Original articleOsmokinetics: A new dynamic concept in dry eye diseaseOsmocinétique : un nouveau concept dynamique dans la sècheresse oculaire
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.
References (22)
- et al.
Basal and reflex human tear analysis. I. Physical measurements: osmolarity, basal volumes, and reflex flow rate
Ophthalmologu
(1981) A new approach for better comprehension of diseases of the ocular surface
J Fr Ophtalmol
(2007)- et al.
Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting
Ocul Surf
(2013) - et al.
TFOS DEWS II Report Executive Summary
Ocul Surf
(2017) - et al.
Tear fluid hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea
Pain
(2014) - et al.
TFOS DEWS II pain and sensation report
Ocul Surf
(2017) - et al.
An objective approach to dry eye disease severity
Invest Ophthalmol Vis Sci
(2010) - et al.
Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction
Br J Ophthalmol
(2016) - et al.
Tear osmolarity as a biomarker for dry eye disease severity
Invest Ophthalmol Vis Sci
(2010) - et al.
Inflammatory cytokine and osmolarity changes in the tears of dry eye patients treated with topical 1% methylprednisolone
Yonsei Med J
(2014)
Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases
Curr Eye Res
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