INTRODUCTION
OVERVIEW OF DRY EYE
Dry eye, as defined by the Dry Eye Workshop (DEWS) in 2007, is a complex condition affecting the tears and ocular surface, leading to discomfort, visual disturbances, and instability of the tear film This multifactorial disease can cause damage to the ocular surface and is characterized by increased tear film osmolarity and inflammation.
A recent epidemiological study on office workers found that dry eye conditions are primarily linked to tear film instability and ocular surface abnormalities, rather than a decrease in tear secretion The instability of the tear film can arise from various mechanisms, with components such as lipids, aqueous secretory mucins, and membrane-associated mucins playing a crucial role in maintaining tear film stability.
It has been known for some time that the tear film has three layers (Wolff,
The eye's surface features a structured tear film composed of three distinct layers: a mucus layer adjacent to the epithelium, an aqueous layer situated outside of it, and an outer oily layer that protects the aqueous surface This tear film typically measures between 30 to 40 micrometers in thickness.
Figure 1.1 Diagram of the structure of the tear film [12] a Oily layer
The thickness of the oily layer differs depending on the width of the palpebral fissure and varies across different areas of the exposed globe This layer consists of multiple components that contribute to its overall function.
Meibomian glands produce four oily substances that play a crucial role in stabilizing the tear film However, when these meibomian secretions are combined with a thin layer of water, their effectiveness appears to diminish significantly.
The oily layer of the tear film acts like a sheet suspended from the upper eyelid, thickening during closure and thinning upon opening This inhomogeneous layer, composed of lipid complexes, varies in thickness but has minimal impact on visual function Its primary role is to minimize the evaporation of aqueous tears, maintaining a normal evaporation rate of 0.085 Ill/minute, likely due to the influence of the oily layer When disrupted by sebum, the layer breaks down, leading to increased evaporation Additionally, it helps reduce the surface tension of the aqueous phase, preventing wave formation as the aqueous fluid moves across the cornea with eye and eyelid movements.
The oily layer of the tear film plays a crucial role in shielding the eye from small dust particles, as demonstrated in studies where one eye is examined without a contact lens and the other with one Volunteers exposed to a dusty environment show that the eye without a contact lens remains relatively free of particles, while the contact lens, which disrupts the lipid layer, becomes heavily contaminated Interestingly, even significant variations in the lipid layer do not appear to impact visual acuity significantly.
The aqueous layer in humans is approximately 7 micrometers deep and is primarily produced by accessory lacrimal glands Its key functions include providing lubrication between the eye and its surrounding structures, removing foreign particles, and supporting the health of the corneal and conjunctival epithelia Additionally, there is likely an aqueous layer beneath the mucus covering the bulbar and palpebral conjunctivae, which helps mitigate the stress of eyelid movements on the epithelium Given that the lacrimal gland releases its watery secretions into the upper canthus, the presence of this aqueous layer is essential for maintaining ocular health.
The tear film's aqueous layer plays a crucial role in maintaining its osmolarity, which is vital for eye health This layer contains various soluble mucins that help hydrate the mucus layer, facilitating inward flow from the aqueous to ensure optimal moisture levels.
The aqueous layer of the tear film facilitates the lubrication of eyelid movements over the eye, while mucus coats the gliding surfaces to enhance this motion The lipid layer acts as a barrier, allowing for a relative sliding speed of 15-25 cm/sec and a sheer rate of 20,000 sec^-1 With a low viscosity of approximately 1.1 cps, the sheer stress at the mucus/aqueous interface measures 150 dynes/cm² Due to the higher viscosity of mucus, sheer stress diminishes rapidly, becoming negligible at the ocular cellular surface This mechanism effectively protects the corneal and conjunctival epithelium from potential damage caused by blinking eyelids.
A stable aqueous layer is essential beneath the eyelid, as the tear film's structure and the movements of the lid and globe necessitate a hydrodynamic lubrication mechanism In contrast, if a mucus/mucus interface were present, boundary lubrication would fail to protect the ocular surface tissue from damage.
Wearing contact lenses destroys the integrity of the oily layer, and Maurice
(1961) has shown that the tear evaporation rate then becomes significant Mishima's
Research from 1965 indicates that the normal eye experiences a minimal loss of water through evaporation, suggesting that a basic tear flow rate exceeding this amount would lead to overflow or drainage via the nasolacrimal system It seems impractical for the eye to have a tear production rate significantly higher than necessary to counteract evaporation, especially considering the presence of a robust reflex tear flow for emergencies Additionally, the eye's heightened sensitivity to variations in the tear film implies the existence of specialized receptors that detect even minor changes in tear composition.
The mucus layer in the eye differs from the lung's mucus layer as it is less mobile and not propelled by cilia Instead, it remains static and is anchored to the microvilli.
The mucus released from goblet cells is observed to spread outwards, creating a confluent layer between adjacent cells This spread often does not align accurately with the boundaries of the underlying cells, indicating a lack of precise registration.
The tear film is nutrient-rich, yet its role in corneal epithelial metabolism remains unclear It plays a crucial role in facilitating the diffusion of oxygen and gases to and from the epithelium When this pathway is obstructed by impermeable contact lenses, it can quickly result in corneal damage.
Whereas the aqueous provides the cleavage plain for movements of the eyelids, it is the mucus layer that protects the underlying epithelium from sheer damage
DRY EYE AND GLAUCOMA
Glaucoma is the primary cause of irreversible blindness globally, affecting an estimated 3.5% of individuals aged 40 to 80 in 2021 As the population of older adults continues to rise, projections indicate that the number of people with glaucoma could reach 111.8 million by 2040.
1.2.1.1 Glaucoma diagnosis a Definition: The glaucoma is a group of optic neuropathies characterized by progressive degeneration of retinal ganglion cells These are central nervous system neurons that have their cell bodies in the inner retina and axons in the optic nerve Degeneration of these nerves results in cupping, a characteristic appearance of the optic disc and visual loss [24], [25] b Pathophysiology: Glaucoma is a multifactorial disease process, and its pathogenesis is incompletely understood Although much attention is focused on the role of intraocular pressure (IOP), other factors such as abnormal ocular blood flow, abnormal structural susceptibility of the lamina cribrosa, low intracranial pressure, autoimmunity, and mitochondrial dysfunction may also be involved
Elevated intraocular pressure (IOP) is believed to harm the lamina cribrosa, disrupting the structural and metabolic support for retinal ganglion cell axons and hindering axoplasmic transport This decrease in neurotrophic signaling to retinal ganglion cells may trigger apoptosis Reducing IOP is currently the only verified method to prevent or slow glaucoma progression.
Glaucoma is primarily classified into two types: open-angle glaucoma and angle-closure glaucoma The condition arises from the production of aqueous humor by the ciliary body in the posterior chamber, which then flows through the pupil into the anterior chamber The fluid exits the eye via the anterior chamber's iridocorneal angle, utilizing the trabecular meshwork for conventional outflow and the ciliary body face for unconventional outflow.
Open-angle glaucoma is characterized by increased intraocular pressure (IOP) due to resistance in the trabecular meshwork, despite no visible obstruction In contrast, primary angle closure results from anatomical crowding of the iris and crystalline lens, which creates abnormal resistance to aqueous humor flow through the pupil This condition leads to a pupillary block, hindering the aqueous humor's movement and causing elevated pressure behind the iris, ultimately causing it to bow forward and obstruct the trabecular meshwork.
Figure 1.4 Aqueous Humor Drainage Pathways of Healthy and Glaucomatous
(2021 American Academy of Ophthalmology; Used with permission)
Primary open-angle glaucoma (POAG) is the most common form of glaucoma, accounting for about 80% of cases in the United States This chronic optic neuropathy progresses without effective treatment, leading to potential vision loss The primary goal of glaucoma therapy is to prevent optic nerve damage and preserve vision throughout the patient's life Reducing intraocular pressure (IOP) is a key modifiable risk factor that has been shown to slow the progression of optic nerve damage Treatment options for POAG include both ophthalmic medications and surgical interventions.
Primary angle closure glaucoma requires laser therapy or surgical intervention to reduce intraocular pressure, followed by the use of pressure-lowering eye drops for ongoing management Symptoms often remain unnoticed until the condition is advanced, indicating that the actual number of individuals affected by glaucoma may be significantly higher than reported Surveys in Britain reveal that only 10% to 50% of those with glaucoma are aware of their condition.
Glaucomatous vision loss is often misunderstood as tunnel vision; however, patients typically report blurred areas rather than absolute scotomas, except in very advanced cases As glaucoma progresses, individuals may describe their vision as foggy or dark, eventually leading to total loss of light perception in late stages Symptoms associated with a sudden increase in intraocular pressure (IOP) include deep eye pain, headaches, blurred vision, halos around lights, eye redness, and nausea, often triggered by pupillary block.
Source: https://www.researchgate.net/figure/Levels-of-glaucoma-case-definition_tbl2_237060894
1.2.2 Treatment and specially Glaucoma surgery
Reducing intraocular pressure (IOP) is the only established method to slow or stop the progression of glaucoma Patients with primary open-angle glaucoma (POAG) who have a baseline IOP of 21 mm Hg or lower also benefit from additional IOP reduction The first-line treatments generally include topical IOP-lowering medications or laser trabeculoplasty.
Topical glaucoma medications decrease IOP by reducing aqueous humor production or improving outflow Approximately half of patients require 2 or more medications to adequately decrease their IOP [28]
Glaucoma medications are categorized based on their active ingredients, which include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, and rho kinase inhibitors For patients needing multiple treatments, combination drugs are also available.
Prostaglandin analogs include Xalatan® (latanoprost), Lumigan® (bimatoprost),
Travatan Z® (Travoprost), Zioptan™ (tafluprost), and Vyzulta™ (latanoprostene bunod) are prostaglandin analogs that enhance fluid outflow from the eye While they generally have minimal systemic side effects, they can cause noticeable changes in the eye, such as iris color alteration and eyelash growth The effectiveness and side effects of these medications can vary by individual, making one option potentially more suitable than others Notably, treatment with prostaglandin analogs has been linked to more severe hyperemia compared to other monotherapy regimens.
Beta blockers, particularly timolol, are the second most commonly prescribed medications for reducing fluid production and are often available in cost-effective generic forms Timolol also comes in a preservative-free version To minimize systemic side effects, users can close their eyes after application or employ punctal occlusion, which prevents the medication from entering the tear drainage duct and systemic circulation.
Alpha agonists, such as Alphagan®P (brimonidine) and Iopidine®, effectively reduce fluid production and enhance drainage in the eye Alphagan P contains a purite preservative that decomposes into natural tear components, making it a more tolerable option for individuals with sensitivities to preservatives found in other eye drops Additionally, Alphagan is offered in a generic version, providing a cost-effective alternative.
Carbonic anhydrase inhibitors (CAIs) effectively lower eye pressure by reducing the production of intraocular fluid These medications are offered in both eye drop formulations, such as Trusopt® (dorzolamide) and Azopt® (brinzolamide), and oral tablets like Diamox (acetazolamide) and Neptazane® (methazolamide) Notably, all CAIs, except for brinzolamide, are available in generic versions.
Rho khinase inhibitors [Rhopressa® (netarsudil)] increase the drainage of intraocular fluid This new class of glaucoma drug has been available since April
Combined medications provide a practical solution for patients requiring multiple treatments, allowing them to use a single eyedrop bottle instead of two, which also reduces exposure to preservatives Additionally, there may be financial benefits depending on the patient's insurance plan For example, Cosopt® combines a beta blocker (timolol) with a carbonic anhydrase inhibitor (dorzolamide) and is available in both generic and preservative-free options (Cosopt® PF) Similarly, Combigan® merges an alpha agonist (brimonidine) with a beta blocker (timolol), while Simbrinza® offers a beta blocker-free alternative, combining brinzolamide and brimonidine.
Side Effects of Glaucoma Medications
Following are some of the potential side effects of glaucoma medications
Prostaglandin Analogs: eye color change, darkening of eyelid skin, eyelash growth, droopy eyelids, sunken eyes, stinging, eye redness, and itching
Beta Blockers: low blood pressure, reduced pulse rate, fatigue, shortness of breath; rarely: reduced libido, depression
Alpha Agonists: burning or stinging, fatigue, headache, drowsiness, dry mouth and nose, relatively higher likelihood of allergic reaction
Carbonic Anhydrase Inhibitors: in eye drop form: stinging, burning, eye discomfort; in pill form: tingling hands and feet, fatigue, stomach upset, memory problems, frequent urination
Rho Kinase Inhibitors: eye redness, corneal deposits, stinging, and small bleeds on the white of the eye [29]
SOME POTENTIAL RISK FACTORS INFLUENCE ON DRY EYE
GLAUCOMA PATIENTS AFTER USING PRESSURE LOWERING EYE DROPS
While there is currently a lack of research specifically addressing dry eye syndrome in glaucoma patients post-surgery, various factors known to affect dry eye syndrome in general are likely to impact patients who have undergone glaucoma surgery In the following sections, I will discuss these influencing factors in detail.
1 Age: In addition to increasing age being a primary risk factor for DED, with decreasing tear production, tendency of being more prone to diseases such as diabetes and arthritis, which have also been independently associated with DED [44]
2 Gender: Female gender has been identified as a risk factor of DED, mainly due to the hormonal changes that occur during pregnancy, using birth control pills or menopause Moreover it is known to disproportionately affect women, with some studies estimating that prevalence among women is almost twice as high as that among men [45]
3 Digital screen exposure, contact lens wear: according to a research carried on in Thailand, it is shown that from univariate analysis, contact lens use and high screen time were significantly associated with higher risk of DED with the ORs (95% CI) of 2.43 (1.92, 3.07) and 1.48 (1.18, 1.86), respectively [46]
4 Eating a diet that is low in vitamin A, which is found in liver, carrots and broccoli, or low in omega-3 fatty acids, which are found in fish, walnuts and vegetable oils
5 Environment and lifestyle factors: Things like the weather, smoking or allergies can increase the risk of dry eye
6 Medications: Taking certain medications can increase the risk of dry eye, including some that treat depression, allergies, blood pressure, menopause and pain Anticholinergics, oral contraceptives and systemic retinoids can increase your risk as well Preservatives in eye drops is an example in this case Besides, different types of lowering pressure eye drop also lead to different side effects on eyes
7 Medical conditions: Many different neurological conditions, eye conditions, autoimmune conditions and endocrine conditions can raise risk of dry eye
8 Surgeries: Some eye surgeries increase your risk of dry eye, including LASIK, cataract surgery and surgery on your cornea
In Vietnam, there is a lack of research on the risk factors associated with dry eye in glaucoma patients who manage their intraocular pressure (IOP) with pressure-lowering eye drops Consequently, we have chosen to investigate this important topic.
SUBJECT AND METHODOLOGY
RESEARCH SUBJECTS
Patients with glaucoma who have been controlled intraocular pressure by eye drops are being treated at the National Eye Hospital
The patients with primary glaucoma and the patients experiencing glaucoma surgeries have been controlled intraocular pressure by eye drops
We excluded the following patients from the study:
- Open angle glaucoma due to corticosteroids
- Patients under 18 years of age because the clinical picture may be different and complex
- The patient is suffering from an anterior segment infection
- Patient is using artificial tears
- Patient is wearing contact lenses or has had refractive surgery
- The patient did not agree to participate in the study
2.1.3 Formula to calculate sample size α: significance level, with α=0.05
Z1-α/2: confidence level with the value = 95% Z1-α/2 = 1.96
P: according to the recent research carried by Anjan Palikhey about dry eye disease among patients with Glaucoma under Topical Antiglaucoma Agents, the proportion of dry eye disease is 72% [38] we selected p=0.72 n: sample size
In fact, we conducted the research on 30 eyes of 16 patients
RESEARCH METHODS
Clinical cross-sectional descriptive study
Patients with glaucoma are treated by pressure lowering eye drops
Do diagnostic tests for dry eyes
↓ Eligible dry eye patients were included in the study group
- Led slit lamps with purple filter light
- Goldman Model R900 manometer is mounted on SHV machine
- Paper tape absorbent fluorescein 10%, rose Bengal
- Patient monitoring sheet (detailed monitoring sheet in the appendix)
2.2.4.1 Generalindex and index relating dry eye evaluation a General index
- Age: divided into 3 groups: 18-40 years old, 40-60 years old and > 60 years old
- Gender: divided into 2 groups: male and female
- Geography: divided into 2 groups: rural areas and urban areas
-Working environment: divided into 4 groups: smoke, using computers, approach to air conditions regularly and others environment b Eye characteristics
- History of eye disease and history of glaucoma surgery
- Intraocular pressure c Dry eye evaluation
- Degree of inflammation of the Meibomius gland
- Assessment of symptoms: according to the OSDI questionnaire
- Assess the extent of corneal conjunctival epithelial damage: according to the Oxford assessment table
- Evaluation of tear film status: according to BUT test and Schirmer I test
2.2.4.2 Index of factors influencing on dry eye symptoms of glaucoma patients
- Age, gender, occupation, geography, working environment
- Time of taking IOP drugs, the type of eye drops used
- Time of approaching with preservatives in anti-glaucoma drugs, history of eye diseases
- The test is conducted in a room with normal temperature, no wind, normal humidity, patients sit quietly, do not talk or laugh
- Place the test paper in the correct position Follow up on time
Before administering any eye medication, it is crucial to conduct the test BUT, as it can be influenced by the use of local anesthetics, ointments, or manual eyelid manipulation This test should be performed with continuous observation under a microscope to ensure accurate results.
- Must be the same person to conduct and evaluate the results
- Full name, age, gender, geography, occupation
- The reason for coming to the doctor and the symptoms of the disease
- The course of the disease
- History of eye diseases and surgery history
- Family history: Having a close relative with glaucoma
2.2.5.2 Evaluation of dry eye condition of study patients
We used the OSDI (Eye Surface Disease) questionnaire
Index) consists of 12 questions (scale from 0 to 100) divided into 3 evaluation groups
The patient's accompanying dry eye symptoms:
- Group of symptoms of eyeball surface discomfort from sentences 1 to 3
- The group of symptoms of visual disturbances from sentences 4 to 9
- The group of symptoms caused by environmental factors starts from questions
For each question we give a score from 1 - 4 according to the table below:
Table 2.1: Ocular Surface Disease Index
Source: https://www.researchgate.net/figure/Ocular-surface-disease-index_fig1_5874558
OSDI=[(sum of scores for all questions answered) × 100]/[(total number of questions answered) × 4] [47]
Mild dry eye: OSDI= 13-22 points Moderate dry eye: OSDI = 23-32 points Severe dry eye: OSDI = 33-100 points
To perform the procedure, apply a paper tape saturated with a 10% fluorescein solution onto the conjunctiva Instruct the patient to blink multiple times to ensure the fluorescein is evenly distributed across the eyeball's surface After waiting for one minute, conduct an examination using LED slit lamps to observe the presence of purple-blue dots on the corneal surface.
To conduct the procedure, apply a paper bandage soaked in 1% Rose-Bengal solution to the conjunctiva Instruct the patient to blink multiple times to ensure even distribution of the Rose-Bengal across the eyeball's surface After waiting for one minute, examine the eye using a LED slit lamp to observe the presence of pink dots on the corneal conjunctiva.
To evaluate corneal conjunctival damage, we utilized the 2003 Oxford table, which features a scoring system ranging from 0 to 5 points This table illustrates the cornea and two contact areas of the conjunctiva, represented by colored dots, as depicted in the accompanying figure.
0 points: no chroma dots 3 points: 100 chroma dots
1 point: 10 chroma dots 4 points: 316 chroma dots
2 points: 32 chroma dots 5 points: > 316 chroma dots
Source: https://www.touchophthalmology.com/anterior-segment/journal-articles/diagnostic-tools- for-dry-eye-disease/
Tests to assess the state of tears
- Remove two strips from the sterile packet and label them „R‟ (right) and „L‟ (left) (Bend each strip, at the notch, to a 90-degree angle
- Ask the patient to look up and, with an index finger, gently pull down the lower eyelid
- Hook the bent end of the strip over the center of the lower eyelid and allow it to „sit‟ inside
- Repeat the procedure for the other eye
- Ask the patient not to squeeze, but just to keep the eyes gently closed
- After five minutes, ask the patient to open both eyes and look upwards
- Using the package scale, measure the length of the moistened area on the
35 strip, from the notch, and indicate this with a pen mark
Insert the strips into the patient's documentation and note the measurements beneath each strip, such as “10 mm in 5 minutes.” If the strips are fully saturated before the five-minute mark, document accordingly, for example, “30 mm in 3 minutes.”
For patients with dry eyes, we divide the degree of change in total tear secretion as follows:
Tear film breaking time (TBUT):
To perform the procedure, apply a paper tape soaked in a 10% Fluorescein solution to the conjunctiva, instructing the patient to blink and then close their eye to ensure even distribution of the fluorescein over the corneal surface Next, have the patient open their eyes and direct their gaze into the LED slit lamp Utilize the slit lamp with cobalt blue light to enhance visibility of the corneal surface Finally, measure the time taken from the moment the eye is opened until dark spots or streaks appear on the cornea.
Evaluation of results: Record the tear film destruction time in 3 tests, calculate the average value of 3 times (in seconds)
♦ Dry eye: If < 10s Tear film destruction time in dry eye patients is also divided into degrees:
The assessment of dry eye severity involves evaluating various factors, including tear film quality, corneal conjunctival staining, and tear secretion levels This evaluation is categorized into three distinct levels to accurately determine the degree of dryness and its impact on ocular health.
- Mild dry eye: TBUT > 6s, at least 1 mild surface staining test, Schirmer I test > 6mm
- Moderate dry eye: TBUT 3-6s, at least 1 moderate surface staining test, Schirmer I test 3-6 mm
- Severe dry eye: TBUT