Pasquale Aragona

Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye

Background/aims: Several studies have reported that sodium hyaluronate is able to improve both symptoms and signs in patients with dry eye but none have demonstrated an improvement of conjunctival epithelial cell abnormalities of the ocular surface. The aim of this study was to explore the effect of sodium hyaluronate-containing eye drops on the ocular surface of patients with dry eye during long term treatment. Methods: A randomised double blind study was undertaken in 86 patients with medium to severe dry eye (that is, rose bengal and/or fluorescein test score of at least 3, tear film break up time <10 seconds, or Schirmers test <5.5 mm). Patients were treated with either preservative-free sodium hyaluronate or saline for 3 months at a dose of one drop 4–8 times a day. Bulbar impression cytology, slit lamp examinations, and subjective symptoms were evaluated after 1, 2, and 3 months. Impression cytology was considered the primary efficacy parameter of the study. Results: The efficacy analysis was performed on a total of 44 patients who were able to fully adhere to the protocol. After 3 months of treatment sodium hyaluronate improved impression cytology score (p = 0.024 v baseline). At the same time also the difference with respect to placebo was statistically significant (p = 0.036). Study medication was well tolerated and no treatment related adverse events occurred during the study. Conclusions: Sodium hyaluronate may effectively improve ocular surface damage associated with dry eye syndrome.

Role of Hyperosmolarity in the Pathogenesis and Management of Dry Eye Disease: Proceedings of the OCEAN Group Meeting

Dry eye disease (DED), a multifactorial disease of the tears and ocular surface, is common and has a significant impact on quality of life. Reduced aqueous tear flow and/or increased evaporation of the aqueous tear phase leads to tear hyperosmolarity, a key step in the vicious circle of DED pathology. Tear hyperosmolarity gives rise to morphological changes such as apoptosis of cells of the conjunctiva and cornea, and triggers inflammatory cascades that contribute to further cell death, including loss of mucin-producing goblet cells. This exacerbates tear film instability and drives the cycle of events that perpetuate the condition. Traditional approaches to counteracting tear hyperosmolarity in DED include use of hypotonic tear substitutes, which have relatively short persistence in the eye. More recent attempts to counteract tear hyperosmolarity in DED have included osmoprotectants, small organic molecules that are used in many cell types throughout the natural world to restore cell volume and stabilize protein function, allowing adaptation to hyperosmolarity. There is now an expanding pool of clinical data on the efficacy of DED therapies that include osmoprotectants such as erythritol, taurine, trehalose and L-carnitine. Osmoprotectants in DED may directly protect cells against hyperosmolarity and thereby promote exit from the vicious circle of DED physiopathology.

Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients

Aim: To study the effect of the treatment of dry eye in Sjögrens syndrome patients with hypotonic or isotonic hyaluronate eye drops. Methods: 40 Sjögrens syndrome patients were divided in two groups and treated as follows: group 1 with hypotonic (150 mOsm/l) 0.4% hyaluronate eye drops; group 2 with isotonic 0.4% hyaluronate eye drops. The eye drops were instilled six times a day for 90 days. Grading of subjective symptoms, break up time (BUT), corneal fluorescein staining, conjunctival rose bengal staining, Schirmers I test, and conjunctival impression cytology were carried out at 0 and 15, 30, 90 days from the beginning of the study. Patients were examined in a blind fashion. For the statistical analysis the Students t test, Mann-Whitney U test, and χ2 test were performed. Results: Symptoms were statistically significantly improved at day 15 in both groups but group 1 patients had a global score statistically significantly better group 2 (p=0.02). At day 15 group 1 patients had an improvement from baseline values of BUT (p=0.003), fluorescein, and rose bengal score (p=0.000001 and p=0.0004 respectively). Group 2 patients had, at day 15, an improvement of BUT and fluorescein score compared to baseline values (p=0.05 and p=0.0001 respectively). A comparison between the two groups showed better results for group 1 patients at day 15 for rose bengal stain (p=0.01) and for BUT (p=0.05) and fluorescein score (p=0.0003) at day 90. The conjunctival impression cytology showed that group 1 had a statistically significant better total score than group 2 starting from day 15 and lasting throughout the study (p<0.02). Also group 2 patients showed an improvement from baseline values starting from day 30 (p=0.000005). Conclusion: Hyaluronate eye drops are useful for treating severe dry eye in Sjögrens syndrome patients. The use of a formulation with pronounced hypotonicity showed better effects on corneoconjunctival epithelium than the isotonic solution.

A multicentre, double-masked, randomized, controlled trial assessing the effect of oral supplementation of omega-3 and omega-6 fatty acids on a conjunctival inflammatory marker in dry eye patients

Purpose:  To determine whether oral supplementation with omega‐3 and omega‐6 fatty acids can reduce conjunctival epithelium expression of the inflammatory marker human leucocyte antigen‐DR (HLA‐DR) in patients with dry eye syndrome (DES).

Diagnosing the severity of dry eye: a clear and practical algorithm

Dry eye disease (DED) is a distressing ocular condition. Due to its multifactorial nature, clinical and biological signs of DED can be inconsistent and sometimes discordant with symptomatology. Consequently, no gold-standard model for determining DED severity exists. This can impact treatment decisions and complicate evaluation of disease progression, particularly within the stringent context of clinical trials. The multinational ODISSEY European Consensus Group is comprised of ophthalmologists who contend with ocular surface disease issues on a daily basis. This group convened to establish a clear and practical algorithm for evaluation and diagnosis of severe DED. Using a consensus-based approach, they assessed 14 commonly used DED severity criteria. The panel agreed that following confirmed DED diagnosis, just two criteria, symptom-based assessment and corneal fluorescein staining were sufficient to diagnose the presence of severe DED in the majority of patients. In the event of discordance between signs and symptoms, further evaluation using additional determinant criteria was recommended. This report presents the ODISSEY European Consensus Group recommended algorithm for DED evaluation, which facilitates diagnosis of severe disease even in the event of discordance between signs and symptoms. It is intended that this algorithm will be useful in a clinical and developmental setting.

Impression cytology of the conjunctival epithelium in patients with vernal conjunctivitis.

The alterations in the conjunctival epithelium during the course of vernal conjunctivitis were examined by conjunctival impression cytology. The study was carried out on 53 patients with vernal conjunctivitis and 20 normal subjects as control. The results of impression cytology demonstrated that all cytological parameters were significantly modified in vernal conjunctivitis patients; the earliest alterations were found in the distribution of goblet cells, in the intercellular junctions, in the chromatin morphology and in the degree of keratinisation. The morphometric comparison showed that in vernal conjunctivitis patients the mean number of goblet cells per field was significantly higher than in controls. Moreover the mean diameter of goblet cells was smaller in patients than in controls. Impression cytology can, therefore, be a simple, non-invasive and cheap method for the study of the ocular surface in vernal conjunctivitis.

The effects of the topical administration of non-steroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects

Purpose To study the changes in the corneal epithelium and corneal sensitivity of healthy subjects after the topical administration of non-steroidal anti-inflammatory drugs (NSAIDs; diclofenac, indomethacin, flurbiprofen and ketorolac) frequently used in ocular therapy.Methods A double-masked parallel clinical study was undertaken on 90 subjects (45 men, 45 women; Caucasian; age 21–46 years, mean SD 27.1 5 years). The subjects were divided into six groups: group 1 was treated with placebo, group 2 with 0.1% diclofenac, group 3 with 0.1% indomethacin, group 4 with 0.03% flurbiprofen, group 5 with 0.5% ketorolac and group 6 with 0.4% oxybuprocaine. One eye was randomly treated with the study drug and the fellow eye was treated with placebo. The medications were instilled four times, at 5 min intervals. Assessment of the corneal epithelium was carried out by vital fluorescein stain before instillation and 5, 15, 30 and 60 min after instillation of the last drop. Subjective burning sensation was assessed by asking participants to rate burning on a scale from 0 (none) to 3 (severe). After 1 week, assessment of corneal sensitivity was carried out by the Cochet-Bonnet method, repeating the above scheme of instillation and measurement times.Results None of the study drugs, with the exception of oxybuprocaine, produced evident epithelial damage. All the drugs caused a mean burning sensation greater than the placebo. The diclofenac-treated group showed a statistically significant decrease in corneal sensitivity (p 0.001) at the measurement carried out 15 min after instillation of the last drop and lasting up to the end of the study, when the corneal anaesthesia was similar to that induced by the topical anaesthetic treatment. No significant changes weredemonstrated for the other NSAIDs when compared either with the placebo-treated eyes or with the fellow eyes.Conclusions Despite a similar mechanism of action and analgesic activity to the other NSAIDs tested, diclofenac was able to induce a reduction in corneal sensitivity. More studies are needed to determine the mechanism of action responsible for this effect.

Meibomian gland dysfunction and ocular discomfort in video display terminal workers

PurposeMeibomian gland dysfunction (MGD) is one of the most common ocular disorders encountered in clinical practice. The clinical manifestations of MGD are related to the changes in the tear film and ocular surface with symptoms of ocular discomfort. In recent years, many surveys have evaluated symptoms associated with the use of Video Display Terminals (VDT), and VDT use is recognized as a risk factor for eye discomfort.The aim of the present study was to determine if the presence of MGD contributes to the signs and symptoms of ocular discomfort during the use of VDT.MethodsIn course of a routine health surveillance programme, a group of 70 subjects fulfilled the inclusion criteria and responded to a questionnaire about symptoms of ocular discomfort. The following ocular tests were performed: tear break-up time, fluorescein corneal stain, and basal tear secretion test.ResultsA total of 52 subjects out of 70 (74.3%) had MGD. A statistically significant correlation between the symptoms of ocular discomfort and hours spent on VDT work was observed in the total population (r=0.358; P=0.002; 95% CI 0.13–0.54) and in the group of subjects with MGD (r=0.365; P=0.009; 95% CI 0.103–0.58). Such correlation was not shown in subjects without MGD.ConclusionsThe high prevalence of MGD among the subjects with symptoms of ocular discomfort suggests that this diagnosis should be considered when occupational health practitioners encounter ocular complaints among VDT operators. It appears that MGD can contribute to the development of ocular discomfort in VDT operators.

Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren's syndrome patients.

Aim and purposeTo evaluate the effects of two NSAIDs on corneal sensitivity and ocular surface in Sjögrens syndrome (SS) patients.MethodsIn all, 20 SS patients with epithelial corneal defects, were randomly divided into two groups: group 1 (10 females, age 35–63 years), treated with 0.1% indomethacin, one drop three times a day; group 2 (nine females, one male, age 38–65 years) treated with 0.1% diclofenac, at the same regimen. No systemic NSAIDs were allowed. Use of tear substitute was allowed. Corneal sensitivity, corneal staining, BUT, and ocular discomfort, were evaluated before and after 15, 30 days of treatment and 7 days after NSAID discontinuation. For statistical analysis, the Students t-test and Mann–Whitney U test were used.ResultsBoth groups showed at day 30 a statistically significant reduction of corneal sensitivity (P<0.05), although the diclofenac-treated group showed a statistically significant lower sensitivity if compared to the indomethacin-treated group (P<0.05). Corneal fluorescein score showed a statistically significantly worst alteration in group 2, 7 days after the discontinuation of the therapy (P=0.02). The ocular discomfort score was statistically significantly reduced in both groups starting from day 15 (P<0.05).DiscussionThe results indicate that NSAIDs can be useful in resolving symptoms of ocular discomfort in SS patients. However, they should be used with caution and under close monitoring, and the treatment should be promptly discontinued if corneal epithelial defects develop or worsen during treatment.

Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction

Meibomian gland dysfunction (MGD) is the most frequent cause of dry eye disease (DED). Eyelid inflammation, microbial growth, associated skin disorders as well as potentially severe corneal complications culminate to make MGD a complex multifactorial disorder. It is probable that MGD is a heterogeneous condition arising from any combination of the following five separate pathophysiological mechanisms: eyelid inflammation, conjunctival inflammation, corneal damage, microbiological changes and DED resulting from tear film instability. The pathogenesis of both MGD and DED can be described in terms of a ‘vicious circle’: the underlying pathophysiological mechanisms of DED and MGD interact, resulting in a double vicious circle. The MGD vicious circle is self-stimulated by microbiological changes, which results in increased melting temperature of meibum and subsequent meibomian gland blockage, reinforcing the vicious circle of MGD. Meibomian gland blockage, dropout and inflammation directly link the two vicious circles. MGD-associated tear film instability provides an entry point into the vicious circle of DED and leads to hyperosmolarity and inflammation, which are both a cause and consequence of DED. Here we propose a new pathophysiological scheme for MGD in order to better identify the pathological mechanisms involved and to allow more efficient targeting of therapeutics. Through better understanding of this scheme, MGD may gain true disease status rather than being viewed as a mere dysfunction.