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.

Glaucoma drop study - another nail in the BAK coffin... right?

I enjoyed reading this study titled "Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye" (scroll down for the abstract)

On the face of it, it is all about glaucoma drops and dry eye. But don't be fooled by the absence of the word "preservative" in the text of the abstract. I checked with the authors to verify a few details because the complete text had not yet been released. As suspected, the paper is really mostly about the known and despised toxic effects of the preservative benzalkonium chloride (BAK), also known as dry eye inducing poison for your eyes.

There is a plethora of literature on the toxic effects of BAK to the cornea. Much of the attention has been given to BAK in the context of glaucoma medication. This is presumably because glaucoma patients (1) have to take drops every day for years, which means long term exposure to the risks, and (2) are older, which means they are already at higher risk, even without additional risk factors common in their age group, such as cataract surgery and the many health conditions requiring medications that are known to be drying to the eyes. Why would we put people to this kind of long term completely avoidable risk? On the other hand, there's probably a much simpler reason for the proportionally high attention to glaucoma drops: (3) glaucoma patients are relatively easy to study as there's so many of them, and they have to take the drops. Bit of a captive audience.

In relatively recent years, preservative free glaucoma medications began seeping onto the market and - much too slowly - began displacing the preserved ones. I remember the first PF glaucoma drop - Travatan Z - and how long it took before I ever heard from dry eye patients whose doctors prescribed it without specifically being asked to by the patient. (You'd think the glaucoma doctors and the cornea doctors might at least occasionally chat over a water cooler?) Thankfully, things are much better now than they were. - That is, specifically in the world of glaucoma medications, and specifically in the US. (Dr Craig mentioned that no preservative free publicly funded options are available yet in New Zealand.)

One of the areas I continue to be very, very concerned about when it comes to dry eye and corneal damage from BAK overexposure is in over-the-counter eyedrops in the US. Drugstore shelves are crammed with all kinds of BAK preserved drops, ranging from lubricants to antihistamines to vasoconstrictors - plus, my most hated crowd: the combo multi-purpose drops. A little bit of lubricant, a vasoconstrictor, an antihistamine, pick a random collection of benefits, stir them up and put a pretty label on them. The majority of such drops are preserved with BAK and as such they pose serious risks to people who buy them and use them regularly.

To me this is a painful failure on the part of the FDA as the warning language in the packaging is completely inadequate. Drops that promise relief of irritation and redness should not contain substances that are known to cause harm if you continue using them. Many of the people these drops are marketed to rarely visit an eye doctor because the level of eye irritation is not severe. There is no one to tell them they are in harm's way.

Anyway, circling back to glaucoma: If you are using glaucoma drops, and you do not know whether they are or aren't preserved, please find out, and talk to your doctor about whether there are preservative free alternatives that would be appropriate for you.

Ocul Surf. 2018 Mar 3. pii: S1542-0124(17)30311-7. doi: 10.1016/j.jtos.2018.03.002. [Epub ahead of print]

Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye.
Wong ABC1, Wang MTM1, Liu K1, Prime ZJ1, Danesh-Meyer HV1, Craig JP2

Abstract
PURPOSE:
To assess tear film parameters, ocular surface characteristics, and dry eye symptomology in patients receiving topical anti-glaucoma medications.

METHODS:
Thirty-three patients with a diagnosis of open angle glaucoma or ocular hypertension, receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross-sectional, investigator-masked, paired-eye comparison study. Tear film parameters, ocular surface characteristics, and dry eye symptomology of treated and fellow eyes were evaluated and compared.

RESULTS:
The mean ± SD age of the participants was 67 ± 12 years, and the mean ± SD treatment duration was 5.3 ± 4.4 years. Treated eyes had poorer non-invasive tear film break-up time (p = 0.03), tear film osmolarity (p = 0.04), bulbar conjunctival hyperaemia (p = 0.04), eyelid margin abnormality grade (p = 0.01), tear meniscus height (p = 0.03), and anaesthetised Schirmer value (p = 0.04) than fellow eyes. There were no significant differences in dry eye symptomology, meibomian gland assessments, and ocular surface staining between treated and fellow eyes (all p > 0.05)

CONCLUSIONS:
Adverse changes in tear film stability, tear osmolarity, conjunctival hyperaemia, and eyelid margins were observed in treated eyes. This suggests that inflammatory mechanisms may be implicated in the development of dry eye in patients receiving long term topical anti-glaucoma therapy.