The term ‘Dry Eyes’ was first coined in 1950 by the Ophthalmologist Andrew De Roeth (1893–1981): a dacryologist who introduced the term dry eye. For decades it was thought dry eyes was limited to a reduction in the aqueous phase of the tear film. It was as recent as 1995 that dry eyes was eventually recognised as a multifaceted ocular pathology which was due to decreased tear production and increased tear evaporation . In this chapter we will focus on the latter, specifically looking at meibomian gland dysfunction.
An estimate of the prevalence of dry eyes is difficult given that many sufferers may be asymptomatic or dismissive of subjective questionnaires of their symptoms if mild. Various studies estimate the prevalence as between 7.4% to 33.7% [2-3]. The epidemiology of dry eye depends on the mode of diagnosis, population surveyed and study cited.
Large American epidemiological studies estimate symptomatic dry eyes to affect 7% of women and 4% of men over the age of 50 years in the United States . Similar data is seen in Australian studies . The far eastern studies report the largest proportion of dry eye sufferers with Taiwan having the highest at 33.7%  followed by Japan and Indonesia .
2. Meibomian gland dysfunction
The meibomian glands, named after the German physician Meibom in 1966, are specialised sebaceous glands within the eyelids. They number 20-5 on the lower lids and up to 50 on the upper lid. Meibomian glands are responsible for secretion of a lipid rich mixture call meibum onto the tear surface through small openings found on the lid margin. A single gland consists of a central duct linked to multiple acini via ductules. Meibum is loaded into acini and released into the central duct where it moves to the openings on the lid margin and ocular surface. The glands undergo constant renewal and are delicate owing to their holocrine nature.
Diagram courtesy of International Workshop on Meibomian Gland Dysfunction
It is widely thought that reduced meibum quality and quantity in addition to hyperkeratinisation of the ductal epithelium are the main reasons for meibomian gland dysfunction (MGD). Hyperkeratinised ducts and thicker meibum secretions lead to obstruction of the ducts. A progressive increase in pressure from continuous meibum secretion causes widening of the duct, acinar atrophy with cornification of duct epithelia. Ultimately there is reduced meibum secretion and gland drop out causing an unstable tear film. 
The tear film lubricates the ocular surface, which is vital to its maintaining its function and well being. It also forms a vital role in light refraction in the air-tear-cornea interface. Tear film is structured into 3 primary layers: The inner layer comprises mucin and a layer of glycocalyx that is synthesised by the conjunctiva and epithelial cells. The lacrimal gland primarily secretes the middle aqueous layer. The outermost lipid layer is secreted by the meibomian gland. This superficial layer stabilises the tear film by preventing its evaporation. Meibomian gland dysfunction is the most common cause of evaporative dry eye. Left untreated dry eye initially causes irritating ocular surface symptoms and signs that can threaten visual impairment, cause corneal perforation and blindness.
Broadly meibomian gland dysfunction can be defined as a chronic, diffuse abnormality of the meibomian glands commonly characterized by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. It may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease[9-10].
Meibomian gland dysfunction can affect many different groups.
Age is a major risk factor for the development of MGD. It is more common in the elderly. Studies in humans seem to mirror the effects in animals . Decreased acinar proliferation, atrophy and altered localisation of the lipogenesis factor PPARγ (regulates meibomian differentiation and secretion) are seen in mice. Elderly patients have been noted to have a higher rate of meibomian glad dropout [10-11] with half as many functioning glands between 20 to 80 years of age. Human cadaveric studies show gland orifice metaplasia and narrowing [12-13] with hyperkeratinisation and lipogranulomatous inflammatory changes. Additionally meibum composition changes with age yielding a reduced volume and increased viscosity [10-14].
Androgens are known to be integrally involved in differentiation of sebaceous glands all over the body and have been shown to promote genes essential for meibomian function [13-14] Furthermore, complete androgen insensitivity syndrome has been shown to have altered meibomian glands and composition of lipid secretions that resulted in clinically apparent signs and symptoms of MGD [15-16].
Confusingly, chronic blepharitis has been suggested as a cause for MGD. Whilst MGD itself is a cause of chonic blepharitis, there is considerable overlap with other causes of chronic blepharitis that may accentuate MGD. One study showed 74% (42 of 57) chronic blepharitis sufferers had evidence of meibomian gland loss on meibography whereas 20% (4) of matched normal patients had any dropout. More detailed understanding is needed regarding the overlap of MGD with chronic blepharitis [18-19].
Demodex mites are the most common ectoparasites found in human skin. Of this species D.brevis is thought to be the most pertinent in MGD . Current thinking is that the mite burrows deep into sebaceous and meibomian glands to feed on sebum and meibum respectively, as this forms as its main food source. Its chitinous exoskeleton causes a granulomatous reaction which ultimately leads to a mechanical blockage of the gland. D.brevis has been found in the centre of granulomatous meibomian glands surrounded by histocytes, epithelioid cells, fibroblasts and plasma cells which may thus offer a potential explanation for refractory and recurrent chalazia in some patients. 
Contact lens wear can increase the risk of MGD. Studies utilising meibography have shown that contact lenses alter meibomian gland morphology with greater rates of dropout than non-contact lens wearers. The duration and type of contact lens was weakly associated with this. By inserting and removing contact lenses, desquamated epithelial cells have been shown to obstruct the duct orifice leading to stagnation and atrophy [22-23]. While some studies show a statistically significant increase in MGD in contact lens wearers [22-24] others did not show significant differences [25-26]. It is important however to bear in mind these studies defined meibomain gland dysfunction differently. Damage to stem cells at the limbus is likely to be different based on duration on contact lens wear and may help account for the differences.
Environment may play a role in MGD. It is likely that factors such as temperature, humidity and visual undertaking have an accentuating impact rather than develop MGD. For example, concentrated computer use may be associated with reduced blink rate, exacerbating symptoms of MGD. One study of 70 patients found 74% of video display terminal users had MGD . Decreased conjunctival temperature has been suggested to cause obstructive MGD through increased meibum viscosity [28-29].
Various medical conditions have been associated with MGD. Polycystic ovary syndrome (PCOS), where there is often insulin resistance and hyperinsulinaemia can result in increased androgen synthesis. Androgen receptors have been found in meibomian glands with a possible effect on function [30-33]. Twenty two (22)% of PCOS patients had MGD compared to 13% of normals in one study .
Dyslipidaemia appears to be associated with MGD. Patients with moderate to severe MGD have a higher incidence of dyslipidemia with respect to elevated total cholesterol than the general population [35-36]. Higher meibomian cholesterol ester levels are associated with MGD in humans .
Sjorgen’s syndrome has been shown to have a higher incidence of MGD. One study found a higher incidence of MGD in MGD related dry eye to other causes of dry eye. The actual association, whether causative or a consequence of dry eye is not established and further study is needed [38-39]
Multiple medications have been implicated as possible risk factors for MGD. Studies looking at the acne treatment isotretinoin, 13-cis retinoic acid, have found that this resulted in altered meibum secretion, atrophy of the gland, reduced tear break up time and dry eye symptoms [40-41]. Other studies have looked at medication under the umbrella category of dry eye, not specially MGD. There may however be some overlap with MGD. Included in this category are antihistamines. One study has shown that treatment of allergic conjunctivitis with once daily loratidine resulted in signs of ocular dryness [42-43].
Post-menopausal hormone therapy has been associated with MGD [44-47] although the pathophysiology is not fully understood. Whilst established that sex hormone levels change from pre-to post-menopause, it is presumed that PMH results in changes to meibum gland secretions that can lead to MGD. Higher estrogen levels post-menopausally have been implicated in reduced tear function . The largest of the studies, looking at 3500 patients from the Blue Mountain Study has shown a statistically significant 60% higher prevalence of dry eye in PMH users. A longer duration of use has been associated with longer symptoms .
Anitidepressant use has been associated with a higher risk of evaporative dry eye symptoms. Often many such medications simply have visual blurring only as a side effect without any mention of dry eye disease [48-51].
Omega 3 oils have been shown to have a beneficial effect on MGD whilst omega 6 oils have an opposite effect. Both are essential for growth and development. The omega 3 oils are found naturally in Mediterranean diets, flaxseed and cod liver oil . Omega 6 oils are found typically in Northern European diets containing high red meat and less of the above . The most detailed study to date showed a reduction in meibum thickness, dry eye signs and tear break up time in those with a high omega 3 to omega 6 ratio , agreeing with previous findings [52, 54. 55]. These oils compete for an enzyme involved in the inflammatory pathwaytherefore it is the ratio of omega 3 and 6 that is crucial. The ideal omega 6:3 ratio is 4:1 but typical Northern European and American diets are in the realm of 14:1 A higher omega 6 to 3 ratio results in overproduction of pro-inflammatory PGE2 from omega 6 and underproduction of anti-inflammatory PGE1 and PGE3 via omega 3 that induces MGD .
Meibomian gland dysfunction is the leading cause of evaporative dry eye. As such patients will present with dry eye symptoms.
Most patients with MGD are likely to be asymptomatic. The vast majority will not experience any symptoms unless it is moderate in nature or exacerbated by other causes of evaporative dry eye. Burning, irritation, redness, watering or intermittent visual blur are frequently described. It is important to ask what time of day this occurs to try to distinguish from other causes of dry eye. Blepharitis is typically worse in the morning with redness, crusting, puffiness, itchy lids or a ‘gritty sensation’ within the eyes.
5. Clinical assessment
There are different ways to assess meibomian gland dysfunction. Whilst a slit lamp is certainly beneficial and the commonest form of assessment, one can simply use a direct ophthalmoscope for those in primary care settings. Though it does not give as detailed a view the principles are the same as for slit lamp examination. The key is to observe the meibomian glands and ocular surface. With the ophthalmoscope one needs to place on high magnification to view the state of the meibomian glands which are located posterior to the greyline Often orifices can be seen to be plugged, or pouting. Surrounding tissue can be erythematous with telangiectatic vessels. Misdirected eyelashes can also be a sign of eyelid inflammatory changes. A good clinical examination will also include eversion of the eyelids which will often show white, hard deposits called concretions on the tarsal conjunctiva, follicles or granulomatous changes from previous chalazia. The ocular surface should also be assessed. Important to evaporative dry eyes is assessment of the tear film break up (TFBUT). This is done by instilling fluorescein sodium 2% (although 0.25% is an acceptable alternative) and asking the patient to blink a few times. The patient should then be asked to keep their eyes open and careful note of the time taken for vacuoles to appear in the tear film. A normal time frame is 10-15 seconds. The ocular surface should also be noted for punctate epithelial erosions which can be wide-spread or mainly inferior. In severe cases mucous filaments have been noted on the cornea. Abrasions can also be seen in those with associated in-turned eyelashes. The conjunctiva can be injected to varying degrees. As MGD is almost always bilateral, a unilateral presentation must alert the clinician of the possibility of basal cell carcinoma or meibomian cell carcinoma.
There is no universal classification system of MGD. Different approaches have been used. The International Workshop Meibomian Gland subcommittee have recommended categorisation into 4 subtypes, although this is not universally applied.
MGD alone Asymptomatic Symptomatic (noncicatricial, cicatricial)
MGD with associated with ocular surface damage
MGD-related evaporative dry eye
MGD associated with other ocular disorders.
Alternatively, clinical measurement has been described. This is based on lid signs and meibum quality. Meibum can be graded on the Oxford score scale 0-3 (0=clear, 1=cloudy, 2=cloudy/particulate and 3=toothpaste like) .
A common misnomer is that MGD and posterior blepharitis are interchangeable terms [56-58]. Some previous literature has used the terms as such. MGD though, is one cause of posterior blepharitis (inflammation of the lid margins) and must be distinguished from other causes based on the anatomical structures of the posterior lid. Other causes include conjunctivitis (allergic or infective) and dermatological (acne rosacea or sebhorreic dermatitis).
Anterior blepharitis is another differential. This refers to inflammation anterior to the gray line, particularly around the lashes. The gray line anatomically subdivides the anterior and posterior lamellae of the lid. Anterior blepharitis can result in scurf on lashes, collarettes at the lash base and vascular changes of the eyelids.
5.2. Treatment principles
Typically treatment is predominantly based on the general term ‘lid hygeine’, ocular lubricants and antibiotics. There are more recent advances in the field and these are described further below.
Lid hygeine as a method varies across different centres . Currently there is no standardised method. Commonly patients are told to either to place a warm compress over the lids at least twice daily or massage the lids for 10 minutes during each session. Compresses alone have been shown to cause transient visual blurring [60-61]. Active massage is encouraged. MGD secretions have been shown to have higher melting (35 C) points relative to normal (32C) [62-63]. The warmness melts the pathological meibum within the glands and active massage helps to unblock the glands. The authors feel that cotton wool whilst more gentle on the eye is often not firm enough to dislodge meibum that a flannel or towel is able to do. Lid hygeine is made more efficient by encouraging active massage just under the lashes themselves so the patient can directly affect the glands themselves. This needs to be demonstrated to patients directly. By pressing the lateral canthus firmly, traction can be provided and using a flannel the pulp of the finger swept gently over the inner aspect of the upper and lower lids. This needs to be balanced against any possible damage to the ocular and careful explanation and assessment of patient technique needs to be balanced against this [64-65]. The use of mild baby shampoo over the lids has also been advocated as part of lid hygeine. Ultimately patients need to be educated that lid hygiene is the basis upon which MGD will be controlled and that compliance is crucial in not only reducing symptoms but preventing recurrence.
Physical expression of the meibomian glands has been described [66-67]. Methods vary from gentle lid palpation to forceful squeezing of the lids. Use of a finger on the outer lid and a rigid object on the inner aspect like a metal paddle have been reported . Often considerable force is needed to express pathological meibum and transient visual blurring owing to corneal distortion has been reported [60-61]. We believe that the risks involved and potential discomfort from this outweigh any benefit and do not recommend this.
Ocular lubricants are helpful to provide symptomatic relief. They help to alleviate symptoms experienced secondary to evaporative dry eye and do not treat the MGD itself. It is important for patients to realise that they are not a cure but give temporary respite. Ocular lubricants are helpful in bolstering the tear film volume, spreading of tears  and providing a layer over the cornea that reduced the possibility of corneal erosion from friction of the lid moving over the cornea by blinking [70-71]. The ocular lubricants may also help wash away pro-inflammatory molecules and dilute the concentration of inflammatory cytokines in tears. This has not been tested and remains a speculative theory presently.
Much research has been based around the contents of ocular lubricants. Preservatives can cause discomfort and toxicity to the corneal epithelium. Frequently used preservatives like benzylalkonium chloride and polyquaternium have been shown to decrease goblet cell density and thus affect tear film stability [72-77]. There is no evidence nor consensus on frequency of usage. It should be based on an individual level. Preservative free drops are recommended in severe dry eye where high frequency drops are required. More recently so called vanishing preservatives such as sodium perborate or sodium chlorite have been incorporated into artificial tears. There is a lack of data to date to suggest whether these have the intended less preservative toxicity than the traditional preservatives mentioned.
Lipid supplemented tears have been shown of benefit in MGD [79-84]. Patients have reported reduced symptoms with an increased tear break up time and thicker lipid layer of the tear film. Castor oil drops have been shown to reduce tear break up time in a randomised control trial . Temporary visual blurring has been reported in older studies that used ointments but more recent formulations have not been shown to have this problem 
Leading from this is the viscosity of the ocular lubricant. The greater the viscosities the more benefit in bulking tear film thickness and volume in dry eyes [85-87] as well as increased transit time on the eye. This needs to be counterbalanced against visual blurring and inconvenience.
Antibiotics are often used in MGD. The exact pathogenesis of bacteria remains not entirely understood. However the presence of bacterial flora on the lid surface, notably staphylococcus epidermidis, staph aureus, propion acnes amongst others is known. It may be the case that the keratinisation of the meibum and abnormal lipids provide prime conditions for normal bacterial flora to produce enzymes such as lipases and exotoxins resulting in proinflammatory changes. Thus an antibiotic would need to be effective against common flora.
Macrolides are commonly used. Studies have shown that they exert many anti-inflammatory effects. Neutrophil activity is affected by downregulating adhesion protein expression . Phagocytosis and chemotaxis are affected through this. A reduction in proinflammatory cytokines has been demonstrated [89-90].
Tetracyclines have multiple helpful anti-inflammatory properties, including influencing neutrophil chemotaxis and proliferation of lymphocytes [91-92]. Matrix metalloproteinases and inflammatory cytokines like IL1 are suppressed as are anti-angiogenesis properties [93-94]. Collagenase 2 (matrix metalloproteinase P8) is directly suppressed by doxycycline specifically. They have been established for treatment of acne rosacea. Lipase production of the typical bacterial flora such as S epidermidis is suppressed. The lipases are responsible for production of pro-inflammatory free fatty acids that can detstabilise the tear film and directly alter meibum composition. The tetracyclines as a group have varying lipophillicity that alters individual drug pharmacokinetics. The international workshop on meibomian gland dysfunction recommend the use of doxycycline and minocycline . These have been shown to be clinically effective at lower doses relative to tetracycline, which is poorly lipophilic and has been found at lower relative concentrations in tears after 5 days [97-100]. Typically doxycycline or monocycline are given at 100mg dosage for 2 months.
Dietary modification have been popular treatments amongst patients. Omega 3 rich foods as can be found in flax seed or cod-liver oil have been shown to have improved meibum scores, tear break up time and surface signs [100-102]. Omega 6 rich foods such as red meat have a counter effect and should be discouraged .
Surgical management is reserved for complications from MGD. Typically this would occur where the MGD is severe. Chalazia can be treated with incision and curettage where they are inflamed and affecting vision. Eyelid cicatrisation may cause trichiatic lashes that can commonly undergo epilation or electrolysis. Lid laxity, ectropion or entropion may be treated surgically.
Recently, devices have been created to be worn by patients to help with lid hygiene. These include blepharitis goggles, which aim to provide heat and moisture via steam to unclog blocked meibomian glands [103-104].LipiFlow® Thermal Pulsation System is similar but provides heat therapy and physical pressure to express the meibomian glands . These variables can be adjusted accordingly, and seems to offer more favourable outcomes over 12 months than typical lid hygiene and lubricating drops . The evidence base for such devices is currently limited further studies on outcomes and potential side effects are needed.
5.3. Primary care setting
It is understandably difficult to make an unambiguous diagnosis of meibomian gland dysfunction without a slit lamp in primary care or on the ward.
However through careful history of symptoms and possible risk factors mentioned earlier, along with a direct ophthalmoscope on high magnification, an informed judgment can be made. Use of the direct ophthalmoscope does require practice to look at anterior surface structures in detail. Most hand held ophthalmoscopes have a cobalt blue mode, meaning that with available fluroscein drops an evaluation of the tear break up time and state of the corneal surface can be undertaken.
Where MGD is suspected, we would recommend starting lid hygiene, taking care to assess whether the patient is capable of performing this safely without damage to anterior structures. If there is suspicion of anterior surface structure damage from unsafe hygiene measures or possible other causes we recommend referral without starting lid hygiene. Prescribing suitable preservative free lubricating eye drops is recommended before ophthalmic referral.
Meibomian gland dysfunction is the most common ocular sign encountered in patients and cause of evaporative dry eye. Whilst awareness of the condition improves and research continues to be undertaken, a universal consensus on the definition, pathophysiology, signs and management is still being awaited. This is needed to allow for earlier detection and optimal structured treatment for MGD. Further questions do need to be answered regarding meibomian gland dysfunction too. Owing to a lack in consensus over definition and clinical tests performed in studies there is difficulty comparing results in different studies. The International Workshop for Meibomian Gland Dysfunction have suggested future research aim to prioritise a specific validated questionnaire for symptoms, a standard grading system of signs and validated outcomes for MGD . It is hoped this will provide greater clarity in diagnosing, understanding the extent and severity of disease. Ultimately this would allow the most suitable treatment to be started improving the level of patient care in meibomian gland dysfunction.