Osmokinetics: A new dynamic concept in dry eye disease

Summary

Introduction

Tear fluid osmolarity has been increasingly accepted as an accessible parameter in the diagnosis of ocular surface and dry eye disease. After having been proposed as the gold standard, recent results have put this into question. However, the most recent guidelines for dry eye disease identify specific values of osmolarity as thresholds to help to differentiate between various stages of severity of ocular surface disease. The limits of this approach were investigated to propose a new concept, that of osmokinetics.

Materials and Methods

Available data on tear fluid osmolarity in normal and diseased eyes were compared. The possibility of normo-osmolar dry eye was investigated and repeated measurements of osmolarity performed.

Results

The currently applied static model of a threshold value of osmolarity for diagnosing dry eye disease is apparently insufficient. Not only does it not take into account normo-osmolar dry eye, but it also applies too much significance to a single parameter. Instead, it was found that there is a daily variation in osmolarity (DVO), which appears to be higher in eyes with tear film deficiencies than in healthy eyes.

Discussion

Tear film osmolarity does vary considerably throughout the day. Its value should be considered in a kinetic model taking into account the dynamics of osmolarity changes moreso than the current static model. The terms of osmotic stress and diurnal variation of osmolarity were found to offer a more physiological understanding of osmolarity.

Conclusion

A more dynamic model for osmolarity is presented in which not the value itself but the daily variation of osmolarity is identified. It is suggested that the amplitude of change in osmolarity over the course of a day or even shorter time periods could play a decisive role as a stress factor for the surface cells. The varying osmolar stress could be one of the key mechanisms leading to the cell death, inflammation, apoptosis, and goblet cell disappearance as observed in dry eye disease. Perhaps it is the mean osmolarity level at which these changes occur together with the magnitude of DVO which could identify the level of severity of dry eye disease.

Résumé

Introduction

L’osmolarité des liquides lacrymaux est de plus en plus reconnue comme un paramètre accessible dans le diagnostic des maladies de la surface oculaire et de la sécheresse oculaire. Après avoir été proposés comme un gold standard, des résultats récents ont remis en question la mesure de l’osmolarité lacrymale. Pourtant, les plus récents workshops sur la sécheresse oculaire identifient encore des valeurs spécifiques d’osmolarité comme seuils permettant de différencier les différents stades de gravité de la maladie. Les limites de cette approche ont été examinees pour proposer un nouveau concept, l’osmocinétique.

Matériels et méthodes

Les données disponibles sur l’osmolarité du liquide lacrymal dans les yeux normaux et malades ont été comparées. La possibilité d’un œil sec normo-osmolaire a été étudiée et des mesures répétées de l’osmolarité ont été effectuées.

Résultats

Le modèle statique actuel d’une valeur seuil d’osmolarité pour le diagnostic de la sécheresse oculaire n’est apparemment pas suffisant. Non seulement il ne considère pas l’œil sec normo-osmolaire, mais il accorde également une importance excessive à l’interprétation d’une seule mesure. Au lieu de cela, il a été constaté qu’il existe une variation quotidienne de l’osmolarité (DVO), qui semble être plus élevée dans les yeux présentant des atteintes du film lacrymal que dans les yeux en bonne santé.

Discussion

L’osmolarité du film lacrymal varie considérablement au cours de la journée. Sa valeur devrait être prise en compte dans un modèle cinétique respectant davantage la dynamique des changements d’osmolarité que le modèle statique actuel. Les termes de stress osmotique et de variation diurne de l’osmolarité se sont révélés offrir une compréhension plus physiologique de l’osmolarité.

Conclusion

Un modèle plus dynamique pour l’osmolarité est présenté dans lequel non pas la valeur elle-même mais la variation quotidienne de l’osmolarité est identifiée. Il est suggéré que le changement d’amplitude de l’osmolarité au cours de la journée ou même à des périodes plus courtes pourrait jouer un rôle décisif en tant que facteur de stress pour les cellules de surface. La variation du stress osmolaire pourrait être l’un des mécanismes clés conduisant à la mort cellulaire, à l’inflammation, à l’apoptose, à la disparition des cellules caliciformes observée dans les cas de sécheresse oculaire. Peut-être est-ce le niveau moyen d’osmolarité auquel ces changements se produisent, associé à l’amplitude de la DVO, qui pourrait permettre identifier le niveau de gravité de la maladie de l’œil sec.

Introduction

Osmolarity has been advocated as a measurable parameter for dry eye disease since the 80s [1]. However it was not until measurement of microvolumes was accurate enough to establish values that could refer to normal conditions. Pathologically high values led to the presumption that this was associated with the severity of dry eye disease due to processes such as evaporation [2]. This is well in accordance to the current model of the vicious circle of dry eye disease initially presented 2007 [3] and in it's modified and updated form [4], [5]. The DEWS II has considered osmolarity itself as one of the key mechanisms of dry eye pathophysiology and a threshold value had been assigned at the level of 308 mOsmol/L [6] which is very close to the area of normality as published earlier [7], [8]. Effects of gender and ages have been known since the initial publication [1], emphasizing higher values in females and aged over 40. Meanwhile there is no consensus about osmolarity thresholds for various intensities of dry eye disease, as low or normal osmolarity levels may be encountered even in most severe dry eye conditions. Available studies suggesting values less than 305 mOsm/L as cut-off for dry eye, 309 mOsm/L for moderate dry eye and 318 mOsm/L for severe dry eye [9]. These values, however, somehow disregard the reality in their interpretation as even in normal tear film the distribution around the “normal” values has been found approximately to be ± 20 mOsmol/L [7], [8]. Additionally to this could other factors contribute to osmolar challenge [10] as well as the reported effects of seasonality in dry eye disease [11].

The recent report of normal or hypo-osmolar ocular surface fluid in very severe dry eyes which were entirely dependent on tear fluid substitutes does cast a new light on the issue if surface hyperosmolarity is mandatory for the diagnosis of dry eye disease [12]. In a randomized study investigating the substitution of human serum in severe dry eye disease we found osmolarity in the fluid covering the ocular surface to be between 280 and 315 mOsmol/L [12]. This supports other observations that severe dry eye is encountered even in normo-osmolar conditions. Instead we have found a diurnal variation of osmolarity, indicating highest levels of osmolarity during early morning and evening hours. This confirms an early observation in a study in which multiple samples were collected throughout the day. Here, tear osmolarity was found to differ significantly between morning and afternoon in normal subjects [13]. In our recent studies we have confirmed this and found that the diurnal variation is highest in the patients with tear fluid insufficiency. In eyes with moderate to severe dry eye the difference, herein named daily amplitude of osmolarity, or possibly more correct diurnal variation of osmolarity (DVO) reached Δ 50 mOsmol/L between morning and afternoon measurement and reflects the dynamics of tear osmolarity (Fig. 1).

Hyperosmolarity by itself is known to cause cell stress as the ocular surface resulting in significant cellular reactions triggering, amongst others inflammatory events [10], [14], [15]. However, it is known that changes of osmolarity, both toward the hypo-osmolarity and toward the hyperosmolarity sides, cause osmotic stress [16]. As dry eye disease may apparently also occur at normal levels of osmolarity on the surface, it is therefore herewith suggested that not the absolute value of osmolarity depicting a certain level may be as such alone decisive for intensity of ocular surface disease. This is in contrast with the considerations based on the idea that single measurement of tear osmolarity could provide sufficient sensitivity and specificity for dry eye disease diagnostics [17]. Instead, it is apparently the dynamics of changes in osmolarity that imposes the greatest pathophysiological challenge on the ocular surface experienced as cellular stress. It is the cell stress in dry eye disease that secondarily does trigger and maintain the vicious circle as so well described earlier [4], [5]. Dry eye pathophysiology hence appears to be a matter of osmokinetics. Of course does the level of osmolarity at which the dynamics takes place play a role. Here, one may speculate that the higher the level of osmolarity the more sensitive the ocular surface is to changes in osmolarity over a period of time imposing additional stress to the hyperosmotic stress already prevailing. In other words the more severe the dry eye disease the less tolerance to additional changes there can be. This again allows to incorporate and understand the model of pain sensations in severe dry eye disease when triggered by corneal cold thermoreceptors, the numbers of which increase in mouse cornea, when osmolarity is raised from 310 mOsm/L (control) to values greater than 340 mOsm/L [18]. It has been reported that, in addition to sensing changes in temperature, the HB-LT corneal cold thermoreceptors detect mild to moderate changes in osmolarity [19]. As the variation of osmolarity (DVO) apparently is more likely to exceed the required amount of changes to trigger these receptors, the amplitude of osmotic shift over a certain time, the extent of which needs to be determined, naturally causes the thermoreceptors to fire and with this, the sensation of pain which triggers the neurological pathway contributing to inflammation.

As stated in DEWS II, does persistent stress from desiccation stimulate the local release of a variety of chemical mediators from the cells at the ocular surface [19]. However, the redundancy of osmotic stress resulting from variation of osmolarity (DVO) could be possibly even more important, especially in the initial stages of dry eye where some regulatory mechanisms might be still intact and the surface has not yet entirely entered the vicious circle of dry eye disease. The resulting repeated osmotic roller-coaster, recently referred to as osmotic JoJo (Fig. 2) may over time lead to exhaustion of normal cell mechanisms of repair and defense and make them more easily accessible to changes pushing the ocular surface into the vicious circle.

In conclusion, the importance of osmolarity in dry eye pathophysiology is commonly accepted. However, it is apparently a very variable indicator, which is influenced by time, location and environment. The resulting variations may be of major importance, especially if diurnal variation does occur with peaks creating a considerable shift that is large enough to cause osmotic stress. Osmotic stress is a potent regulator of the normal function of cells that are exposed to osmotically active environments under physiologic or pathologic conditions [20]. Hence the concept of osmokinetics, compromising ad hoc values as well as changes of osmolarity over time and location, could define the pathophysiology of dry eye disease better than the terms osmolarity or hyperosmolarity alone. The rigidity of current models imposing sole numerical threshold values should be reconsidered. Evidence does suggest a more dynamic model in which not the value itself but the daily variation of osmolarity, plays a major role as stress factor for the surface cells. The varying osmolar stress could be on of the key mechanisms leading to cell death, and apoptosis, goblet cell vanishing as observed in dry eye disease. It may well be that as in other diseases, such as in glaucoma the variation of pressure over a time period, i.e. the dynamics/kinetics is more important than the pressure value or pressure level itself (unless extremely high). Likewise low-tension glaucoma may impose a severe threat for sight, even normo-osmolarity may camouflage the threat to the surface caused by considerable alterations of osmotic pressure over a certain time. The future will show to which amplitude of osmolarity change/time the ocular surface with the tears may adopt to and which threshold values do exist. The application of osmokinetics to the field of dacryology and dry eye disease will possibly lead to more physiological and efficient therapies of dry eye disease, namely osmoregulators, when looking at osmolarity at the ocular surface from a different, more dynamic perspective. Osmoregulation here is much more than just arbitrarily adding hyposomolar solution to a osmolarity instable or hyperosmolar environment as this could lead to hyposmotic shock by the sudden change in the solute concentration around the cell, which causes a rapid change in the movement of water across its cell membrane [21]. This would contribute to the osmotic stress already present and possibly lead to increased apoptosis [22]. However, identifying the issue of osmokinetics and the presence of osmotic stress at the ocular surface of dry eye patients may be seen as another step towards optimized and adapted therapy of dry eye disease.