NMNAT2 is a druggable target to drive neuronal NAD production.

Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

Influence of Laser Trabeculoplasty on Combined Phacoemulsification/Kahook Dual Blade Goniotomy.

Purpose: To investigate the influence of laser trabeculoplasty (LTP) on subsequent surgery with combined phacoemulsification/Kahook Dual Blade goniotomy (phaco-KDB) in patients with open-angle glaucoma or intraocular hypertension. Patients and Methods: Patients undergoing phaco-KDB between 2019 and 2021 were divided into previously LTP treated and previously non-LTP treated, and LTP-treatment included argon laser trabeculoplasty (ALT) and selective laser trabeculoplasty (SLT). The primary goal was to investigate if previous LTP influenced later surgical outcome of phaco-KDB. The secondary goal was to investigate if the outcome of LTP could be predictive of the outcome of subsequent phaco-KDB. We also compared IOP- and medication reductions between LTP and non-LTP treated patients. Results: A total of 111 LTP treated patients were compared to 139 non-LTP treated patients. In LTP treated patients, surgical success of phaco-KDB was 82.9%, compared to 88.5% in non-LTP treated patients (P=0.20). Reductions in IOP and medications were similar between groups. Furthermore, within the LTP group, patients with successful LTP-treatment had a subsequent surgical success of phaco-KDB in 80.7%, compared to 83.0% in patients with unsuccessful LTP-treatment (P=0.765). Conclusion: Previous LTP treatment does not predict the outcome of phaco-KDB. Furthermore, no correlation was found between the LTP effect and a later surgical success of phaco-KDB.

The Glaucoma Intensive Treatment Study (GITS): A Randomized Controlled Trial Comparing Intensive and Standard Treatment on 5 Years Visual Field Development.

PURPOSE: To assess the effect of an intensive initial intraocular pressure (IOP)-lowering treatment strategy on the progression of visual field damage. DESIGN: A randomized, controlled, open-label, 2-center clinical trial. METHODS: A total of 242 patients with newly detected early or moderate untreated open-angle glaucoma were enrolled at 2 university hospitals in Sweden. Participants were randomly allocated (1:1) to either initial treatment with intensive IOP-lowering medications followed by 360° laser trabeculoplasty (LTP), or to traditional mono-therapy, which was increased when deemed necessary. The primary study outcome of interest was the predicted remaining visual field, as measured by the visual field index (VFI) at projected end of life. RESULTS: The median untreated IOP was 24 mm Hg in both treatment groups. During follow-up, median and mode IOP were 17 mm Hg in the mono- and 14 mm Hg in the multi-treatment group. In the mono-treatment group, the median VFI at projected end of life was 79.3% and in the multi-treatment group 87.1% (P = .15). The annual rate of progression of visual field damage was faster in mono-treatment than in multi-treatment participants; median losses per year were 0.65 and 0.25 percentage units, respectively (P = .09). Progression events occurred in 21% of the mono- and in 11% of the multi-treatment participants (P = .03). Adverse events, mostly mild, were reported in 25% of the mono- and in 36% of the multi-treatment participants. Differences in visual field outcomes between treatment groups were more pronounced in participants having higher baseline IOP, defined by median split of untreated IOP values. CONCLUSIONS: In the overall analysis, the visual field outcomes were not overwhelmingly better in the multi-treatment group, but post hoc analysis showed definite benefit in patients with higher untreated IOP. Based on the results of this study, initial intensive treatment may be considered in glaucoma patients with high untreated IOP at diagnosis, although we found no evidence that multi-therapy should be given routinely to all glaucoma patients.

Missed Opportunities in Screening for Glaucoma.

PURPOSE: To create a holistic and realistic view regarding current knowledge, understanding, and challenges of screening in general and in glaucoma. METHODS/RESULTS: Based upon available literature, all systems suffer from the same challenges: huge variability of care practices (despite guidelines), simultaneous under care and over care, as well as the unsustainable increase of costs. While the magnitude of these challenges differs immoderately between well-off and developing countries, the Western world has already demonstrated that simply doing more than what we currently do is not the solution. System outcomes also matter in screening, that is, its benefits should outweigh any harms (over-care, false positives/negatives, uncertain findings, etc.) and be cost-effective. However, even when the evidence does not support screening (as is currently the case in glaucoma), it may feel justified as "at least we are doing something." Strong commercial interests, lobbying and politics star as well and will influence the control arm even in high-quality randomized screening trials (RCT). CONCLUSIONS: As resources will never be sufficient for all health care activities that providers wish to deliver and what people wish to receive, we need to ask big questions and adopt a public health perspective in glaucoma and eye care. How can we create and maintain a sustainable balance between finding and treating underserved high-risk patients without burdening the broader patient population and societies with over-diagnostics and treatments? Considering numerous biases related to screening, including the variability in care practices, a high-quality RCT for the screening of glaucoma would be very challenging to organize and evaluate its universal usefulness.

Prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume.

Leber's hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust neuroprotective effect against mitochondrial and metabolic dysfunction in other retinal injuries. We explored the potential for nicotinamide to protect mitochondria in LHON by modelling the disease in mice through intravitreal injection of the Complex I inhibitor rotenone. Using MitoV mice expressing a mitochondrial-tagged YFP in retinal ganglion cells we assessed mitochondrial morphology through super-resolution imaging and digital reconstruction. Rotenone induced Complex I inhibition resulted in retinal ganglion cell wide mitochondrial loss and fragmentation. This was prevented by oral nicotinamide treatment. Mitochondrial ultrastructure was quantified by transition electron microscopy, demonstrating a loss of cristae density following rotenone injection, which was also prevented by nicotinamide treatment. These results demonstrate that nicotinamide protects mitochondria during Complex I dysfunction. Nicotinamide has the potential to be a useful treatment strategy for LHON to limit retinal ganglion cell degeneration.

Changes in intraocular pressure during the first 24 h after transscleral cyclophotocoagulation.

AIMS: To estimate the changes in intraocular pressure (IOP) during the first 24 h after transscleral cyclophotocoagulation (TCP). METHODS: A prospective single-centre study, where patients with glaucoma destined for treatment with TCP were asked for participation. The IOP was measured prior to TCP and at 1, 2, 4, 6 and 24 h post-TCP. An IOP spike was defined as an elevation of IOP of ≥5 mmHg compared with baseline. The visual acuity (VA) was examined at baseline and after 24 h. RESULTS: The mean IOP prior to TCP in 58 eyes of 58 patients was 26.2 (±8.9 SD) mmHg. Twenty-three eyes (40%) experienced an IOP spike at some examination timepoint during the first 24 h. The mean value of the IOP spike was 12.1 (±6.9) mmHg. Fifty-six per cent of the eyes with pseudoexfoliation glaucoma (PEXG) experienced an IOP spike, and 16% had an IOP spike ≥20 mmHg. The IOP was significantly reduced at the 24 h examination by 8.1 (±7.8) mmHg (n = 58). The VA 24 h after TCP was unchanged compared with baseline. CONCLUSION: Clinically significant IOP spikes were common in the first 24 h post-TCP. Almost one in five eyes had an increase of 10 mmHg and in almost one in 10 eyes, the IOP increase was 20 mmHg or higher. Eyes with PEXG had a higher occurrence of IOP spikes and displayed a greater magnitude of IOP elevation. Prophylactic post-operative IOP-lowering medication should be considered to prevent further glaucoma damage.

European Glaucoma Society research priorities for glaucoma care.

BACKGROUND/AIMS: The goal of health research is to improve patients care and outcomes. Thus, it is essential that research addresses questions that are important to patients and clinicians. The aim of this study was to develop a list of priorities for glaucoma research involving stakeholders from different countries in Europe. METHODS: We used a three-phase method, including a two-round electronic Delphi survey and a workshop. The clinician and patient electronic surveys were conducted in parallel and independently. For phase I, the survey was distributed to patients from 27 European countries in 6 different languages, and to European Glaucoma Society members, ophthalmologists with expertise in glaucoma care, asking to name up to five research priorities. During phase II, participants were asked to rank the questions identified in phase I using a Likert scale. Phase III was a 1 day workshop with patients and clinicians. The purpose was to make decisions about the 10 most important research priorities using the top 20 priorities identified by patients and clinicians. RESULTS: In phase I, 308 patients and 150 clinicians were involved. In phase II, the highest-ranking priority for both patients and clinicians was 'treatments to restore vision'. In phase III, eight patients and four clinicians were involved. The top three priorities were 'treatments to stop sight loss', 'treatments to restore vision' and 'improved detection of worsening glaucoma'. CONCLUSION: We have developed a list of priorities for glaucoma research involving clinicians and patients from different European countries that will help guide research efforts and investment.

Long-term follow-up of laser trabeculoplasty in multi-treated glaucoma patients.

PURPOSE: To evaluate the long-term effect of laser trabeculoplasty (LTP) in patients randomized to multi-treatment in the Glaucoma Intensive Treatment Study (GITS). METHODS: Patients with untreated newly diagnosed open-angle glaucoma were treated with three intraocular pressure (IOP)-lowering substances for 1 week and then 360° argon or selective LTP was performed. IOP was measured just before LTP and repeatedly during the 60-month study period. Our previous report on 12 months follow-up data revealed no effect of LTP in eyes having an IOP <15 mmHg before the laser treatment. RESULTS: Before LTP, the mean IOP ± standard deviation in all 152 study-eyes of 122 multi-treated patients was 14.0 ± 3.5 mmHg. Three eyes of three deceased patients were lost to follow-up during the 60 months. After exclusion of eyes that received increased therapy during follow-up, the IOP was significantly reduced at all visits up to 48 months in eyes with pre-LTP IOP ≥15 mmHg; 2.6 ± 3.1 mmHg at 1 month and 1.7 ± 2.8 mmHg at 48 months, n = 56 and 48, respectively. No significant IOP reduction was seen in eyes with pre-LTP IOP <15 mmHg. Seven eyes, i.e., <13%, with pre-LTP IOP ≥15 mmHg at baseline had required increased IOP-lowering therapy at 48 months. CONCLUSION: LTP performed in multi-treated patients may provide a useful IOP reduction that is maintained over several years. This was true on a group level when the initial IOP was ≥15 mmHg, but if the pre-laser IOP was lower than that, chances of LTP success were small.

Optic Nerve Subarachnoid Space Posture Dependency - An MRI Study in Subjects With Normal Tension Glaucoma and Healthy Controls.

Purpose: The purpose of this study was to examine the differences of optic nerve subarachnoid space (ONSAS) volume in patients with normal tension glaucoma (NTG) and healthy controls in different body positions. Methods: Eight patients with NTG and seven healthy controls underwent magnetic resonance imaging (MRI) examinations in head up tilt (HUT) +11 degrees and head down tilt (HDT) -5 degrees positions according to a randomized protocol determining the starting position. The ONSAS volume in both body positions was measured and compared between the two groups. The results were analyzed using a generalized linear model. Results: Between HDT and HUT, the postural ONSAS volume change was dependent on starting position (P < 0.001) and group (P = 0.003, NTG versus healthy). A subgroup analysis of those that were randomized to HUT examination first, coming directly from an upright position, showed that the patients with NTG had significantly larger positional ONSAS volume changes compared to the healthy controls; 121 ± 22 µL vs. 65 ± 37 µL (P = 0.049). Analysis of the ONSAS volume distribution showed different profiles for patients with NTG and healthy controls. Conclusions: There was a significant difference in ONSAS volume change between patients with NTG and healthy subjects when subjected to posture changes, specifically when going from upright to head-down posture. This indicates that patients with NTG had been exposed to a lower ONSAS pressure when they came from the upright posture, which suggests an increased translaminar pressure difference in upright position. This may support the theory that NTG has a dysfunction in an occlusion mechanism of the optic nerve sheath that could cause abnormally negative ONSAS pressures in upright posture.

Nicotinamide Prevents Retinal Vascular Dropout in a Rat Model of Ocular Hypertension and Supports Ocular Blood Supply in Glaucoma Patients.

Purpose: To investigate whether nicotinamide (NAM) modulates retinal vasculature in glaucoma. Methods: This was a prospective controlled clinical trial investigating animal and human histopathology. Participants included normotensive and ocular hypertensive rats, postmortem human ocular tissue, glaucoma patients (n = 90), and healthy controls (n = 30). The study utilized histopathology, computer-assisted retinal vasculature analysis, optical coherence tomography angiography (OCTA), and NAM treatment. The main outcome measures included retinal vascular parameters in rats as assessed by AngioTool; retinal vasculature integrity in rats and humans as assessed by histopathology, antibody-staining, and ImageJ-based measurements; and retinal perfusion density (PD) and flux index in humans as assessed by OCTA. Results: A number of vessel parameters were altered in ocular hypertension/glaucoma compared to healthy controls. NAM treatment improved the retinal vasculature in ocular hypertensive rats, with an increase in mean vessel area, percentage area covered by vessels, total vessel length, total junctions, and junction density as assessed by AngioTool (all P < 0.05); vessel wall integrity as assessed by VE-cadherin antibody staining was also improved (P < 0.01). In humans, as assessed by OCTA, increases in PD in the optic nerve head and macula complete image (0.7%, P = 0.04 and 1.0%, P = 0.002, respectively) in healthy controls, and an increase in the temporal quadrant of the macula (0.7%, P = 0.02) in glaucoma patients was seen after NAM treatment. Conclusions: NAM can prevent retinal vascular damage in an animal model of glaucoma. After NAM treatment, glaucoma patients and healthy controls demonstrated a small increase in retinal vessel parameters as assessed by OCTA.

Outcomes of iStent Inject Versus Kahook Dual Blade Surgery in Glaucoma Patients Undergoing Cataract Surgery.

PRCIS: iStent Inject implantation (iStent) or Kahook Dual Blade goniotomy (KDB) in combination with phacoemulsification have a similar IOP-lowering effect in all stages of glaucoma, and medications are significantly reduced, especially after KDB. PURPOSE: To compare the 2-year efficacy and safety of iStent or KDB in combination with phacoemulsification in eyes with mild to advanced open angle glaucoma. METHODS: A retrospective chart review of 153 patients that received iStent or KDB in combination with phacoemulsification at a single center between March 2019 and August 2020. The main outcome parameters at 2 years were: (1) intraocular pressure (IOP)-reduction ≥20%, with a postoperative IOP ≤18 mm Hg, and (2) a reduction of ≥1 medication. Results were stratified by glaucoma grade. RESULTS: After 2 years, mean IOP was reduced from 20.3±6.1 to 14.2±4.1 mm Hg in the phaco-iStent group ( P <0.001) and from 20.1±6.1 to 14.7±3.6 mm Hg in the phaco-KDB group ( P <0.001). The mean number of medications was reduced from 3.0±0.9 to 2.6±1.1 in the Phaco-iStent group ( P =0.001) and from 2.3±1.0 to 1.5±1.3 in the Phaco-KDB group ( P <0.001). Success regarding IOP-reduction ≥20% with a postoperative IOP ≤18 mm Hg was met by 46% in the phaco-iStent group and by 51% in the phaco-KDB group. A reduction of ≥1 medication was met by 32% in the phaco-iStent group and by 53% in the phaco-KDB group ( P =0.013). Eyes with mild to moderate and advanced glaucoma responded equally well to the success criteria. CONCLUSIONS: iStent and KDB, in combination with phacoemulsification, both lowered IOP effectively in all stages of glaucoma. More medications were reduced after KDB, suggesting that it may be a more effective procedure compared with iStent.

Kahook Dual-Blade Goniotomy with and without Phacoemulsification in Medically Uncontrolled Glaucoma.

Purpose: To evaluate the 2-year efficacy and safety of Kahook dual-blade (KDB) goniotomy in patients with medically uncontrolled glaucoma. Methods: This was a retrospective case-series study of 90 consecutive patients with primary open-angle glaucoma (POAG) or pseudoexfoliation glaucoma (PEXG) that underwent KDB goniotomy alone (KDB-alone group) or KDB goniotomy in combination with phacoemulsification (KDB-phaco group) during 2019-2020. All patients were uncontrolled on three or more medications. Surgical success was defined as an IOP reduction ≥20% and/or a reduction of one or more medications at 24 months. We also report IOP levels and number of medications from baseline to 24 months, as well as the need for further glaucoma interventions. Results: At 24 months, mean IOP had reduced from 24.8±8.3 to 15.0±5.3 mmHg in the KDB-alone group (P<0.001) and from 22.3±5.8 to 13.9±3.0 mmHg in the KDB-phaco group (P<0.001). Medications had reduced from 3.5±0.6 to 3.1±0.9 in the KDB-alone group (P=0.047) and from 3.3±0.5 to 2.3±1.1 in the KDB-phaco group (P<0.001). An IOP reduction ≥20% and/or a reduction with one or more medications was achieved by 47% of eyes in the KDB-alone group and by 76% of eyes in the KDB-phaco group. Eyes with PEXG and POAG responded equally well to the success criteria. During the 24-month follow-up, additional glaucoma surgery or transscleral photocoagulation was performed in 28% of eyes in the KDB-alone group and in 12% of eyes in the KDB-phaco group. Conclusion: In patients with medically uncontrolled glaucoma, KDB had a significant IOP-lowering effect after 24 months, but success rates were higher when KDB was performed in combination with cataract surgery compared to stand-alone treatment.

Threat to fixation and vision-related quality of life in early open-angle glaucoma - results from the Glaucoma Intensive Treatment Study.

PURPOSE: To determine the effect of glaucomatous visual field (VF) damage close to the point of fixation, called threat-to-fixation (TTF), on vision-related quality of life (VRQoL) in open-angle glaucoma. METHODS: A total of 239 patients from the Glaucoma Intensive Treatment Study (GITS) were included in this analysis. The second VF of patients with newly diagnosed primarily early glaucoma was evaluated for the presence or absence of TTF. TTF was defined as VF loss including one or more of the four innermost test points depressed at p < 1% in the total deviation probability map of Humphrey 24-2 SITA Standard visual fields. VRQoL was evaluated using Rasch-analysed National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25) scores. The correlation between VRQoL and TTF was evaluated using uni- and multivariable regression analyses. RESULTS: TTF was present in at least one eye in 115 patients (48%); located in the superior hemifield alone in 47% (54 of 115), in the inferior hemifield alone in 23% (27 of 115), and in 30% (34 of 115) in both hemifields. The median Rasch-calibrated NEI VFQ-25 scores were identical when comparing patients with TTF (VRQoL score 66, 95% CI: 23-100) and those with no-TTF (VRQoL score 66, 95% CI: 21-100) (p = 0.925). Neither the presence of TTF (R2  = -0.004, p = 0.968) nor the location of TTF (R2  = 0.023, p = 0.103) was significantly correlated to Rasch-calibrated NEI VFQ-25 scores. CONCLUSION: The presence of TTF did not influence VRQoL, as measured by the NEI-VFQ-25, in this relatively large group of patients with mainly early glaucoma.

Widespread retina and optic nerve neuroinflammation in enucleated eyes from glaucoma patients.

Neuroinflammation is recognized as a key component of neurodegenerative disease. In glaucoma, a common neurodegenerative disease and the leading cause of irreversible blindness, the evidence for neuroinflammation in patients is lacking. Animal models have demonstrated significant pro-inflammatory activation of resident glia in the retina, as well as influx of blood-derived monocytes and pro-inflammatory factors. Confirmation of this in human donor tissue has been challenging due to a lack of well-preserved and well-characterized post-mortem tissue. To address this we utilize archived, wax embedded eyes fixed immediately following enucleation from living glaucoma patients. We compared glaucoma to control eyes (enucleated for uveal melanoma where the tumor did not impact the central retina or optic nerve). We performed immunolabelling for neurodegenerative and glial markers (CD45, CD163, IBA1, GFAP, Vimentin) which were quantified by high-resolution light microscopy and image analysis in FIJI. Glaucoma eyes demonstrated significant neural loss consistent with advanced neurodegeneration. IBA1 and GFAP were significantly increased in the retina and optic nerve head of the glaucomatous eyes indicating that significant neuroinflammation had occurred which support findings in animal models. Inflammation is a treatable symptom of many diseases and as such, identification of earlier inflammatory processes in glaucoma could be important for potential future treatment options.

The glaucoma intensive treatment study: interim results from an ongoing longitudinal randomized clinical trial.

PURPOSE: The aim of the study was to determine the perimetric rate of glaucoma progression in the ongoing Glaucoma Intensive Treatment Study (GITS) after 3 years of follow-up. DESIGN: This is a randomized, two-centre, prospective open-labelled treatment trial for open-angle glaucoma (OAG). PARTICIPANTS: The participants of this study were treatment-naive patients with newly diagnosed OAG, aged 46-78 years, with early to moderate glaucomatous visual field loss scheduled to be followed for 5 years within the study. METHODS: Patients were randomized to initial treatment with either topical monotherapy or with an intensive approach using drugs from three different classes, plus 360° laser trabeculoplasty. Changes in treatment were allowed. Standard automated perimetry and tonometry were performed and side-effects documented. All results are presented using intention-to-treat analysis. RESULTS: A total of 242 patients were randomized. After 3 years of follow-up, eight patients were lost to follow-up, six of whom were deceased. The median untreated baseline intraocular pressure (IOP) was 24 mmHg in both arms. The median IOP was almost constant over the 3 years of follow-up: ≈17 mmHg in the mono-arm and ≈14 mmHg in the multi-treatment arm. Treatment was intensified in 42% of the mono-treated patients and in 7% of the multi-treated patients. Treatment was reduced in 13% of the multi-treated patients. The median perimetric rate of progression was -0.5%/year in the mono-treated group and -0.1%/year in the multi-treated group (p = 0.03). CONCLUSION: The rate of disease progression was significantly slower in the multi-treated patients than in the mono-treated patients. Further follow-up will show whether this difference is sustained over time.

Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction.

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.