Glaucoma-related ocular surface disease (G-OSD) is a prevalent, multifaceted, and visually significant ocular co-morbidity. Yet, the role of G-OSD in effective long-term management of glaucoma is frequently underestimated. Although the dire consequence of inappropriately high intraocular pressure (IOP) and irreversible blindness associated with glaucoma are well understood, the significant impact of an unhealthy ocular surface on ocular structures and the effect on quality of life (QOL) is only now beginning to garner the attention of the ophthalmic community.
To understand the impact of dry eye syndrome (DES) in “real-world” terms, one only needs to look at its utility score. Utility scores quantify how many years a patient would give up from the end of their lives in exchange for avoiding a certain illness. The utility scores for moderate to severe DES are comparable to that of angina and dialysis.1,2 Furthermore, DES and glaucoma are both associated with a high prevalence of mood disorders, depression, and anxiety.3–6 It should also be noted the presence of dry eye symptoms in glaucoma patients adds to the substantial social, economic, and public health burden of these diseases. A recent article reported that in Australia, 39% of patients with glaucoma suffered from significant dry eye disease, and the associated economic burden was calculated to be 330.5 million AU$ per year.7 Additionally, decrease in work productivity from mild to severe dry eye has been well documented.8
Across continents, a comprehensive review of literature9–18 demonstrates the widespread prevalence of these 2 significant ocular comorbidities and supports the importance of early recognition and treatment. This international review provides a summary of the literature on the prevalence of ocular surface disease (OSD) and glaucoma, pathogenesis and risk factors for its development, evaluation, diagnosis, and management.
PREVALENCE OF G-OSD
OSD and glaucoma often coexist and both typically manifest with advancing age. When looking at data that combines signs and symptoms of dry eyes, the prevalence of dry eye generally varies worldwide from 8% to 30% in the normal population,12 with increased prevalence in South East Asian populations.12 However, the prevalence of OSD in the glaucoma population varies from 40% to 59%. Prevalence data for G-OSD was first reported by Pisella et al in 200214 and confirmed in subsequent studies (Table 1). Studies consistently show that Asian populations tend to have a higher prevalence of G-OSD, with greater incidence of tear break-up time (TBUT) alteration and increased corneal staining.7,10,18
TABLE 1 -
Prevalence of Dry Eye in Glaucoma Patients
||Diagnostic Methods for Dry Eye
|Pisella et al (2002)14
||General questions on symptomsConjunctival hyperemiasuperficial punctatae keratitis
|Leung et al (2008)15
||OSDIShirmer I testCorneal and conjunctival stainingTBUT
|Rossi et al (2009)16
||Signs (TBUT+corneal staining)OSDI (moderate to severe)
|Fechtner et al (2010)17
||Ethnicities (Caucasian 64%, Black 8%, Asian 8%, other 10%)
|Chan et al (2013)7
|Rossi et al (2013)21
|Ramli et al (2015)18
|Ruangvaravate et al (2018)10
||OSDITBUTCorneal stainingShirmer I test
|Bulat et al (2020)9
||OSDIShirmer I test
OSDI, ocular surface disease index; TBUT, tear break-up time.
The variability in prevalence data is likely related to the definition of dry eye used, i.e. whether the study focused on signs, symptoms, or both. Studies in which the diagnosis was primarily based on signs generally reported more variable rates of disease, up to 99%, with differences by race. The signs examined vary and differ among studies, but the 3 standard clinical tests performed in all the studies are TBUT, corneal fluorescein staining, and Schirmer I testing (without anesthesia). More recent studies have also examined other parameters including measures of tear film quantity, quality and stability. For reporting symptoms, some authors have utilized general questionnaires, for example, 25-item National Eye Institute Visual Function (NEIVFQ-25), but most have implemented disease specific instruments. In relation to G-OSD, the most used disease-specific instruments are the ocular surface disease index (OSDI),11 the Glaucoma Symptom Scale (GSS),7 and the glaucoma QOL 15 questionnaire (GQL 15).12
EFFECT ON QOL
Utilizing these tools, several studies have demonstrated the negative impact of dry eye in glaucoma patients on overall QOL.19–22 OSD is well known to cause burning, pain, stinging, irritation, and impact general well-being.19 In addition, even if visual acuity is normal according to Snellen measurements, the instability of the tear film generates aberrations that may result in an alteration of visual function and a decrease in the visual quality. Fluctuations in the tear film can also cause an increase in irregular astigmatism and impair visual performance resulting in worsening contrast sensitivity and visual acuity.16,20–22 Also, importantly in the management of glaucoma, a poor ocular surface may affect the reliability of perimetry.23 It has been shown that the use of an artificial tear significantly improves reliability parameters and visual field indices,24 and reduces visual field test times.25 Furthermore, QOL assessments in glaucoma patients with OSD have shown a negative impact on social life and daily activities such as reading, driving, watching television, and using smartphones, PCs, and tablets.21–22 A study by Sun et al26 also demonstrated that glaucoma patients and dry eye patients with poor total OSDI scores both reported greater visual difficulty with text-based search.
PATHOGENESIS AND RISK FACTORS FOR DEVELOPMENT OF OSD IN GLAUCOMA
The pathogenesis of dry eye can be characterized as a vicious cycle: once induced, numerous inflammatory mechanisms are triggered and tend to self-perpetuate. Tear film instability is associated with a chain reaction which leads to a release of inflammatory cytokines and mediators that consecutively cause the alteration of the quality of tears.27 Reduced reflex lacrimation in DES would also result in higher ocular surface drug concentrations as a consequence of reduced dilution capacity. Mechanisms of dry eye in patients with glaucoma are likely a combination of tear film abnormalities and instability due to decreased tear production from chronic inflammation and increased tear evaporation from Meibomian gland dysfunction further worsened by topical anti-glaucoma medications. Therefore, recognizing risk factors for dry eye disease in general and understanding the additional risk factors present in glaucoma patients that may exacerbate OSD is crucial (Table 2). In addition, some patients may suffer with worsening symptoms from OSD related to allergic reactions to topical antiglaucoma medications and repeated exposure to preservatives and excipients. In more severe cases, cicatricial conjunctival changes may occur from a pseudo-pemphigoid reaction, induced by antiglaucoma medications.
TABLE 2 -
Risk Factors for Development of Ocular Surface Disease and Additional Risk Factors for development of OSD in Treated Glaucoma Patients
|Risk Factors for Ocular Surface Disease66∗
||Additional Risk Factors for Glaucoma-Related OSD 28,30–31,36,48
||Baseline OSD present
|Systemic diseases:Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, autoimmune liver disease, lymphoma, AIDS, sarcoidosis, graft-versus-host disease, diabetes mellitus, hypertension, thyroid disease, Parkinson disease, depression, obstructive sleep apnea
||Prolonged use of preservatives, especially BAK
|Systemic drug side effects: Antihypertensives—beta-blockers, diuretics, ACE inhibitors (captopril), angiotensin II receptor antagonists (losartan) Antidepressants—tricyclicmonoamine oxidase inhibitors Antihistamines—diphenhydramine, promethazine, cetirizine loratadine Anticholinergics—oxybutynin, ipratropium Antiarrhythmics—amiodarone, disopyramide Antiosteoporotic drugs—bisphosphonates (alendronate, etidronate Anticancer drugs—aromatase inhibitors, methotrexate Antiwrinkle drugs – botulinum toxin Antiacne drugs – isotretinoin Antiulcer drugs – cimetidine, ranitidine Anti-Parkinson's drugs – benzhexol, levodopa Antithyroid drugs – carbimazole, propylthiouracil Other drugs – marijuana Hormonal treatments (hormone replacement therapy, antiandrogens)
||Number of glaucoma medications used
|Ocular conditions:Contact lens wearOcular allergyPterygiumEyelid malpositionBlepharitisMeibomian gland diseasePost refractive surgeryPost-cataract surgeryPost-blepharoplasty
||Number of daily drops
|Other factors:AlcoholSmokingCosmeticsPollutionAllergensComputer useHigh altitude
||Possible additional risk factors:Bleb heightConjunctivochalasisPost Trabeculectomy
BAK indicates benzalkonium chloride; OSD, ocular surface disease.
A more exhaustive list is provided in Coroneo M. High and dry: an update on dry eye syndrome. Medicine Today 2013;14: 53–6166
Medical therapy of glaucoma can profoundly disrupt the homeostasis of the tear film and ocular surface.28–29 The severity of toxic or allergic reactions to topical anti-glaucoma medications is related to the number of daily drops, the duration of treatment, and the presence of preservatives.28,30–31 The main structural alterations from chronic use of these eye drops include dysfunction and loss of the goblet cell, Meibomian gland, and accessory lacrimal glands. Furthermore, this leads to disruption of the corneal epithelium and a reduction in corneal sensitivity, which subsequently results in disruption of the tear film and thinning of the mucus, aqueous, and lipid layers.21–36
Ocular surface inflammation may manifest within as early as three months after initiation of anti-glaucoma therapy.37 For instance, a fixed combination of a prostaglandin analog and timolol increased expression of the inflammatory markers HLA-DR and interleukin-6.37 Tear proteins detected in eyes with medication-induced dry eyes also may differ from those of primary dry eyes.30 Although the expression of inflammation-associated tear cytokines and chemokines may occur to a greater degree in topically treated glaucoma patients, data are split on whether this is due to the glaucoma medication itself30 or the preservative.32 These findings suggest the involvement of a variety of signaling pathways in the pathogenesis of G-OSD.
The topical use of antiglaucoma medications may alter conjunctival, corneal, corneoscleral limbus, and Meibomian gland structures.29,32–36,38–42 In an in vivo confocal microscopy study of the conjunctiva, Zhu et al39 found significantly decreased goblet cell density, increased dendritic cell density, and increased subepithelial fibrosis altered after chronic use of anti-glaucoma eye drops. These structural alterations translate into low mucin production that affects tear film stability, chronic ocular surface inflammation, and conjunctival scarring. Similarly, another in vivo confocal microscopy by Mastropasqua et al showed increased corneal epithelial dendritic cell density in eyes with anti-glaucoma eye drops, with higher density at the limbus compared to the central cornea.40,42 The magnitude of change demonstrated worsening with a greater number of medications.40 Beta-blockers, particularly preserved timolol maleate, have been shown in several studies to disrupt tear film stability, reduce basal and reflective tear secretions, and cause xerotic alterations in conjunctival epithelium potentially leading to cicatrization.43–47 In addition, a study by Kocabeyoglu et al48 suggested that glaucoma patients with a more advanced stage of conjunctivochalasis had evidence of worsening TBUT, lissamine green staining, Schirmer testing, and a higher OSDI score.
Although preliminary evidence suggests that a prostaglandin analog may have the least effect on conjunctival fibrosis, it has been shown to induce obstructive Meibomian gland dysfunction.39,41 For instance, in vivo confocal microscopy of the Meibomian glands by Agnifili et al and Ha et al showed abnormal Meibomian gland features in eyes with topical anti-glaucoma medications,33 with a lesser degree in fixed combination (timolol/prostaglandin) and preservative-free drops, compared to a regimen with separate timolol and prostaglandin.33 Ha et al35 also showed abnormal Meibomian gland features in eyes with monotherapy of prostaglandin, with a lesser degree in preservative-free, compared to a preservative-containing regimen. Likewise, pilocarpine and timolol directly affect Meibomian epithelial cells and may influence their morphology, survival, and proliferative capacity.45 Furthermore, the Meibomian gland changes after monotherapy prostaglandin analog use was also related to worse OSD and poor compliance in a study by Lee at al.34 For practical implications, these findings support the use of preservative-free regimens to improve compliance and to minimize the adverse effects of antiglaucoma eye drops on conjunctival, corneal, and Meibomian gland structures.
The most commonly used preservative, benzalkonium chloride (BAK), can severely disrupt the ocular surface and alter corneal sensitivity.29,31 Its potential responsibility in filtering surgery failure has been suggested,49 and its cellular toxicity, even at low concentrations, has been experimentally demonstrated in in vitro studies of a continuous human conjunctiva-derived cell lines.50 BAK is a quaternary ammonium compound that has been shown to alter ocular surface structures widely and especially adversely effect on the cornea. Specifically, Van Went et al investigated the effect of BAK on corneal sensitivity with the Cochet-Bonnet aesthesiometer. They found that the chronic use of BAK-containing antiglaucoma medication could severely impair corneal sensitivity.31 The study demonstrated a dose-response—the corneal sensitivity was further reduced in eyes with a higher number of eye drops, and longer duration of treatment.31 Although, corneal sensitivity correlated with dosage and duration, it is important to note the lack of correlation between ocular signs and symptoms of medication-induced dry eyes.31 This lack of correlation between may be explained by the reduction in corneal sensitivity. The discordance further highlights the importance of screening for baseline OSD, as early detection of iatrogenic dry eye can help prevent permanent disruption of the ocular surface and ultimately improve ocular comfort and compliance. In addition, the use of BAK-preserved glaucoma medications has been associated with more severe OSD and worse QOL: higher OSDI scores, lower GSS scores, and higher GLQ-15 scores in several studies.13–14
There is also conflicting evidence in the literature on the role of surgically induced conjunctival modifications as a risk factor in the pathogenesis of G-OSD. Iyer et al51 reported an increase in tear osmolarity and a four-fold increase in the use of ocular lubricants in patients who underwent MMC-augmented trabeculectomy. A retrospective case control study of 399 patients by Ono et al. found ocular surface complications in approximately 15% of patients after trabeculectomy: corneal epitheliopathy (11%), filamentary keratitis (3%) and dellen formation (1.7%).52 In a study by Ji et al, bleb height was negatively correlated with TBUT and positively correlated with corneal staining.53 However, Lee et al54 pointed out that clinicians should be aware that dry eye symptoms and increased osmolarity may occur in post-trabeculectomy patients in the absence of TBUT and Schirmer test abnormality.
On the contrary, a study 3-year study by Ambaw et al demonstrated that after undergoing successful trabeculectomy, patients had reduced tear levels in 37 of 40 pro-inflammatory lipid mediators.55 Furthermore, the authors noted that underlying inflammation in the ocular surface may predispose the bleb to failure and require additional procedures such as bleb needling.55 Agnifili et al studied the ocular surface of 38 patients undergoing trabeculectomy using laser scanning confocal microscopy and impression cytology and found an increase in goblet cell density, and a decrease in limbal dendritic cell density, subbasal corneal nerve inhomogeneity, Meibomian gland density, and HLA-DR positivity, corresponding to an overall objective improvement of the ocular surface after successful trabeculectomy surgery.56
DIAGNOSIS OF OSD IN THE GLAUCOMA PATIENT
Pisella et al's study of 4107 patients revealed the most frequently encountered DES symptoms reported by glaucoma patients using preserved drops were excessive discomfort after drops instillation (43%), pressure behind eyelids (40%), foreign body sensation (31%), sensation of ocular dryness (23%), excessive refractory tearing (21%) and eyelid itching (18%).14 The diagnosis of OSD in glaucoma patients is based on the same tests used to assess dry eye patients, taking into consideration the specific issues that glaucoma treatments can cause on the ocular surface.
Assessment of Symptoms
The OSDI questionnaire, designed for patients with dry eye,57 has been used to assess the symptoms related to OSD in glaucoma patients, showing higher scores in these patients than in controls.58–61 However, patients with glaucoma can show an increased OSDI score due to factors other than OSD, mainly visual field loss,58 and therefore it always has to be considered alongside other more objective methods to assess OSD. Most studies have reported higher OSDI scores associated with higher number of glaucoma drops used.60,62–64
A thorough medical history may point at other ocular surface conditions. For example, a history of oral ulcers or difficulty swallowing in the context of conjunctival scarring suggest autoimmune mucous membrane pemphigoid, which needs to be differentiated from pseudo-pemphigoid secondary to glaucoma medications.65 A complete systemic review is also necessary to diagnose and optimize management of systemic diseases such as hypertension, depression, and seasonal allergies, the treatment of which may further exacerbate symptoms of DES and glaucoma.66
Assessment of the Tear Volume
The Schirmer test I is performed without anesthesia to assess reflex tear production.67 A result of <10 mm indicates inadequate tear production. Results have been reported to be lower in glaucoma patients compared to healthy subjects.61,68
The quantitative assessment of the tear menisci is the most direct approach to study the tear film volume,69 and it is non-invasive. Glaucoma patients seem to have significantly lower tear meniscus height than control subjects, measured with keratography59 or anterior segment optical coherence tomography.62
The tear film osmolarity is increased in dry eye disease69 and can now be easily measured in the clinical setting.70 A positive result is considered to be ≥308 mOsm/L in either eye or an interocular difference >8 mOsm/L.69 In glaucoma patients, tear osmolarity has been shown to be correlated with the number of glaucoma drugs used, especially with preserved drops.63
Fluorescein 2% is applied to assess the fluorescein tear break-up time (FBUT) and the surface staining. The FBUT is a measure of the stability of the tear film; <10 seconds is considered abnormal.69 It has been shown to be negatively correlated with the number of preserved drops used by glaucoma patients.63
To avoid the use of corneal dyes, the noninvasive tear break-up test (NIBUT) was developed.67,71 It uses the projection of a pattern onto the tear film and measures the time taken for the image to break after a blink. Glaucoma patients have shown worse NIBUT compared to controls measured by the Keratograph 5 M (Oculus, Wetzlar, Germany).59 The use of NIBUT is recommended over FBUT. If only the FBUT is available, it should be done after the osmolarity test.69
Ocular Surface Staining
The Oxford grading scheme was developed to describe the ocular surface staining in dry eye patients67 and it has also been used in glaucoma patients with OSD, with the number of glaucoma drops used daily being reported as predictive of corneal staining severity.58 When using fluorescein under blue illumination, a complementary yellow filter should be used for a more accurate assessment of the conjunctival staining.67,72 If not available, then lissamine green is used to assess conjunctival staining.67
The level of conjunctival hyperemia should be assessed in each quadrant. Studies using the Keratograph 5 M have shown worse bulbar redness in patients under glaucoma treatment than in control patients,59 with a significant correlation between conjunctival hyperemia and number of daily drops,60 especially in the nasal sectors.73 The use of prostaglandins was also associated with worse hyperaemia.73
The conjunctiva should be assessed carefully for signs of scarring. Pseudo-pemphigoid can develop in patients under long-term glaucoma medication. To differentiate it from mucous membrane pemphigoid, the appropriate immunohistologic studies should be conducted.65
It has been reported that Meibomian gland disease is frequently encountered in patients being treated for glaucoma,36 with worse meibography grades compared to controls.59 Glaucoma medication has been associated with thinning of the tear film lipid layer measured by ocular surface interferometry, with the thickness negatively correlated with total duration of glaucoma medication.64,74
Matrix Metalloproteinase 9
Matrix metalloproteinase 9 (MMP-9) is an inflammatory biomarker which is elevated in the tears of patients with dry eyes and can now be measured with a commercial diagnostic device.75 It has been shown to be increased in patients using BAK-preserved drops76,77 with the levels of MMP-9 correlating with other clinical markers of OSD.76
Confocal microscopy in glaucoma patients has shown decreased nerve density and increased number of inflammatory cells compared to healthy eyes.61 Not being routinely required for the clinical diagnosis of OSD in glaucoma patients is useful in studying the structural changes caused by long-term medication.
In summary, a combination of symptoms and objective measurements is required to diagnose OSD in glaucomatous patients. The least invasive tests should be used first, and, as a guide, following this order: symptoms and history, NIBUT and tear meniscometry, osmolarity, MMP-9 if available, FBUT, ocular surface staining, and conjunctival and meibomian gland assessment.
A PRAGMATIC TREATMENT APPROACH
Modern approaches to the treatment of OSD have been extensively reviewed78 but can be nuanced in the glaucomatous patient. A key factor is the understanding that chronic ocular surface inflammation plays a critical role in DES,79 likely exacerbated by a proinflammatory effect of topical glaucoma medications,80 their excipients, and preservatives. Chronic inflammation may also induce scleral and episcleral scarring, further impairing aqueous outflow. The minimization/modulation of this ocular surface inflammatory response is central to both patient comfort (and likely, compliance) and improving IOP control. In a small study of patients with severe OSD with primary open angle glaucoma refractory to medical therapy, treatment of the OSD resulted in improved IOP control.81
In general, interventions center around 2 guiding principles:
- 1) Minimize the effect of glaucoma therapy on the ocular surface.
- 2) Recognize and treat OSD as early as possible in management course.
Whether the ophthalmologist chooses to tackle alternative glaucoma therapies first, initiate OSD treatment, or address both diseases concomitantly largely depends on the stage of glaucoma, severity of OSD, and therapies available within the particular health care system.
As a basic tenet of therapy, every effort should be made to minimize the use of preserved topical glaucoma medications.82 The literature overwhelmingly supports the use of preservative free glaucoma medications in comparison to preserved medications.13,14,18,19,44,66,78,81–83 (Figs. 2, 3). Switching to preservative-free glaucoma medications may in fact decrease the need for ocular lubrication.83 Data from the LiGHT trial suggest clinicians may consider SLT more frequently in mild glaucoma cases as first line therapy in lieu of topical glaucoma medications with similar efficacy and decreased cost compared to topical drops.84 Furthermore, ophthalmologists should consider choosing combination topical hypotensive therapies when needed to minimize number of drops placed on the ocular surface.85 Innovations in drug delivery for glaucoma management also may offer new opportunities to effectively lower IOP while sparing the ocular surface. Sustained drug delivery is presently available via a bimatoprost ocular insert,86 and development is underway for several forthcoming novel systems including travoprost and latanoprost punctal plugs, latanoprost-eluting contact lenses, and bimatoprost and travoprost intraocular implants.87
Although the role of cataract surgery in uncontrolled angle-closure glaucoma is well accepted,88 there is good evidence of sustained reduction of IOP post cataract surgery in primary open angle glaucoma as well.89 Therefore, when appropriate, cataract surgery should also be considered in the management of G-OSD and earlier intervention may be warranted.
Finally, depending on factors such as the age, ability of the patient to comply to treatment, and the severity of disease, there is a growing body of evidence that shows minimally invasive glaucoma procedures such as intraocular micro-stenting, trabeculotomy or viscocanalostomy, conjunctival and corneal sparing surgeries, either alone or in conjunction with cataract surgery, may avoid or decrease reliance on topical glaucoma drugs and potentially reduce the risk of progression of OSD.90
Once IOP is under good control and/or no further modifications to the glaucoma treatment can be made, treatment of OSD in the glaucoma patient must also be implemented. Unfortunately, preservative-free glaucoma medications are not readily available in all countries and may be cost prohibitive. However, Mylla Boso et al demonstrated significant improvement in bulbar redness and reduction in OSDI scores with rigorous OSD treatment, despite the maintenance of all preserved glaucoma eyedrops previously in use.91 Studies have also shown improvement of up to 2 lines in best corrected visual acuity in post-trabeculectomy glaucoma patients when OSD is adequately treated.92 In addition to the use of preservative-free lubricants, early intervention with ocular surface immune-modulating agents such as cyclosporine or lifitegrast may help minimize long term chronic changes to the ocular surface. A small study by Saini et al93 showed cyclosporine 0.05% given for 6 months in chronic glaucoma patients on long-term topical antiglaucoma therapy demonstrated statistically significant improvement in Schirmer scores, ocular surface staining scores, OSDI, corneal sensation, and increased central corneal subbasal nerve density.
Additionally, some smaller studies have also shown the utility of other specialized treatments for OSD in the glaucoma patient. Roberti et al demonstrated improvement of the ocular surface in glaucoma patients in a prospective clinical trial of 39 patients treated with a preservative-free hypotonic formulation of hyaluronic acid (HA) 0.4% and taurine (TAU) compared to a preservative free isotonic solution of HA 0.2% without TAU.93 Changes over 90 days showed statistically significant improvement in TBUT of 15% over baseline and increase in conjunctival goblet cell density in the HA 0.4%/TAU groups throughout the follow-up, whereas changes of Schirmer I, OSDI, and GSS scores of over time were statistically similar between groups. The addition of amino acids to the ocular lubrication may be an important component in treatment of OSD related to glaucoma as TAU, the most abundant amino acid in the tear film, and is thought to exert a protective activity against damage caused by oxidative agents to the ocular surface.94 Di Zazzo et al95 performed a limited clinical trial showing improvement in conjunctival hyperemia, Schirmer scores, and TBUT with use of topical palmitoylethanolamide. Yoon et al96 evaluated the use of 20% autologous serum on the ocular surface of 10 patients with toxic epitheliopathy induced by antiglaucoma medications. They found significant improvement in symptoms measured (OSDI scores from 25.5 ± 20.9 to 10.5 ± 12.0), FTBUT (from 3.1 ± 1.8 seconds to 5.4 ± 2.3 seconds), corneo-conjunctival staining scores (from 7.7 ± 1.8 to 1.8 ± 1.9 NEI scale), corneal sensitivity (from 4.6 ± .9 cm to 5.8 ± .5 cm), and metalloproteinase-9 levels.96 Schirmer scores and tear cytokine levels measured on multiplex assays showed no change over the 30-day period.96 In addition, a small pilot study of 6 post-trabeculectomy glaucoma patients who developed secondary OSD nonresponsive to conventional treatment showed improvement when given plasma rich in growth factors 4 times a day for approximately 6 months.97
Limited studies are available on the use of punctal plugs as a potential treatment in the management of OSD in glaucoma patients. However, these studies have shown not only a decrease in dry eye symptoms with instillation of temporary or permanent punctal plugs, but also a decrease in IOP.98,99
Furthermore, meibomian gland disease should be addressed and treated in the glaucoma patient as well. Uzunosmanoglu et al36 reported mild to moderate MGD present in 80% of glaucoma patients studied on topical long-term therapy. The authors postulated that “repeated induction of eyelid inflammation (from BAK) with subsequent terminal duct obstruction may be a gradual end result of OSD.” Treatment, therefore, of MGD with warm compresses, pulsed light therapy and thermal vectored pulsation with meibomian gland expression should not be overlooked in the glaucoma patient.
Glaucoma affects millions of patients around the world and chronic use of topical glaucoma medications may negatively impact the patient's ocular surface, symptoms, and vision. Understanding the pathogenesis of G-OSD, recognizing its risk factors and incorporating diagnostic and therapeutic strategies that restore and maintain ocular surface homeostasis will result in improved care for our patients. As a chronic and sight-threatening disease, glaucoma treatment demands lifetime management and strict compliance. Effective management of G-OSD will lead to improvement not only in long-term visual outcomes, but also in patient compliance, QOL, and satisfaction with care.
Special thanks to Ms. Margaret Chervinko, MFA, MLIS, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago for her assistance in research for this article.
1. Schiffman RM, Walt JG, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology
2. Buchholz P, Steeds CS, Stern LS, et al. Utility assessment to measure the impact of dry eye disease. Ocul Surf
3. Ayaki M, Kawashima M, Negishi K, Tsubota K. High prevalence of sleep and mood disorders in dry eye patients: survey of 1,000 eye clinic visitors. Neuropsychiatr Dis Treat
4. Kitazawa M, Sakamoto C, Yoshimura M, et al. The relationship of dry eye disease with depression and anxiety: a naturalistic observational study. Transl Vis Sci Technol
5. Zheng Y, Wu X, Lin X, Lin H. The prevalence of depression and depressive symptoms among eye disease patients: a systematic review and meta-analysis. Sci Rep
2017; 7:46453Published 2017 Apr 12. doi:10.1038/srep46453.
6. Ayaki M, Tsubota K, Kawashima M, et al. Sleep disorders are a prevalent and serious comorbidity in dry eye. Invest Ophthalmol Vis Sci
7. Chan CC, Crowston JG, Tan R, et al. Ocular surface disease in patients with glaucoma from Australia. Asia Pac J Ophthalmol (Phila)
8. Patel VD, Watanabe JH, Strauss JA, Dubey AT. Work productivity loss in patients with dry eye disease: an online survey. Curr Med Res Opin
9. Bulat N, Cuşnir VV, Procopciuc V, et al. Diagnosing the dry eye syndrome in modern society and among patients with glaucoma: a prospective study. Rom J Ophthalmol
10. Ruangvaravate N, Prabhasawat P, Vachirasakchai V, Tantimala R. High prevalence of ocular surface disease among glaucoma patients in Thailand. J Ocul Pharmacol Ther
11. Saini M, Vanathi M, Dada T, et al. Ocular surface evaluation in eyes with chronic glaucoma on long term topical antiglaucoma therapy. Int J Ophthalmol
12. DEWS II. The epidemiology of dry eye disease: report of the International Dry Eye Workshop (DEWS II). Ocul Surf
13. Baudouin C. Detrimental effect of preservatives in eye drops: implications for the treatment of glaucoma. Acta Ophthalmol
14. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol
15. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma
16. Rossi GC, Tinelli C, Pasinetti GM, et al. Dry eye syndrome-related quality of life in glaucoma patients. Eur J Ophthalmol
17. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea
18. Ramli N, Supramaniam G, Samsudin A, et al. Ocular surface disease in glaucoma: effect of polypharmacy and preservatives. Optom Vis Sci
19. Kumar S, Singh T, Ichhpujani P, et al. Correlation of Ocular Surface Disease and Quality of Life in Indian Glaucoma Patients: BAC-preserved versus BAC-free Travoprost. Turk J Ophthalmol
20. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol
21. Rossi GC, Pasinetti GM, Scudeller L, Bianchi PE. Ocular surface disease and glaucoma: how to evaluate impact on quality of life. J Ocul Pharmacol Ther
22. Enoch J, Jones L, Taylor DJ, et al. How do different lighting conditions affect the vision and quality of life of people with glaucoma? A systematic review. Eye
23. Sagara H, Sekiryu T, Imaizumi K, et al. Impact of tear metrics on the reliability of perimetry in patients with dry eye. Plosone
24. Yenice O, Temel A, Orüm O. The effect of artificial tear administration on visual field testing in patients with glaucoma and dry eye. Eye (Lond)
25. Özyol P, Özyol E, Karalezli A. Evaluation of visual field test parameters after artificial tear administration in patients with glaucoma and dry eye. Semin Ophthalmol
26. Sun MJ, Rubin GS, Akpek EK, Ramulu PY. Impact of glaucoma and dry eye on text-based searching. Transl Vis Sci Technol
2017; 6:24Published 2017 Jun 29. doi:10.1167/tvst.6.3.24.
27. Nijm LM, Dunbar GE. Understanding the science behind the inflammatory cascade of dry eye disease. US Ophthalmic Review
2019; 12:15–16. https://doi.org/10.17925/USOR.2019.12.1.15
28. Mastropasqua R, Agnifili L, Mastropasqua L. Structural and molecular tear film changes in glaucoma. Curr Med Chem
29. Roberti G, Tanga L, Manni G, et al. Tear film, conjunctival and corneal modifications induced by glaucoma treatment. Curr Med Chem
30. Wong TT, Zhou L, Li J, et al. Proteomic profiling of inflammatory signaling molecules in the tears of patients on chronic glaucoma medication. Invest Ophthalmol Vis Sci
31. Van Went C, Alalwani H, Brasnu E, et al. [Corneal sensitivity in patients treated medically for glaucoma or ocular hypertension]. J Fr Ophtalmol
32. Martinez-de-la-Casa JM, Perez-Bartolome F, Urcelay E, et al. Tear cytokine profile of glaucoma patients treated with preservative-free
or preserved latanoprost. Ocul Surf
33. Agnifili L, Mastropasqua R, Fasanella V, et al. Meibomian gland features and conjunctival goblet cell density in glaucomatous patients controlled with prostaglandin/timolol fixed combinations: a case control, cross-sectional study. J Glaucoma
34. Lee TH, Sung MS, Heo H, Park SW. Association between meibomian gland dysfunction and compliance of topical prostaglandin analogs in patients with normal tension glaucoma. PLoS One
35. Ha JY, Sung MS, Park SW. Effects of preservative on the meibomian gland in glaucoma patients treated with prostaglandin analogues. Chonnam Med J
36. Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, et al. Meibomian gland dysfunction in patients receiving long-term glaucoma medications. Cornea
37. Russ HH, Nogueira-Filho PA, Barros Jde N, et al. Ocular surface evaluation in patients treated with a fixed combination of prostaglandin analogues with 0.5% timolol maleate topical monotherapy: a randomized clinical trial. Clinics (Sao Paulo)
38. Benitez-Del-Castillo J, Cantu-Dibildox J, Sanz-Gonzalez SM, et al. Cytokine expression in tears of patients with glaucoma or dry eye disease: a prospective, observational cohort study. Eur J Ophthalmol
39. Zhu W, Kong X, Xu J, Sun X. Effects of long-term antiglaucoma eye drops on conjunctival structures: an in vivo confocal microscopy study. J Ophthalmol
40. Mastropasqua R, Agnifili L, Fasanella V, et al. In vivo distribution of corneal epithelial dendritic cells in patients with glaucoma. Invest Ophthalmol Vis Sci
41. Mocan MC, Uzunosmanoglu E, Kocabeyoglu S, et al. The association of chronic topical prostaglandin analog use with meibomian gland dysfunction. J Glaucoma
42. Mastropasqua R, Agnifili L, Fasanella V, et al. Corneoscleral limbus in glaucoma patients: in vivo confocal microscopy and immunocytological study. Invest Ophthalmol Vis Sci
43. Coakes RL, Mackie IA, Seal DV. Effects of long-term treatment with timolol on lacrimal gland function. Br J Ophthalmol
44. Kuppens EV, de Jong CA, Stolwijk TR, et al. Effect of timolol with and without preservative on the basal tear turnover in glaucoma. Br J Ophthalmol
1995; 79 (4):339–342. doi:10.1136/bjo.79.4.339.
45. Zhang Y, Kam WR, Liu Y, et al. Influence of pilocarpine and timolol on human meibomian gland epithelial cells. Cornea
46. Aydin Kurna S, Acikgoz S, Altun A, et al. The effects of topical antiglaucoma drugs as monotherapy on the ocular surface: a prospective study. J Ophthalmol
47. Fiore PM, Jacobs IH, Goldberg DB. Drug-induced pemphigoid. A spectrum of diseases. Arch Ophthalmol
48. Kocabeyoglu S, Mocan MC, Irkec M, et al. Conjunctivochalasis as a contributing factor for the development of ocular surface disease in medically treated glaucoma patients. J Glaucoma
49. Boimer C, Birt CM. Preservative exposure and surgical outcomes in glaucoma patients: The PESO study. J Glaucoma
50. Vitoux MA, Kessal K, Melik Parsadaniantz S, et al. Benzalkonium chloride-induced direct and indirect toxicity on corneal epithelial and trigeminal neuronal cells: proinflammatory and apoptotic responses in vitro. Toxicol Lett
51. Iyer JV, Zhao Y, Lim FPM, et al. Ocular lubricant use in medically and surgically treated glaucoma: a retrospective longitudinal analysis. Clin Ophthalmol
52. Ono T, Yuki K, Ozeki N, et al. Ocular surface complications after trabeculectomy: incidence, risk factors, time course and prognosis. Ophthalmologica
53. Ji H, Zhu Y, Zhang Y, et al. Dry eye disease in patients with functioning filtering blebs after trabeculectomy. PLoS One
2016; 11:e0152696Published 2016 Mar 31. doi:10.1371/journal.pone.0152696).
54. Lee SY, Wong TT, Chua J, et al. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity. Eye (Lond)
55. Ambaw YA, Wong T, Chong R, et al. Change of tear lipid mediators in a post-trabeculectomy cohort [published online ahead of print, 2020 Jul 2]. Ocul Surf
56. Agnifili L, Brescia L, Oddone F, et al. The ocular surface after successful glaucoma filtration surgery: a clinical, in vivo confocal microscopy, and immune-cytology study. Sci Rep
2019; 9:11299Published 2019 Aug 5. doi:10.1038/s41598-019-47823-z.
57. Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol
2000; 118: 615-21.sc.
58. Mathews PM, Ramulu PY, Friedman DS, et al. Evaluation of ocular surface disease in patients with glaucoma. Ophthalmology
59. Portela RC, Fares NT, Machado LF, et al. Evaluation of ocular surface disease in patients with glaucoma: clinical parameters, self-report assessment, and keratograph analysis. J Glaucoma
60. Guarnieri A, Carnero E, Bleau AM, et al. Relationship between OSDI questionnaire and ocular surface changes in glaucomatous patients. Int Ophthalmol
61. Baghdasaryan E, Tepelus TC, Vickers LA, et al. Assessment of corneal changes associated with topical antiglaucoma therapy using in vivo confocal microscopy. Ophthalmic Res
62. Agnifili L, Brescia L, Scatena B, et al. Tear meniscus imaging by anterior segment-optical coherence tomography in medically controlled glaucoma. J Glaucoma
63. Labbé A, Terry O, Brasnu E, et al. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea
64. Lee SY, Lee H, Bae HW, et al. Tear lipid layer thickness change and topical anti-glaucoma medication use. Optom Vis Sci
65. Thorne JE, Anhalt GJ, Jabs DA. Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology
66. Coroneo M. High and dry: an update on dry eye syndrome. Medicine Today
67. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea
68. Jandroković S, Suić SP, Kordić R, et al. Tear film status in glaucoma patients. Coll Antropol
2013; 37: (suppl 1): 137–140.
69. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf
70. Jacobi C, Jacobi A, Kruse FE, et al. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea
71. Mengher LS, Bron AJ, Tonge SR, et al. A non-invasive instrument for clinical assessment of the pre-corneal tear film stability. Curr Eye Res
72. Eom Y, Lee JS, Keun Lee H, et al. Comparison of conjunctival staining between lissamine green and yellow filtered fluorescein sodium. Can J Ophthalmol
73. Pérez Bartolomé F, Martínez de la Casa JM, Arriola Villalobos P, et al. Ocular redness measured with the keratograph 5 M in patients using anti-glaucoma eye drops. Semin Ophthalmol
74. Lee SM, Lee JE, Kim SI, et al. Effect of topical glaucoma medication on tear lipid layer thickness in patients with unilateral glaucoma. Indian J Ophthalmol
75. Sambursky R, Davitt WF Jr, Latkany R, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmol
76. Zaleska-Żmijewska A, Strzemecka E, Wawrzyniak ZM, et al. Extracellular MMP-9-based assessment of ocular surface inflammation in patients with primary open-angle glaucoma. J Ophthalmol
77. Kim DW, Seo JH, Lim SH. Evaluation of ocular surface disease in elderly patients with glaucoma: expression of matrix metalloproteinase-9 in tears. Eye (Lond)
78. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf
79. Stern ME, Pflugfelder SC. Inflammation in dry eye. Ocul Surf
80. Tauber J, Melamed A, Foster S. Glaucoma in patients with ocular cicatricial pemphigoid. Ophthalmology
81. Batra R, Tailor R, Mohamed S. Ocular surface disease exacerbated glaucoma: optimizing the ocular surface improves intraocular pressure control. J Glaucoma
82. Katz G, Springs CL, Craven ER, Montecchi-Palmer M. Ocular surface disease in patients with glaucoma or ocular hypertension treated with either BAK-preserved latanoprost or BAK-free travoprost. Clin Ophthalmol
83. Goldberg I, Graham SL, Crowston JG, d’Mellow G. Australian and New Zealand Glaucoma Interest Group. Clinical audit examining the impact of benzalkonium chloride-free anti-glaucoma medications on patients with symptoms of ocular surface disease. Clin Exp Ophthalmol
84. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. [published correction appears in Lancet. 2019 Jul 6;394(10192):e1]. Lancet
85. Konstas AG, Boboridis KG, Kapis P, et al. 24-Hour efficacy and ocular surface health with preservative-free
tafluprost alone and in conjunction with preservative-free
dorzolamide/timolol fixed combination in open-angle glaucoma patients insufficiently controlled with preserved latanoprost monotherapy [published correction appears in Adv Ther. 2020 May;37(5):2572-2573]. Adv Ther
86. Medeiros FA, Walters TR, Kolko M, et al. Phase 3, randomized, 20-month study of bimatoprost implant in open-angle glaucoma and ocular hypertension (ARTEMIS 1) [published online ahead of print, 2020 Jun 13]. Ophthalmology
2020; S0161-6420(20)30555-8. doi:10.1016/j.ophtha.2020.06.018.
87. Aref AA. Sustained drug delivery for glaucoma: current data and future trends. Curr Opin Ophthalmol
88. Roberts TV, Francis IC, Lertusumitkul S, et al. Primary phacoemulsification for uncontrolled angle-closure glaucoma. J Cataract Refract Surg
89. Boussard T, Pershing S. Intraocular pressure changes after cataract surgery in patients with and without glaucoma: an informatics-based approach [published online ahead of print, 2020 Jun 9]. Ophthalmol Glaucoma
90. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular surface disease and glaucoma medications: a clinical approach. Eye Contact Lens
91. Mylla Boso AL, Gasperi E, Fernandes L, et al. Impact of ocular surface disease treatment in patients with glaucoma. Clin Ophthalmol
92. Lam J, Wong TT, Tong L. Ocular surface disease in posttrabeculectomy/mitomycin C patients. Clin Ophthalmol
93. Saini M, Dhiman R, Dada T, et al. Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications. Eye (Lond)
94. Roberti G, Agnifili L, Berardo F, et al. Prospective, randomized, single masked, parallel study exploring the effects of a preservative-free
ophthalmic solution containing hyaluronic acid 0.4% and taurine 0.5% on the ocular surface of glaucoma patients under multiple long-term topical hypotensive therapy. Adv Ther
95. Di Zazzo A, Roberti G, Mashaghi A, et al. Use of topical cannabinomimetic palmitoylethanolamide in ocular surface disease associated with antiglaucoma medications. J Ocul Pharmacol Ther
96. Yoon CH, Lee HJ, Park HY, et al. Effects of topical autologous serum on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs. Int Ophthalmol
97. Sánchez-Avila RM, Merayo-Lloves J, Fernández ML, et al. Plasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma. Int Med Case Rep J
98. Chen M, Yung Choi S. Preliminary outcomes of temporary collagen punctal plugs for patients with dry eye and glaucoma. Med Hypothesis Discov Innov Ophthalmol
99. Sherwin JC, Ratnarajan G, Elahi B, et al. Effect of a punctal plug on ocular surface disease in patients using topical prostaglandin analogues: a randomized controlled trial. Clin Exp Ophthalmol