What are the symptoms of long-term benzalkonium chloride use in the eyes? How does the benzalkonium chloride-induced loss of corneal sensation and reduced corneal epithelial healing manifest? Does it resolve after benzalkonium chloride use is stopped?
Symptoms of long-term benzalkonium chloride (BAK) use in the eyes include ocular surface disease (OSD) manifestations such as ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, and corneal surface impairment. Chronic exposure to BAK can lead to dry eye disease (DED) and other neurosensory abnormalities, including ocular pain and reduced corneal sensitivity.[1-5]
Benzalkonium chloride-induced loss of corneal sensation and reduced corneal epithelial healing manifest as decreased corneal sensitivity, increased ocular pain, and delayed wound healing. BAK exposure results in significant reductions in corneal nerve density and tear secretion, leading to corneal hypoesthesia and impaired epithelial healing. These effects are dose- and time-dependent, with higher concentrations and prolonged exposure causing more severe damage.[3][5][7]
Resolution after cessation of BAK use: Studies indicate that some of the adverse effects of BAK on the corneal epithelium and nerves can improve after discontinuation. For instance, corneal epitheliopathy and nerve density showed improvement after stopping BAK treatment. However, the extent of recovery may vary, and some damage, particularly to corneal nerves, may be irreversible depending on the severity and duration of exposure. Therefore, it is advisable to minimize or avoid long-term use of BAK-containing ophthalmic solutions whenever possible.[3][5][8]
This question came up in the context of the healing properties of topical insulin for the corneal. (And that topic came up because of topical insulin's potential for RNFL regeneration, which is currently under study. Check other posts here for more about that: https://ask.fiteyes.com/t/insulin/) Here's some information on how topical insulin might help heal the damage caused by BAK.
Chronic use of glaucoma medications containing benzalkonium chloride (BAK) may reduce corneal sensation via nerve damage and impair corneal epithelial healing.
The use of insulin in corneal diseases began in 1945 -- 80 years ago. It's strange that we're still speaking of it as an emerging new treatment. However, that's the case.
We can say that topical insulin seems promising as a therapy for promoting corneal wound healing in multiple conditions and addressing underlying pathologies, including dry eye disease. Fortunately, interest in topical insulin among ophthalmologists is growing rapidly now.
Insulin References
The role of topical insulin in ocular surface restoration: A review - ScienceDirect
Neurotrophic Keratitis - EyeWiki
The Utilization of Topical Insulin for Ocular Surface Diseases: A Narrative Review - PubMed
Effectiveness of topical insulin for the treatment of surface corneal pathologies - PubMed
The role of topical insulin in ocular surface restoration: A review - PubMed
BAK References:
Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S.
Eye (London, England). 2022;36(2):361-368. doi:10.1038/s41433-021-01668-x.
Preservatives in multidose formulations of topical ophthalmic medications are crucial for maintaining sterility but can be toxic to the ocular surface. Benzalkonium chloride (BAK)-used in approximately 70% of ophthalmic formulations-is well known to cause cytotoxic damage to conjunctival and corneal epithelial cells, resulting in signs and symptoms of ocular surface disease (OSD) including ocular surface staining, increased tear break-up time, and higher OSD symptom scores. These adverse effects are more problematic with chronic exposure, as in lifetime therapy for glaucoma, but can also manifest after exposure as brief as seven days. Multiple strategies are available to minimize or eliminate BAK exposure, among them alternative preservatives, preservative-free formulations including sustained release drug delivery platforms, and non-pharmacological therapies for common eye diseases and conditions. In this paper, we review the cytotoxic and clinical effects of BAK on the ocular surface and discuss existing and emerging options for ocular disease management that can minimize or eliminate BAK exposure.
Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F.
Progress in Retinal and Eye Research. 2010;29(4):312-34. doi:10.1016/j.preteyeres.2010.03.001.
Leading Journal
There is a large body of evidence from experimental and clinical studies showing that the long-term use of topical drugs may induce ocular surface changes, causing ocular discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis, corneal surface impairment, and the potential risk of failure for further glaucoma surgery. Subclinical inflammation has also been described in patients receiving antiglaucoma treatments for long periods of time. However, the mechanisms involved, i.e., allergic, toxic, or inflammatory, as well as the respective roles of the active compound and the preservative in inducing the toxic and/or proinflammatory effects of ophthalmic solutions, is still being debated. The most frequently used preservative, benzalkonium chloride (BAK), has consistently demonstrated its toxic effects in laboratory, experimental, and clinical studies. As a quaternary ammonium, this compound has been shown to cause tear film instability, loss of goblet cells, conjunctival squamous metaplasia and apoptosis, disruption of the corneal epithelium barrier, and damage to deeper ocular tissues. The mechanisms causing these effects have not been fully elucidated, although the involvement of immunoinflammatory reactions with the release of proinflammatory cytokines, apoptosis, oxidative stress, as well as direct interactions with the lipid components of the tear film and cell membranes have been well established. Preservative-induced adverse effects are therefore far from being restricted to only allergic reactions, and side effects are often very difficult to identify because they mostly occur in a delayed or poorly specific manner. Care should therefore be taken to avoid the long-term use of preservatives, otherwise a less toxic alternative to BAK should be developed, as this weakly allergenic but highly toxic compound exerts dose- and time-dependent effects. On the basis of all these experimental and clinical reports, it would be advisable to use benzalkonium-free solutions whenever possible, especially in patients with the greatest exposure to high doses or prolonged treatments, in those suffering from preexisting or concomitant ocular surface diseases, and those experiencing side effects related to the ocular surface. Indeed, mild symptoms should not be underestimated, neglected, or denied, because they may very well be the apparent manifestations of more severe, potentially threatening subclinical reactions that may later cause major concerns.
Suanno G, Fonteyne P, Ferrari G.
Experimental Eye Research. 2023;232:109516. doi:10.1016/j.exer.2023.109516.
This study aimed to use a mouse model of dry eye disease (DED) induced by topical administration of benzalkonium chloride (BAK) and assess its stability and the presence of neurosensory abnormalities, including ocular pain. Eight-week-old C57BL6/6 N male mice were used in this study. Mice were treated with 10 μL of 0.2% BAK dissolved in artificial tears (AT), administered twice daily for 7 days. After one week, animals were randomized into two groups: one was administered with 0.2% BAK in AT once per day for 7 days, while the other was not further treated. Corneal epitheliopathy was quantified at days 0, 3, 7, 12, and 14. Moreover, tear secretions, corneal nociception, and corneal nerve integrity were measured after BAK treatment. After sacrifice, corneas were dissected to assess nerve density and leukocyte infiltration by immunofluorescence. Topical BAK instillation for 14 days significantly increased corneal fluorescein staining (p < 0.0001) compared to day 0. On the other hand, interruption of BAK instillation was associated with improvement of corneal epitheliopathy (day 12, p < 0.0001; day 14, p < 0.001). BAK treatment increased ocular pain (p < 0.0001) and resulted in a significant increase in leukocyte infiltration in the cornea (p < 0.01). Moreover, corneal sensitivity was reduced (p < 0.0001), together with corneal nerve density (p < 0.0001) and tear secretion (p < 0.0001). One week twice a day, followed by one additional week once a day, of 0.2% BAK topical administration induces stable clinical and histological signs of DED, which is associated with neurosensory abnormalities, including pain.
Vitoux MA, Kessal K, Melik Parsadaniantz S, et al.
Toxicology Letters. 2020;319:74-84. doi:10.1016/j.toxlet.2019.10.014.
Benzalkonium chloride (BAK), a quaternary ammonium compound widely used as disinfecting agent as well as preservative in eye drops is known to induce toxic effects on the ocular surface with inflammation and corneal nerve damage leading to dry eye disease (DED) in the medium-to-long term. The aim of this study was to evaluate in vitro the toxicity of a conditioned medium produced by corneal epithelial cells previously exposed to BAK (BAK-CM) on trigeminal neuronal cells. A human corneal epithelial (HCE) cell line was exposed to 5.10% BAK (i.e. 0.005% BAK) for 15 min and let recover for 5 h to prepare a BAK-CM. This BAK concentration is the lowest one found in eye drops. After this recovery period, BAK effect on HCE cells displayed cytotoxicity, morphological alteration, apoptosis, oxidative stress, ATP release, CCL2 and IL6 gene induction, as well as an increase in CCL2, IL-6 and MIF release. Next, a mouse trigeminal ganglion primary culture was exposed to the BAK-CM for 2 h, 4 h or 24 h. Whereas BAK-CM did not alter neuronal cell morphology, or induced neuronal cytotoxicity or oxidative stress, BAK-CM induced gene expression of Fos (neuronal activation marker), Atf3 (neuronal injury marker), Ccl2 and Il6 (inflammatory markers). Two and 4 h BAK-CM exposure promoted a neuronal damage (ATF-3, phospho-p38 increases; phospho-Stat3 decreases) while 24 h-BAK-CM exposure initiated a prosurvival pathway activation (phospho-p44/42, phospho-Akt increases; ATF-3, GADD153, active Caspase-3 decreases). In conclusion, this in vitro model, simulating paracrine mechanisms, represents an interesting tool to highlight the indirect toxic effects of BAK or any other xenobiotic on corneal trigeminal neurons and may help to better understand the cellular mechanisms that occur during DED pathophysiology.
Sarkar J, Chaudhary S, Namavari A, et al.
Investigative Ophthalmology & Visual Science. 2012;53(4):1792-802. doi:10.1167/iovs.11-8775.
Purpose: The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro.
Methods: Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth.
Results: BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001).
Conclusion: Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production.
Ivakhnitskaia E, Souboch V, Dallacasagrande V, et al.
The Ocular Surface. 2022;26:88-96. doi:10.1016/j.jtos.2022.07.012.
Purpose: Corneal nerves comprise the densest sensory network in the body. Dysfunction of the corneal cold sensitive neurons (CSN) is implicated in ophthalmic disorders, including Dry Eye Disease, the most common ocular surface disorder. The preservative Benzalkonium chloride (BAK) and the mydriatic agent Phenylephrine hydrochloride (PHE) are considered to be inactive at the level of the CSNs. The purpose of this study is to test the impacts of continuous exposures to BAK or PHE at their clinically used concentrations on corneal nerve structure and function.
Methods: In vivo extracellular electrophysiology of the rat trigeminal ganglion was used to monitor CSN functional response to stimuli mimicking physiological states and stressors of the cornea. Corneal nerve structure was evaluated by immunostaining.
Results: Among the tested stimuli, cold probe receptive field stimulation and hyperosmolar stress were the most sensitive methods of detecting activity changes. CSN activity was attenuated after 30 min exposure to either PHE or BAK. After an hour-long washout period, BAK-treated neurons failed to recover activity while PHE-treated neurons showed signs of functional recovery. Intraepithelial nerve density was reduced and nerve fragmentation was increased in BAK-treated corneas, while PHE exposure left corneal nerves structurally intact.
Conclusions: Our study suggests that prolonged ocular instillations of BAK or PHE alter CSN activity through two different processes - irreversible neuronal damage in the case of BAK vs. reversible attenuation in the case of PHE.
Chen W, Zhang Z, Hu J, et al.
Cornea. 2013;32(12):1599-606. doi:10.1097/ICO.0b013e3182a8196f.
Purpose: To investigate the effect of benzalkonium chloride (BAK) on corneal nerves.
Methods: Fifty-four adult New Zealand Albino rabbits were randomly divided into 3 groups. BAK at concentrations of 0.005%, 0.01%, or 0.02% was applied once daily to 1 eye of each rabbit for 9 days. The contralateral untreated eyes were used as controls. Corneal mechanical sensitivity, aqueous tear production, tear break-up time (BUT), fluorescein, and Rose Bengal staining scores were compared with those of control values on days 3, 6, and 9. Corneal whole mounts were immunostained with a specific antitubulin βIII antibody to label nerve fibers. Epithelial superficial nerve terminal, subbasal, and stromal nerve fiber densities were quantified. The structure of the central cornea was examined by means of in vivo confocal microscopy on day 9.
Results: The topical application of BAK resulted in lower corneal sensitivity and higher Rose Bengal staining scores on day 3, whereas there were no significant changes in the BUT, Schirmer, and corneal fluorescein scores. Decreased nerve densities in superficial and subbasal layers were observed in BAK-treated eyes on days 3 and 6, respectively. The eyes treated with 0.02% BAK exhibited significantly reduced Schirmer scores, BUT, and stromal nerve fiber density, and increased fluorescein staining scores on day 9. Corneal superficial epithelial cell size was significantly larger in all BAK-treated eyes compared with that in control eyes.
Conclusions: The topical application of BAK can quickly cause corneal hypoesthesia without tear deficiency. Changes in corneal innervation significantly correlate with BAK-induced ocular surface changes.
Aguayo Bonniard A, Yeung JY, Chan CC, Birt CM.
Expert Opinion on Drug Metabolism & Toxicology. 2016;12(11):1279-1289. doi:10.1080/17425255.2016.1209481.
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