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.

Symptoms and signs, and signs and symptoms, oh my

Have you learned about the difference between dry eye symptoms and dry eye signs yet? Great time to learn!

Symptoms = what you experience (pain, burning, light sensitivity, blurred vision, grittiness, dry sensation, redness, etc)

Signs = what the doctor can observe during an exam (hyperosmolarity, low TBUT, ocular surface staining, etc)

These two things might match, or they might occur in different proportions (you hurt a lot worse than you look or vice versa) or you might have one without the other. 

For patients, the mismatch between these two things causes all kinds of problems. Here's a few:

• Communication problems with your doctor, especially if your symptoms are worse than your signs.

• Difficulty sticking to a treatment plan, because we patients naturally tend to do the treatments that make us feel better and ditch the treatments that don't

• Difficulty getting a grip on what actually "works", because we define success by sensation while doctors define success by improved clinical findings

The excerpt below from TFOS DEWS II tries to explain some of the situations when the sign-symptom mismatch happens. Distilling it down a bit:

1. You could have "dry eye pain" that's actually not from dry eye but instead neuropathic. Dry eye treatment won't fix it.

2. You could have symptoms off and on but not be diagnosed because you're in early stages. If you're in that bucket, you might be at higher risk of getting dry eye from medical treatments ("iatrogenic" dry eye).

3. You could have bad dry eye but not feel it because dry eye itself could have reduced your corneal sensitivity.

4. You could look like you have dry eye, but not be feeling it (yet), for all kinds of reasons.

TFOS DEWS II Definition and Classification Report

7.3 Symptoms without signs: neuropathic pain
The Pain and Sensation Subcommittee report describes a clinical scenario of neuropathic pain due to either a lesion or disease in the somatosensory system, in which ocular pain symptoms disproportionally outweigh the clinical signs [8]. This is an important distinction in the diagnosis, and the required pain management falls outside the scope of DED therapy [8].

7.4 Symptoms without signs: pre-clinical dry eye state
It is further recognized that symptoms consistent with DED, but in the absence of clinical signs, especially when the symptoms are intermittent, might indicate a pre-clinical dry eye state, or a scenario of emerging episodic dry eye. Ongoing evaluation for the development of signs and the control of symptoms through education and prevention are suggested. Studies evaluating the natural history of short and long-term preventative efforts in this patient group are needed [9]. Determination of whether such individuals are at higher risk of developing iatrogenic DED, in comparison to those who are non-symptomatic, is also deserving of further investigation [17].

7.5 Signs without symptoms: reduced corneal sensitivity
Patients exhibiting signs of ocular surface disease, but reporting no symptoms of discomfort, require consideration of whether dry eye management is indicated. Corneal nerve damage secondary to longstanding DED is a recognized phenomenon and the reduced corneal sensitivity can mask discomfort. The dysfunctional sensation is a function of the underlying disease process. Other forms of corneal disease exist, where corneal sensation is reduced, and these should also be managed accordingly [17].

7.6 Signs without symptoms: predisposition to dry eye
Ocular surface changes in the absence of presenting symptoms may be noted during a preoperative examination for cataract or refractive surgery, for example, and signify early disease that might place the patient at risk of developing symptomatic DED following the surgical event [17]. Preventative management should be considered, as described in more detail in the Iatrogenic report [17]. Recently, asymptomatic MGD has been reported with a prevalence of double that of symptomatic MGD in a Caucasian population [20]. While there are limited data on the natural history of DED, symptoms do become more common with age [9] and individuals with MGD are more likely to report an increase in severity of their symptoms with time [21], all of which may support an argument for intervention.

References from this excerpt:

[8] Belmonte C, Nichols JJ, Cox SM, Brock JA, Begley CG, Bereiter DA, et al. TFOS DEWS II pain and sensation report. Ocul Surf 2017;15:404–437.
[9] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II Epidemiology report. Ocul Surf 2017;15:334–365.
[17] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, et al. TFOS DEWS II Iatrogenic report. Ocul Surf 2017;15:511–538.
[21] Lienert JP, Tarko L, Uchino M, Christen WG, Schaumberg DA. Long-term natural history of dry eye disease from the Patient's perspective. Ophthalmology 2016;123(2):425–433.

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.

TFOS DEWS II... and a dry eye briefing for Congress!

TFOS DEWS II is an exciting international medical consensus project spanning nearly two years of work by well over a hundred top researchers and clinicians from around the world.

The fruit of their efforts, a lengthy report on everything from dry eye pathophysiology to treatments to everything we know about pain and sensation in dry eye disease, will be released July 15th in the ophthalmology journal Cornea. I've been privileged to serve on their public awareness and education committee and am so thrilled to see this long awaited day approaching. Chomping at the bit to start getting this much needed information into the hands of the people who need it most!

Meantime, on Wednesday, July 12, TFOS are giving a congressional briefing, with highlights of the report!

TFOS DEWS II

TFOS Press Release