Meibomian Gland Damaging By Glaucoma Treatments
Overview
Glaucoma is one of the leading causes of blindness worldwide, with a strong link to elevated intraocular pressure (IOP). Effective management of glaucoma primarily involves lowering IOP, usually through the use of topical eye drops. The health of the meibomian glands is crucial for maintaining a stable tear film, as their dysfunction is the most frequent cause of dry eye disease. There is increasing concern that topical glaucoma medications, particularly those with preservatives, may harm the meibomian glands and, consequently, the ocular surface.
Preserved glaucoma medications are associated with meibomian gland dysfunction and atrophy. When compared to preservative-free alternatives, preserved formulations are more likely to induce dry eye symptoms, tear film instability, inflammation, and meibomian gland dropout. However, even preservative-free options may compromise gland function and, depending on the active ingredient, potentially lead to glandular death. These negative effects can impair the patient’s quality of life, adherence to treatment, and overall prognosis.
This review examines the current evidence on how IOP-lowering eye drops impact the meibomian glands, highlighting the importance of considering these effects when managing glaucoma.
Introduction
The ciliary body of the eye is responsible for producing aqueous humor, which is primarily drained through the trabecular meshwork. The balance between the production and drainage of this fluid maintains intraocular pressure (IOP) within a normal range of 10–21 mmHg. Glaucoma, a leading cause of irreversible blindness globally, is a progressive optic neuropathy often linked to elevated IOP. The primary treatment for glaucoma involves the use of topical eye drops designed to reduce IOP.
The ocular tear film consists of an inner mucoaqueous layer, produced mainly by the lacrimal glands and goblet cells on the ocular surface, and an outer lipid layer derived from meibum secreted by the meibomian glands (MGs). The meibomian glands are modified sebaceous glands located along the eyelids, and their secretions are crucial for maintaining the tear film’s stability. The tear film itself plays a vital role in nourishing, lubricating, and protecting the ocular surface, while its lipid layer reduces surface tension and prevents evaporation of the underlying layers, thereby protecting the eye from dehydration.
Meibomian gland dysfunction (MGD) is the most prevalent cause of dry eye disease (DED), a condition affecting a significant portion of the adult population and leading to considerable humanistic and economic impacts. Given the importance of the MGs in maintaining tear film stability, this review aims to specifically assess the effects of IOP-lowering medications used in glaucoma treatment on the function of these glands. This focus is crucial, as the proper functioning of meibomian glands is essential for a stable tear film and overall ocular health.
Method
A comprehensive search was conducted on PubMed and EMBASE using the keywords “dry eye disease,” “meibomian gland dysfunction,” “meibography,” “topical medications,” “eye drops,” and “glaucoma” on May 12, 2023. The search yielded 5,212 and 4,455 results, respectively.
Articles that appeared relevant were carefully evaluated, initially based on title, followed by abstract, and finally, the full text. References from selected articles were also thoroughly reviewed. Ultimately, 24 research articles were deemed suitable for inclusion.
The American Academy of Ophthalmology recently adopted the Scottish Intercollegiate Guideline Network (SIGN) criteria to assess the strength of evidence, as summarized in Table S2 (Akpek et al., 2019). The included studies’ designs are outlined in Table 1. All clinical studies fell within level II evidence, with no randomized trials and only two prospective trials (Agnifili et al., 2019; Guo et al., 2020). However, several well-designed in vitro studies were included (Han et al., 2018, 2020; Jiang et al., 2022; Kam et al., 2016; Rath et al., 2019; Zhang et al., 2017).
Inclusion Criteria
To be included in the study, articles had be in accordance with the following requirements:
- Full-text availability.
- Published in English.
- Original research focused on topical glaucoma medications.
- Quantitative results and outcome measures related to the meibomian glands (MGs).
- Experiments conducted on human or animal cultured MG epithelial cells for in vitro studies.
Exclusion Criteria
Exclusion criteria were abstract-only publications, non-English language articles, and those lacking relevance to the topic. Additionally, conference abstracts, letters to the editor, and review articles were not considered.
Result
The reviewed clinical studies investigating the effects of topical medications on meibomian glands (MGs) are comprehensively summarized in Tables 2 and 3. Among the 18 clinical studies included, 12 involved topical medications containing preservatives, with benzalkonium chloride (BAC) being the most common, used in concentrations from 0.004% to 0.025%. BAC has been shown to reduce the proliferation and viability of human MG cells even at very low concentrations. Out of the 12 studies on preservative-containing (PC) medications, eight focused on dry eye symptoms. Six of these reported an increase in symptoms, one found no difference, and one observed fewer symptoms among treated patients. Tear film stability was also examined, with six of seven studies reporting a decrease, while one found no change. Similarly, studies on non-invasive tear film break-up time had mixed results, with some reporting reduced stability and others finding no difference. Additionally, studies noted worsened meibum quality and increased lid margin abnormalities, with most reporting greater MG atrophy in patients treated with these medications.
The impact of preservative-free (PF) glaucoma medications was evaluated in six clinical and five in vitro studies. Only three of the clinical studies directly compared PF medications to controls. One study found increased dry eye symptoms, one noted diminished tear film stability, and one reported thickened meibum among patients using PF medications. There were no significant differences in lid margin abnormalities, although MG atrophy was more pronounced in patients treated with PF medications.
Experimental studies also explored the effects of different drugs on MG cells. For instance, pilocarpine and timolol were shown to decrease meibomian gland cell survival in a dose-dependent manner, while brimonidine had detrimental effects at high concentrations. However, at clinically relevant concentrations, these effects were not observed. Other studies revealed that drugs like dorzolamide could inhibit cell proliferation and alter cellular processes, potentially affecting meibomian gland health.
In comparing preserved and unpreserved glaucoma medications, preserved formulations were more likely to cause dry eye symptoms, reduce tear film stability, and worsen meibum quality. They were also associated with a higher degree of MG atrophy, although this was sometimes exacerbated by the specific medication rather than the preservative alone. Overall, the presence of preservatives in topical glaucoma medications was linked to more adverse effects on MGs compared to preservative-free alternatives.
Conclusion
The detrimental effects of topical medications on the ocular surface, particularly those containing preservatives, have gained significant attention in recent years. Benzalkonium chloride (BAC), a common preservative in ocular formulations, has been shown to be cytotoxic to various ocular cell lines, including meibomian glands (MGs), at concentrations lower than those used in clinical settings. Clinical studies have demonstrated that preservative-containing (PC) glaucoma medications can lead to dry eye disease (DED) symptoms and MG dropout. Among the studies reviewed, most found increased MG atrophy in eyes treated with PC glaucoma medications, especially prostaglandin analogs (PGAs), compared to untreated controls. It was observed that the use of these medications can initiate glandular changes, leading to inflammation, stagnation of meibum, and ultimately, meibomian gland dropout.
The relationship between the duration and amount of glaucoma treatment and MG atrophy remains unclear. While some studies found no correlation between the number of medications used and MG distribution, others reported increased MG dropout with longer treatment durations and more frequent daily applications. Notably, studies using in vivo confocal microscopy (IVCM) have supported these findings, showing that both the number of preserved installations and the preservative burden correlate with the degree of inflammation and acinar atrophy.
The impact of preservative-free (PF) glaucoma medications on MGs has been less studied. While some evidence suggests that PGAs themselves can cause MG dropout, this effect is exacerbated by the presence of preservatives like BAC. Comparisons between PC and PF formulations indicate that preservative-containing medications cause more significant MG dropout and associated ocular surface changes. However, the specific mechanisms driving MG atrophy in glaucoma patients remain unclear.
Research suggests that certain glaucoma medications may affect MGs directly through specific receptors, such as muscarinic acetylcholine and β-adrenergic receptors. Cytotoxic effects on human meibocytes have been observed in vitro for medications like pilocarpine and timolol, though the long-term effects of these drugs on MG structure and function in vivo are not well understood.
Overall, the presence of preservatives in topical glaucoma medications is the most significant factor associated with meibomian gland damage. PF formulations appear less harmful, but still may cause MG dropout, albeit at a slower rate than their preserved counterparts. The literature highlights a need for further research, particularly prospective, randomized studies, to better understand the effects of different glaucoma medications on MGs and the ocular surface. Additionally, the development of preservative-free medications and novel preservative alternatives is crucial in reducing the iatrogenic burden on glaucoma patients, many of whom suffer from DED due to long-term topical treatment. Clinicians must recognize and address ocular surface disease in this patient population to improve treatment adherence, quality of life, and overall prognosis.
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