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Issue: August 2008 Understanding the Intricacies of Lid Margin Disease

Understanding the Intricacies of Lid Margin Disease

Learn how to detect this under-diagnosed condition and its associated complications to make better treatment decisions.

By Paul M. Karpecki, O.D., F.A.A.O

Common, problematic and often under-diagnosed, lid margin disease (LMD) is at the root of many cases of dry eye, complaints from patients about ocular discomfort and high contact lens dropout rates.

The relationship between LMD and dry eye is also troublesome. It doesn't matter which condition develops first. One always exacerbates the other. LMD causes reduced lipid production on the ocular surface, leading to tear evaporation and, therefore, dry eye. In the case of dry eye, decreased tear production reduces the eye's ability to wash away bacteria from the lid margins, enabling bacteria to infect the meibomian glands and eyelash follicles, which in turn further degrades the tear film.

LMD is divided into two classifications: posterior blepharitis, sometimes called meibomitis or meibomian gland disease (MGD), and anterior blepharitis. (MGD refers to the early stages of the disease, but once inflammation is present meibomitis is likely to be the more accurate terminology.)

MGD affects the oil-producing meibomian glands in the back of the eyelids, while anterior blepharitis occurs on the lash margin in front of the eyelids. MGD is the more common form of LMD, affecting about 40% of patients who come in for routine visits.1 Symptoms of MGD include redness on the lid margin, flaky debris or mattering, fluctuating vision, burning and stinging.

In this article, I'll discuss why LMD often eludes us, define the different types, the causes, associated complications and how to diagnose it more accurately.

Under-diagnosed Condition

Given the prevalence of lid problems, the question is why are they often under-diagnosed? In my years of practice, focusing solely on ocular surface disease, I've discovered three reasons why eyecare practitioners overlook LMD:

1. It looks familiar. When we see something so often, as we do with LMD, we tend to overlook it. LMD often presents very mildly, requiring doctors to express the meibomian glands to detect it, which they don't do routinely. Often, mild conditions that are very common appear benign to clinicians. They may even treat other related conditions without acknowledging the lid issues.

2. Patients complain later. Unlike problems such as corneal infections, LMD doesn't cause patients to complain in its early stages of development. Patients often ignore mild signs and symptoms because they're not too bothersome. Generally, symptoms have to become advanced before patients make an appointment to see you.

3. It doesn't exist alone. LMD may accompany a systemic disease or help contribute to dry eye, both of which can distract you from examining the eyelids. Rather than giving the patient a single diagnosis, you may need to deliver two or three.

With these factors influencing your diagnosis, it's essential for doctors to keep LMD on the checklist for routine eye exams. When key signs and symptoms of the problem exist, extra measures, such as expressing the meibomian glands for MGD, can help detect it.

Defining MGD

When I examine a dry eye patient with lid disease, I find that about 90% have meibomianitis compared with 10% who have anterior blepharitis — although there's some overlap of symptoms with the two types. The meibomian glands, which form rows on the inside of the eyelids, secrete lipids that combine with and coat the tear film. This essential component of the tear film prevents tears from evaporating to keep eyes moist and comfortable. Meibomitis is a chronic inflammation of the glands that impairs their functioning, throwing off the balance of the tear film and causing tears to evaporate more rapidly.

Clearly, increased tear evaporation leads to dry eyes, and MGD and dry eye syndrome, or dysfunctional tear syndrome, go hand in hand. MGD is often at the root of dry eye, so treating the MGD is key to alleviating symptoms, such as a gritty, foreign body sensation, burning, dryness, light sensitivity, blurred vision and contact lens intolerance. Treating dry eye alone without addressing the underlying MGD won't be succeessful.

As mentioned earlier, the prevalence of MGD — 40% of patients in my practice —may be higher or lower in your practice, depending on certain demographic factors.

First, the incidence of MGD increases with age. We believe that a neurotransmitter called vasoactive intestinal polypeptide and the hormone androgen control meibum secretion.2 Women's androgen levels drop during and after menopause, and post-menopausal women have an increased prevalence of MGD, so this may indicate a hormonal connection.3 As further proof, topical antiandrogen treatments reduce meibum levels, while topical use of the androgen precursor dehydroepiandrosterone increases meibum levels.4

In addition, recurring bacterial conjunctivitis is common among patients with MGD. The same factors that make the lid margin susceptible to infection make the eye susceptible as well. Both conditions require similar treatment, including antibiotics and anti-inflammatory agents, as well as long-term care as needed for dry eye and other contributing problems.

Patients with acute or early stage meibomian gland disease have a frothy tear film, or bubbles, which is evident here at the lid margin.

MGD also is associated with rosacea, a skin condition that primarily affects fair-skinned patients. Rosacea causes red, inflamed skin on the cheeks and nose, as well as ocular inflammation. In the course of diagnosing MGD, eyecare professionals often are placed on the front lines of diagnosing rosacea, which many patients don't know they have. (See "Identifying and Treating Rosacea," below.) For the best results, we need to treat a patient's rosacea along with MGD.

Finally, bacterial infection may be present in MGD. The compromised tear film fails to cleanse the eye properly, which can cause bacteria to colonize the meibomian glands.

Identifying and Treating Rosacea
Rosacea is a condition that causes skin on the cheeks and nose to become red and inflamed. Primarily it affects people with fair skin and women more than twice as often as men, starting around age 30.1,2 Many patients who present with LMD haven't been diagnosed with rosacea, but the eyecare professional must make the diagnosis and treat the disease to help resolve its ocular manifestations.
Patients with rosacea may exhibit:
• Erythema
• Telangiectasia
• Small pustules
• Prominent sebaceous glands
• Rhinophyma.
Women tend to have redness on the cheeks, whereas men are more likely to have redness on their noses.
I treat rosacea with 20 mg or 50 mg of doxycycline twice a day for at least 2 months, followed by once a day for an additional month. I use a kit that includes 60 tablets of 20-mg doxycycline with lid cleansers. For longer-term use, I keep patients on 20 mg of doxycycline once or twice a day. Once the problem is controlled, I prescribe metronidazole 1% cream.
Patients with rosacea should be educated about triggers that can cause flare-ups, such as sun and wind exposure, exercise, foods like red wine and hot beverages and harsh creams.

References

1. Berg M, Liden S. An epidemiological study of rosacea. Acta Derm Venereol. 1989;69:419-423.
2. Kligman AM. Ocular rosacea. Current concepts and therapy. Arch Dermatol. 1997;133:89-90.

Recognizing MGD

Patients with MGD typically present with signs and symptoms consistent with dry eye. In mild cases, patients may not complain, but asking the right questions and performing a thorough examination often will reveal the problem.

Sticky debris, or mattering, on the eyelids in the morning is common with MGD — a symptom that patients typically divulge only when asked. The symptoms patients do complain about are redness, lid swelling, foreign body sensation, burning and stinging. They notice that their vision fluctuates, especially in the morning, in contrast to dry eye-related fluctuation or other symptoms that occur later in the day. Contact lens wearers may experience intolerance.

Patients with acute or early stage MGD may have a foamy tear film or bubbles (surfactants) present in the tear film, which includes breakdown components of sebaceous secretions. These components react to bacterial enzymes and create a soapy effect in the tear film, which is particularly evident along the lash margin. Foam doesn't have to be present to conclude that tears are unhealthy, but it's a definitive finding. In severe cases, poor apposition, lid laxity, and ectropion or entropion may occur, encouraging further tear evaporation, inflammation and opportunity for infection.

But this list of easily observable signs and symptoms wouldn't be complete without the diagnostic clincher: the changed appearance of the meibomian glands and the expressed lipid secretions. Instead of looking like baby oil, the secretion looks turbid or cheesy. In advanced cases, some of the glands may be inspissated or capped, and in chronic cases, inflamed blood vessels on the lid margin are evident. Transillumination may reveal that some glands are missing, leaving a divot in the lid.

Exploring Questions About Blepharitis
Here are some recent answers to important questions about meibomian gland disease (MGD) and anterior blepharitis based on studies that have examined the pathology, diagnosis and treatment options of lid margin disease.

Meibomian Gland Disease
• Should you use oral doxycycline? We use oral doxycycline for ocular surface disease, including rosacea and MGD, because it inhibits matrix metalloproteinase (MMP) activity and interleukin-1 (IL-1) and MMP synthesis. But does it reach the tear film in high enough concentrations to be effective? Researchers1 found that although MMPs were reduced to curb ocular surface disease, the doxycycline present in patients' blood wasn't detected in their tears, so a direct relationship is questionable.
• How do lipid secretions from MGD patients differ from healthy ones? Researchers2 found that meibum secretions in patients with MGD contain more branched-chain fatty acids, which could be a marker for MGD. These primary lipids of meibum can affect the lipid layer's fluidity and stability.

Anterior Blepharitis
• What's the role of inflammation in atopic blepharoconjunctivitis (ABC)? MMP-8 is associated with inflammatory diseases, including ocular rosacea. Researchers3 have found that patients with ABC have a higher mean concentration and activation of MMP-8 in their tear fluid, compared with patients without ABC. This may indicate that ABC is associated with persistent inflammatory and collagenolytic activity.
• Which drugs are most effective for ocular inflammation? Researchers4 compared the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% (Zylet, Bausch & Lomb) with dexamethasone 0.1%/tobramycin 0.3% (Tobradex, Alcon) for treating blepharokeratoconjunctivitis. Those who received dexamethasone 0.1%/tobramycin 0.3% had a greater increase in IOP. Other research5 shows that azithromycin ophthalmic solution 1% (Azasite, Inspire Pharmaceuticals) suppressed pro-MMP-9 levels by 33% in human corneal epithelial cells in vitro.

References
  1. Smith VA, Khan-Lim D, Anderson L, Cook SD, Dick AD. Does orally administered doxycycline reach the tear film? Br J Ophthalmol. 2008;92:856-859.
  2. Joffre C, Souchier M, Grégoire S, et al. Differences in meibomian fatty acid composition in patients with meibomian gland dysfunction and aqueous-deficient dry eye. Br J Ophthalmol. 2008;92:116-119.
  3. Määttä M, Kari O, Tervahartiala T, et al. Elevated expression and activation of matrix metalloproteinase 8 in tear fluid in atopic blepharoconjunctivitis. Cornea. 2008;27:297-301.
  4. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin. 2008;24:287-296.
  5. Jacot JL, Jacot TA, Sheppard JD, Lattanzio FA, Williams PB, Brubaker K. Evaluation of MMP 2/9 Modulation by azithromycin and DuraSite on human corneal epithelial cells and bovine corneal endothelial cells in vitro. Poster presented at the 2008 annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla.

Know the Stages of MGD

Currently, no universally accepted classification system exists for MGD, but I define the disease by using the following stages and treat accordingly:

This patient has one of the symptoms of stage 3 meibomian gland disease: inspissated, or capped glands and visible blood vessels on the lid margin.

This patient has a sebaceous cell carcinoma, a rare neoplasm that can be highly malignant, infiltrative and prone to metastasis.

Stage 1. Frothy tear film.

Stage 2. Stage 1 symptoms plus a turbid, cheesy secretion from the meibomian glands.

Stage 3. Stage 1 and 2 symptoms plus chronic inflammation/irritation, inspissated or capped glands and visible blood vessels on the lid margin.

Stage 4. Stage 1, 2 and 3 symptoms plus meibomian glands that no longer function or are missing.

It's important to note that when a patient with stage 4 MGD loses a meibomian gland, or glands, leaving a divot in the lid, you need to photograph the mark and watch carefully for skin cancers, such as sebaceous cell carcinomas. This cancer is rare, although the risk is higher in patients with unilateral presentation.5

The disease usually originates from meibomian glands and can be highly malignant, infiltrative and prone to metastasis. Mortality from the disease may reach 30%. Diagnosis can be tricky because the carcinoma may masquerade as chronic meibomitis or as a chalazion. One of the key signs of sebaceous cell carcinoma is madarosis or loss of lashes. Thus, a suspicious area on the lid margin with missing lashes may prompt the need for a biopsy.

No matter what stage the patient is in, you can successfully treat and manage MGD. In my practice, I address both the MGD and the resulting dry eye simultaneously, which involves treating the inflammatory and infectious components of the disease. However, I always explain to patients that MGD is chronic, like high blood pressure or arthritis, and that we need to continue long-term treatments to keep their eyes healthy, moist and comfortable.

Anterior Blepharitis

Anterior blepharitis is characterized by inflammation of the eyelids around the lashes caused by Staphylococcus aureus and Staphylococcus epidermidis. The infection sometimes occurs as a result of dry eye, when the eyes don't have an adequate amount of tears to wash away the bacteria. With this in mind, it's easy to see how anterior blepharitis may exist concurrently with MGD.

Seborrheic dermatitis is the most common cause of anterior blepharitis. Patients may have dandruff or complain of itching and redness of the scalp and upper chest. Many factors can contribute to this condition, including various hygiene and health problems, stress or sleep loss, poor diet, hormonal imbalance, family history and lifestyle behaviors.6 Environmental factors like dry weather, heating and cosmetics also can play a role.

Like MGD, anterior blepharitis has some of the same symptoms as dry eye and typically occurs concurrently with dry eye. Patients experience redness, sticky eyes, crusting of the eyelids in the morning, a tired appearance, itching or rubbing, photophobia, debris and scaling. Blurred vision may occur, but it's less typical.

In more chronic or recurring cases, you can see long-term effects, such as inflamed blood vessels, thickened eyelids, chemosis, missing eyelashes, trichiasis, and ectropion or entropion. Corneal erosion may be present, as well as deposits called collarettes along the base of the lashes.

Anterior blepharitis is treated alongside its concurrent conditions, such as seborrheic dermatitis and dry eye. Antibiotics and anti-inflammatory drugs bring the infection and its symptoms under control. Treatment of the dermatitis can help prevent future occurrences, and long-term dry eye management encourages a healthier tear film and discourages bacterial colonization.

Truth Behind Inflammatory Dry Eye

Treating LMD and associated dry eye usually isn't something you do once and you're done. Some patients have chronic inflammatory dry eye, which continually recurs and compromises the lid margin.

The tear film, eyelids, meibomian glands and tear ducts create a delicate balance that keeps eyes healthy, moist and comfortable. They continually refresh the tear film, washing away harmful substances and keeping bacteria levels safe. When dry eye compromises the tear film, irritation and infection can cause LMD. So it's important to understand which patients have chronic inflammatory dry eye that creates this risk.

Chronic dry eye is associated with various changes in the tear film, including increased osmolarity, or decreased mucin content, and changes in protein and inflammatory cytokine composition.7 The eye reacts to these changes by means of a neural feedback loop, which helps the structures involved in tear film production interact with the ocular surface. The loop senses the tear composition on the ocular surface and tells the brain, which alerts glands to change the amount of tear production based on this information.

Patients with chronic inflammatory dry eye may encounter a disruption in the synergy of the neural feedback loop. For example, as abnormal tears inflame the ocular surface, cytokines can disrupt the neural arc, causing the brain to make the lacrimal glands activate T-cells, which deliver cytokines to the ocular surface. When cytokines reach the ocular surface, they create an inflammatory cascade by signaling migrating T-cells and other inflammatory cells to come to the ocular surface, or site of inflammation.

Medication to address chronic inflammatory dry eye is a necessary part of the comprehensive treatment of LMD. The only way to alleviate LMD for an extended period is to treat inflammatory dry eye immediately and aggressively, including long-term management if necessary. OM


Dr. Karpecki works in cornea/external disease and advanced ocular surface disease research at the Cincinnati Eye Institute. You can reach him at paul@karpecki.com.

References
  1. Hom MM, Martinson JR, Knapp LL, Paugh JR. Prevalence of Meibomian gland dysfunction. Optom Vis Sci. 1990;67:710-712.
  2. O'Brien PD, Collum LMT. Dry eye: diagnosis and current treatment strategies. Curr Allergy Asthma Rep. 2004;4:314-319.
  3. Sullivan DA, Sullivan BD, Evans JE, et al. Androgen deficiency, meibomian gland dysfunction, and evaporative dry eye. Ann NY Acad Sci. 2002;966:211-222.
  4. Zelligs MA, Gordon K. Dehydroepiandrosterone therapy for the treatment of dry eye disorders. Int Patent Application WO. 94:1994.
  5. Sawada Y, Fischer JL, Verm AM, Harrison AR, Yuan C, Huang AJW. Detection by impression cytologic analysis of conjunctival intraepithelial invasion from eyelid sebaceous cell carcinoma. Ophthalmology. 2003;110:2045-2050.
  6. Terry MA. Dry eye in the elderly. Drugs & Aging. 2001;18:101-107.
  7. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584-589.
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