Introduction
Meibomian gland dysfunction (MGD) is among the most commonly encountered chronic ocular conditions in clinical practice, and is acknowledged to be a leading contributor of evaporative dry eye disease. The condition is characterized by chronic and diffuse abnormality of the meibomian glands, including terminal duct obstruction and/or qualitative and quantitative changes in glandular secretions. This culminates in alteration of the tear film, clinically apparent inflammation, and ocular surface disease. The associated symptoms of ocular dryness, irritation, and visual disturbance are recognized to have profound impacts on quality of life, visual function, and work productivity.
Anatomy and Physiology
The meibomian glands are sebaceous glands, arranged in a parallel fashion within the tarsal plates and perpendicular to the eyelid margin ( Fig. 8.1 ). There are upwards of 30 glands situated in the upper eyelid and around 25 glands in the lower eyelid.
Each meibomian gland consists of a central duct which is connected to smaller ductules, and multiple acini that are separated from the tarsal tissue by a fine basement membrane. The contents of the acini are released via a holocrine mechanism into the ductules, and then travel through the central duct which opens directly onto the posterior lid margin. Epithelial cells of the meibomian glands or meibocytes are continually produced and migrate toward the center of the acini during maturation, before they degenerate and shed the entirety of their cell contents into the lumen of the ductules. The cell contents comprise lipids, proteins, and nucleic acids, which contribute to the final product secreted by the glands, known as meibum. The secretory force which facilitates the delivery of lipids to the posterior lid margin is driven primarily by the continuous production and migration of meibocytes toward the center of the acnini. The mechanical forces generated by the orbicularis oculi and the muscles of Riolan during blinking compress the tarsal plate and meibomian glands, which further supplements the secretory drive for the delivery of meibomian lipids to the lid margin. In addition, the blinking mechanism also facilitates the distribution of meibum across the ocular surface, where it forms the superficial lipid layer of the precorneal tear film. In contrast to other sebaceous glands distributed throughout the body, which are regulated primarily via hormonal mechanisms, the meibomian glands also receive parasympathetic innervation. This is consistent with the neural supply to other components of the lacrimal functional unit, including the lacrimal and accessory glands and the conjunctival goblet cells.
The surface lipid layer of the precorneal tear film ( Fig. 8.2 ) is formed by the meibomian secretions and fulfills a number of key functions, including inhibition of aqueous tear evaporation, maintenance of a smooth optical refracting surface, and it confers protection to the underlying ocular surface tissues from external debris and pathogens. , The superficial lipids of the tear film comprise two distinct components. An outer hydrophobic layer exposed to the air consists primarily of nonpolar wax and cholesteryl esters, while an aqueous-facing, inner hydrophilic layer contains water-soluble polar lipids, including short-chain and hydroxylated fatty acids, glycosylated lipids, and phospholipids. These are intercalated by lipid-binding proteins, and facilitate the spreading of the nonpolar lipids of the hydrophobic layer over the underlying muco-aqueous phase of the tear film.
Pathogenesis
MGD is a multifactorial condition, which involves complex interactions between a myriad of host, microbial, hormonal, metabolic, and environmental factors. , The current understanding is that MGD and dry eye disease are intricately linked, forming a self-perpetuating double vicious circle ( Fig. 8.3 ).
Obstruction of the meibomian glands is understood to be driven by two key mechanisms, including excess epithelial keratinization of the ductal system and increased viscosity of the meibomian lipid secretions. The susceptibility of the meibomian gland ductal epithelium to excess keratinization is thought to be attributable to the similar embryological origins to the eyelash follicles. In addition, the pathophysiological effects associated with aging, hormonal imbalance, medication use, and other exogenous factors are also believed to contribute to the release of intrinsic physiological inhibition of keratinization and the aberrant differentiation of progenitor cells. Concurrent changes in lipid composition of meibum can lead to increased melting points and greater viscosity of the gland secretions, thereby further contributing to blockage of the ductal system. Overall, these pathophysiological changes culminate in diminished delivery of meibum to the lid margin and tear film, leading to excessive aqueous tear evaporation, and initiation of a vicious circle of tear film instability, hyperosmolarity, ocular surface epithelial damage. The subsequent loss of tear film and ocular surface homeostasis and the resulting inflammatory responses can then trigger further excess keratinization of the meibomian gland orifices. ,
Ductal obstruction and meibum stasis can also lead to intrinsic changes to the meibomian glands that further perpetuate the double vicious circle of MGD and dry eye disease. , Stasis of the meibomian lipids within the ductal system can lead directly to increased viscosity, thereby exacerbating pre-existing obstruction of the ductal system. Blockage of the meibomian gland orifices in combination with continuous secretory activity within the acini culminates in progressive increase in the intraluminal pressure of the meibomian glands. The prolonged exposure to higher intraluminal pressure can, in turn, induce activation of the ductal epithelium which exacerbates keratinization. In addition, chronic elevation of pressure can also lead to ductal system dilation, structural atrophy of the acini, and ultimately meibomian gland dropout, which further diminishes the secretion and delivery of meibum to the tear film. , Meibum stasis also predisposes toward the overcolonization of commensal bacteria, present on the lid margin and in the meibomian glands, that secrete a variety of lipid-degrading enzymes, including lipases and esterases. The resulting degradation of meibomian lipids and release of toxic mediators and free fatty acids induces further destabilization of the tear film. Ensuing inflammatory responses involving the ocular surface, lid margin, and meibomian glands then further exacerbate excess keratinization. , ,
Epidemiology
There is considerable variation in the prevalence estimates for MGD reported in the current literature, which is likely attributed in part to the methodological heterogeneity and differences in disease definition used in existing epidemiological studies. , The global consensus Tear Film and Ocular Surface Society (TFOS) International Workshop on Meibomian Gland Dysfunction reported that the prevalence of MGD varies from 3.5% to 70% in different parts of the world, while another meta-analysis reported a pooled prevalence estimate of 36% among population-based studies. A summary of population-based studies assessing the prevalence of MGD is presented in Table 8.1 .
| Study | Location | Age Group, Years | Sample Size | Prevalence (95% CI), % |
|---|---|---|---|---|
| Craig et al., 2020 | Dunedin, New Zealand | 45 | 885 | 7.3 (5.8–9.3) |
| Han et al., 2011 | Yongin, South Korea | ≥65 | 139 | 51.8 (43.6–59.9) |
| Hashemi et al., 2017 | Shahroud, Iran | ≥45 | 4700 | 26.3 (24.5–28.1) |
| Hashemi et al., 2021 | Tehran, Iran | ≥60 | 3284 | 71.2 (68.3–74.1) |
| Jie et al., 2009 | Beijing, China | ≥40 | 1957 | 68.0 (65.6–70.4) |
| Lekhanont et al., 2006 | Bangkok, Thailand | ≥40 | 550 | 46.2 (42–51) |
| Lin et al., 2003 | Taipei, Taiwan | ≥65 | 1361 | 60.8 (59.5–62.1) |
| McCarty et al., 1998 | Melbourne, Australia | ≥40 | 926 | 19.9 (17.4–22.7) |
| Schein et al., 1997 | Salisbury, Maryland, US | ≥65 | 2482 | 3.5 (2.8–4.4) |
| Siak et al., 2012 | Singapore | 40–80 | 3271 | 56.3 (53.3–59.4) |
| Uchino et al., 2006 | Chiba, Japan | ≥60 | 113 | 61.9 (52.1–70.9) |
| Viso et al., 2012 | O Salnés, Spain | >40 | 619 | 30.5 (27.0–34.3) |
In recent decades, there has been a growing interest in the epidemiology of MGD, on account of the potential to inform targeted screening and risk factor modification strategies in clinical practice. Systemic and ocular risk factors of MGD that have been identified to date are summarized in Table 8.2 . ,
| Systemic Risk Factors | Ocular Risk Factors |
|---|---|
| Aging Antidepressant therapy Antihistamine therapy East Asian ethnicity Androgen deficiency Atopy Benign prostate hyperplasia Cicatricial pemphigoid Complete androgen-insensitivity syndrome Discoid lupus erythematosus Ectodermal dysplasia syndrome Hematopoietic stem cell transplantation Hormone replacement and contraceptive therapy Hypertension Isotretinoin therapy Menopause Migraine headaches Parkinson’s disease Pemphigoid Polycystic ovarian syndrome Psoriasis Rosacea Sjögren’s syndrome Stevens–Johnson syndrome Thyroid disease Toxic epidermal necrolysis Turner syndrome | Aniridia Anterior or posterior blepharitis Contact lens wear Eyelid tattooing Floppy eyelid syndrome Giant papillary conjunctivitis Ichthyosis Incomplete blinking Salzmann nodular degeneration Ocular Demodex infestation Trachoma |
Aging is one of the most consistently identified risk factors for MGD. , Indeed, advancing age is associated with an increased frequency and severity of anatomical changes in lid margin architecture, keratinization, vascularization, and telangiectasia being reported. This is accompanied by a clinically apparent decline in the quality and quantity of gland secretions, as well as alterations in the lipid profile on laboratory analysis. , Nevertheless, the etiological drivers underlying the association between aging and MGD remain yet to be fully understood, and are thought to involve cumulative lifetime exposure to a combination of environmental and physiological factors, that lead to changes in hormonal regulation, neurosensory pathways, and ocular surface homeostasis. , The higher prevalence of MGD in postmenopausal women, as well as patients with androgen deficiency, would also appear to corroborate the role of hormonal regulation in the development of MGD. ,
The increased prevalence of MGD among the East Asian ethnic group has also been consistently highlighted by a large number of epidemiological studies. , , , The propensity of the East Asian ethnic group to the development of MGD is thought to be partially attributed to anatomical differences, including greater axial length and the more inferior attachment point of the levator palpebrae superioris aponeurosis, which contributes to increased eyelid tension and incomplete blinking. These factors, in turn, appear to promote stasis of the meibomian secretions and lead to accelerated gland dropout.
Contact lens wear is also a common risk factor for the development of MGD and evaporative dry eye disease. , Meibomian gland dropout and atrophy have been reported to occur with greater frequency and severity among contact lens wearers, although the underlying pathophysiological mechanisms remain yet to be established. , In addition, contact lens wear can also destabilize the structural integrity of the superficial lipid layer, predisposing toward excessive aqueous evaporation from the precorneal tear film. , ,
Diagnosis and Assessment
Evaluation of MGD involves two main components, including assessment of meibomian gland morphology and function, as well as clinical signs and symptoms of secondary dry eye disease. The recent global consensus Tear Film and Ocular Surface Society Dry Eye Disease Workshop II (TFOS DEWS II) recommends that diagnostic assessment for dry eye disease occurs prior to the subtype classification testing for potential underlying etiological drivers, such as aqueous tear deficiency and MGD.
Dry Eye Disease Diagnosis
The global consensus TFOS DEWS II criteria for dry eye disease is summarized in Table 8.3 , and mandates the presence of both subjective symptoms and clinical signs before a diagnosis of dry eye disease can be confirmed. The validated symptomology questionnaires of choice includes the 5-item Dry Eye Questionnaire (DEQ-5) and the Ocular Surface Disease Index (OSDI), with a positive symptom score requiring either a DEQ-5 score ≥6, or an OSDI score ≥13. , Clinical signs of ocular surface homeostatic disturbance can be confirmed by positive scores in noninvasive tear film stability (breakup time <10s), tear osmolarity (absolute measurement in either eye ≥308 mOsm/L, or interocular difference of >8 mOsm/L), or ocular surface staining (corneal staining >5 spots, conjunctival staining >9 spots, lid margin staining ≥ 2 mm length and ≥25% width). Automated objective noninvasive measurements of tear film break-up time are preferred, such as those obtained from the Oculus Keratograph 5M ( Fig. 8.4 ) or Medmont E300, although subjective measurements using clinical devices such as the EasyTearView +, Polaris, and Tearscope, can be used as an alternative. The instillation of aqueous sodium fluorescein is recognized to destabilize the tear film and artificially shorten break-up time measurements, and should therefore be considered only when noninvasive instruments are unavailable. Excess fluid should be shaken off wetted fluorescein strips prior to application to ensure that minimal amounts are instilled. ,
| Component | Criteria |
|---|---|
| Dry eye symptoms |
And |
| Dry eye signs | One of the following:
|
Tear osmolarity is most commonly assessed using the TearLab osmometer in the clinical setting, and measurements from both eyes are required to provide absolute measurements and calculate interocular variability. Following instillation of both sodium fluorescein and lissamine green dyes, corneal, conjunctival, and lid margin staining ( Fig. 8.5 ) are assessed by slit lamp biomicroscopy, ideally with use of a yellow barrier filter to optimize visibility of the fluorescein staining. ,
Aqueous Tear Production Assessment
Following confirmation of a diagnosis of dry eye disease, as described, subtype classification testing to evaluate the underlying etiological drivers, including aqueous tear deficiency and MGD, can be helpful for guiding subsequent management. The rate of tear flow is not typically affected in MGD, and therefore assessment of tear production can be helpful in differentiating purely aqueous deficient dry eye disease, from evaporative or mixed etiology dry eye disease.
Noninvasive tear meniscus height measurement ( Fig. 8.6 ), with a diagnostic threshold of <0.2 mm, is the recommended diagnostic test for aqueous tear deficiency, while invasive methods such as the Schirmer and phenol red thread test are less preferable and exhibit poorer reliability and repeatability.
Meibomian Gland Dysfunction Workup
Assessment of lid margin morphology, meibography, and gland expression is integral for the diagnostic workup for MGD, while the evaluation of the tear film lipid layer interferometry is also recommended, where possible, as a sensitive marker of meibomian gland function. , ,
Lid margin morphology can be assessed by slit lamp biomicroscopy ( Fig. 8.7 ), and signs typically associated with MGD are summarized in Table 8.4 . Lid margin irregularity and notching occur secondary to meibomian gland dropout and loss of tissue, and can be accompanied by a scalloped appearance of the tear meniscus. Hyperkeratinization can also be detected, where keratinized tissue encroaches on the normally smooth and nonkeratinized lid margin mucous membrane.
| Lid Margin Signs |
|---|
|
Retroplacement or a posterior shift of the mucocutaneous junction can also be observed in some cases ( Fig. 8.8 ). Less commonly, the positions of the meibomian gland orifices can shift with squamous metaplasia or become obscured by keratinized epithelium, while anteroplacement is a relatively rare finding. A reduction in the number of meibomian gland orifices, or the formation of hard-surfaced oil domes capping the orifices are also common signs. Chronic cicatrization of the surrounding submucosal tissue can lead to distortion of the gland orifice shape from round to oval, while narrowing and loss of definition of the orifices and the development of surrounding telangiectasia are also frequently observed.
In vivo visualization of meibomian gland morphology can be achieved through noncontact infrared meibography ( Figs. 8.1 and 8.9 ), following eversion of the superior and inferior eyelids in turn, using instruments such as the Oculus Keratograph 5M or Johnson & Johnson Vision TearScience LipiView. , A number of morphological features, including gland dropout ( Fig. 8.9 ), shortening, dilation, and tortuosity can be assessed. Meibomian gland dropout is commonly graded subjectively using the qualitative meiboscore ( Table 8.5 ), or using objective quantification methods by image analysis software that calculates the proportion of the area of tarsal conjunctiva devoid of visible glands relative to the total area.
