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Journal Français d'Ophtalmologie
Volume 36, n° 6
pages 543-547 (juin 2013)
Doi : 10.1016/j.jfo.2013.03.005
Received : 12 February 2013 ;  accepted : 11 Mars 2013
From pathogenic considerations to a simplified decision-making schema in dry eye disease
Un schéma simplifié pour la prise en charge des syndromes secs oculaires
 

M. Labetoulle a, , b , C. Baudouin c, d
a Service d’ophtalmologie, université Paris-Sud, hôpital Bicêtre, AP–HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre cedex, France 
b UMR 3296 CNRS, laboratoire de virologie moléculaire et structurale, bâtiment 14B, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette cedex, France 
c Centre national d’ophtalmologie des Quinze-Vingts, 28, rue de Charenton, 75012 Paris, France 
d Inserm UMRS 968, institut de la vision, 17, rue Moreau, 75012 Paris, France 

Corresponding author.
Summary

The modern definition of Dry Eye Disease (DED) combines objective findings, subjective symptoms and mechanistic considerations, among which hyperosmolarity and inflammation play a key role. Historically, DED were classified as due to either insufficient production or impaired stability of tears. There is now evidence that such a dichotomous classification does not fit with the reality of clinical practice, since any abnormality of the ocular surface can trigger disequilibrium in all the other components of tear dynamics. This results in a vicious circle with as many ways to enter as there are causes of destabilization of the ocular surface. Eventually, the patient develops a self-sustaining, and finally severe, DED. Based on these data, we propose a simplified decision-making schema with the goal of assisting ophthalmologists in daily practice in choosing the first line treatment for dry eye disease, and then, if necessary, adapting treatment for the long-term.

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Résumé

La définition moderne du syndrome de sécheresse oculaire combine une analyse des constatations objectives, des symptômes subjectifs et des considérations mécanistiques, parmi lesquelles l’hyperosmolarité et l’inflammation jouent un rôle clé. Historiquement, les sécheresses oculaires étaient classées comme dues à une production insuffisante des larmes, ou à leur hyperévaporation. Il est maintenant admis qu’une telle classification dichotomique ne correspond pas à la réalité de la pratique clinique. En effet, n’importe quelle anomalie de la surface oculaire peut provoquer un déséquilibre de chacune des autres composantes de la dynamique des larmes, ce qui entraîne un cercle vicieux avec autant de façons d’y entrer qu’il y a de facteurs de déstabilisation de la surface oculaire. Avec le temps, le patient risque de développer une sécheresse oculaire sévère, dont les mécanismes s’auto-entretiennent. Sur la base de ces données, nous proposons une procédure simplifiée pour la prise de décision thérapeutique face à un syndrome de sécheresse oculaire, dont le but est d’être utile en pratique quotidienne pour le choix du traitement de première ligne, et si nécessaire, pour adapter les traitements à plus long terme.

The full text of this article is available in PDF format.

Keywords : Dry eye, Sicca syndrome, Ophthalmic solutions, Hyperosomolarity, Osmoprotection, Inflammation, Cyclosporine

Mots clés : Œil sec, Sécheresse oculaire, Solutions oculaires, Hyperosomolarité, Osmoprotection, Inflammation, Ciclosporine


The definition of Dry Eye Disease, as released in 2007 by the Dry Eye WorkShop (DEWS), combines objective findings, subjective symptoms and mechanistic considerations, among which hyperosmolarity and inflammation have a key role [1]. This definition is in keeping with the classical, albeit too simple, distinction between dry eyes due to decreased secretion or increased evaporation of tears. There are now evidences that such a dichotomous classification does not fit with the reality of clinical practice [2, 3]. Indeed, one of the central events of most dry eye diseases is tear film instability, since it can be due to a pure lack of tears, to abnormalities in any of the layers of the ocular surface, including the layers of tears themselves, or to a combination between these two abnormalities influencing tear dynamics. According to the surface of the eye involved by the tear film instability, there will be local or diffuse hyperosmolarity of the tear film, with localized spots of very high hyperosmotic tears [4]. Experimental studies have shown that hyperosmolarity induces several disorders of the ocular surface, including damage of superficial epithelial cells of cornea and/or conjunctiva, and stimulation of resident inflammatory cells, resulting in the onset of chronic inflammation [5, 6]. With time, the direct consequences of hyperosmolarity per se and those of inflammation will combine. By the mean of apoptosis, the cell damage may worsen, inducing both superficial punctuate keratitis and conjunctivitis. Simultaneously, hyperosmolarity and chronic inflammation induce damage of goblet cells, resulting in further tear film instability/imbalance due to the impairment of mucous production [7]. All these mechanisms act on the reflex neurosensory arc between the eye surface and the brainstem [8, 9], which results in stimulating neurogenic inflammation of both lacrimal and meibomian glands [10, 11, 12]. At this stage, the dry eye disease is thus self-sustaining, with continuous release of inflammatory cytokines and metalloproteinase activation from every part of the ocular surface [13].

A simplified schema has been proposed to show how these multiple aspects of the dry eye disease combine with time, and finally constitute a vicious circle with several ways to enter (Figure 1) [1, 14]. During the initial steps of the disease, any possible acute or chronic cause of ocular surface disorder may favor or trigger the disequilibrium of the ocular surface integrity. This stage can be reversible if correctly and specifically managed, whenever possible. For the physician, identifying the cause of this emerging dry eye disease thus permits to propose the optimal treatment, aimed at reducing symptoms of course, but first attempting to tackle the aetiology of the disequilibrium of the ocular surface.



Figure 1


Figure 1. 

The vicious circle theory in Dry Eye Disease (DED).

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In case of further involvement in the biological cascades centered by tear film imbalance and inflammatory stimulation, the ocular surface will eventually enter a vicious circle leading to severe DED, whatever the way(s) the patient entered the loop [14]. At this stage, the physician has to deal with the multiple aspects of the disease, which becomes much complex, as clinical factors lack specificity and are weakly indicative of the disease mechanisms [15, 16]. This analysis, indeed, is based on the assessment of the severity and the nature of subjective symptoms, together with the measurement of the level of the several objective signs of DED (including corneal and conjunctival staining, tear break up time, Schirmer I test, eyelid inflammation). We propose herein a clinical-based approach to facilitate the evaluation of DED in routine clinical practice and to provide the ophthalmologists with some simple tools to address ocular surface disease and alleviate patients’ symptoms.

On a practical level, there are three possibilities: the subjective symptoms may appear much more severe than objective signs (especially the levels of corneal and conjunctival staining), or the contrary, or finally there may be some consistency between objective and subjective disorders (Figure 2).



Figure 2


Figure 2. 

First step of the simplified decision-making schema: analysis of symptoms and signs, and main objectives of treatment.

Zoom

In the first case (subjective>objective), the main diagnosis to be evoked is Meibomian Gland Disease (MGD) [3, 15]. A recent report has clarified the decision making for the management of MGD [17]. Mood disorders may also increase the rate of subjective symptoms in comparison to the objective signs, with a patient who focuses stress and self-attention on ocular symptoms. Remarkably, these patients may also be treated with mood regulators, among which some have anticholinergic properties, leading to a real impairment of tear secretion. Finally, there are some DED that may become suddenly painful because of abnormalities of nerve endings into the superficial cornea, leading to hyperesthesia or allodynia [18]. Taking in charge these patients usually includes a management of the psychological aspects of symptoms, together with a re-assessment of the optimal mood regulator treatments (Figure 3).



Figure 3


Figure 3. 

Second step of the simplified decision-making schema: the physician may use different types of ophthalmic solutions according to the conclusion of the previous step. Re-assessment of the clinical settings and re-staging are important to adapt the treatment to the evolution of the disease. It may also be time to consider some alternative diagnoses.

Zoom

On the opposite spectrum of ocular sicca syndrome, there are some patients with mild discomfort, if not at all, despite severe objective disorders. This is typical of patients affected for many years by DED, as corneal sensitivity decreases with the severity of the sicca syndrome. These patients have to be usually managed as severe DED, including anti-inflammatory drugs (i.e. topical cyclosporine) before considering punctual plugging. Alternatively, patients with severe corneal defects despite low discomfort may also be affected by neurotrophic keratitis, sometimes misdiagnosed as severe primary DED. The treatment is based on the eviction of any potentially toxic ophthalmic solution (avoid preservatives and antibiotics), the use of moisturizing eye drops, and eventually autologous serum eye drops.

The third clinical condition, and the more frequently challenging type of DED patients, is the one with consistent levels of subjective symptoms and objective disorders. In such cases, the type of ocular staining (with fluorescein±lissamine green) may help the physician to set up the first line treatment:

When the maximum staining is localized in the upper part of the cornea and the superior conjunctiva, the most probable condition is a superior limbic keratitis. It may be treated with lubricants, and anti-inflammatory eye drops (short courses of steroids±cyclosporine). If the superior conjonctivo-chalasis does not reduce with time, a surgical approach may be discussed. Alternatively, superior staining may also indicate allergy, especially when the upper tarsal conjunctiva is affected. The usual management of ocular allergy is frequently successful.

A maximum staining localized in the lower part of the eye, in front of the contact between inferior eyelid and the corneal and conjunctival epithelia, is likely due to “toxic tear syndrome”, secondary either to MGD or toxic eyedrops (with preserved ophthalmic solutions as the first cause). The etiological treatment usually resolves this condition.

If the main staining is localized on the whole cornea, as a superior punctuate keratitis, the first aim of treatment is to restore the quality of the corneal epithelium. All types of eye drops that increase hydration, restore osmolarity and mimic the role of mucous are useful to improve the interface between tears and the corneal epithelium, and thus reverse the cell damage process.

A maximum staining throughout the interpalpebral area, both on cornea and conjunctiva, is very suggestive of a chronic inflammation of the whole ocular surface, such as the one observed in primary or secondary Sjögren disease. In such patients, it is important to address the two main key points of the disease, i.e. the hyperosmolarity and inflammation process. Osmoprotective eye drops, usually associated with ophthalmic solution that have moisturizing and/or mucomimeting properties, are very useful, since they will reduce the impact of hyperosmolarity and its own pro-inflammatory consequences. There are several levels of viscosity in ophthalmic eyedrops. The most fluid have the advantage of improving the turnover of debris and inflammatory elements (cells, cytokines, enzymes…) while polymers are able to both increase the level of hydration due to their chemical properties and to act as protection for the apical part of the ocular surface. If this first line treatment does not improve the quality of the ocular surface and/or the subjective symptoms in a delay of 3 months, a long-term anti-inflammatory treatment has to be considered. Cyclosporine eyedrops (0.05%) are mostly used in such patients (off-label however in Europe, to date). The results are often satisfying, providing that the patient has been educated on the risk of burning/stinging during the first hour of cyclosporine instillation and the fact that improvement usually takes 2 to 3 months to be observed by the physician and the patient himself [19, 20].

The more aggressive condition of DED is observed when filaments are present on the ocular surface. The first line treatment for filamentous kerato-conjunctivitis is to improve dramatically the lubrication of the ocular surface (combination of very frequent saline eyedrops+osmoprotective/mucomimeting ophthalmic solutions). If there is no clear improvement within a delay of one month, it is usually useful to set a chronic anti-inflammatory topical treatment (i.e. 0.05% cyclosporine) and to consider punctual plugging in a delay of 3 months, giving the fact that premature plugging could increase the corneal damage due to persistent inflammation of tears.

This simplified decision-making schema is not aimed at providing an ultimate answer for all the several types of DED patients, but rather at being helpful for general ophthalmologists in choosing the first line treatment for dry eye syndrome, and then, if necessary, to adapt medications for long-term follow-up.

Disclosure of interest

The authors declare that they have no conflict of interest concerning this article.

References

International Dry Eye W The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007) Ocul Surf 2007 ;  5 : 75-92
International Dry Eye W Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007) Ocul Surf 2007 ;  5 : 108-152
Lemp M.A., Crews L.A., Bron A.J., Foulks G.N., Sullivan B.D. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study Cornea 2012 ;  31 : 472-478 [cross-ref]
Luo L., Li D.Q., Corrales R.M., Pflugfelder S.C. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface Eye Contact Lens 2005 ;  31 : 186-193 [cross-ref]
Versura P., Profazio V., Schiavi C., Campos E.C. Hyperosmolar stress upregulates HLA-DR expression in human conjunctival epithelium in dry eye patients and in vitro models Invest Ophthalmol Vis Sci 2011 ;  52 : 5488-5496 [cross-ref]
Pelegrino F.S., Pflugfelder S.C., De Paiva C.S. Low humidity environmental challenge causes barrier disruption and cornification of the mouse corneal epithelium via a c-jun N-terminal kinase 2 (JNK2) pathway Exp Eye Res 2012 ;  94 : 150-156 [cross-ref]
Moore J.E., Vasey G.T., Dartt D.A., McGilligan V.E., Atkinson S.D., Grills C., and al. Effect of tear hyperosmolarity and signs of clinical ocular surface pathology upon conjunctival goblet cell function in the human ocular surface Invest Ophthalmol Vis Sci 2011 ;  52 : 6174-6180 [cross-ref]
Stern M.E., Gao J., Siemasko K.F., Beuerman R.W., Pflugfelder S.C. The role of the lacrimal functional unit in the pathophysiology of dry eye Exp Eye Res 2004 ;  78 : 409-416 [cross-ref]
M’Garrech M., Rousseau A., Kaswin G., Sauer A., Barreau E., Bourcier T., and al. Impairment of lacrimal secretion in the unaffected fellow eye of patients with recurrent unilateral herpetic keratitis Ophthalmology 2013 ; [In Press].
Battat L., Macri A., Dursun D., Pflugfelder S.C. Effects of laser in situ keratomileusis on tear production, clearance, and the ocular surface Ophthalmology 2001 ;  108 : 1230-1235 [cross-ref]
Kam W.R., Sullivan D.A. Neurotransmitter influence on human meibomian gland epithelial cells Invest Ophthalmol Vis Sci 2011 ;  52 : 8543-8548 [cross-ref]
Beuerman R.W., Stern M.E. Neurogenic inflammation: a first line of defense for the ocular surface Ocul Surf 2005 ;  3 : S203-S206
VanDerMeid K.R., Su S.P., Ward K.W., Zhang J.Z. Correlation of tear inflammatory cytokines and matrix metalloproteinases with four dry eye diagnostic tests Invest Ophthalmol Vis Sci 2012 ;  53 : 1512-1518 [cross-ref]
Baudouin C. A new approach for better comprehension of diseases of the ocular surface JFrOphtalmol 2007 ;  30 : 239-246 [inter-ref]
Nichols K.K., Nichols J.J., Mitchell G.L. The lack of association between signs and symptoms in patients with dry eye disease Cornea 2004 ;  23 : 762-770 [cross-ref]
Sullivan B.D., Crews L.A., Messmer E.M., Foulks G.N., Nichols K.K., Baenninger P., and al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications Acta Ophthalmol 2012 ; 10.1111/aos.12012[Epub ahead of print].
Tomlinson A., Bron A.J., Korb D.R., Amano S., Paugh J.R., Pearce E.I., and al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee Invest Ophthalmol Vis Sci 2011 ;  52 : 2006-2049 [cross-ref]
Rosenthal P., Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle Ocul Surf 2012 ;  10 : 2-14 [cross-ref]
Sall K., Stevenson O.D., Mundorf T.K., Reis B.L. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group Ophthalmology 2000 ;  107 : 631-639 [cross-ref]
Cross W.D., Lay L.F., Walt J.G., Kozma C.M. Clinical and economic implications of topical cyclosporin A for the treatment of dry eye Manag Care Interface 2002 ;  15 : 44-49



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