Stefano A. Gandolfi

Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and ocular hypertension.

A multicenter, randomized, investigator-masked, parallel-group trial compared bimatoprost and latanoprost for efficacy and safety in patients with glaucoma or ocular hypertension. Patients received bimatoprost 0.03% (n = 119) or latanoprost 0.005% (n = 113) once daily in the evening for 3 months. Visits were at prestudy, baseline (day 0), week 1, and months 1, 2, and 3. Primary outcome measures were mean IOP and the percentage of patients achieving IOP of 17 mm Hg or lower at 8:00 am. Secondary outcome measures were diurnal IOP measurements (8:00 am, 12 noon, 4:00 pm, 8:00 pm) at month 3 and safety measures including adverse events. Mean IOP was lower with bimatoprost than with latanoprost at all time points during the 3-month follow-up, although the between-group difference was not always statistically significant. At month 3 at 12 noon, mean IOP was as much as 1.0 mm Hg lower with bimatoprost (P = .021 ). Target pressures of ≤17 mm Hg were reached more often with bimatoprost than with latanoprost at 8:00 am (53% vs 43%;P= .029). Over all diurnal measurements at month 3, low target pressures of ≤13, ≤14, and ≤15 mm Hg were achieved significantly more often with bimatoprost (P≤.006). Both drugs were safe and well tolerated. Conjunctival hyperemia was more common with bimatoprost, while headache was more frequent with latanoprost. Bimatoprost provided lower mean pressures than latanoprost at every time point throughout the study and was statistically superior in achieving low target pressures. More patients reached low target pressures with bimatoprost.

Correlation between optical coherence tomography, pattern electroretinogram, and visual evoked potentials in open-angle glaucoma patients

OBJECTIVE [corrected] To correlate the nerve fiber layer (NFL) thickness and the visual function evaluated by electrophysiologic retinal and cortical responses assessed in open-angle glaucoma (OAG) eyes. DESIGN Prospective case-control study. PARTICIPANTS Thirty glaucoma patients (mean age, 47.1 +/- 7.15 years; refractive error range, +/- 2 spherical equivalent) with a mean deviation of computerized static perimetry (24/2 Humphrey, Dublin, CA) from -5 to -28 dB and intraocular pressure less than 21 mmHg on pharmacologic treatment and 14 age-matched control participants. METHODS Nerve fiber layer thickness was measured by optical coherence tomography. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli (the single check edges subtend 15 minutes of the visual arc) reversed at the rate of two reversals per second. Linear regression analyses were adopted to establish the correlation between NFL thickness and PERG and VEP parameters. MAIN OUTCOME MEASURES Nerve fiber layer thickness measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and then averaged (12 values averaged) and identified as NFL overall, whereas the data obtained in the temporal quadrant only (three values averaged) were identified as NFL temporal. PERG P50 implicit time and P50-N95 amplitude and VEP P100 implicit time and N75-P100 amplitude were also measured. RESULTS In OAG eyes, we found a significant (P < 0.01) reduction in NFL thickness in both NFL overall and NFL temporal evaluations with respect to the values observed in control eyes. PERG and VEP parameters showed a significant (P < 0.01) delay in implicit time and a reduction in peak-to-peak amplitude. In OAG eyes, the NFL overall and NFL temporal values were significantly correlated (P < 0.01) with the PERG P50 implicit time and P50-95 peak-to-peak amplitude. No correlations (P > 0.01) between NFL values and VEP parameters were found. CONCLUSIONS There is a correlation between PERG changes and NFL thickness, but there is no correlation between VEP changes and NFL thickness in patients affected by OAG.

A Randomized Trial of a Schlemm's Canal Microstent with Phacoemulsification for Reducing Intraocular Pressure in Open-Angle Glaucoma

PURPOSE To assess the safety and effectiveness of the Hydrus Microstent (Ivantis, Inc, Irvine, CA) with concurrent cataract surgery (CS) for reducing intraocular pressure (IOP) in open-angle glaucoma (OAG). DESIGN Prospective, multicenter, randomized, single-masked, controlled clinical trial. PARTICIPANTS One hundred eyes from 100 patients 21 to 80 years of age with OAG and cataract with IOP of 24 mmHg or less with 4 or fewer hypotensive medications and a washed-out diurnal IOP (DIOP) of 21 to 36 mmHg. METHODS On the day of surgery, patients were randomized 1:1 to undergo CS with the microstent or CS alone. Postoperative follow-up was at 1 day, 1 week, and 1, 3, 6, 12, 18, and 24 months. Washout of hypotensive medications was repeated at 12 and 24 months. MAIN OUTCOME MEASURES Response to treatment was defined as a 20% or more decrease in washed out DIOP at 12 and 24 months of follow-up compared with baseline. Mean DIOP at 12 and 24 months, the proportion of subjects requiring medications at follow-up, and the mean number of medications were analyzed. Safety measures included change in visual acuity, slit-lamp observations, and adverse events. RESULTS The proportion of patients with a 20% reduction in washed out DIOP was significantly higher in the Hydrus plus CS group at 24 months compared with the CS group (80% vs. 46%; P = 0.0008). Washed out mean DIOP in the Hydrus plus CS group was significantly lower at 24 months compared with the CS group (16.9±3.3 mmHg vs. 19.2±4.7 mmHg; P = 0.0093), and the proportion of patients using no hypotensive medications was significantly higher at 24 months in the Hydrus plus CS group (73% vs. 38%; P = 0.0008). There were no differences in follow-up visual acuity between groups. The only notable device-related adverse event was focal peripheral anterior synechiae (1-2 mm in length). Otherwise, adverse event frequency was similar in the 2 groups. CONCLUSIONS Intraocular pressure was clinically and statistically significantly lower at 2 years in the Hydrus plus CS group compared with the CS alone group, with no differences in safety.

Effect of a YAG laser iridotomy on intraocular pressure in pigment dispersion syndrome.

PURPOSE To determine whether an iridotomy can prevent an increase in intraocular pressure (IOP) in patients with pigment dispersion syndrome. METHODS Consecutive subjects (n = 21) recruited into this randomized, controlled clinical trial in a hospital-based outpatient referral center, had pigment dispersion syndrome in both eyes, and underwent a YAG laser iridotomy in one eye (randomly chosen); no intervention was performed in the fellow eye. A significant elevation of IOP was arbitrarily defined as an increase of more than 5 mmHg. RESULTS Eleven (52.3%) untreated eyes versus 1 (4.7%) treated eye showed a significant elevation of IOP during the 2-year follow-up. The IOP difference between the untreated and the fellow treated eye at the end of the 2-year follow-up period is inversely related to the age of each patient. CONCLUSION YAG laser iridotomy may reduce the incidence of ocular hypertension in eyes affected by pigment dispersion syndrome. This effect, being less pronounced after 40 years of age, may be of clinical relevance in young subjects.

A Novel Mouse Model for Neurotrophic Keratopathy: Trigeminal Nerve Stereotactic Electrolysis through the Brain

PURPOSE To develop a mouse model of neurotrophic keratopathy by approaching the trigeminal nerve through the brain and to evaluate changes in corneal cell apoptosis and proliferation. METHODS Six- to 8-week-old male C57BL/6 mice underwent trigeminal stereotactic electrolysis (TSE) to destroy the ophthalmic branch of the trigeminal nerve. Clinical follow-up using biomicroscopy of the cornea was performed at days 2, 4, 5, and 7. To confirm the effectiveness of the procedure, we examined the gross nerve pathology, blink reflex, and immunohistochemistry of the corneal nerves. TUNEL-positive apoptotic and Ki-67-positive proliferating corneal cells were evaluated to detect changes from the contralateral normal eye. RESULTS TSE was confirmed by gross histology of the trigeminal nerve and was considered effective if the corneal blink reflex was completely abolished. TSE totally abolished the blink reflex in 70% of mice and significantly reduced it in the remaining 30%. Animals with absent blink reflex were used for subsequent experiments. In these mice, a progressive corneal degeneration developed, with thinning of the corneal epithelium and eventually perforation after 7 days. In all mice, 48 hours after TSE, corneal nerves were not recognizable histologically. Seven days after TSE, an increase in cellular apoptosis in all the corneal layers and a reduction in proliferation in basal epithelial cells were detected consistently in all mice. CONCLUSIONS TSE was able, in most cases, to induce a disease state that reflected clinical neurotrophic keratitis without damaging the periocular structures. Moreover, corneal denervation led to increased apoptosis and reduced proliferation of epithelial cells, formally implicating intact nerve function in regulating epithelial survival and turnover.

Mammalian lens inter-fiber resistance is modulated by calcium and calmodulin

The relationship between Ca2+ and lens fiber cell communication was investigated in the isolated intact rat lens by using radiotracer and electrophysiological techniques. The lens internal calcium was increased by adding the SH oxidant diamide (1 mM), by incubating in a sodium-free (n-methylglucamine) solution or by increasing external calcium from 1 to 10 mM. A 12 hours incubation in diamide produced a ten-fold increase in 45Ca uptake into the lens which was accompanied by a ten-fold increase in internal resistance. Incubation in Na-free solution or in 10 mM Ca2+ both produced a 5-fold increase in 45Ca content, while the increase in internal resistance was five and six fold respectively. This uncoupling was prevented in the diamide and Na-free treated lenses by omitting Ca2+ from the incubation medium. Fiber cell uncoupling was noticed in each of these experimental conditions after approximately 5 hours incubation, and good recovery was obtained in the high calcium solution if the stress was removed. The calmodulin antagonists calmidazolium (3 microM) and W7 (100 microM) both prevented uncoupling in the high calcium solution, provided there was a 2 hours preincubation period in calcium-free solution containing antagonist before the stress was applied. These data indicate that lens fiber cell communication is required by Ca2+ and calmodulin.

The Outflow Pathway: A Tissue With Morphological and Functional Unity

The trabecular meshwork (TM) plays an important role in high‐tension glaucomas. Indeed, the TM is a true organ, through which the aqueous humor flows from the anterior chamber to Schlemms canal (SC). Until recently, the TM, which is constituted by endothelial‐like cells, was described as a kind of passive filter. In reality, it is much more. The cells delineating the structures of the collagen framework of the TM are endowed with a cytoskeleton, and are thus able to change their shape. These cells also have the ability to secrete the extracellular matrix, which expresses proteins and cytokines, and are capable of phagocytosis and autophagy. The cytoskeleton is attached to the nuclear membrane and can, in millionths of a second, send signals to the nucleus in order to alter the expression of genes in an attempt to adapt to biomechanical insult. Oxidative stress, as happens in aging, has a deleterious effect on the TM, leading eventually to cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility, and (ultimately) increased IOP. TM failure is the most relevant factor in the cascade of events triggering apoptosis in the inner retinal layers, including ganglion cells. J. Cell. Physiol. 231: 1876–1893, 2016.

Comparison of Travoprost and Bimatoprost plus Timolol Fixed Combinations in Open-Angle Glaucoma Patients Previously Treated with Latanoprost plus Timolol Fixed Combination

PURPOSE To compare the ocular hypotensive effect of bimatoprost plus timolol and travoprost plus timolol fixed combinations in glaucoma patients whose disease was controlled but had not reached their target intraocular pressure (IOP) with the fixed combination of latanoprost plus timolol. DESIGN A 2 × 3-month, multicenter, prospective, randomized, double-masked, cross-over clinical trial. METHODS Eighty-nine open-angle glaucoma (OAG) patients were included. After a 6-week run-in period with latanoprost plus timolol, patients were randomized to either travoprost plus timolol or bimatoprost plus timolol for 3 months. Patients then switched to the opposite therapy for 3 additional months. The primary end point was the comparison of mean daily IOP after 3 months of each treatment. RESULTS At baseline, mean IOP was 16.5 mm Hg (95% confidence interval, 16.0 to 17.0 mm Hg) with treatment with latanoprost plus timolol. Both bimatoprost plus timolol and travoprost plus timolol statistically significantly reduced the mean IOP from baseline (P < .0001). Mean IOP at month 3 was statistically significantly lower in the bimatoprost plus timolol group compared with the travoprost plus timolol group (14.7 mm Hg [95% confidence interval, 14.3 to 15.3 mm Hg] vs 15.4 mm Hg [95% confidence interval, 15.0 to 15.9 mm Hg]; P = .0041). IOP was lower during bimatoprost plus timolol treatment at all time points and statistical significance was reached at 8 am, 11 am, and 5 pm, but not at 2 pm and 8 pm. Both treatments showed similar tolerability profile. CONCLUSIONS Bimatoprost plus timolol and travoprost plus timolol can provide additional IOP-lowering effect in patients not fully controlled with latanoprost plus timolol. The observed additional IOP reduction was greater with bimatoprost plus timolol with a similar tolerability profile.

Long-term perimetric fluctuation in patients with different stages of glaucoma

Aim To evaluate the long-term perimetric fluctuation (LF) in patients with different stages of glaucoma according to the Glaucoma Staging System 2 (GSS2). Methods This multicentre retrospective study included 161 eyes of 161 stable glaucoma patients undergoing four visual-field tests (Humphrey SITA-Standard program over the central 24° or 30°) over a 2-year period. For each patient, the stage of the disease was classified according to GSS2. LF was then calculated as the mean of the standard deviations of point-to-point threshold sensitivities in the four repetitions. LF in GSS2 stages was compared using the t test. Results LF progressively increased from stage 0 to stage 4, and then decreased at stage 5. Stage 4 had a peak of 3.19±0.94 dB, with statistically significant differences compared with all the other stages. The lowest LF (1.65±0.60 dB) was found for normal subjects, whereas similar data were found for borderline patients and those at stages 1 and 5 (2.09±0.58, 2.13±0.57 and 2.22±0.89 dB, respectively; p>0.13). Visual fields with generalised defects had a lower LF (1.90±0.81) than those with mixed (2.84±0.87, p=0.0003) and localised (2.63±0.72, p=0.004) defects. Conclusions In this study, the authors showed that the lower the visual-field defect, the lower was LF, except at stage 5 of GSS2. As test–retest changes exceeding LF could represent a sign of progression, the authors suggest that clinicians using this classification system calculate LF, in order to better differentiate true progression from variability.

86-Rb Efflux in normal and cataractous human lenses

86Rb efflux has been studied in normal lenses and in human senile cataracts. The rate constant (Ki) of the efflux gradually increases in cataractous lenses with progression of lens damage. Efflux experiments run in the presence of BaC12 suggest that a progressive activation of BaC12 inhibitable efflux routes occurs in cataractous lenses. In the final stages of opacification the ineffectiveness of BaC12 enriched or Ca++ free media on the efflux suggests that a direct disruption of the lens membranes has occurred.