Mark R. Lesk

Canadian Glaucoma Study: 2. Risk Factors for the Progression of Open-angle Glaucoma

OBJECTIVE To determine systemic and ocular risk factors for visual field progression in open-angle glaucoma. METHODS In the Canadian Glaucoma Study, a multicenter prospective longitudinal study of 258 patients (131 men and 127 women; median age, 65.0 years), baseline systemic measures included assessment of peripheral vasospasm and markers for hematopathology, coagulopathy, and immunopathology. Patients were followed up at 4-month intervals with perimetry, optic disc imaging, and a standardized interventional protocol for intraocular pressure control. Univariate and proportional hazards models were used to identify factors that predicted progression. MAIN OUTCOME MEASURE Visual field progression with standard automated perimetry. RESULTS Median follow-up was 5.3 years, with 167 patients (64.7%) completing 5 years or more and 67 patients (26.0%) completing 7 years or more. Abnormal baseline anticardiolipin antibody levels (hazard ratio [HR], 3.86; 95% confidence interval [CI], 1.60-9.31), higher baseline age (HR per year, 1.04; 95% CI, 1.01-1.07), female sex (HR, 1.94; 95% CI, 1.09-3.46), and higher mean follow-up intraocular pressure (HR per 1 mm Hg, 1.19; 95% CI, 1.05-1.36) before progression were associated with progression. CONCLUSIONS The Canadian Glaucoma Study identified 4 independent predictive factors for glaucomatous field progression. Application to Clinical Practice While confirming the importance of intraocular pressure in glaucoma progression, this study determined other risk factors that merit awareness.

Reversal of optic disc cupping after glaucoma surgery analyzed with a scanning laser tomograph

Abstract Objective To detect and quantitate changes in optic nerve morphology after glaucoma surgery using the Heidelberg Retina Tomograph (HRT, Heidelberg Instruments, Heidelberg, Germany). Design Nonconsecutive observational case series. Participants and intervention The authors prospectively enrolled 21 adult patients undergoing incisional glaucoma surgery for progressive glaucoma damage. Quantitative analysis of the optic nerve head by scanning laser tomography and automated perimetry were performed before and after glaucoma surgery. Main outcome measures Changes in optic nerve parameters were subjected to linear regression analysis with respect to percent of postoperative reduction of intraocular pressure (IOP), as well as with respect to age, refraction, preoperative cup:disc ratio, and change in visual field parameters. Results Seventeen patients had pre- and postoperative images suitable for analysis. Mean IOP at the time of image acquisition before surgery was 30.5 ± 12 mmHg, and after surgery 11.8 ± 5.2 mmHg (mean follow-up, 26 ± 7 weeks). Eleven of 13 (85%) patients having IOP reduction of greater than 40% showed improvement in optic disc parameters. All four patients with less than 25% reduction in IOP showed worsening of most parameters. Changes in optic disc parameters were highly correlated with percent IOP reduction and with age. The parameters in which change most strongly correlated with percent change of IOP were cup area, rim area, cup:disc ratio, and mean cup depth (each, P P P = 0.025). Conclusion Most patients showing a 40% lowering of IOP after glaucoma surgery show improved optic nerve morphology as measured by the HRT. The amount of improvement correlated highly with the percent reduction of IOP.

Determinants of adherence to glaucoma medical therapy in a long-term patient population.

PurposeEstimate patient adherence to glaucoma medications and identify potential determinants of nonadherence. DesignDescriptive study. MethodsTwo hundred patients with open angle glaucoma, ocular hypertension, or glaucoma suspects were interviewed regarding their glaucoma and its treatment and their charts were reviewed. Their ophthalmologist completed a brief assessment form. Drug utilization data were extracted from the provincial drug program database. Patients were defined as adherent if they filled at least 75% of the prescribed medication necessary for their treatment. ResultsData were available for 181 patients. About 62.9% were female and the mean age (±SD) was 75.1±8.8 years. The mean number of years of glaucoma treatment was 10.7±9.3. Self-reported treatment adherence was 88.3%. On the basis of the drug database, the proportion of patients who were adherent to treatment was 71.8%. According to physicians, 74.6% of patients were adherent. Among patients considered by physicians as nonadherent, 71.1% (32/45) were adherent and among patients predicted as adherent, 72.1% (98/136) were adherent. There was no significant difference in adherence according to age, sex, education, and income. However, patients using fewer agents (P=0.041), who were widowed (P=0.041), or who lived alone (P=0.042) were more adherent. Patients using prostaglandins analogs or β-blockers were more adherent than those using carbonic anhydrase inhibitors (P<0.05). ConclusionsFewer medications, use of prostaglandin analogs or β-blockers, living alone, and being widowed were significantly associated with adherence. Physicians were unable to significantly predict which patients are adherent.

The Penetration of Oral Ciprofloxacin Into the Aqueous Humor, Vitreous, and Subretinal Fluid of Humans

We examined ciprofloxacin levels in the aqueous humor, vitreous, or subretinal fluid in 40 patients undergoing cataract extraction, vitrectomy, or scleral buckling. Ciprofloxacin, 750 mg, was administered orally an average of 17 1/2 and 5 1/2 hours preoperatively. We obtained mean ciprofloxacin levels of 0.53 microgram/ml in aqueous humor, 0.51 microgram/ml in vitreous, and 0.71 microgram/ml in subretinal fluid. These vitreous levels exceed the minimum inhibitory concentration (MIC)90 of Staphylococcus epidermidis, Propionibacterium species, Pseudomonas aeruginosa, Proteus mirabilis, and Haemophilus influenzae, as well as the MIC70 of S. aureus and Bacillus cereus. Therefore, ciprofloxacin may have a role in the management and prevention of endophthalmitis.

Evaluation of Optic Nerve Head and Peripapillary Retinal Blood Flow in Glaucoma Patients, Ocular Hypertensives, and Normal Subjects

PURPOSE To compare optic nerve head (ONH) and peripapillary retinal blood flow in subjects with open-angle glaucoma (OAG), ocular hypertension (OHT), and normal eyes (NOR) using full-field perfusion analysis of scanning laser Doppler flowmetry (SLDF) images. DESIGN Prospective, nonrandomized clinical trial. METHODS Twenty uncontrolled OAG patients, 20 uncontrolled OHT patients, and 20 normal volunteers were prospectively enrolled. Mean ONH and peripapillary retinal blood flow measurements were performed by SLDF version 3.3 using five Heidelberg Retina Flowmeter (Heidelberg Engineering, Heidelberg, Germany) images. Statistical evaluations were performed on the three study groups using one-way analysis of variance. Flow values of the neuroretinal rim of the ONH, nasal peripapillary retina, and temporal peripapillary retina were then correlated with the clinical parameters of age, cup/disk (C/D) ratio, intraocular pressure (IOP), visual field mean defect, maximum-recorded IOP, and ocular perfusion pressure. Neuroretinal rim blood flow in the OAG group was 158 +/- 79 arbitrary units (au), whereas in the OHT group it was 277 +/- 158 au, and in the NOR group it was 272 +/- 93 au. Differences were statistically significant between the OAG group and each of the other groups (P =.001) but not between OHT and NOR groups (P =.91). Peripapillary retinal flow values showed no statistically significant differences between groups (P =.76 nasal and 0.93 temporal). RESULTS Neuroretinal rim flow values showed a significant inverse correlation with C/D ratio (P =.001). Mean neuroretinal rim blood flow was significantly higher (350 +/- 184 au) in the 10 OHT patients with C/D ratios < 0.4 when compared with the 10 OHT patients with larger C/D ratios (203 +/- 79 au) (P =.039). Conversely, peripapillary retinal blood flow showed no significant correlation with any clinical parameter. CONCLUSION Open-angle glaucoma patients had significantly lower blood flow in the ONH compared with OHT patients and normal volunteers. No significant differences in ONH blood flow were found between ocular hypertensives and normal volunteers. For peripapillary retinal blood flow, no significant difference was seen between any groups. Neuroretinal rim blood flow was significantly inversely correlated to increased C/D ratio. Ocular hypertensives with larger C/D ratios demonstrated significantly lower rim blood flow compared with those with smaller C/D ratios, suggesting that rim perfusion might be reduced in high-risk ocular hypertensives before the manifestation of visual field defects.

Phacoemulsification and goniosynechialysis in the management of unresponsive primary angle closure.

Purpose:To evaluate the effectiveness of phacoemulsification and goniosynechialysis (PEGS) in managing acute and subacute primary angle closure unresponsive to conventional therapy. Materials and Methods:Retrospective series of patients of six glaucoma-trained surgeons with primary angle closure that did not respond to medical management, Nd:YAG laser peripheral iridotomy, or argon laser peripheral iridoplasty. Results:A total of twenty-one patients with an average age of 65.6 years were included. Underlying mechanism of angle closure included pupillary block (n = 18) and plateau iris (n = 3). Average intraocular pressure (IOP) immediately prior to PEGS was 40.7 mm Hg, and mean follow-up time after PEGS was 11.7 months. PEGS decreased mean IOP by 25 mm Hg (62%), and mean number of medications from 3.8 pre-surgery to 1.7 post-surgery (55%). Mean LogMar visual acuity improved after PEGS, from 0.64 to 0.44 (Paired t test t = 4.120 P = 0.001). Subsequent trabeculectomy was necessary in one case (5%). Conclusions:Phacoemulsification with goniosynechialysis may be an effective treatment option for primary angle closure unresponsive to conventional therapy.

Canadian Glaucoma Study: 3. Impact of risk factors and intraocular pressure reduction on the rates of visual field change.

OBJECTIVES To determine rates of visual field change associated with risk factors for progression in the Canadian Glaucoma Study (abnormal anticardiolipin antibody level, age, female sex, and mean follow-up intraocular pressure [IOP]), and to evaluate the effect of IOP reduction on subsequent rates of visual field change in progressing patients. METHODS Two hundred sixteen patients (median age, 65.2 years) were followed up at 4-month intervals with perimetry and were monitored for progression. Patients reaching an end point based on total deviation analysis underwent 20% or greater reduction in IOP. Rates of mean deviation (MD) change were calculated. RESULTS Patients with 0, 1, and 2 end points had a median of 18, 23, and 25 examinations, respectively. The median MD rate in progressing patients prior to the first end point was significantly worse compared with those with no progression (-0.35 and 0.05 dB/y, respectively). An abnormal anticardiolipin antibody level was associated with a significantly worse MD rate compared with a normal anticardiolipin antibody level (-0.57 and -0.03 dB/y, respectively). Increasing age was associated with a worse MD rate, but female sex and mean follow-up IOP were not. After the first end point, the median IOP decreased from 18.0 to 14.8 mm Hg (20% in individual patients), resulting in a significant MD rate change from -0.36 to -0.11 dB/y. CONCLUSIONS Patients with abnormal anticardiolipin antibody levels and increasing age had faster visual field change. Modest IOP reduction in progressing patients significantly ameliorated the rate of visual field decline. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00262626.

Transplantation of Mesenchymal Stem Cells Promotes Tissue Regeneration in a Glaucoma Model Through Laser-Induced Paracrine Factor Secretion and Progenitor Cell Recruitment†‡§

Among bone marrow cells, hematopoietic and mesenchymal components can contribute to repair damaged organs. Such cells are usually used in acute diseases but few options are available for the treatment of chronic disorders. In this study, we have used a laser‐induced model of open angle glaucoma (OAG) to evaluate the potential of bone marrow cell populations and the mechanisms involved in tissue repair. In addition, we investigated laser‐induced tissue remodeling as a method of targeting effector cells into damaged tissues. We demonstrate that among bone marrow cells, mesenchymal stem cells (MSC) induce trabecular meshwork regeneration. MSC injection into the ocular anterior chamber leads to far more efficient decrease in intraocular pressure (IOP) (p < .001) and healing than hematopoietic cells. This robust effect was attributable to paracrine factors from stressed MSC, as injection of conditioned medium from MSC exposed to low but not to normal oxygen levels resulted in an immediate decrease in IOP. Moreover, MSC and their secreted factors induced reactivation of a progenitor cell pool found in the ciliary body and increased cellular proliferation. Proliferating cells were observed within the chamber angle for at least 1 month. Laser‐induced remodeling was able to target MSC to damaged areas with ensuing specific increases in ocular progenitor cells. Thus, our results identify MSC and their secretum as crucial mediators of tissue repair in OAG through reactivation of local neural progenitors. In addition, laser treatment could represent an appealing strategy to promote MSC‐mediated progenitor cell recruitment and tissue repair in chronic diseases. STEM Cells 2013;31:1136–1148

Changes in optic nerve head blood flow after therapeutic intraocular pressure reduction in glaucoma patients and ocular hypertensives

PURPOSE To detect and quantify changes in optic nerve head (ONH) and peripapillary retinal blood flow by scanning laser Doppler flowmetry (SLDF) in open-angle glaucoma (OAG) and ocular hypertension (OHT) after therapeutic intraocular pressure (IOP) reduction. DESIGN Prospective, nonrandomized, self-controlled trial. PARTICIPANTS Twenty patients with OAG and 20 patients with OHT with clinical indications for therapeutic IOP reduction were prospectively enrolled. INTERVENTION IOP reduction was achieved by medical, laser, or surgical therapy. All patients had IOP reductions more than 20% and a minimum of 4 weeks follow-up. MAIN OUTCOME MEASURES Blood flow measurements were performed by SLDF analysis software (version 3.3) using Heidelberg Retina Flowmeter images. Statistical evaluations were performed on both groups using a two-tailed distribution paired t test. RESULTS Twenty patients with OAG had a mean IOP reduction of 37% after treatment. In these patients, mean (+/- standard deviation) rim blood flow increased by 67% (from 158 +/- 79 arbitrary units to 264 +/- 127 arbitrary units, P = 0.001), whereas mean temporal peripapillary retinal flow decreased by 7.4% (P = 0.24), and mean nasal peripapillary retinal flow increased by 0.3% (P = 0.96). Twenty OHT patients had a mean IOP reduction of 33% after treatment. In contrast to the OAG group, neither the mean rim blood flow (7.5% increase from 277 +/- 158 arbitrary units to 298 +/- 140 arbitrary units, P = 0.41) nor the mean temporal (P = 0.35) or nasal (P = 0.88) peripapillary retinal flow changed significantly. CONCLUSIONS For a similar percentage of IOP reduction, OAG patients had a statistically significant improvement of blood flow in the neuroretinal rim of the ONH, whereas OHT patients did not demonstrate such a change. Peripapillary retinal blood flow, expected to be affected less in glaucoma, remained stable in both groups. In addition to indicating a response to therapy in OAG patients, the reported changes in rim perfusion suggest that ONH autoregulation may be defective in OAG while intact in OHT.

Postmenopausal Hormone Therapy Increases Retinal Blood Flow and Protects the Retinal Nerve Fiber Layer

PURPOSE To investigate whether postmenopausal hormone therapy (HT) increases retinal and ONH blood flow (BF) and protects ONH topography and the function of retinal ganglion cells in postmenopausal women (PMW). The effect of estradiol (E(2)) treatment on retinal tissue perfusion was also investigated in ovariectomized rats, an animal model for menopause. METHODS Sixty-four healthy PMW were recruited, 29 of whom never used HT ( HT) and 35 of whom had used HT (+HT) continuously since the onset of menopause. Blood flow of the inferotemporal retinal artery (ITRA), peripapillary retina, and ONH rim were measured in one eye. The ONH stereometric parameters and the pattern electroretinogram (PERG) were also measured. In ovariectomized rats, the retinal tissue perfusion was assessed using the BF tracer N-isopropyl-p-[(14)C]-iodoamphetamine ([(14)C]-IMP) in rats treated with either E(2) (n = 7) or placebo (n = 5). RESULTS Compared with the HT group, the +HT group presented significantly greater BF of the ITRA (P = 0.006), greater rim volume for the entire ONH region (P = 0.032), and greater rim volume (P = 0.042), height variation contour (P = 0.011), mean thickness (P = 0.033), and cross-sectional area (P = 0.020) of the retinal nerve fiber layer for the inferotemporal region of the ONH when adjusted for age, ocular perfusion pressure, and age at menarche. In ovariectomized rats, E(2) treatment significantly increased retinal perfusion in a range of 22% to 45%. CONCLUSIONS These findings indicate that estrogens and HT increase retinal blood flow and protect the retinal nerve fiber layer.