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Anna Barkander,1 Mario A Economou,2,3 Gauti Jóhannesson1,4,5 1Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden; 2Division of Ophthalmology and Vision, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 3Department of Ophthalmology, Capio Sophiahemmet Hospital, Stockholm, Sweden; 4Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden; 5Department of Ophthalmology, University of Iceland, Reykjavik, IcelandCorrespondence: Anna Barkander, Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, SE-901 85, Sweden, Tel +46 63 15 30 00, Email anna.barkander@regionjh.sePurpose: 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.Keywords: Kahook dual blade, medically uncontrolled glaucoma, phacoemulsification, pseudoexfoliation glaucoma, primary open-angle glaucoma

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.

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. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these 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 NAM treatment as a neuroprotective therapy for human glaucoma.One Sentence SummaryThe NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.

To retrospectively evaluate the efficacy and safety of all transscleral cyclophotocoagulation (TCP) treatments performed during a 5-year period.Medical records of all patients, who had undergone TCP treatment between 2010 and 2014 at Umeå University Hospital, Sweden, were evaluated. Clinical data including intraocular pressure (IOP), visual acuity (VA), number of topical glaucoma medications, use of oral acetazolamide, retreatments and complications during a 2-year follow-up were registered. Global success was defined as IOP 6-18 mmHg with or without glaucoma medication.Three hundred patients underwent TCP during the time period. Mean IOP at baseline was 29.3 ± 11.0 (mean ± standard deviation) mmHg (n = 297) with a mean reduction of 11.5 (±12.0) mmHg at 1 year (n = 258; p 0.001) and 12.6 (±12.0) mmHg at 2-year follow-up (n = 245; p 0.001). Global success at 2 years was 64%, achieved by a mean of 1.2 treatments (n = 257). The number of topical glaucoma medications at baseline was 3.1 (±1.0; n = 296) and was reduced by 0.9 (±1.0) medications at 2 years (n = 244; p 0.001). Use of oral acetazolamide decreased from 30% (n = 90) at baseline to 5.3% (n = 13) at 2 years. In eyes with Snellen VA ≥ 0.1, the mean VA at baseline was 0.55 (±0.3) logarithm of the minimum angle of resolution (logMAR; n = 132) and 1.1 (±0.9) logMAR (n = 76) at 2 years (p 0.001). No cases of phthisis bulbi were found.This study displays a substantial and long-term reduction of IOP following TCP with a decrease in topical and oral glaucoma medications. The treatment appears to be safe but the decrease in VA during follow-up is a concern that needs further evaluation.

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 degrees 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: approximate to 17 mmHg in the mono-arm and approximate to 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.

PURPOSE: We hypothesize that a collapse of the optic nerve subarachnoid space (ONSAS) in the upright posture may protect the eyes from large translamina cribrosa pressure differences (TLCPD) believed to play a role in various optic nerve diseases (e.g., glaucoma). In this study, we combined magnetic resonance imaging (MRI) and mathematical modeling to investigate this potential ONSAS collapse and its effects on the TLCPD. METHODS: First, we performed MRI on six healthy volunteers in 6° head-down tilt (HDT) and 13° head-up tilt (HUT) to assess changes in ONSAS volume (measured from the eye to the optic canal) with changes in posture. The volume change reflects optic nerve sheath (ONS) distensibility. Second, we used the MRI data and mathematical modeling to simulate ONSAS pressure and the potential ONSAS collapse in a 90° upright posture. RESULTS: The MRI showed a 33% decrease in ONSAS volume from the HDT to HUT (P < 0.001). In the upright posture, the simulations predicted an ONSAS collapse 25 mm behind lamina cribrosa, disrupting the pressure communication between the ONSAS and the intracranial subarachnoid space. The collapse reduced the simulated postural increase in TLCPD by roughly 1 mm Hg, although this reduction was highly sensitive to ONS distensibility, varying between 0 and 4.8 mm Hg when varying the distensibility by ± 1 SD. CONCLUSIONS: The ONSAS volume along the optic nerve is posture dependent. The simulations supported the hypothesized ONSAS collapse in the upright posture and showed that even small changes in ONS stiffness/distensibility may affect the TLCPD.

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering effect of laser trabeculoplasty (LTP) in eyes which IOP had been substantially reduced by intensive topical treatment for one week.METHODS: Patients with newly diagnosed open-angle glaucoma were randomized to treatment with three IOP-lowering substances. One week later, 360° argon or selective LTP was performed. IOP was measured before LTP and at one-, three-, six- and 12-month post-LTP. The patients were part of the Glaucoma Intensive Treatment Study (GITS).RESULTS: Mean IOP (± SD) in 152 eyes of 122 patients was 14.0 (± 3.5) mmHg just before LTP. For every mmHg higher IOP prior to LTP, the IOP was reduced by an additional 0.6 mmHg at 12 months. The IOP was significantly reduced at all follow-up visits from -2.6 (± 3.1) mmHg at one month to -2.1 (± 3.8) mmHg at 12 months in eyes with pre-LTP IOP ≥ 15 mmHg, while no significant IOP reduction was seen in eyes with pre-LTP IOP < 15 mmHg. Older age, argon LTP and male sex were associated with larger IOP reduction after 12 months, whereas presence of exfoliation syndrome was associated with a smaller IOP reduction. No severe complications were reported.CONCLUSION: Success of LTP was highly dependent on the IOP level prior to LTP treatment. A sustained significant IOP reduction was seen in eyes with pre-LTP IOP ≥ 15 mmHg whereas no such effect was seen in eyes with pre-LTP IOP < 15 mmHg. Thus, LTP can be considered in eyes with multi-treatment when target pressure of < 15 mmHg is not achieved. (Less)

PURPOSE: To investigate if decrease of IOP affects the volumetric blood flow rate in the ophthalmic artery (OA) in patients with previously untreated ocular hypertension. METHODS: Subjects with untreated ocular hypertension (n = 30; mean age 67 +/- 8 years; 14 females) underwent ophthalmologic examination and a 3-Tesla magnetic resonance imaging investigation. The magnetic resonance imaging included three-dimensional high-resolution phase-contrast magnetic resonance imaging to measure the OA blood flow rate. The subjects received latanoprost once daily in the eye with higher pressure, the untreated eye served as control. The same measurements were repeated approximately 1 week later. RESULTS: The mean OA blood flow rate before and after treatment was 12.4 +/- 4.4 and 12.4 +/- 4.6 mL/min in the treated eye (mean +/- SD; P = 0.92) and 13.5 +/- 5.2 and 13.4 +/- 4.1 mL/min in the control eye (P = 0.92). There was no significant difference between the treated and control eye regarding blood flow rate before (P = 0.13) or after treatment (P = 0.18), or change in blood flow rate after treatment (0.1 +/- 3.1 vs.-0.1 +/- 4.0 mL/min, P = 0.84). Latanoprost decreased the IOP by 7.2 +/- 3.1 mm Hg in the treated eye (P < 0.01). CONCLUSIONS: The results indicate that a significant lowering of IOP does not affect the blood flow rate of the OA in ocular hypertension subjects. The ability to maintain blood supply to the eye independent of the IOP could be a protective mechanism in preserving vision in subjects with ocular hypertension.

Publisher's version (útgefin grein), Purpose: Compare (a) nonmitomycin C (MMC) trabeculectomy and 1.5% dexamethasone nanoparticle (DexNP) eye drops postoperatively with (b) trabeculectomy with MMC and Maxidex® eye drops postoperatively. Methods: Randomized prospective single masked clinical trial with 20 patients with primary open-angle glaucoma undergoing primary trabeculectomy. The study group consisted of 10 patients without MMC intraoperatively and postoperative DexNP eye drops, and the control group consisted of 10 patients treated with MMC intraoperatively and postoperative Maxidex®. The drops were tapered out over 8 weeks. The main outcome measures were as follows: rates of complete success, that is intraocular pressure (IOP) within target pressures at different time-points without IOP-lowering medication, or reoperation. Secondary outcome measures included the following: relative success rate (with IOP-lowering medications), number of glaucoma medications and reoperations. Patients were followed for 36 months. Results: Both groups showed similar postoperative course and IOP reduction. Intraocular pressures (IOPs) in the DexNP group and in the control group were 25.6 and 24.4 mmHg, respectively, at baseline. Intraocular pressures (IOPs) were reduced to 13.2 and 14.5 mmHg at 12 months, 11.7 and 12.6 mmHg at 24 months and 11.7 and 12.1 mmHg at 36 months, respectively. There were no statistically significant differences between the groups in absolute (p = 0.36) or relative (p = 1.0) success rates, number of medications (p = 0.71) or reoperations (p = 1.0) between the groups at any time-point. Conclusions: DexNP eye drops are effective postoperative treatment following trabeculectomy. The potent anti-inflammatory and antifibrotic effect of DexNP may offer an alternative to mitomycin C in glaucoma surgery., The authors have received unrestricted grants from the Icelandic Technology Development Fund, Knut and Alice Wallenberg Foundationand and Swedish Society for Medical Research

PURPOSE: To test the hypothesis that normal-tension glaucoma (NTG) is caused by an increased pressure difference across the lamina cribrosa (LC) related to a low intracranial pressure (ICP).DESIGN: ...

Objective: The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important impl ...

The purpose of this study was to assess the intraocular pressure (IOP) - reducing effect of latanoprost in treatment-naïve patients with newly detected open-angle glaucoma with no restriction of the level of untreated IOP.Eighty-six patients (105 eyes) with a diagnosis of open-angle glaucoma received IOP-lowering therapy with latanoprost. The IOP reduction 1 and 3 months after initiation of treatment was recorded.Mean untreated IOP for all eyes was 26.2 mm Hg (ranging from 10 to 51 mm Hg). The mean pressure reduction was 7.9 mm Hg (28%), with equivalent average levels at 1 and 3 months. The reduction in IOP ranged from -2.3 to 25.3 mm Hg after 1 month, and from -1.3 to 33.3 mm Hg after 3 months. The pressure-lowering effect was considerably more pronounced in eyes with higher untreated IOP; the reduction increased by 0.55 mm Hg per mm Hg higher untreated IOP. Four eyes, with untreated IOP within statistically normal limits, had no or negative IOP-reduction. A regression model predicted that IOP reduction ended at untreated IOP≤16 mm Hg. Multiple regression analysis showed that an additional IOP-lowering effect of 1.28 mm Hg was achieved in eyes with pseudoexfoliation glaucoma.To the best of our knowledge, this paper is the first to report the IOP-reducing effect of latanoprost treatment at all untreated IOP levels in newly detected glaucoma patients. The effect was proportional to the untreated IOP at all levels above 16 mm Hg and better at higher untreated IOP levels, also in relative terms. Our results further confirm the indication of latanoprost as a first-line therapy for glaucoma.

Purpose of Review: A 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 Findings: For normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory. Summary: Data 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.

Purpose To study newly diagnosed glaucoma patients given mono‐ or multi‐therapy regarding differences in initial intraocular pressure (IOP) reduction, target IOP levels reached and influence of untreated baseline IOP on IOP reduction. Methods Patients newly diagnosed with manifest primary open‐angle glaucoma and included in the Glaucoma Intensive Treatment Study (GITS) were randomized to immediate intensive treatment with any of three different IOP‐lowering substances supplied in two bottles plus 360° laser trabeculoplasty or to conventional stepwise treatment starting with a single‐drug. Intraocular pressure reduction was analysed 1 month after initiation of treatment. Results One hundred eighteen patients (143 eyes) received mono‐therapy and 122 patients (152 eyes) multi‐therapy. Median baseline IOP was 24.0 (min: 9.7, max: 56.0) mmHg in mono‐therapy eyes and 24.0 (min: 12.3, max: 48.5) mmHg in multi‐therapy eyes (p = 0.56). After 1 month in the two groups, respectively, values for median IOP reduction were 6.3 (range: −5.3–31.0) and 11.0 (range: 0.7–34.5) mmHg, and for mean relative decline 26.8 (range: −32.0–55.4) and 46.0 (range: 4.6–81.6) % (p = 0.000). A larger proportion of the multi‐therapy patients reached each target IOP level (p = 0.000). The higher the baseline IOP, the larger the observed pressure reduction, considering both absolute and relative figures. The effect was more pronounced in eyes with multi‐therapy than in those with mono‐therapy (p = 0.000). For every mmHg higher IOP at baseline, the IOP was reduced by an additional 0.56 (mono‐therapy) or 0.84 (multi‐therapy) mmHg. Conclusion Intensive treatment led to considerably greater IOP reduction than mono‐therapy. Among patients with IOP ≥30 mmHg at diagnosis an IOP of

The primary objective of the ongoing Glaucoma Intensive Treatment Study (GITS) is to evaluate the effectiveness of immediate intensive treatment in comparison with the commonly recommended stepped regimen on the predicted visual field. The two treatment arms are also being compared regarding quality of life (QoL), intraocular pressure (IOP) reduction, frequency of reported side-effects, adverse events and adherence to prescribed treatment.A randomized, two-centre, prospective open-labelled treatment trial for open-angle glaucoma.Individuals aged 40-78 years with previously untreated and newly diagnosed glaucoma with early to moderate visual field loss were eligible.Patients were randomized to initial treatment either using drug monotherapy in accordance with common glaucoma guidelines or using a more intensive approach including eyedrops containing drugs from three different classes combined with 360° laser trabeculoplasty. The patients are to be followed for 5 years at visits including standard automated perimetry, optical coherence tomography (OPT) and tonometry. Change of treatment is allowed and decided upon jointly with the patient as in conventional glaucoma management.The estimated predicted preserved visual field and QoL at end of expected lifetime.A total of 242 patients, 45% females, mean age 68 years, were randomized. The median untreated IOP was 24 mm Hg, and the median visual field index (VFI), indicating the percentage of a full field, was 92%.Glaucoma Intensive Treatment Study is a clinical trial in which two groups of patients randomized to different initial intensities of IOP-reducing treatment are being compared with regard to rate of visual field progression and prediction of serious glaucomatous visual field loss at estimated at end of life.

To compare in a randomized, controlled trial topical 1.5% dexamethasone γ-cyclodextrin nanoparticle eye drops (DexNP) with posterior subtenon injection of triamcinolone acetonide in diabetic macular oedema (DME).In this prospective, randomized, controlled trial, 22 eyes of 22 consecutive patients with DME were randomized to (i) topical treatment with DexNP ×3/day (4 weeks), ×2/day (4 weeks) and ×1/day (4 weeks) or (ii) one posterior subtenon injection of 20 mg triamcinolone acetonide. Study visits were at baseline and 4, 8, 12 and 16 weeks.The logMAR (Snellen) visual acuity (mean ± SD) improved significantly with DexNP from 0.41 ± 0.3 (Snellen 0.39) to 0.32 ± 0.25 (0.48) and 0.30 ± 0.26 (0.50) at 4 and 8 weeks, respectively. One-third of the DexNP group improved more than 0.3 logMAR units. For triamcinolone, logMAR changed significantly from 0.42 ± 0.28 (0.38) at baseline to 0.32 ± 0.29 (0.48) at 4w and 0.33 ± 0.37 (0.47) at 12w. The central macular thickness (CMT) decreased significantly with DexNP from 483 ± 141 μm to 384 ± 142 μm at 4w and 342 ± 114 μm at 8w. For triamcinolone, CMT decreased significantly at all time-points: 494 ± 94 μm, 388 ± 120, 388 ± 145, 390 ± 136 and 411 ± 104 μm at 0, 4, 8, 12 and 16 weeks, respectively. There was a modest increase in intraocular pressure (IOP) at all time-points with DexNP while no increase was seen with triamcinolone. Serum cortisol was affected by both treatments.Topical DexNP significantly improve visual acuity and decrease macular thickness in patients with DME. The effect is similar to that from subtenon triamcinolone. A modest increase in IOP was seen with the nanoparticle eye drops, but IOP normalized after the discontinuation of treatment.

To test the hypothesis that normal-tension glaucoma (NTG) is caused by an increased pressure difference across the lamina cribrosa (LC) related to a low intracranial pressure (ICP).Prospective case-control study.Thirteen NTG patients (9 women; median 71 [range: 56-83] years) were recruited for investigation with the same protocol as 11 healthy volunteers (8 women; 47 [30-59] years). A larger control group (n = 51; 30 women; 68 [30-81] years) was used only for ICP comparison in supine position.ICP and intraocular pressure (IOP) were simultaneously measured in supine, sitting, and 9° head-down tilt (HDT) positions. Trans-lamina cribrosa pressure difference (TLCPD) was calculated using ICP and IOP together with geometric distances estimated from magnetic resonance imaging to adjust for hydrostatic effects.ICP, IOP, and TLCPD in different body positions.Between NTG patients and healthy volunteers, there were no differences in ICP, IOP, or TLCPD in supine, sitting, or HDT (P ≥ 0.11), except for IOP in HDT (P = 0.04). There was no correlation between visual field defect and TLCPD, IOP, or ICP and in any body position (P ≥ 0.39). Mean ICP in supine was 10.3 mmHg (SD = 2.7) in the NTG group (n = 13) and 11.3 (2.2) mmHg in the larger control group (n = 51) (P = 0.24).There was no evidence of reduced ICP in NTG patients as compared with healthy controls, either in supine or in upright position. Consequently, the hypothesis that NTG is caused by an elevated TLCPD from low ICP was not supported.

Dorzolamide nanoparticle γ-cyclodextrin eye drops may prolong the effect of dorzolamide on intraocular pressure. We test whether the nanoparticle drops have an irritating or toxic effect on the eye in an in vivo rabbit model.Eighteen pigmented rabbits were divided into 4 groups receiving dorzolamide nanoparticle γ-cyclodextrin eye drops×1/day or×2/day, Trusopt® (dorzolamide HCl)×3/day, and untreated controls that received no drops. The rabbits received treatment for 1 month. After sacrifice, 33 eyes and 25 Harderian glands were evaluated for histopathology in a masked way.Mild inflammation was seen in 19/31 eyes and 13/23 Harderian glands. The difference in inflammation (n=eyes/n=glands)between the γ-cyclodextrin nanoparticle eye drops×1/day (n=5/5),×2/day (n=5/3), Trusopt (n=7/4), or untreated control (n=2/0) groups was nonsignificant in both eyes and glands (P=0.87 and P=0.92) Acute inflammation was seen in 1 Harderian gland that received γ-cyclodextrin nanoparticle eye drops×2/day. The difference in conjunctival injection between the groups was nonsignificant (P=0.30).Dorzolamide γ-cyclodextrin nanoparticle eye drops are no more locally toxic or irritating to the eye than Trusopt.

The discovery of a posture-dependent effect on the difference between intraocular pressure (IOP) and intracranial pressure (ICP) at the level of lamina cribrosa could have important implications for understanding glaucoma and idiopathic intracranial hypertension and could help explain visual impairments in astronauts exposed to microgravity. The aim of this study was to determine the postural influence on the difference between simultaneously measured ICP and IOP.Eleven healthy adult volunteers (age = 46 ± 10 years) were investigated with simultaneous ICP, assessed through lumbar puncture, and IOP measurements when supine, sitting, and in 9° head-down tilt (HDT). The trans-lamina cribrosa pressure difference (TLCPD) was calculated as the difference between the IOP and ICP. To estimate the pressures at the lamina cribrosa, geometrical distances were estimated from magnetic resonance imaging and used to adjust for hydrostatic effects.The TLCPD (in millimeters of mercury) between IOP and ICP was 12.3 ± 2.2 for supine, 19.8 ± 4.6 for sitting, and 6.6 ± 2.5 for HDT. The expected 24-hour average TLCPD on earth-assuming 8 hours supine and 16 hours upright-was estimated to be 17.3mmHg. By removing the hydrostatic effects on pressure, a corresponding 24-hour average TLCPD in microgravity environment was simulated to be 6.7mmHg.We provide a possible physiological explanation for how microgravity can cause symptoms similar to those seen in patients with elevated ICP. The observed posture dependency of TLCPD also implies that assessment of the difference between IOP and ICP in upright position may offer new understanding of the pathophysiology of idiopathic intracranial hypertension and glaucoma. Ann Neurol 2016;80:269-276.

To evaluate intraocular pressure (IOP) measurements 24 months after laser-assisted subepithelial keratectomy (LASEK) with 3 tonometry methods-Goldmann applanation tonometry (GAT), Pascal dynamic contour tonometry (DCT), and applanation resonance tonometry (ART)-and to compare them with measurements taken preoperatively and 3 and 6 months postoperatively.Department of Ophthalmology, Umeå University, Umeå, Sweden.Prospective randomized single-center.One randomized eye per person from myopic healthy individuals who had LASEK was included. Visual acuity, central corneal thickness (CCT), corneal curvature, and IOP were measured at all time points. Six IOP measurements were performed per method, with a 5-minute lapse between methods.The study evaluated 38 eyes. Two years after LASEK, dynamic ART was the only method that did not measure significantly lower IOP than before LASEK (mean -0.2 mm Hg ± 1.6 [SD]). The greatest difference was with GAT (mean -1.9 ± 1.7 mm Hg) followed by static ART (mean -1.2 ± 1.6 mm Hg) and then DCT (mean -0.9 ± 1.3 mm Hg). All methods measured significantly lower IOP at 3 months and 6 months.Dynamic ART, which analyses IOP measurement during indentation, showed no significant difference in measured IOP after 24 months. The convex tip of the ART device and the continuous sampling of data during corneal indentation seem to be factors in why dynamic ART was less affected by corneal properties and therefore more suitable for IOP measurement in LASEK-treated eyes, although this must be confirmed in larger trials.

To prospectively evaluate 3 tonometry methods--the gold standard, Goldmann applanation tonometry, a new method, Pascal dynamic contour tonometry (PDCT), and a method under development, applanation resonance tonometry (ART)--with respect to intraocular pressure (IOP) measurements before, 3 and 6 months after laser-assisted subepithelial keratectomy (LASEK).One randomly assigned eye of each of 53 healthy individuals, who underwent LASEK surgery for myopia was studied. Visual acuity, central corneal thickness, corneal curvature, and IOP were measured at each visit. Six IOP measurements/methods with 5 minutes pause between methods were performed.All tonometry methods measured a significantly lower IOP after LASEK correction by a mean of -3.1 diopters. The IOP reduction was largest after 6 months for Goldmann applanation tonometry (-1.7 ± 1.8 mm Hg) followed by ARTstat (-1.2 ± 1.5 mm Hg), PDCT (-1.1 ± 1.6 mm Hg), and ARTdyn (-1.0 ± 1.5 mm Hg). The reduction of IOP did not differ significantly between different methods (P=0.11). There was a significant further reduction of measured IOP for PDCT between 3 and 6 months (-0.5 ± 1.0 mm Hg). Uncorrected visual acuity improved significantly between 3 and 6 months postoperatively from 1.32 ± 0.28 to 1.43 ± 0.27.All tonometry methods measured a significant, but low, reduction of IOP 3 and 6 months after LASEK. Further change in visual acuity and IOP measurements between 3 and 6 months suggest a still ongoing postoperative process.

Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3;-cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye.

Ocular drug delivery to the posterior segment of the eye can be accomplished by invasive drug injections into different tissues of the eye and noninvasive topical treatment. Invasive treatment involves the risks of surgical trauma and infection, and conventional topical treatments are ineffective in delivering drugs to the posterior segment of the eye. In recent years, nanotechnology has become an ever-increasing part of ocular drug delivery. In the following, we briefly review microspheres and nanotechnology for drug delivery to the eye, including different forms of nanotechnology such as nanoparticles, microparticles, liposomes, microemulsions and micromachines. The permeation barriers and anatomical considerations linked to ocular drug delivery are discussed and a theoretical overview on drug delivery through biological membranes is given. Finally, in vitro, in vivo and human studies of x03B3;-cyclodextrin nanoparticle eyedrop suspensions are discussed as an example of nanotechnology used for drug delivery to the eye.

In recent years, Applanation Resonance Tonometry (ART) has been suggested for intraocular pressure (IOP) measurements. The manual version of ART (ART(manual) ) has been further developed, and to improve usability, an automatic servo-controlled prototype (ART(servo) ) has been proposed. The aim of this study was to assess the limits of agreement (LoA) of ART(manual) and ART(servo) as compared with the reference method, Goldmann Applanation Tonometry (GAT).This was a prospective single-centre study on 152 eyes from 77 subjects. It was designed according to International Standard Organization's (ISO) requirements for tonometers (ISO 2001). Intraocular pressure was measured six times/method in a standardized order. The ART technique has two available analysis procedures: a dynamic one that measures IOP during the indentation phase and a static one that causes a Goldmann-like measurement during two seconds of full applanation. The 95% LoA was defined as ±1.96 × standard deviation of difference against GAT.Mean IOP for GAT was 19.1 mmHg (range: 10-37 mmHg). The 95% LoA of ART(manual) was ±4.5 mmHg for both dynamic and static analyses. The 95% LoA of ART(servo) was ±5.7 mmHg for dynamic and ±4.9 mmHg for static analyses.This study confirms that the ART methodology is feasible. The further developed ART(manual) fulfilled the ISO standard with both the dynamic and the static analysis techniques. ART(servo) with static analysis was close to fulfilling the standard but failed to do so in the highest IOP range. ART(servo) has the potential to greatly improve usability if further development is completed.

To compare intraocular pressure (IOP) measurements by Pascal, ICare and Goldmann applanation tonometry (GAT), to evaluate the effects of central corneal thickness (CCT) and curvature on IOP measurement and to estimate the intra-observer variability.A prospective, single-centre study of 150 eyes with a wide range of pressures. Six masked IOP measurements/method; corneal thickness and curvature were studied for each eye. GAT was the reference.IOPPascal and IOPICare correlated with IOPGAT (r = 0.91, 0.89). Mean ICare measurement exceeded GAT by 2 mmHg. Pascal measured higher than GAT at low IOPs and lower at high IOPs. For every 10 mmHg increase in IOP above 31 mmHg, Pascal measured 2 mmHg lower than GAT and vice versa. CCT was correlated significantly with IOPGAT (r = 0.23) and IOPICare (r = 0.43) but not with IOPPascal (P = 0.12). CCT was correlated with age. In a subgroup (50 years), ICare and the difference between IOPGAT and IOPPascal were affected significantly by the CCT, whereas IOPGAT and IOPPascal were not. Corneal curvature was correlated significantly with IOPGAT (r = -0.27) and IOPPascal (r = -0.26) but not with IOPICare (P = 0.60). Intra-observer variability within each set of six measurements was approximately 2 mmHg, irrespective of method.This study showed a reasonable overall correlation and concordance between the IOP obtained with the three instruments. None of the methods were completely independent of the biomechanical properties of the cornea. ICare showed a significant dependency upon CCT, whereas GAT and Pascal showed a significant dependency on corneal curvature. All methods showed intra-observer variability, which leaves room for further improvement of methods.

To investigate the effect of aging on ocular parameters, including intraocular pressure (IOP), measured with different tonometry methods in healthy young (HY) and healthy elderly (HE) subjects and to study the effect of corneal parameters on tonometry methods.In this prospective, cross-sectional study, fifty eyes of 50 HY subjects (28 females, 22-31 years of age) and 43 eyes of 43 HE subjects (22 females, 64-79) were included. IOP was measured with four tonometry methods in a standardized order: ocular response analyser (ORA), dynamic contour tonometry (DCT), applanation resonance tonometry (ART) and Goldmann applanation tonometry (GAT). Other measurements included axial length (AL), central corneal thickness (CCT), corneal curvature (CC), anterior chamber volume (ACV), corneal hysteresis (CH) and corneal resistance factor (CRF).The mean IOP (HY/HE; mmHg ± standard deviation (SD)) was 12.2 ± 2.2/14.1 ± 3.5 with GAT. IOP was significantly higher (difference ± standard error) in HE compared to HY measured with an ORA (+3.1 mmHg ± 0.6), GAT (+1.9 ± 0.6) and DCT (+1.6 ± 0.6). No significant difference was found in IOP measured with ART. CH and ACV were significantly lower in HE compared to HY. There was no difference between the groups in CCT, CC, AL or CRF. No tonometry method was dependant on CCT or CC.IOP measured with an ORA and via DCT and GAT was higher in HE compared to HY Swedish subjects, while IOP measured with ART did not differ between the groups. In these homogeneous groups, tonometry methods were independent of CCT and CC.

PURPOSE: To explore the possibility of estimating the prevalence of open-angle glaucoma (OAG) on the west coast of Iceland using a clinical retrospective material, and to compare that estimate with ...

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.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.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.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 test a new drug delivery platform with dorzolamide γ-cyclodextrin (γCD) nanoparticle eye drops for intraocular pressure (IOP) control and safety and compare with Trusopt.(®)Self-aggregating γCD nanoparticle eye drops containing 3% dorzolamide were given once a day (QD) and compared with Trusopt given three times a day (TID) in a prospective randomized single masked crossover trial over 24 h. Seventeen subjects with IOP over 18 mmHg were recruited. IOP was measured with an Icare Tonometer Pro.(®)There was no statistically significant difference in the IOP lowering effect of dorzolamide nanoparticle eye drops QD and Trusopt TID. At peak (4 h), the IOP reduction from baseline was 3.8±2.6 mmHg (18%, P0.05) in the nanoparticle eye drop group and 3.1±3.7 mmHg in the Trusopt group (14%, P0.05, P=0.97 between groups). At trough (24 h), the IOP reduction was 1.4±2.8 mmHg (6%, P0.05) in nanoparticle eye drop group and 1.5±2.0 mmHg (7%, P0.05) in the Trusopt group (P=0.23 between groups). Burning sensation measured on the visual analogue scale (1-100) was less from the nanoparticle eye drops (12±15) than from the Trusopt (37±30), (P=0.0038). Visual acuity and conjunctival hyperemia did not differ between the two groups.Dorzolamide cyclodextrin nanoparticle eye drops QD lower IOP and the effect seems comparable to Trusopt given TID. The nanoparticle eye drops are well tolerated and seem to have a better safety profile than Trusopt.

We have developed nanoparticle γ-cyclodextrin dexamethasone (DexNP) and dorzolamide (DorzNP) eye drops that provide sustained high drug concentrations on the eye surface. To test these characteristics, we measured dexamethasone and dorzolamide levels in tear fluid in humans following eye drop administration.Concentration of dexamethasone was measured by mass spectrometry. One drop of DexNP was instilled into one eye. Tear fluid was sampled with microcapillary pipettes at seven time-points after drop instillation. Control eyes received Maxidex(®) (dexamethasone). The same procedure was performed for dorzolamide with DorzNP and Trusopt(®) .Six subjects were included in each group. The peak concentration (μg/ml ± standard deviation) of dexamethasone for DexNP eye drops (636.6 ± 399.1) was up to 19-fold higher than with Maxidex(®) (39.3 ± 18.9) (p 0.001). At 4 hr, DexNP was still 10 times higher than Maxidex(®) . In addition, DexNP resulted in about 30-fold higher concentration of dissolved dexamethasone in the tear fluid of extended time period allowing more drug to partition into the eye tissue. The overall concentration of dorzolamide was about 50% higher for DorzNP (59.5 ± 76.9) than Trusopt(®) (40.0 ± 76.7) (p 0.05).The results indicate high and extended concentration of dissolved dexamethasone with DexNP, which can explain the greater and longer lasting effect of dexamethasone in the cyclodextrin nanoparticle drug delivery platform. Dexamethasone seems to fit the cyclodextrin nanoparticle suspension drug delivery platform with longer duration and higher concentrations in tear fluid than available commercial drops, while dorzolamide is less suitable.

Recent development of magnetic resonance imaging (MRI) offers new possibilities to assess ocular blood flow. This prospective study evaluates the feasibility of phase-contrast MRI (PCMRI) to measure flow rate in the ophthalmic artery (OA) and establish reference values in healthy young (HY) and elderly (HE) subjects.Fifty HY subjects (28 females, 21-30 years of age) and 44 HE (23 females, 64-80 years of age) were scanned on a 3-Tesla MR system. The PCMRI sequence had a spatial resolution of 0.35 mm per pixel, with the measurement plan placed perpendicularly to the OA. Mean flow rate (Qmean), resistive index (RI), and arterial volume pulsatility of OA (ΔVmax) were measured from the flow rate curve. Accuracy of PCMRI measures was investigated using a vessel-phantom mimicking the diameter and the flow rate range of the human OA.Flow rate could be assessed in 97% of the OAs. Phantom investigations showed good agreement between the reference and PCMRI measurements with an error of7%. No statistical difference was found in Qmean between HY and HE individuals (HY: mean ± SD = 10.37 ± 4.45 mL/min; HE: 10.81 ± 5.15 mL/min, P = 0.655). The mean of ΔVmax (HY: 18.70 ± 7.24 μL; HE: 26.27 ± 12.59 μL, P0.001) and RI (HY: 0.62 ± 0.08; HE: 0.67 ± 0.1, P = 0.012) were significantly different between HY and HE.This study demonstrated that the flow rate of OA can be quantified using PCMRI. There was an age difference in the pulsatility parameters; however, the mean flow rate appeared independent of age. The primary difference in flow curves between HE and HY was in the relaxation phase of the systolic peak.

To investigate the effects of repeated measurements of intraocular pressure (IOP) using Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) to identify mechanisms contributing to the expected IOP reduction.A prospective, single-centre study with six healthy volunteers. Consecutive repeated series (six measurements/serie/method) were made alternately on both eyes for 1 hr with oxybuprocaine/fluorescein in the right eye and tetracaine in the left. The left eye was Pentacam(®) photographed before and repeatedly for 20 min after the IOP measurements. On a separate occasion, the same volunteers received the same amount of anaesthetic drops for 1 hr but without repeated IOP measurements.A significant IOP reduction occurred with both ART and GAT in the oxybuprocaine-treated eye, -4.4 mmHg and -3.8 mmHg, respectively and with ART in the tetracaine eye, -2.1 mmHg. There was a significant difference in IOP reduction between the oxybuprocaine and tetracaine eyes with ART. There was a significant drop in anterior chamber volume (ACV) immediately after the IOP measurements, -12.6 μl that returned to pretrial level after 2 min. After 1 hr of receiving anaesthetic eye drops (without IOP measurements), the IOP decreased significantly in the oxybuprocaine eye for both ART and GAT, -3.1 and -1.7 mmHg, respectively, but not in the tetracaine eye (p = 0.72).The IOP reduction cannot be explained solely by aqueous humor being pressed out of the anterior chamber. While significant IOP reduction occurred with both tetracaine and oxybuprocaine after repeated mechanical applanation, the IOP reduction was significantly greater with oxybuprocaine.

Purpose To measure the volume flow rate of the ophthalmic artery (OA). A phase contrast magnetic resonance imaging (PCMRI) protocol was developed to assess volume flow rate of OA in healthy young (HY) and elderly (HE). Methods The study was performed with a 3-Tesla scanner on HY (n=51,28females,age=64-80ys) and HE (n=51,28females,age=21-30ys). The OA were localized by a 3D time of flight (3DTOF) sequence. To measure the volume flow rate, a 2D PCMRI sequence was optimized to reach a spatial resolution of 0.35mm/pixel. Based on 3DTOF data, the flow measurement was perpendicular to OA. Mean volume flow rate (Qmean), resistive index (RI), arterial volume change (ΔV) and symmetry index (SI) were computed from the volume flow rate curve. Accuracy of MRI measures was studied using a vessel-phantom (O=1.4mm). Six constant flow rates (5.54-34.41mL/min) were used as reference. Results Phantom investigation showed good agreement between the reference and MRI measurements with a percentage error 0.05). Conclusion Volume flow rate measurement of OA vessels using PCMRI is possible. Contrary to color Doppler imaging, PCMRI technique does not alter IOP during the measurements. This method may provide a precise description of the dynamics of the volume flow rate of OA during the cardiac cycle.

Purpose The purpose of this study was to evaluate the effect of repetitive applanation tonometry measurements on IOP and aqueous humor volume in the anterior chamber. Methods This is an ongoing study where four healthy volunteers have participated so far. Consecutive repeated series of six measurements with Goldmann applanation tonometry (GAT) and applanation resonance tonometry (ART) were made alternately on both eyes for one hour. Using an Oculus Pentacam, the anterior chamber of the left eye was photographed before the measurements and then consecutively for 20 min. Finally, one additional measurement was performed with both GAT and ART. Results In this abstract we present the results from the first four subjects. The results show that there was a significant reduction in IOP on the right eye both with GAT and ART. After one hour of measurements, IOP was reduced by 5.5 mmHg (range 4.3-7.2 mmHg) for GAT and 3.1 mmHg (range 1.0-4.1 mmHg) for ART. The decrease in aqueous humour volume after IOP measurements was less than 10 % for all subjects. Conclusion Although Bechrakis showed as early as 1966 that repetitive measurements result in significant IOP reduction, the mechanism behind this is still matter of debate. Our preliminary results confirm the occurrence of IOP reduction after repetitive measurements, but indicate that it could not be explained by the decrease in volume of the anterior chamber.