Alcon thanks those who have contributed to this digital version of the Vicious Circle of Dry Eye Model,and sharing their insights.
©2022 Alcon. IMG-DEOH-2200021
Work carried out by a Scientific Committee (Pr Bourcier, Pr Bremond-Gignac, Dr Doan, Dr Elmaleh, Pr Mortemousque, Pr Pisella, Dr Auger) and coordinated by Pr Baudouin. Adapted from Baudouin C, et al. The Ocular Surface, 2013 and Baudouin C, et al. Br J. Ophthalmol 2016.
Work carried out by a Scientific Committee (Pr Bourcier, Pr Bremond-Gignac, Dr Doan, Dr Elmaleh, Pr Mortemousque, Pr Pisella, Dr Auger) and coordinated by Pr Baudouin. Adapted from Baudouin C, et al. The Ocular Surface, 2013 and Baudouin C, et al. Br J. Ophthalmol 2016.
Patient/condition related factors
Meibomian gland dysfunction (MGD) is an abnormality affecting the quality or quantity of meibum - the oil produced by the palpebral meibomian glands. Meibum forms the lipid layer of the tear film, and limits tear evaporation. MGD is the most common cause of dry eye, taking all causes into account, due to evaporative dryness and tear instability. It leads to a reduction in Break Up Time (BUT).
Blepharitis is the inflammation of the eyelid margin. It may or may not be associated with MGD. It can cause evaporative dryness as well as inflammation of the ocular surface, creating a double entry point into the vicious circle.
The main causes of MGD and blepharitis are rosacea, seborrhoeic dermatitis, menopause, retinoid therapy, chronic allergies and chronic conjunctival inflammation.
Dr S. DOAN
Patient/condition related factors
The tear film is one of the essential components on the surface of the eyeball to combat dry eye. This suggests that the film has a suitable composition and a minimum volume. However, it also implies ongoing structuring and regulation to balance the permanent swirling movements of the surface when in action. Blinking is a recurrent movement aimed at re-distributing the tear film evenly over the entire surface with each blinking movement. For optimal efficiency, an equal thickness and quality must be maintained over the entire surface. In this context, the eyelid margin functions best when it is smooth and regular, acting as an "artificial windscreen wiper". Several eyelid anomalies can interfere by triggering an imbalance in natural tear film statics leading to dry eyes.
- In dermatochalasis or ptosis, the upper eyelid becomes heavier and blinking leads to irregular, stronger friction. This culminates in abnormal film distribution, thereby creating random areas of corneal dryness.
- In eversion or inversion of the eyelids (ectropion or entropion), the rim unevenly rubs the ocular surface. This is accentuated by the incorrect positioning of the eyelashes. In such cases, inadequate orbicularis contractions during blinking contribute to the onset of surface aberrations resulting in dry syndrome.
Instability and uneven distribution of the tear film triggered either by irregularity of the upper or lower margin of the eyelid or by abnormal palpebral weight is a major risk factor in dry eye and entry into the vicious circle of dry eye.
Pr D. BREMOND GIGNAC
Patient/condition related factors
Stimulation of lacrimal secretion occurs via a neuronal arch originating from the ocular surface, the efferent pathway of which is the naso-ciliary branch of the trigeminal nerve (V1) and of which comprises parasympathetic fibres (salivary nucleus) of the facial nerve (VII). Damage to one of these pathways will lead to an alteration of lacrimal reflex secretion either on the hyposecretory side or, more rarely, on the hypersecretory side..
Pr B. MORTEMOUSQUE
Environmental factors
Conjunctival allergy leads to a certain number of changes both in the conjunctival palpebral area and in tear composition.
On contact with the allergen(s), inflammatory cytokines are secreted and the conjunctival surface is gradually transformed by allergenic pro-inflammatory action. Follicles and papillae may appear in the tarsal conjunctiva, and sometimes even giant papillae in vernal keratoconjunctivitis. Both of these trigger factors can lead to a vicious circle of dry eye.
- Inflammatory cytokines affect the composition of the tear film by creating an imbalance.
- Irregularities in the tarsal conjunctiva contribute to the instability and uneven distribution of the tear film.
Despite allergy-induced tearing, both factors may combine dry eye with an allergic condition.
Pr D. BREMOND GIGNAC
Environmental factors
Severe infectious conjunctivitis (and keratitis) can trigger or exacerbate dry eye disease. Multiple mechanisms are involved: infiltration or obstruction of the lacrimal glands, damage to the Meibomian glands, corneal nerves, destruction of mucus cells or limbal stem cells. Dryness may appear acutely or progressively after the infectious episode. Adenovirus, enterovirus, herpes simplex virus, varicella zoster virus, epstein barr virus, hepatitis B or C virus, HIV, HTLV1 (human T-lymphotropic virus type 1) and, very recently, SARS-CoV-2 are the main viruses linked to dry eye. It should be noted that 10% of patients with chronic hepatitis C (with or without secondary Sjögren's syndrome) and 38% of HIV patients have dry eyes. Chlamydia trachomatis, the pathogen of trachoma, is the main bacterium responsible for post-infection dryness.
Pr T. BOURCIER
Environmental factors
The environment plays a vital role in dry eye. This is clearly evidenced by the seasonal nature of the condition, with dry eye syndrome being exacerbated during the spring and summer months. Exposure to the sun, pollen, air pollution, in the case of outdoor activities, and air conditioning are all aggravators.
However, indoor environmental factors can also play a significant role: prolonged computer work, in an office atmosphere, which is known to contain often significant indoor pollutants such as volatile organic compounds (VOCs), or air conditioning.
Controlling the environment is therefore essential by eliminating the aggressive factors and increasing local humidity whenever possible.
Pr C. BAUDOUIN
Treatment-related iatrogenic factors
Wearing contact lenses is one of the many causes of dry eye syndrome. Indeed, contact lenses alter the normal structure of the tear film by splitting it into a pre-lens and post-lens film. The stability of the tear film ensures comfortable wear by thoroughly lubricating the lenses. Thus a precarious balance has to be maintained between the ocular surface and the foreign body represented by the lens.
Contact lenses increase tear osmolarity. This hyperosmolarity is secondary to tear instability caused by the contact lens on the tear film and to hypoesthesia triggered by the lens which tends to reduce tear production. Mechanical stress is another mechanism. Acting as a foreign body causing discomfort to the conjunctival epithelium, the friction triggered on blinking activates an inflammatory cascade per se, which leads to tear hyperosmolarity.
These changes in the ocular surface can occur regardless of the type of lens (soft or rigid) and are more or less symptomatic depending on the material and in particular its coefficient of friction (representing the mechanical friction between the lens and the ocular surface and the tarsal conjunctiva , in particular).).
Thus, in a patient with normal lacrimal secretion and an absence of hyper-evaporative factors, any "aggression" caused by the contact lens on the ocular surface will be tolerable. However, in a patient with dry eye, the comfortable wearing of contact lenses will pose a real challenge. It will be necessary to adapt the material (new silicone hydrogel materials, low friction coefficient / high lubricity), the type of renewal (daily vs. monthly, bi-monthly) and the contact lens solutions.
Dr V. ELMALEH
Treatment-related iatrogenic factors
Dry eyes can be caused or exacerbated by iatrogenic factors such as contact lens wearing, certain surgical procedures (cornea, cataract, eyelids) as well as systemic or topical drugs. The topical drugs that trigger iatrogenic factors act on the cells, glands, nerves and microbiota of the ocular surface by exerting toxic, allergic or immune effects. All of these mechanisms trigger or exacerbate inflammation of the ocular surface. The main therapeutic groups concerned are hypotonic agents, antiviral agents, anaesthetics, mydriatic agents, vasoconstrictor agents and non-steroidal anti-inflammatory drugs (NSAIDs). The active substance, excipient, or preservative, especially benzalkonium chloride (BAK or BAC), which is particularly toxic during prolonged use and/or following application to fragile areas, may be involved. The latter acts like detergents on the tear film by dissolving the lipidic film. New preservatives have recently been developed to reduce their toxic effects on the cells and the tear film.
Pr T. BOURCIER
Treatment-related iatrogenic factors
The quality of post-operative vision is the focal point for these patients. However, dry eye, the first complication of refractive surgery, adversely affects their quality of vision and quality of life in addition to causing pain.
Dry eye is the second most common cause of post-operative visual impairment. Indeed, the tear film is the first refractive surface of the eye representing approximately one dioptre and any damage can lead to a refractive change of more than one dioptre.
Dry eye syndrome, which can lead to surface pain, occurs in 85% of patients within the first week. LASIK lamellar ablation damages the corneal nerves to greater extent than PRK (photoreactive keratectomy). Only the nerves from the flap hinge are preserved and regrowth is usually complete within 3 to 6 months. SMILE is an interesting alternative to LASIK as it spares the subepithelial nerve plexus.
Pre-operative sensitivity is recovered at 6 months on average. Nerve recovery and therefore sensitivity will differ depending on the surgical techniques used.
The first step in the management of dry eye syndrome is carried out prior to surgery and involves: screening subjects at risk, screening for incipient dryness or corneal surface disease and providing patient information. Post-operative management is comparable to that of other causes of dry eye syndrome: tear substitutes and/or anti-inflammatory drugs.
Dr A. AUGER, Pr PJ. PISELLA
Treatment-related iatrogenic factors
Any eye surgery can cause dry eye, but it can also be a victim of dry eye, as in glaucoma surgery where ocular surface and subconjunctival tissue inflammation contributes to postoperative fibrosis culminating in failure.
Cataract surgery can decompensate pre-existing dryness that is more or less symptomatic and not always identified at the pre-operative stage. Intra- and post-operative medication can also be implicated in the same way as the incision per se and even photic stress associated with the operating microscope. Post-operative dryness can have a negative impact on visual quality and can lead to significant visual discomfort even in subjects with excellent visual acuity.
Other types of surgery may also be involved, such as vitreoretinal surgery and retinal lasers, or palpebral, cosmetic or reconstructive surgery, which may impact blinking quality and frequency.
Pr C. BAUDOUIN
Treatment-related iatrogenic factors
Many systemic drugs can promote the emergence of dry eye disease by reducing basal tear secretion due to their anticholinergic effects (some anti-depressants, anti-psychotic agents, anti-spasmodic agents or anti-histamines, especially first generation). Some anti-hypertensives, anti-arrhythmic agents, anti-thyroid agents and opioid analgesics may also be involved. Beta-blockers and lithium also reduce tear secretion, while retinoids and anti-androgens (by extension oestrogens through androgen imbalance) deregulate the meibomian function.
Finally, conventional chemotherapies can also have a toxic effect on cell renewal on the ocular surface, while more recent anti-cancer drugs can generate iatrogenic autoimmune syndromes involving the ocular surface (targeted therapies and/or immune checkpoint inhibitors), or have a direct toxic effect on the corneal epithelium, mimicking some aspects of dry eye (antibody-cytotoxic conjugates).
Pr M. LABETOULLE
Patient/condition related factors
Sjögren’s syndrome is the most typical cause of dry eye disease due to aqueous deficiency, although some degree of meibomian dysfunction is detected in at least 60% of cases (primarily due to the overall loss of ocular surface homeostasis and/or autoimmune involvement of the meibomian glands).
Sjögren’s syndrome has recently been redefined internationally (ACR-EULAR 2016). In the new classification, two signs of dry eye (Schirmer I < 5 mm at 5 min and ocular surface staining > 5 on the OSS score) are sufficient to validate the diagnosis if complemented by a high level of positive SSA antibodies or histological signs on salivary gland biopsy or reduced salivary flow (≤ 0.1 mL/min).
A distinction is made between primary (isolated) Sjögren's syndrome and Sjögren's syndrome secondary to other autoimmune diseases (see "autoimmune diseases"). Primary Sjögren's syndrome is a relatively rare disease with an annual incidence of around 5 per 100,000 (i.e. 300 new cases per annum in France) and a prevalence of 2 to 10 per 10,000 inhabitants (i.e. 12,000 to 60,000 cases in France).
Pr M. LABETOULLE
Patient/condition related factors
Several autoimmune diseases can be the cause or consequence of dry eye disease. The most well-known of these is Sjögren's syndrome (see above), either primary (isolated) or secondary, i.e. in the context of other auto-inflammatory diseases such as rheumatoid arthritis, lupus, Wegener's disease, primary biliary cirrhosis, periarteritis nodosa, scleroderma. Other autoimmune diseases may also be complicated by dry eye disease apart from Sjögren's syndrome. This typically occurs with graft-versus-host disease (in bone marrow transplant patients), mucous membrane pemphigoid/cicatricial pemphigoid or even pemphigus vulgaris.
Pr M. LABETOULLE
Patient/condition related factors
One of the most striking characteristics of dry eye is that it is more common in women than in men. This difference appears to be due to hormonal actions involving sex steroids in particular. Androgens play a key role in regulating the ocular surface. Androgen deficiency predisposes to tear dysfunction and an increased frequency of meibomian gland dysfunction (MGD). The role of oestrogens is less well defined.
In post-menopausal women, the ovaries are no longer capable of producing oestrogen. The body then converts androgens, still secreted by the ovaries and adrenal cortex, into oestrogens by aromatization. This increases androgen deficiency in post-menopausal women and largely accounts for the symptoms of dry eye associated with it.
Pr B. MORTEMOUSQUE
Dry eye is not simply a lack of water. It is defined as an abnormal tear film in terms of volume, composition, stability or regulation. Numerous causes can impact these parameters leading to disease onset, either individually or through comorbidities and cumulative risk factors.
It is useful to distinguish between hyposecretion (secretion deficiency) and tear instability, mostly due to hyper-evaporation, linked to a lipid deficiency, but also due to poor adhesion of the tear film to the ocular surface as a result of mucinic anomalies. But combinations of both types of dryness commonly occur, namely hypo-secretory and instability. However, one or the other or a combination of both lead to common biological mechanisms which will trigger and promote the vicious circle.
Pr C. BAUDOUIN
Hyperosmolarity is the physicochemical consequence of hyposecretion or excessive evaporation by hyper-concentration of osmolytes which constitute the tear film. If the tear film is destabilised too quickly and repeatedly, biological defence mechanisms will be stimulated in the tissue. In particular, hyperosmolarity triggers signalling pathways aimed at increasing the concentration of protective osmolytes and stimulates the secretion of proinflammatory cytokines which will attract immune defence cells. Similarly, hyperosmolarity, albeit an isolated and transient event, stimulates cold receptors, particularly TRPM8. These receptors are involved in regulating blinking and physiological secretion, but repeated overstimulation can trigger a response that is not only a cause of symptoms of pain and discomfort, but also of chronic inflammation.
Pr C. BAUDOUIN
Chronic hyperosmotic stress as well as the desiccation of exposed areas by a deficient or overly unstable tear film, adversely affect the corneal and conjunctival cells. The latter will be altered, triggering an apoptotic process resulting in increased desquamation and, in the severest of cases, squamous metaplasia possibly culminating in epithelial keratinisation.
Pr C. BAUDOUIN
Chronic hyperosmotic stress as well as the desiccation of exposed areas by a deficient or overly unstable tear film, adversely affect the corneal and conjunctival cells. The latter will be altered, triggering an apoptotic process resulting in increased desquamation and, in the severest of cases, squamous metaplasia possibly culminating in epithelial keratinisation.
Pr C. BAUDOUIN
The corneal nerves have several types of receptors: nociceptive, mechanical and polymodal, and cold receptors sensitive to cooling and hyperosmolarity. Normally unconscious these receptors which regulate blinking can also respond with pain and inflammation. Indeed, in the event of chronic or repetitive overstimulation, the corneal nerves cause inflammatory reactions, not only along the trigeminal pathway, which can lead to autonomous pain, ultimately becoming neuropathic pain, but also towards the cornea with the release of mediators capable of stimulating the immune cells and triggering local inflammatory responses.
Pr C. BAUDOUIN
Inflammation has now emerged as the core of dry eye disease, at least in its chronic and/or severe forms. It can be triggered directly by the cause of dryness, as in autoimmune disease, by neuronal overstimulation, hyperosmolarity, chronic mechanical stress, or simply by mechanisms secondary to chronic dryness and tissue changes. The immune system is in fact activated by the various mechanisms mentioned above: they result in attraction/activation of innate immunity cells (dendritic cells, macrophages) and adaptive immunity (T lymphocytes), release of proinflammatory and chemotactic cytokines, and activation of enzymatic pathways including metalloproteinases which, in turn, activate inflammatory phenomena and tissue repair.
Pr C. BAUDOUIN
Mucocytes are essential cells in stabilising the tear film and regulating the ocular surface. The soluble mucins secreted by conjunctival mucocytes actually cover the ocular surface and combine with the membrane mucins present on the entire surface, including the cornea. This mechanism makes the naturally hydrophobic epithelial surface hydrophilic. Without mucocytes, the tear film cannot extend and stabilise. Furthermore, mucins play protective, mechanical and immuno-regulatory roles. However, these cells are highly sensitive to chronic inflammatory reactions which destroy them or at least inhibit their function. The loss of mucous cells is the characteristic sign of dry eye on cytological examination of a conjunctival impression.
Pr C. BAUDOUIN
MGDs are another feature of the vicious circle of dry eye. They themselves are subject to a self-perpetuating pathological phenomenon in the eyelids and the Meibomian glands. The local flora benefits from stagnation of the meibomian lipid content, both as a nutrient and as a shelter. But natural skin pathogens also modify the local environment in their favour by secreting enzymes which modify the melting temperature of the lipids, i.e. making them viscous or even solid at the temperature of the eyelids. The meibum stagnates and the obstructed glands are colonised by microbes and sometimes even by demodex mites, and then become inflammatory. Inflammation of the glands and the eye lid stimulates keratinisation which perpetuates the phenomenon.
This vicious circle is combined with that of dryness because the stagnant meibum that accumulates in the glands is missing from the tear film. The latter becomes unstable and triggers the inflammatory cascades of the vicious tear circle. A double circle therefore emerges at eyelid and tear levels. The second one sometimes takes the ascendancy, particularly since patients tend not to differentiate between ocular symptoms and palpebral inflammation.
Pr C. BAUDOUIN
Mucocytes are essential cells in stabilising the tear film and regulating the ocular surface. The soluble mucins secreted by conjunctival mucocytes actually cover the ocular surface and combine with the membrane mucins present on the entire surface, including the cornea. This mechanism makes the naturally hydrophobic epithelial surface hydrophilic. Without mucocytes, the tear film cannot extend and stabilise. Furthermore, mucins play protective, mechanical and immuno-regulatory roles. However, these cells are highly sensitive to chronic inflammatory reactions which destroy them or at least inhibit their function. The loss of mucous cells is the characteristic sign of dry eye on cytological examination of a conjunctival impression.
Pr C. BAUDOUIN
Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017)
If the options proposed at stage 1 are not appropriate, consider:
Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017)
If the options proposed at stages 1 and 2 are not appropriate, consider:
Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017)
If the options proposed at stages 1 to 3 are not appropriate, consider:
Craig JP, et al., TFOS DEWS II Report Executive Summary, The Ocular Surface (2017)
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