Fig. 1.1
Etiological classification of dry eye
Aqueous–deficient dry eye is due to lacrimal disease or dysfunction, whereby tear hyperosmolarity is caused by evaporation from a reduced volume of tears. Reduced lacrimal secretion may come about from:
1.
Organic disease of the lacrimal gland, as in Sjögren syndrome
2.
Obstruction to its outflow, as in cicatricial pemphigoid
3.
An interference with the homeostatic mechanism
In the latter case a reflex sensory blockade may be brought about by topical anaesthesia or trigeminal nerve section, and efferent blockade may result from damage to the pterygopalatine ganglion and third-order neurones (Slade et al. 1986). Additionally, lacrimal secretion may be inhibited pharmacologically by certain systemic drugs (Fraunfelder et al. 2012).
There are two major classes of dry eye:
1.
Aqueous-deficient dry eye
2.
Evaporative dry eye
Both lead to tear hyperosmolarity.
Evaporative dry eye results from increased evaporation from the tear film in the presence of a normally functioning lacrimal gland. Since the tear film lipid layer is the major barrier to evaporation from the ocular surface, it is not surprising that Meibomian gland dysfunction (MGD), which causes a deficiency of the tear film lipid layer, is the chief cause of EDE. But evaporation can also be increased by a prolonged blink interval or a widened palpebral aperture, so that these too may cause EDE (Tsubota and Yamada 1992; Tsubota and Nakamori 1995).
MGD is the chief cause of evaporative dry eye.
It is important to recognise that, although the above distinction is clinically convenient, all forms of dry eye are in fact evaporative, since tear hyperosmolarity of consequence can only arise from evaporative water loss.
Tear hyperosmolarity is key mechanism of both aqueous-deficient and evaporative dry eye and, with inflammation, is the primary driver of its pathogenic sequelae.
1.3.2 Homeostasis at the Ocular Surface
Whatever the cause of tear hyperosmolarity, it initiates a homeostatic response which causes an increased sensory drive to the lacrimal gland via the LFU. In EDE, since the lacrimal gland is healthy, this stimulates a lacrimal secretory response that is able to compensate, in some measure, for the rise in tear hyperosmolarity. Ultimately the level of tear hyperosmolarity reached in the steady state would be offset by a greater than normal tear volume and flow. This possibility of a high-volume dry eye is supported by the increased tear secretion (based on the Schirmer I test) in patients with MGD compared to normal (Shimazaki et al. 1995), although this evidence requires support by studies using more sophisticated tests of tear flow.
The same increase in sensory drive from the ocular surface would be expected in ADDE, but because of the basic lacrimal gland insufficiency, the level of osmolar compensation would be less, and in the steady state, this form of dry eye would be characterised by tear hyperosmolarity with a low tear volume and flow (Bron et al. 2009).
Both ADDE and EDE lead to an increased reflex drive to the lacrimal gland. In EDE, the lacrimal gland responds sufficiently to compensate at least initially; in ADDE, it cannot.
As an aside it may be noted that, experimentally, excessive reflex stimulation of the lacrimal gland may induce a neurogenic inflammatory cytokine response within the gland, leading to the sequence of glandular autoantigen expression, T-cell targeting, and the release of inflammatory mediators into the tears (Stern et al. 2004; Beuerman and Stern 2005). It has also been considered to induce a state of “lacrimal exhaustion” due to excessive reflex stimulation of the lacrimal gland (Tang et al. 2000).
1.3.2.1 The Role of the Environment in Dry Eye
Either form of disease is equally susceptible to environmental and behavioural conditions which can increase tear evaporation and raise tear osmolarity. These conditions can therefore exacerbate any form of dry eye or trigger its onset in those who are predisposed. These circumstances arise in everyday life in situations where ambient humidity is low or wind speeds high and are encountered regularly when individuals are exposed to air conditioning and/or high altitude, as during air travel, or in adverse climatic conditions.
Similarly, evaporation is increased by personal factors, which may be looked upon as the internal environment. Thus, tear hyperosmolarity may be induced by an extended blink interval or a widened palpebral aperture, which occur during VDT use, reading, microscopy and the performance of difficult visual tasks which reduce the blink rate, or extended periods with the eyes held up in gaze, as when searching for goods on high shelves in the supermarket or when playing games like snooker. Additionally, systemic drugs which reduce lacrimal secretion are a potential cause of tear hyperosmolarity and may be a risk factor for dry eye (DEWS 2007b-Epidemiology). The relationship between activities of daily living and the symptoms of dry eye disease has been explored by Iyer et al. (2012).
Evaporation may be increased by environmental factors such as:
Wind/air conditioning
Prolonged visual attention, e.g. computer use, reading
Some of these factors play an important part in the symptoms of dry eye that occur in the workplace and affect, for instance, office workers and airline staff. Vulnerability to such exposure may influence suitability for work or the outcome of surgery, such as LASIK. Knowledge of such influences may allow preventative measures to be devised and instituted.
1.3.2.2 Hyperosmolarity: The Proximate Cause Dry Eye
Tear hyperosmolarity is regarded as the central mechanism of any form of dry eye disease, occurring either directly, as a response to reduced tear flow or increased tear evaporation, or indirectly, as a result of tear film instability. Once tear hyperosmolarity is established at the surface of the eye, it gives rise to a vicious circle of events that results, initially, in symptoms and compensatory responses but also in inflammatory responses, chronic ocular surface damage and ultimately in self-perpetuated disease (Baudouin 2007; DEWS 2007a).
Tear hyperosmolarity stimulates a cascade of inflammatory events in the epithelial cells of the ocular surface, involving MAP kinases and NF-kB signalling pathways (Li et al. 2004) and the generation of inflammatory cytokines (IL-1α, IL-1β, TNF-α) and MMPs (e.g. MMP9) (De Paiva et al. 2006). These arise from or activate inflammatory cells at the ocular surface (Baudouin 2001) and lead to reduced expression of glycocalyx mucins, apoptotic death of surface epithelial cells and loss of goblet cells (Yeh et al. 2003). Epithelial cell damage or death is the basis for ocular surface staining in dry eye and is contributed to by loss of glycocalyx mucins, which removes a barrier for dye entry and which also compromises ocular surface wetting (Bron et al. 2015). Goblet cell loss is a feature of every form of dry eye (Kunert et al. 2002; Brignole et al. 2000), demonstrable by conjunctival biopsy and impression cytology and reflected by reduced levels of the gel mucin MUC5AC (Zhao et al. 2001; Argüeso et al. 2002).
Once tear hyperosmolarity is established at the surface of the eye, it gives rise to a vicious circle of events that results, initially, in symptoms and compensatory responses but also to in inflammatory responses, chronic ocular surface damage and ultimately to in self–perpetuated disease
These events contribute to the clinical picture of dry eye in a number of ways, by stimulating sensory nerve endings in the cornea and to a lesser extent the conjunctiva. Symptoms of discomfort can be caused by tear hyperosmolarity, algaesic inflammatory mediators and by increased shear stress imparted during blinking and eye movements with loss of the lubricative goblet cell mucin. Surface damage, and particularly the loss of the epithelial glycocalyx, leads to defective wettability, tear film instability and to a progressive shortening of the tear film break-up time until a point is reached when break-up occurs within the blink interval. This is a potential turning point in the evolution of any form of dry eye, since tear break-up itself initiates a wave of hyperosmolarity which spreads across the corneal surface as the zone of break-up expands and whose peak is located at the origin of the break-up (Peng et al. 2014). The shorter the break-up time, the greater the level of local hyperosmolarity achieved and the longer the period of exposure of the eye to this hyperosmolarity.
Tear break-up in the blink interval is the event which completes the vicious circle in the mechanism of dry eye and perpetuates the disease (Baudouin 2007). Break-up augments hyperosmolar surface damage and, in turn, increased damage causes greater tear film instability; this amplifies the hyperosmolarity and so on. In this way it is thought that dry eye can become a semi-autonomous condition, in which the initiating cause could play a secondary role.
Tear break-up within the blink interval is the tipping point of dry eye. This augments the hyperosmolar surface damage, which then leads to even greater tear instability.
More importantly, stimulation of trigeminal nerve terminals, in addition to causing pain, is responsible for compensatory events in dry eye, acting through the LFU, such as increased lacrimal secretion and blink rate, which tend to offset the development of tear hyperosmolarity (Tsubota 1998). These influence the clinical features of dry eye and are dealt with in a later section dealing with hybrid forms of dry eye.
1.4 An Etiological Classification of Dry Eye (Fig. 1.1)
1.4.1 Aqueous-Deficient Dry Eye
1.4.1.1 Sjögren Syndrome Dry Eye (SSDE)
Sjögren syndrome is an exocrinopathy in which the lacrimal and salivary glands are targeted by a widespread autoimmune process. Other organ systems are also affected. The lacrimal and salivary glands are infiltrated by activated T-cells, which cause acinar and ductular cell death and hyposecretion of tears or saliva. Inflammatory activation within the glands leads to the expression of autoantigens at the surface of epithelial cells (e.g. fodrin, Ro and La) (Nakamura et al. 2006) and the retention of tissue-specific CD4+ and CD8+ T-cells (Hayashi et al. 2003). Salivary gland infiltration ranges from scattered T-cell invasion in mild disease, to diffuse inflammation in severe disease, with B-cells predominating and with progressive loss of glandular tissue. Historically, Th1 cells and their products such as INF ϒ were considered to be the chief instruments of tissue damage, but there is now evidence for a major role for Th-17 cells (T follicular (Tf), Th22 and Treg cells – the IL-17 axis) and their products, especially IL-17, in the salivary and lacrimal glands (Alunno et al. 2014; Zhang et al. 2012). Hyposecretion is amplified by a potentially reversible neurosecretory block due to the effects of locally released inflammatory cytokines or to the presence of circulating antibodies (e.g. anti-M3) (Zoukhri 2006; Dawson et al. 2006). Sjögren syndrome is termed secondary when it is part of a defined autoimmune or connective tissue disorder such as rheumatoid arthritis, systemic lupus erythematosis, scleroderma, primary biliary sclerosis and dermatomyositis. Rheumatoid Sjögren syndrome is the commonest form. Primary Sjögren syndrome is an autoimmune disorder in its own right.
Sjögren syndrome is not uncommonly accompanied by Meibomian gland dysfunction (MGD) which is a potential cause of evaporative dry eye so that the dry eye in these patients may include an interaction between ADDE and EDE (Shimazaki et al. 1998).
1.4.1.2 Non-Sjögren Syndrome Dry Eye (NSDE)
Primary Lacrimal Deficiencies
Non-Sjögren syndrome dry eye (NSDE) is any form of ADDE due to lacrimal disease or dysfunction where systemic autoimmune features, characteristic of SSDE, have been excluded. However, unless otherwise stated, the term NSDE will be used here to refer to age-related lacrimal deficiency (see below).
Congenital Alacrima
Lacrimal Gland Ablation
Dry eye may be caused by ablation of the lacrimal gland at any age or by severance of the ducts, which enter into the superolateral fornix, during lid surgery. Dry eye is not an inevitable outcome, since the accessory glands and conjunctival secretions may compensate in some cases (Scherz and Dohlman 1975).
Age-Related Lacrimal Gland Deficiency
Age-related lacrimal gland deficiency is the commonest form of NSDE and is encountered chiefly in older subjects. In the past it was referred to as keratoconjunctivitis sicca (KCS) (Lemp 1995; DEWS 2007a). With ageing, in the normal population, there is an increasing infiltration of lacrimal glands with CD4+ and CD8+ T-cells, leading to a gradual destruction of lacrimal acinar and ductal cells and a reduction in lacrimal secretion. Histopathologically, a low-grade dacryoadenitis leads to periductal fibrosis, interacinar fibrosis, paraductal blood vessel loss and acinar cell atrophy (Obata 2006). The clinical features resemble those of SSDE, but, in general, its age of onset is later, its rate of progression slower and its severity generally less marked than in SSDE.
Secondary Lacrimal Gland Deficiencies
Alacrima
Alacrima may occur as part of an inherited syndrome.
(i)
Triple A or Allgrove syndrome. Triple A or Allgrove syndrome is a progressive, recessively inherited disorder, in which congenital alacrima is associated with achalasia of the cardia, Addison’s disease, a central neurodegeneration and autonomic dysfunction. It is caused by mutations in the AAAS gene, encoding the protein ALADIN (Brooks et al. 2005; Sarathi and Shah 2010).
(ii)
Familial Dysautonomia (Riley–Day Syndrome). Familial dysautonomia (Riley-Day syndrome) is an autosomal recessive disorder due to mutations in a gene encoding an IkB kinase-associated protein (Gold-von Simson and Axelrod 2006).
Dry eye and corneal damage are major features of the disorder, with a marked lack of emotional and reflex tearing and a loss of sensory innervation of the ocular surface. There is a congenital, generalised insensitivity to pain. Lacrimal dysfunction is caused by a loss of autonomic innervation to the lacrimal gland.
Alacrima can also be associated with blepharophimosis (Athappilly and Braverman 2009), lacrimal-auriculo-dental-digital syndrome (LADD) and Pierre Robin sequence.
Lacrimal Gland Infiltration
In certain systemic diseases, tear secretion may be reduced by other forms of inflammatory infiltration of the lacrimal gland.
(i)
Sarcoidosis. Dry eye is caused by infiltration of the lacrimal gland with sarcoid granulomata (James et al. 1964).
(iii)
AIDS. AIDS-related dry eye is caused by T-cell infiltration of the lacrimal gland, predominantly by CD8+ suppressor cells, unlike the situation in SSDE, where CD4+ helper cells are involved (Itescu et al. 1990).
Graft Versus Host Disease (GVHD)
Dry eye is a common complication of GVHD disease, occurring typically around 6 months after haematopoietic stem cell transplantation (Ogawa and Kuwana 2003). Immune attack is directed to the lacrimal glands and to the whole of the ocular surface. As a result, a complex, combined form of dry eye occurs, with features of both ADDE and EDE and additionally, ocular surface inflammation due to the primary disease itself. Lacrimal gland fibrosis is due to the co-localization of periductal T-lymphocytes (CD4+ and CD8+) with antigen-presenting fibroblasts in the glands (Ogawa et al. 2003). Evaporative dry eye results from cicatricial MGD and is associated with extensive Meibomian gland atrophy and drop-out (Ban et al. 2011).
Lacrimal Gland Duct Obstruction
Obstruction of the ducts of the main, palpebral and accessory lacrimal glands by scar tissue may occur with any form of cicatrising conjunctivitis, causing a secondary ADDE. The scarring process may, in addition, cause a cicatricial form of MGD, so that an evaporative component is added to the dry eye and this may be exacerbated by lid deformity with its consequent effects on aqueous dynamics.
Conditions giving rise to lacrimal duct obstruction include trachoma, cicatricial pemphigoid and mucous membrane pemphigoid, erythema multiforme and chemical and thermal burns.
Reflex Block
This refers to a reduction in lacrimal secretion due to interference with the reflex arc of the LFU. Lacrimal tear secretion in the waking state is maintained by a trigeminal sensory drive arising chiefly from the cornea, probably arising, in particular, from the cold modality sensory fibres. When the eyes are closed, as during sleep, lacrimal secretion is at its lowest, since the sensory input falls to a minimum. When the eyes are open, there is an increased reflex sensory drive from the exposed ocular surface.
(i)
Afferent Blockade. A reduction in sensory drive from the ocular surface is thought to favour the occurrence of dry eye in two ways: first, by decreasing reflex-induced lacrimal secretion and, second, by reducing the blink rate and, hence, increasing evaporative loss in the blink interval. Bilateral, topical proparacaine decreases the blink rate by about 30 % and tear secretion by 60–75 % (Jordan and Baum 1980).
In addition, it has recently been found that tear osmolarity is influenced by the internal environment and reflects the level of body hydration. Thus, plasma osmolarity is increased in patients with dry eye, and increased tear osmolality and, conversely, tear osmolarity is increased in patients with decreased body hydration, a condition that is not uncommon in the aged and may be life threatening (Fortes et al. 2011; Walsh et al. 2012). There is therefore an interest in using tear osmolarity to detect body dehydration, since the measurement of tear osmolality is a quick and reliable test.
(ii)
Efferent blockade. Parasympathetic denervation of the human lacrimal gland may result from a peripheral, VIIth cranial nerve palsy involving the N. intermedius (Tamura et al. 2008), which may, for instance, follow surgery for acoustic neuroma. Since the main palpebral and accessory glands are similarly innervated, there is no opportunity for secretory compensation. Furthermore, since the VIIth nerve palsy causes lagophthalmos, there will be an additional exposure element to the keratopathy due to incomplete or absent lid closure.
1.4.2 Evaporative Dry Eye
Evaporative dry eye results from an excessive rate of evaporation from the ocular surface in the presence of normal lacrimal function. Its causes may be lid–related or ocular surface–related (Fig. 1.1), also referred to as intrinsic and extrinsic EDE, respectively.
1.4.2.1 Lid-Related Evaporative Dry Eye
Meibomian Gland Dysfunction
The Meibomian glands are embedded in the tarsal plates, and their orifices lie just anterior to the mucocutaneous junction. Meibomian oil is delivered onto the skin of the free margin of the lid from whence it is spread onto the surface of the tear film in the up-phase of each blink.
Meibomian gland dysfunction (MGD) is the most common cause of evaporative dry eye (Foulks and Bron 2003; Bron and Tiffany 2004; Bron et al. 2004). It was recently defined at the International Workshop on MGD as follows, and further details may be found in that report (Nichols et al. 2011; Nelson et al. 2011):
Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands, commonly characterised by terminal duct obstruction and/or qualitative/quantitative changes in the glandular secretion. This may result in alteration of the tear film, symptoms of eye irritation, clinically apparent inflammation, and ocular surface disease.
MGD may be primary or secondary to other local ocular or systemic diseases. Cicatricial and non-cicatricial forms exist (Foulks and Bron 2003) (Fig. 1.2). In primary MGD, there is no associated local or systemic disease.
Fig. 1.2
Mechanisms of dry eye
Non-Cicatricial MGD
In non–cicatricial MGD, probably the commonest form of MGD, the terminal ducts are obstructed by a process of hyperkeratinisation and possibly by increased lipid viscosity. The gland orifices remain located in the skin of the lid margin, anterior to the mucocutaneous junction (Jester et al. 1989a, b; Knop et al. 2011). This has therapeutic implications, since, if gland function can be restored, the orifices are in the proper position for oil delivery. Obstruction is accompanied by a thickening and clouding of expressed Meibomian secretions (meibum), which blocks the ducts and may cause plugging of the orifices. Obstruction leads to secondary gland atrophy, which appears as gland “drop out” on meibography. Non-cicatricial MGD most commonly occurs as a primary disorder, seen with increasing frequency after the age of 50 years. It also has multiple secondary associations, including dermatoses such as rosacea, seborrhoeic dermatitis and atopic dermatitis (McCulley and Sciallis 1977; McCulley et al. 1982). Additionally, it should be noted that the retinoid, isotretinoin, used in the treatment of acne vulgaris causes reversible Meibomian gland atrophy, with features of MGD (Fraunfelder et al. 1985; Mathers et al. 1991a). Also, occurring in rare epidemics, systemic exposure to polychlorinated biphenyls, through ingestion of contaminated cooking oils, has caused a chronic disorder with gross and extensive acneiform skin changes, Meibomian seborrhoea with thick excreta and glandular cyst formation (Ohnishi et al. 1975; Fu 1984).
Meibomian gland atrophy is the end result of chronic MGD.
Therefore:
The current MGD guidelines recommend proactive treatment even if minimal symptoms are present to prevent Meibomian gland damage.
Some patients with end-stage MGD and atrophic Meibomian glands may be unresponsive to treatment.
Cicatricial MGD
In primary, cicatricial MGD, duct obstruction is due to an elongation, stretching and narrowing of the terminal ducts and due to a very local conjunctival scarring process in the region of the terminal duct and orifice. As a result, each affected orifice and associated duct is dragged from its position anterior to the mucocutaneous junction into the neighbouring marginal conjunctival mucosa. The key diagnostic feature is the presence of tell-tale elevated ridges in the occlusal mucosa of the free margin of the lid, which represent the dragged terminal ducts exposed under a thinned mucosal epithelium. Cicatricial MGD may affect scattered glands, in the same lid, in conjunction with non-cicatricial MGD (see below).
In non-cicatricial MGD, diagnosis is based on the morphologic features of the gland acini and duct orifices; the presence of orifice plugging, thickening and clouding or absence of expressed excreta. Methods exist to grade the degree of MGD (Bron et al. 1991; Mathers et al. 1991b) and measure the degree of gland dropout (meibography) (Mathers et al. 1991b; Arita et al. 2008, 2010), the amount of oil in the lid margin reservoir (meibometry) (Chew et al. 1993; Yokoi et al. 1999) and the appearance and spreading characteristics of the tear film lipid layer (interferometry) (Yokoi et al. 1996; Goto and Tseng 2003).
Secondary, cicatricial MGD is a more diffuse process caused by conjunctival scarring and occurs in cicatricial conjunctival diseases such as trachoma, pemphigoid, Stevens-Johnson syndrome and after chemical burns. It may also accompany rosacea and vernal kerato-conjunctivitis. The process is more extensive than in primary disease, and the ducts, together with their orifices, are dragged into the tarsal mucosa. In severe disease they may no longer be visible as they are absorbed into the scar tissue. In both forms of disease, even at an early stage when the ducts are still patent, the glands are unable to deliver their oil onto the surface of the tear film.
The Symptoms of MGD
MGD is a symptomatic condition in its own right, which can be associated with a normal tear evaporation rate (Shimazaki et al. 1995). However, with progression of the disease, the degree and extent of obstruction results in a tear film lipid layer deficiency and loss of its barrier function to evaporation (Craig and Tomlinson 1997). Contributing factors are thinning and irregularity of the Tear Film Lipid Layer (TFLL), a reduced spread time with each blink and probably, lipid compositional changes (Foulks et al. 2010). This leads to an increase in tear evaporation rate, which ultimately may cause evaporative dry eye (Mathers 1993; Mathers et al. 1996; Shimazaki et al. 1995, 1998; Goto et al. 2003; Tomlinson and Khanal 2005).
Disorders of Lid Aperture and Lid/Globe Congruity or Dynamics
An increase in palpebral fissure width or globe prominence exposes the tear film to greater evaporation (Gilbard and Farris 1983) and the risk of ocular desiccation and tear hyperosmolarity. In Graves’ disease the effect of proptosis on exposure is compounded by lid retraction and lid lag, incomplete blinking or lid closure and by restriction of eye movements, which plays a part in tear spreading (Yokoi et al. 2014). In normal subjects, increased ocular surface exposure and evaporation also occurs in upgaze (Tsubota and Yamada 1992), so that, as noted, desiccating stress may be imposed in the workplace by activities that demand attention to goods placed on high shelves and in activities such as snooker, where, while aiming, the head is inclined downward and the eyes are in extreme upgaze.
Incomplete lid closure or lid deformity, leading to increased exposure or poor tear film resurfacing, is accepted as a cause of ocular surface drying and occurs with VIIth cranial nerve palsy or after plastic surgery to the lids (Rees and Jelks 1981), but incomplete lid closure of some degree is not uncommon in normal subjects (Himebaugh et al. 2009; Pult et al. 2013). Elevations on the surface of the globe, close to the limbus, may also impair tear spreading and cause localised drying and dellen formation (Kymionis et al. 2011). This may occur in relation to local tumours, chemosis and conjunctival haemorrhage, with filtering blebs, after pterygium, strabismus and cataract surgery and in Graves’ disease.
Low Blink Rate
Drying of the ocular surface may be caused by a reduced blink rate, which lengthens the blink interval and extends the period for evaporation of tears before the next blink (Abelson and Holly 1977; Collins et al. 2006). Reduced blink rate may occur during tasks involving increased concentration, e.g. working at video terminals (Nakamori et al. 1997), with video games, and at microscopes, and also occurs when the eyes are in downgaze, as in reading. It also accompanies the extrapyramidal disorder Parkinson’s disease (PD), where it may be the basis for dry eye and in progressive ophthalmoplegia, where, in addition, the spreading of tears is impaired by a reduction in eye movements. Other contributing factors in PD may be reduced Meibomian oil delivery, decreased reflex tearing due to autonomic dysfunction (Magalhaes et al. 1995), and the effects of androgen deficiency on the lacrimal and Meibomian glands (Okun et al. 2002).
1.4.2.2 Ocular Surface Related Disorders: Extrinsic Causes
Disease of the exposed ocular surface may lead to imperfect surface wetting, early tear film break-up, tear hyperosmolarity, and dry eye. Causes include vitamin A deficiency and the effects of chronically applied topical anaesthetics and preservatives. Contact lenses may be responsible for increased water loss from the eye.
Vitamin A Deficiency
In vitamin A deficiency, (xerophthalmia), dry eye is caused by a reduction in conjunctival goblet cell numbers and a reduced expression of glycocalyx mucins (Tei et al. 2000), leading to an unstable tear film and a reduced tear break-up time. In addition, damage to the lacrimal gland may result in a true aqueous-deficient dry eye (Sommer and Emran 1982).
Topical Drugs and Preservatives
Topical drugs and preservatives can induce an inflammatory response at the ocular surface, leading to dry eye (Rolando et al. 1991). Glaucoma patients, receiving preserved drops on a long-term basis, particularly benzalkonium chloride, are especially at risk (Jaenen et al. 2007). In an unmasked study of 4,107 glaucoma patients, ocular surface changes were twice as common in those receiving preserved drops than in those receiving unpreserved drops, and the frequency of signs and symptoms was dose related but reversible on switching to unpreserved preparations (Pisella et al. 2002). Short-term exposure to preservative can reduce tear film stability and increase epithelial permeability (Ishibashi et al. 2003). In the longer term, the chain of events appears to be that inflammatory events, e.g. signified by increased HLA-DR and ICAM-1 expression, lead to cell damage and apoptotic death and epitheliopathy, including goblet cell loss, reduced MUC5AC expression and poor ocular surface wettability (Baudouin et al. 1999, 2010). Fraunfelder has drawn attention to the multiple ways in which systemic or topical polypharmacy may interact and give rise to dry eye disease (Fraunfelder et al. 2012).
Topical Anaesthesia
Topical anaesthesia causes drying in two ways. It reduces lacrimal secretion by reducing sensory drive to the lacrimal gland (Jordan and Baum 1980) and also reduces the blink rate. Chronic use of topical anaesthetics can cause a neurotrophic keratitis and lead to corneal perforation (Pharmakakis et al. 2002; Chen et al. 2004).
Contact Lens Wear
Chronic contact lens (CL) wear may induce epithelial changes (Knop and Brewitt 1992) and the expression of inflammatory surface markers (HLA-DR and ICAM-1) (Pisella et al. 2001). The effect on goblet cell density (Connor et al. 1994, 1997; Lievens et al. 2003) and mucin expression (Pisella et al. 2001; Hori et al. 2006) has varied in different studies. Nonetheless, about 50 % of CL wearers report dry eye symptoms (Doughty et al. 1997; Begley et al. 2000, 2001), which are about 12 times more likely than in emmetropes and five times more likely than in spectacle wearers (Nichols et al. 2005). Women report dry eye symptoms more frequently than men (Nichols and Sinnott 2006). Dry eye symptoms in contact lens wearers are associated with a higher tear osmolarity, but not in the range normally associated with dry eye tear hyperosmolarity (Nichols and Sinnott 2006). Although there are conflicting reports (Cedarstaff and Tomlinson 1983; Schlanger 1993; Fonn et al. 1999), in general it is accepted that high water content lenses are associated with a thinner tear film lipid layer, a faster tear film thinning time, a higher evaporative water loss and a greater likelihood of dry eye symptoms. Poor lens wettability may also play a part in the increased evaporation. Efron et al. found that patients wearing low-water CLs, which maintained their hydration, were free from symptoms (Efron and Brennan 1988). Conversely, various studies suggest that features compatible with a dry eye state may predispose an individual to CL intolerance (Glasson et al. 2003).
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