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Introduction different influencing factors and the term

Introduction

Dry Eye Disease (DED) is one of the most
common ocular surface diseases that can significantly affect one’s quality of
life. The definition of DED has continuously developed in the past decades.
The goal of the Tear Film and Ocular Society (TFOS) Dry Eye Workshop (DEWS) is
to create an evidence-based definition and classification system as well as
appropriate diagnosis and management algorithm for DED1. In
2007, the first TFOS DEWS definition of DED was published2. In 2017, TFOS DEWSII has amended the definition of DED to be a “multifactorial disease of the ocular surface
characterized by a loss of homeostasis of the tear film, and accompanied by
ocular symptoms, in which tear film instability and hyperosmolarity, ocular
surface inflammation and damage, and neurosensory abnormalities play
etiological roles”1. The
term ‘multifactorial’ indicates that
the disease is due to different influencing factors and the term ‘etiological roles’ suggests various
involved pathways in the causation of DED1.  The two predominant categories of DED are (i)
evaporative dry eye (EDE) and (ii) aqueous deficient dry eye (ADDE) 2. EDE is related to lid conditions such as meibomian gland
dysfunction (MGD), poor blinking effort and lid disorders, it is also related
to poor ocular surface conditions such as prolonged contact lens wear, frequent
use of topical drug preservatives and immune related ocular surface disorders
including atopic keratoconjunctivitis. ADDE is primarily due to conditions
affecting the lacrimal gland function such as Sjogren’s syndrome3, lacrimal gland duct obstruction and side effects from systemic drugs.
Epidemiological evidence suggests that DED is mainly evaporative in nature4,5, and
it is often associated with MGD6-8.

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This review is to provide an update on the
association between meibomian gland dysfunction and dry eye disease, its
diagnosis and management.

 

Epidemiology

The prevalence of DED was reported to range
from 5 to 50%4. The
prevalence of MGD varies widely from 3.5% to almost 70%9-13,
however, the prevalence of MGD appears to be higher in Asian populations7. MGD alone has been reported to contribute to 60% of all cases of
DED, and an additional 20% if caused by aqueous deficiency as well14.

 

Pathophysiology of DED

All forms of DED are primarily due to water
loss from the tear film, leading to tear hyperosmolarity, it is caused by either
or both of the two mechanisms (EDE or ADDE)5.
Evidence has shown that in EDE, hyperosmolarity results from excessive evaporation
of tears but normal lacrimal function, whereas in ADDE, hyperosmolarity is due
to insufficient lacrimal secretion but a normal rate of evaporation15. Environmental factors affect the precipitation of hyperosmolarity
on the ocular surface, which may trigger the onset of DED or even worsen the
condition.

 

Pathophysiology of MGD
MGD is classified by the rate of gland secretion16. Low delivery state is defined as meibomian gland hyposecretion or more
likely, obstruction, whereas high delivery state is defined as meibomian gland
hypersecretion16. Within these categories, the most common mechanism is a low
delivery state due to gland obstruction17.  The cause is reported to be
due to epithelial hyperkeratinization leading to duct obstruction, meibum
stasis and eventually, gland dropout18-20.

 

Association between DED and MGD

Tear film consists of three distinct
layers, namely lipid, aqueous and mucus layers. The lipid layer is derived from
meibomian glands, which is a key component to the tear film. The lipid layer
prevents water evaporation from ocular surface and is crucial in maintaining a
healthy ocular surface21.  A dysfunction in meibomian
glands leads to an imbalance in lipid secretion, which increases the rate of ocular
surface evaporation and causes tear hyperosmolarity. Studies have showed that
patients with MGD has an increased in tear evaporation rate as compared to
normal subjects22. This shows that EDE has a direct correlation with the integrity
and quality of the meibum on ocular surface.

 

Risk factors

Many risk factors associated with DED plays
a role in MGD. DED and MGD are closely related and risk factor modifications
can improve both disease states.

Gender

Female sex is a significant risk factor for
the development of DED and MGD8,7. This
is possibly due to the effect of hormonal changes on meibomian secretion.
Androgen and estrogen receptors are both present within the meibomian glands15. It is reported that androgens stimulate meibum secretion and
suppress inflammation, whereas estrogens reduce meibum secretion and increase
inflammation23. Dysfunction in meibomian gland secretion and alterations in lipid
layer were described in patients with androgen depletion24,25. Female
sex is also a known risk factor in developing autoimmune diseases leading to
DED such as Sjogren syndrome26.

 

Topical medications

Topical medications can cause both DED and
MGD. Topical medications may cause ocular surface disturbance due to various
mechanisms including allergic response, epithelial toxicity and inflammatory
effects from chronic chemical irritation. Multiple studies have shown a clear
relationship between the prevalence of dry eye with the number of eye drops
used27-29. The
main reason is due to the presence of benzalkonium chloride (BAK) preservative
agent in topical medications. BAK has been well reported to cause DED, as it
dissolves lipid tear film layer and has been shown to disrupt tear film
osmolarity30. DED and MGD are also commonly reported in glaucoma patients on
topical glaucoma medications. Besides containing BAK, glaucoma medications are
also shown to be associated with changes in meibomian gland structure, leading
to MGD31.

 

Contact lens wear

Contact lens (CL) wear is commonly
associated with DED and MGD. Epidemiological study has shown that 50% of CL
wearers experience dry eye symptoms as compared to 22% in non-CL wearers32. CL wear can be either inducing dry eyes (CLIDE) or associated with
dry eyes (CLADE). CLIDE is due to changes of the tear film integrity. A thinner
lipid layer was noticed in CL wearer, which causes an increased tear
evaporation rate and tear hyperosmolarity33.  CLADE is due to
environmental factors such as prolonged usage of visual display devices, air
pollution and seasonal changes. As for MGD, the use of contact lens has been
hypothesized to be due to chronic inflammation34 and clogging of gland orifices by accumulated desquamated
epithelial cells35. Contact lens wearer has a high percentage of meibomian gland
dropout and reduction in gland function, and is reported to be directly related
to the duration of wear36.

 

Refractive surgery

Currently, laser in situ keratomileusis
(LASIK) is the most common corneal refractive surgery being performed
worldwide. DED is often associated with LASIK, and it can be aggravated by
factors in both pre-operative and post-operative states. Pre-operatively, the
risk of DED is significantly increased in long term CL wearer and eyes with
pre-existing tear film instability37. Intra-operatively, it has been reported that factors concerning
flap thickness, flap hinge location and flap angle, may also contribute to the
risk of DED38,39. The
degree of correction is also directly associated with the incidence of DED.  As the higher the refractive correction, the
deeper the ablation required, the larger the extent of sensory nerve damage
caused, this leads to dampening of corneal sensitivity and subsequently leads
to neuropathic dry eyes37. Corneal refractive surgery has also been shown to reduce corneal
epithelial integrity as well as conjunctival globlet cell concentration40, it also causes changes in meibomian gland function, and was
reported to be related to a reduction in lipid layer thickness41,
leading to chronic tear film dysfunction and DED42.

 

Diet

Evidence has shown essential fatty acid
(EFA) supplements to be beneficial in the treatment of DED and MGD, especially
by the intake of omega-3 fatty acids rich food such as flaxseed oil and fish
oil43,44. EFA
is hypothesized to be associated with modifications in lipid profile and
decreases the fatty acid content in meibomian gland secretions45. EFA also enhances lipid layer, retards tear evaporation and
decreases apoptosis of lacrimal gland cells46,47. EFA is
reported to display anti-inflammatory properties, specifically by the
production of prostaglandin48,49. All
these contributes to an improved in tear secretion and tear content.

 

Demodicosis

Demodex
folliculorum and Demodex brevis are the only two species of mites that affects the
human skin50,51. It
is reported that D. folliculorum
infests the lash follicles, while D.
brevis infests the meibomian glands52. Demodicosis of the eyelids is another factor worth considering in
the causation of MGD. Recent study has shown that the higher the D. brevis count, the more severe the MGD53. Demodex infestation is related to MGD and the eradication of
Demodex notably helps in relieving related ocular symptoms54.

 

Ocular surface signs and symptoms

Many signs and symptoms of DED overlap with
those of MGD. However, most patients with MGD are actually asymptomatic and if
symptomatic, their symptoms does not often directly correlate with the severity
of ocular surface damage55.  In a population based study
in China, 22% of the studied population were found to have asymptomatic MGD,
while 9% were symptomatic MGD10. When MGD is symptomatic, patients do report dry eye symptoms and foreign
body sensation 56. This maybe due to chronic inflammation in MGD or mechanical
friction between the accumulated meibum in the gland orifices and the ocular
surface15.

 

Diagnosis

As
DED and MGD are common ophthalmic problems, a clear diagnosis is crucial for
suitable management. Appropriate tests should be able to diagnose and monitor
DED according to the revised TFOS DEWSII definition. TFOS DEWS II has proposed
a DED diagnostic test battery 57 (Fig.
3).

 

The diagnostic test starts with triaging
questions and risk factor analysis to be followed by screening of symptomology
by standardized questionnaires including DEQ-5 (The Dry Eye Questionnaire 5) or
OSDI (Ocular Surface Disease Index). Diagnostic testing by homeostasis markers
include measures of tear break up time (TBUT), tear osmolarity and ocular
surface staining of cornea, conjunctiva or lids (Fig. 4). TBUT is a non-invasive
measurement and is defined by the time where the tear film breaks up before the
patient can no longer refrain from blinking57. A
TBUT of =308 mOsm/L in the measured eye or an
interocular difference of >8mOsm/L between two eyes59,60.  Ocular surface staining is done by fluorescein
staining for corneal damage and lissamine green staining for conjunctival and
lid margin damage57. A
positive result is defined as >5 corneal spots (Fig. 5)61,
>9 conjunctival spots61, >=2mm
in length or >=25% sagittal width of the lid margin62.

 

 

Subtype classification tests including
identification of MGD features, lipid thickness and tear volume assessment are
then carried out to determine the causation of the disease to be either EDE or
ADDE. Lastly, the severity of the category of disease is measured, and the
International Workshop on Meibomian Gland Dysfunction has reported a grading
system for MGD to guide management (Table 1) 63.

 

The role of imaging in diagnosis

In recent years, imaging modalities have
been introduced to improve the diagnosis of DED and MGD. These modalities aim
at evaluation of the structural and dynamic properties of the tear film64. Topographic systems have been used to determine the changes in
edges of the mires of a placido disc in cases of DED with tear film instability65. Anterior segment optical coherence tomography aims at measuring
the height of the tear meniscus66,67.
Infrared meibography has been shown to be useful in the diagnosis of MGD by
providing an objective evaluation of gland structures68. Tear film lipid layer thickness has been measured by interferometry,
which allows an objective and quantitative measurement of tear film integrity69. DED and MGD have been reported to cause a reduction in ocular
surface temperature (OST). In DED, the increase in tear film evaporation rate
causes heat vaporization leading to a reduction in OST70. In MGD, a decreased in tarsal conjunctival temperature was
observed, which increases the viscosity of meibum, causing worsening of gland function71. Therefore, thermography plays a considerable role in the diagnosis
of DED and MGD by measuring its OST. The advancement in imaging modalities
improves the accuracy and standardizes the diagnosis of DED and MGD.

 

Management

There are many management options advocated
for the treatment of DED and MGD. A stepwise staged approach is necessary in
standardization of management of disease72. TFOS
DEWS II derived an algorithm to implement various management options according
to disease severity 72. To
begin with, patients are to be educated regarding environmental and dietary
modifications (including EFA supplements) and to eliminate potential causations
of DED including CL wear, topical and systemic medications. Ocular lubricants
are suggested for mild DED, preferably those without BAK preservatives. In the
presence of MGD, lid hygiene and warm compression is highly advocated to reduce
lipid by-products. Lid scrubs with mildly diluted baby shampoo has always been
the widely accepted therapy73,74.
However, studies have shown that baby shampoo causes a reduction in ocular
surface antibodies, suggesting a possible adverse effect on gland function75.
Besides baby shampoo, there are now a wide variety of lid cleansing products
available.

If the above options are insufficient, tear
conservation by the means of punctual occlusion or moisture chamber goggles are
potential options. Punctal plugs act by trying to retain tears on the ocular
surface through blocking lacrimal drainage via its punctum.  Moisture chamber goggles are useful as it provides
a humid environment and reduces airflow to ocular surface, which slows down the
evaporation of tears72.

As for MGD, additional treatment options
include warming of the lids and expression of meibomian glands either manually or
with the use of specially designed devices such as LipiFlow® or
intense pulsed light therapy (IPL). Lipiflow® is designed to
transfer heat through the eyelid tissue to evacuate the gland contents at a
therapeutic temperature of 42.5oC76,77.
Studies have shown a promising result of LipiFlow® treatment, which
significantly improves symptoms78,79,76.  IPL was first reported a decade ago for the
treatment of MGD. Reports have shown improvement in tear film quality and
quantity and a reduction in symptoms80. A study has shown a 77% improvement in meibomian gland function
and an 89% improvement in dry eye symptoms post IPL treatment81. It is also shown to be safe and effective82.

Fig 5. Manual meibum
expression

 

In the presence of MGD, blepharitis or
rosacea, topical or oral antibiotics are of use. Tetracycline and macrolides
are reported to be useful in the treatment of MGD related DED72. It
is hypothesized that an inhibition in lipase production results in a reduction
in lipid breakdown, which may contribute to the improvement in MGD83. Macrolides, specifically azithromycin, besides its
anti-inflammatory property, is shown to significantly increase the cellular
accumulation of cholesterol, which can be the reason for a suitable treatment
of choice in MGD related DED84.

In the presence of Demodicosis, many treatment options have been described, including
the use of topical 2% metronidazole85, and more recently, the use of tea tree oil (TTO) 86 has gain popularity. TTO is a natural essential oil comprising
4-Terpineol, it is antimicrobial, anti-inflammatory and is shown to be toxic to
Demodex87,88.  Promising results have
shown that TTO lid scrubs are an appropriate management for Demodex related MGD89-92.

As for moderate to severe DED, in 2003, the
FDA approved topical non-glucocorticoid immunomodulatory drugs such as topical cyclosporine
as a treatment option. As ocular surface inflammation plays an important role
in the development of DED, anti-inflammatory mechanisms are to be addressed.
Cyclosporine is an immunomodulatory drug with anti-inflammatory properties93,94, treatment
with cyclosporine is shown to reduce inflammatory markers 95,96.
Evidences have proven topical cyclosporine to be efficacious in the treatment
of DED97-99.

In severe cases, autologous serum eye drops
can be considered. Autologous serum is the fluid component of own blood that
remains after centrifugation. The advantage is due to its similar biochemical properties
as that of tears72. It
is reported that autologous serum contains specific factors that enhance epithelial
regeneration and is able to inhibit the release of inflammatory cytokines 100,101.

In cases where medical treatment is
insufficient, surgery is another option. Surgical punctual occlusion acts like
punctual plugs to block tear drainage and improves tear retention. Permanent
surgical closure can be considered when patients cannot tolerate punctual
plugs. Surgical closure can be done by cauterization102,103,
conjunctival flap104 or even canalicular ligation105. Systematic review has shown that when combined with other DED
treatment, punctual occlusion improves dry eye symptoms106.

Severe DED can lead to corneal erosions,
persistent epithelial defects, corneal ulceration and eventually corneal scarring.
Amniotic membrane transplant (AMT) is a reasonable option in these cases. AMT is
shown to contain multiple neurotransmitters and neurotrophic factors which are
beneficial for the management of severe cases107.

In cases of severe dry eyes with persistent
epithelial defects that are refractive to medical treatment, tarsorrhaphy has
been suggested. Tarsorrhaphy is a surgical procedure to temporarily or
permanently, partially or totally close the eyelids. By a reduction in ocular
surface exposure, the rate of evaporation of tears decreases and DED can improve108. Due to unfavourable aesthetic outcomes, it is usually one of the
last reserves in the management of severe DED.

 

Suggested guideline in referral of DED or MGD to
Ophthalmologists

DED and MGD are one of the most common
ophthalmological presentations to medical practitioners. To address the
condition, risk factors are to be identified and modified. Lubricants can be
prescribed on a pro re nata basis for
symptomatic relief. If symptoms do not resolve, BAK preservative free
lubricants are to be considered. In the presence of MGD related symptoms, lid
hygiene and warm compression are highly suggested for symptomatic control. TTO
lid scrubs can be considered if the presence of Demodex is suspicious. If the above measures fail, a referral to
Ophthalmologists for further treatment is deemed reasonable.

 

Summary

DED is a common ophthalmic problem and the
cause is often multifactorial. MGD is an important contributor to DED due to an
imbalance in lipid secretion affecting the rate of tear evaporation. When tear
evaporates quickly, tear osmolarity increases and leads to DED. There are many
risk factors contributing to the two etiologies and many overlap. A clear
diagnosis is vital in guiding the management of DED. Various treatment options
are available for DED and MGD, a step-wise staged approach is often crucial in appropriate
management. This review aims to provide the relation between DED and MGD and to
update on the diagnosis and treatment options available.  

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