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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.Neurodegenerative disease is a significant global health and economic burden. NAD homoeostasis is a critical factor that influences neurodegeneration and neuroprotection. Increasing levels of NAD provide neuroprotection in multiple cell and animal models of disease and in human clinical trials 1 . Glaucoma is one of the most prevalent neurodegenerations which affects ~80 million people worldwide 2 . In glaucoma, the progressive dysfunction and loss of retinal ganglion cells (RGCs; the output neuron of the retina whose axons make up the optic nerve) results in irreversible blindness. There are no clinically available neuroprotective strategies.Recent animal and human studies have uncovered metabolic dysfunction occurring early in RGCs in glaucoma, in particular the critical dependency of RGCs on sufficient levels of NAD 3-5 . In neurons, NAD levels are maintained predominantly through the NAD-salvage pathway's two terminal enzymes; NMNAT1 (localized to the nucleus) and NMNAT2 (localized in the cytoplasm 6 ). Protein expression of

Purpose of ReviewA pressure difference between the intraocular and intracranial compartments at the site of the lamina cribrosa has been hypothesized to have a pathophysiological role in several optic nerve head diseases. This paper reviews the current literature on the translamina cribrosa pressure difference (TLCPD), the associated pressure gradient, and its potential pathophysiological role, as well as the methodology to assess TLCPD.Recent FindingsFor normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory.SummaryData from studies on the elevated TLCPD as a pathophysiological factor of NTG are equivocal. From the identification of potential postural effects on the cerebrospinal fluid (CSF) communication between the intracranial and retrolaminar space, we hypothesize that the missing link could be a dysfunction of an occlusion mechanism of the optic nerve sheath around the optic nerve. In upright posture, this could cause an elevated TLCPD even with normal ICP and we suggest that this should be investigated as a pathophysiological component in NTG 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.

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.

Background/AimsThe 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.MethodsWe 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.ResultsIn 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’.ConclusionWe 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.

Purpose To evaluate the effect of intracameral air on intraocular pressure (IOP) measurements using Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) in an in-vitro porcine eye model. Methods IOP was measured on thirteen freshly enucleated eyes at three reference pressures: 20, 30, and 40 mmHg. Six measurements/method were performed in a standardized order with GAT and ART respectively. Air was injected intracamerally in the same manner as during Descemet’s stripping endothelial keratoplasty (DSEK) and Descemet’s membrane endothelial keratoplasty (DMEK), and the measurements were repeated. Results Measured IOP increased significantly for both tonometry methods after air injection: 0.7 ± 2.1 mmHg for GAT and 10.6 ± 4.9 mmHg for ART. This difference was significant at each reference pressure for ART but not for GAT. Conclusions Although slightly affected, this study suggests that we can trust GAT IOP-measurements in eyes with intracameral air, such as after DSEK/DMEK operations. Ultrasound-based methods such as ART should not be used.

To evaluate the 2-year efficacy and safety of Kahook dual-blade (KDB) goniotomy in patients with medically uncontrolled glaucoma. 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. At 24 months, mean IOP had reduced from 24.8±8.3 to 15.0±5.3 mmHg in the KDB-alone group ( <0.001) and from 22.3±5.8 to 13.9±3.0 mmHg in the KDB-phaco group ( <0.001). Medications had reduced from 3.5±0.6 to 3.1±0.9 in the KDB-alone group ( =0.047) and from 3.3±0.5 to 2.3±1.1 in the KDB-phaco group ( <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. 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.

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 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. 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). 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.

ForewordWe practice medicine in times of exponentially increasing medical knowledge. In 1950, it was estimated that the doubling time was 50 years; by 1980, it was 7 years and by 2010, 3.5 years. In 2020, it was projected to be just 73 days! To continue to practice evidence-based medicine and to provide the best possible care for our patients, clinicians need to adapt their strategies to keep their knowledge up to date. There will always be a role for critical appraisal of individual studies in the field of a clinician’s practice, but with such an increase in the volume of published research, it becomes impossible to appraise all relevant material. For this reason, sources of distilled knowledge, such as the EGS Guidelines, become essential references for best practice medicine.Rigorous methods for evidence synthesis, such as the systematic reviews overseen by Cochrane, provide a comprehensive summary of the current state of knowledge for important clinical questions. However, for many clinical uncertainties, there is little or no high-quality evidence, let alone an evidence synthesis. Where evidence is lacking, practice guidance needs to be built from expert opinion and consensus, while acknowledging the limitations of such an approach. Expert opinion, derived from sound medical knowledge and years of practice experience, also has an important role in understanding the relevance of lines of evidence and the nuances of implementing them in practice. Thus, the expert commentary around the evidence base given in these Guidelines is essential for proper implementation of published evidence. Importantly, the EGS Guidelines also include ‘Choosing wisely’ elements indicating actions which should be avoided due to insufficient evidence and/or unsubstantiated belief.Guidelines need regular updating to take account of new knowledge and aspects of clinical care that have not been given sufficient emphasis in the past. This 6th Edition of the EGS Guidelines includes an updated ‘evidence based’ section with new clinical questions and evidence-based answers. The section ‘What matters to patients’ has also been updated, recognising that, because Guidelines are typically written by clinicians for clinicians, there have been gaps in understanding the patient perspective. The updated section now has direct input from the Expert by Experience patient advisors in the EGS Patient Involvement Project and includes eight Tips for Doctors in their communication with patients.The Guidelines team, led by Drs Pazos, Traverso and Viswanathan, is to be congratulated for the 6th Edition of the Guidelines, updating and enhancing the previous edition, while maintaining the highly success format which gives a framework for glaucoma care, based on evidence synthesis and consensus expert opinion, and presented as a ‘How to’ manual for patient diagnosis and management.David (Ted) Garway-HeathGlaucoma UK Professor of Ophthalmology, UCLIntroductionThe European Glaucoma Society Guidelines are at the heart of our educational mission serving not only our members, but all involved in glaucoma care. Previous editions have been among the most widely accessed documents in the field, helping navigate the growing complexity of glaucoma research and clinical practice.This sixth edition reaffirms our commitment to evidence-based, patient-centred care. It builds on the solid foundations of past editions while embracing key innovations that reflect new scientific insights, emerging technologies, and evolving priorities in glaucoma care.For the first time, we collaborated closely with patient representatives through the Experts by Experience (EbE) group. Their contributions helped shape clinical questions and emphasized the importance of empathy, communication, and psychological support in managing glaucoma.The Guidelines maintain a dual purpose: to answer clinically relevant questions through a rigorous evidence-based approach, and to offer comprehensive, practical knowledge for daily use. We have updated existing recommendations and added new topics, including artificial intelligence, cost-effectiveness, adherence strategies, and paediatric glaucoma. A new “Choosing Wisely” section provides clear guidance to avoid low-value interventions. We extend our heartfelt thanks to all contributors and collaborators. This includes the many colleagues who authored and reviewed chapters with great care and expertise, the patient representatives who generously shared their lived experiences, and the team at the University of Genoa, who worked tirelessly to refine content and layout, ensuring clarity and consistency throughout.A very special word of thanks goes to the Editors Marta Pazos, Carlo Traverso, and Ananth Viswanathan, whose relentless dedication, critical oversight, and countless hours of work were instrumental in shaping the high quality and coherence of this edition. Their leadership and perseverance have been extraordinary. Together, these collective efforts have made this edition a cornerstone of our vision: to foster innovation, strengthen education, enhance communication, and promote best practices in glaucoma care across Europe and beyond.Ingeborg Stalmans and Luis Abegao Pintowww.eugs.orgEditorsMarta PazosCarlo E. TraversoAnanth ViswanathanEvidence-Based Working GroupMethodological oversightAugusto Azuara-Blanco Manuele MichelessiLeaders of evidence reviewAugusto Azuara-Blanco Manuele Michelessi (EGS)Marta Pazos (EGS)Riaz Qureshi (US Cochrane Eyes and Vision Group)Evidence reviewAugusto Azuara-Blanco João Barbosa Breda Carlo Alberto CutoloGerhard GarhöferManuele MichelessiMarta PazosVerena ProkoshAndrew TathamEvidence consensus panelLuís Abegão PintoAugusto Azuara-BlancoGauti JóhannessonMarta PazosNorbert PfeifferIngeborg StalmansAndrew TathamCarlo E. TraversoAnanth ViswanathanEvidence patient’s feedback panelStelios GeorgoulasMarta PazosAndrew TathamThe Guidelines Task ForceLuís Abegão PintoEleftherios AnastasopoulosFlorent AptelAugusto Azuara-Blanco (advisor)João Barbosa BredaLuca BagnascoChiara BonzanoRupert BourneCarlo Alberto CutoloTheodoros FilippopoulosPanayiota FountiGerhard GarhöferGus GazzardDimitrios GiannoulisMichele IesterAndreas KatsanosAnthony KhawajaMiriam KolkoAntoine LabbéSophie LemmensManuele MichelessiAna MiguelFrancesco OddoneMarta Pazos (chair)Verena ProkoschAlessandro RabioloAlexander K SchusterCédric SchweitzerRiccardo ScottoAndrew TathamMarc Toeteberg-HarmsFotis TopouzisCarlo E. Traverso (chair)Ananth Viswanathan (chair)The Guidelines Writers, Authors and ContributorsLuís Abegão PintoIke AhmedZeynep AktasAugusto Azuara-BlancoAlessandro BagnisJoão Barbosa BredaChiara BonzanoRupert BournePaola CassotanaMaria Francesca CordeiroCarlo Alberto CutoloBarbara CvenkelPanayiota FountiJulian García-FeijooGerhard GarhöferTed Garway-HeathDaniele GaudenziGus GazzardStelios GeorgoulasFrancisco GoñiFranz GrehnAnders HejilEsther HoffmanMichele IesterGauti JóhannessonAnthony KhawajaAnthony KingMiriam KolkoEvgenia KonstantakopoulouYves LachkarSanna LeinonenSophie LemmensKarl MerciecaManuele MichelessiFrancesco OddoneMarta PazosDorothea PetersNorbert PfeifferVerena ProkoschLuca RossettiJohn SalmonLeopold SchmettererCédric SchweitzerRiccardo ScottoIngeborg StalmansGordana Sunaric-MégevandIan TapplyAndrew TathamJohn ThygessenFotis TopouzisCarlo E. TraversoNeeru VallabhAnanth ViswanathanThe Guidelines Internal ReviewersLuís Abegão PintoElefterios AnastasopoulosFlorent AptelJoão Barbosa BredaHenny BeckersChiara BonzanoRupert Bourne (ccordinator)Alain BronCarlo A. CutoloBarbara CvenkelTheodoros FilippopoulosPanayiota FountiGerhard GarhöferDimitrios GiannoulisFranz GrehnIngrida JanulevicieneStylianos KandarakisAndreas KatsanosAnthony KhawajaAnthony KingJames KirwanMiriam KolkoAntoine LabbéSanna LeinonenSophie LemmensKeith MartinJose Maria Martinez de la CasaFrances Meier-GibbonsStefano MigliorAna MiguelGiovanni MontesanoMarta PazosSergei PetrovVerena ProkoschAlessandro RabioloCédric SchweitzerAlexander K SchusterIngeborg StalmansMarc Toeteberg-HarmsFotis TopouzisCarlo E. TraversoAnja TuulonenAnanth ViswanathanZoya VeselovskayaIlgaz YalvaçMia Zoric GeberThe Experts by Experience Group (patients’ panel)Kate BackhausCarol BronzeAsle HaaukasMona KriegDeborah LoiDora RoloSarah TaylerTeam of Clinica Oculistica - University of Genova, Policlinico Ospedale San martino IRCCS - for medical editing and graphicsLuca BagnascoAlessandro BagnisChiara BonzanoPaola Cassottana (EGS Fellow)Carlo CattiCarlo Alberto CutoloDaniele Gaudenzi (EGS Fellow)Michele IesterMaria MusolinoRiccardo ScottoCarlo E. TraversoExternal Reviews from Glaucoma Societies AGSAPGSWGALAGSPAGSThe EGS Executive CommitteeIngeborg Stalmans (President)Luís Abegão Pinto (Vice President)Norbert Pfeiffer (Treasurer)Fotis Topouzis (Past President)Gauti Jóhannesson (Secretary)Marta Pazos (Adjunct Secretary)Panayiota FountiSanna LeinonenLuca RosettiThe Board of The EGS FoundationCarlo E. TraversoFotis TopuzisJohn ThygesenFranz GrehnAnders HeijlAll contributors have provided the appropriate COI visible in detail at www.eugs.org/pages/guidesurgical/Glossary5-FU 5-fluorouracilAAC Acute angle closureACG Angle closure glaucomaAGIS Advanced glaucoma intervention studyAH Aqueous humourAI Artificial intelligenceALT Argon laser trabeculoplastyANA-LIS Singapore asymptomatic narrow angles laser iridotomy studyAS-OCT Anterior Segment OCTBAC Benzalkalonium chlorideCCT Central corneal thicknessCDR Cup to disc ratioCGRN Childhood glaucoma research networkCIGTS Collaborative initial glaucoma treatment studyCNTGS Collaborative normal tension glaucoma studyDCT Dynamic contour tonometryEAGLE Effectiveness of early lens extraction for the treatment of primary angle closure glaucomaEbE Expert by experienceEGPS European glaucoma prevention studyEGS European glaucoma societyEMA The European Medicines AgencyEMGT Early manifest glaucoma trialFC Fixed combinationFc Flow chartFDT Frequency doubling technologyFL Fixation lossesFN False ne