It's all about the burning!

Another study just came out on depression and dry eye. But it's not really about depression and dry eye. (Old news.) It's about SYMPTOMS and depression, and of those symptoms, burning specifically.

Clinical signs of eye disease are the driving force behind how optometry and ophthalmology address dry eye. It's the clinical signs that drive what gets written in the chart and on the Rx pad - but it's the symptoms that drive the patients to the doctor, and failure to get relief for those symptoms that drive patients to doctors #2, #3 and #4 and at some stage into depression as well.

Dry eye patients are ruled by symptoms. (Call it pain, actually.) Pure and simple. We do not sink into clinical depression because of our TBUT, osmolarity or meibography scores or our ocular surface staining. We are driven there when we do not get relief from the unremitting burning sensation in our eyes. (It's not a hard concept to understand; sit there with your eyes open for 60 seconds and extrapolate that to "all day" and see how that prospect suits you.)

Eyecare professionals, we need you to listen, and not get so distracted by what you are, or, even more likely, are not seeing under your slit lamp that you fail to see the big picture needs of the patient seeking help. 

Industry and FDA, we need you to listen and not get so hung up on the near impossibility of improving both signs and symptoms that you lose the bigger picture of the NECESSITY of bringing symptom relief to market.

Dear authors of the study linked below: Thank you, thank you, and thank you again for documenting this. We need every bit of increased emphasis on the role of dry eye symptoms that we can get, and especially that key word, "burning".

A thorough understanding of symptoms and patient goals should be driving dry eye research and dry eye treatment and management plans. It should also be playing a more central role in the FDA's dry eye drug approval process.

Am J Ophthalmol. 2018 Apr 12. pii: S0002-9394(18)30164-8. doi: 10.1016/j.ajo.2018.04.004. [Epub ahead of print]
How Are Ocular Signs and Symptoms of Dry Eye Associated with Depression in Women with and without Sjögren's Syndrome?
Gonzales JA1, Chou A2, Rose-Nussbaumer JR1, Bunya VY3, Criswell LA4, Shiboski CH5, Lietman TM1.

Abstract
PURPOSE:
To determine whether ocular phenotypic features of keratoconjunctivitis sicca (KCS) and/or participant-reported symptoms of dry eye disease are associated with depression in women participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA).

DESIGN:
Cross-sectional study.

METHODS:
Women enrolled in the SICCA registry from 9 international research sites. Participants met at least one of five inclusion criteria for registry enrollment (including complaints of dry eyes or dry mouth, a previous diagnosis of Sjögren's syndrome (SS), abnormal serology (positive anti-Sjögren's syndrome-related antigen A and/or B (anti-SSA and/or anti-SSB), or elevated anti-nuclear antibody and rheumatoid factor), bilateral parotid gland enlargement, or multiple dental caries). At baseline, participants had oral, ocular, and rheumatologic examination, blood and saliva collection, and a labial salivary gland biopsy (LSGB). They also completed an interview and questionnaires including assessment of depression with the Patient Health Questionnaire 9 (PHQ-9). Univariate logistic regression was used to assess the association between depression and demographic characteristics, participant-reported health, phenotypic features of Sjögren's syndrome, and participant-reported symptoms. Mixed effects modeling was performed to determine if phenotypic features of KCS and/or participant-reported symptoms of dry eye disease were associated with depression, controlling for health, age, country or residence, and gender and allowing for non-independence within geographic site.

RESULTS:
Dry eye complaints produced a 1.82-fold (95% CI 1.38-2.40) higher odds of having depression compared to being symptom-free (p < 0.001). Additionally, complaints of specific ocular sensations were associated with a higher odds of depression including burning sensation (OR 2.25, 95% CI 1.87-2.72, p < 0.001) compared to those without complaints. In both women with or without SS, the presence of symptoms of dry eyes and/or dry mouth rather than SS itself resulted in higher odds of depression. One particular ocular phenotypic feature of SS, a positive ocular staining score, was inversely correlated with depression.

CONCLUSIONS:
Participant-reported eye symptoms, particularly specific ocular sensations such as burning, were found to be positively associated with individual American College of Rheumatology/EUropean Union League Against Rheumatism (ACR/EULAR) SS criteria items.

The DREAM study disappointment

If only it could be as simple as a pill.

Alas, I think that the DREAM study results may have put that dream to bed. And while I'm personally deeply disappointed, at the same time, in my opinion, it's about time we learned something conclusive about whether Omega 3 supplements do, or do not, predictably tend to help people with dry eye. That is, before every last huckster in the industry has one privately labeled.

THE NEWS: The long-awaited results of a very large, extensive, carefully planned and executed, NEI-funded study of Omega 3 supplements and dry eye, called the DREAM study, were finally published today in the New England Journal of Medicine. Drumroll... the benefits were no better than placebo. 

THE BACKGROUND: Ever since the Women's Health Study results were published in 2005 drawing a correlation between DIETARY intake of Omega 3/6 and lower dry eye risk, everyone has been promoting, or, even more commonly, formulating or private-labeling and hawking Omega 3 dry eye supplements of every possible description. And why not? After all, they're supposed to be good for health generally and if they can help our dry eye to boot, good. And after all (forgive the cynicism, but...) dry eye patients take a lot of chair time and produce little revenue, the least they can do is shell out for some supplements. The only thing really going against the logic has been the lack of scientific support for the concept. It's not that there haven't been dozens, or maybe hundreds, of studies done on Omega 3 supplements since 2005. In fact, it's quite the opposite. But studies are one thing. Good studies are another. REPEATABLE studies yet another. TFOS DEWS II's Management and Therapy report, which reviewed >10 years worth of such studies, cited a long list of issues preventing the kind of meta-analysis that we would need in order to draw actual conclusions from those studies. 

THE STUDY: Multi-center, double-blind clinical trial. A whopping 923 patients were screened. Eligibility was based on a combination of symptoms and clinical signs of dry eye (with the clinical signs tested at two separate visits). These were patients with moderate to severe dry eye despite other treatments. The final analysis included results from 499 patients. They took a daily dose of 3,000 mg of fish oil (2,000 mg EPA, 1,000 mg DHA) or an olive oil placebo for ONE YEAR. Their OSDI (symptom score), conjunctival staining, corneal staining and Schirmer scores and other clinical signs were assessed before, at 6 months, and at 12 months. And in the end? Everybody got better, a bit, in some ways. Including... those taking the placebo.

MY THOUGHTS: I only recently read the TFOS DEWS II conclusions about Omega 3 supplements, and honestly, while it didn't give any good news about the efficacy of supplements, I was so RELIEVED at the inconclusive-cum-politely-disparaging nature of their conclusions. I've watched study after study after study get published over the years, and felt vaguely inadequate to understand any of them in context. When everyone conducts their studies so differently, you can't aggregate and you can't generalize. Who do you believe, especially when they all have pretty small patient cohorts a host of exclusions, a relatively short treatment period and other issues? So it was at least comforting to see a large group of experts come to that conclusion.

But I was still holding out hope that the DREAM study would give us some good news. Heaven knows we could use some.

Alas, it was not to be. The consolation prize is the high confidence level. If something doesn't work, we need to know. To be clear, I don't think this means no Omega 3 supplements help anyone. Rather, I think it proves that the broad-brush conventional wisdom that ALL dry eye patients should take Omega 3 supplements is not necessarily supported by scientific evidence.

SO: Where do the DREAM study results leave us as regards the relationship between Omega 3 and dry eye?

Perhaps exactly where the Women's Health Study left us 13 years ago: DIET.

Though, trust me, you're not going to be seeing ANY randomized double blind studies on THAT in the next 13 years. 

The damaging effects of preservative BAK (from TFOS DEWS II Iatrogenic Report)

It's no secret that BAK is damaging to the cornea. It both causes and worsens dry eye. This is well studied and well documented.

Nevertheless, even today:

BAK is the preservative used commonly in prescription eyedrops (excluding, obviously, the unpreserved ones like Restasis and Xiidra) such as corticosteroids, antibiotics, antihistamines, etc. Historically, it has been used in the vast majority of glaucoma eyedrops; this latter has been changing, because of the well documented and profound effects on glaucoma patients, but even that single trend away from BAK in one single drug group has been happening far too slowly.

BAK is also the preservative used in a large number of over-the-counter eyedrops, including allergy and decongestant (redness reliever) drops, many combination drops, and even some lubricant drops intended solely for dryness. These products have no warning on their labels specific to the effects of the preservative, so people who self-treat minor eye irritations over the long term without guidance from an eye doctor on what's safe (this happens commonly - they think it's not worth seeing a doctor about) can experience lasting harm without any way to know or prevent it.

The excerpt below from the Iatrogenic (i.e. medically caused) dry eye report summarizes what we know about all the different ways BAK can harm us:

• Causes damage to the goblet cells and mucous (sticky) layer of the tear film

• Causes damage to the lipid layer

• Increases tear osmolarity

• Causes inflammation and leads to an inflammatory vicious cycle

• Is more damaging to people who already have dry eye (poorer tissue defenses)

• Is toxic to trigeminal nerve endings

• Reduces nerve density and corneal sensitivity (meaning people who don't seem to have symptoms from the BAK may have damage all the same)

It's a long and painful list. We need to keep raising awareness.

TFOS DEWS II Iatrogenic Dry Eye Report
4.3.2.1 Role of preservatives and excipients

....BAK may cause or aggravate DED through various mechanisms such as its toxic and proinflammatory effects, as well as its detergent properties, which have been well demonstrated in numerous experimental and clinical investigations [125]. Goblet cells produce soluble mucins and contribute to tear film stability and immune defenses. These cells are extremely sensitive to toxic and inflammatory stress, decreased in density in humans after short exposure to BAK or BAK-containing timolol [127]. MUC1 and MUC16 were found to be reduced after exposure to BAK in human corneal and limbal epithelial cells. Transmission electron microscopy revealed alteration of the mucus layer after exposure to 0.01% BAK for 5 or 15 min, whereas more prolonged exposure (60 min) to 0.01% BAK destroyed the mucous layer [128]. These toxic effects were also found by Kahook and Noecker, who reported significantly lower densities of goblet cells in animals receiving BAK-containing latanoprost compared to preservative-free artificial tears, even though the specific effects of latanoprost alone were not addressed [129].

In addition, as a tensioactive compound, BAK is also a detergent for the lipid layer of the tear film. Thus, while an unpreserved betablocker did not impact upon tear stability, decreased TBUT was observed with a preserved betablocker [118]. Increased tear osmolarity was also observed in patients receiving preserved eyedrops compared to those who received unpreserved topical medication [122]. Following the loss of its protective properties, the impaired tear film not only results in dry eye symptoms and corneal damage, but also may convey cytotoxic inflammatory mediators throughout the ocular surface. Hence, increased corneal epithelial permeability has been shown in dry eye with additional impairment when using artificial tears containing BAK compared to nonpreserved eyedrops [130]. Tear film alterations may therefore stimulate a series of biological changes in the ocular surface, leading to subsequent neurogenic inflammation and further impairment of the tear film, creating a vicious cycle [131].

BAK causes disruption of the tight junctions of the corneal epithelium, an effect that has led to BAK being considered an enhancer of drug penetration into the anterior chamber [125]. The cytotoxic effects of BAK have been shown to be increased experimentally when cells are previously subjected to a hyperosmotic stress mimicking dry eye in vitro. Therefore, BAK can cause some level of toxicity in normal or glaucomatous eyes, which can be compensated by tissue defenses, but causes a much greater level in dry eyes, consistent with clinical findings. However, as BAK may progressively cause tear instability and hence hyperosmolarity, this compound is likely to change the conditions of its own tolerance and result in increasing toxicity levels [132].

Additionally BAK has shown neurotoxic effects to the trigeminal nerve endings [133], consistent with the results of a large study comparing the effects of preserved and unpreserved antiglaucoma drugs on corneal nerves using in vivo confocal microscopy (IVCM) [134]. The density of superficial epithelial cells and the number of sub-basal nerves were reduced in the preservative-containing groups, and stromal keratocyte activation and bead-like nerve shaping were higher in the glaucoma preservative therapy groups than in the control and preservative-free groups. Moreover, this study identified decreased corneal sensitivity, based on esthesiometry, in all preserved groups compared to control or unpreserved prostaglandin and betablocker groups. This neurotoxic property of BAK could thus contribute to apparent tolerance in some patients receiving BAK-containing eyedrops.

Experimental data also demonstrated direct proinflammatory effects of BAK with the release of inflammatory cytokines or increased expression of receptors to chemokines and cytokines [135,136]. Additionally, BAK breaks down conjunctival immunological tolerance in a murine model [137]. In humans, using immunocytological and flow cytometry methods, higher expression of HLA-DR, a marker of inflammation, occurred in impression cytology specimens over the ocular surface with preserved eyedrops [138]. Other inflammation-related markers, such as ICAM-1, interleukin (IL)-6, IL-8, IL-10, CCR4 or CCR5, were also found to be overexpressed in glaucoma patients and even more with multiple therapies and preserved eyedrops [139]. A significant infiltration of the central cornea with dendritic inflammatory cells is observed with IVCM in healthy volunteers receiving BAK-containing eye drops compared to a non-preserved solution [140].
New preservatives recently developed as alternatives to BAK, such as Polyquad®, Purite® and sofZia®, result in significantly lower cytotoxic effects [125,136,141–143]. However, their possible effects on the tear film and tolerance in dry eye patients have not been fully investigated.

References in this excerpt:
[118] Baudouin C, de Lunardo C. Short-term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol 1998;82(1):39–42.
[122] Labbé A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea 2012;31(9):994–999.
[125] Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010;29(4):312–334.
[126] Uter W, Lessmann H, Geier J, Schnuch A. Is the irritant benzalkonium chloride a contact allergen? A contribution to the ongoing debate from a clinical perspective. Contact Dermat 2008;58(6):359–363.
[127] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology 1992;99(7):1082–1088.
[128] Chung SH, Lee SK, Cristol SM, Lee ES, Lee DW, Seo KY, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Mol Vis 2006;12:415–421.
[129] Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008;25(8):743–751.
[130] Göbbels M, Spitznas M. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. Ophthalmology 1992;99(6):873–878.
[131] Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf 2013;11(4):246–258.
[132] Clouzeau C, Godefroy D, Riancho L, Rostène W, Baudouin C, Brignole-Baudouin F. Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. Mol Vis 2012;18:851–863.
[133] Sarkar J, Chaudhary S, Namavari A, Ozturk O, Chang JH, Yco L, et al. Corneal neurotoxicity due to topical benzalkonium chloride. Investig Ophthalmol Vis Sci 2012;53(4):1792–1802.
[134] Martone Gianluca, Frezzotti Paolo, Tosi Gian Marco, Traversi Claudio, Mittica Vincenzo, Malandrini Alex, et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147(4):725–735.
[135] Denoyer A, Godefroy D, Célérier I, Frugier J, Riancho L, Baudouin F, et al. CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal Immunol 2012;5(6):702–711.
[136] Lee HJ, Jun RM, Cho MS, Choi KR. Comparison of the ocular surface changes following the use of two different prostaglandin F2α analogues containing benzalkonium chloride or polyquad in rabbit eyes. Cutan Ocul Toxicol 2015;34(3):195–202.
[137] Galletti JG, Gabelloni ML, Morande PE, Sabbione F, Vermeulen ME, Trevani AS, et al. Benzalkonium chloride breaks down conjunctival immunological tolerance in a murine model. Mucosal Immunol 2013;6(1):24–34.
[138] Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignole F, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Investig Ophthalmol Vis Sci 2004;45(5):1360–1368.
[139] Baudouin Christophe, Liang Hong, Hamard Pascale, Riancho Luisa, Creuzot-Garcher Catherine, Warnet Jean-Michel, et al. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both t-helper 1 and t-helper 2 pathways. Ophthalmology 2008;115(1):109–115.
[140] Zhivov A, Kraak R, Bergter H, Kundt G, Beck R, Guthoff RF. Influence of benzalkonium chloride on langerhans cells in corneal epithelium and development of dry eye in healthy volunteers. Curr Eye Res 2010;35(8):762–769.
[141] Brignole-Baudouin F, Riancho L, Liang H, Nakib Z, Baudouin C. In vitro comparative toxicology of polyquad-preserved and benzalkonium chloride-preserved travoprost/timolol fixed combination and latanoprost/timolol fixed combination. J Ocul Pharmacol Ther 2011;27(3):273–280.
[142] Labbé A, Pauly A, Liang H, Brignole-Baudouin F, Martin C, Warnet JM, et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol Ther 2006;22(4):267–278.
[143] Kahook MY, Noecker RJ. Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008;27:339–343.

Dry eye diagnosis: Sorting out the puzzle pieces

TFOS DEWS II tells us that dry eye diagnosis can get surprisingly confusing and complex amidst all the things that mimic it, masquerade as it, and are "co-morbid" with it (i.e. other conditions you also have at the same time).

I was reminded of this particular issue repeatedly this week while on the phone with one person after another who seems to be experiencing dry eye symptoms, but also maybe ocular allergy symptoms, but doesn't think they have allergies, and oh yes they have a little bleph, and one of their doctors once told them they have a poor blink, etc, etc, etc.

I've excerpted below a couple of paragraphs from TFOS DEWS II Definition and Classification report.  If it's just too heavy on the medical-speak, here's the bottom line:

1. Lots of things can have the same symptoms as dry eye without being dry eye

2. Lots of things may be happening at the same time as dry eye (the example given below is incomplete eyelid closure, but there are many others) as a result of which JUST treating dry eye won't work - you have to deal with the other things too.

Several years ago I sat in on a very nice presentation of Lipiflow to a group of doctors. A key TearScience salesperson said, and it always stuck with me: "If you have an incomplete blink, there's no way Lipiflow will fix your dry eye. It just can't." I wish every patient I know who's had Lipiflow had been told the same thing. Solutions are designed for specific problems, not for clusters, especially when the pieces are unrelated except for the fact that they all ultimately affect the tear system.

It's so important that we have the complete picture of our "ocular surface disease" - all the pieces of the puzzle, not just the dry eye piece. Successful dry eye treatment and management ALWAYS begins with getting a thorough diagnosis. It's particularly important during allergy season, because figuring out which solutions will help more than they will harm, or relieve more than they irritate, is not always straightforward. Don't let your eye doctor get away with the "just dry eye" line - educate yourself and go armed with questions to every appointment.

TFOS DEWS Definition and Classification report

7.2. Other ocular surface disease differential diagnoses

Ocular surface disease is the broad category that is considered to include a multitude of ocular surface conditions, some of which closely mimic or masquerade as DED, and many that can occur concurrently with DED [15]. Because of this complexity and overlap, dry eye is frequently treated as a diagnosis of exclusion. The TFOS DEWS II Diagnostic Methodology report presents “triaging questions” [15], which can be used, in combination with clinical findings, to differentially diagnose other ocular surface conditions that may require specific management, and result in relief of signs and symptoms that might otherwise be attributed to DED.

It is important to note that many ocular surface diseases can be co-morbid with dry eye, thus a step-wise approach to management, with subsequent follow-up to monitor signs and symptoms is warranted. For example, symptoms and tear film changes commensurate with DED might well occur in a condition such as lagophthalmos, due to poor lid to globe apposition, preventing formation of a stable inter-blink tear film. However, resolution with dry eye therapies alone is unlikely to succeed, as the surfacing problem cannot be resolved without managing the lagophthalmos. The converse of this scenario is that restoration of lid-globe apposition through surgical management of the lagophthalmos has the potential to fully resolve the dry eye symptoms and signs without the need for dedicated dry eye therapies [[16], [19]]. Further research is needed regarding co-morbid ocular surface conditions that induce a “secondary” dry eye.

References in this excerpt:
[15] Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf 2017;15:539–574.
[16] Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, Dana R, Deng SX, et al. TFOS DEWS II Management and Therapy report. Ocul Surf 2017;15:575–628.
[19] Latkany RL, Lock B, Speaker M. Nocturnal lagophthalmos: an overview and classification. Ocul Surf 2006;4(1):44–53.