PRÉCIS:We have developed through a consensus process 24 clinical recommendations for the comprehensive management of ocular surface inflammation in glaucoma patients, including diagnostic criteria, prevention measures, and treatment strategies according to ocular surface disease severity. PURPOSE:To obtain expert consensus on the diagnosis, prevention, and management of ocular surface inflammation (OSI) in patients with glaucoma. METHODS:An international steering committee of glaucoma and/or ocular surface disease (OSD) experts and a wider faculty of members from the Educational Club of Ocular Surface and Glaucoma (ECOS-G) collaborated to develop clinical recommendations on best practice in the management of OSI in glaucoma patients using a nonanonymous interactive quasi-Delphi process. Clinical recommendations were formulated by the steering committee based on an analysis of the recent literature to determine unmet needs, together with a web-based interactive survey of faculty members' opinion in seven identified areas of OSI management in glaucoma. Topics included (1) diagnosis of OSD, (2) diagnosis of OSI, (3) causes of OSI, (4) impact of OSD/OSI, (5) prevention of OSI, (6) treatment of OSI, and (7) inflammation and the deep structures of the eye. Faculty members were invited to vote on the clinical recommendations, and the steering committee then determined whether consensus had been achieved. RESULTS:Consensus was obtained on 24 clinical recommendations by 80%-100% of faculty members. There was consensus that OSI should be investigated in all glaucoma patients. The main prevention measure in glaucoma patients with pre-existing OSD was the elimination/minimisation of preserved medications, especially BAK-preserved eye drops. A subtractive treatment strategy rather than an additive strategy is recommended according to OSI/OSD severity to improve the ocular health and/or before glaucoma surgery. CONCLUSION:These recommendations for the management of OSI in glaucoma should be useful to guide decision-making in clinical practice.

Objectives To evaluate the validity and reliability of the new Fast Assessment of the Ocular Surface Trouble (FAST®) questionnaire for identifying glaucoma or ocular hypertension (OHT) patients at risk of ocular surface disease (OSD). Methods A multicenter, international, cross-sectional, epidemiological survey evaluated the most accurate interview items and ocular signs on the initial 14-item version of FAST® to develop a shorter version for routine, quick clinical use. Rasch analysis and least absolute shrinkage and selection operator (LASSO) method was used to reduce the number of items on the questionnaire. Sensitivity and specificity of FAST® were assessed with receiver operating characteristic (ROC) curves for the detection of OSD with the questionnaire and ophthalmic assessment. Results A total of 2308 eyes (1154 patients) were analyzed in this study by 92 ophthalmologists. The initial version of the FAST® indicated 60% of the subjects had OSD. Rasch analysis allowed removal of some clinical signs. The LASSO method allowed elimination of some items from the original questionnaire for a 9-item and a 6-item version of FAST®. For the 6-item questionnaire, the sensitivity and specificity were 71.9% and 74.3% respectively and the area under the curve was 0.815. Conclusions The FAST® questionnaire is a valid and reliable tool for use in routine clinical practice and in clinical trials. The short versions of the questionnaire allow quick detection of the majority of patients with OHT or glaucoma at risk of dry eye.

Preservatives used in topical glaucoma medications have a plethora of well-described toxic effects on the ocular surface. Such ocular toxicity is manifest clinically as ocular surface disease (OSD) and has been confirmed in epidemiologic, prospective clinical trials and studies in which patients are switched from preservative-added to preservative-free topical therapy. Such toxicity has implications not only for tolerability, but also for adherence and persistence with therapy that is known to be poor in glaucoma. Glaucoma medication is now widely available in preservative-free formulations, and the question arises as to which patients should receive preservative-free glaucoma therapy in preference to preservative-added medication. A case can be made for several subpopulations of patients who might particularly benefit from preservative-free medication: patients with existing OSD, older patients, younger adult patients, female patients, pediatric and juvenile patients, patients who work in air-conditioned environments or who use electronic screens frequently, patients with medical risk factors for OSD, patients in whom trabecular surgery may become indicated in the future, contact lens users, perhaps patients with Asian ethnicity and patients with severe or treatment-refractory glaucoma. Whilst arguments could be made for selecting patients for preservative-free medication on the basis of their existing risk of OSD, collectively, these patients form a significant proportion of the glaucoma patient population as a whole and, in the absence of any cost premium or positive indication for preservative-added medication, preservative-free glaucoma medication for all patients seems an appropriate strategy.

Preservatives used in topical glaucoma medications have a plethora of well-described toxic effects on the ocular surface. Such ocular toxicity is manifest clinically as ocular surface disease (OSD) and has been confirmed in epidemiologic, prospective clinical trials and studies in which patients are switched from preservative-added to preservative-free topical therapy. Such toxicity has implications not only for tolerability, but also for adherence and persistence with therapy that is known to be poor in glaucoma. Glaucoma medication is now widely available in preservative-free formulations, and the question arises as to which patients should receive preservative-free glaucoma therapy in preference to preservative-added medication. A case can be made for several subpopulations of patients who might particularly benefit from preservative-free medication: patients with existing OSD, older patients, younger adult patients, female patients, pediatric and juvenile patients, patients who work in air-conditioned environments or who use electronic screens frequently, patients with medical risk factors for OSD, patients in whom trabecular surgery may become indicated in the future, contact lens users, perhaps patients with Asian ethnicity and patients with severe or treatment-refractory glaucoma. Whilst arguments could be made for selecting patients for preservative-free medication on the basis of their existing risk of OSD, collectively, these patients form a significant proportion of the glaucoma patient population as a whole and, in the absence of any cost premium or positive indication for preservative-added medication, preservative-free glaucoma medication for all patients seems an appropriate strategy.

The etiology of glaucoma is multifactorial. Intraocular pressure (IOP) is the only modifiable factor in glaucoma management proven to alter the natural course of the disease. Currently, based on evidence-based glaucoma therapy, the only approach proven to be efficient in preserving visual function is lowering IOP. Lowering IOP by 20-40% has been shown to reduce the rate of progressive visual field loss by half. Despite the fact that IOP-lowering interventions reduce the risk of progression and delay the onset of glaucoma, its pathogenesis is controversial and not completely understood. In this matter, non-IOP-dependent risk factors appear to be responsible for around 50% of glaucoma cases. New drugs are now entering the clinic, along with new ways to deliver them. There is growing consensus that the future of glaucoma management will be based more on the optic nerve pathway from the retina to the visual cortex and will not be strictly limited to improving outflow or reducing inflow. But still, many future IOP-lowering options will be developed, including neuroprotective strategies aiming to directly prevent or significantly hinder neuronal cell damage. The goal of glaucoma treatment is to maintain the patient's visual function and related quality of life at a sustainable cost. The cost of treatment in terms of inconvenience and side effects as well as financial implications for the individual and society requires careful evaluation. In conclusion, IOP lowering is the only proven therapy for glaucoma at present. Neuroprotection may be clinically useful (based on one trial), but this needs to be confirmed. So far, we have no evidence of potential therapies related to ocular blood flow and glaucoma care, and evidence to support the use of acupuncture, vitamins, minerals, or herbal medicines such as marijuana for treating glaucoma is insufficient. (C) 2016 S. Karger AG, Basel

The purpose of the present study was to describe the prevalence, incidence and geographic variation of glaucoma in Denmark in the period from 1996 to 2011. Moreover, the aim was to identify the treatment patterns of glaucoma within the studied period.All Danish citizens were included throughout the study period. The National Prescription Registry was used to identify all claimed prescriptions for glaucoma medication.A total of 116,592 incident glaucoma patients were identified. Average age at onset was 66 years (range: 0-105 years), 55% were women. The prevalence of glaucoma increased from 0.79% to 1.72% during the investigated period. In 2011 glaucoma affected 3.76% of the population above 50 years and 10% in patients above 80 years. The age-specific incidence rate of glaucoma seemed to be constant and the increasing prevalence was primarily attributed to an aging population. We found the highest prevalence of glaucoma in the capital region of Denmark. Within the studied period the use of prostaglandin analogs and combination drugs increased, whereas the use of β-blockers, carbon anhydrase inhibitors and parasympathomimetic drugs decreased (p<0.001). Finally, the use of α2-adrenergic agonists remained unchanged. A total of 75% of the patients were treated with two or more glaucoma medications.Over all, the present study is the first to assess the frequency and the development of glaucoma in Denmark over a 15-year period. We find that glaucoma affects a little less than 2% of the total population and increases with age to reach a prevalence of more than 10% amongst people above 80 years. Generally, the present study is the largest nation-wide study ever made and must be a close-to-real-life-picture of the utilization of glaucoma medication on a national scale. Our findings confirm other recent estimations on an increasing burden of glaucoma globally.

A 9-year-old girl with neurofibromatosis type 1 (NF1) (Fig. 1A) and a 1-year history of controlled left unilateral juvenile glaucoma, related to congenital ectropion uveae, presented with a rapid, unexplained, painless visual loss in the left eye. Eight months after the onset of visual loss, best corrected visual acuity was 20/20 in the right and 20/200 in the left eye. A relative afferent pupillary defect was observed in the left eye. Right eye examination was normal. There was a left minimal proptosis and a mild congenital ptosis. Slit-lamp examination disclosed ectropion uveae (Fig. 1B) and fundoscopy showed a glaucomatous cupped optic disc with a normally coloured neuro–retinal rim (Fig. 1C, D). Ishihara colour vision and eye motility were normal. Intraocular pressure was 14/14 mmHg on topical prostaglandin analogue treatment. Automated visual fields disclosed an unexplained left central scotoma, in addition to glaucoma-related arcuate defects (Fig. 1E, F). Cerebral and orbital magnetic resonance imaging (MRI) revealed a lesion surrounding the left intracranial portion of the optic nerve, extending into the posterior part of the optic canal (Fig. 1G).The lesion was isointense to cerebrospinal fluid (CSF) on T1- and T2-weighted images without enhancement after gadolinium injection, and an arachnoid cyst was suspected. The patient underwent decompression surgery with removal of thin, lobulated cysts around the chiasm and optic nerve. Vision did not recover postoperatively. Histopathological examination by routine paraffin technique and light microscopy demonstrated cyst walls composed of a collagen-rich, fibrillar tissue, surrounding spaces partially lined by an epithelium-like cell layer (Fig. 1H). A few psammoma bodies were found (Fig. 1I). Prussian blue stain depicted large areas of previous spontaneous bleedings within the lesion (Fig. 1J). Immunohistochemistry demonstrated that the cells of the walls reacted with vimentin antibodies (clone 3B4,), but the epithelium-like cells did not (Fig. 1H). All cells were negative for cytokeratins, (clone AE1/AE3 + 8/18, detecting cytokeratins no.: 1, 4, 5, 7, 8, 10, 13, 14, 18 and 19), glial fibrillar acidic protein (polyclonal antibody) and S-100 protein (polyclonal antibody). In summary, the tissue morphology indicated thickened dura mater and leptomeninges with a few meningothelial cells, consistent with an arachnoid cyst. (A) 9-year-old girl with neurofibromatosis type 1, showing typical café-au-lait skin pigmentations. (B) Congenital ectropion uveae of the left iris. (C) Normal right optic disc. (D) Left cupped optic disc. (E) Left visual field disclosing a paracentral scotoma in addition to glaucoma-related arcuate defects. (F) Normal right visual field (Octopus©) shown for comparison. (G) T2-weighted coronal MRI scan disclosing an arachnoid cyst surrounding the left optic nerve (asterisk). (H) Micrograph of the arachnoid cyst. The cyst wall consists of fibrillar material lined by a few epithelial-like cells. (Haematoxylin and eosin stain [H&E]; original magnification × 100.) (I) Cyst wall in higher magnification. A psammoma body is seen in purple. (H&E; original magnification × 250.) (J) Part of cyst wall. The blue areas indicate iron deposition from previous bleedings. (Prussian blue stain; original magnification × 50). Optic neuropathies are common findings in NF1 and are usually related to gliomas. Our patient had stable juvenile glaucoma caused by congenital ectropion uveae, a neural-crest-derived anterior segment dysgenesis syndrome which can be associated with NF1 (Trovó-Marqui et al. 2004). The occurrence of unexplained central visual loss, despite controlled glaucoma, prompted neuroimaging, which disclosed an intracranial arachnoid cyst extending into the optic canal, possibly precipitating the central visual loss by compression. Radiologically, orbital arachnoid cysts may mimic gliomas because the high water content of gliomatous tissue produces MRI signals identical to those of CSF (Brodsky 1993; Akor et al. 2003). In our case the lack of contrast enhancement supported the arachnoid cyst diagnosis (Cincu et al. 2007), but did not rule out the glioma. Arachnoid cysts are intracranial, space-occupying lesions of unknown pathogenesis. They are typically stable in size over time and mass symptoms are exceedingly rare (Cincu et al. 2007). Symptomatic cyst expansion can, among other causes, be related to intracystic haemorrhage (Cincu et al. 2007) and histopathology in the present case indicated previous bleeding in the cyst wall. Benign distension of normal fibrovascular tissue surrounding the visual pathways has been reported as a possible cause of compressive optic neuropathies (Akor et al. 2003). Although, as in our case, vision may not improve after surgery, biopsy for diagnosis and decompression may be warranted in atypical cases. In conclusion, in NF1, an intracranial arachnoid cyst can precipitate visual loss in a glaucomatous optic nerve, related to ectropion uveae. Glaucoma does not cause reduced central vision before the end stage of the disease, whereas central visual loss can be the presenting feature of a compressive optic neuropathy (Akor et al. 2003; Claes et al. 2006). Early detection by neuroimaging is prompted when unexplained, central visual loss occurs in glaucoma.

The risk of developing glaucoma after paediatric cataract surgery is substantial. A number of risk factors have been associated with the post-operative development of glaucoma, the most important and consistent one being age at the time of surgery. Glaucoma occurs in up to one-third of patients who have had cataract surgery at an early age (<9 months), with a particularly high risk when surgery is performed during the first four weeks of life. The discovery of glaucoma in children <2 years of age often requires additional measurements apart from the intraocular pressure measurement. Young children have elastic eye bulbs, and an increase in axial length, an increase in corneal diameter and/or an increase in excavation of the optic disc may be the only indication of glaucoma. The risk of glaucoma after paediatric cataract surgery continues throughout life, and it is therefore pertinent to perform glaucoma evaluation of these patients during follow-up.

PURPOSE:To determine the risk of glaucoma after surgery for pediatric cataract and to evaluate risk factors for glaucoma. METHODS:A population-based cohort of all children in Denmark aged 0 to 17 years during the period 1977 to 2001, who underwent surgery for pediatric cataract, was established by retrospective chart review. Glaucoma cases were defined as those in which glaucoma surgery (trabeculectomy and/or diode laser transscleral cyclophotocoagulation) was performed and/or permanent medical therapy prescribed after cataract surgery. RESULTS:Of 946 eyes (595 patients) undergoing pediatric cataract surgery, 72 eyes (48 patients) had subsequent development of glaucoma. Early surgery (<9 months of age) was associated with a 7.2-fold increased risk of glaucoma compared with late surgery (> or =9 months of age). Ten years after cataract surgery, glaucoma developed in 31.9% (95% confidence interval [CI], 24.4-41.1) of children undergoing surgery before 9 months of age compared with 4.1% (95% CI, 2.4 to 6.8) of children aged > or =9 months at the time of surgery. Glaucoma cases continued to occur more than 10 years after cataract surgery. After adjustment for age at surgery, no other risk factor appeared important. CONCLUSIONS:The risk of glaucoma after surgery for pediatric cataract is substantial and particularly high for those below 9 months of age at the time of surgery. Because the increased risk persists for many years after surgery, careful continuous monitoring for glaucoma is mandatory.

PURPOSE:Is the new micropenetrating, clear-cornea procedure, intrastromal diathermal keratostomy (IDK), an alternative to the intricate "modern trabeculectomy"? METHODS:Prospective multicenter study. Four surgeons from 4 Danish eye departments attended an IDK course and subsequently decided when to start their consecutive IDK series. The data were analyzed centrally. Injection of preoperative, subconjunctival doses of mitomycin C (MMC) was recommended according to risk-of-failure. A total of 54 eyes from 48 patients with advanced and complicated glaucomas (mean age 65 y) and preoperative mean intraocular pressure (IOP) of 29 mm Hg were studied. RESULTS:At 10 months (range: 3 to 34 mo) the total success rate, employing traditional IOP success criteria (IOP< or =18 mm Hg and postoperative IOP decrease > or =30%), was 87% (47 of 54 eyes). In the 69% (37 of 54 eyes) without medication, the final IOP+/-SD was 11+/-3.5 mm Hg. Employing new IOP success criteria (IOP< or =15 mm Hg and postoperative IOP decrease> or =30%) for severe glaucoma (cup/disc ratio> or =0.8) and traditional criteria for moderate glaucoma (cup/disc ratio< or =0.7) the success rates were 76% and 80% and the mean postoperative IOP+/-SD were 10+/-2.5 mm Hg and 13+/-2.5 mm Hg, respectively. No serious complications (malignant glaucoma, endophthalmitis) were seen. The success rate for the most experienced and the less experienced surgeons, with risk-of-failure factors per eye of 1.3 and 1.2, was similar at 88% and 86%, respectively. The "knife time" for the experienced surgeon averaged 15 minutes (range: 10 to 20 min). The success rate (traditional criteria) after IDK revision with internal needling was 69%. CONCLUSIONS:MMC IDK seems to be simpler and quicker than the modern trabeculectomy, and with similar success rate and safety. Revision by internal needling is easy and efficient. Thus, MMC IDK may be a valid alternative and may also be recommended after failed MMC trabeculectomy, replacing shunting. Randomized, controlled studies are indicated.

This Acta Ophthalmologica supplement includes two papers describing the clinical effects of tafluprost (Taflotan®; Santen Oy, Helsinki, Finland), a new bi-fluorinated prostaglandin F2α analogue developed for the treatment of glaucoma. The first article reports an investigation into the systemic pharmacokinetics and intraocular pressure (IOP)-lowering effects of tafluprost in healthy volunteers (Uusitalo et al. 2008). The second paper compares the IOP-lowering efficacy of tafluprost in a conventional preserved formulation with that of preservative-free tafluprost in patients suffering from glaucoma or ocular hypertension (Hamacher et al. 2008). Tafluprost is the first prostaglandin analogue to be available in a preservative-free formulation. The efficacy and safety of tafluprost has been investigated in several clinical trials. A 6-month study showed that tafluprost 0.0015% once/day was at least as effective as timolol 0.5% twice/day (achieving IOP reductions of 5–7 mmHg and 4–6 mmHg, respectively). This effect was maintained for ≤ 12 months (Taflotan Summary of Product Characteristics; [2008]). Another 6-month study showed IOP reductions of 6–8 mmHg with tafluprost 0.0015% once/day and 7–9 mmHg with latanoprost 0.005% once/day (Taflotan Summary of Product Characteristics; [2008]). These data demonstrate that tafluprost is effective at lowering IOP. Preservatives are added routinely to multi-dose antiglaucoma medications. The most commonly used preservative is benzalkonium chloride (BAC). Historically, BAC has been used as a preservative and ocular penetration enhancer for topically applied medications because it destroys tight junctions and thus may facilitate paracellular diffusion across the ocular surface (Okabe et al. 2005; McCarey & Edelhauser 2007; Majumdar et al. 2008). There is a perception that BAC is required for ocular penetration and good drug activity. However, Pellinen & Lokkila (2008) found equivalent concentrations of tafluprost acid in the aqueous humour of rabbits following topical applications of preserved and preservative-free tafluprost solutions. Uusitalo et al. (2008) report comparable reductions in IOP by preservative-free and preserved formulations of tafluprost. Hamacher et al. (2008) compared the IOP-lowering efficacy of preserved versus preservative-free tafluprost eyedrops in patients diagnosed with either primary open-angle glaucoma or ocular hypertension. No differences were found between the two groups of patients in terms of the IOP-lowering efficacy of the medications throughout the 4-week treatment period of this study (Hamacher et al. 2008). Likewise, no differences in IOP reductions were found between BAC-preserved and BAC-free formulations of β-blockers (Baudouin & de Lunardo 1998; Bron et al. 2003; Easty et al. 2006) and travoprost (Lewis et al. 2007). These data provide clear evidence that BAC is not required for IOP reduction, at least not with lipophilic drugs such as prostaglandins. Virtually, all preservatives have inherent toxic properties associated with their mechanism as preservatives, and there is an increasing body of evidence to support the hypothesis that BAC has a concentration-dependent toxic action on the ocular surface (De Saint Jean et al. 1999; Debbasch et al. 2001). In vitro studies have demonstrated that high concentrations of BAC induce oxidative stress (Debbasch et al. 2001), promote the expression of inflammatory and apoptotic markers (De Saint Jean et al. 1999), and result in epithelial cell death (Rolando et al. 1991). In vivo models have also confirmed the adverse effects of BAC (Labbé et al. 2006). In rabbit models, preserved formulations of antiglaucoma medications display significantly more adverse effects than preservative-free formulations (Pisella et al. 2000). The relative toxicity of preserved antiglaucoma formulations appears to be directly proportional to their respective concentrations of BAC (Guenoun et al. 2005; Brasnu et al. 2008). In the two short-term studies reported in this supplement, both the preserved and preservative-free tafluprost formulations were generally well tolerated (Hamacher et al. 2008; Uusitalo et al. 2008). In clinical practice, many patients with glaucoma use several medications simultaneously, leading to substantial exposure to preservatives such as BAC. Ocular signs and symptoms have been reduced when patients switch from preserved to preservative-free formulations, or reduce the number of preserved eyedrops administered (Pisella et al. 2002; Jaenen et al. 2007). Thus, the data from the studies published in this supplement (Hamacher et al. 2008; Uusitalo et al. 2008) demonstrate that the preservative-free tafluprost formulation achieves a reduction in IOP equivalent to that obtained by the preserved formulation. Further larger-scale and longer-term studies are required to assess the effects of preservative-free tafluprost ophthalmic solution in the treatment of glaucoma. For patients suffering from dry or sensitive eyes, tafluprost seems to be a beneficial addition to the prostaglandin glaucoma medications group. The author has acted as a paid consultant to Santen Inc.

Background: In the clinical management of patients at risk for or diagnosed with primary open-angle glaucoma (POAG), the aim of medical treatment is to reduce intraocular pressure (IOP) and then maintain it over time at a level that preserves both the structure and function of the optic nerve.Objective: The objective of this report was to establish a consensus on the criteria that should be used to determine the characteristics of IOP-lowering medication.Methods: Discussion was held among a panel of 12 physicians considered to be experts in glaucoma to develop a consensus on the criteria used by them to determine the characteristics of the IOP-lowering medication chosen for initial monotherapy and adjunctive treatment of ocular hypertension (OHT) or POAG. Consensus development combined available evidence and the impressions of these physicians regarding the clinical effectiveness of IOP-lowering medication for OHT and POAG. Once the panel identified the criteria, the order of priority and the relative importance of these criteria were then established in the setting of 3 risk categories (low, medium, and high) for a patient to experience significant visual disability from glaucoma over their expected life span.Results: The panel identified 5 criteria to determine the characteristics of IOP-lowering medication for OHT and POAG: IOP-lowering effect, systemic adverse events (AEs), ocular tolerability, compliance/administration, and cost of treatment. IOP-lowering effect was consistently ranked as the highest priority and cost as the lowest. The priority of compliance/administration did not vary by clinical situation. Systemic AEs and ocular tolerability were ranked as higher priorities in initial monotherapy than in adjunctive treatment and ranked lower as the risk for visual disability increased. The priority given to the criteria used to determine clinical effectiveness varied both with the risk for functional vision loss from glaucoma and whether initial monotherapy or adjunctive treatment was being considered.Conclusion: Glaucoma treatment should be assessed with regard to the need not only to lower IOP but also to minimize systemic and ocular AEs, promote patient compliance, and minimize cost. The order of priority and relative importance given to these treatment criteria will vary as part of individualizing patient care.