Systemic PTEN-Akt1-mTOR pathway activity in patients with normal tension glaucoma and ocular hypertension: A case series.

Glaucoma is the most common optic neuropathy in humans and the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP), while increasing evidence suggests that systemic mitochondrial abnormalities may also be implicated in its pathogenesis. We have recently shown that patients who have not developed glaucoma despite being exposed for many years to high IOP (ocular hypertension - OHT) have more efficient mitochondria, measured in peripheral blood lymphocytes, when compared to age-similar controls and fast progressing normal tension glaucoma (NTG) patients. In this prospective case series we aimed to explore some of the molecular pathways involved in mitochondrial efficiency in glaucoma resistance by measuring the systemic activity (in peripheral blood) of key mitochondrial regulators: the mammalian target of rapamycin (mTOR) and its major upstream regulators and downstream effectors that form the PTEN-Akt1-mTOR signalling pathway. We found no statistically significant difference in the systemic mTOR activity between the three groups (control, NTG and OHT). In line with the mTOR results, there was no significant difference in the activity of both the two major upstream mTOR regulators (PTEN and Akt1) and its two main downstream effectors (S6K and 4EBP1). In a single NTG patient, with history of Raynaud's, significantly higher mTOR activity was noted. We conclude that the PTEN-Akt1-mTOR pathway does not appear to play a central role in mitochondrial efficiency in OHT.

In Vivo 3-Dimensional Strain Mapping of the Optic Nerve Head Following Intraocular Pressure Lowering by Trabeculectomy.

PURPOSE: To map the 3-dimensional (3D) strain of the optic nerve head (ONH) in vivo after intraocular pressure (IOP) lowering by trabeculectomy (TE) and to establish associations between ONH strain and retinal sensitivity. DESIGN: Observational case series. PARTICIPANTS: Nine patients with primary open-angle glaucoma (POAG) and 3 normal controls. METHODS: The ONHs of 9 subjects with POAG (pre-TE IOP: 25.3±13.9 mmHg; post-TE IOP: 11.8±8.6 mmHg) were imaged (1 eye per subject) using optical coherence tomography (OCT) (Heidelberg Spectralis, Heidelberg Engineering GmbH, Heidelberg, Germany) before (<21 days) and after (<50 days) TE. The imaging protocol was repeated for 3 controls in whom IOP was not altered. In each post-TE OCT volume, 4 tissues were manually segmented (prelamina, choroid, sclera, and lamina cribrosa [LC]). For each ONH, a 3D tracking algorithm was applied to both post- and pre-TE OCT volumes to extract IOP-induced 3D displacements at segmented nodes. Displacements were filtered, smoothed, and processed to extract 3D strain relief (the amount of tissue deformation relieved after TE). Strain relief was compared with measures of retinal sensitivity from visual field testing. MAIN OUTCOME MEASURES: Three-dimensional ONH displacements and strain relief. RESULTS: On average, strain relief (averaged or effective component) in the glaucoma ONHs (8.6%) due to TE was higher than that measured in the normal controls (1.07%). We found no associations between the magnitude of IOP decrease and the LC strain relief (P > 0.05), suggesting biomechanical variability across subjects. The LC displaced posteriorly, anteriorly, or not at all. Furthermore, we found linear associations between retinal sensitivity and LC effective strain relief (P < 0.001; high strain relief associated with low retinal sensitivity). CONCLUSIONS: We demonstrate that ONH displacements and strains can be measured in vivo and that TE can relieve ONH strains. Our data suggest a wide variability in ONH biomechanics in the subjects examined in this study. We further demonstrate associations between LC effective strain relief and retinal sensitivity.

Are Eye Clinics Safe For The Road? An Observational Report.

We report an observational study, based on the examination of 319 medical records, identifying the proportion of patients whose driving status was documented on the first and subsequent glaucoma clinic visits. We also established the proportion of patients with documented Driving and Vehicle Licencing Agency (DVLA)-related advice when they did not meet driving standards based on their visual acuity and/or visual fields (VF). On presentation, driving status was assessed in 61% (n=195) patients. Of the remaining 124, 44% (n=55) had their driving status documented at a subsequent visit, on an average 8 years later. Of all patients (78%, n=250) whose driving status was assessed at some stage, 42% (n=134) were drivers. Of the 203 patients who were either drivers or whose driving status was unknown, 37% (n=75) were assessed as having a visual acuity or bilateral VF defect that was below the legal limit for driving, 39 of whom were known drivers. Only 13 were advised to inform the DVLA, and only 5 patients were advised to update their spectacles or listed for surgery to improve their vision. We therefore potentially failed to perform our DVLA duty in 76% (n=57) of patients. We have made suggestions for improving the current performance in this respect based on the findings of this study.

Trabeculectomy for normal tension glaucoma: outcomes using the Moorfields Safer Surgery technique.

AIMS: To evaluate long-term outcomes and complications of trabeculectomy for normal tension glaucoma (NTG) with contemporary surgical techniques. METHODS: Retrospective consecutive, non-comparative case series of 131 eyes of 98 patients undergoing trabeculectomy between 2007 and 2013 in a dedicated NTG clinic. Data collected during routine clinical care were analysed. Assessment of clinical outcomes included intraocular pressure (IOP) reduction, bleb function, final visual acuity, evidence of glaucoma progression, postoperative complications and further surgical intervention. Surgical failure was defined as a failure to meet specified IOP-related criteria, the need to undergo further glaucoma surgery for raised IOP or loss of light perception vision. A further analysis was also performed which considered failure as glaucoma progression following surgery. Outcomes were evaluated using Kaplan-Meier life-table analysis. RESULTS: The cumulative percentages of unqualified success as defined by a ≥30% reduction of IOP from baseline preoperative maximum (95% CI; IOP of all eyes: mean±SD) at 1, 2, 3 and 4 years after surgery were 91.1% (84.1% to 95.1%; 9.7±2.9 mm Hg), 74.1% (63.7% to 81.8%; 10.3±3.0 mm Hg), 64.8% (52.7% to 74.6%; 10.6±2.5 mm Hg) and 62.1% (49.3% to 72.6%; 10.2±2.1 mm Hg), respectively. At 2 years of follow-up there was no significant association between either previous cataract surgery or ethnicity and failure. Cumulative percentages of unqualified success at 4 years after surgery as defined by a filtering trabeculectomy bleb or absence of glaucoma progression were 91.6% (83.2% to 95.9%) and 92.3% (81.3% to 97.0%), respectively. Postoperative complications such as early (2.3%) and late (0.8%) hypotony were significantly lower than suggested by the current literature. CONCLUSIONS: Trabeculectomy in NTG patients undertaken using contemporary surgical techniques and intensive postoperative management is associated with more successful long-term outcomes and fewer complications than the currently available literature suggests.

Resistance to the most common optic neuropathy is associated with systemic mitochondrial efficiency.

Glaucomatous optic neuropathy, an important neurodegenerative condition and the commonest optic neuropathy in humans, is the leading cause of irreversible blindness worldwide. Its prevalence and incidence increase exponentially with ageing and raised intraocular pressure (IOP). Using glaucomatous optic neuropathy as an exemplar for neurodegeneration, this study investigates putative factors imparting resistance to neurodegeneration. Systemic mitochondrial function, oxidative stress and vascular parameters were compared from isolated lymphocytes, whole blood and urine samples between 30 patients who have not developed the neuropathy despite being exposed for many years to very high IOP ('resistant'), 30 fast deteriorating glaucoma patients despite having low IOP ('susceptible'), and 30 age-similar controls. We found that 'resistant' individuals showed significantly higher rates of ADP phosphorylation by mitochondrial respiratory complexes I, II and IV, hyperpolarised mitochondrial membrane potential, higher levels of mitochondrial DNA, and enhanced capacity to deal with cytosolic calcium overload and exogenous oxidative stress, as compared to both controls and glaucoma patients. While it has been known for some years that mitochondrial dysfunction is implicated in neurodegeneration, this study provides a fresh perspective to the field of neurodegeneration by providing, for the first time, evidence that systemic mitochondrial efficiency above normal healthy levels is associated with an enhanced ability to withstand optic nerve injury. These results demonstrate the importance of cellular bioenergetics in glaucomatous disease progression, with potential relevance for other neurodegenerative disorders, and raise the possibility for new therapeutic targets in the field of neurodegeneration.

Results of the betaxolol versus placebo treatment trial in ocular hypertension.

PURPOSE: To determine whether treatment with betaxolol can delay or prevent the conversion from ocular hypertension to early glaucoma on the basis of visual field criteria, by means of a prospective, randomised, placebo-controlled trial. METHODS: Three hundred and fifty-six ocular hypertensives were randomized to treatment with either betaxolol drops or placebo drops during the period 1992-1996. Each patient was followed prospectively with 4-monthly visits. Examination at each visit included visual field testing, intra-ocular pressure (IOP) measurement and optic disc imaging. Conversion to early glaucoma was defined on the basis of visual field change by AGIS criteria. An intent-to-treat analysis compared visual field conversion after 3 years in the treatment and placebo arms. Normal visual field survival analysis was also performed. The IOP characteristics of the two treatment groups were compared. RESULTS: Two hundred and fifty-five patients completed the study, which ended in 1998, with a range of follow-up of 2-6 years. Sixteen (13.2%) of 121 patients in the placebo group converted to glaucoma, compared with 12 (9.0%) of 134 patients in the betaxolol group. The intent-to-treat analysis demonstrated no evidence of any difference in conversion rates between the betaxolol and placebo groups after 3 years. Visual field survival analysis demonstrated no significant difference between the betaxolol and placebo groups. The betaxolol-treated group had significantly lower post-treatment IOP values. Converters had significantly higher pre- and post-treatment IOP values than non-converters. CONCLUSIONS: Betaxolol significantly lowered the IOP level compared with placebo. Conversion to glaucoma was found to be related to both the baseline and post-treatment IOP levels. However the intent-to-treat analysis did not demonstrate a statistically significant reduction in the conversion rate in the betaxolol-treated group.