Spotlight: treatment of dry eyes

The descriptive term ‘’dry eye’’ is used as a global phrase to describe the end results of tear deficiency and dysfunction. An ageing population and rapid advances in the recognition of the pathophysiology and adverse sequelae of untreated dry eye disease have led to an expansion of therapeutic eye drops.

Tears are a vital physiological necessity. All land mammals produce tears to lubricate and to protect their eyes, but humans are probably the only animals to have evolved the ability to generate tears in response to emotional stress.

Charles Darwin felt that certain primates and elephants could produce tears in response to emotions, although it is now generally believed that only humans are able to produce emotional tears. This is believed to be an evolutionary adaptation of our prolonged childhood, where the early vocal crying in infants to attract attention (in common with other mammals) then changes to a silent visual distress signal (tears) in older children, which indicates distress and promotes social bonding. It is not necessarily seen in other mammals because of their relatively short childhoods.¹

The exposed surface of the human eye (cornea/conjunctiva) is prone to dessication (extreme dryness through evaporation of tears), friction and injury from noxious agents, infection and dust particles. Hence, evolution has provided all land animals with tears, which provide a continuous, dynamic and transparent protective film over the vulnerable eye surface. The centrally placed cornea manifests the highest sensitivity in the entire body, with the density of pain receptors in the cornea being 300-600 times greater than the skin and 20-40 times greater than dental pulp.² The cornea has three primary physiological functions; it conducts external light into the eye, focuses it, together with the lens, on the retina, and provides rigidity to the centre of the eye. By the nature of its optical functions, the cornea is transparent and is devoid of any blood vessels. Derived from the ectoderm, which is the outer of the 3 germ layers in the embryo and later forms the epidermis of the skin, the cornea can therefore be considered as transparent skin.³

A continuously secreted and replenished tear film covers the cornea and acts as a conduit for nourishing electrolytes and regulatory molecules, whilst lubricating and moisturising this highly sensitive surface.

Tears are produced and secreted by the lacrimal glands, located on the upper lateral aspect of the upper eyelids. The tear fluid then spreads over the corneal surface, primarily with the blinking movement of the eyelids and also with capillary action. This is the ability of liquids to flow in narrow spaces (such as water in a capillary tube) without the assistance of gravity due to the adhesive forces between the liquid (tears) and the tube walls (lids).

 Figure 1: Tear secreting glands

The natural exit for the tears on the eye surface is through the drainage points, which are the upper and lower puncta on the medial aspect of the palpebral fissure into the lacrimal sac. In addition to the main lacrimal glands, there is a scattering of tiny, accessory, solitary tear secreting glands in the conjunctiva described as the glands of Wolfring and Krause.⁴

 

Tear flow

Three types of tear flow are generated by the main human lacrimal glands:

1. Continuous basal tears
2. Reflex tears due to irritation, foreign body or inflammation
3. Emotional tears in response to emotional stress.

Tear composition

The chemical composition of tears has been extensively evaluated in scholarly studies and shows broadly similar results. The electrolyte content of the basal tears (continuously flowing tears) has been analysed in several studies, as depicted in Table 1. The Potassium content, however, stands out as it is at a much higher level in the lacrimal tears (6-42mmols) than in the plasma (3.5-5mmol). The physiological significance of this has not been adequately ascertained.

 

 

Lipids, mucin, proteins and immunoglobulins

Lipids from the meibomian glands in the eyelid margins and mucin from the goblet cells in the conjunctiva and the corneal surface epithelial cells are incorporated into the aqueous tears from the lacrimal glands and are now recognised as having significant physiological functions on the corneal surface. Numerous types of protein molecules are present in the aqueous tears with several glycoproteins and mucopolysaccharides in the mucin component.

Variations in the composition have been suggested to be due to the different types of tear flow listed above. For example, reflex tears due to inflammation may have a higher content of lactoferrin (a protein with antibacterial and antiviral properties as well as anti-inflammatory effects), lysozyme (an anti-microbial enzyme that causes lysis of bacterial cell walls) and IgA (provides the primary defence mechanism against local infections).⁶

 

The human tear film tends to collapse or ‘break up’ unless it is re-established by a blink

 

Tear osmolality

The basal tears, which are continuously produced, are iso-osmotic, or slightly hypotonic to the plasma. The predominant abnormality of the tears in patients with dry eye disease (DED) is that the tears are hyper-osmolar. The tear osmolality is a measure of the number of osmotically-active particles in a given volume of tears. In normal eyes it is generally less than 312mOsmol, whereas in mild-moderate dry eyes, the osmolality is in the range of 312-323mOsmol and in more established cases it is around 324-344mOsmol or higher. The varied results are due to the technique used (vapour pressure or freezing point) and the calibration process.⁷ Thus, in dry eye states due to increased evaporation of water, the concentration of the residual osmotically active particles increases in the tear film. This hyperosmolality is a key part of the vicious cycle of the pathophysiology of DED. Hyperosmolality causes the dessication of the corneal epithelium and leads to secondary inflammation, causing cell death and desquamation.

In 1946, Wolff developed the “three layer’’ concept of the tear film, and then in 1988 Tiffany suggested a “six layer’’ model for the human tear film.⁸

An authoritative consensus opinion by the TFOS DEWS team (Tear film and ocular surface Dry eye workshop), in its reports published in 2007 and in 2017, considered the three layer structural model and a two layer functional model for the pre-corneal tear film.⁹

The major component of the three layer sandwich is the middle aqueous component with electrolytes, proteins, glucose and enzymes. The basal mucus layer is viscous and offers anchoring to the corneal surface, while the top surface lipid layer offers a seal to prevent evaporation of the water component and gives a low friction surface. It is now accepted that the mucus layer and the aqueous layer form a gel phase with fragments of the mucus molecules in the basal layer being dispersed in the middle aqueous layer, meaning a two layer functional tear film is formed.

 FIGURE 2

The ultimate physiological result of the tear film structure is its ability to remain stable and adherent to the corneal surface. This is measured as TBUT (tear break up time). The human tear film tends to collapse or ‘break up’ unless it is re-established by a blink. This occurs mainly due to evaporation from the tear film, and thus measurement of the time taken for the pre-corneal tear film to break up (i.e. TBUT is an indicator of the ability of the tear film to prevent evaporative losses). This is measured by instilling fluorescein in the eye to stain the tear film and measuring the time taken after a blink for the appearance of the first break in the fluorescein-stained tear film. The TBUT is generally 15-40 seconds in the normal human eye. It is reduced considerably when the tear film is thin or is not adherent to the corneal surface or it evaporates quickly due to an insufficient lipid seal on the surface.

The tear film thickness over the central cornea in a healthy young adult is about 10 micrometres (μm) immediately after blinking and decreases to 4.5 microns in between blinks due to friction and evaporation. Its triple layered structure is as follows (see Fig 2):

1. Top lipid layer 0.1μm (Meibomian secretions)
2. Middle aqueous layer 8-9μm (Lacrimal secretions)
3. Basal layer next to the cornea 0.05μm (Goblet cell secretions).

 FIGURE 3 

Tear film deficiency and dysfunction symptoms

DED is now an accepted terminology. The TFOS DEWS 2 report 2017, redefines dry eyes as: “….a multi factorial disease of the ocular surface characterised by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage and neurosensory abnormalities play etiological roles.”⁹ Damage to the cornea and inflammation causes peripheral nerve dysfunction generating pain symptoms.

Affected individuals may experience eye soreness and irritation, gritty feeling in the eye, redness of the conjunctiva and lid margins, visual blurring, visual distortion and corneal neuropathic pain. The symptom clusters are related to two basic causative clinical types DED:

1. Tear deficiency dry eye (Sjogren’s and non-Sjogren’s, such as systemic drugs with anti-muscarinic effects)  
2. Evaporative dry eye (meibomian deficiency, vitamin A deficiency, lid aperture abnormality, low blink rate, contact lens wear).

Prescribing for dry eye symptoms/DED

This sector of the pharmaceutical industry has shown an expansion of therapeutic eye drops, together with innovative combination drugs and special delivery devices. This reflects the increasing disease burden due to an ageing population and rapid advances in the recognition of the pathophysiology and adverse sequelae of untreated of DED. Eye lubricants and moisturising eye drops and ointments are recommended to patients and general members of the public by a wide range of healthcare professionals, including opticians, pharmacists, nurses and doctors.

The Beaver Dam study in the USA estimated that about 14% of the adult population above the age of 50 years have symptomatic DED. The prevalence in Canada is 25% and in Taiwan and Japan it is 33%.¹⁰

In the UK, NICE has not produced specific prescribing guidelines for DED as yet. One of the obvious difficulties with choosing tear replacement therapy is that no ideal ‘’three component’’ tears exist, and in spite of the vast range of combination eye drops, there is no clear published evidence by way of comparative trials. As a means of making sense of this, primary care clinical commissioning groups in the UK have arbitrarily printed lists of eye lubricants and wetting agents as “first choice,” “second choice’’ and “third choice’’ drugs. In most cases, the cost seems to be the common denominator, rather than the individual merits of the eye drops or the practicalities of their usage.

We do not wish to replicate the BNF (British National Formulary) nor do we wish to produce new flow charts or algorithms. Our focus is on a pharmacologically structured choice so as to encourage general practitioners, pharmacists and optometrists to familiarise themselves with the bio-active ingredients of tear drops and be aware of the various viscoelastic and moisturising agents.

 

Figure 4: Lissamine green staining of desquamated/devitalised epithelial areas of the cornea. The normal, healthy epithelium remains unstained

 

Recommending or prescribing supplementary eye drops or replacement eye drops, requires a reliable screening tool, and in some cases may need specific objective diagnostic tests. There are several validated, reproducible questionnaires that have been published, which can be used as screening tests on the basis of which health professionals could recommend the use of eye moisturising and lubricating medication.

The Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED), designed by Korb and Blackie, has eight items and gives a score of 0-28.¹¹ The sensitivity and specificity for this questionnaire are 0.90 and 0.80 respectively.¹² The Ocular Surface Disease Index (OSDI) is a 12 item questionnaire, with a final score from 0-100, with a score of 0-12 being normal.¹³ The OSDI questionnaire takes up to 5 minutes to complete and the SPEED questionnaire is slightly quicker.  

There are diagnostic tests that are possible in primary care, but these are usually performed in specialist eye clinics. They include the traditional Schirmer’s test for tear flow and eye wetness assessment, which is conducted using an appropriate sterile paper test strip. The eye surface staining tests use vital dyes such as fluorescein or Lissamine Green (see Fig 4), both of which are easily and cheaply available, commercially, as sterile eye drops or as sterile strips of paper impregnated with the dye.

Figure 5: Hand held probe for tear osmolarity test

The Schirmer’s test is only reliable for advanced DED, such as in keratoconjunctivitis sicca and requires some patience and perseverance, but is technically easy. The vital dye tests are quick and give immediate objective evidence of the dry and devitalised areas on the cornea and the conjunctiva. The “vital stains” are a misnomer, as they do not stain the normal healthy tissues in the living state, but offer a negative staining of the devitalised and disrupted epithelial cells. Further biophysical confirmation may be done by using a portable electronic probe for measuring the tear osmolarity (see Fig 5 and 6).

While the tear osmolarity measurement is the gold standard for the confirmation DED, it is not an essential prerequisite for initiating medication to protect the cornea. In the UK, tear osmolarity measuring probes are available with some specialist opticians in the community, whereas most district general hospitals have not invested in this technology and seem to rely on more traditional methods of assessment.

Figure 6: tear osmolarity test toolkit

An overview of the current prescribing data from the Isle of Wight, with a stable population of around 140,000, shows that during the 12 calendar months of January 2017 to December 2017, primary care (GPs) issued 20,849 scripts for eye drops to treat dry eyes at a cost of £82,708. Almost all these prescriptions will be on a long-term repeat list, with more numbers accumulating every year as the awareness and the diagnostic tools improve. In addition to these numbers and costs, a large budgetary spend for dry eye prescribing is from secondary care. For primary care prescribing, one would aim to choose eye drops with the following preferential factors in mind:

1. Visco-elastic agents for the tear film to adhere to the cornea
2. Hydrating agent to moisturise
3. Lubricating agent to reduce eyelid friction
4. Tear surface lipid film to reduce evaporative tear loss
5. Sterile, infection resistant container.

There are other eye drop ingredients which are acceptable, but are not ideal, as they are prone to cause local corneal irritation, deposition or crystallisation in the tear film in some patients. These include:

1. Preservative chemicals (benzalkonium, cetrimide etc.)
2. Phosphates
3. Congealing derivatives of cellulose. (e.g. high strength hypromellose).

In the healthy eye, the human eyes blink rate ranges from 7,000-10,000 per day and the resultant friction is reduced due to a continuous lubricant basal tear flow. The sweep of the “blink” spreads the tear film on the surface of the eyeball, particularly the cornea. This is relevant to pathophysiology and the prescriber should be aware of the shear stress generated at the cornea-lid interface that needs to be adequately lubricated by prescribing drops at appropriate frequency.

Moisturising and lubricating eye drops are listed below as per their essential constituents to assist the prescriber in their choice (note: not all products are listed, please refer to BNF for full list).

 

 

Conflict of interest: None declared

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Dr Rajiv Ghurye
GP
Shanklin Medical Centre,
Isle of Wight

Mr Francisco Alvarez
Community Pharmacist
Sandown Medical Centre,
Isle of Wight

Mr Javeed Khan
Consultant and lead Clinician
St Mary’s Hospital NHS Trust,
Isle of Wight