Lifting the lid on dry eye practice – part 5: quantity, quality or both?

Closing Date: 08/05/2017

Ocular examination Ocular disease Options

As a practitioner, whether you are an IP optometrist, optometrist, contact lens optician or dispensing optician, it is fair to say that you will likely spend a significant amount of time during your working week discussing dry eye or dealing with dry eye-related issues; whether you realise it or not. Even our support staff - receptionists, clinical assistants or ‘the otherwise named’ will no doubt occasionally be asked about dry eye by the Great British public. Our pharmacist, GP and ophthalmology colleagues are in a similar boat with swathes of patients seeking their input for a variety of eye related ailments, which can often be attributed, however inaccurately, as dry eye.

Whether you work in a practice with a dedicated dry eye clinic, hospital eye clinic, specialist contact lens practice, high street optical chain, independent optical practice or somewhere in between, dry eye patients pose several challenges to your practice from contact lens drop out, spectacle non-tolerance to simply filling our appointment diaries with at times challenging patients. Such patients, in my opinion, offer us an opportunity to gain a patient for life ¬ a rare commodity these days with so much

competition on the high street. If you take the time to actively listen to the patient’s woes, dust off your anatomy and physiology, flex your diagnostic muscles with a detailed and systematic examination, provide some hand-holding and somehow manage to solve or at least ease their symptoms – or in some cases suffering – such patients become your biggest fan and more importantly a strong and active advocate for your practice. You may even enjoy yourself, finding the process professionally rewarding.

In parts one to four of this series we dealt with neuropathic dry eye (NDE) and evaporative dry eye (EDE), offering an overview of the aetiology of each and providing case histories highlighting some of the treatment methodologies available to us as practitioners. Parts five and six will deal with aqueous deficient dry eye (ADDE), the less common but often more challenging of the ‘big two’.

Function of the tear film

The tear film is the primary interface of the eye, situated between the ocular surface and the outside environment. As has been previously discussed, it plays a critical role in the health and optical performance of the eye. Maintenance of the quality and quantity of the tear film requires a dynamic system, consisting of tear production, tear drainage through the nasolacrimal duct, fluid absorption or exchange through the conjunctival and corneal epithelium, and evaporation to the air.1 An adequate volume of tears is an important prerequisite for a healthy and clear ocular surface.  A reduction in the volume of tears gives rise to a greater propensity for developing signs and symptoms associated with ocular dryness and thus causing a significant disturbance in the optical surface of the cornea.2

Mechanisms of DED

While great emphasis is placed on correctly identifying and sub-dividing the diagnosis of DED into its various forms and providing some insight into the severity to help guide our treatment advice, it is also important to remember the delicate interplay between different forms of dry eye. A clear diagnosis of ADDE or EDE is not always possible. Simultaneous ADDE and EDE cases are not impossible nor uncommon. EDE patients are likely to dominate your clinic, however, cases of ADDE in my experience are often more challenging to treat and involve some of the most visually at risk patients you will encounter.

As way of a massively simplified summary, the following aims to explain the complex interplay of factors that comprise the drivers of DED depicted in figure 1.

Figure 1: Mechanism of dry eye disease

The viscous cycle – a brief overview

The core mechanisms of dry eye are driven largely by tear film hyperosmolarity and tear film instability.3 The cycle of events in figure 1 outlines and highlights the complexity, the interactions and the plethora of factors that can drive DED.  

Tear film hyperosmolarity causes damage to the corneal surface epithelium by initiating a cascade of inflammatory events at the ocular surface, triggering the subsequent release of inflammatory mediators into the tears.4 Corneal epithelial damage involves cell death, as a result of apoptosis, loss of goblet cells and disturbance of mucin expression, leading to tear film instability.5-7 This induced tear film instability in turn exacerbates ocular surface hyperosmolarity, culminating in and completing the viscous cycle.8

Why the symptoms?

DED induced epithelial injury stimulates corneal nerve endings leading to the patient’s symptoms of discomfort, increased

blinking and compensatory reflex lacrimal tear secretion.9 The symptoms are further exacerbated by the increased frictional resistance between the lids and globe as a result of loss of normal tear mucins.10-11

Tear hyperosmolarity

Tear hyperosmolarity is the central mechanism causing ocular surface inflammation, damage, and symptoms, and the initiation of compensatory events in dry eye.12-13 Reduced aqueous tear flow induced by lacrimal failure and/or increased tear film evaporation offer the most likely cause of tear hyperosmolarity.14

Environmental conditions of low humidity and high air flow can cause increased evaporative loss, which can also be caused by meibomian gland dysfunction (MGD).15 The result is an increasingly unstable tear film lipid layer. The impaired delivery of lacrimal fluid into the conjunctival sac causes reduced aqueous tear flow. This can also be induced by certain systemic drugs including antihistamines and anti-muscarinics, but may also be a feature of normal ageing.16 However, inflammatory lacrimal damage, which is seen in autoimmune disorders such as Sjögren’s syndrome dry eye (SSDE) and also in non-Sjögren’s syndrome dry eye (NSSDE), is the most common cause of tear film hyperosmolarity, causing both tissue destruction and neurosensory block.17-20

Reflex block

Various aetiologies may cause dry eye as a result of reflex sensory block, resulting in a loss of sensory reflex drive to the lacrimal gland from the ocular surface.21-24 These include refractive surgery (LASIK dry eye),25-28 chronic use of topical anaesthetics29-30 and contact lens wear.31-37 Cicatricial conjunctival scarring can obstruct tear delivery which, like reflex sensory block, can lead to lower tear delivery.38-40 The chronic surface damage induced by both can lead to reduced corneal sensitivity and thus a reduction reflex tear secretion, this culminates in another vicious cycle.

The overlap – ADDE and EDE

Clinical and anecdotal experience tells us that clinical separation in the diagnosis of ADDE and EDE may in many cases be difficult based on substantive tests. While there are many studies that conclude that, as one would expect, tear evaporation rate is increased in meibomian gland dysfunction (MGD),41-42 in some groups of MGD evaporation rate may be normal.43 The same contradictions can be found within ADDE groups with studies reporting increased evaporation rate44-45 and others reporting decreased evaporation rates.46

Contradictions can also be found in reduced tear flow, a hallmark of ADDE. Numerous studies confirm reduced tear flow in ADDE patients,47 but similar findings have also been reported with MGD patient groups.48 Such contradictions may simply highlight our limited understanding of these conditions, but should also highlight the importance of a systematic unbiased approach to the evaluation of the dry eye patient. There is evidence of reduced or retarded tear film lipid layer spreading in severe ADDE, which has been attributed to the effect of the thinned aqueous phase of the tear film. Is has also been suggested that loss of corneal sensitivity in EDE could reduce the reflex drive to tear secretion and therefore result in a combined form of dry eye. Such interaction occurring over prolonged periods of time may explain the overlap in findings in EDE and ADDE, as explained by figure 1 and the summary above.

Aqueous deficient dry eye (ADDE) – the detail

Aqueous tear-deficient dry eye implies that dry eye is due to the failure of lacrimal tear secretion because of lacrimal acinar destruction or dysfunction, culminating in progressively reduced lacrimal secretion and overall tear volume. As explained earlier this in turn likely causes tear hyperosmolarity. The reasoning behind the change in tear osmolarity is simple – the aqueous evaporates from the ocular surface at a normal rate, however it is evaporating from a reduced aqueous tear pool and therefore leads to hyperosmolarity. ADDE has two major subclasses – SSDE and NSSDE as shown in figure 2.

Figure 2: Aqueous deficiency

Sjögren syndrome dry eye (SSDE)

Sjögren syndrome (SS) is an exocrinopathy in which the lacrimal glands, salivary glands and other organs are targeted by an autoimmune process. The resultant chronic inflammation leads to xerostomia (dry mouth) and keratoconjunctivitis sicca in about 95% of patients.49 The lacrimal and salivary glands are infiltrated by activated T-cells which cause acinar and ductular cell death resulting in hyposecretion of the tears and/or saliva.17,50 This hyposecretion is further fuelled by neurosensory block due to the effects of inflammatory cytokines or as a result of circulating antibodies directed against muscarinic receptors within the glands.51  The frequency of MGD is higher in patients with SS than in the normal population.43 Dry eye syndrome with SS is often more severe than non-SS dry syndrome.55-56 Lack of both basic and reflex tearing resulting from lacrimal gland destruction leads to severe ocular surface staining.57

SS can be sub-divided into two forms; primary SS and secondary SS.52

Primary SS

Primary SS consists of ADDE in combination with xerostomia, the presence of autoantibodies, evidence of reduced salivary secretion and a positive focus score on minor salivary gland biopsy.53

Secondary SS

Secondary SS consists of the features of primary SS in conjunction with overt autoimmune connective disease such as rheumatoid arthritis (the most common), systemic lupus erythematosus, Wegener’s granulomatosis, primary biliary sclerosis, systemic sclerosis, polyarteritis nodosa, scleroderma or mixed connect tissue disease.54

Table 1: Conditions associated with non-Sjögren syndrome dry eye

Non-sjögren syndrome dry eye (NSSDE)

NSSDE is a form of ADDE caused by lacrimal dysfunction with the important distinction that systemic autoimmune characteristics of SSDE have been excluded. NSSDE can be further sub-divided into four sub-categories (as shown in table 1):

  1. Primary lacrimal gland deficiencies
  2. Secondary lacrimal gland deficiencies
  3. Obstruction of the lacrimal gland ducts
  4. Reflex hyposecretion

Primary lacrimal gland deficiencies

This most common of the primary lacrimal gland deficiencies is age-related dry eye (ARDE). Studies have shown significant age-related correlations in tear evaporation, volume, flow and osmolarity,58 with further studies showing an age-related relationship in tear turnover,59 tear evaporation60 and lipid layer.61 An increase in ductal pathology that could promote obstructive lacrimal gland dysfunction has been shown with increasing age in the normal human population.62 Periductal fibrosis, interacinar fibrosis, paraductal blood vessel loss and acinar cell atrophy are all thought to be potential causes, with a study reporting lymphocytic glandular infiltrates in 70% of lacrimal glands studied, this is considered to be the basis of the fibrosis.63 Subclinical conjunctivitis is also suggested as being responsible for stenosis of the excretory ducts. Other less common causes of primary lacrimal gland deficiencies include congenital alacrima64-67 and familial dysautonomia.68,69

Secondary lacrimal gland deficiencies

A number of potential causes of secondary lacrimal gland deficiencies have been reported including lacrimal gland infiltration, sarcoidosis, lymphoma, AIDS, graft vs host disease (GVHD), lacrimal gland ablation and lacrimal gland denervation.  

In lacrimal gland infiltration, lacrimal secretion may be reduced or fail because of inflammatory infiltration of the gland.  Similarly, in sarcoidosis infiltration of the lacrimal gland by sarcoid granulomata70 and in lymphoma infiltration of the lacrimal gland by lymphomatous cells may cause dry eye.71 In autoimmune deficiency syndrome (AIDS) patients, there is a predominance of CD8 suppressor cells, rather than CD4, helper cells leading to DED.72 Dry eye is a common complication in GVHD, occurring around six months after hematopoietic stem cell transplantation as a result of lacrimal gland fibrosis.73,74 Dry eye may be caused by ablation of 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 conjunctiva secretions may compensate in some cases.75 Parasympathetic denervation of the human lacrimal gland may also cause dry eye.76

Obstruction of the lacrimal gland ducts

Obstruction of the ducts of the main palpebral and accessory lacrimal glands leads to ADDE and can be caused by various forms of cicatrising conjunctivitis including trachoma, cicatricial pemphigoid, mucous membrane pemphigoid, erythema multiforme, and chemical and/or thermal burns. In these conditions, conjunctival scarring can also lead to cicatricial obstructive MGD. This effect is seen in trachoma where a combination of tarsal and conjunctival scarring leads to cicatrizing meibomian gland obstruction and trichiasis which causes dry eye as a result of lacrimal obstruction, lid malposition and a deficient tear film lipid later, ultimately leading to corneal opacity and blindness.77 Dry eye caused by lacrimal obstruction, cicatricial MGD, and/or poor lid apposition is also seen in cicatricial and mucous membrane pemphigoid, mucocutaneous disorders characterised by blistering of the skin and mucous membranes, leading to severe and progressive conjunctival scarring.78-80 Conjunctival scarring caused by diffuse chemical and thermal burns, and as a result of erythema multiforme (an acute, self-limiting mucocutaneous disorder usually precipitated by drugs, infection or malignancy) can also all lead to dry eye in this manner.81,82

Reflex hyposecretion

Reflex hyposecretion can be sub-divided into:

  1. Reflex sensory block
  2. Reflex motor block.

A summary of the causes of ocular sensory loss are provided in table 2.

Table 2: Causes of ocular sensory loss

Reflex sensory block

In reflex sensory block, several factors have been shown to be of influence including contact lens wear (hard and extended wear contact lens wear),83 LASIK refractive surgery,84 diabetes mellitus85-88 and neurotrophic keratitis.89 Trigeminal sensory input arising mainly from the nasolacrimal passages and the ocular surface of the eye drives lacrimal tear secretion in the waking state.  When the eye is open increased reflex sensory drive occurs from the exposed ocular surface. A reduction in sensory drive from the ocular surface is thought to cause dry eye by decreasing reflex-induced lacrimal secretion and by reducing the blink rate, therefore increasing evaporative loss.90 The conditions listed above can lead to trigeminal denervation and bilateral sensory loss, thus reducing both tear secretion and blink, and therefore leading to DED.91

Reflex motor block

Damage to the VII cranial nerve leads to dry eye due to loss of lacrimal secretomotor function, resultant lacrimal hyposecretion and lagophthalmos. Multiple neuromatosis and systemic drug use have also been noted by several studies to induce dry eye as a result of decreased lacrimal secretion.92 Drugs including antihistamines, beta blockers, antispasmodics, diuretics, tricyclic antidepressants, selective serotonin reuptake inhibitors and psychotropic drugs have all been linked to dry eye.93

Conclusion

Dry eye is a complex multifactorial disease with symptoms ranging from mildly irritable to severely debilitating. ADDE is in itself a complex and multifactorial condition requiring careful questioning of patient symptoms, ocular health history, general health and medication use, family health and lifestyle to help guide the clinical exam to ascertain an accurate diagnosis. Patients with more serious underlying health concerns may first attend your practice with symptoms of dry eye, therefore it is important that as practitioners we are aware of the myriad of potential reasons for DED and how to identify them.

Keeping a clear and open mind, following a systematic but reactive examination process will better enable a clearer understanding of the route of a patients’ symptoms and therefore how best to treat them. ADDE and EDE should not be considered in isolation but as potentially a continuum or at the very least overlapping condition.
Part six of the series will look at examining the ADDE patient, the treatment options available and will include a case history highlighting both. 

Craig McArthur is involved in a dedicated anterior eye clinic service at Peter Ivins Eyecare practice in Glasgow.

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