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The aim of this study was to examine the 2‑year results of filtering trabeculotomy (FTO) compared to conventional trabeculectomy (TE) in primary open-angle glaucoma, pseudoexfoliation glaucoma, and pigmentary glaucoma.Thirty consecutive patients after FTO and 87 patients after TE were included in the study. Both groups were matched 1:3 according to age and intraocular pressure (IOP). The primary endpoint was reaching the target IOP after 2 years. An IOP without medication of ≤ 18 mm Hg and an IOP reduction of ≥ 30% were defined as complete success, and as qualified success with medication. Secondary endpoints were mean IOP reduction, resulting visual acuity, complications and subsequent operations. The surgical technique of the FTO is available as a video for this article.The 2‑year data from 27 patients with FTO and 68 patients with TE were evaluated. The patients in both groups were matched according to age and IOP but were also homogeneous with respect to visual acuity, gender, and medication. The preoperative IOP with glaucoma medication was 23.0 mm Hg in both groups. According to the defined criteria, a qualified 2‑year success was achieved in 70.4% of the FTO group and in 77.6% of the TE group (p = 0.60) and a complete 2‑year success in 33.3% of the FTO group and 56.7% of the TE group (p = 0.07). The IOP was significantly reduced after 24 months in both surgical groups (p 0.001) and was 12.8 mm Hg in the FTO group and 11.0 mm Hg in the TE group. Visual acuity was moderately reduced postoperatively but did not differ significantly between the two groups. Complication and reoperation rates were low and not different between both groups.The results of FTO and TE are largely similar after 2 years in terms of complete and qualified success rate, lowering of IOP, visual acuity, and complications.ZIEL: Ziel dieser Studie war es, die 2‑Jahres-Ergebnisse der filtrierenden Trabekulotomie (FTO) im Vergleich zur konventionellen Trabekulektomie (TE) bei primärem Offenwinkelglaukom, Pseudoexfoliationsglaukom und Pigmentglaukom zu untersuchen.Es wurden 30 konsekutive Patienten nach FTO und 87 Patienten nach TE nach intraokularem Druck (IOD) und Alter im Verhältnis 1:3 gematcht. Primärer Endpunkt war das Erreichen des Zieldrucks nach 2 Jahren. Als vollständiger Erfolg wurde ein IOD ohne Medikamente von ≤ 18 mm Hg bei gleichzeitiger IOD-Reduktion um ≥ 30 % definiert, als qualifizierter Erfolg, wenn hierfür zusätzlich Medikamente erforderlich waren. Sekundäre Endpunkte waren mittlere Drucksenkung, resultierende Sehschärfe, Komplikationen und nachfolgende Operationen. Die Operationstechnik der filtrierenden Trabekulotomie ist als Video zu diesem Beitrag abrufbar.Zwei-Jahres-Daten konnten von 27 Patienten aus der FTO-Gruppe und 68 Patienten aus der TE-Gruppe erhoben werden. Die Patienten beider Gruppen wurden vor Beginn der Studie bezüglich Alter und IOD gematcht, waren aber auch bezüglich Sehschärfe, Geschlecht und Medikation nicht unterschiedlich. Der Median des präoperativen IOD unter Therapie betrug in beiden Gruppen 23,0 mm Hg. Nach den oben genannten Kriterien wurde ein qualifizierter 2‑Jahres-Erfolg bei 70,4 % der FTO-Gruppe und bei 77,6 % der TE-Gruppe erzielt (p = 0,60), ein vollständiger 2‑Jahres-Erfolg bei 33,3 % der FTO-Gruppe und bei 56,7 % der TE-Gruppe (p = 0,07). Beide Operationsmethoden senkten den Augeninnendruck nach 24 Monaten signifikant (p 0,001), und zwar auf 12,8 mm Hg in der FTO-Gruppe und 11,0 mm Hg in der TE-Gruppe. Die Sehschärfe war postoperativ bei beiden Gruppen etwas verringert, unterschied sich jedoch nicht signifikant zwischen beiden Gruppen. Komplikations- und Reoperationsrate waren gering und unterschieden sich nicht zwischen den Gruppen.FTO und TE sind nach 2 Jahren weitgehend gleichwertig bezüglich Zieldruck, IOD-Senkung, Sehschärfe und Komplikationen.

The primary therapy of all forms of primary and secondary congenital glaucoma is surgical. In the last few decades, the options for customized surgical approach to different types of childhood glaucoma have significantly developed. In particular, circumferential trabeculotomy has shown some superiority over conventional trabeculotomy and is now also used to treat secondary congenital glaucoma. Goniotomy is still a valid alternative. Tube implants in childhood glaucoma still need improvements.

To quantify the results of childhood glaucoma treatment over time in a cohort of children with different types of childhood glaucoma. A retrospective cohort study of consecutive cases involving children with primary congenital glaucoma, primary juvenile, and secondary juvenile glaucoma at the Childhood Glaucoma Center, University Medical Center Mainz, Germany from 1995 to 2015 was conducted. The main outcome measure was the long-term development of intraocular pressure. Further parameters such as surgical success, refraction, corneal diameter, axial length, and surgical procedure in children with different types of childhood glaucoma were evaluated. Surgical success was defined as IOP < 21 mmHg in eyes without a need for further intervention for pressure reduction. A total of 93 glaucomatous eyes of 61 childhood glaucoma patients with a mean age of 3.7 ± 5.1 years were included. The overall mean intraocular pressure at first visit was 32.8 ± 10.2 mmHg and decreased to 15.5 ± 7.3 mmHg at the last visit. In the median follow-up time of 78.2 months, 271 surgical interventions were performed (130 of these were cyclophotocoagulations). Many (61.9%) of the eyes that underwent surgery achieved complete surgical success without additional medication. Qualified surgical success (with or without additional medication) was reached by 84.5% of the eyes.

Childhood glaucoma is a heterogeneous disease and can be associated with various genetic alterations. The aim of this study was to report first results of the phenotype–genotype relationship in a German childhood glaucoma cohort. Forty-nine eyes of 29 children diagnosed with childhood glaucoma were prospectively included in the registry. Besides medical history, non-genetic risk factor anamnesis and examination results, genetic examination report was obtained (23 cases). DNA from peripheral blood or buccal swab was used for molecular genetic analysis using a specific glaucoma gene panel. Primary endpoint was the distribution of causative genetic mutations and associated disorders. Median age was 1.8 (IQR 0.6; 3.8) years, 64% participants were female. Secondary childhood glaucoma (55%) was more common than primary childhood glaucoma (41%). In 14%, parental consanguinity was indicated. A mutation was found in all these cases, which makes consanguinity an important risk factor for genetic causes in childhood glaucoma. CYP1B1 (30%) and TEK (10%) mutations were found in primary childhood glaucoma patients. In secondary childhood glaucoma cases, alterations in CYP1B1 (25%), SOX11 (13%), FOXC1 (13%), GJA8 (13%) and LTBP2 (13%) were detected. Congenital cataract was associated with variants in FYCO1 and CRYBB3 (25% each), and one case of primary megalocornea with a CHRDL1 aberration. Novel variants of causative genetic mutations were found. Distribution of childhood glaucoma types and causative genes was comparable to previous investigated cohorts. This is the first prospective study using standardized forms to determine phenotypes and non-genetic factors in childhood glaucoma with the aim to evaluate their association with genotypes in childhood glaucoma.

Purpose To evaluate long-term results of glaucoma surgery in newborn and infants with glaucoma. Methods Seventy-nine eyes of 52 children (age: 3 weeks-15.3 years) with primary congenital or secondary glaucoma treated between 2015 and 2017 were included. The median follow-up time was 3.9 years. Conventional probe trabeculotomy, 360° catheter-assisted trabeculotomy, filtering and cyclodestructive surgery were compared. Strict criteria for surgical success were applied: Complete surgical success (IOP below target IOP, no further surgery) and incomplete surgical success (additional surgery allowed) were analyzed, and IOP at baseline and last follow-up was compared. Results Intraocular pressure (IOP) was significantly reduced in primary congenital (preoperative IOP: 27.8 ± 7.5 mmHg vs. postoperative IOP: 14.2 ± 4.5 mmHg) and secondary glaucoma (preoperative IOP: 29.2 ± 9.1 mmHg vs. postoperative IOP: 16.6 ± 4.7 mmHg). 90% of all eyes reached target IOP with or without medication allowing for additional surgeries. As first surgery, 360° catheter-assisted trabeculotomy had a tendency to higher surgical success than other surgical approaches, while cyclodestructive procedures had lowest. Conclusions We found very promising surgical results in our childhood glaucoma patient group. Surgical success in both congenital and secondary glaucoma was high.

Severe congenital ophthalmological malformations and glaucoma might be an important occasional feature in patients with Coffin-Siris syndrome (CSS), especially Coffin-Siris syndrome 9 (CSS9, OMIM #615866) caused by SOX11 mutation. Recently, primary (open-angle) glaucoma was described in two children with the most common form of Coffin-Siris syndrome, CSS1 (OMIM #135900) by ARID1B (AT-rich interaction domain-containing protein 1B) gene mutation. In this article, we present the first report of glaucoma with Coffin-Siris syndrome 9 as well as the first report of secondary glaucoma with any form of Coffin-Siris syndrome. These findings indicate that secondary glaucoma is an occasional finding in patients with Coffin-Siris syndrome.A child with secondary childhood glaucoma and additional ocular manifestations was evaluated and treated at the childhood glaucoma centre in Mainz, Germany. Examination under general anaesthesia revealed ocular anterior segment dysgenesis (ASD) (Peters type iridocorneal dysgenesis) in combination with congenital limbal stem cell deficiency (LSCD), aniridia, and cataract. The patient also had multiple other congenital anomalies and severe developmental delay. To explain his combination of anomalies, molecular genetic analysis from peripheral blood was performed in late 2018 and early 2019. Following normal findings with a panel diagnostic of 18 genes associated with congenital glaucoma, whole exome sequencing was performed and revealed a novel likely pathogenic heterozygous variant c.251GT, p.(Gly84Val) in the SOX11 gene (SRY-related HMG-box gene 11). The variant had occurred de novo. Thus, the multiple congenital anomalies and developmental delay of the patient represented Coffin-Siris syndrome 9 (CSS9, OMIM #615866).When eye diseases occur in combination with other systemic features, genetic analysis can be seminal. Results indicate that glaucoma is an occasional feature of patients with Coffin-Siris syndrome. As early treatment may improve the visual outcome of patients with glaucoma, we suggest that patients with Coffin-Siris syndrome should receive specific ophthalmological screening.

PurposeWe used exact matching for a highly balanced comparison of ab interno trabeculectomy (AIT) with the trabectome to trabeculectomy with mitomycin C (TRAB).Methods5485 patients who underwent AIT were exact-matched to 196 TRAB patients by baseline intraocular pressure (IOP), number of glaucoma medications, and glaucoma type. Nearest-neighbor-matching was applied to age. Success was defined as a final IOP of less than 21 mmHg, IOP reduction of at least 20% reduction from baseline, and no secondary surgical interventions. Outcomes were measured at 1, 3, 6, 12, 18, and 24 months.Results165 AIT could be matched to 165 TRAB. The mean baseline IOP was 22.3±5.6 mmHg, and the baseline number of glaucoma medications was 2.7±1.1 in both groups. At 24 months, IOP was reduced to 15.8±5.2 mmHg in AIT and 12.4±4.7 mmHg in TRAB. IOP was lower than baseline at all visits (p0.01). Secondary surgical interventions had the highest impact on success and became necessary in 15 AIT and 59 TRAB patients. Thirty-two challenging events occurred in TRAB and none in AIT.ConclusionBoth AIT and TRAB reduced IOP and medications. This reduction was more significant in TRAB but at the expense of four times as many secondary interventions.Key messagesDespite vastly different IOP reduction and safety profile, ab interno trabeculectomy with the Trabectome and trabeculectomy with mitomycin C are both used as primary glaucoma surgeries. Exact matching allowed us to strictly focus on identical IOP and medications to create highly similar patient pairs for a balanced comparison that cannot be accomplished short of a randomized controlled trial. We found that trabeculectomy could achieve low IOPs and independence from drops, but trabeculectomies often required postoperative interventions. Trabectome patients had a lesser reduction of IOP and drops but needed far fewer interventions.

Purpose We used exact matching for a highly balanced comparison of ab interno trabeculectomy (AIT) with the trabectome to trabeculectomy with mitomycin C (TRAB). Methods A total of 5485 patients who underwent AIT were exact-matched to 196 TRAB patients by baseline intraocular pressure (IOP), number of glaucoma medications, and glaucoma type. Nearest-neighbor–matching was applied to age. Success was defined as a final IOP of less than 21 mmHg, IOP reduction of at least 20% reduction from baseline, and no secondary surgical interventions. Outcomes were measured at 1, 3, 6, 12, 18, and 24 months. Results A total of 165 AIT could be matched to 165 TRAB. The mean baseline IOP was 22.3 ± 5.6 mmHg, and the baseline number of glaucoma medications was 2.7 ± 1.1 in both groups. At 24 months, IOP was reduced to 15.8 ± 5.2 mmHg in AIT and 12.4 ± 4.7 mmHg in TRAB. IOP was lower than baseline at all visits (p p p p > 0.01). Secondary surgical interventions had the highest impact on success and became necessary in 15 AIT and 59 TRAB patients. Thirty-two challenging events occurred in TRAB and none in AIT. Conclusion Both AIT and TRAB reduced IOP and medications. This reduction was more significant in TRAB but at the expense of four times as many secondary interventions.

PurposeTo compare 2-year results of a filtering trabeculotomy (FTO) to conventional trabeculectomy (TE) in open-angle glaucoma by exact matching.Methods110 patients received an FTO and 86 a TE. FTO avoided the need for an iridectomy due to a preserved trabeculo-Descemet window anterior to the scleral flap. TE employed a trabecular block excision and iridectomy. Mitomycin C was used in both. FTO and TE were exact-matched by baseline intraocular pressure (IOP) and the number of glaucoma medications. Complete and qualified success (IOP ≤18 mmHg and IOP reduction ≥ 30%, with or without medication) were primary endpoints. IOP, visual acuity (BCVA), complications and intervention were secondary endpoints.Results44 FTO were exact-matched to 44 TE. The IOP baseline in both groups was 22.5±4.7 mmHg on 3±0.9 medications. At 24 months, complete success was reached by 59% in FTO and 66% in TE and qualified success by 59% in FTO and 71% in TE. In FTO, IOP was reduced to 12.4±4.3 mmHg at 12 months and 13.1±4.1 mmHg at 24 months. In TE, IOP was 11.3±2.2 mmHg at 12 months and 12.0±3.5 mmHg at 24 months. Medications could be reduced at 24 months to 0.6±1.3 in FTO and 0.2±0.5 in TE. There were no significant differences between the two groups in IOP, medications, complications or interventions at any point.ConclusionModifying aqueous flow through a limited trabeculotomy in FTO yielded clinical outcomes similar to traditional TE but allowed to avoid an iridectomy.

Background: To compare two-year results of a filtering trabeculotomy (FTO) to conventional trabeculectomy (TE) in open-angle glaucoma by exact matching. Methods: 110 patients received an FTO and 86 a TE. FTO avoided the need for an iridectomy due to a preserved trabeculo-descemet window anterior to the scleral flap. TE employed a trabecular block excision and iridectomy. Mitomycin C was used in both. FTO and TE were exact matched by baseline intraocular pressure (IOP) and the number of glaucoma medications. Complete and qualified success (IOP ≤18 mmHg and IOP reduction ≥ 30%, with or without medication) were primary endpoints. IOP, visual acuity (BCVA), complications and intervention were secondary endpoints. Results: 44 FTO were exact matched to 44 TE. The IOP baseline in both groups was 22.5±4.7 mmHg on 3±0.9 medications. At 24 months, complete success was reached by 59% in FTO and 66% in TE, and qualified success by 59% in FTO and 71% in TE. In FTO, IOP was reduced to 12.4±4.3 mmHg at 12 months and 13.1±4.1 mmHg at 24 months. In TE, IOP was 11.3±2.2 mmHg at 12 months and 12.0±3.5 mmHg at 24 months. Medications could be reduced at 24 months to 0.6±1.3 in FTO and 0.2±0.5 in TE. There were no significant differences between the two groups in IOP, medications, complications or interventions at any point. Conclusion: Modifying aqueous flow through a limited trabeculotomy in FTO yielded clinical outcomes similar to traditional TE but allowed to avoid an iridectomy.

Purpose To compare the outcomes of canaloplasty and trabeculectomy in open-angle glaucoma. Methods This prospective, randomized clinical trial included 62 patients who randomly received trabeculectomy (n = 32) or canaloplasty (n = 30) and were followed up prospectively for 2 years. Primary endpoint was complete (without medication) and qualified success (with or without medication) defined as an intraocular pressure (IOP) of ≤18 mmHg (definition 1) or IOP ≤21 mmHg and ≥20% IOP reduction (definition 2), IOP ≥5 mmHg, no vision loss and no further glaucoma surgery. Secondary endpoints were the absolute IOP reduction, visual acuity, medication, complications and second surgeries. Results Surgical treatment significantly reduced IOP in both groups (p

Background The topic of retinal neurodegeneration in PD is controversial, therefore the objective was to compare macular ganglion cell complex (mGCC) and peripapillary retinal nerve fiber layer (pRNFL) thickness in PD using 2 Spectral-Domain (SD) Optical Coherence Tomography (OCT) devices. Methods In total, 146 eyes of 130 age-similar patients were included, of these 46 eyes of 30 PD patients, 60 eyes of 60 glaucoma patients and 40 eyes of 40 healthy controls. Peripapillary RNFL and mGCC were measured. Correlation analyses were performed for evaluation of association between pRNFL or mGCC and PD severity using the Movement Disorder Society (MDS)-Unified Parkinson Disease Rating Scale (UPDRS). Scatterplots were used to evaluate relationships between disease duration, dopamine dose, olfactory assessment and retinal thickness. Results No significant difference was found for both eyes of PD patients compared to healthy subjects neither for overall mGCC nor each sector. However, the ipsilateral eye to the most-affected body side with bradykinesia in PD patients had a statistically significant thinner superior pRNFL compared to healthy controls (P = 0.03). There was no significant correlation between pRNFL or mGCC and disease severity; also, the scatterplots did not indicate a correlation between disease duration, dopamine dose, olfactory testing and OCT results. Conclusions Imaging of the retina revealed thinning of some retinal layers of the ipsilateral eye to the most-affected body side in PD patients compared to healthy controls. Peripapillary RNFL and mGCC did not correlate to disease severity; however, this was a fairly small and heterogeneous group of PD patients.

In this editions’ ‘Experts Opinion’, the management of hy-potony and choroidal effusion following glaucoma filtration surgery is discussed. We are delighted to welcome Clinical Associate Professor Ivan Goldberg and Professor Franz Grehn and Paul Chew to the panel to provide opinion on this very challenging clinical situation.

Juliane Matlach,1,* Matthias Hipp,1,* Martin Wagner,2,3 Peter U Heuschmann,2,3 Thomas Klink,1 Franz Grehn11Department of Ophthalmology, 2Institute of Clinical Epidemiology and Biometry, 3Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany*These authors contributed equally to this workPurpose: The objective of the study reported here was to evaluate the outcome of a modified filtering trabeculotomy (FTO) without iridectomy in open-angle glaucoma compared with that of conventional trabeculectomy (trab).Patients and methods: Thirty eyes of 30 patients who underwent modified FTO were prospectively followed for 1 year and were compared with 87 conventional trab patients (87 eyes), matched for age and preoperative intraocular pressure (IOP). The FTO procedure consisted of a deep sclerectomy and trabeculotomy preserving the trabeculo-Descemet membrane, without iridectomy. Main outcome measures were complete success (IOP /=30% IOP reduction, without medication), IOP, visual acuity, medication, complications, and subsequent surgeries.Results: In the conventional trab group, the median preoperative IOP was 23.0 mmHg (interquartile range 20.0–27.0) with 3.0 (2.0–3.0) medications, compared with 23.0 mmHg (20.0–27.0) and 3.0 (2.8–4.0) in the modified FTO group. Median postoperative IOP at 12 months was 12.0 mmHg (10.0–13.0) in the conventional trab and 11.0 mmHg (8.0–14.0) in the modified FTO group (P=0.3). The complete success rate at 1 year was 83.1% and 79.3% in the conventional trab group and modified FTO group, respectively (P=0.8). The complications hypotony (20.7%, 24.1%), choroidal detachment (2.3%, 10.3%), and bleb scarring (17.2%, 13.8%), were present in the conventional trab group and modified FTO group, respectively.Conclusion: The outcomes of reduced IOP and medications in the FTO group were not different to those in the conventional trab group over 1 year, but some complications were more often seen with the modified FTO technique. The new filtration trabeculotomy, however, has the advantage of avoiding iridectomy, thus reducing the risk of cataract formation, and may result in the development of more favorable blebs by controlling the flow over two resistance levels.Keywords: glaucoma surgery, open-angle glaucoma, outflow resistance, iridectomy, trabeculectomy

Since glaucoma was recognized as an eye disease related to elevated intraocular pressure (IOP) in the 19th century, treatment was mostly directed towards lowering IOP to a “normal” range (1).

Purpose To evaluate quality of life (QoL) with a new questionnaire after canaloplasty (CP) and trabeculectomy (TE). Patients and methods We assessed outcomes of surgery, rate of revision surgeries, patients’ mood, and influence of postoperative care on QoL, surgery interference with daily activities, and postsurgical complaints. Patients completed the QoL questionnaire 24 months after surgery. Results Patients who underwent CP (n=175) were compared to TE patients (n=152). In the CP group, 57% of patients expressed high satisfaction, while 41% of patients in the TE group said they were highly satisfied. The satisfaction difference was statistically significant (P=0.034). Significantly fewer second surgeries were needed after CP (8% CP versus 35% TE, P

Purpose Scarring after glaucoma filtering surgery remains the most frequent cause for bleb failure. The aim of this study was to assess if the postoperative injection of bevacizumab reduces the number of postoperative subconjunctival 5-fluorouracil (5-FU) injections. Further, the effect of bevacizumab as an adjunct to 5-FU on the intraocular pressure (IOP) outcome, bleb morphology, postoperative medications, and complications was evaluated. Methods Glaucoma patients (N = 61) who underwent trabeculectomy with mitomycin C were analyzed retrospectively (follow-up period of 25 ± 19 months). Surgery was performed exclusively by one experienced glaucoma specialist using a standardized technique. Patients in group 1 received subconjunctival applications of 5-FU postoperatively. Patients in group 2 received 5-FU and subconjunctival injection of bevacizumab. Results Group 1 had 6.4 ± 3.3 (0–15) (mean ± standard deviation and range, respectively) 5-FU injections. Group 2 had 4.0 ± 2.8 (0–12) (mean ± standard deviation and range, respectively) 5-FU injections. The added injection of bevacizumab significantly reduced the mean number of 5-FU injections by 2.4 ± 3.08 (P ≤ 0.005). There was no significantly lower IOP in group 2 when compared to group 1. A significant reduction in vascularization and in cork screw vessels could be found in both groups (P < 0.0001, 7 days to last 5-FU), yet there was no difference between the two groups at the last follow-up. Postoperative complications were significantly higher for both groups when more 5-FU injections were applied. (P = 0.008). No significant difference in best corrected visual acuity (P = 0.852) and visual field testing (P = 0.610) between preoperative to last follow-up could be found between the two groups. Conclusion The postoperative injection of bevacizumab reduced the number of subconjunctival 5-FU injections significantly by 2.4 injections. A significant difference in postoperative IOP reduction, bleb morphology, and postoperative medication was not detected.

Glaucoma is a frequent eye disease in the elderly and the second leading cause of irreversible blindness both in developed and developing countries (Resnikoff et al. 2004). Presently, about 50 million people are blind from glaucoma worldwide, a number that has not significantly changed over the last decade (Resnikoff et al. 2004; Thylefors et al. 1995). Without a doubt, glaucoma remains an unsolved problem of high significance in ophthalmology. Glaucoma is characterized by a chronic, progressive optic neuropathy that occurs in parallel to the formation of a typical excavation of the optic nerve head. The primary damage is restricted to retinal ganglion cells and the location of initial damage appears to be at the optic disc where their axons exit the eye. For a long time, intraocular pressure (IOP) had been suspected to cause or to contribute to axonal damage in glaucoma and since Adolph Weber introduced pilocarpine as an IOP-lowering therapy in 1876 (Weber 1876), medical therapy of glaucoma has been aimed at reducing IOP. This concept was challenged more recently, because of the observation that a significant percentage (up to 30–50 %) of patients suffering from glaucomatous neurodegeneration (Shiose et al. 1991; Anderson 2003) have IOPs in the statistically normal range of 10–21 mmHg (mean±2SD: 15.5±5.5 mmHg). Evidence for a causative or contributing role of IOP has finally been obtained through a number of randomized prospective multi-center studies that clearly identified IOP as the major risk factor for the pathogenesis of glaucoma (Collaborative Normal-Tension Glaucoma Study Group 1998a, b; Gordon et al. 2002; Kass et al. 2002; Leske et al. 2003; The AGIS Investigators 2000). Apparently, therapy that reduces IOP in patients with glaucoma is neuroprotective in the sense that it delays the structural and functional damage of retinal ganglion cell perikarya and their axons. Still, compliance to medical therapy is often unsatisfactory as daily eye-drop application is required (Reardon et al. 2011; Sleath et al. 2011). Although most patients are first treated with medical therapy, IOP-lowering operations come into play when medical therapy is no longer efficient, or when the patient is incompliant or does not tolerate topical eye drops. Presently, a large array of surgeries is available, all of which try to provide IOP reduction more than medical therapy can achieve with minimal surgical side effects. The advantage of the most effective surgical procedures is that very low IOPs (approx. 10–12 mmHg) can be achieved. In this respect, glaucoma surgery is the strongest neuroprotective measure on the basis of IOP lowering. However, surgery in glaucoma may not be successful, because of surgical complications and inappropriate wound healing. Moreover, there are only a limited number of randomized clinical trials assessing the success of surgical procedures in glaucoma (Coleman 2012). Considering the current limits of glaucoma therapy, there is need for the development of novel and alternative treatment strategies that save retinal neurons from glaucomatous injury or have the potential to repair neurons that have already been damaged. This Special Issue is aimed at providing a synopsis of therapeutically strategies with the potential to act neuroprotectively in glaucoma and independently from the reduction of IOP. Another purpose of the Special Issue is to review the obstacles that make the translation of experimental neuroprotective therapies into clinical practice E. R. Tamm (*) Institute of Human Anatomy and Embryology, University of Regensburg, Universitatstr. 31, 93053 Regensburg, Germany e-mail: Ernst.Tamm@vkl.uni-regensburg.de

Purpose To assess the outcomes of pars plana vitrectomy for the treatment of malignant glaucoma in patients with and without previous filtration surgery. Patients and methods Data of 15 patients developing malignant glaucoma after trabeculectomy (60%) or following ophthalmic interventions other than filtration surgery (40%) were recorded retrospectively. Pars plana vitrectomy was performed in case of failed medical or laser treatment recreating the normal pathway of aqueous humor. The main outcome measures were the postoperative intraocular pressure (IOP), the frequency of complications, and success rate based on the following criteria: IOP reduction by ≥20% and to ≤21 mmHg (definition one) or an IOP < 18 mmHg (definition two) with (qualified success) and without (complete success) glaucoma medication. Results Vitrectomy reduced IOP from baseline in eyes with and without previous trabeculectomy during a median follow-up of 16.4 months (range 7 days to 58 months); although the majority of patients required glaucoma medication to reach desired IOP. The complete success rates were 11% (both definitions) for patients with filtering blebs and none of the patients without previous trabeculectomy had complete success at the 12-month visit. Complications were few and included transient shallowing of the anterior chamber, choroidal detachment, corneal decompensation, filtering bleb failure, and need for further IOP-lowering procedures. Conclusion Pars plana vitrectomy is equally effective for malignant glaucoma caused by trabeculectomy or interventions other than filtration surgery, although IOP-lowering medication is necessary in nearly all cases to maintain target IOP.

Purpose To gain further insight into a possible role of biomechanical cues in glaucoma, the authors assessed the influence of extracellular matrix (ECM) elasticity on TGF-β2-induced changes in trabecular meshwork (TM) cells. Methods Human TM cells derived from donor cornea rings were plated on rigid collagen-coated tissue culture plastic or polyacrylamide gels of different elasticity and treated with vehicle or TGF-β2. Activation of Smad-2/3, ERK, and AKT signaling and expression of α-SMA and PAI-1 proteins were assessed by Western blot analysis. Subcellular localization of α-SMA was determined by confocal immunofluorescence microscopy. Transcription of collagen-I, -IV, and -VI, α-SMA, PAI-1, fibronectin, fibrillin-1, cochlin, and MGP-1 was studied by RT-qPCR. The contribution of non-Smad signaling pathways to TGF-β-induced α-SMA and PAI-1 expression was assessed using the small molecule inhibitors U0126 and LY294002. Results TGF-β2-induced activation of Smad-2/3, ERK, and AKT signaling as well as expression of collagen-1, α-SMA, fibulin, and MGP-1 were attenuated with increasing elasticity. In contrast, TGF-β2-induced collagen-6, fibronectin, PAI-1, and cochlin expression were enhanced on elastic substrates. The MEK-inhibitor U0126 blocked TGF-β-induced PAI-1 expression, whereas α-SMA expression was enhanced. PI3K inhibition with LY294002 reduced α-SMA expression. Conclusions ECM elasticity modulates TGF-β-induced signaling and protein expression in human TM cells. Non-Smad signaling contributes to TGF-β-induced alterations. Increasing ECM elasticity in vitro promotes protein expression patterns reminiscent of patterns reported in primary open-angle glaucoma. Therefore, changes in TM elasticity and mechanical load may have a significant role in primary open-angle glaucoma.

Sezolamide, a potent topical carbonic anhydrase inhibitor previously known as MK-417, was studied to determine its ocular hypotensive activity in patients with elevated intraocular pressure while on continuing therapy with topical timolol. This was a three-centre, double-masked, randomised, placebo-controlled, parallel study in 36 patients with bilateral primary open angle glaucoma or ocular hypertension on therapy receiving 0.5% timolol twice daily, with a morning intraocular pressure greater than or equal to 22 mmHg in both eyes 2-4 hours following an 8 a.m. dose of timolol. Sezolamide 1.8% or placebo twice daily was added to treatment with timolol on the evening of day 1 and continued for 2 weeks. Twelve-hour diurnal curves were performed before the study on day 1 (timolol alone) and on day 15. Intraocular pressure measurements were also taken on days 2 and 8 at 8 a.m. and 9 a.m. Patients who received timolol and sezolamide showed additional intraocular pressure reductions from day 1 (timolol alone) of 8.0 to 15.5%, which were significant at all times. At hours 1, 2, 4 and 8 the reductions in intraocular pressure observed in the group receiving sezolamide and timolol were significantly greater than those in the group receiving timolol and placebo.

PURPOSE. The transdifferentiation of Tenon fibroblasts to myofibroblasts is a pivotal step in filtering bleb scarring. It is mediated by the cytokine TGF-, Rho-dependent contractility, and cell‐matrix interactions in an interdependent fashion. HMG-CoA-reductase inhibitors (statins) have been shown to inhibit Rho-GTPase signaling; therefore, the authors studied the influence of lovastatin on TGF-‐mediated myofibroblast transdifferentiation to assess the potential use of statins in wound healing modulation. METHODS. Human Tenon fibroblasts were grown in culture, pretreated with lovastatin, lovastatin and mevalonate, or specific inhibitors of farnesyl transferase or geranylgeranyl transferase and were stimulated with TGF-1. -Smooth muscle actin (-SMA) and connective tissue growth factor (CTGF) transcription were assessed by real-time PCR. -SMA protein expression and localization were studied by Western blot and confocal immunofluorescence microscopy. Cell contractility was determined in collagen gel contraction assays. Phosphorylation of the signaling proteins Smad-2/3 and p38 were detected by Western blot, and Smad-2/3 localization was determined by confocal immunofluorescence microscopy. RESULTS. Lovastatin inhibited TGF-‐induced CTGF transcription, -SMA expression and incorporation into actin stress fibers, and subsequent collagen gel contraction. These effects were reversed by mevalonate. The inhibition of geranylgeranyl transferase but not farnesyl transferase blocked TGF-‐induced -SMA expression. Lovastatin decreased TGF-‐induced p38 activation, whereas Smad-2/3 phosphorylation and nuclear translocation were preserved. CONCLUSIONS. Lovastatin inhibits TGF-‐induced myofibroblast transdifferentiation in human Tenon fibroblasts, most likely by interfering with Rho-signaling. Statins may, therefore, serve to inhibit scarring after filtering glaucoma surgery. (Invest Ophthalmol Vis Sci. 2008;49:3955‐3960) DOI:10.1167/iovs.07-1610

Purpose Extracellular matrix (ECM) composition, tension, and rigidity modulate cell-ECM interactions and have substantial impact on cell functions. The authors studied the effects of ECM rigidity on human trabecular meshwork (HTM) cells to assess ECM rigidity as a possible pathophysiologic factor in glaucoma. Methods Trabecular meshwork cells derived from donor cornea rings and passaged three to seven times were plated on collagen-coated tissue culture plastic or polyacrylamide gels of different rigidity. Cell spreading and focal adhesions were assessed by immunofluorescence microscopy. Expression of focal adhesion kinase (FAK), alpha-smooth muscle actin (alpha-SMA), tubulin, alpha-B-crystallin and GAPDH, as well as phosphorylation of FAK and serum-induced activation of ERK, were studied by Western blot. The subcellular distributions of alpha-SMA and fibronectin were examined by confocal immunofluorescence microscopy. Results ECM rigidity modulated cell spreading and focal adhesion size. FAK activation and serum-induced ERK phosphorylation increased with rising substrate rigidity. Expression of alpha-SMA and recruitment of alpha-SMA to stress fibers were enhanced on rigid substrates, whereas myocilin and alpha-B-crystallin expression increased on soft substrates. The structure of fibronectin deposits differed on stiff and soft matrices. Conclusions Extracellular matrix rigidity modulates cytoskeletal structures, protein expression patterns, signal transduction, and fibronectin deposition in HTM cells. ECM changes altering trabecular meshwork resiliency may therefore have significant effects on ocular outflow tract functions with implications in glaucoma.

Purpose The cytokine transforming growth factor-β (TGF-β), and the ED-A splice variant of the extracellular matrix protein fibronectin modulate wound healing and scar formation. To further elucidate their possible role in filtering bleb scarring after glaucoma surgery in human eyes in vivo, we studied the cell type specific localization of TGF-β receptors and the presence of ED-A fibronectin in sections of normal conjunctiva and scarred filtering blebs. Methods Cryosections of normal conjunctiva (four patients) and scarred filtering blebs (seven patients) were studied by double-label immunofluorescence. Antibodies against PECAM-1 and prolyl-4-hydroxylase allowed for specification of vascular endothelial cells and activated fibroblasts, respectively. TGF-β receptor type II (TGF-β-RII), α-smooth muscle actin, O-linked sialoglycoprotein, fibronectin and the ED-A fibronectin splice-variant were also detected using specific antibodies. Labeled sections were viewed with a confocal laser scanning microscope. Results Vascular endothelial cells expressed TGF-β-RII in both normal and scarred tissue. TGF-β-RII was sparsely detected in the fibroblasts of normal conjunctiva while it was strongly expressed in most fibroblasts of the scarred filtering blebs. Similarly, ED-A fibronectin was not detected in the extracellular matrix of normal conjunctiva but abundantly present in scarred filtering blebs. Conclusions Filtering bleb scarring is associated with an abundant expression of TGF-β receptors in activated fibroblasts and the deposition of the fibrogenic ED-A fibronectin splice-variant. These data support the concept of targeting TGF-β signaling to prevent scar formation after filtering glaucoma surgery.

Purpose The role of mitogen-activated protein kinase (MAPK) pathways in TGF-beta-induced myofibroblast transdifferentiation of human tenon fibroblasts (HTFs) was investigated to identify potential pharmacologic targets for the inhibition of scarring after glaucoma surgery. Methods TGF-beta-dependent activation of Smad2, p38, and Erk-1/2 was examined by Western blot analysis. TGF-beta-induced mRNA expression of collagen Ialpha1, fibronectin, and the myofibroblast transdifferentiation marker alpha smooth muscle actin (alpha-SMA) was analyzed by real-time RT-PCR. alpha-SMA protein expression and subcellular distribution were determined by Western blot analysis and immunofluorescence cytochemistry. Fibroblast contractility was assessed in three-dimensional collagen gel contraction assays, stress fiber assembly with rhodamine-phalloidin stains, and confocal microscopy. Cell proliferation was measured with an MTT assay. Specific pharmacologic kinase inhibitors were used to characterize the involvement of MAPK-dependent pathways. Results TGF-beta stimulation of HTF induced a rapid and transient activation of Smad2 and Erk, whereas p38 activation was biphasic and sustained. After 24 hours of TGF-beta stimulation, increased levels of collagen Ialpha1, fibronectin, and alpha-SMA transcripts were detected. After 3 days of stimulation, HTF displayed increased alpha-SMA protein levels, enhanced contractility, and assembly of actin stress fibers. TGF-beta also induced HTF proliferation. Specific p38 inhibitors prevented all these aspects of TGF-beta-induced myofibroblastic transdifferentiation. Conclusions Pharmacologic inhibition of p38 abrogates TGF-beta-induced myofibroblast transdifferentiation, reduces extracellular matrix protein expression and HTF proliferation, and may therefore serve to inhibit scarring after glaucoma surgery.

AIMS—To assess the involvement of the recently identified human homogentisate 1,2-dioxygenase gene (HGO) in alkaptonuria (AKU) in two unrelated patients with ochronosis of the conjunctiva, sclera, and cornea. METHODS—A mutation screen of the entire coding region of the HGO gene was performed using single stranded conformational analysis after polymerase chain reaction with oligonucleotide primers flanking all 14 exons of the HGO gene. Fragments showing aberrant mobility were directly sequenced. RESULTS—Two homozygous missense mutations, L25P and M368V, were identified, each of which leads to the replacement of a highly conserved amino acid in the HGO protein. CONCLUSIONS—The authors describe a novel mutation, L25P, in the German population and bring to 18 the total number of known HGO mutations.

Glaucoma is a chronic neurodegenerative eye disease characterized by a loss of retinal ganglion cells associated with structural changes in the ocular outflow tract, disturbed intraocular pressure regulation and changes in tissue biomechanics. Earlier studies revealed a strong influence of ECM stiffness on protein expression patterns and growth factor signaling in cells of the ocular outflow tract (trabecular meshwork). To gain further insight into possible regulatory mechanisms, we asked whether ECM stiffness would alter expression of short non-coding microRNAs.Human trabecular meshwork cells were plated on tissue culture plastic or polyacrylamide gel substrata (E-moduli approx. 40 or 120kPa) of different stiffness and allowed to adjust for 7 days. Subsequently, miRNA expression levels were studied by Affymetrix arrays and qPCR. Genes targeted by at least five mechanoresponsive miRNAs (stiffness-related change >2 fold) were determined using R software. Protein expression of selected targets was assessed by western blot. At least 26 miRNAs were differentially expressed and 24 genes were predicted targets of 5 or more mechanoresponsive miRNAs. ECM stiffness-dependent protein expression changes were confirmed for the predicted targets NF-kB, AKT, E2F1, p53, p21 and cyclin-D1. These data suggest a mechanoresponsive regulation of miRNA levels with a possible role in cell differentiation and disease.

Purpose The effects of TGF-β2 on cadherin-mediated cell-cell adhesion in human trabecular meshwork (HTM) cells were characterized, since TGF-β-induced changes in the cytoskeleton, cell-cell, and cell-matrix interactions of HTM cells are suggested to have a significant role in primary open angle glaucoma. Methods The HTM cells were derived from donor cornea rings and treated with TGF-β2 or vehicle, and protein expression was studied by Western Blot, while protein localization was studied by fractionation of lysates and by confocal immunofluorescence microscopy. Cell-cell adhesion was assessed functionally in dissociation experiments and N-cadherin-mediated cell contact formation in cell spreading experiments on cadherin-coated substrates. A rho-associated protein kinase (ROCK) inhibitor was used to evaluate the contribution of cytoskeletal tension to TGF-β2-induced changes in protein expression and localization. Results TGF-β2 activated Smad-2/3, serine-threonine kinase (AKT), and extracellular signal-regulated kinase (ERK) signaling, and enhanced expression of β-catenin as well as N- and OB-cadherin. The nuclear fraction of β-catenin was not enhanced by TGF-β2. Immunofluorescence microscopy revealed an increased localization of N-cadherin and β-catenin to cell-cell adhesions, and an increase in F-actin. The TGF-β2 increased cell-cell adhesion strength and enhanced N-cadherin-mediated cell contact formation. This effect was blocked by inhibition of mitogen-activated protein kinase kinase (MEK) or AKT. Cytoskeletal relaxation by a ROCK inhibitor did not prevent a TGF-β2-induced increase in cadherin and β-catenin expression. Conclusions The cytokine TGF-β2 enhances cadherin-mediated cell-cell adhesion and β-catenin expression in HTM cells. Increased cell-cell adhesion may contribute to biomechanical alterations in glaucomatous trabecular meshwork (TM), and changes in β-catenin levels and its possible sequestration to cell adhesion sites may affect Wnt signaling. Thus, the crosstalk of TGF-β2 and Wnt signaling in TM may deserve further investigation.

Primary open-angle glaucoma (POAG) is a leading cause of blindness due to chronic degeneration of retinal ganglion cells and their optic nerve axons. It is associated with disturbed regulation of intraocular pressure, elevated intraocular levels of TGF-β2, aberrant extracellular matrix (ECM) deposition and increased outflow resistance in the trabecular meshwork (TM). The mechanisms underlying these changes are not fully understood. Cell-matrix interactions have a decisive role in TM maintenance and it has been suggested that TGF-β-induced inhibition of matrix metalloproteases may drive aberrant ECM deposition in POAG. Invadopodia and podosomes (invadosomes) are distinct sites of cell-matrix interaction and localized matrix-metalloprotease (MMP) activity. Here, we report on the effects of TGF-β2 on invadosomes in human trabecular meshwork cells. Human TM (HTM) cells were derived from donor tissue and pretreated with vehicle or TGF-β2 (2 ng/ml) for 3d. Invadosomes were studied in ECM degradation assays, protein expression and MMP-2 activity were assessed by western blot and zymography and ECM protein transcription was detected by RT-qPCR. HTM cells spontaneously formed podosomes and invadopodia as detected by colocalization of Grb2 or Nck1 to sites of gelatinolysis. Pretreatment with TGF-β2 enhanced invadosomal proteolysis and zymographic MMP-2 activity as well as MMP-2, TIMP-2 and PAI-1 levels in HTM cell culture supernatants. Rho-kinase inhibition by H1152 blocked the effects of TGF-β2. Concomitant transcription of fibronectin and collagens-1, -4 and -6 was increased by TGF-β2 and fibrillar fibronectin deposits were observed in areas of invadosomal ECM remodelling. In contrast to a current hypothesis, our data indicate that TGF-β2 induces an active ECM remodelling process in TM cells, characterized by concurrent increases in localized ECM digestion and ECM expression, rather than a mere buildup of material due to a lack of degradation. Invadosomal cell adhesion and signaling may thus have a role in POAG pathophysiology.

Juliane Matlach, Niels Hoffmann, Florentina J Freiberg, Franz Grehn, Thomas KlinkDepartment of Ophthalmology, University of Wuerzburg, Wuerzburg, GermanyBackground: The purpose of this study was to compare the outcomes of trabeculectomy using single sutures or releasable sutures.Methods: This retrospective study analyzed the medical records of 61 patients who had undergone trabeculectomy using single sutures (n = 33, 54.1%) or releasable sutures (n = 28, 45.9%). The scleral flap was secured with a mean 3.9 (range 3–5) single sutures in 33 patients and with three releasable sutures in 28 patients. Primary outcomes were the success rate, based on intraocular pressure and medication usage, and the frequency of complications and postsurgical interventions. The criteria used to determine complete success were, first, intraocular pressure

PURPOSE Extracellular matrix and the cytokine TGF-β influence scar formation in an interdependent fashion. In this study, the impact of extracellular matrix elasticity on TGF-β-induced signal transduction and myofibroblast transdifferentiation was examined. METHODS Primary human tenon fibroblasts were seeded on collagen-coated glass coverslips (rigid environment) or collagen or polyacrylamide gels (elastic environment) of different compliance and stimulated with TGF-β. Myofibroblast transdifferentiation was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis for the marker gene α-smooth muscle actin (SMA), and SMA incorporation into stress fibers was determined by confocal immunofluorescence microscopy. CTGF transcription was assessed by RT-qPCR. Signaling pathways were examined by Western blot using phosphospecific antibodies and by immunofluorescence microscopy. RESULTS TGF-β-dependent myofibroblast transdifferentiation was enhanced in a stiff environment. Increasing matrix elasticity attenuated TGF-β-induced myofibroblast transdifferentiation and the associated CTGF expression. TGF-β-induced p38 activation was reduced on elastic substrates. CONCLUSIONS The results suggest that matrix elasticity influences TGF-β-dependent activation of p38 signaling and subsequent myofibroblast transdifferentiation. Biomechanical cues represent an important determinant of scarring processes. Therefore, cellular signals elicited by mechanotransduction deserve consideration in the design of novel antifibrotic strategies.

PURPOSE To assess the significance of Rho-kinase-dependent contractility in TGF-beta-induced myofibroblast transdifferentiation of human tenon fibroblasts to characterize possible pharmacological targets for the inhibition of postoperative scarring after glaucoma surgery. METHODS Human tenon fibroblasts (HTFs) were grown in culture and stimulated with TGF-beta1. The effect of TGF-beta on Rho-GTPase activity was assessed by GST-rhotekin binding domain pulldown assay and detected by Western blot analysis. Contractility was evaluated in a silicone substrate wrinkling assay and in fibroblast-populated collagen gels. The actin cytoskeleton and focal adhesions were visualized by immunofluorescence microscopy. alpha-SMA transcripts were measured by real-time RT-PCR. TGF-beta-induced Smad- and p38-activation and expression of alpha-SMA were detected by Western blot analysis. Nuclear translocation of Smad2/3 was determined by confocal immunofluorescence microscopy. The influence of Rho-dependent kinase (ROCK) and myosin light chain kinase (MLCK) were studied by using specific kinase inhibitors (Y-27632, HA-1077, H-1152, and ML-7). RESULTS Within 10 minutes of stimulation, TGF-beta induced Rho activation that was associated with an increase in cell tension and followed by actin stress fiber enhancement. ROCK inhibitors released cell tension and averted TGF-beta-induced cytoskeletal changes, p38 activation and subsequent alpha-SMA expression, whereas Smad2-phosphorylation and nuclear translocation were preserved. MLCK inhibition also blocked alpha-SMA expression. In fibroblast-populated collagen lattices, ROCK inhibitors prevented TGF-beta-induced stress fiber assembly and contraction. CONCLUSIONS TGF-beta induces a rapid contractile response in HTFs that precedes myofibroblast transdifferentiation. ROCK inhibitors release this contraction and block subsequent TGF-beta-induced myofibroblast transdifferentiation and may therefore serve to modulate postoperative scarring after glaucoma filtering surgery.

PURPOSE To obtain experimental in vivo information on the functional properties of myocilin for aqueous humor (AH) outflow and to study in vivo the processing of mutated Tyr437His myocilin. Myocilin is a secreted glycoprotein that is mutated in some forms of primary open-angle glaucoma (POAG), and patients with the Tyr437His mutation have severe phenotypes. METHODS The chicken betaB1-crystallin promoter was used to overexpress wild-type human myocilin and mutated Tyr437His myocilin in the lenses of transgenic mice. Expression of transgenic mRNA was monitored by Northern blot analysis and in situ hybridization. The localization and secretion of transgenic myocilin was investigated by Western blot analysis and light and electron microscopy. Intraocular pressure (IOP) was measured by anterior chamber cannulation. RESULTS Two independent lines were established with each of the constructs that showed a strong expression of transgenic mRNA in their lenses. Transgenic expression resulted in a 4.7 +/- 1.8-fold increase of secreted normal myocilin in mouse AH, compared with its concentration in human AH. Immunoreactivity for transgenic myocilin was observed along the surfaces of lens and corneal endothelium, and in the chamber angle. At 12 weeks of age, the ultrastructure of the trabecular meshwork in mice expressing normal myocilin was not different from that of control eyes, and IOP of transgenic animals did not significantly differ from that of control littermates. In contrast, mutated Tyr437His myocilin was not secreted from lens fibers, but accumulated in dilated cisterns of rough endoplasmic reticulum. Although no structural changes were observed in lenses of animals expressing normal myocilin, lenses with Tyr437His expression developed nuclear cataracts, completely lost transparency, and eventually ruptured. Structural changes in lenses of Tyr437His expressing mice were correlated with a significant increase in IOP. CONCLUSIONS The results do not support the concept that increasing amounts of myocilin in the outflow tissues obstruct the system and directly cause an increase in outflow resistance. Mutated Tyr437His myocilin is not secreted in vivo and causes severe alterations of cellular structure and function. A comparable mechanism may cause POAG in patients with myocilin mutations.