-3-acid ethyl esters (Lovaza, GlaxoSmithKline) and over-the-counter fish oil capsules or flax seed also can be used. Although anterior and posterior blepharitis have an inflammatory component, omega fatty acid supplementation shouldn't be expected to have an immediate effect on LMD. This is especially true in the more acute, anterior infection-based cases, where an antibiotic and/or a steroid will have more immediate effects.

Long-term Management of LMD

Even when the available therapies are effective, LMD tends to be a chronic condition, and this is particularly true in cases of posterior blepharitis. However, patients with anterior staphylococcal blepharitis seem to be susceptible to the offending bacteria, and therefore are prone to repeated infections. Although flare-ups of anterior blepharitis can be controlled relatively quickly, these cases can become chronic. The eyelids struggle to recover after each bout, and tissue destruction and scarring can result.

Because each case of LMD is different, long-term management must be tailored specifically to each patient. After initial treatment, some patients may maintain a healthy ocular state using lid hygiene alone. Others may require some form of medical therapy to address flare-ups, followed by lid hygiene alone. Still others may require long-term use of the azithromycin topical formulation or oral doxycycline in addition to lid hygiene to achieve optimal ocular health.

Clinicians should schedule frequent follow-up visits for LMD patients to tailor treatment appropriately. (See "A Case of Lid Margin Disease," below.) They must make patient education and communication a priority, because successful treatment of LMD requires the ongoing co-operation of the patient. The clinician must ensure that each patient understands the chronicity of LMD, the importance of lid hygiene, medical therapy when necessary and the consequences of not complying with therapy recommendations. Elderly patients, for example, often consider the symptoms of LMD a normal part of aging. However, if the clinician explains his clinical findings and how they correlate with ocular comfort, many patients prefer to be treated. For patients considering cataract surgery, resolution of LMD is crucial for decreasing the risk of developing a severe ocular infection postoperatively.

A Case of Lid Margin Disease

Presentation A 38-year-old Caucasian woman presented with low-grade, chronic "dryness" and "discomfort" and difficulty wearing daily disposable contact lenses. She was refitted two times over the past 3 years, and reported "late afternoon blurry vision," especially when she wore a 2-week disposable lens and was in the second week of wear. She had a sty in the past, and her eyelids appeared red on occasion. Objective Testing Slit lamp examination revealed a reduced tear breakup time (TBUT) of 3 seconds OD and 4 seconds OS (contact lenses weren't worn to the examination). Trace superficial punctate keratitis was noted in the inferior corneal region in both eyes. Lissamine green staining showed Grade 1 staining in the inferior and nasal regions of both eyes. Schirmer testing measured 18 mm OD and 20 mm OS/5 minutes. Lid and lash anatomy was normal, and there was slight telangectasia of the lid margin vessels OU. Expression of the meibomian glands revealed grade 1+ to grade 2 obstruction, with mildly opaque secretions inferiorly OU. Assessment Dry eye symptoms related to chronic mild obstructive meibomian gland disease (posterior blepharitis) OU. Management and Follow-up Lid scrubs with warm compress therapy OU, with follow-up in 3 weeks. After 3 weeks, the patient reported mild symptom improvement, and TBUT was slightly improved. Corneal staining (fluorescein and lissamine green) was similar to previous visit. There was mild improvement in ease of lipid expression with no improvement in color/quality. The patient was prescribed azithromycin ophthalmic solution 1% (Azasite, Inspire Pharmaceuticals) qhs OU in addition to continued lid scrubs and warm compresses, and was asked to return for follow-up in 3 weeks. At the next follow-up visit, the patient reported more substantial improvement in symptoms. TBUT and corneal staining findings were similar to that observed in the previous visit. There was improved quality of meibomian gland secretions and reduced lid margin redness. The patient was instructed to continue warm compresses, lid scrubs and topical azithromycin qhs and to return for follow-up in 3 weeks. Lissamine green staining shows Grade 1 staining in the inferior and nasal region of the eye. Hypothetical Presentation At the next visit, if the previous improvements in clinical signs and symptoms are maintained, the clinician should consider an individualized longer-term management plan. Such a plan could involve continued lid hygiene and tailored, less frequent maintenance dosing of topical azithromycin. Alternatively, it would be feasible to discontinue topical azithromycin to determine whether lid hygiene alone controls signs and symptoms. If signs and symptoms reappear at a future follow-up visit, topical azithromycin can be restarted. If the patient had presented with a reduced Schirmer score or more significant corneal staining, lubricants and/or topical cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) therapy could be initiated per the DEWS treatment paradigm. Expression of the meibomian glands revealed mild obstructive meibomian gland disease in this patient.

Expect Further Progress

The latest scientific research indicates that the meibomian glands and related eyelid structures and functions play a critical role in overall ocular health. As a result, new therapies for LMD have been, and will continue to be, introduced. For example, an ophthalmic formulation of the macrolide azithromycin is now available to clinicians, and topical formulations of omega fatty acids and doxycycline are being explored. Also in development is an instrument that would make routine measurement of tear osmolarity possible in the clinic. Because meibomian gland disease may lead to increased tear osmolarity, the instrument would be a valuable tool in the management of LMD patients.

Finally, a DEWS-type effort centered on LMD has been suggested and would establish a knowledge base from which further research and progress could occur. OM

Dr. Nichols is an associate professor at The Ohio State University College of Optometry. You can reach her at knichols@optometry.osu.edu.