Dry eye blepharitis syndrome: The simple role of biofilm in dry eye


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).

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.

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 prep and, 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). 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. These genes encode virulence factors such as lipases, proteases, cytolytic toxins, scalded skin syndrome toxins and super-antigens (toxic shock syndrome) among others. 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.

Is dry eye disease truly multifactorial? 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. 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. 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.

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. 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 known as BlephEx could potentially bring relief to millions and forever change the way we treat this chronic debilitating disease. It really is all about the biofilm.



Weekly roundup: Memory trick, cataract reversal, generous gift

MAR 09, 2018

By Anni Griswold and Keng Jin Lee

Cataract/Anterior Segment, Comprehensive Ophthalmology, Retina/Vitreous

A weekly roundup of ophthalmic news from around the web.

A 22-year old woman’s mysterious visual and auditory symptoms led ophthalmologists on a trail of discovery in an “Images in Medicine” feature published last week. After ruling out syphilis, herpes and tuberculosis, clinicians settled on a rare diagnosis: Cogan’s syndrome. Systemic glucocorticoids quickly curbed the inflammatory condition, restoring the woman’s sight and hearing within 1 month of initiating treatment. New England Journal of Medicine

The eyes use a special trick to memorize details of visual scenes, researchers report. An eyetracking study revealed that adults move their eyes in a distinct pattern as they memorize objects on a screen, then repeat that pattern when they stare at a blank screen and recall the objects. “The same way a person repeats the digits of a phone number to remember it, the eyes help the brain strengthen the memory by repeating the same pattern of eye movements,” said lead author Jennifer Ryan, a psychology and psychiatry professor at the University of Toronto. EurekAlert!

Retinopathy at age 60 could portend cognitive decline decades later, a study finds. Damage to the blood vessels in the retina could mirror similar changes in the brain, according to a study of 12,317 people who took memory tests and retinal photographs at an average age of 60, 66 and 80 years. Researchers say if they can confirm the results, changes in retinal integrity may provide an early indicator of cognitive decline. EurekAlert!

An investigational sterol eyedrop for reversing cataracts is attracting investors, raising $35 million in series B financing. CEO Dr. Leah Makley describes the novel compound—which is capable of restoring lens transparency in mice—in this interview from AAO 2015. Viewpoint Therapeutics

The NEI has launched an international study to understand natural history of AMD progression. The study will track 500 people with early AMD over 5-year period. “The findings will contribute to our understanding of the underlying biology driving the transition from early to late-stage disease so that therapies can be developed to halt its progression,” said lead investigator, Emily Y. Chew, MD. NEI

In other AMD-related news, Bascom Palmer Eye Institute has received a $12 million gift to establish a center for research on AMD and retinal diseases. The gift from distinguished philanthropist Lois Pope represents the largest single donation that Bascom Palmer has received in its 56-year history. The 21,000-square-foot Lois Pope research center will be equipped with the latest research, diagnostic and imaging technology, and educational facilities. PR Newswire



Suprachoroidal injection of triamcinolone meets primary endpoint in phase 3 trial

MAR 07, 2018

By Keng Jin Lee

Clearside Biomedical


Clearside Biomedical announced that their proprietary formulation of triamcinolone acetonide (CLS-TA) improved vision in patients with macular edema noninfectious uveitis.

Injecting triamcinolone into the suprachoroidal space with a single-use microinjector enabled efficient delivery to the posterior segment, while limiting exposure to the anterior segment.

The phase 3 PEACHTREE trial included 160 patients. Ninety-six were randomized to the treatment arm and received two 4.0 mg doses of suprachoroidal CLS-TA 12 weeks apart. The remaining 64 patients underwent sham procedures at the same 12-week interval. 

At the 24-week follow-up, 47% of CLS-TA patients gained at least 15 ETDRS letters, compared with 16% of controls (P<0.001). The study arm also showed significantly better mean improvements in BCVA (13.7 vs. 2.9 letters) and central subfield thickness (-157 vs. -19 microns) relative to controls.

The treatment was generally well tolerated and produced no serious adverse events.  Through 24 weeks, corticosteroid-related elevated intraocular pressure adverse events were reported for approximately 11.5% of patients in the CLS-TA treatment group, compared with 0% of controls.

“The PEACHTREE study was the first pivotal phase 3 clinical trial of a drug candidate for patients with uveitic macular edema in which a BCVA measure was the primary efficacy endpoint, potentially raising the bar for future trials in this population,” said investigator Rahul N. Khurana, MD, adding that suprachoroidal CLS-TA could potentially shift the treatment paradigm for these patients, pending additional positive results and FDA approval.

Clearside said it expects to file a marketing application with FDA in the fourth quarter of 2018. Suprachoroidal CLS-TA is also being studied for diabetic macular edema and macular edema associated with retinal vein occlusion.   


Surgical correction of blepharoptosis: Which technique is best?

MAR 05, 2018

Ocular Pathology/Oncology

Investigators of this prospective study compared the efficacy of Müller muscle-conjunctival resection (MMCR) to external levator advancement (ELR) for aponeurotic blepharoptosis repair.

Study design

Patients with mild to moderate ptosis with good levator function and a positive phenylephrine test were randomized to MMCR (38 eyes) or ELR (39 eyes).

The primary outcome was margin reflex distance 1 (MRD1) at 1 month after surgery. Secondary outcomes were cosmetic outcomes, complications and operating time.


Both groups showed significant and comparable improvements in MRD1 at 1-month postop.

Cosmetic outcomes were significantly better in the MMCR group than the ELR group (3.07 vs. 2.69, respectively; P=0.020), whereas average operating room time was similar between the 2 procedures (71 vs. 75 minutes, respectively; P=0.439). One eye in the MMCR group and 3 eyes in the ELR group underwent reoperation.


The main strength of this study is its randomized design. However, the participants in this study were all Asian. Thus, the findings may not be applicable to other patient populations because cosmetic outcomes in Asian patients center mainly on the eyelid crease, which is affected differently by these 2 procedures. 

The average operating time seemed rather long. A longer follow-up would have been desirable. 

Clinical significance

The debate of ELR vs. MMCR continues. This study supports the efficacy of both procedures in eyelid elevation in patients with mild to moderate ptosis with good levator function and a positive phenylephrine test. However, this study also suggests that MMCR offers a better cosmetic result than ELR in Asian patients.


Do vitreoretinal patients need to be seen on postoperative day 1?

MAR 06, 2018


Patients who undergo uncomplicated vitreoretinal surgery can safely be examined on the second postoperative day without negative effects, according to this small study.

Study design

This was a single-surgeon retrospective review of 134 patients who underwent vitreoretinal surgery. Each was seen on the second, but not the first day, after surgery. All patients received a phone call from a technician on the first day after surgery to assess for pain and vision issues.


Six patients had IOP greater than 30 mm Hg on the second postoperative day; all were managed medically. Only 1 patient was seen on the first postoperative day due to pain and elevated pressure.

There were no cases of endophthalmitis.


The very rare but potential complication of endophthalmitis can be missed if a patient is not seen on postoperative day 1. The effect of elevated IOP—even for 1 day—in a patient with ischemic retina could lead to some loss of vision.

Most importantly, since postoperative day 1 visit has been standard of care, deviating from it could put physicians at a medico-legal risk in the event on an unfavorable outcome.

Clinical significance

It is unlikely that a significant postoperative complication would be missed by examining a patient on the second postoperative day. Having a technician speak to the patient on day 1 does add a measure of safety, according to this study.

With surgeons often visiting multiple offices, having patients seen on the second day, rather than the first, could create a more flexible and convenient option for patients.


Alert: Iridex recalls TruFocus LIO Premiere laser indirect ophthalmoscope

FEB 27, 2018

By Anni Griswold


Cataract/Anterior Segment, Comprehensive Ophthalmology, Retina/Vitreous

Iridex has voluntarily recalled its TruFocus LIO Premiere laser accessory following 3 reports of permanent vision loss from focal cataracts and retinal burns during laser treatments with the device, according to an announcement on the company’s website. The LIO is a headmounted indirect ophthalmoscope that connects to an IRIDEX laser console.

The company is urging clinicians to stop using TruFocus LIO Premiere ophthalmoscopes with part numbers 87300, 87301, 87302, 87303 and 87304. Recalled products were distributed from June 5, 2017 to January 29, 2018.

Iridex has notified the Food and Drug Administration of the recall, and has asked distributers and customers to return the 104 TruFocus LIO Premiere units currently in circulation worldwide. Questions can be directed to the company’s technical support team at +1-844-357-9485 (United States), +1-650-962-8100 (international) or techsupport@iridex.com.

Physicians and patients can report adverse reactions or quality issues to the FDA through the MedWatch Adverse Event Reporting site or by mail or fax (1-800-FDA-0178).


Long-haul space missions reshape the optic nerve head


Comprehensive Ophthalmology, Neuro-Ophthalmology/Orbit, Ocular Pathology/Oncology

Spaceflight-associated neuro-ocular syndrome is a newly described condition characterized by hyperopic shift, disc edema, globe flattening, choroidal folds and cotton wool spots following space travel and prolonged exposure to microgravity. Using OCT, the authors describe changes in the optic nerve head and surrounding tissue in astronauts after a 6-month mission.

Study design

The authors monitored 15 astronauts who underwent OCT imaging before and after a 6-month long mission to the International Space Station. They quantified morphological changes in various ocular structures, and compared findings from the astronauts and 43 healthy controls.


After returning from their mission, investigators noted increases in total retinal thickness and retinal nerve fiber layer thickness, which were most pronounced in the region closest to the optic nerve head rim margin. There were no changes in choroidal thickness.

Perhaps the most interesting finding was that the Bruch membrane opening (BMO) was recessed in the astronauts before embarking on missions compared with controls, presumably due to prior spaceflight. The BMO further deepened after the space mission (median change of -9.9µm).

Approximately 27% of the astronaut eyes had choroidal folds on their preflight OCTs, which increased to 60% after the space mission.


The main limitation of this study was that the OCT images were obtained an average of 5 days after returning to Earth rather than during space flight. Therefore, some of these changes could be diminished or rebound compensatory changes might have occurred, which could explain the paradoxical BMO orientation. Because the astronaut data were confidential, it was not possible to know which astronauts had undergone space travel prior to the current trip. Lastly, lumbar puncture opening pressures were not available for these astronauts and therefore an association between opening pressure and OCT changes could not be determined.

Clinical significance

The findings here add more evidence that long-term space missions have a negative impact on astronaut’s eyes. The changes that were noted in the BMO is the opposite of what occurs in terrestrial papilledema, where the raised intracranial pressure causes a forward bowing of the BMO upward toward the vitreous body. The authors speculate that the downward BMO deflection in astronauts may be due to the return to Earth’s gravity resulting in rapid resumption of hydrostatic drainage and resultant fluid shifts.

Another observation is the predominance of choroidal folds in astronauts, which suggests a different pathophysiology of extraterrestrial versus terrestrial papilledema.

Future and ongoing studies include OCT imaging during space flight, which will provide more insight into the changes that are occurring from microgravity during space travel. This is an important area of research as the U.S. prepares for even longer-duration spaceflights to the International Space Station, moon, asteroid belt or Mars.