Article

Mastering Meibomitis Management

Questions still abound, but recent innovations could soon bring relief to patients. Here’s what you need to know.

Mastering Meibomitis Management

Questions still abound, but recent innovations could soon bring relief to patients. Here's what you need to know.

By Joseph Tauber, MD

Breakthrough technology excites doctors, eager to learn about the latest high-tech approach to improve how we deliver eye care. The past few years have brought incredible advances, including laser cataract surgery, corneal cross-linking, selective and ultra-selective corneal transplantation and new applications for antiangiogenic medications. Given all that, it may seem surprising how much attention has been given to the treatment of meibomian gland dysfunction (MGD). Though it seems a minor annoyance to some, MGD may very well be the most prevalent disease we encounter, responsible for the majority of visits to eyecare providers.

Much attention has been (deservedly) paid to the milestone report published in March 2011 from the Tear Film and Ocular Surface Society (TFOS) Workshop on Meibomian Gland Dysfunction.1 Consisting of individual reports addressing classification, anatomy, epidemiology, diagnosis, treatment and more, all nine papers of the report were ranked among the top 13 read articles in 2011, according to David Sullivan, head of TFOS. In-depth, current knowledge about MGD is well summarized there, and will not be repeated in this brief update. Instead, I'm going to focus on the cutting-edge approaches to treatment of this prevalent condition.

Many Sufferers, Few Answers

Why so much attention directed to MGD? Because it affects an estimated 50-75% of patients seeking eye care, often with an unrelated chief complaint.1 Numerous studies looking at diverse patient populations seeking contact lens fitting, laser vision correction, premium IOL cataract surgery or treatment for age-related macular degeneration have reported a high prevalence of MGD findings. The diagnostic confusion in separating aqueous-deficient dry eye from evaporative dry eye (most often related to MGD) has been the subject of workshops and educational courses at the annual meeting of the American Academy of Ophthalmology for years. I have personally co-taught a course addressing this issue for the past seven years, typically to a filled room. But are we getting better at helping our patients?

The challenges in measuring MGD or even reproducibly assessing patient complaints make this a difficult question to answer. Even validated instruments for assessing patient complaints and dysfunction related to dry eye (OSDI) may not be fully applicable to MGD. Reviewing published literature for the state-of-the-art treatment for MGD reveals the limited data from good quality, controlled trials in this field. Data support recommendations for lid warming and for lid hygiene/compression, though techniques vary from practitioner to practitioner. Published data supports the use of systemic medications such as the tetracyclines (including doxycycline and minocycline)2,3 and azithromycin4 to reduce inflammation and alter the nature of eyelid lipids, and also the use of systemic omega-3 supplements5 and topical lipid formulations.6 Less solid data support the widespread clinical impression that anti-inflammatory medications, i.e., corticosteroids, have an important role in treating exacerbations of this chronic disease (discussed below).

Novel Approaches

While new treatments for MGD are out there, they face the difficult challenge of demonstrating efficacy in the absence of validated symptom instruments and with non-standardized grading scales for MGD. Though the TFOS report has proposed a grading scale, only time will tell if this will be widely adopted. Despite the challenges of conceiving a new treatment approach and of proving its efficacy, however, several hopeful ideas have come forward that warrant our attention. Here are some of the devices and techniques on the horizon.

■The use of intense pulsed light treatments (IPL) for the treatment of dry eye complaints was put forward by Dr. Rolando Toyos in 2003 and remains an intriguing approach to facilitate expression of the abnormal meibomian gland secretions. Different from the idea of lid warming, Dr. Toyos proposes that IPL closes blood vessels within the eyelid tissues, limiting their ability to release inflammatory mediators that could affect the function of the meibomian gland. Though large clinical trials have not been performed to date, Dr. Toyos has described his approach to repeating treatments four to six times at one-month intervals, and has presented data on 109 patients treated this way, demonstrating improved TBUT and symptom relief.

■ Meibomian gland duct probing, a procedure to mechanically open obstructions postulated to occur at the orifice and within the lumen of the meibomian gland, is a novel approach first described by Dr. Steven Maskin (Figures 1 and 2).7 Since 2009, published reports of several small series of patients suggest a substantial percentage of patients experience subjective relief of symptoms, lasting for months. In a 2011 AAO presentation, Dr. Maskin reported 33% of original series of patients required retreatment at an average of 10 months. Challenges of this procedure include achieving good lid anesthesia for the procedure, which is somewhat uncomfortable, and also determining when retreatment is appropriate. Dr. Maskin has found his patients are well anesthetized and tolerate the procedure with the use of jojoba-containing anesthetic ointment containing 8% lidocaine. The jojoba wax esters appear to increase delivery of anesthetic into the meibomian glands.

Figure 1. Maskin Meibomian Gland Intraductal Probe inside MG of a patient with obstructive meibomian gland dysfunction.

Figure 2. Maskin Probe inside MG of a patient with reconstructed lid and obstructive meibomian gland dysfunction. COURTESY OF STEVEN MASKIN, MD

For retreatment, Dr. Maskin emphasizes the importance of treating comorbid disease, as allergy, aqueous tear deficiency, anterior blepharitis and others can all have an adverse impact on meibomian gland function. Retreatment is indicated if lid tenderness or other symptoms of MGD occur in spite of eliminating comorbid disease, or to restore meibum-secreting lid functionality in the absence of symptoms to prevent end-stage gland atrophy.

Dr. Maskin has indicated interest in exploring the use of intraductal tubes to instill medications directly into the glands. His 2011 AAO presentation showed probing plus steroid instillation directly into the gland led to a 91% reduction in symptoms by one to three months compared to probing alone, which showed a 79% reduction in symptoms at the same follow-up point. He concluded that introduction of intraductal steroid at time of probing may be especially useful in the setting of more severe cases, significant co-morbid disease, retreatment and chalazion.

■ The Lipiview/Lipiflow System, from TearScience, was approved by the FDA in 2011. This novel system8 employs tear interferometry to visualize and measure the thickness of the tear film lipid layer before and following treatment with a “thermal pulsation system” that simultaneously warms the eyelid glands and expresses secretion using an inflatable bladder to compress the lids (Figure 3). Citing a considerable body of literature to support the concept that secretions are more easily expressed from the warmed eyelid, the 12-minute Lipiflow treatment delivers a gentle pressure shown to be more effective than manual lid expression. Study of a small series of patients suggests benefits may persist up to one year, but this data is preliminary.

Figure 3. The Lipiflow system measures tear thickness using interferometry, then warms the glands and expresses secretion. COURTESY OF TEARSCIENCE

On the Pharmacologic Side…

As our pathophysiologic understanding of MGD improves, we are beginning to understand MGD as another inflammatory ocular surface condition, just as we now understand aqueous deficient dry eye to be primarily an imbalance in inflammatory and immunologic homeostasis. It seems likely that pharmacologic approaches to treating MGD will emerge to safely address the insidious inflammation within the meibomian gland. Medications should be prescribed to treat the primary pathophysiologic process, related inflammation and the symptoms and dysfunction caused by a disease.

Condensing a great deal of information from the TFOS report into a very brief explanation, MGD (Note: this refers to dysfunction — the precursor to blepharitis and meibomitis) can be understood as a disease of abnormal regulation of keratin metabolism within the meibomian gland (Figure 4). Over time, abnormal keratin occludes the lumen and orifices of the glands, leading to acinar dilation and atrophy, inflammation and infection (Figure 5). Whether microbial presence or overload precedes or causes the altered keratin metabolism is unknown, leaving unanswered the question of whether the use of antibiotics in the treatment of MGD treats the disease itself or merely its complications. Also uncertain is whether an inflammatory process is the initial abnormality in MGD or a consequence of stagnated secretions.

Figure 4. Representation of keratin granules within the lumen of meibomian glands.

Figure 5. Representation of occluded orifices of meibomian glands. COURTESY OF A LCON LABORATORIES

Clinicians currently rely primarily on oral tetracyclines, oral omega-3 supplements and, recently, on topical azithromycin as medications to change the character of meibomian secretions in patients with symptomatic lid margin disease. It should be noted that few large, randomized, controlled studies have ever been performed to study treatment of meibomian gland dysfunction.

The Challenges of Corticosteroids

The role of topical steroids in the treatment of external diseases with components of both microbial infection and inflammation (blepharitis, meibomitis and keratitis) has been controversial for many years, with well-informed advocates on both sides of the debate, and with few controlled studies to support strongly voiced opinions. Likely all would agree that topical anti-inflammatory medications can be used effectively to manage destructive inflammatory processes that can lead to vision-limiting complications; however, like the double-edged sword that may harm both user and enemy, they must be respected to avoid complications, dependency and misuse. The astute clinician makes treatment decisions mindful of the disease process involved, the specific ocular tissues affected and the available alternatives.

Catch Them at ASCRS
Those interested in learning more about Dr. Toyos' intense pulsed-light treatment for dry eye or Dr. Maskin's intraductal probing technique for MGD will have the opportunity to do so at this month's ASCRS meeting in Chicago.

Dr. Toyos will present a video, “Meibomian Gland Expression After Intense Pulsed-Light Treatment for Evaporative Dry-Eye Syndrome,” that demonstrates the technique and several examples.

Dr. Maskin's presentation, “Restoration of Meibum Secreting Lid Functionality After Meibomian Gland Orifice Penetration and Intraductal Probing for Meibomian Gland Dysfunction,” discusses the impact of the technique on “the restoration of meibomian gland functionality for non-functional meibum-secreting lids.” The study examined 67 lids of 36 patients and found that non-functioning lids became functional at average 2.55 ± 2.13 weeks post probing; pre-probing the lids averaged 2.31 + 1.45 expressible glands while post-probing average last recorded expressible gland count increased to 8.10 ± 2.26 glands. The effect persisted to at least seven months.

Topical anti-inflammatory medications (generally corticosteroids alone or in combination with antibiotics) are often prescribed in the treatment of lid-margin disease, even without randomized, controlled clinical trials to guide patterns of practice. Often, acute flare-up of lid-related irritative symptoms cannot be brought under control without a course of topical corticosteroids lasting one or several weeks or months. In a different scenario, most practitioners have encountered the patient who has become dependent on chronic corticosteroid therapy, sometimes on a once-daily dosing schedule or every few days.

Certain ocular diseases that are likely precipitated by MGD or meibomitis (e.g., Staphylococcal marginal keratitis, phlyctenulosis, corneal neovascularization) are very difficult to manage without at least a course of topical corticosteroids. In each of these clinical scenarios, practitioners are well advised to prescribe corticosteroids, but must remain diligent in scheduling appropriate follow-up visits to monitor potential side effects, such as elevated intraocular pressure, bacterial superinfection, recurrence of herpetic keratitis or dermatitis and more. Because of the diversity of situations in which corticosteroid therapy is appropriately prescribed, it is challenging to precisely define the role of anti-inflammatory medications in the treatment of lid-margin disease. This challenge is even greater when one considers the nature of the inflammatory process in greater depth.

Inflammation's Role

Inflammation is a term widely used in ocular surface disease, but one that can encompass very different processes. Celsus (30 BC – 45 AD) first described inflammation as “rubor (redness), calor (warmth), tumor (swelling) and dolor (pain)” and his words are still taught in every medical school today. Skin, lid and conjunctival redness and swelling are common findings in lid-margin disease, whether anterior (blepharitis) or posterior (meibomitis). It is important to differentiate clinically evident inflammation from “tissue inflammation” which describes a cellular and/or molecular process that may be pathogenic either before or in the absence of clinical signs of inflammation. If the primary abnormality in MGD remains obscure, less is known about the roles of different pathways of inflammation.

Most clinicians understand that there are important differences in the pathogenesis and treatment strategies for allergic, cell-mediated and cytokine-mediated inflammation. Fewer clinicians are knowledgeable about the nuances of inflammation mediated by T helper cell subsets TH1, TH2 and TH17 or the family of mitogen-activated protein (MAP) kinase pathways; these include ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38.9-13 Peroxisome proliferator-activated receptors (PPAR family) have been recently reported to have an important role in lipid metabolism, apoptosis and inflammation. Currently available anti-inflammatory medications for ocular disease include mast cell-stabilizing agents, nonsteroidal anti-inflammatory agents, immunomodulators (cyclosporine, tacrolimus) and corticosteroids.

With all of these choices, it is still not possible to specifically suppress isolated pathways of inflammation. The most powerful anti-inflammatory medications available (corticosteroids) are non-specific in their actions, and produce side effects presumably related to their actions on multiple receptors in multiple cell types. Future pharmaceutical refinements will surely bring selective anti-inflammatory medications to our armamentarium, that target receptors limited the actions of the medication to more specific therapeutic pathways. Studies of such selective anti-inflammatory agents have begun to appear,14 and will eventually reach our treatment armamentarium.

The ideal treatment for MGD would achieve these three goals:

1. Normalize the secretory product of the meibomian glands.
2. Mobilize the secretions.
3. Stabilize the compromised tear film.

Our current state of knowledge is inadequate to fully define what changes in meibomian excreta initiate and propagate the process of obstruction of the gland orifice and the development of irritative symptoms and evaporative dry eye disease, but progress is accelerating in the management of this prevalent disease. OM

References
1. The international workshop on meibomian gland dysfunction (nine reports). IOVS 2011. 52(4): 1917-2085.
2. Shine WW, McCulley JP, Pandya AG. Minocycline effect on meibomian gland lipids in meibomianitis patients. Exp Eye Res 2003. 76: 417-420.
3. Ta CN, Shine WE, McCulley JP, Pandya A, Trattler W, Norbury JW. Effect of minocycline on the ocular flora of patients with acne rosacea or seborrheic blepharitis. Cornea 2003. 22(6): 545-548.
4. Foulks GN, Borchman D, Yappert M, Kim SH, McKay JW. Topical azithromycin therapy for meibomian gland dysfunction: clinical response and lipid alterations. Cornea 2010. 29(7):781-8.
5. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc 2008. 106:336-356.
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7. Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland dysfunction. Cornea. 2010 Oct; 29(10):1145-11452.
8. Korb DR, Blackie CA. Restoration of Meibomian Gland Functionality with Novel Thermodynamic Treatment Device. Cornea. 2010. Aug; 29(8):930-933.
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10. Li DQ, Luo L, Chen Z, Kim HS, Song XJ, Pflugfelder SC. JNK and ERK MAP kinases mediate induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res. 82(4):588-96, 2006.
11. Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder SC. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci. 45(12):4293-30, 2004.
12. Nien CJ, Massei S, Lin G, Nabavi C, Tao J, Brown DJ, Paugh JR, Jester JV. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Bensinger SJ, Tontonoz P. Nature 2008. 454 (7203): 470-477.
13. Tontonoz P. Nature 454 (7203): 470-477, 2008. Effects of age and dysfunction of human meibomian glands. Arch Ophthalmol 129(4): 462-469, 2011.
14. Shafiee A, Bucolo C, Budzynski E, Ward KW, López FJ. In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease. IOVS 2011. 52(3):1422-30.

Dr. Joseph Tauber specializes in dry eye and ocular surface diseases and the medical and surgical treatment of corneal and external diseases. He is an author of the International Workshop Report on Meibomian Gland Dysfunction. Contact him at jt@taubereye.com.