• Comprehensive Ophthalmology, Cornea/External Disease
    Written By: James M. Rynerson, MD

    Blepharitis has long been the neglected stepchild of eye pathologies, never receiving the attention bestowed upon cataracts, glaucoma and retinal disease. Another poorly understood syndrome, dry eye disease, is seemingly all the rage now with articles, new treatment modalities and specialty treatment centers. It is possible that these 2 elusive diseases are not only closely related, but one and the same in terms of etiology, pathology and progression?

    New approach to dry eye

    Standard dogma dictates that dry eye disease is quite complicated, with an overlapping disease presentation that stems from multiple etiologies. Based on this understanding, it would be heresy to suggest that dry eye is anywhere close to a simple process.

    A new theory of dry eye has recently emerged, however, and is gaining traction among eye practitioners as well as opinion leaders in eye disease. In a 2016 paper in Clinical Ophthalmology, we proposed that blepharitis and dry eye are actually one simple condition: dry eye blepharitis syndrome (DEBS).1

    If we take a step back from standard dogma and examine dry eye from a fresh perspective, we may uncover simple new treatments that provide long-anticipated relief for patients and practitioners alike.

    What are biofilms?

    Understanding DEBS is easy if we first grasp the significance of a biofilm: a slimy, sticky film of bacteria that coats a surface.2

    Bacteria are survivors, and they have done so for eons with their evolving survival skills. In nature, most bacteria exist not as free-floating individuals but rather as highly organized communities called biofilms. A biofilm is composed of a well-hydrated matrix of bacteria and their glycocalyx, a sugary coating that allows cells to adhere to and communicate with each other. This protective armor is highly difficult to penetrate–even by antibiotics, surgical iodine prepand, believe it or not, human white cells.

    We propose that these bacterial survival skills are the very factors that cause dry eye disease.

    Biofilms can form on any surface that provides moisture and nutrients. The eyelid margin—with its moisture, nutrients and warmth—is the perfect environment to cultivate a thriving bacterial biofilm. In fact, it would be unrealistic to suggest that a biofilm does not exist on the lid margin. A biofilm probably begins forming just after birth when the lids become colonized with bacteria.

    The growth of the biofilm

    A single bacterium has a low chance of survival. However, a biofilm containing billions of bacteria can easily survive. Within a biofilm, bacterial cells communicate with one another by secreting a chemical called homoserine lactone (HSL).4 The biofilm of a 2-year old child contains very low concentrations of HSL, thus the biofilm is non-pathogenic. The biofilm of a 50- or 60-year-old, however, has had decades to thicken, increase its bacteria load and produce high levels of HSL. This is a critical component of dry eye pathogenesis.

    Once the bacterial colony senses that its numbers have reached a critical mass, as indicated by a high concentration of HSL, the bacteria use a process called quorum sensing to activate genes that elicit an inflammatory response in their human host.5 These genes encode virulence factors such as lipases, proteases, cytolytic toxins, scalded skin syndrome toxins and super-antigens (toxic shock syndrome) among others.6 Presumably, these virulence factors are tasked with liberating a larger food source for the burgeoning bacterial population.

    Why does the biofilm wait to produce virulence factors once a critical mass has been reached? Because bacteria do not want to produce an inflammatory response from the host until they know they are abundant enough to withstand the host’s immune attack. So, the colony waits until they reach a quorum, indicating that they are safe within their thick biofilm armor.

    Different strains, different styles

    It is important to realize that not all strains of a species—such as the blepharitis-causing bacterium Staphylococcus aureus—are identical. Some strains of S. aureus are apt to create a biofilm that matures quickly and releases highly inflammatory toxins, which could produce severe blepharitis and chalazions in an 8-year-old. Other strains may produce thin, slow-growing biofilms that release relatively mild virulence factors over a person’s lifetime, and therefore spare an 80-year-old of any significant lid margin disease. It all depends on the strain of S. aureus.7,8

    Is dry eye disease truly multifactorial?9 Many factors exacerbate dry eye (e.g, medications, hormonal state and reduced blinking), but the underlying etiology stems from a biofilm, present from infancy, that eventually achieves quorum-sensing gene activation and releases virulence factors.

    What about the oft-noted “over-lapping presentations of different diseases,” which suggests that lacrimal dry eye disease is distinct from meibomian gland disease, which are both distinct from anterior blepharitis? Understanding how these different presentations relate to one another is easy, given the etiology of biofilm and an understanding of lid anatomy.

    Stages of DEBS

    Stage 1. Folliculitis: inflammation and edema of the lash follicles. This is always the first stage of disease, as it permits easy migration of the encroaching biofilm down the lash. Folliculitis eventually progresses from a small “volcano sign” to profound tissue edema around the lash. In severe cases, a sheathing of the lash with biofilm—often mistaken as cylindrical dandruff—can be observed once the lash grows out from the follicle.10 A thick biofilm attaches to and molds around the lash during dormancy, and then reveals itself once the lash leaves the follicle. Pull back the slit lamp and prepare to be amazed at how many patients have stage 1 DEBS, especially contact lens wearers.

    Stage 2. Meibomian gland dysfunction (MGD): impaction and inflammation of the MG. Due to the MG’s size relative to the lash follicle and the small ductule with constant efflux of lipids, it simply takes longer for biofilm to accumulate and thicken within the MG. First, a simple plugging of the MG with meibofilm—a mixture of biofilm and meibum—reduces the quantity and quality of the meibum, sometimes referred to as non-obvious MGD with minimal inflammation. As the biofilm thickens within the gland, it eventually undergoes quorum-sensing and begins releasing virulence factors. This produces the inflammation referred to as posterior blepharitis. At this point, domes of meibofilm appear over each meibomian ductule.

    It has long been thought that these little cream-colored domes over the MG were “caps” of keratin.11 But since the posterior lid margin consists of a non-keratinized stratified squamous epithelium, this explanation is highly unlikely. Within the context of biofilms, it is easy to understand the true source of these domes.

    As the thickened meibofilm accumulates within the MG, the gland eventually reaches capacity. It may leak through the wall of the gland, causing a chalazion. The column of meibofilm gets forced up the ductule in an effort to escape the gland, but instead encounters a 40- to 50-year-old biofilm that has literally sealed off the orifice. The meibofilm bulges up against this original biofilm but cannot escape. Imagine covering the top of a toothpaste tube with a clear plastic wrap, then squeezing the tube. This is what happens to the MG when little domes of meibofilm become trapped atop each orifice. During MG probing, it is the penetration of this original biofilm that the practitioner may feel as the probe “pops” through.12

    Stage 3. Lacrimilitis: impaction and inflammation of the accessory lacrimal glands of Krause and Wolfring. This always occurs after MGD. This is easy to understand if one reviews the lid anatomy and location of these tear glands. The glands of Wolfring are located along the top of the tarsal plate, and the glands of Krause are deep within the fornices.13 These 2 areas are quite distant from the margin, delaying access to a growing biofilm. However, biofilms can “seed” new areas by constantly dispersing tiny bits of biofilm into their environment (in this case, the tear film). If this happens hundreds of times a day, for 60 to 70 years, it is not inconceivable that a microscopic bit of biofilm eventually accesses these glands. It is also possible for biofilms to slowly creep up the inside of the palpebral conjunctive in an attenuated state (due to the constant blinking of the lids) and, after many years, reach the lacrimals by direct extension.

    Could aqueous insufficiency underlie DEBS?

    It may be difficult for some to accept that aqueous insufficiency shares a common etiology with MGD. However, many patients present with watery eyes, difficulty reading for long periods and a burning sensation. These patients are typically difficult to refract, as their vision changes with every blink. A low tear break-up time (TBUT), few meibomian puddles and occluded ductules confirm the diagnosis of evaporative dry eye disease. But patients may have difficulty understanding that diagnosis, given the tears running down their cheeks.

    Patients with diseased MG and healthy lacrimal glands have the most common form of dry eye disease. However, patients often present with the exact opposite scenario: lots of lipids, perhaps a drop of oil running down the cheek, yet no aqueous. Except for Sjögren's autoimmune disease, which is an entirely separate pathology from lid margin disease, it is rare to encounter someone with a healthy MG and aqueous insufficiency.

    This brings us to a key question: If aqueous insufficiency is truly a separate overlapping disease, wouldn’t we expect it to present prior to meibomian gland disease? At least once? But we never do, because it is simply a later stage of the same disease. It can’t happen because the morphology and anatomical location of the tear glands preclude it from happening. There is one common etiology: biofilm. It truly explains everything we see.

    One might expect, after years of examining and unsuccessfully treating dry eye disease and blepharitis, that the biofilm theory would be a fait accompli! Unfortunately, decades-old dogma is difficult to dislodge. This new theory could bring relief to millions of patients, but it will likely take decades to be fully accepted. Meanwhile, few rigorous studies have been performed to support the current thinking.

    An enlightened view of dry eye disease

    Let’s take a step back, open our minds and lend credence to the simplest of explanations: Blepharitis and dry eye are actually one simple disease process.

    In the field of dentistry, practitioners have achieved great success by simply educating patients on the importance of oral hygiene, plaque (biofilm) removal and the prevention of gingivitis and tooth loss. By educating patients about eyelid hygiene and prevention of blepharitis, the field of ophthalmology could enjoy similar success. A thorough and regular microblepharoexfoliation procedure could potentially bring relief to millions and forever change the way we treat this chronic debilitating disease. It really is all about the biofilm.

    Author Disclosures

    Dr. Rynerson is the President and CEO of BlephEx, LLC. 

    References

    1. Rynerson JM, Perry HD. DEBS – a unification theory for dry eye and blepharitis. Clin Ophthalmol. 2016; 10: 2455–2467. [PubMed]
    2. Lappin-Scott H, Burton S, Stoodley P. Revealing a world of biofilms – the pioneering research of Bill Costerton. Nat Rev Microbiol. 2014;12(11):781–787.  [PubMed]
    3. Kıvanç SA, Kıvanç M, Bayramlar H. Microbiology of corneal wounds after cataract surgery: biofilm formation and antibiotic resistance patterns. J Wound Care. 2016 Jan;25(1):12, 14-9. [PubMed]
    4. Mireille Ayé A, Bonnin-Jusserand M, Brian-Jaisson F, Ortalo-Magné A, Culioli G, Koffi Nevry R, Rabah N, Blache Y, Molmeret M. Modulation of violacein production and phenotypes associated with biofilm by exogenous quorum sensing N-acylhomoserine lactones in the marine bacterium Pseudoalteromonas ulvae TC14. Microbiology. 2015 Oct; 161(10):2039-51. [PubMed]
    5. Wolf D, Rippa V, Mobarec JC, Sauer P, Adlung L, Kolb P, Bischofs IB. The quorum-sensing regulator ComA from Bacillus subtilis activates transcription using topologically distinct DNA motifs. Nucleic Acids Res. 2016 Mar 18; 44(5):2160-72. [PubMed]
    6. Knecht LD, O'Connor G, Mittal R, Liu XZ, Daftarian P, Deo SK, Daunert S. Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host. EBioMedicine. 2016 Jul; 9():161-169.[PubMed]
    7. Suzuki T, Kawamura Y, Uno T, Ohashi Y, Ezaki T. Prevalence of Staphylococcus epidermidis strains with biofilm-forming ability in isolates from conjunctiva and facial skin. Am J Ophthalmol. 2005 Nov; 140(5):844-850. [PubMed]
    8. Miyanaga Y.  A new perspective in ocular infection and the role of antibiotics. Ophthalmologica. 1997; 211 Suppl 1():9-14. [PubMed]
    9. Bzdrenga J, Daudé D, Rémy B, et al. Biotechnological applications of quorum quenching enzymes. Chem Biol Interact. 2016 May 22; Epub.  [PubMed]
    10. Gao YY, Di Pascuale MA, Li W, Liu DT, Baradaran-Rafii A, Elizondo A, Kawakita T, Raju VK, Tseng SC. High prevalence of Demodex in eyelashes with cylindrical dandruff. Invest Ophthalmol Vis Sci. 2005 Sep; 46(9):3089-94. [PubMed]
    11. Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, Karakaya J, Irkec M. Meibomian Gland Dysfunction in Patients Receiving Long-Term Glaucoma Medications. Cornea. 2016 Aug; 35(8):1112-6. [PubMed]
    12. Knop E, Korb DR, Blackie CA, Knop N. The lid margin is an underestimated structure for preservation of ocular surface health and development of dry eye disease. Dev Ophthalmol. 2010; 45():108-22. [PubMed]
    13. Stevenson W, Pugazhendhi S, Wang M. Is the main lacrimal gland indispensable? Contributions of the corneal and conjunctival epithelia. Surv Ophthalmol. 2016 Sep-Oct; 61(5):616-27. [PubMed]