Gysbert van Setten

Dysfunctional Tear Syndrome A Delphi Approach to Treatment Recommendations

Purpose: To develop current treatment recommendations for dry eye disease from consensus of expert advice. Methods: Of 25 preselected international specialists on dry eye, 17 agreed to participate in a modified, 2-round Delphi panel approach. Based on available literature and standards of care, a survey was presented to each panelist. A two-thirds majority was used for consensus building from responses obtained. Treatment algorithms were created. Treatment recommendations for different types and severity levels of dry eye disease were the main outcome. Results: A new term for dry eye disease was proposed: dysfunctional tear syndrome (DTS). Treatment recommendations were based primarily on patient symptoms and signs. Available diagnostic tests were considered of secondary importance in guiding therapy. Development of algorithms was based on the presence or absence of lid margin disease and disturbances of tear distribution and clearance. Disease severity was considered the most important factor for treatment decision-making and was categorized into 4 levels. Severity was assessed on the basis of tear substitute requirements, symptoms of ocular discomfort, and visual disturbance. Clinical signs present in lids, tear film, conjunctiva, and cornea were also used for categorization of severity. Consensus was reached on treatment algorithms for DTS with and without concurrent lid disease. Conclusion: Panelist opinion relied on symptoms and signs (not tests) for selection of treatment strategies. Therapy is chosen to match disease severity and presence versus absence of lid margin disease or tear distribution and clearance disturbances.

Growth factors and ocular wound healing

Protein growth factors regulate many of the processes in vitro that are essential for the process of normal ocular wound healing, including migration, mitosis and differentiation of cells. This has led to the hypothesis that peptide growth factors play key roles in regulating normal ocular wound healing in vivo. A corollary to this concept is that insufficient action of growth factors causes impaired healing, and prolonged action of growth factors produces excessive scarring. If both of these concepts are correct, then the addition of exogenous protein growth factors should enhance healing of chronic ocular wounds and reducing prolonged actions of growth factors should limit excessive scarring. Although much remains to be understood about the role of growth factors in ocular development and wound healing, results of a substantial number of laboratory and clinical experiments indicate that these hypotheses are generally correct. This article reviews the results of pre-clinical experiments and clinical trials investigating the roles of protein growth factors in ocular development and wound healing.

Connective tissue growth factor in pterygium: simultaneous presence with vascular endothelial growth factor - possible contributing factor to conjunctival scarring.

Abstract Background. Various growth factors have been detected in pterygium and been associated with its vasculogenesis. The basic pathophysiological mechanisms responsible especially for the fibrotic activity in pterygium are, however, not yet known. Connective tissue growth factor (CTGF) has been shown to be substantially involved in various processes of fibrosis. We report on the presence of CTGF in pterygium and its simultaneous presence with vascular endothelial growth factor (VEGF). Methods. Samples of pterygium were collected during surgery with informed consent of the patients. Specific, non-commercial primary antibodies against CTGF were used to detect CTGF using immunohistochemistry. Specificity of antibodies was confirmed with Western-blot analysis. The same specimens were stained with commercial antibodies for VEGF. Additionally RT-PCR analysis was performed from pterygium samples. Results. CTGF was detected in the epithelium of all samples as well as in some stromal keratocytes. The RT-PCR confirmed the identity of CTGF in these samples. The staining pattern differed slightly from that of VEGF, which was detected in all samples. The control sections were negative. Conclusion. CTGF is present in the epithelium of a majority of pterygia and probably contributes to fibrosis. Simultaneous presence with VEGF suggests growth factor interaction and possible involvement in apoptotic dysregulation.

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.

Transforming growth factor-alpha is a constant component of human tear fluid

Growth factors are known as a family of polypeptides with powerful influences on angiogenesis, tumor growth and wound healing. Transforming growth factor-alpha (TGF-α) and epidermal growth factor (EGF) are structurally related peptides which bind to the same receptor, EGF-R, and also exert similar effects. EGF is a natural component of human tears, and ocular disease leads to decreased concentrations in tear fluid. Using a sensitive radioimmunoassay we investigated whether TGF-α is also to be considered a natural component of tear fluid and in which concentrations it occurs. All of 46 tear fluid samples from 24 volunteers contained TGF-α. The mean concentration was 161.4 pg TGF-α/ml (SD 11.6 pg). No statistically significant correlation was found between tear fluid flow and TGF-α concentration in the sample. However, the concentration of TGF-α in tear fluid decreased significantly with increasing total time of tear fluid collection (P = 0.002). TGF-α levels in samples collected from males (n=16) appeared to be higher (mean 247.0 pg/ml, SD 15.3 pg/ml) than in those from females (n=30; mean 180.0 pg/ml, SD 8.5 pg/ml; P = 0.05). No correlation was found between the age of the individuals and the concentration of TGF-α in their tear fluid. The findings show that TGF-α is, like EGF, a constant component of human tear fluid. The dependence of TGF-α concentration on tear fluid flow and the physiological importance of its presence for corneal integrity and ocular surface physiology, however, require further investigation.

Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye disease: a multicenter randomized trial.

Purpose The SANSIKA study was conducted to assess the treatment effect of 0.1% cyclosporine A cationic emulsion (CsA CE) eye drops on signs and symptoms of patients with severe dry eye disease (DED). Methods This was a multicenter, randomized, double-masked, 2-parallel-arm, 6-month phase III study with a 6-month open-label treatment safety follow-up. Patients with severe DED with corneal fluorescein staining (CFS) grade 4 on the modified Oxford scale were randomized to receive once-daily CsA CE (Ikervis®) or its vehicle. Results A total of 246 patients were randomized. The proportion of patients achieving ≥2 grades improvement in CFS and a 30% improvement in symptoms (Ocular Surface Disease Index [OSDI]) by month 6 was 28.6% with CsA CE vs 23.1% with vehicle (p = 0.326) (primary endpoint). Assessment of corneal damage showed greater improvement with CsA CE over vehicle in mean adjusted CFS change from baseline to month 6 (-1.764 vs −1.418, p = 0.037). There was a reduction in ocular surface inflammation assessed by human leukocyte antigen DR expression in favor of CsA CE at month 6 (p = 0.021). The mean OSDI change from baseline was −13.6 with CsA CE and −14.1 with vehicle at month 6 (p = 0.858). The main adverse event was instillation site pain (29.2% vs 8.9% in the CsA CE and vehicle groups, respectively), and it was mostly mild. Conclusions CsA CE was well-tolerated and effective in improving corneal damage and ocular surface inflammation and confirmed the positive benefit-risk ratio of this new formulation of CsA for the treatment of severe keratitis in DED.

Basic fibroblast growth factor in human tear fluid: detection of another growth factor

Abstract• Background: Topical application of various growth factors have shown promising experimental data in speeding up corneal wound healing. Similar effects have been reported for another group of proteins, fibroblast growth factors (FGFs). One of them, basic FGF (bFGF), stimulates the proliferation of cells of mesodermal as well as of neuroectodermal origin and is highly angiogenic. The aim of the present study was to investigate the presence of bFGF in human tear fluid. • Methods: After establishing an advanced enzyme-linked immunosorbent assay technique, tear fluid was collected from 15 healthy individuals before and after stimulation of reflex tearing. • Results: In none of the tear fluid samples collected prior to induction of reflex tearing could FGF be detected. Of the 15 samples collected during reflex tearing, six (40%) contained measurable amounts of bFGF. The amount of bFGF appeared to decrease with increasing tear fluid flow, suggesting a dilution effect. • Conclusion: This study gives strong evidence that bFGF, as previously shown for epidermal growth factor and transforming growth factor-α, may occur in human tear fluid of healthy individuals after induction of reflex tearing and, in very low concentrations, under normal conditions. Whether bFGF can to be considered a constant component of tear fluid, however, remains to be investigated.

Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting

Dry eye disease (DED) is a common, multifactorial ocular condition with major impact on vision and quality of life. It is now well recognized that the pathophysiology of chronic DED can include a cycle of inflammation involving both innate and adaptive immune responses. Recently, in vitro/in vivo models have been used to obtain a better understanding of DED‐related inflammatory processes at molecular/cellular levels although they do not truly reproduce the complex and chronic hallmarks of human DED. In clinical DED research, advanced techniques such as impression cytology, conjunctival biopsy, in vivo confocal microscopy and multiplex tear analyses have allowed an improved assessment of inflammation in DED patients. This was supported by the identification of reliable inflammatory markers including matrix metalloproteinase‐9, human leucocyte antigen‐DR or intercellular adhesion molecule‐1 in tears and impression cytology samples. One of the current therapeutic strategies focuses on breaking the inflammatory cycle perpetuating the ocular surface disease, and preclinical/clinical research has led to the development of promising anti‐inflammatory compounds. For instance, cyclosporine, already approved in the United States, has recently been authorized in Europe to treat DED associated with severe keratitis. In addition, other agents such as corticosteroids, doxycycline and essential fatty acids, through their anti‐inflammatory properties, show encouraging results. We now have a clearer understanding of the inflammatory processes involved in DED, and there is hope that the still emerging preclinical/clinical findings will be translated into new and highly effective therapies for patients in the near future.

Evidence of seasonality and effects of psychrometry in dry eye disease.

Current models consider the development of dry eye disease (DED) as a more or less continuous process with only minor daily variations. Clinical evidence, however, does suggest the existence of phase‐like recurring dry eye complaints that may be linked to seasonal environmental conditions. In this survey‐based study, we examined the influence of seasonality in dry eye pathophysiology.

Anterior lenticonus : Histological evaluation and approach for cataract surgery

Abstract Purpose: To present 2 cases of anterior lenticonus in patients without Alport’s syndrome, a surgical technique of cataract extraction in eyes with anterior lenticonus, and histological results of lenticonus specimens obtained intraoperatively. Setting: From St. Eriks Eye Clinic, Karolinska Institute, Stockholm, Sweden. Methods: Two otherwise healthy patients presented with anterior lenticonus but no history of Alport’s or other pathology. Best corrected visual acuity (BCVA) was decreased. Both patients had cataract extraction by phacoemulsification with intraocular lens implantation under topical anesthesia. Two continuous curvilinear capsulorhexes (CCCs) were created. The entire lenticonus was embedded in formaldehyde buffer 4% for histological analysis. Results: In the first patient, BCVA did not improve postoperatively because of amblyopia. The patient subjectively reported a substantial improvement in visual field clarity. The surgical and postoperative course in the other patient was uneventful. The sections were positive for collagen types IV and VI, and the arrangement of the collagen fibers was highly irregular. Conclusion: Anterior lenticonus was detected in patients without Alport’s syndrome who were otherwise healthy. A modified 2-step CCC technique can be used to make cataract surgery in such eyes safe and relatively easy.Purpose: To present 2 cases of anterior lenticonus in patients without Alports syndrome, a surgical technique of cataract extraction in eyes with anterior lenticonus, and histological results of lenticonus specimens obtained intraoperatively. Setting: From St. Eriks Eye Clinic, Karolinska Institute, Stockholm, Sweden. Methods: Two otherwise healthy patients presented with anterior lenticonus but no history of Alports or other pathology. Best corrected visual acuity (BCVA) was decreased. Both patients had cataract extraction by phacoemulsification with intraocular lens implantation under topical anesthesia. Two continuous curvilinear capsulorhexes (CCCs) were created. The entire lenticonus was embedded in formaldehyde buffer 4% for histological analysis. Results: In the first patient, BCVA did not improve postoperatively because of amblyopia. The patient subjectively reported a substantial improvement in visual field clarity. The surgical and postoperative course in the other patient was uneventful. The sections were positive for collagen types IV and VI, and the arrangement of the collagen fibers was highly irregular. Conclusion: Anterior lenticonus was detected in patients without Alports syndrome who were otherwise healthy. A modified 2‐step CCC technique can be used to make cataract surgery in such eyes safe and relatively easy.