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Management of Meibomian Gland Dysfunction: A Review

Saama Sabeti, MD, MPH, Ahmad Kheirkhah, MD, Jia Yin, MD, PhD, Reza Dana, MD,
MPH, MSc

PII: S0039-6257(19)30253-X
DOI: https://doi.org/10.1016/j.survophthal.2019.08.007
Reference: SOP 6898

To appear in: Survey of Ophthalmology

Received Date: 11 January 2019

Revised Date: 20 August 2019
Accepted Date: 23 August 2019

Please cite this article as: Sabeti S, Kheirkhah A, Yin J, Dana R, Management of Meibomian
Gland Dysfunction: A Review, Survey of Ophthalmology (2019), doi: https://doi.org/10.1016/
j.survophthal.2019.08.007.

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Management of Meibomian Gland Dysfunction: A Review
1,2
Saama Sabeti, MD, MPH, 3,4Ahmad Kheirkhah, MD, 3Jia Yin, MD, PhD, 3Reza Dana,

MD, MPH, MSc.

1
University of Ottawa Eye Institute, The Ottawa Hospital, Ottawa, ON, Canada
2
Harvard T.H. Chan School of Public Health, Boston, MA, USA
3
Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School,

Boston, MA, USA

4
Department of Ophthalmology, University of Texas Health Science Center at San Antonio, San

Antonio, TX, USA

Funding: None

Financial Disclosure: None of the authors has any financial interest in the materials and

methods mentioned in this manuscript.

Corresponding Author:

Reza Dana, MD, MPH, MSc

Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA

Tel +1 617 912 7401

Fax +1 617 573 4300

Email: Reza_Dana@meei.harvard.edu
ABSTRACT

Meibomian gland dysfunction (MGD) is the leading cause of evaporative dry eye disease and is one of

the most common conditions encountered by eye care providers. MGD is characterized by obstruction of

the meibomian gland terminal ducts and/or changes in their glandular secretion, resulting in changes in

tear film stability, inflammation, and symptoms of irritation. There is no gold standard treatment for

MGD, but rather a diversity of options. Conservative measures include warm compresses and lid hygiene,

but there is growing interest and need for medical treatments and procedures. Potential medical treatments

include antibiotics, non-steroidal and steroidal anti-inflammatory agents, essential fatty acid

supplementation, hormone therapy, and control of Demodex infestation. Procedures include intraductal

meibomian gland probing, the use of electronic heating devices, intense pulsed light therapy, and

intranasal neurostimulation. We provide an update on MGD treatments based on recent studies.

I. INTRODUCTION

Meibomian gland dysfunction (MGD) is the leading cause of evaporative dry eye97 and one of the most

common conditions encountered by eye care providers.98 It is a type of posterior blepharitis that involves

inflammation posterior to the gray line of the lid margin.97 Symptoms of MGD can have a significant

impact on quality of life, causing not only ocular irritation, but also the sequelae of ocular surface

inflammation and resultant deficits in visual function.

According to the International Workshop on Meibomian Gland Dysfunction (IWMGD), “meibomian

gland dysfunction is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by

terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion.”97 This

terminal duct obstruction occurs due to hyperkeratinization of the ductal epithelium and increased

viscosity of meibum, and can lead to gland dropout, atrophy, and decreased secretion.98 The development

of this obstructive process has been shown to be influenced by numerous factors, both endogenous and

exogenous, including age, sex, hormone levels, as well as medications.98 Reduced delivery of lipids to the

ocular surface can cause evaporative dry eye disease, hyperosmolarity, and tear film instability.98

The tear film lipid layer consists of an outer non-polar layer and an inner polar layer at the level of the air-

lipid and aqueous-lipid interfaces, respectively.16 The outer non-polar layer serves as a lubricant, with its

water barrier function preventing tear evaporation, while the inner polar layer acts as a surfactant that

allows the entire lipid layer to spread across the ocular surface and also provides an interface between the

aqueous and outer non-polar lipid layers.51,95 Sphingolipids comprise 30% of the polar lipid layer, levels

of which have been shown to increase in the setting of MGD.95,102,110 Elevated meibum concentration of

the sphingolipid metabolite ceramide has been shown to cause an increase in meibum melting temperature

and resulting tear film lipid layer instability.5,110 Furthermore, sphingolipids have been shown to regulate

cellular processes including cell growth, differentiation, migration, proliferation, apoptosis, and

inflammation, thus reflecting other potential roles of these lipids in the pathophysiology of MGD.40,55
The goal of treatment for MGD is to improve the flow of meibomian gland secretions and ultimately help

re-establish tear film stability.143 In addition to eyelid hygiene and warming, numerous medical and more

invasive treatment options have emerged over the years. In 2011, the IWMGD released an extensive

report on MGD which included an evidence-based summary of management options.44 We shall provide

an update on MGD treatments based on studies published since the IWMGD report. Medical treatments

discussed in this article include antibiotics, non-steroidal and steroidal anti-inflammatory agents, essential

fatty acid supplementation, hormone therapy, and control of Demodex infestation. Procedures discussed

include intraductal meibomian gland probing, the use of electronic heating devices, intense pulsed light

therapy, and intranasal neurostimulation.

II. MEDICAL MANAGEMENT

II.1. ANTIBIOTICS

It is not entirely clear whether bacterial colonization of the lid margin in patients with MGD indicates that

infection is the underlying cause of disease or just that the lid environment in patients with MGD is more

amenable to colonization by bacteria compared to normal subjects.44 The effects of bacteria on the

pathophysiologic processes of MGD are mediated in part by the production of directly toxic products,

such as lipases, as well as pro-inflammatory molecules, such as matrix metalloproteinases (MMPs).

Regardless of the exact impact of bacteria on the disease process, commensal bacterial species that are

found on the lid margins of normal individuals are present in increased numbers in those with

blepharitis,69 and thus antibiotics have been used for years in the management of MGD.

II.1.1. Tetracyclines

Tetracyclines are bacteriostatic antibiotics used in the treatment of MGD primarily for their anti-

inflammatory properties rather than their antibiotic effects.44 They have been shown to suppress the
production of bacterial lipases as well as the release of pro-inflammatory molecules, particularly free fatty

acids, both of which cause instability of the tear film and inflammation within the meibomian

glands.26,27,120,123 Furthermore, they modulate neutrophil and lymphocyte function and provide anti-

oxidative effects through various mechanisms including the inhibition of MMPs and inflammatory

cytokines such as tumor necrosis factor (TNF)-α,33 MMP-8,88 and MMP-9.88 Finally, they may be anti-

angiogenic and anti-apoptotic at the ocular surface.80

There are a multitude of studies on the use of tetracyclines in the treatment of MGD, but very few are

classified as level I (randomized, placebo-controlled) studies.80 One randomized controlled trial compared

60 patients with MGD assigned to either artificial tears only versus artificial tears plus oral minocycline,

and showed a statistically significant improvement in the minocycline group with regards to all clinical

signs and symptoms measured, including tear break-up time (TBUT), Schirmer test, corneal and

conjunctival fluorescein staining, lid margin appearance, and meibum quality.77 Furthermore, the

minocycline group also showed statistically significant reductions in inflammatory cytokines Interleukin

(IL)-6, IL-1β, IL-17α, TNF-α, and IL-12p70 after two months of treatment, whereas the control group

only showed statistically significant reductions in levels of IL-1β and monocyte chemotactic protein

(MCP)-1.

Of note, doxycycline and minocycline are more lipophilic compared to tetracycline or oxytetracycline and

are therefore more concentrated in ocular and lid tissues at lower doses56 (i.e. 50-100 mg dosed at once or

twice a day for the former compared to 250 mg once to four times a day for the latter).44 These doses

generally allow for only anti-inflammatory rather than antibiotic effects at the ocular surface, except for

minocycline, which has been shown to also reduce the population of lid flora in patients with rosacea.6,132

The main side effects of tetracyclines include photosensitivity and gastrointestinal symptoms, and their

use is contraindicated in pregnant women and children.140

II.1.2. Azithromycin

Azithromycin is a macrolide antibiotic that is used off-label to treat MGD. Macrolides provide

predominantly Gram-positive coverage, inhibiting bacterial protein synthesis by binding to the 23S rRNA

molecule of the 50S ribosome subunit. Azithromycin has been found to not only reduce the growth of lid

bacteria, but also suppress bacterial lipases134 and conjunctival inflammation.85 It has been shown that it

reduces the expression and release of pro-inflammatory molecules including nuclear factor-kappa B,1 IL-

6, IL-8,1 TNF-α,44 IL-18, and MMP-9 mRNA,146 and increases the expression of transforming growth

factor (TGF)-β1 which has anti-inflammatory effects.146 Furthermore, macrolides can influence the

functions of neutrophils and phagocytes.146 Azithromycin has been shown in experimental studies to

promote the differentiation of immortalized human meibomian gland cells and stimulate phospholipidosis

through the accumulation of cholesterol, neutral lipids, and lysosomes.146 Moreover, it restores and

promotes differentiation of carotenoids in meibum.38 Azithromycin has been used in both topical and oral

formulations for the treatment of MGD.

II.1.2.1. Topical azithromycin. Topical azithromycin is available in the United States as an ophthalmic

solution 1% (AzaSite®, Inspire Pharmaceuticals, Inc., Durham, NC, USA). The efficacy of topical

azithromycin for treatment of MGD has been shown in a number of studies. A cohort study evaluating the

use of topical azithromycin 1% twice a day for one month in 26 patients showed statistically significant

improvements in TBUT, Schirmer test, and corneal and conjunctival staining.100 Symptom scores,

including Ocular Surface Disease Index (OSDI) scores, also improved. Furthermore, a randomized trial

examining the duration of topical azithromycin 1.5% treatment showed that a longer course of treatment

(1 month versus 3 days) provided longer lasting results that persisted for 3 months after treatment.32 The

same study showed improvement in signs and symptoms in both groups by 1 week and minimal irritation

with use of the drug. Finally, a retrospective study looking at outcomes of 35 patients with MGD treated

with topical azithromycin 1.5% twice daily for 2 days then once daily for a total of 30 days in addition to

daily lid hygiene with diluted baby shampoo found statistically significant improvements in meibomian
gland grading score, Schirmer score, TBUT, and corneal fluorescein staining at 1 month, but no

significant change from baseline at 3 months.8

II.1.2.2. Oral azithromycin. There has been growing interest in the use of oral azithromycin not only for

reasons of effectiveness in treating MGD but also improved compliance, since oral azithromycin usually

involves once daily dosing for several days, sometimes in weekly cycles, as compared to daily use of

tetracyclines for weeks or months. It has been shown that a single 1-gram dose of oral azithromycin

results in high drug concentrations in the conjunctival tissue and tear fluid lasting for at least 14 days.133 A

cohort study examining 26 patients using oral azithromycin 500 mg per day for 3 days in 3 cycles with 7-

day intervals showed statistically significant improvements in lid debris, telangiectasia, and redness.59

Furthermore, there were statistically significant improvements in symptoms including lid itching, eye

itching, ocular hyperemia, and ocular mucus secretion. Another cohort study examining 32 patients with

meibomitis found that 75% had improvements in symptoms after using 1 gram of oral azithromycin once

a week for 3 weeks in addition to topical steroid treatment.47 Furthermore, one randomized trial of 110

patients assigned to either oral azithromycin for 5 days (500 mg on day 1 followed by 250 mg on days 2-

5) versus oral doxycycline 200 mg daily for one month showed that the former resulted in a significantly

greater improvement in bulbar conjunctival redness and ocular surface staining.64 Of note, azithromycin

has been reported to cause adverse cardiac events, most notably QT-prolongation. The risk of such has

been found to be higher in those with a pre-existing long QT interval, those on other QT-prolonging

medications, or those with baseline cardiovascular abnormalities.90,A

II.2. ANTI-INFLAMMATORY AGENTS

The role of inflammation in the pathophysiology of MGD is not entirely understood. However, patients

with blepharitis demonstrate increased meibum levels of phospholipase A2, which plays a role in the

synthesis of inflammatory mediators such as prostaglandins and leukotrienes.69 Local inflammation in

turn can cause activation of ocular surface epithelial cells which then produce inflammatory cytokines
such as TNF-α and -β.69 Furthermore, the concentration of IL-1α, mature IL-1β, and MMP-9 are known to

be increased in the tear fluid of patients with MGD.122 The presence of inflammatory cytokines including

IL-1α can cause increased epithelial proliferation and keratinization thereby contributing to obstructive

meibomian gland disease,39 and are therefore a target of anti-inflammatory agents in the management of

MGD.

II.2.1. Cyclosporine A

Cyclosporine A, a calcineurin inhibitor available as a topical 0.05% emulsion (Restasis®, Allergan Inc.,

Irvine, CA, USA), was the first FDA-approved treatment for dry eye disease.44 Calcineurin is a molecule

which induces transcription factors involved in the transcription of IL-2, a cytokine which activates T-

helper lymphocytes and is necessary for their replication. By inhibiting calcineurin, cyclosporine A

effectively inhibits T-cell proliferation.115 In addition to increasing aqueous production in inflammatory

dry eye disease, cyclosporine A has also been shown to play a role in the management of MGD,

contributing to improvements in lid margin redness, meibomian gland inclusions, telangiectasia, and

corneal staining,105 as well as in the quality of meibomian gland secretions.26

There are numerous studies evaluating the effectiveness of topical cyclosporine A in managing dry eye

disease, but very few assessing its use in the treatment of MGD specifically. A double-masked,

randomized controlled trial of 70 patients with symptomatic MGD found that, in comparison to controls

treated with preservative-free artificial tears, twice daily dosing of topical cyclosporine A 0.05% for 3

months resulted in statistically significant improvements from baseline in terms of OSDI, TBUT, lid

margin inflammation, meibomian gland expressibility, and tarsal injection; furthermore, it resulted in a

longer TBUT and a greater change of TBUT from baseline compared to the control group.107 The most

common side effect and reason for discontinuation of cyclosporine A is a stinging sensation.118

Pretreatment with topical loteprednol 0.5% has been shown to reduce discomfort associated with use of
cyclosporine A.118 Overall, the anti-inflammatory properties of cyclosporine A that have made it an

effective treatment option for aqueous-deficient dry eye disease appear to also play a role in tackling the

inflammatory contributions to disease in MGD.

II.2.2. Lifitegrast

Lifitegrast is a lymphocyte function-associated antigen (LFA)-1 antagonist that blocks T-cell binding to

intercellular adhesion molecule (ICAM)-1, a ligand expressed on inflamed ocular epithelial and vascular

endothelial cells.116 This prevents the release of pro-inflammatory cytokines including interferon (IFN)-γ,

TNF-α, macrophage inflammatory protein 1α, as well as IL-1α, 1β, 2, 4, and 6.116 Topical Lifitegrast

ophthalmic solution 5.0% (Xiidra®, Shire, Lexington, MA, USA) is the second and most recent drug

approved by the FDA for management of dry eye disease. The results of the OPUS-3 phase 3 trial

comparing twice daily dosing of Lifitegrast ophthalmic solution 5.0% to placebo showed that Lifitegrast

provided greater improvement in eye dryness score (measured on a visual analog scale) at day 14, 42, and

84.57 Subjects using Lifitegrast experienced greater improvement in itching, foreign body sensation, and

ocular discomfort at day 42 compared to placebo. The most common adverse effect of topical Lifitegrast

is transient, intermittent instillation site irritation or discomfort, primarily at the time of the initial dose.119

To date, there have been no published studies evaluating the use of Lifitegrast in the treatment of MGD

specifically.

II.2.3. Corticosteroids

According to the IWMGD report released in 2011, no published study had supported long-term

maintenance therapy with steroids. Rather, steroids have proven useful in the setting of acute bouts of

inflammatory complications of MGD, such as chalazia or marginal keratitis.57 Considering the risk of

cataract development and elevation of intraocular pressure, the benefits of steroid therapy must be

measured against the risks. Several studies have demonstrated the efficacy of short-term treatment with
steroids in the management of patients with dry eye disease;17,78 however, the literature available on

steroid use in the treatment of MGD is limited.

A randomized controlled trial on 70 eyes with MGD showed that treatment with 0.5% loteprednol

etabonate ophthalmic suspension four times a day, in addition to the control treatment of eyelid scrubs

and warm compresses twice a day, demonstrated more improvement in TBUT, meibum quality,

conjunctival fluorescein staining, and meibomian gland expressibility at 1 month compared to controls.76

Another study randomized 20 patients to either N-acetylcysteine 5% or betamethasone 0.1%-

sulfacetamide sodium 10% (a steroid-antibiotic combination) used topically 4 times a day for one month;

all patients were instructed to apply lid hygiene once daily.2 Statistically significant improvements in

TBUT, Schirmer test, and symptoms of ocular burning, itching, and intermittent filmy or blurry vision

were seen in both groups at one month compared to baseline; there was no significant difference between

the two groups and intraocular pressure measurements were within normal limits for both groups.

II.2.4. Anakinra

Interleukin-1 (IL-1) is a pro-inflammatory cytokine produced by inflamed epithelial cells74 and a key

mediator of ocular surface inflammation. IL-1 activates and recruits leukocytes, facilitates T cell

differentiation, and promotes the production and activity of other pro-inflammatory molecules, including

IL-6, IL-8, granulocyte macrophage colony-stimulating factor, MMP enzymes, and TNF-α.35,117 IL-1

levels have been found to be elevated in tears of patients with moderate evaporative dry eye disease29 and

MGD122 and are correlated with severity of ocular surface epithelial disease.74,122 IL-1 receptor antagonist

(IL-1RA) is a cytokine that suppresses IL-1α and IL-1β activity by competitively binding to the type 1 IL-

1 receptor.25 Anakinra (KineretTM; Amgen Inc.) is a recombinant version of human IL-1RA approved for

treatment of rheumatoid arthritis25 and used off-label for other conditions,86 including dry eye disease.

Although Anakinra has been reported to be efficacious in treating dry eye disease,4 there are no published
studies to date on its use in treating MGD. Of note, it is not currently commercially available in the

United States.

II.3. SEX HORMONES

Androgens, estrogen, and progesterone have been found to regulate a number of meibomian gland genes

through their action on local meibomian gland receptors, with variable effects in females and

males.31,66,126,128,129 Androgens have been found to suppress genes associated with keratinization, stimulate

genes associated with lipogenesis, and influence the maturation of acinar cells leading to increased lipid

secretion.113,114,124,126 Androgen deficiency, androgen receptor dysfunction and insensitivity, and the use of

anti-androgen medications have been shown to be associated with obstructive MGD.19,72,79,92,125,127

Whereas androgens exert a pro-sebaceous effect on meibomian glands, estrogens have been found to do

the opposite,138 reducing the size and lipid output of sebaceous glands and negatively influencing lipid

secretion from meibomian glands through the inhibition of lipogenesis and upregulation of lipid

catabolism.138 Estrogens, particularly 17-β-estradiol, have been found to have a pro-inflammatory effect

on the ocular surface.130

The exact relationship between serum sex hormone levels and dry eye disease, including MGD

specifically, still remains unclear to date. For example, postmenopausal women on hormone replacement

therapy (HRT) have been shown to have a greater risk of dry eye disease compared to those not on

HRT;112 a potential reason for this may be the suppression of the hypothalamic-pituitary-adrenal axis in

the presence of exogenous estrogen, thus reducing adrenal androgen production. In contrast, others have

found decreased symptoms and increased tear production in patients on HRT.60 A more recent study

showed a statistically significant improvement in TBUT, lid meiboscore, excretion difficulty, and corneal

fluorescein staining at 1, 3, and 6 months in perimenopausal women on HRT compared to those not on

HRT.62
II.3.1. Hormone therapy. A paucity of literature exists with regards to the use of sex hormone therapy in

the management of dry eye disease in general and, to an even greater extent, MGD. Feng and coworkers

showed improved tear production in postmenopausal patients on HRT who were <50 years old.34 Connor

and colleagues demonstrated an increase in TBUT and a reduction of OSDI in females aged 22-65 years

using 5% testosterone cream to the eyelids twice daily for 3 weeks, with greater benefit in peri- and

postmenopausal patients.B Schiffman and associates showed in a randomized, vehicle-controlled trial that

the use of topical 0.03% testosterone ophthalmic solution significantly improved meibomian gland

secretion viscosity compared to vehicle after 6 months of treatment.C Worda and coworkers had also

shown that topical androgens enhance meibomian gland function as measured by increased lipid layer

thickness and TBUT.142 With regards to determining which patients are candidates for hormonal

treatment of dry eye disease, it has been suggested that age and endogenous hormonal levels are the most

important considerations.103 To date, there has not been an approved topical testosterone product for

treatment of dry eye symptoms due to inadequate evidence;138 likewise, there is currently inadequate

evidence to support the use of dehydroepiandrosterone (DHEA) and DHEA-S (sulfate) for relief of MGD

symptoms in postmenopausal patients, in whom these adrenal precursors to estrogen and androgens are

naturally deficient.138 Overall, there is limited literature on the use of topical or systemic sex steroid

agents in the treatment of MGD, and further research is needed in this area.

II.4. ESSENTIAL FATTY ACIDS

Essential fatty acids (EFAs) have been found to have anti-inflammatory effects, and oral supplementation

with omega-3 fatty acids has been found to be associated with a change in the fatty acid saturation content

in meibum.89 Multiple studies have shown a beneficial effect of oral supplementation with EFAs in dry

eye disease.11,14,63,82,141,144 Omega-3 fatty acids have been associated with improved TBUT82,89 and

Schirmer test scores.82 There are still few studies examining the effect of EFAs on MGD, however, and

their mechanism of action in improving signs and symptoms of MGD is not clearly understood. It has

been suggested that omega-3 fatty acids suppress inflammation while omega-6 fatty acids promote
inflammation.18 Another hypothesis is that omega-3 fatty acid supplementation may influence the fatty

acid composition and thus lipid properties of meibum.89

II.4.1. EFA supplementation. In 2008, Dana and coworkers compared the use of topical 0.2% alpha-

linolenic acid (omega-3) to 0.2% linoleic acid (omega-6) as well as to a combination of 0.1% alpha-

linolenic acid and 0.1% linoleic acid, all used once daily in mice with induced dry eye. This study found a

significant decrease in corneal staining, CD11b+ cell number, and corneal IL-1a and TNF-a

concentrations in the omega-3 group compared to both the omega-6 and the combined omega-3 and -6

groups; no beneficial effects were found for the latter two groups.108 With regards to oral

supplementation, a randomized controlled trial of 61 patients with MGD compared daily use of an omega-

3 supplement (BrudySec® 1.5 g, containing omega-3, glutathione, and vitamin A) to an oral placebo

control.99 The omega-3 group was found to have significant improvements in both Physical Component

Summary and Mental Component Summary scores compared to baseline and compared to the control

group at 3-month follow-up. In another non-randomized, placebo-controlled study, 60 patients were

allocated alternately to either a control group receiving warm compresses, lid massages, and artificial tear

substitutes, or to a treatment group receiving 1.2 g of omega-3 fatty acid supplement daily in addition to

the control group regimen. Significantly greater improvement in contrast sensitivity was found in the

treatment group compared to the control group, as was the case with OSDI scores, TBUT, ocular surface

staining, meibum quality, and meibum expressibility.91 Another study randomized 54 patients to receive

omega-3 (1680 mg eicosapentaenoic acid / 560 mg docosahexaenoic acid) and 51 patients to receive the

control omega-6 (3136 mg linoleic acid), both receiving treatment daily for 12 weeks.30 The omega-3

group showed a statistically significant reduction in tear osmolarity at weeks 6 and 12 compared to the

control group, as well as a statistically significant increase in TBUT at week 12. There was a statistically

significant reduction in MMP-9 levels as well as OSDI scores in the omega-3 group versus the controls.

In contrast to these reports of success using omega-3 supplementation, in 2018, the Dry Eye Assessment

and Management (DREAM) Study Research Group published the results of a multicenter, double-blind
clinical trial in which patients with moderate-to-severe dry eye disease were randomly assigned to receive

either fish-derived omega-3 supplementation (daily oral dose of 2000 mg eicosapentaenoic acid / 1000

mg docosahexaenoic acid) or an olive oil placebo (5000 mg daily dose) for 12 months.7 The primary

analysis included 329 patients in the active supplement group and 170 patients in the placebo group.

Although both groups improved significantly with respect to mean OSDI score, it was found that the

difference between their mean score changes was not statistically significant. There was also no

statistically significant difference between the two groups with respect to conjunctival staining score,

corneal staining score, TBUT, or Schirmer test results. Note that this study had fewer restrictions on

inclusion criteria than the aforementioned studies and did not include only patients with MGD-related dry

eye disease. Regardless, considering the conflicting results of these recent studies on essential fatty acid

supplementation in the management of both MGD-related as well as other forms of dry eye disease,

further randomized controlled trials evaluating their effectiveness would continue to provide valuable

insight into their utility.

II.5. DEMODEX TREATMENT

Demodex mites are the most common ectoparasite found on human skin,9 many species of which are

obligatory commensals of the pilosebaceous unit of mammals.73 Colonization of Demodex mites in

humans has been shown to increase with age, with up to 100% of adults infested beyond the age of 70.106

The most common species identified in humans are Demodex folliculorum, found primarily in lash

follicles, and Demodex brevis, found mainly in the sebaceous and meibomian glands of the lids.28

Although there is no clear evidence of a causal relationship with MGD,44,73,81 a study of 150 patients

demonstrated the presence of Demodex in 90% of those with anterior blepharitis and 60% of those with

MGD.10 Demodex is thought to cause blepharitis via several mechanisms. D. folliculorum directly

damages cells at the base of the hair follicle, causing reactive hyperkeratinization and resulting in the

formation of cylindrical dandruff. D. brevis physically blocks the meibomian glands, resulting in a

granulomatous reaction from tissue irritation and thus predisposing to MGD and chalazia.83 Furthermore,
Demodex mites can serve as a vector for certain bacteria, triggering an inflammatory response in the host,

and can cause a delayed hypersensitivity reaction particularly in patients with rosacea.45

II.5.1. Tea tree oil. Tea tree oil (TTO), an essential oil derived from the leaf of the plant Melaleuca

alternifolia,135 has been found to be an effective treatment for blepharitis associated with Demodex.41,42,67

A one-month treatment of weekly 50% TTO lid scrubs in the clinic and 10% lid scrubs daily at home has

been shown to eradicate ocular Demodex,42,70 reduce inflammation of the lid margin, conjunctiva, and

cornea,41,67 decrease tear concentrations of IL-1β and IL-17,68 and improve ocular surface irritation.41,67,70

More recently, home therapy with daily lid massage and 5% TTO ointment has also been found to

significantly decrease mite counts by four weeks and provide significant relief from itching.43 Aside from

its miticidal effects, TTO may also have antibacterial, antifungal, and anti-inflammatory properties that

improve signs and symptoms of blepharitis.44 In light of adverse effects such as contact dermatitis and

hypersensitivity reactions attributed to certain ingredients found in TTO such as terpinolene, α-terpinene,

ascaridol, and 1,2,4-trihydroxymethane,23,111,134 it has been suggested that terpinen-4-ol – the most

effective ingredient for killing the mites – be used alone for treatment of Demodex.135 This ingredient has

both antimicrobial and anti-inflammatory functions and is what composes the product Cliradex® (Bio-

Tissue, Inc.).21 Cliradex® is applied to the lids once daily for mild symptoms or twice a day for moderate

to severe symptoms, for an initial trial of two months duration.134

II.5.2. Other agents used to treat Demodex. Other agents such as mercury oxide 1%, or sulfur ointment,

pilocarpine gel, and camphorated oil have been used to physically trap the mites as they attempt to

emerge from one follicle and move on to the next overnight.83 Twice-daily topical application of 0.25%

povidone-iodine in a dimethylsulfoxide vehicle has been reported to improve signs of anterior and

posterior blepharitis attributed to Demodex.104 In a study of 24 eyes of 12 patients with refractory

posterior blepharitis with the presence of D. folliculorum in lash samples, treatment with oral ivermectin

(200 µg/kg) taken at one dose on day 0 and again on day 7 showed statistical improvement in the absolute
number of D. folliculorum found in the lashes, as well as statistically significant improvement in Schirmer

I test results and TBUT;58 no statistically significant improvement was observed in average tear meniscus

height or value of corneal fluorescein and rose Bengal staining after treatment with oral ivermectin.

III. PROCEDURES FOR MGD MANAGEMENT

III.1. EXPRESSION OF MEIBUM

According to the IWMGD definition of MGD, terminal duct obstruction is a key feature of the disease

process and, therefore, mechanical opening of the terminal duct as well as meibum expression play an

important role in management. Both intraductal meibomian gland probing and electronic heating devices

act to assist locally with ease of meibum expression through mechanical opening of the duct orifice and/or

heating of meibum to allow for better outflow.

III.1.1. Intraductal Meibomian Gland Probing

Intraductal meibomian gland probing can be performed at the slit lamp. It involves mechanically opening

and dilating blocked meibomian gland orifices and ducts through the insertion of probes of varying sizes.

The gland orifice is initially penetrated using a 1 or 2 mm Maskin probe (Rhein Medical, Tampa, FL,

USA), followed by either a 4 or 6 mm probe, depending on the length of the gland, in order to achieve

ductal patency. Probing can help release accumulated meibum, improve ductal patency, and potentially

increase accessibility of the diseased meibomian glands to treatment with topical medications.87 Probing

has been shown to improve both objective signs of disease – including TBUT,87,121 meibum lipid levels

and viscosity,96 lid margin abnormalities,87,121 and conjunctival hyperemia121 – as well as

symptoms.87,121,139 In a retrospective cohort study of 25 patients treated with probing by Maskin,93,D 96%

of patients had immediate symptom relief post-probing,93 and 66.7% of patients required only one

treatment during an average follow-up duration of 30.3 months.C Probing improved lid functionality

(defined as ≥5 expressible glands in a lid) in 62 of 67 lids (92.5%) over a follow-up range of several days
to 7 months (average follow-up of 7.65 weeks).C In a randomized controlled trial of 49 patients with

MGD randomized to either probing plus 0.1% fluorometholone or 0.1% fluorometholone alone, 76% of

patients experienced immediate symptomatic relief one day post-probing before application of topical

medications.87 A recent study has reported an increase in meibomian gland area on meibography at 4.5 to

12 months after probing, suggesting that glandular growth may be promoted through the establishment of

a patent duct.94

A modified technique called dynamic intraductal meibomian probing has been described by Syed and

Sutula131 in which the patient lies supine in a procedure chair under an operating microscope and the lid is

grasped with forceps and pulled in the direction opposite to that of the movement of the probe. This offers

greater magnification of the duct orifices as well as probing against resistance, and has shown good

effects in a retrospective chart review, with 92% of 22 patients reporting symptomatic improvement.131

III.1.2. Electronic Heating Devices

The melting point of meibomian lipids ranges from approximately 19°C to 32°C,89 allowing meibum to

remain in a fluid state in the setting of ocular surface and eyelid temperatures which range from

approximately 33°C to 37°C.16 Meibomian gland dysfunction has been shown to cause an alteration in the

composition of meibum which results in an increase in the melting point, thus requiring higher gland

temperatures to liquefy materials that otherwise cause obstruction.13,65 Increased eyelid temperatures have

been shown to decrease meibomian lipid viscosity and increase lipid levels present on the lid margin.16

Prior studies have demonstrated that temperatures of greater than 40°C are required for liquefaction of

obstructive glandular material in severe MGD.13 This concept forms the basis for the role of heat therapy

in MGD management, either in the form of warm compresses or through electronic heating devices, the

latter of which will be discussed here.

LipiFlow®. LipiFlow® (TearScience, Morrisville, NC, USA) is a single-use sterile vectored thermal

pulsation system which employs simultaneous application of heat to the palpebral conjunctival surfaces of

the upper and lower eyelids along with distal to proximal pulsatile pressure to the outer eyelid surfaces in

order to express meibomian gland contents.75 A single treatment is 12 minutes in duration. LipiFlow® is

currently the only device able to apply heat to the internal lid surface.65 This treatment has been shown to

be effective in improving objective measures of disease including meibomian gland secretion

scores,12,49,50 TBUT,48,50,54,71,75 number of expressible glands,36,37,71 lipid layer thickness,37 bulbar redness,37

and lid margin parallel conjunctival folds.37 Studies have also shown significant subjective improvements

in dry eye and irritation symptoms as measured by the OSDI questionnaire36,37,48–50 and the Standard

Patient Evaluation of Eye Dryness (SPEED) questionnaire.37,48–50,54 An observational cohort study of 40

eyes showed that a single LipiFlow® treatment resulted in statistically significant improvements in

meibomian gland secretion scores, OSDI scores, and SPEED scores at 1 month, and these improvements

persisted at 3 years after LipiFlow® treatment.49 There was also a statistically significant increase in

TBUT at 1 month, but this improvement was not sustained at 3-year follow-up; a similar finding occurred

in a study by Zhao and colleagues in which TBUT was modestly improved at 1 month but was no

different from the warm compress control group at 3 months.147 An open-label randomized controlled trial

using 400 eyes showed a greater mean improvement in meibomian gland secretion and dry eye symptoms

in patients who had received a single LipiFlow® treatment compared to those using twice daily 10-

minute warm compress and eyelid hygiene therapy using the EyeGiene® Insta-WarmthTM (Eyedetec

Medical, Inc. Danville, CA, USA) system and OCuSOFT® Lid ScrubTM Original (OCuSoft, Rosenberg,

TX, USA), when measured at 3 months.12 At 12-month follow-up, 86% of the LipiFlow® group only

required a single treatment and sustained a significant mean improvement in meibomian gland secretion

and dry eye symptoms. Early treatment was positively correlated with improved outcomes. A recent

randomized trial comparing a single 12-minute LipiFlow® treatment to daily doxycycline for 3 months

found that the former resulted in significantly better SPEED scores while performing at least as well as
doxycycline in terms of improvements in TBUT, corneal and conjunctival staining, and meibomian gland

function.54

III.1.3. MiBo Thermoflo®. MiBo Thermoflo® (Mibo Medical Group, Dallas, TX, USA) is another

electronic heating device using an external paddle heated to 42.2˚C (108˚F) and applied to the lids with an

ultrasound gel buffer. There is currently a paucity of literature on the efficacy of this device in the

management of MGD. One case report comparing palpebral conjunctival temperature pre- and post-use of

four different heating devices (Bruder mask, Blephasteam®, MiBo Thermoflo®, and LipiFlow®), found

that MiBo Thermoflo produced the smallest increase in temperature after a 12-minute treatment – an

increase from 36.3˚C to 36.5˚C for the upper eyelid, and no change from 36.8˚C for the lower eyelid.65 On

the other hand, LipiFlow® provided the greatest increase in temperatures, increasing that of the upper

eyelid from 36.9˚C to 41.1˚C and that of the lower eyelid from 37.0˚C to 42.0˚C.

As the evidence does not clearly point toward one heating device as superior to another, the decision to

pursue a specific therapeutic option should involve considerations of patient comfort, cost, ease of follow-

up, and individual response to therapy.

III.2. INTENSE PULSED LIGHT THERAPY

Intense pulsed light (IPL) therapy has been used for years in dermatology practices to improve the

appearance of skin101,109 and is a known treatment for rosacea.24 It utilizes a high-intensity non-laser light

source, producing wavelengths ranging from 500-1200 nm.46 When applied to skin, the absorption of light

by oxyhemoglobin in blood cells travelling within vessels near the skin surface results in heat generation

and local coagulation, leading to thrombosis of the blood vessels and therefore decreasing redness caused

by abnormal telangiectasias and eliminating this source of inflammatory mediators.46,136 Furthermore, IPL

has been shown to eradicate bacteria on treated areas of the skin.46,136 Since the pathophysiology of MGD

involves a combination of microbial overgrowth, inflammation, abnormal blood vessel growth

surrounding and causing dysfunction of the meibomian glands, and resultant abnormal meibum

production, IPL therapy should theoretically improve MGD. Major mechanisms by which IPL is thought

to improve signs and symptoms of MGD include thrombosis of abnormal blood vessels, heating and

liquefaction of meibum allowing greater ease of secretion and expression, reduction in epithelial turnover,

local photomodulatory effects, activation of fibroblasts, enhancement of collagen synthesis, and

destruction of Demodex mites.24

Studies evaluating the effectiveness of IPL in the treatment of MGD have reported improvements in lid

margin edema, redness and vascularity,3,53 meibum viscosity53 and secretion quality,3,61 meibomian gland

expressibility,3,61 oil flow scores,53 lipid layer grade,137 tear film osmolarity,24 TBUT,3,24,53,61,136,137 corneal

fluorescein staining, 3,24 and conjunctival injection.3,61 Of note, however, a randomized controlled trial of

28 patients having undergone IPL treatment on day 1, 15, and 45 showed no difference in tear

evaporation rate or tear meniscus height from baseline.22 A recent cohort study of 35 patients comparing

IPL to eyelid hygiene found that IPL induced alterations in meibomian gland structure, with a significant

increase in meibomian gland acinar longest diameter and unit density, as well as a decrease in

inflammatory cells surrounding the glands.145 Furthermore, a randomized controlled trial of 88 eyes

comparing IPL therapy to sham found that after 3 consecutive treatments 4 weeks apart IPL significantly

reduced tear concentrations of IL-17α and IL-6.84 Patients have reported significant improvement in

ocular surface symptoms after IPL therapy.3,22,24,53,61,136,137 A retrospective cohort study of outcomes after

combination therapy with IPL and meibomian gland expression demonstrated a significant improvement

in dry eye symptoms in 89% of 35 patients.137 No serious adverse events have been reported with use of

IPL for treatment of MGD, but redness and swelling have been documented in up to 13% of patients.136

III.3. NEUROSTIMULATION
Intranasal tear neurostimulation makes use of the nasolacrimal reflex, connecting neural pathways from

the nasal mucosa to cellular structures that are involved in tear film maintenance. Pulsed stimulation of

the anterior ethmoid nerve occurring over 3 minutes per day and applied daily for 3 weeks in

experimental animals resulted in an increase in tear volume as well as lipid and protein concentrations,

and a decrease in tear osmolarity.15 A randomized controlled trial in human subjects comparing the

Allergan TrueTear® Intranasal Tear Neurostimulator (ITN) to sham found that the former induced

degranulation of conjunctival goblet cells.52 An open-label, non-randomized study assessing outcomes of

intranasal tear neurostimulation performed at least 4 times a day for 180 days found increased Schirmer

scores, reduced corneal and conjunctival staining, and improved symptoms after treatment.20 Pondelis and

coworkers found that the Allergan ITN changes meibomian gland morphology after 3 minutes of

stimulation, significantly reducing both area and perimeter, suggesting release of meibum.E Furthermore,

Green and colleagues found that, after 3 minutes of stimulation, the device significantly increases tear

meniscus height while maintaining a similar lipid concentration, suggesting an increase in lipid

production as well.F Watson and associates found that use of the ITN significantly increases lower central

meibomian gland temperature as well as the lipid layer thickness, further demonstrating the effect of the

device on meibomian glands.G

IV. CONCLUSION

There are a multitude of studies evaluating the use of various medical treatment strategies and devices in

the management of MGD, but few classify as level I evidence; most of the evidence available for this

review included retrospective and prospective cohort studies. Antibiotics such as tetracyclines and

azithromycin have been shown to effectively decrease signs of eyelid inflammation, but their side effect

profiles are not insignificant and must be considered when prescribing to patients on a case-by-case basis.

Topical cyclosporine A (Restasis®) has proven to be an effective modality for dry eye disease and MGD;

furthermore, Lifitegrast (Xiidra®), although to date only approved for aqueous-deficient dry eye, is a
promising alternative in the treatment of the inflammatory pathways related to MGD. Omega-3

supplementation has been shown to change the lipid properties of meibum and improve signs and

symptoms of MGD. Treatment of Demodex has clear benefits in improving blepharitis and contributes to

improvements in eyelid inflammation. The utility of hormone therapy in treating MGD is still an active

area of research. With regards to more invasive treatments, meibomian gland duct probing has proven to

be an effective measure taken in the office setting but may be limited by time and discomfort. Of the

available electronic heating devices, LipiFlow® is the only one that offers vectored thermal pulsation,

with directional pressure applied to the heated lids in order to further facilitate the outflow of meibum

from the glands. Intense pulsed light therapy offers an alternative route to decreasing the delivery of

inflammatory markers to the lids by targeting telangiectatic vessels and also decreasing bacterial load

around the eyelids. Finally, intranasal tear neurostimulation not only increases tear secretion, but also

stimulates lipid production and the secretion of meibum from meibomian glands. As is evidenced by this

review, there are a host of treatment options available for the management of MGD, each of which must

be catered to the individual patient based on ease of use, level of comfort with the treatment strategy, cost,

side effect profile, and response. Continued efforts to conduct research studies, particularly randomized

controlled trials, are necessary to further establish the role and order of escalation of treatment options in

the management of MGD.

V. LITERATURE SEARCH

This review was compiled using articles identified by searching Ovid MEDLINE from 1946 to the

present. The intention of this review was to provide a literature update on evidence behind medical and

invasive management strategies for MGD based on studies published since the release of the report by the

IWMGD in 2011. Therefore, although some select articles published before this date are included for

historical purposes or in the case where only a very limited number of studies are available on a certain

discussed topic, the review is based primarily on articles published from 2011 onward. An overall search
was conducted using the keywords: “meibomian gland dysfunction treatment”, “meibomian gland

dysfunction management”. In order to ensure that all studies published on the specific treatments

discussed in the review were mentioned, individual searches were conducted for each treatment strategy

using terms for the treatment in combination with the following keywords: meibomian glands, meibomian

gland dysfunction, meibomian gland disease, dry eye syndromes, and posterior blepharitis. The search

terms used for each individual treatment search included: tetracyclin* or doxycycline, azithromycin,

cyclosporin* or Restasis, adrenal cortex hormones or topical* (steroid* or corticosteroid*), interleukin 1

receptor antagonist* or Anakinra or Kineret, sex hormone* or gonadal steroid hormones or

dehydroepiandrosterone or estradiol or anabolic agents or androgens or estrogens or progestins, fatty

acid* or omega 3 or omega 6, mite or Demodex or mite infestations, phototherapy or intense pulsed light

therapy or pulse* light, thermal pulsation or Lipiflow, probe* or probing. All relevant articles in English

were included. Those in languages other than English were considered if English abstracts were available.

VI. ACKNOWLEDGEMENTS

We would like to acknowledge Ms. Risa Shorr, librarian at The Ottawa Hospital, for her assistance with

conducting an extensive literature search.

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