A retrospective review of XEN implant surgery: efficacy, safety and the effect of combined cataract surgery.

OBJECTIVES: To investigate the safety and efficacy of glaucoma XEN stent implantation and examine the effect of undergoing combined phacoemulsification and XEN versus XEN implant alone. METHODS: A retrospective case note review of patients who underwent XEN implantation by a single surgeon over a 24-month period was performed. Outcomes included changes in IOP and medication use after XEN implant insertion as well as complications post-surgery. Subgroup analysis was also performed, separating phaco-XEN (phacoemulsification and XEN implantation) and stand-alone XEN implantation. RESULTS: 186 XEN implant procedures were included in this study from a total of 143 patients. Intraocular pressure changes with time were as follows: preoperative 18.1 mmHg (± 5.77), 6 months 13.2 mmHg (SD ± 3.9), 12 months 13.7 mmHg (SD ± 5.6) and 24 months 12.6 mmHg (SD ± 3.1). For visits up to 12 months, comparison from preoperative IOP was significant at the < 0.0001 level; for 18 and 24 months, significance was < 0.05. Medication usage with time was as follows: preoperative 2.5 (SD ± 1.1) 6 months 0.7 (SD ± 0.9), 12 months 0.8 (SD ± 0.97), and 24 months 1.7 (SD ± 1.7). All results were significant at < 0.05 level. Subgroup analysis of separate phaco-XEN and stand-alone XEN groups did not reveal significant differences in IOP; however, there was a significant difference between the two groups preoperatively. Initial hypotony occurred in 75 cases (40%). There were 9 cases of hypotonous maculopathy, 3 cases of persistent choroidal effusions, 3 cases of IOP spikes, 1 cases of cyclodialysis cleft and 1 case of corneal decompensation. 25 (13%) cases had needling during their treatment. CONCLUSION: The XEN implant appears to be safe and effective at reducing intraocular pressure and medication usage in glaucoma patients. XEN implantation is an effective treatment option for a range of glaucoma types and can be used as a stand-alone procedure or combined with cataract surgery to treat glaucoma patients.

Peripapillary Hyperreflective Ovoid Mass-Like Structures in Stickler Syndrome.

PURPOSE: To report a previously undescribed finding of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in Stickler syndrome. DESIGN: Noncomparative case series. SUBJECTS: Twenty-two eyes with anomalous optic disc from 11 Stickler syndrome patients were identified and imaged. METHODS: Peripapillary hyperreflective ovoid mass-like structures were graded using enhanced-depth imaging OCT (EDI-OCT) according to the consensus recommendations of the Optic Disc Drusen Studies Consortium. All EDI-OCT scans were obtained using the Heidelberg Spectralis (Heidelberg Engineering) with a dense horizontal raster (15 × 10°, 97 sections) centered on the optic nerve head and graded by 2 independent assessors. In case of disagreement, the image was graded by a third assessor. The presence of any coexisting optic disc drusen was also assessed using EDI-OCT and autofluorescence. MAIN OUTCOME MEASURES: The presence of PHOMS, clinical characteristics and genetic mutations. RESULTS: A pilot sample of 22 eyes with phenotypic optic disc abnormalities from 11 Stickler syndrome patients were identified and imaged. Eight patients were female and 3 were male. The mean age was 31 years (13-58 years). Peripapillary hyperreflective ovoid mass-like structures were present in 91% (n = 20) of imaged eyes. Seventy percent (n = 14) were type 1 Stickler syndrome and 30% (n = 6) were type 2 Stickler syndrome. All eyes were myopic and the degree of myopia did not seem to affect whether or not PHOMS was present in this cohort. One eye with PHOMS had retinal detachment, and 77.3% (n = 17) of eyes had undergone 360o prophylactic retinopexy. Thirty-two percent (n = 7) of eyes with PHOMS were present in patients with coexisting hearing loss and 22.7% (n = 5) had orofacial manifestation of Stickler syndrome in the form of a cleft palate. Seventy-seven percent (n = 15) of eyes with PHOMS were present in patients who reported joint laxity or symptoms of arthritis. No coexisting optic disc drusen were identified and raised intracranial pressure was also excluded after neurological investigation. CONCLUSIONS: These data suggest that PHOMS are a novel finding in Stickler syndrome patients and should be considered when evaluating the optic nerves of these patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluating multidisciplinary glaucoma care: visual field progression and loss of sight year analysis in the community vs hospital setting.

BACKGROUND: A variety of shared care models have been developed, which aim to stratify glaucoma patients according to risk of disease progression. However, there is limited published data on the rate of glaucoma progression in the hospital vs community setting. Here we aimed to compare rates of glaucomatous visual field progression in the Cambridge Community Optometrist Glaucoma Scheme (COGS) and Addenbrooke's Hospital Glaucoma Clinic (AGC). METHODS: A retrospective comparative cohort review was performed. Patients with five or more visual field tests were included. Zeiss Forum software was used to calculate the MD progression rate (dB/year). Loss of sight years (LSY) were also calculated for both COGS and AGC. RESULTS: Overall, 8465 visual field tests from 854 patients were reviewed. In all, 362 eyes from the AGC group and 210 eyes from COGS were included. The MD deterioration rate was significantly lower in the COGS patients compared with the AGC group (-0.1 vs -0.3 dB/year; p < 0.0001). No patients in the COGS group were predicted to become blind within their lifetime by LSY analysis. Fifteen patients were at risk in the AGC group. CONCLUSION: This service evaluation shows that COGS is an effective scheme to stratify lower risk glaucoma patients, increasing the capacity within hospital eye services. COGS patients have a lower rate of visual field deterioration compared to AGC patients. Effective communication between community and tertiary schemes is essential to facilitate transfer of patients requiring further hospital management reliably and efficiently, with the potential for low-risk patients to be followed safely in the community.

Aqueous outflow imaging techniques and what they tell us about intraocular pressure regulation.

Recent advances in the medical and surgical management of open-angle glaucoma have increased the number of treatment options available. Several new intraocular pressure (IOP)-lowering treatments target the conventional aqueous outflow (AO) system. However, success rates are variable and outcomes in individual patients are often difficult to predict. Variable treatment responses remain unexplained and highlight deficiencies in our current understanding of AO regulation and IOP homeostasis. Imaging is often relied upon to confirm diagnoses and monitor treatment responses in other ocular and systemic pathologies. As yet no suitable AO imaging tool has been developed to fulfil this role in glaucoma. A variety of imaging techniques have been used to study the AO tracts of humans and animals in ex vivo and in vivo eyes. In this review, results from novel imaging techniques that assess aqueous drainage through the episcleral venous system are considered and we argue these provide new insights into AO regulation. We suggest that the ability to objectively measure AO responses to interventions would be a significant clinical advance, and we have demonstrated that this can be achieved with direct visualisation of aqueous drainage. We predict that the evolution of AO imaging technology will continue to reveal critical components of AO and IOP regulation, and that personalised IOP-lowering treatment in glaucoma care may well become a reality in the near future.

Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery.

Gene replacement approaches are leading to a revolution in the treatment of previously debilitating monogenic neurological conditions. However, the application of gene therapy to complex polygenic conditions has been limited. Down-regulation or dysfunction of receptor expression in the disease state or in the presence of excess ligand has been shown to compromise therapeutic efficacy. Here, we offer evidence that combined overexpression of both brain-derived neurotrophic factor and its receptor, tropomyosin receptor kinase B, is more effective in stimulating axonal transport than either receptor administration or ligand administration alone. We also show efficacy in experimental glaucoma and humanized tauopathy models. Simultaneous administration of a ligand and its receptor by a single gene therapy vector overcomes several problems relating to ligand deficiency and receptor down-regulation that may be relevant to multiple neurodegenerative diseases. This approach shows promise as a strategy to target intrinsic mechanisms to improve neuronal function and facilitate repair.

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine.

Purpose: The eye is currently at the forefront of translational medicine and therapeutics. However, despite advances in technology, primary open-angle glaucoma remains the leading cause of irreversible blindness worldwide. Traditional intraocular pressure (IOP)-lowering therapies are often not sufficient to prevent progression to blindness, even in patients with access to high-quality healthcare. Neuroprotection strategies, which aim to boost the ability of target cells to withstand a pathological insult, have shown significant promise in animal models but none have shown clinically relevant efficacy in human clinical trials to date. We sought to evaluate the current status of neuroprotection clinical trials for glaucoma and identify limitations which have prevented translation of new glaucoma therapies to date.Methods: Literature searches identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library and Web of Science databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings and conference proceedings, and clinical trial registries.Results: We discuss six key neuroprotective strategies for glaucoma that have reached the clinical trial stage. Delivery of neurotrophic factors through gene therapy is also progressing towards glaucoma clinical trials. Refinements in trial design and the use of new modalities to define structural and functional endpoints may improve our assessment of disease activity and treatment efficacy. Advances in our understanding of compartmentalised glaucomatous degeneration and continued progress in the molecular profiling of glaucoma patients will enable us to predict individual risk and tailor treatment.Conclusion: New approaches to future glaucoma neuroprotection trials could improve the prospects for new glaucoma therapies. Glaucoma treatment tailored according to an individual's unique risk profile may become increasingly common in the future.

The Effects of Trabecular Bypass Surgery on Conventional Aqueous Outflow, Visualized by Hemoglobin Video Imaging.

PRECIS: Hemoglobin Video Imaging (HVI) provides a noninvasive method to quantify aqueous outflow (AO) perioperatively. Trabecular bypass surgery (TBS) is able to improve, and in some cases re-establish, conventional AO. PURPOSE: The purpose of this study was to use HVI to illustrate and quantify effects of TBS on AO through the episcleral venous system. DESIGN: This is a prospective observational cohort study. PARTICIPANTS: Patients were recruited from Sydney Eye Hospital, Australia. The study included 29 eyes from 25 patients, 15 with glaucoma and 14 normal controls. TBS (iStent Inject) was performed on 14 glaucomatous eyes (9 combined phacoemulsification/TBS and 5 standalone TBS). Cataract surgery alone was performed on the remaining eye from the glaucoma group and 2 eyes from the control group. METHODS: We used HVI, a novel clinic-based tool, to visualize and quantify AO perioperatively during routine follow-up to 6 months. Angiographic blood flow patterns were observed within prominent aqueous veins on the nasal and temporal ocular surface. Aqueous column cross-section area (AqCA) was compared before and after surgery. MAIN OUTCOME MEASURES: AqCA, number of aqueous veins, intraocular pressure (IOP) before and after surgery, and number of IOP-lowering medications. RESULTS: Patients with glaucoma had reduced AqCA compared with normal controls (P=0.00001). TBS increased AqCA in 13 eyes at 1 month (n=14; P<0.002), suggesting improved AO. This effect was maintained at 6 months in 7 eyes (n=9, P≤0.05). All patients with unrecordable AO before surgery (n=3; 2 standalone TBS, 1 combined cataract/TBS) established measurable flow after TBS. IOP and/or medication burden became reduced in every patient undergoing TBS. Cataract surgery alone (n=3) increased AqCA in nasal and temporal vessels at 4 weeks after surgery. CONCLUSIONS: HVI provides a safe method for detecting and monitoring AO perioperatively in an outpatient setting. Improvement of AO into the episcleral venous system is expected after TBS and can be visualized with HVI. TBS is able to improve, and in some cases re-establish, conventional AO. Cataract surgery may augment this. Some aqueous veins were first seen after TBS and these patients had unstable postoperative IOP control, which possibly suggests reorganization of aqueous homeostatic mechanisms. HVI may confirm adequacy of surgery during short-term follow-up, but further work is required to assess the potential of HVI to predict surgical outcomes and assist with personalized treatment decisions.

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.

Hemoglobin Video Imaging Provides Novel In Vivo High-Resolution Imaging and Quantification of Human Aqueous Outflow in Patients with Glaucoma.

Purpose: Noninvasive, detailed measurement of the dynamics of human aqueous outflow is difficult to achieve with currently available clinical tools. We used hemoglobin video imaging (HVI) to develop a technique to image and quantify human aqueous outflow noninvasively and in real time. Design: A prospective observational study to describe characteristics of aqueous veins and a pilot prospective interventional feasibility study to develop quantification parameters. Participants: Patients were recruited from the Cambridge University Hospitals NHS Foundation Trust Glaucoma clinic. The observational study included 30 eyes, and the pilot interventional feasibility study was performed on 8 eyes undergoing selective laser trabeculoplasty (SLT). Our SLT protocol also included the installation of pilocarpine and apraclonidine eye drops. Methods: Participants underwent HVI alongside their usual clinic visit. Main Outcome Measures: The change in cross-sectional area (CSA) of the aqueous column within episcleral veins was correlated with intraocular pressure (IOP) reduction and change in visual field mean deviation (MD) before and after intervention. Fluctuations in contrast and pixel intensity of red blood cells in an aqueous vein were calculated to compare the flow rate before and after intervention using autocorrelation analysis. Results: Hemoglobin video imaging enables the direct observation of aqueous flow into the vascular system. Aqueous is seen to centralize within a laminar venous column. Flow is pulsatile, and fluctuations of flow through globe pressure or compression of the aqueous vein are observed. There was a significant increase in the aqueous column after the administration of our SLT protocol (n = 13; P < 0.05). This correlated with the degree of IOP reduction (n = 13; Pearson's correlation coefficient 0.7; P = 0.007) and the improvement in MD observed postintervention (n = 8; Pearson's correlation coefficient 0.75; P = 0.03). Autocorrelation analysis demonstrated a faster rate of decay in an aqueous vein after intervention, indicating an increase in flow rate. Conclusions: Hemoglobin video imaging can be incorporated into a routine clinic slit-lamp examination to allow a detailed assessment and quantification of aqueous outflow in real time. It has the potential to be used to help target therapeutic interventions to improve aqueous outflow and further advance our understanding of aqueous outflow dysregulation in the pathogenesis of glaucoma.

Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling.

Previous studies have demonstrated that intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury. BDNF gene therapy can improve RGC survival in experimental models of glaucoma, the leading cause of irreversible blindness worldwide. However, the therapeutic efficacy of BDNF supplementation alone is time limited at least in part due to BDNF receptor downregulation. Tropomyosin-related receptor kinase-B (TrkB) downregulation has been reported in many neurological diseases including glaucoma, potentially limiting the effect of sustained or repeated BDNF delivery.Here, we characterize a novel adeno-associated virus (AAV) gene therapy (AAV2 TrkB-2A-mBDNF) that not only increases BDNF production but also improves long-term neuroprotective signaling by increasing expression of the BDNF receptor (TrkB) within the inner retina. This approach leads to significant and sustained elevation of survival signaling pathways ERK and AKT within RGCs over 6 months and avoids the receptor downregulation which we observe with treatment with AAV2 BDNF alone. We validate the neuroprotective efficacy of AAV2 TrkB-2A-mBDNF in a mouse model of optic nerve injury, where it outperforms conventional AAV2 BDNF or AAV2 TrkB therapy, before showing powerful proof of concept neuroprotection of RGCs and axons in a rat model of chronic intraocular pressure (IOP) elevation. We also show that there are no adverse effects of the vector on retinal structure or function as assessed by histology and electroretinography in young or aged animals. Further studies are underway to explore the potential of this vector as a candidate for progression into clinical studies to protect RGCs in patients with glaucoma and progressive visual loss despite conventional IOP-lowering treatment.