UNASSIGNED: Glaucoma is the leading cause of irreversible blindness worldwide. Normal tension glaucoma (NTG) is a distinct subtype characterized by intraocular pressures (IOP) within the normal range (< 21 mm Hg). Due to its insidious onset and optic nerve damage, patients often present with advanced conditions upon diagnosis. NTG poses an additional challenge as it is difficult to identify with normal IOP, complicating its prediction, prevention, and treatment. Observational studies suggest a potential association between NTG and abnormal lipid metabolism, yet conclusive evidence establishing a direct causal relationship is lacking. This study aims to explore the causal link between serum lipids and NTG, while identifying lipid-related therapeutic targets. From the perspective of predictive, preventive, and personalized medicine (PPPM), clarifying the role of dyslipidemia in the development of NTG could provide a new strategy for primary prediction, targeted prevention, and personalized treatment of the disease.
UNASSIGNED: In our study, we hypothesized that individuals with dyslipidemia may be more susceptible to NTG due to a dysregulation of microvasculature in optic nerve head. To verify the working hypothesis, univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were utilized to estimate the causal effects of lipid traits on NTG. Drug target MR was used to explore possible target genes for NTG treatment. Genetic variants associated with lipid traits and variants of genes encoding seven lipid-related drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). GWAS data for NTG, primary open angle glaucoma (POAG), and suspected glaucoma (GLAUSUSP) were obtained from FinnGen Consortium. For apolipoproteins, we used summary statistics from a GWAS study by Kettunen et al. in 2016. For metabolic syndrome, summary statistics were extracted from UK Biobank participants. In the end, these findings could help identify individuals at risk of NTG by screening for lipid dyslipidemia, potentially leading to new targeted prevention and personalized treatment approaches.
UNASSIGNED: Genetically assessed high-density cholesterol (HDL) was negatively associated with NTG risk (inverse-variance weighted [IVW] model: OR per SD change of HDL level = 0.64; 95% CI, 0.49-0.85; P = 1.84 × 10-3), and the causal effect was independent of apolipoproteins and metabolic syndrome (IVW model: OR = 0.29; 95% CI, 0.14-0.60; P = 0.001 adjusted by ApoB and ApoA1; OR = 0.70; 95% CI, 0.52-0.95; P = 0.023 adjusted by BMI, HTN, and T2DM). Triglyceride (TG) was positively associated with NTG risk (IVW model: OR = 1.62; 95% CI, 1.15-2.29; P = 6.31 × 10-3), and the causal effect was independent of metabolic syndrome (IVW model: OR = 1.66; 95% CI, 1.18-2.34; P = 0.003 adjusted by BMI, HTN, and T2DM), but not apolipoproteins (IVW model: OR = 1.71; 95% CI, 0.99-2.95; P = 0.050 adjusted by ApoB and ApoA1). Genetic mimicry of apolipoprotein B (APOB) enhancement was associated with lower NTG risks (IVW model: OR = 0.09; 95% CI, 0.03-0.26; P = 9.32 × 10-6).
UNASSIGNED: Our findings supported dyslipidemia as a predictive causal factor for NTG, independent of other factors such as metabolic comorbidities. Among seven lipid-related drug targets, APOB is a potential candidate drug target for preventing NTG. Personalized health profiles can be developed by integrating lipid metabolism with life styles, visual quality of life such as reading, driving, and walking. This comprehensive approach will aid in shifting from reactive medical services to PPPM in the management of NTG.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13167-024-00373-5.

Optineurin (OPTN) is a gene associated with familial normal tension glaucoma (NTG). While NTG involves intraocular pressure (IOP)-independent neurodegeneration of the visual pathway that progresses with age, how OPTN dysfunction leads to NTG remains unclear. Here, we generated an OPTN knockout mouse (Optn-/-) model to test the hypothesis that a loss-of-function mechanism induces structural and functional eye deterioration with aging. Eye anatomy, visual function, IOP, retinal histology, and retinal ganglion cell survival were compared to littermate wild-type (WT) control mice. Consistent with OPTN\'s role in NTG, loss of OPTN did not increase IOP or alter gross eye anatomy in young (2-3 months) or aged (12 months) mice. When retinal layers were quantitated, young Optn-/- mice had thinner retina in the peripheral regions than young WT mice, primarily due to thinner ganglion cell-inner plexiform layers. Despite this, visual function in Optn-/- mice was not severely impaired, even with aging. We also assessed relative abundance of retinal cell subtypes, including amacrine cells, bipolar cells, cone photoreceptors, microglia, and astrocytes. While many of these cellular subtypes were unaffected by Optn deletion, more dopaminergic amacrine cells were observed in aged Optn-/- mice. Taken together, our findings showed that complete loss of Optn resulted in mild retinal changes and less visual function impairment, supporting the possibility that OPTN-associated glaucoma does not result from a loss-of-function disease mechanism. Further research using these Optn mice will elucidate detailed molecular pathways involved in NTG and identify clinical or environmental risk factors that can be targeted for glaucoma treatment.

OBJECTIVE: To investigate the surgical effectiveness of combined cataract surgery with microhook ab-interno trabeculotomy (phaco-µLOT) or iStent trabecular micro-bypass stent (phaco-iStent) in eyes with primary open-angle glaucoma (POAG) and preoperative intraocular pressure (IOP) controlled below 15 mmHg (low-teen IOP).
METHODS: This retrospective cohort study included consecutive patients with POAG and low-teen IOP who underwent phaco-µLOT or phaco-iStent as their initial glaucoma surgery and were followed up for 1 year postoperatively. Surgical failure was defined as the inability to achieve the following criteria twice in a row: (A) IOP of 6-15 mmHg with over 20% IOP reduction; (B) IOP of 6-12 mmHg with over 20% IOP reduction.
RESULTS: A total of 75 eyes from 75 subjects were included, with 48 in the phaco-µLOT group and 27 in the phaco-iStent group. The mean preoperative IOP and number of antiglaucoma medications were 13.1 ± 2.1 mmHg and 3.4 ± 0.9 in the phaco-µLOT group, and 12.6 ± 2.0 mmHg and 2.5 ± 1.2 in the phaco-iStent group, respectively. The number of antiglaucoma medications was significantly reduced to 2.5 ± 0.9 (phaco-µLOT) and 2.0 ± 1.1 (phaco-iStent) at 1-year postoperatively (all p < 0.05). For criteria A and B, the survival rates were significantly higher in the phaco-µLOT group than in the phaco-iStent group (all p < 0.01).
CONCLUSIONS: Both phaco-µLOT and phaco-iStent hold promise in reducing the need for antiglaucoma medications in POAG eyes with low-teen IOP. Phaco-µLOT may be more effective than phaco-iStent in controlling IOP.
CONCLUSIONS: What is known Minimally invasive glaucoma surgeries (MIGS) procedures target the pressure gradient pathways in patients with higher preoperative intraocular pressure (IOP) levels, however, evidence on their effectiveness in normotensive glaucoma patients remains limited. What is new Combined cataract surgery with microhook ab-interno trabeculotomy (phaco-µLOT) or iStent trabecular micro-bypass stent (phaco-iStent) significantly reduced the number of antiglaucoma medications in primary open-angle glaucoma (POAG) eyes with preoperative IOP controlled below 15 mmHg (low-teen IOP). Phaco-µLOT may be more effective than phaco-iStent in controlling IOP. These procedures should be limited to reducing the number of antiglaucoma medications used, as they did not significantly reduce the postoperative IOP in POAG eyes with low-teen IOP.

The aim of this study was to compare vessel density (VD) in the retina and choroid in eyes with primary open angle glaucoma (POAG), normal tension glaucoma (NTG) and controls. Patients with POAG, NTG and controls underwent OCT scanning of the macula and the disc followed by 6 × 6 mm macula OCT angiography (OCTA) imaging. Global and hemifield VD were recorded for the superficial (SVP) and deep (DVP) vascular plexus and the choriocapillaris (CC). The OCT thickness of the nerve fiber layer (NFL) and ganglion cell layer (GCC) was also measured. Data from 65 POAG, 33 NTG and 40 control eyes matched for age were analyzed. Mean SVP VD was lower in NTG and POAG eyes compared to controls (38.8 ± 5.3, 40.7 ± 6.8 and 48.5 ± 4.0%, p < 0.001). Mean DVP VD was lower in NTG and POAG eyes compared to controls (43.1 ± 6.1, 44.5 ± 7.6 and 48.6 ± 5.8%, p = 0.002). There was no difference in SVP VD or DVP VD between the glaucoma groups (p > 0.050). No difference was noted in CC VD between the groups (68.3 ± 2.3, 67.6 ± 3.7 and 68.5 ± 2.6%, p = 0.287). Lower SVP and DVP VD was seen in eyes with glaucoma compared to normal eyes. NTG and POAG eyes had similar VD loss. Eyes with glaucoma manifested similar CC VD compared to controls.

OBJECTIVE: The aim of this study was to evaluate the lamina cribrosa curvature index in different types of glaucoma in comparison with clinical findings and conventional measurement methods.
METHODS: Patients older than 18 years who were followed up in Glaucoma Unit of Department of Ophthalmology at Fırat University Faculty of Medicine, whose disease had been under control at least for 1 year, who had at least three reliable visual fields, whose refractive error was between - 6 and + 5 diopter and who did not have any disease other than glaucoma that would affect the visual field, were included in the study. Clinical and demographic characteristics, visual field, optical coherence tomography and lamina cribrosa curvature index (LCCI) results were evaluated. The study patients were divided into six groups: early-stage primary open-angle glaucoma (POAG) as group 1 and intermediate-advanced stage POAG as group 2, pseudo-exfoliation glaucoma (PEXG) as group 3, normal tension glaucoma (NTG) as group 4, ocular hypertension patients whom subsequently developed POAG as group 5 and healthy control as group 6.
RESULTS: A total of 189 eyes of 101 patients were included in our study. Forty-seven patients were male (46.5%) and 54 were female (53.5%). The mean age was 62.43 ± 1.49 years. LCCI, mean deviation (MD), visual field index (VFI), pattern standard deviation (PSD) and retinal nerve fiber layer thickness (RNFL) values were analyzed in all groups and Pearson correlation analysis showed statistically significant correlation between PSD and RNFL measurements with LCCI values in all groups. MD value was correlated with LCCI in groups 2, 3 and 4, while VFI value was correlated with LCCI in all groups except group 5. When the groups were compared with each other according to the Post-Hoc Tamhane test, LCCI measurement showed statistically significant results in accordance with MD, VFI, PSD and RNFL values.
CONCLUSIONS: The LCCI assessment is mostly consistent with conventional tests. In this study, in which different types of glaucoma and healthy subjects were examined simultaneously, LCCI shows promise as a detailed and reliable assessment method.

Background: While clinical research has indicated a potential link between Helicobacter pylori infection and the onset of glaucoma, the causality of this association remains uncertain due to the susceptibility of observational studies to confounding factors and reverse causation. Methods: A comprehensive two-sample bidirectional Mendelian randomization (MR) analysis was conducted to assess the causal connection between H. pylori infection and glaucoma. Glaucoma was categorized into primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and pseudo-exfoliation glaucoma (PEG). Various methods, including inverse variance weighted, MR-Egger regression, weighted median, and mode-based estimator, were employed for effect estimation and pleiotropy testing. To enhance result robustness, a sensitivity analysis was performed by excluding proxy single nucleotide polymorphisms. Results: Genetic predisposition for H. pylori infection has no causal effect on glaucoma: (OR 1.00; 95% CI 0.95-1.06, p = 0.980), (OR 0.97; 95% CI 0.86-1.09, p = 0.550), and (OR 0.99; 95% CI 0.90-1.08, p = 0.766) with POAG, NTG, and PEG, respectively. An inverse MR showed no causal effect of POAG, NTG, and PEG on H. pylori infection (OR 1.01; 95% CI 0.97-1.05, p = 0.693), (OR 1.00; 95% CI 0.98-1.03, p = 0.804), and (OR 0.99; 95% CI 0.96-1.01, p = 0.363), respectively. Heterogeneity (p > 0.05) and pleiotropy (p > 0.05) analysis confirmed the robustness of MR results. Conclusion: These results indicated that there was no genetic evidence for a causal link between H. pylori and glaucoma, suggesting that the eradication or prevention of H. pylori infection might not benefit glaucoma and vice versa.

BACKGROUND: This systematic review and meta-analysis quantitatively examines the efficacy of angle-based minimally invasive glaucoma surgery (MIGS) in normal tension glaucoma (NTG).
METHODS: A literature search was performed on Medline, Embase, PubMed, CINAHL and Cochrane Library from inception until 20 December 2022. Pilot, cohort, observational studies and randomised controlled trials including at least 5 subjects undergoing angle-based MIGS (trabecular-bypass devices, excisional trabeculotomy, goniotomy and ab-interno canaloplasty) for NTG, with or without cataract surgery, were included. Meta-analysis of continuous outcome using the meta routine in R version 2022.12.0+353 was performed to determine mean intraocular pressure (IOP) and anti-glaucoma medication (AGM) reduction post-operatively.
RESULTS: Of the 846 studies initially identified, 15 studies with a pooled total of 367 eyes which underwent combined phacoemulsification and angle-based MIGS were included for final meta-analysis. Outcomes of the iStent were reported in 5 studies, iStent inject in 7 studies, Hydrus Microstent in 1 study, Kahook Dual Blade in 3 studies, and Trabectome in 2 studies. There was significant reduction in both IOP and AGM post-operatively at 6 months (2.44 mmHg, 95%CI: 1.83-3.06; 1.21 AGM, 95%CI: 0.99-1.44), 12 months (2.28 mmHg, 95%CI: 1.71-2.84; 1.18 AGM, 95%CI: 0.90-1.47), 24 months (2.10 mmHg, 95%CI: 1.51-2.68; 1.26 AGM, 95%CI: 0.85-1.68) and 36 months (2.43 mmHg, 95%CI: 1.71-3.15, 0.87 AGM, 95%CI: 0.21-1.53) (all p < 0.05). Subgroup analysis on combined phacoemulsification-iStent inject surgery demonstrated a reduction in both IOP (2.31 mmHg, 95%CI: 1.07-3.56, p < 0.001) and AGM (1.07 AGM, 95%CI: 0.86-1.29, p < 0.001) at 12 months post-operatively.
CONCLUSIONS: Angle-based MIGS combined with phacoemulsification effectively reduces IOP and AGM in NTG eyes for up to 36 months after surgery.

OBJECTIVE: To assess the necessity of neuroimaging in patients with neurological or atypical findings of normal tension glaucoma (NTG) who do not exhibit typical glaucoma manifestations.
METHODS: A retrospective analysis was conducted on 90 atypical NTG patients who underwent cranial magnetic resonance imaging (MRI) due to atypical symptoms. The demographic characteristics, clinical parameters, and radiological findings were recorded.
RESULTS: Among the patients, 66.7% had abnormal radiology results, with the most common findings being gliosis (34.4%), sequelae of cerebrovascular events and vascular malformations (14.4%), and benign intracranial mass lesions (11%). Non-glaucomatous visual field defects were more frequently observed in patients with abnormal neuroimaging results. However, there were no significant differences in intraocular pressure, optic disc parameters, retinal nerve fiber layer thickness, and visual field indices between patients with normal and abnormal radiological results. The mean age of the patients was 58.74y. Interestingly, there was a significant age difference, with the abnormal radiology group having a higher median age (P=0.021).
CONCLUSIONS: The study highlights the importance of cranial imaging in older NTG patients to detect underlying pathologies and prevent misdiagnosis. It suggests that neuroimaging may be warranted in NTG patients with atypical visual field defects incompatible with glaucoma. However, routine neuroimaging in all NTG patients without classic neurological signs may not be necessary.

Normal tension glaucoma (NTG) is a progressive neurodegenerative disease in glaucoma families. Typical glaucoma develops because of increased intraocular pressure (IOP), whereas NTG develops despite normal IOP. As a subtype of open-angle glaucoma, NTG is characterized by retinal ganglion cell (RGC) degeneration, gradual loss of axons, and injury to the optic nerve. The relationship between glutamate excitotoxicity and oxidative stress has elicited great interest in NTG studies. We recently reported that suppressing collapsin response mediator protein 2 (CRMP2) phosphorylation in S522A CRMP2 mutant (CRMP2 KIKI) mice inhibited RGC death in NTG mouse models. This study evaluated the impact of the natural compounds huperzine A (HupA) and naringenin (NAR), which have therapeutic effects against glutamate excitotoxicity and oxidative stress, on inhibiting CMRP2 phosphorylation in mice intravitreally injected with N-methyl-D-aspartate (NMDA) and GLAST mutant mice. Results of the study demonstrated that HupA and NAR significantly reduced RGC degeneration and thinning of the inner retinal layer, and inhibited the elevated CRMP2 phosphorylation. These treatments protected against glutamate excitotoxicity and suppressed oxidative stress, which could provide insight into developing new effective therapeutic strategies for NTG.

Glaucoma is a group of optic neuropathies and the world\'s leading cause of irreversible blindness. Normal-tension glaucoma (NTG) is a subtype of glaucoma that is characterized by a typical pattern of peripheral retinal loss, in which the patient\'s intraocular pressure (IOP) is considered within the normal range (<21 mmHg). Currently, the only targetable risk factor for glaucoma is lowering IOP, and patients with NTG continue to experience visual field loss after IOP-lowering treatments. This demonstrates the need for a better understanding of the pathogenesis of NTG and underlying mechanisms leading to neurodegeneration. Recent studies have found significant connections between NTG and cerebral manifestations, suggesting NTG as a neurodegenerative disease beyond the eye. Gaining a better understanding of NTG can potentially provide new Alzheimer\'s Disease diagnostics capabilities. This review identifies the epidemiology, current biomarkers, altered fluid dynamics, and cerebral and ocular manifestations to examine connections and discrepancies between the mechanisms of NTG and Alzheimer\'s Disease.