COVID-19 and the Great Cornea Bank Stickup

by Sam McCommon

That eye banking was hit by the COVID-19 pandemic perhaps won’t come as a shock to most people. Indeed, we’re all painfully aware of just how much it turned the world upside down, so we needn’t further belabor that point. If we can imagine the eye bank as a dusty, small-town deposit bank and the virus as a masked, gun-slinging robber — well, that’s not far off.

The eye banking system in general deserves a closer look vis à vis the virus because there are still some unanswered questions. So, the All India Ophthalmological Society (AIOS) during its first International Ophthalmic Conclave (IOC), or AIOS IOC 2021, turned to Dr. Jennifer Li, professor of ophthalmology and vision sciences at the University of California at Davis and chair of the Medical Advisory Board at the Eye Bank Association of America (EBAA) to shed some light on the situation.

Sand in the gears

It’s an unusual virus we’re dealing with, to be sure, and extreme caution in eye banking has been the go-to rule. This extreme caution led to what was essentially a complete, worldwide collapse of cornea transplants in March and April of 2020. Just to make that clear, there were for all practical purposes no cornea transplants during that period. That’s unprecedented — another word we’re all likely sick of by now.

As Dr. Li noted, U.S. eye banks have recovered to around 80% to 85% of their pre-COVID levels, though international eye banks lag behind. It’s great to see the eye bank world spring back to life, but it’ll take some time before things are running as smoothly as before. We’re not out of the woods yet, anyway.

Just to chart a clear path through said woods so we don’t get lost, let’s take a quick step back and see how we got to that collapse and then how things have progressed from there.

Sticky stuff

Early on in the pandemic, information on just how the virus affected the eyes was scarce. We’ve come a long way, however. The virus behind the pandemic is well known to bind to angiotensin converting enzyme 2 (ACE2) receptors most notably, but others as well.

The ACE2 receptor is present in the conjunctiva, limbus and cornea, as are TMPRSS2 and DC-SIGN/DC-SIGNR. Dr. Li pointed out that TMPRSS2 can allow the virus to enter a cell after it’s bound to an ACE2 receptor via its spike protein. Alternatively, the DC-SIGN/DCSIGNR could be another transmission method for the virus.

So we know that the virus can infect ocular tissue. That’s the bad news. The good news is that it doesn’t appear to be able to replicate in ocular tissue, or

survive there in deceased patients.

To wit, Dr. Li presented a study by Bayyoud et al.¹ consisting of 10 eyes from five patients who had died of COVID-19. Quantitative reverse transcription polymerase chain reaction (RT-PCR) testing for viral ribonucleic acid (RNA) was performed on corneal stroma and endothelium, the bulbar conjunctiva, conjunctival fluid swabs, anterior chamber fluid, and the corneal epithelium.

The result? No viral RNA was detected in any of the ocular tissue or intraocular fluid. So, we’re done here, right?

Not quite. Another, earlier study by Casagrade M. et al.² appears to contradict that notion. Of 11 patients deceased from COVID-19, viral RNA appeared in the corneal tissue of 6 (that’s 55%). The infectivity or structure of the viral proteins couldn’t be confirmed, but it sure left its signature, like a wanted criminal’s calling card. This leaves researchers scratching their heads wondering if the cornea was contaminated via blood or aqueous.

Gimme a clue, Doc

Thus, the sheriff rushed to the scene. The EBAA was quick to consider the implications of the virus in the corneal tissue, with discussion beginning as early as January 21, 2020 — just after the first confirmed case in the U.S. The first screening recommendations were sent on February 3, 2020, not long afterward. Since then, the guidelines have been continuously evolving and we can likely expect them to evolve further.

The most recent update was released on October 20, 2020. Crucially, it aims to balance the needs of transplant recipients and doctors with the safety of the donor pool — and there are some good ways to do this.

Guidelines and rationale

So, for now, we’re left to sort out eligible and ineligible donors. For example, was a deceased person known to be infected with the virus in the last 28 days? They’re not eligible for donation. If they’re negative, or if they were asymptomatic at the time of death? It’s currently not necessary to perform a PCR test to determine if a donor is eligible. They’re good to go.

Before you get concerned, the rationale here is that this relies on a more decentralized system, anchored by the medical expertise of the people on the scene. An overall increase in testing has led to improved screening, and local medical directors are more capable of making decisions regarding the safety of donor tissue than before. In some cases, still, a negative PCR test may be required to check some corneal tissue.

Ocular inflammation, like conjunctivitis, keratitis, and so on, is a contraindication for harvesting corneal tissue. That’s a no-go.

In the event tissue has been deemed safe to harvest, it must be washed at least twice with a 5% povidone-iodine solution between the time of the donor’s death and tissue harvesting.

What happens when things go wrong?

In the event that, somehow, infected corneal tissue is transplanted to a recipient, it’s not the end of the world. This has in fact happened, but no one has been harmed by it.

As far as we know right now, there’s no indication of COVID-19 transmission from corneal tissue. Dr. Li noted there are currently eight known cases of accidental transplant of tissue from donors infected with the virus at the time of their death. Of these eight cases, the recipients are all fine. They did not develop COVID-19 during the postoperative period, and all the grafts were successful. So, hey, even when mistakes happen, people somehow come out of it okay. Thank goodness for that.

REFERENCES:

¹ Bayyoud T, Iftner A, Iftner T, et al. Absence of Severe Acute Respiratory Syndrome-

Coronavirus-2 RNA in Human Corneal Tissues.

Cornea. 2021;40(3):342-347. ² Casagrande M, Fitzek A, Püschel K, et al.

Detection of SARS-CoV-2 in Human Retinal

Biopsies of Deceased COVID-19 Patients. Ocul

Immunol Inflamm. 2020;28(5):721-725.

A successful bank robbery takes split-second timing… or dozens of dynamites.

Editor’s Note:

AIOC IOC 2021 was held virtually from February 19 to 21. Reporting for this story took place during the event. A version of this article was first published at cakemagazine.org on April 1, 2021.

TECNIS Synergy™

Bridging the Gaps in Surgical Correction of Presbyopia

TECNIS Synergy™ unites EDOF and Multifocal technologies for continuous vision that gets the best of both worlds.

Advances in intraocular lens (IOL) technologies have increased patient expectations for postoperative refractive outcomes tremendously. Patients today seek not just good vision, but also total spectacle independence. Indeed, the goal of implanting IOLs for the physician has transitioned from the mere treatment of disease to providing complete visual rehabilitation. The visual demands of daily life have also changed in the last few decades. Intermediate vision is increasingly crucial in carrying out daily activities such as cooking, using computers and smartphones and even looking at the car dashboard.¹ IOL options being available, most have limitations and are not able to meet all of the demands. Patients continue to struggle to achieve high-quality vision at ideal distances at all times of the day. The Extended Depth of Focus (EDOF) IOLs provide good distant and intermediate vision, but adequate near visual acuity. Multifocal and trifocal IOL technologies can provide good near, intermediate and distant visual acuity. However, the light rays are split at distinct focal points, leaving gaps in the visual acuity. Advanced optics that splits light or extends the range of vision is associated with an increase in photic phenomena, which is the leading cause of dissatisfaction among patients after uncomplicated cataract surgery. Achieving good visual acuity at home and in the office is further challenged by the increasing utilization of LEDs in indoor spaces. LEDs emit shorter wavelengths of light that scatter to a greater extent, hindering vision quality.²

Improving vision quality under different light conditions

The TECNIS Synergy™ IOL was designed to overcome the limitations of current IOL technologies. Its innovative design combines the EDOF and Multifocal technologies to deliver continuous high-contrast

vision across the range, even in lowlight conditions.³ The lens is based on the TECNIS® platform, recognized for minimal spherical and chromatic aberrations, Grade 0 glistenings and minimally observed capsule phimosis. The TECNIS® IOLs correct spherical aberrations to essentially zero and provide a sharp quality of vision.4 They have a high Abbe number of 55, which reduces light dispersions and chromatic aberrations.5 The superior material and unique design provide a sharp quality of vision and unmatched image contrast under all lighting conditions.6 Its proprietary ChromAlignTM technology further reduces chromatic aberrations and optimizes contrast vision.7

The performance of TECNIS Synergy™ IOLs is further enhanced by the proprietary violet-light filtration system and a pupil-independent design. The violet-light filtration blocks the shortest wavelengths of visible light (violet), which produce the highest levels of scatter while transmitting the longer wavelengths of light (blue). Blocking the high-energy wavelengths improves vision quality and reduces light scatter, improving safety during daytime and night-time driving.8 The pupilindependent design contributes to the best low-light performance compared to leading trifocal IOLs.9 The unique technology and design of the TECNIS Synergy™ IOL delivers continuous 20/25 vision from far to near, with high contrast vision even in low-light conditions.10 Continuous vision across the range bridges the gaps in vision experienced by patients with trifocal IOLs, and TECNIS Synergy™ empowers the patients to see at their ideal distances.11

Clear vision, no matter the distance

The breakthrough innovative technology has been thoroughly tested through bench and clinical studies with promising results. The TECNIS Synergy™ was compared with the TECNIS Multifocal® +3.25D in a prospective, masked randomized clinical study in patients undergoing cataract surgery with bilateral IOL implantations. The visual acuity was assessed under photopic conditions and defocus curve testing was conducted on follow-up. It was observed that the TECNIS Synergy™ provided 20/20 to 20/25 visual acuity continuously from far, intermediate, through near. The defocus curve testing showed a full range of vision with near up to 33 cm. Overall, the TECNIS Synergy™ provided intermediate and distance vision comparable or better than the multifocal IOL.12

In conclusion, TECNIS Synergy™ IOL overcomes the limitations of existing IOLs to provide continuous high- contrast vision from distance to near, even in low-light settings.

Scan the QR code to visit J&J Surgical Vision APAC website for more information and discover innovative solutions.

* Not all products are approved in each market. Please contact your local sales representative for further information.

REFERENCES:

1. Tognetto D, Cecchini P, Giglio R, Turco G. Surface Profiles of New-generation IOLs With Improved

Intermediate Vision. J Cataract Refract Surg. 2020;46(6):902-906. 2. Data file on PP2019CT4746 TECNIS SynergyTM IOL Limited Launch (EMEA) Message Map Guidance

Document 3. Data file on PP2019CT5141TECNIS SynergyTM IOL — The Continuous-Range-of-Vision IOL from

Johnson & Johnson Vision 4. Data file on PP2020CT4825 TECNIS® Portfolio of IOLs 5. Data file on PP2019CT5141 TECNIS SynergyTM IOL — The Continuous-Range-of-Vision IOL from

Johnson & Johnson Vision 6. Data file on PP2020CT4825 TECNIS® Portfolio of IOLs 7. Data file on PP2019CT5141 TECNIS SynergyTM IOL — The Continuous-Range-of-Vision IOL from

Johnson & Johnson Vision 8. Data file on PP2019CT4746 TECNIS SynergyTM IOL Limited Launch (EMEA) Message Map Guidance

Document 9. Ibid. 10. Ibid. 11. Data file on PP2019CT5141 TECNIS SynergyTM IOL — The Continuous-Range-of-Vision IOL from

Johnson & Johnson Vision 12. Chang D. Visual Outcomes and Defocus Curve Profile of a Next-generation Diffractive Presbyopia-

Correcting Intraocular Lens. 2019. Paper presented at 37th Congress of ESCRS, Paris

©Johnson & Johnson Surgical Vision, Inc, 2021 PP2021CT4610

by Sam McCommon

Picture this scene: A dusty, leatherfaced cowboy hitches his horse to the post on a dirt street, throws open the double doors of the saloon, ambles, bow-legged, to a bar stool, and orders a bourbon, neat. He throws it back quickly, grits his teeth, and rubs his sore, dry eyes with the heels of his palms. He’s been roping young steers all day and the dust they’ve kicked up, combined with hours of squinting from the sun, has left his eyes red and raw.

Now, swap out that cowboy for a modern office worker, the horse for a Toyota, the saloon for a café, the cows for numbers in a spreadsheet, and the dust in the air for smog. The result of these occupational concoctions is the same: a marked increase for the risk of developing dry eye.

The itchiness and irritation that come with dry eye disease (DED) are all too familiar to many, and the prevalence of the condition is spreading like a prairie fire. Roughly 10% of the American population and around 350 million people worldwide suffer from the disease in one form or another,

and ophthalmologists are well aware that DED is one of the most common reasons for clinic visits. Why DED Remains an Unconquered Territory

Amazingly enough, for a problem that’s plagued mankind since the beginning of time, DED represents a frontier yet to be conquered by ophthalmic science. It’s only been in the last few decades that DED was even recognized as a condition in its own right. Indeed, the first definition of it was as recent as 1995, when, we should note, the second “D” stood for “disorder.”

So, why did it take so long to get recognized by the medical community? It’s a valid question, so we asked Dr. Laura Periman to help us better understand it. For reference, she's a board-certified, cornea-trained ophthalmologist based in Seattle at her own clinic that specifically focuses on dry eye. To say she’s made DED her life’s work would be right on the money.

“We didn’t have the right language to diagnose it and talk about it until not too long ago,” Dr. Periman said. “We didn't have the right tools to treat it. Scientific growth needed to happen first.”

“There’s a medical awareness layer that needed to come in,” she continued. “There’s an innovation layer that needed to come in. We needed all the wheels on the wagon before we could really get anywhere.”

One of the major problems in treating DED is it’s a multifactorial condition. Diagnosing the actual cause of a person’s DED is often a challenge. and it can be an exercise in frustration for both doctor and patient.”

A deeper dive into a proper DED diagnosis often requires a bit of sleuthing on an ophthalmologist’s part. When the cause of the condition could be anything from allergies leading to meibomian gland dysfunction (MGD), to autoimmune disorders like Sjogren’s syndrome — or even environmental, dietary, cosmetic or hygienic factors — ophthalmologists may need to connect the dots between the differing medical specialties.

There’s good news, though. There have recently been significant developments for DED treatment, and more are on the way. The condition is finally getting the medical recognition it deserves — because it’s a true quality of life issue, and not simply a minor inconvenience to be brushed off and ignored.

Dr. Periman noted that in the ophthalmic community, there’s been a significant uptick in DED recognition in just the last four or five years. And the pharmaceutical industry has been making significant strides in treatment options as well — which we’ll discuss just now.

Novel Dry Eye Treatments: The Sheriff’s New Posse

Samuel Colt’s revolver changed the nature of the American “Wild West” because it was the first gun that could fire multiple shots before being reloaded. New treatments for DED effectively give doctors multiple shots to target DED’s numerous causes, which at least

That’s why Dr. Periman had to change the structure of her clinic.

“Dry eye is a busy, noisy and messy disease state,” she said. “It’s a big umbrella diagnosis with a bunch of different diagnoses and you can’t solve it in just six minutes. You need more time. The traditional medical care model doesn’t serve the dry eye patient, gives them a fighting chance.

Demodex blepharitis: Mighty overlooked mites

Demodex folliculorum infestations may well be a seriously overlooked problem. Demodex blepharitis is caused by an infestation of pesky, eight-legged mites. These little varmints just love to make eyelashes their home, which can lead to eyelid inflammation, meibomian gland dysfunction, chalazia and severe dry eye, especially in older patients.

A 2010 study¹ showed that 84% of 60-year-olds and 100% of those older than 70 hosted demodex infestations. As aging is a known predisposing factor for dry eye, there may be something to really chew on here. The mites can cause mechanical damage via collarettes — their waste — and can also carry bacteria that leads to other problems, including rosacea. Almost half (45%) of blepharitis cases are caused by demodex mites, so they’ve got to go.

One such treatment that may soon be available is from Tarsus Pharmaceutical (Irvine, California, USA). The company is currently developing the first treatment specifically for demodex blepharitis, and things look promising. Their eye drop, currently named TP-03, has undergone multiple successful trials and is currently in phase 2b/3. Dr. Periman told us that TP-03 can kill the mites for up to six months after a twice daily, four-week treatment regimen.

Interestingly, TP-03 is a lotilaner .25% solution — and was borrowed from the veterinary world, where it’s used to kill

ticks and fleas on dogs. In this case, what’s good for Fido may also be good for Fred.

Another potential treatment for demodex infestations is intense pulsed light (IPL). The in-vitro study2 published by Dr. Periman and her collaborators, Harvey Fishman MD and Ami Shah MD, showed that IPL can

lead to “complete destruction of the organism.” In other words, it kills them dead.

TearClear: More than a lick and a promise

Interestingly, the way topical ophthalmic medications are delivered may soon change — and this can have a significant benefit for dry eye patients. Dr. William Trattler brought our attention to a company called TearClear (Boston, Massachusetts, USA) that’s working to produce a special filter that removes preservatives in eye drops.

Benzalkonium chloride (BAK) is a common eye drop preservative. In the past, it was viewed as potentially beneficial — it appeared to help drugs penetrate the ocular surface and allow for better drug delivery.

However, BAK has come under scrutiny, with many arguing against its use — and it’s been strongly implicated to worsen dry eye. A 2017 study3 pointed out that BAK reduces mitochondrial function in corneal epithelial cells, which could be what causes adverse reactions.

TearClear is currently focusing their efforts on glaucoma medication, but dry eye is in their sights as well. Keep an eye on this startup: A functional preservative filter would be a gamechanger indeed.

DED treatments: Keep ‘em comin’

Another up-and-coming dry eye treatment is Eysuvis (Kala Pharmaceuticals, Watertown, Massachusetts, USA).

It’s a topical corticosteroid that was approved by the FDA as recently as October 2020, and is the first prescription medication specifically indicated as a short-term dry eye treatment. Because it’s tailor-made for dry eye, it’ll likely be one of the most popular choices for ophthalmologists going forward.

Then there are antihistamine treatments for dry eye, which can often be a result of allergies. Rather than take a systemic antihistamine, doctors can recommend Zerviate (Eyevance, Fort Worth, Texas, USA) as a topical antihistamine. It relies on cetirizine, and was approved by the FDA just a few years ago in 2017.

Biologics may have an interesting role to play as well. Lubricin (Lubris Biopoharma, Framingham, Massachusetts, USA) naturally found in the ocular surface, may be a valuable addition to a dry eye regimen. The “lubri-” part of the word is a good clue as to what it does: It prevents friction between the cornea and the conjunctiva during blinking. Studies4 have shown it’s extremely effective at reducing this friction, thus reducing mechanical wear and tear on the ocular surface. It feels good to blink smoothly, doesn’t it?

Reimagining human nerve growth factor drugs has also led to potential success in treating DED. Cenegermin in the form of Oxervate (Dompé, Boston, Massachusetts, USA) was originally developed and approved to treat neurotrophic keratitis, but it has also shown promise as a DED regimen. A recent British study5 showed the drug was safe and effective. It’s very good news for a product that’s already on the market to have multiple uses.

Even Botox has been shown to be useful in the fight against DED, as Dr.

Periman pointed out. “You can use Botox right above the lacrimal sac to decrease the tear clearance pump function in order to create tear conservation without punctal plugs,” she said.

The true grit of Azura’s AZRMD-001

Meibomian gland dysfunction (MGD) is becoming better understood as one of the chief causes of dry eye disease, but there are currently no approved treatments for it. Azura (Tel Aviv, Israel) is looking to treat that, and in early March 2021, they released compellingly positive phase 2 results for their drug, unpoetically named AZRMD-001. Interestingly, the company brands itself as taking a dermatological approach to ocular surface diseases.

The drug’s goal? To reduce the hyperkeratinization of meibomian glands, which blocks the release of sebum. Essentially, a blocked meibomian gland means there’s not a thick enough meibum protecting the top layer of tears from evaporation and lubricating the eyes.

Azura argues that MGD is significantly underdiagnosed, and they may be right. If the treatment proves to be a big of a hit as the company seems to expect, someone could stand to make significant money. We’ll be keen to keep up for further developments.

Good ole at-home treatments Giddy-up! Make DED Dead

It’s taken a lot of work to get where we are now with DED treatments, and a lot more are on the way. Any civilian would probably be shocked to learn just how complicated DED can be, and just how many factors are at play.

The eye’s tears are its natural defense mechanism, and not having enough of them is ironically something to cry about.

We’re very pleased to see the progress occuring in the DED world, and the next few years should turn up further significant improvements. Shining the medical world’s flashlight on DED has proven to be enlightening in more ways than many even in the industry would have anticipated not long ago.

So, let’s conquer this frontier of medicine and get DED corralled for good. If it can be done, it should. Just like any good sheriff protecting his town, it’s the doctors’ job to make sure the townspeople are taken care of.

Hold your horses! Neurostimulators are on the way

Two interesting treatments rely on neurostimulation to induce tear production — a novel, non-eye drop approach. One is Olympic Ophthalmics’ (Issaquah, Washington, USA) iTear100, a device that relies on external vibrations. It was approved by the FDA specifically for this purpose in May 2020. Dr. Periman participated in the phase 3 FDA trials and was a co-author on the paper6 published late 2020.

The iTear100 is pocket-sized and delivers vibrations to the side of the nose for about 30 seconds — which then stimulates tear production. One study demonstrated a 22mm change in the Schirmer score, and another longterm study showed significant Schirmer score improvements over 30 days. Overall, the iTear100 is a neat, reliable buzzy device that produces a complete tear and improves tear production, corneal staining and meibomian gland secretion scores. Simple solutions can be very refreshing sometimes.

Another neurostimulation treatment is a preservative-free nose spray relying on varenicline, a drug often used to treat nicotine addiction. Oyster Point Pharma (Princeton, New Jersey, USA) submitted a new drug application to the FDA as recently as December 2020, for their spray, dubbed OC-01. The spray stimulates the trigeminal nerve via the nose, which stimulates tear production.

It wouldn’t be 2021 if we weren’t discussing at-home treatments, as doing everything at home has been all the (necessary) rage. But patients suffering from DED will likely continue to appreciate these home treatments, even if they can now return to their favorite ophthalmologist.

One notable at-home treatment Dr. Periman is very keen on is called NuLids (NuSight Medical; Rancho Santa Fe, California, USA). It looks like an electric toothbrush and, in fact, has a similar purpose. Its soft tip gently cleans the eyelids while stimulating the meibomian glands.

There’s an additional bonus: The device also helps remove any potential mites in your eyelids by simply sweeping them away. Cool, right?

REFERENCES:

Contributing Doctor

1. Liu J, et al. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10(5):505-510. 2. Fishman HA, Periman LM, Shah AA. Real-Time Video Microscopy of In Vitro Demodex Death by Intense

Pulsed Light. Photobiomodul Photomed Laser Surg. 2020;38(8):472-476. 3. Datta S, Baudouin C, Brignole-Baudouin F, et al. The Eye Drop Preservative Benzalkonium Chloride

Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest

Ophthalmol Vis Sci. 2017;58(4):2406-2412. 4. Schmidt TA, Sullivan DA, Truitt ER, et al. Lubricin Functions as an Ocular Surface Boundary Lubricant.

Invest Ophthalmol Vis Sci. 2010;51(13):3399. 5. Sacchetti M, Lambiase A, Schmidl D, et al. Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study. Br J Ophthalmol. 2020;104(1):127-135. 6. Ji MH, Moshfeghi DM, Periman L, et al. Novel Extranasal Tear Stimulation: Pivotal Study Results. Transl

Vis Sci Technol. 2020;9(12):23. Dr. Laura M. Periman is a boardcertified ophthalmologist, fellowship-trained cornea and refractive surgeon and ocular surface disease (OSD) expert.

Dr. Periman completed her ophthalmology residency and cornea/ refractive fellowship at the University of Washington in Seattle. She has 11 peerreviewed publications and has written extensively on the topic of OSD. As founder and director of Dry Eye Services and Clinical Research at Periman Eye Center in Seattle, Washington, USA, Dr. Periman combines her clinical care passion, scientific drive, and innovative creativity to provide first class OSDmanagement.

dryeyemaster@gmail.com

DEAD or ALIVE

Ringleaders reward: $$$$$

Meibomian Gland Dysfunction

Ocular Allergies

Known accomplices reward: $$$$$

Demodex Blepharitis

Prolonged screen use Cosmetics *Systemic medications

Air pollution and low air humidity

Skin diseases like rosacea and eczema

Autoimmune disorders like Sjogren’s Syndrome, Lupus, or Rheumatoid Arthritis Postmenopausal estrogentherapy Recent ophthalmic surgery

Preservatives in eye drops

Vitamin A deficiency Diabetes Aging

*(antihistamines, antihypertensives, anxiolytics/benzodiazepines, diuretics, systemic hormones, non-steroidal anti-inflammatory drugs, systemic or inhaled corticosteroids, anticholinergic medications, isotretinoin (causes meibomian gland atrophy), and antidepressants)

1. Golden MI, Meyer JJ, Patel BC. Dry Eye Syndrome. Treasure Island (FL): StatPearls Publishing; 2021. 2. Messmer EM. The Pathophysiology, Diagnosis, and Treatment of Dry Eye Disease. Dtsch Arztebl Int. 2015;112(5): 71–82. 3. Liu J, Sheha H, Tsenga SCG. Pathogenic role of Demodex mites in blepharitis. Curr Opin Allergy Clin Immunol. 2010;10(5): 505–510.