The correct diagnosis and therapeutic management of tear dysfunction: recommendations of the P.I.C.A.S.S.O. board

Tear production decreases with age due to the progressive involution of the lacrimal glands and nerve activities that regulate them. The continuous and consistent decrease in basal tear secretion and the resulting eye irritation often lead to an excessive production of reflex tears [2].

In women aged between 40 and 60 years, the secreting portion of lacrimal glands undergoes progressive atrophy due to the new hormonal balance induced by menopause. Moreover, after menopause, androgen/oestrogen imbalance leads to the loss of control over inflammation typical of the androgenic component. Oestrogenic activity, which facilitates inflammation, can occur more easily [2, 16].

High altitude with increased UV exposure, sunny, dry, or windy weather conditions, environments with operating heating or air conditioning systems, increase tear evaporation and oxidative stress, thereby reducing eye lubrication [2].

Their use can increase tear evaporation significantly, causing irritation and infections. Corneal lens disinfecting and lubricating solutions can alter the lacrimal gland and tear production. Moreover, if the eye is not lubricated enough, the lens tends to adhere to the cornea, causing damage, which can be serious (abrasion, keratitis) [2, 17].

Some drugs (hormones, immunosuppressants, decongestants, antihistamines, diuretics, antidepressants, beta blockers, heart disease- and ulcer-treating drugs) can inhibit the production of efficient tears [2].

With age, the number of drugs administered systemically increases. As we have seen, many of these drugs can interfere with tear production (Tables 3, 4).

A fundamental step in taking a medical history is to try to know which drugs have been administered systemically, because every agent that can interfere with one or more tear film components (lipids, water, mucins) can disrupt the stability of the tear film and cause or worsen the typical dry eye symptoms. Physician’s Desk Reference reports that 56% of the top 100 drugs sold in the USA in 2009 can cause eye dryness and 22% has a proven negative effect on tear secretion [18].

With age, there is a significant reduction in tear secretion associated with an increase in the number of systemic medications. After a while of taking drugs for other intercurrent diseases, these patients will start manifesting the typical signs of dry eye, while patients who already suffered from eye dryness will see their symptoms worsen [2, 19‐23].

Most of these preparations lead to eye dryness through an anticholinergic mechanism. In fact, they compete with acetylcholine in the postsynaptic muscarinic receptor in the peripheral and/or central nervous system, thereby blocking the acetylcholine-induced stimulation of lacrimal gland and conjunctival muciparous goblet cell secretion.

The corneal epithelium plays an essential role in the ocular surface system (OSS) because it maintains ocular fluid homoeostasis and contributes to the tear film through the active secretion of water.

The air–tear film interface is the most important refractive surface, and the precorneal ocular surface is responsible for 2/3 of the total refractive power.

Surgery can cause tear film instability, with consequent uneven spreading across the ocular surface. This involves light deflection/scattering with the formation of a blurred image on the retina, which translates into poor visual performance.

As described in a recent publication by Baudouin et al. [40], tear film instability is one of the steps in the vicious circle of ocular surface dysfunction.

In particular, it involves tear hyperosmolarity, which is responsible for cell damage with apoptosis of conjunctival and corneal cells. It also triggers an inflammatory cascade, which further contributes to cell death, including mucin-secreting cells. These alterations worsen tear film instability and trigger a cycle of events that perpetuate the condition (Fig. 3).

Tear film alterations, with resulting epithelial suffering and inflammation, involve central and peripheral neuronal suffering. In particular, peripheral neuronal suffering reduces sensitivity, whereas central neuronal suffering is associated with deafferentation dysaesthesia [41].

The onset of symptoms and TD are consequences of this neuronal suffering.

There is also a characteristic timing in the onset of ocular discomfort symptoms, which get worse approximately one month after the surgery when postoperative anti-inflammatory eye drops are suspended [42].

All this is amplified if the patient has TD even before surgery. In such cases, the test scores return to their initial values approximately 3 months after surgery.

Therefore, it is essential to identify the patients who are at risk of developing this syndrome to prevent the onset of discomfort symptoms [43‐45].

There are numerous clinical conditions and iatrogenic factors that need to be evaluated before directing a patient to anterior segment surgery.

Predisposing conditions that may suggest the development of postoperative complications are the following: advanced age, corneal dystrophy (especially basal membrane dystrophy, which is often not diagnosed), TD, blepharitis, ocular surface inflammation even if not particularly evident, such as in the case of patients wearing contact lenses, or with pseudoexfoliation syndrome, uveitis, eyelid malpositions, use of systemic therapies that can influence tear secretion, use of topical medications that can alter the qualitative composition of the tear film, subepithelial corneal nerve plexus dysfunction and of course a pre-existing TD as well as systemic diseases, such as diabetes and rheumatologic diseases [9, 19, 46‐48].

As for preoperative medications, it is important to consider that systemic drugs can interfere with ocular surface homoeostasis, whereas topical drugs may contain chemical preservatives (detergents), which damage the permeability of the cell membrane and the cytoplasmic content, or oxidising preservatives, which pass through the cell membrane and can interfere with cell functions [49].

At low doses, oxidising preservatives are less dangerous than detergents because the eukaryotic cells produce antioxidant enzymes [50, 51].

Many pre- and postoperative eye drops contain surfactants, which alter the goblet cells and disrupt lipid layer stability. In particular, benzalkonium chloride leads to a glycocalyx alteration already 30 min after its first instillation. Its action is prolonged because the average half-life of this preservative in the conjunctiva is approximately 12 h [52]. Therefore, it is essential to use eye drops without preservatives in the preoperative prophylaxis and improve lubrication using preservative-free tear substitutes during the postoperative period.

Surgical factors (both pharmacological and those related to the surgical technique) are also important. In cataract surgery, for example, it is important to consider the epithelial toxicity of local anaesthetics and disinfectants, such as 5% povidone–iodine.

Moreover, the application of the ocular speculum can cause trauma to eyelid muscles (weakening of the orbicularis muscle) and tissues, which can lead to incomplete blinking and loss of congruence between palpebral and bulbar conjunctiva, as well as floppy eyelid syndrome. Therefore, it is essential to use non-traumatising ocular speculum and avoid “over-tensioning” eyelid opening.

Similar conditions to those observed in cataract surgery occur in the postoperative period of a corneal transplant (due to the unevenness resulting from the suture) and in retinal detachment (both ab externo and ab interno), which leads to the significant remodelling of part of the conjunctiva.

Central epithelial damage is quite frequent in transplant patients due to the poor lubrication of the corneal surface, which has lost sensitivity due to innervation damage. As a result, it undergoes blinking-induced erosions, especially in the event that slightly tight sutures have flattened the surface.

The association of reduced lubrication with an inflammatory state demonstrates the importance of lubrication. In fact, TD in the form of excessive tear evaporation is the most frequently undiagnosed and underestimated cause of ocular surface inflammation. In the event of a corneal transplant, the inflammatory state of the ocular surface will result in the activation of antigen-presenting cells on the ocular surface with transplant rejection [53, 54].

In patients undergoing glaucoma filtration surgery, it is important to prevent the closure of the bleb. Moreover, dry eye can be observed in these patients, and lissamine green staining highlights areas of epithelial damage above the bleb. TD is associated with inflammation and, as a result, fibroblast recruitment. Therefore, it is essential to lubricate the ocular surface to reduce inflammation so preventing fibrosis and the formation of adherence between the conjunctiva and the sclera.

As for photorefractive surgery, both PRK and LASIK determine a significant damage of corneal nerves so inducing altered sensitivity and innervational problems. These trigger compensatory mechanisms that lead to the onset of important symptoms. Postoperative discomfort symptoms can be compared to nerve deafferentation, similar to the condition that occurs in neuropathological or neurosurgical lesions. Residual nerve fibres mediate dysaesthesia, resulting from partial peripheral lesions with loss of small afferent fibres. Pathological pain can be a problem in these patients, because the surgery causes the release of PGE₂ and PGI₂, which determines a sensitisation characterised by a reduced activation threshold, increased response to certain stimuli, and onset of spontaneous nociceptor activity. This sensitisation can manifest itself as hyperalgesia (i.e. an enhanced nociceptive response to certain noxious stimuli) or allodynia (i.e. sensitisation to pain in response to previously non-noxious stimuli). In these cases, the clinical picture, characterised by the typical ocular surface changes, does not justify the symptoms reported [41].

Today, it is known that the corneoconjunctival epithelium is not an inert tissue. In fact, it synthesises proinflammatory cytokines (interleukins and metalloproteases), or molecules that attract immunocompetent cells from the peripheral blood, thereby creating a lymphocyte homing process, which maintains the inflammatory state on the ocular surface.

Being a multifactorial condition, the preventive/therapeutic approach should be dynamic and try to identify the dominating mechanism at each follow-up to define a suitable treatment that aims at correcting the inefficient mechanism [43, 55].

In particular, the following can be very useful: eyelid hygiene in patients with meibomian gland dysfunction, avoiding the use of eye drops with vasoconstrictors, adopting (if possible before the surgery) a therapy with a tear substitute that acts on tear instability, epithelial damage and inflammation (vicious circle) and continuing it during the postoperative period [38, 44].

HA is a mucopolysaccharide with a molecular weight ranging between 2 × 10⁵ and 10 × 10⁶ D. It is composed of repeating disaccharide units forming a highly negatively charged polymer, which can bind large amounts of water. This polymer has rheological properties characterised by non-Newtonian behaviour, i.e. it is provided with high viscosity, which quickly decreases when forces that determine a quick displacement are applied. This is what happens when eyelids close during a blink. This rheological property is very similar to that of normal tears. HA is present on a normal ocular surface, having been found in tears, glycocalyx, at the interface between cells and the basal membrane of the conjunctival epithelium, corneal epithelium, stroma, keratocytes, and in lacrimal gland acinar cells [57, 58]. Moreover, it has been proven that the CD44 receptor for HA is found in the cornea always closely associated with HA, thereby demonstrating the role played by this combination of molecules in modulating adhesion, growth and migration of corneal epithelial cells [57].

It has been demonstrated that the use of HA in dry eye therapies can improve the ocular surface significantly by increasing tear film stability, improving the condition of the corneoconjunctival epithelium, reducing squamous metaplasia and promoting the reappearance of muciparous goblet cells in the conjunctival epithelium [59, 60]. The HA formulation can vary and depends on the molecular weight and concentration used. The molecular weight can also depend on the origin of the molecule, i.e. from rooster comb extraction, bacterial fermentation, or chemical synthesis. The last one can reach an extremely high molecular weight, thanks to the cross-linking technique, which results in a group of molecules called hyalans [57]. The formulation of HA eye drops chosen must be based on the conditions of the ocular surface, in order to restore the normal tear film as far as possible and obtain the best possible microenvironment for the efficient repair of damaged structures [60].

On the other hand, if the inflammation is clinically evident, it is probably due to an initiating stimulus that can alter ocular surface homoeostasis: environmental stress (UV-ROS, chemicals), alterations in the tear film compositions secondary to lacrimal gland inflammation, pathologic changes of neural traffic, hyperosmolarity, microtrauma from eyelids during blinking are the most recognised. These factors could play a role in inducing loss of ocular surface immunohomoeostasis and triggering Dry Eye Disease. This must be worked out in the case of evident epithelial suffering and must begin with a corticosteroid treatment to allow the regression, as quickly as possible, of the production of proinflammatory substances. The molecules used must have medium power and, preferably, a composition that reduces their penetration into the anterior chamber, in order to reduce, as much as possible, intraocular side effects such as increased intraocular pressure and onset of cataract. With this aim, molecules with lipophilic or fluorinated residues are to be preferred [61].

Today, corticosteroids can be associated with cyclosporine, a drug that has been recently introduced in the European market. Its immunosuppressive effect combats the activity and recruitment of T lymphocytes and inhibits apoptosis. It is important to consider that the clinical effectiveness of cyclosporine begins to manifest 2–3 months after administration. Therefore, it is important to start the anti-inflammatory treatment administering corticosteroids and cyclosporine together to obtain a rapid response to the treatment and maintain long-term results with cyclosporine alone, which is less exposed to the onset of side effects [62].

Also omega-3 fatty acids can help reduce the production of proinflammatory substances. In fact, they protect tissues from the inflammatory insult, thanks to the competitive inhibition of prostaglandin E₂ production, and the production of metabolites known as resolvins, which block the inflammation by inhibiting immunocompetent cells [63].

The third pillar of dry eye therapy is the epithelium protection. Nowadays, the conditions of the epithelial cells can be improved not only by intervening on the quality of the tear film but also by supplying substances that can protect the cells from degenerative processes, which trigger the production of proinflammatory and proapoptotic cytokines [40]. It has been demonstrated that some molecules are particularly effective in protecting the epithelium. Among these, trehalose has drawn particular interest in ophthalmology, as several studies have shown that it helps improve the treatment of ocular surface disorders.

This molecule is synthesised by several types of cells as a response to stress represented by extreme cold, hot, oxidation and dehydrating conditions. In particular, trehalose is synthesised by bodies as a reaction to water-deficit stress. In fact, it promotes anhydrobiosis, i.e. the ability to resist water deficit and drought. This molecule is characterised by high stability. Its behaviour when exposed to heat is particularly interesting. It first melts at 97 °C; then, with a further increase in temperature, it chrysalises. It resolidifies at 130 °C and then melts again at 203 °C.

Trehalose preserves the integrity of the cells and their intracellular organelles through multiple mechanisms, which are not yet fully known [64].

In this regard, there are three theories:

The bioprotective effect of trehalose in ocular surface alterations results from the preservation of the integrity of proteins and lipids, protection against oxidative and osmotic stress, and against hypoxia and anoxia and, consequently, from apoptosis-induced cell death.

As for the preservation of the integrity of proteins and lipids, trehalose maintains their configuration by binding with proteins. This explains the protective effect against denaturation under stress conditions, such as dehydration and frostbite.

Protection against denaturation is particularly important for the preservation of intracellular enzyme system functions, cell membrane functional properties (e.g. transport of calcium) and cellular content.

The protective effect against osmotic stress is also important for cytoprotection, as the main ocular surface alteration mechanism is frequently represented by the osmotic imbalance with the extracellular environment. Trehalose has also an antioxidant effect and its use has proven to prevent damage caused by oxygen free radicals combined with heat shock. Moreover, it increases the tolerance to anoxia because by reducing protein aggregation and maintaining their conformation, it promotes recovery after exposure to anoxic conditions.

The results of preclinical studies have shown that trehalose:

Clinical studies based on this evidence have evaluated the efficacy of trehalose in patients with mild to severe TD compared to saline solution [68] or other tear substitutes, such as hyaluronic acid and hydroxymethylcellulose [69].

The results of these studies have shown that trehalose:

Finally, another study evaluating the corneal epithelium exposed to the toxic action of alcohol has shown that trehalose can protect epithelial cells, preserving cell membrane structures and internal organelles. This suggests that a pretreatment with trehalose can help patients who undergo photorefractive keratectomy (PRK) improving epithelial healing after surgery [70].

Meibomian glands dysfunction and innervation alteration are other two therapeutic targets to take care of.

Meibomian gland dysfunction is responsible for the creation of a lipid layer in the poorly efficient tear film, thereby exposing it to increased evaporation, which results in TD [71]. Modifications in the ocular surface microenvironment determine a modification in the bacterial flora, which activates innate immunity through toll-like receptors, with resulting inflammation [72]. Meibomian gland secretion is altered; therefore, it does not liquefy at the temperature of the ocular surface and remains in the excretory ducts of the glands, triggering a chronic inflammatory stimulus. The therapy is based on the use of high temperature (40-45 °C) through warm, wet compresses or eyelid-warming devices, such as Blephasteam, which allow altered lipids to melt by raising the temperature [73]. In addition to eyelid warming, the use of topical and systemic antibiotics can also help. These antibiotics have two mechanisms of action. On the one hand, they promote bacterial flora regularisation, decrease the secretion of bacterial lipases that act on altered lipid secretions and release fatty acids that are irritating to the glandular ducts. On the other hand, they have a direct anti-inflammatory effect, blocking the release of proinflammatory substances, such as metalloproteinases. The classes of antibiotics used to this end are tetracyclines (rolitetracycline, minocycline and doxycycline), administered both topically and systemically, topical macrolides (azithromycin) and topical fluoroquinolones (ofloxacin) [2, 74, 75].

The ocular surface, and especially the cornea, is the most highly innervated structure in the human body. The innervation plays a primary role in the homoeostasis of the functional unit, conditioning the signs and symptoms resulting from its dysfunction. In fact, a reduction in sensitivity involves hypolacrimation, resulting in the reduced production of epithelium trophic factors, such as epidermal growth factor (EGF), which is essential for epithelial trophism. In extreme cases, this epithelial suffering can lead to the formation of neurotrophic ulcers, which could seriously compromise visual function. When sensitivity is highly compromised, the clinical picture can be accompanied by mild discomfort. However, there are cases in which chronic inflammation leads to the stimulation of the nociceptors on the ocular surface, resulting in severe discomfort, which may not correspond with the clinical signs. In such cases, neuropathy can be both peripheral and central. A therapy for ocular surface innervation alterations is yet to be defined, although there are a few measures that can be taken. Again, omega-3 fatty acids can help, because one of their metabolites, neuroprotectin D, has neuroprotective properties [76, 77]. Nerve growth factor (NGF) can be useful in the event of reduced sensitivity. In fact, it has been proven to restore sensitivity and promote the healing of neurotrophic ulcers in association (if necessary) with a therapy with glycosaminoglycan (GAG) analogues, which has been recently made available in the market [78].

Therapies for ocular surface disorders must be complete, i.e. they must deal simultaneously with the alterations of the structures involved in the pathological process and be dynamic. Therefore, it is important to avoid fixed treatment regimens and adopt therapies that can change any time if the patient’s conditions require so [79]. This therapeutic approach (with progressive adjustments to the patient’s conditions) allows for the improvement and stabilisation of the patient’s clinical conditions and an overall improvement in their quality of life.

The treatment for ocular disorder should take into consideration the use of formulations without preservatives [the most commonly used preservative is the benzalkonium chloride (BAK)] [80].

Patients with dry eye are at particular risk; in fact, the low tear volume allows higher concentrations of BAK to remain in contact with the cornea for longer periods of time [81].

Long-term use of preservative-containing artificial tears is associated with an increased risk of adverse events and epithelial surface damage and diminished compliance due to ocular irritation [50].

Experimental studies in cultured conjunctival cells have shown increased cytotoxic effects of BAK in hyperosmolarity conditions with characteristic cell death process, including caspase-dependent and caspase-independent apoptosis and oxidative stress [51]. This suggests that BAK administered in an eye already submitted to hyperosmolar conditions would be more toxic than in a healthy normal ocular surface.

That is why preservative-free formulation is absolutely necessary as well as therapies for ocular surface disorders and for patients with lacrimal dysfunction.