Disturbance or insufficiency of the tear film challenges the regulatory systems of the ocular surfaces. The reaction of the surfaces includes temporary mechanisms engaged in the preservation of homeostasis. However, strong or persisting challenges can lead to the potential exhaustion of the coping capacity. This again activates the vicious circle with chronic inflammation and autocatalytic deterioration. Hence, the factors challenging the homeostasis should be addressed in time. Amongst them are a varying osmolarity, constant presence of small lesions at the epithelium, acidification, attrition with mechanical irritation, and onset of pain and discomfort. Each of them and, especially when occurring simultaneously, impose stress on the coping mechanisms and lead to a stress response. Many stressors can culminate, leading to an exhaustion of the coping capacity, outrunning normal resilience. Reaching the limits of stress tolerance leads to the manifestation of a lubrication deficiency as the disease we refer to as dry eye disease (DED). To postpone its manifestation, the avoidance or amelioration of stress factors is one key option. In DED, this is the target of lubrication therapy, substituting the missing tear film or its components. The latter options include the management of secondary sequelae such as the inflammation and activation of reparative cascades. Preventive measures include the enhancement in resilience, recovery velocity, and recovery potential. The capacity to handle the external load factors is the key issue. The aim is to guard homeostasis and to prevent intercellular stress responses from being launched, triggering and invigorating the vicious circle. Considering the dilemma of the surface to have to cope with increased time of exposure to stress, with simultaneously decreasing time for cellular recovery, it illustrates the importance of the vicious circle as a hub for ocular surface stress. The resulting imbalance triggers a continuous deterioration of the ocular surface condition. After an initial phase of the reaction and adaption of the ocular surface to the surrounding challenges, the normal coping capacity will be exhausted. This is the time when the integrated stress response (ISR), a protector for cellular survival, will inevitably be activated, and cellular changes such as altered translation and ribosome pausing are initiated. Once activated, this will slow down any recovery, in a phase where apoptosis is imminent. Premature senescence of cells may also occur. The process of prematurization due to permanent stress exposures contributes to the risk for constant deterioration. The illustrated flow of events in the development of DED outlines that the ability to cope, and to recover, has limited resources in the cells at the ocular surface. The reduction in and amelioration of stress hence should be one of the key targets of therapy and begin early. Here, lubrication optimization as well as causal treatment such as the correction of anatomical anomalies (leading to anatomical dry eye) should be a prime intent of any therapy. The features of cellular stress as a key hub for the vicious circle will be outlined and discussed.

The loss of ocular surface (OS) homeostasis characterizes the onset of dry eye disease. Resilience defines the ability to withstand this threat, reflecting the ability of the ocular surface to cope with and bounce back after challenging events. The coping capacity of the OS defines the ability to successfully manage cellular stress. Cellular stress, which is central to the outcome of the pathophysiology of dry eye disease, is characterized by intensity, continuity, and receptivity, which lead to the loss of homeostasis, resulting in a phase of autocatalytic dysregulation, an event that is not well-defined. To better define this event, here, we present a model providing a potential approach when homeostasis is challenged and the coping capacities have reached their limits, resulting in the stage of heterostasis, in which the dysregulated cellular stress mechanisms take over, leading to dry eye disease. The main feature of the proposed model is the concept that, prior to the initiation of the events leading to cellular stress, there is a period of intense activation of all available coping mechanisms preventing the imminent dysregulation of ocular surface homeostasis. When the remaining coping mechanisms and resilience potential have been maximally exploited and have, finally, been exceeded, there will be a transition to manifest disease with all the well-known signs and symptoms, with a shift to allostasis, reflecting the establishment of another state of balance. The intention of this review was to show that it is possibly the phase of heterostasis preceding the establishment of allostasis that offers a better chance for therapeutic intervention and optimized recovery. Once allostasis has been established, as a new steady-state of balance at a higher level of constant cell stress and inflammation, treatment may be far more difficult, and the potential for reversal is drastically decreased. Homeostasis, once lost, can possibly not be fully recovered. The processes established during heterostasis and allostasis require different approaches and treatments for their control, indicating that the current treatment options for homeostasis need to be adapted to a more-demanding situation. The loss of homeostasis necessarily implies the establishment of a new balance; here, we refer to such a state as allostasis.

PURPOSE:Lubricant eye drops are the main therapeutic resource for dry eye disease (DED), with each drop representing the equivalent of ocular surface disease treatment. Thus, any reduction in the frequency of eye drop application reflects a degree of therapeutic success. Considering also the socioeconomic burden of DED, we investigated eye drop application frequency (DF) as a parameter to potentially track the success of therapy in severe DED. Hyaluronan (HA)-containing eye drops have become the first choice for tear substitution in many countries, and recent data indicate that the average molecular weight (Mw) of HA determines the therapeutic efficacy of such eye drops. This post-hoc subgroup analysis of a previously published multicentre prospective randomized open-label study, HYLAN M, is set out to compare the effects of very high Mw HA (hylan A) eye drops to comparator eye drops, containing lower Mw HA (control). METHODS:Patients with severe DED (n = 47), recruited as part of the larger HYLAN M prospective, multicentre, open-label study, were randomized into two groups: hylan A and control group. In the hylan A group, 24 patients replaced their HA-containing eye drops with eye drops containing 0.15% hylan A, whereas the 23 control patients continued to use comparator HA eye drops. The DF was recorded daily by all participants over 8 weeks, and other subjective and objective parameters of DED were assessed at the time of inclusion (baseline), as well as at week 4 and 8. RESULTS:There was a significant decrease in DF in the hylan A users between the baseline and week 4 (p = 0.004), remaining stable until week 8. Indeed, in contrast to the baseline, the hylan A group had a significantly lower DF than the control group at weeks 4 (p = 0.018) and 8 (p = 0.008). Likewise, the ocular surface disease index (OSDI) improved significantly between the time of inclusion and week 4 (p < 0.001) in hylan A users, remaining stable until week 8. The OSDI was similar in both groups at the baseline but it was significantly lower in the hylan A group than in the control group at week 4 (p = 0.002), remaining lower at week 8. Such a decrease in the DF and OSDI was not witnessed in the control group at any time point. The objective parameters assessed did not differ significantly within or between the two groups. CONCLUSION:When treating severe DED, the DF can be significantly reduced by using very high Mw HA (3 MDa) lubricant eye drops, which better alleviate DED symptoms and decrease the OSDI scores. These drops not only provide an attractive and comfortable alternative for patients with severe DED but also offer the possibility of reducing the disease's socioeconomic burden, both for affected individuals and society as a whole.

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Zusammenfassung Die neuen Erkenntnisse der Pathophysiolgie des Trockenen Auges erkennen das Zusammenspiel von Tränen, Augenoberfläche und Lidoberfläche als eine funktionelle Einheit an. Der Begriff der Benetzungsfähigkeit der Tränen in Abhängigkeit der mikrotektonischen Anatomie der Augenoberfläche relativiert die Anforderungen an Träne und Tränenersatzmittel. Das Model der Attrition, welches die Effekte der friktionsneutralisierenden Kapazität des Tränenfilms, der Reibung und die Bedeutung der Mechanotransduktionskapazität des Epithels zusammenfasst, wird eingeführt und dessen pathophysiologische Bedeutung erläutert. Attrition und Benetzung bestimmen zusammen grundlegende pathophysiologische Vorgänge in der Augenoberfläche wie Aktivierung von Nerven (subjektive Beschwerden) sowie Entzündung und beeinflussen damit die Dynamik der Pathophysiologie, und den Übergang von vorübergehenden Beschwerden zu einer manifesten Erkrankung des Trockenen Auges. Die Betrachtung der Osmolarität als numerischer statischer Grenzwert zur alleinigen Diagnose des Trockenen Auges ist klinisch nicht haltbar. Das neue, dynamische Model der Osmokinetik, zeigt dagegen eine Alternative auf, in der die Tageschwankungen und die Beachtung des durchschnittlichen Osmolaritätsniveaus gröβere Bedeutung gewinnen und damit der eigentlichen pathophysiologischen Bedeutung der Osmolarität gerechter wird.

The mechanical component in the pathophysiology of dry eye disease (DED) deserves attention as an important factor. The lubrication deficit induced impaired mechano-transduction of lid pressure to the ocular surfaces may lead to the dysregulation of homeostasis in the epithelium, with sensations of pain and secondary inflammation. Ocular pain is possibly the first sign of attrition and may occur in the absence of visible epithelial damage. Attrition is a process which involves the constant or repeated challenge of ocular surface tissues by mechanical shear forces; it is enhanced by the thinning of corneal epithelium in severe DED. As a highly dynamic process leading to pain and neurogenic inflammation, the identification of the impact of attrition and its potential pathogenic role could add a new perspective to the current more tear film-oriented models of ocular surface disease. Treatment of DED addressing lubrication deficiencies and inflammation should also consider the decrease of attrition in order to stimulate epithelial recovery and neural regeneration. The importance of hyaluronic acid, its molecular characteristics, the extracellular matrix and autoregulative mechanisms in this process is outlined. The identification of the attrition and recognition of its impact in dry eye pathophysiology could contribute to a better understanding of the disease and optimized treatment regimens.

Liebe Leserinnen und Leser, ich freue mich sehr, den «OphthalmoCampus» des Kompass Ophthalmologie von Frau Prof. Dr. Joachim übernehmen zu dürfen. Wir werden uns in dieser Rubrik weiterhin mit interessanten und aktuellen Themen aus der Praxis, Klinik, Forschung und Berufspolitik befassen. Mit der aktuellen Ausgabe starten wir den Beginn einer neuen Reihe im OphthalmoCamus: «Die Basics» werden aktuelle Themen aus der Ophthalmologie thematisieren und werden Ihnen die physikalischen, biochemischen und pathophysiologischen Zusammenhänge und Hintergründe auf dem jeweiligen Gebiet erläutern. Haben Sie Fragen oder möchten Sie etwas aus dem diagnostischen, therapeutischen oder pathogenetischen Bereich erklärt haben? Dann schreiben Sie uns (bettina.hohberger @ uk-erlangen.de) – wir werden uns dieser in einer der kommenden Ausgaben von «Die Bascis» widmen. Wir freuen uns über Ihre Zuschriften! Mit der Rubrik «Blickdiagnose» werden wir Ihnen Krankheitsbilder vorstellen – realitätsgetreu Ihrem Praxisund Klinikalltag – nach dem Motto: Ein Blick – eine Diagnose! Die aktuelle Ausgabe setzt den Schwerpunkt auf die hinteren Augenabschnitte: «Die Basics» beginnt Ihre Reihe mit dem physikalischen Background der OCT-Angiographie. Die Rubrik «Blickdiagnose» wird Ihnen einen Patienten mit einem Krankheitsbild aus dem hinteren Augenabschnitt präsentieren. Ein weiterer Beitrag wird Ihnen die RetinaRisk-App vorstellen – speziell entwickelt für Patienten mit Diabetes. Aus aktuellem Anlass haben wir einen Beitrag eines Virologen zu der Thematik «Was ein Augenarzt über das neue Coronavirus wissen sollte» integriert. Wir wünschen Ihnen viel Freude mit der aktuellen Ausgabe des «OphthalmoCampus»!

Abstract The association of severe dry eye disease with elevated osmolarity in the tear film is a subject of ongoing discussions. As the absolute value of osmolarity in tear film is highly variable, the daily variation in osmolarity (DVO) has recently been proposed to further identify the osmotic stress at the ocular surface. However, the DVO alone does not explain the variations in the available published data or allow their use in diagnostic testing or therapy. We therefore investigated and evaluated further details of osmokinetics and their importance for ocular surface disease on the basis of the available literature. Additionally, osmolarity was measured in the tear samples of volunteers in the morning hours between 8 – 10 a. m., midday noon–2 p. m., and afternoon between 3 – 5 p. m., i.e., during normal office hours. The results were compared with available published data which suggested that within the DVO, the daily maximal amplitude of osmotic variation (M-DVO) and the frequency of osmotic cycles (defined as daily osmolarity cycles, DOC) could be the main factors that further characterize osmokinetics. In addition, a decisive role could be the level of osmolarity at which the variation does occurs (L-DVO). The possible effects of these characteristics on ocular surface pathophysiology are discussed, along with their relationship to topical therapy with hypo-osmolar solutions, and the model of the osmotic roller coaster is introduced.

Hyaluronic acid (HA) ophthalmic solution is widely used in dry eye treatment worldwide. However, there are no reports comparing the dry eye treatment effects of high molecular weight HA with low molecular weight HA. Sixty eight-week-old C57BL/6 mice were assigned to the following 6 groups and exposed to environmental dry eye stress (EDES) that mimics office work environment: 1) 0.1% low molecular weight HA (LMWHA) eye drops, 2) 0.3% LMWHA eye drops, 3) 3% diquafosol sodium (DQ) eye drops, 4) 0.15% high molecular weight HA (HMWHA) eye drops, 5) no treatment with exposure to EDES (EDES+/Treatment−), and 6) no treatment without exposure to EDES (EDES−/Treatment−). After EDES, the HMWHA group had significantly longer break-up time (BUT) than the 0.1%, 0.3% LMWHA groups and the DQ group. After EDES, the HMWHA group had significantly lower lissamine green staining scores than the LMWHA and DQ groups. Subepithelial presumed dendritic cell density in the HMWHA group was significantly lower than the EDES+/Treatment− group. After EDES exposure, Conjunctival Muc5AC mRNA expression in the HMWHA group was significantly higher than the 0.1 and 0.3% LMWHA groups. Ophthalmic HMWHA solution may have a better dry eye treatment effect than LMWHA or DQ solution, owing to its anti-inflammatory effect.

The purpose of this study was to investigate the effect of high molecular weight hyaluronan (HMWHA) eye drops on subbasal corneal nerves in patients suffering from severe dry eye disease (DED) and to evaluate the damage of subbasal corneal nerves associated with severe DED. Designed as an international, multicenter study, 16 patients with symptoms of at least an Ocular Surface Disease Index (OSDI) score of 33, and corneal fluorescein staining (CFS) of at least Oxford grade 3, were included and randomized into two study arms. The control group continued to use their individual optimum artificial tears over the study period of eight weeks; in the verum group, the artificial tears were substituted by eye drops containing 0.15% HMWHA. At the baseline visit, and after eight weeks, the subbasal nerve plexus of 16 patients were assessed by confocal laser scanning microscopy (CSLM). The images were submitted to a masked reading center for evaluation. Results showed a significant increase of total nerve fiber lengths (CNFL) in the HMWHA group (p = 0.030) when compared to the control group, where the total subbasal CNFL did not significantly change from baseline to week 8. We concluded that in severe DED patients, HMWHA from topically applied eye drops could cross the epithelial barrier and reach the subbasal nerve plexus, where it exercised a trophic effect.

The aim of the HYLAN M study was to investigate if symptoms and/or signs of patients suffering from severe dry eye disease (DED) can be improved by substituting individually optimized artificial tear therapy by high molecular weight hyaluronan (HMWHA) eye drops. In this international, multicenter study, patients with symptoms of at least ocular surface disease index (OSDI) 33 and corneal fluorescein staining (CFS) of at least Oxford grade 3 were included. A total of 84 per-protocol patients were randomized in two study arms. The control group continued to use their individual optimum artificial tears over the study period of eight weeks; in the verum group, the artificial tears were substituted by eye drops containing 0.15% HMWHA. At the week 8 visit, the average OSDI of the verum group had improved by 13.5 as compared to the control group (p = 0.001). The best corrected visual acuity (BCVA) had improved by 0.04 logMAR (p = 0.033). CFS, tear film break-up time (TBUT), Schirmer I, lid wiper epitheliopathy (LWE), mucocutaneous junction (Yamaguchi score), and tear osmolarity were not significantly different between the verum and control groups (p > 0.050). We conclude that for most patients with severe DED, 0.15% HMWHA eye drops provide excellent improvement of symptoms without impairment of dry eye signs.

Einleitung: Eigenserum-Augentropfen (ESAT) werden zur Behandlung des Trockenen Auges in besonders schweren Fällen eingesetzt. Nachdem mit ihrer Anwendung einmal begonnen wurde, gilt eine Rückkehr zu anderen gleitfördernden Augentropfen oder sonstigen Therapieoptionen auf dem Markt als unmöglich. Material und Methoden: In einer randomisierten Studie wurde 11 Patienten, die seit mindestens 3 Monaten mit ESAT behandelt wurden, angeboten, stattdessen Augentropfen mit langkettiger Hyaluronsäure zu verwenden. Die Kontrollgruppe (n = 5) setzte ihre Behandlung mit ESAT fort. Die Verumgruppe (n = 6) wendete Augentropfen mit sehr langkettiger Hyaluronsäure (Comfort Shield®) anstelle der ESAT an. Ergebnisse: Von 4 der anfänglich 6 Patienten in der Verumgruppe, die die Studie abschlossen, entschieden sich 2 (50%) dafür, auch über den Untersuchungszeitraum hinaus bei den Augentropfen mit langkettiger Hyaluronsäure zu bleiben, die anderen beiden kehrten zu ihrer vorherigen Therapie mit ESAT zurück. Die Kontrollgruppe führte ihre Behandlung fort wie zuvor und schloss die Studie nach 8 Wochen ab. Schlussfolgerung: Erstmals erwiesen sich künstliche Augentropfen in Form von langkettigen Hyaluronsäure-Augentropfen als akzeptable Alternative zu ESAT. Einige Patienten empfanden diese Tropfen als noch besser als die Tropfen aus ihrem Eigenserum. Dies ist die erste Evidenz, dass durch Optimierung der Struktur des Hyaluronsäuremoleküls Augentropfen hergestellt werden könnten, die im Vergleich zu anderen Tränenersatzmitteln und sogar zu Eigenserum als besser wahrgenommen werden. Dies eröffnet neue Perspektiven für die Behandlung von Patienten mit schweren Fällen des Trockenen Auges.

Introduction: Autologous serum eye drops (ASED) are used in the treatment of most severe stages of dry eye. Once introduced, it is currently considered impossible to return to other lubricating eye drops or other commercially available therapeutic regimen. Materials and Methods: In a randomized study, non-preserved high-molecular-weight hyaluronic acid eye drops were offered as an alternative to 11 patients using autologous serum treatment for at least 3 months. The control group (n = 5) continued their treatment with ASED. The verum group (n = 6) used very-high-molecular-weight hyaluronic eye drops (Comfort Shield®) instead of the ASED. Results: From four of initially six patients in the verum group that finished the study, 2 (50%) preferred to stay with the very-high-molecular-weight hyaluronic acid eye drops beyond the trial period, the other two returned to the earlier therapy with ASED. The control group continued their treatment as before and finished the study after 8 weeks. Conclusion: For the first time, artificial eye drops, i.e., high-molecular-weight hyaluronic acid eye drops, offered an acceptable alternative to ASED. Some patients perceived these drops as even better than the patient’s own serum. This is the first evidence that optimization of the molecular structure of hyaluronic acid can be used to create eye drops that are perceived to be better than other tested tear substitutes and even patients’ own serum. This offers a new treatment perspective for patients with very severe dry eye disease.

The “dry eye” continues to gain importance in everyday clinical practice. Not only is it often a challenge from a medical point of view of differential diagnosis, but also therapeutically, the way to success is neither short nor well predictable. The time required for these patients should not be underestimated as well as the often-enormous suffering that is sometimes in no relation to the anatomical or physiological findings. Therefore, the models for dry eye and its pathogenesis are so important, as they often offer the most important guidance in the search for appropriate diagnosis and therapy for the ophthalmologist, especially if there is a lack of measurable findings. Trust in these models carries an obligation. Being a field of great dynamics, subject to newer and deeper insights into the dynamics of events, a constant reassessment and transformation of each model is therefore a compulsory necessity. In comparison to the previous, more static models, we are currently on the threshold of new thinking, appreciating more the dynamics and the physiological variability of the ocular surface and its lubrication dynamics. Most recently, the Tear Film and Ocular Surface Society (TFOS) published in its Dry Eye Work Shop II (DEWS II) report of the current expert consensus on the definition and classification of dry eye as a disease characterized by a loss of homeostasis of the tear film [1]. The definition of tear film homeostasis remained vague, acknowledging the possibility of many different changes that can occur in the tear film and ocular surface. The current classification of dry eye distinguishes two underlying but often overlapping etiologies: aqueous deficient and evaporative tear film. The report concludes that Meibomian Gland Disease is considered the leading cause of dry eye in clinic and population-based studies. The TFOS DEWS II tear film report states that it is purported that the tear film lipid layer is responsible for the resistance of healthy tears against evaporation [2]. On the other hand, King-Smith and colleagues suggested a lack of correspondence between dry eye and both the lipid layer thickness and thinning rate [3]. The thinning rate of the tear film was not affected by apparent thickening of the lipid layer with lipid emulsion-based eye drops, suggesting that lipid was a poor barrier to evaporation [4]. Therefore, the DEWS II report concluded that the thickness of the lipid layer may not affect the evaporation rate unless it is very thin or completely absent. The TFOS pathophysiology report points to the enormous water-binding capacity of gel-forming mucins, like MUC5AC, secreted by the goblet cells of the conjunctiva as well as their moistening effect and lubricative function at the ocular surface [5], [6], [7].

Wound healing is a complex, long-lasting regulatory sequence that involves expression of a number of genes, which are active during the individual's development. Some of the phenomena differ from normal tissue turnover and growth only quantitatively. This article reviews the current data on corneal wound healing, with particular reference to mesenchymal matrix proteins and their integrin receptors, to growth factors and to proteolytic enzymes. Some inflammatory mediators are also discussed. The theoretical basis for therapeutic interventions is also discussed briefly, in the light of present knowledge.