Gianluca Manni

Ocular symptoms and signs with preserved and preservative-free glaucoma medications

Purpose. To compare the prevalence of side effects between eyedrops with or without preservatives, in terms of subjective symptoms and objective signs in patients with open-angle glaucoma. Methods. In a multicenter cross-sectional epidemiologic survey in four European countries, ophthalmologists in private practice enrolled 9658 nonconsecutive patients using preservative (P) or preservative-free (PF) beta-blocking eyedrops between June 1997 and December 2003. Subjective symptoms, conjunctival and palpebral signs, and superficial punctate keratitis were explored before and after a change in therapy. For statistical analysis, a χ2 test was used to calculate the differences in the prevalence of symptoms and signs with or without preservatives. Results. A total of 74% of the patients used P, 12% PF, 10% a P-PF combination, and in 4% the type of medication was unknown. Each recorded symptom and all the palpebral, conjunctival, and corneal signs were significantly more frequent (p<0.0001) in the P-group than in the PF-group, such as pain or discomfort during instillation (48 vs 19%), foreign body sensation (42 vs 15%), stinging or burning (48 vs 20%), and dry eye sensation (35 vs 16%). A total of 68% of the patients had a second visit performed, of whom 63% (6083) had been evaluated on treatment difference. A significant decrease (p<0.0001) of all ocular symptoms and signs was observed in patients in whom the preserved eyedrops were diminished in number or altered into preservative free drops. Conclusions. Compared to preserved eyedrops, preservative free eyedrops are significantly less associated with ocular symptoms and signs of irritation.

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.

The safety and efficacy of brinzolamide 1%/timolol 0.5% fixed combination versus dorzolamide 2%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension.

PurposeThis study compared the intraocular pressure (IOP)-lowering efficacy of 2 fixed combination products, brinzolamide 1%/timolol 0.5% suspension (Azarga, Brinz/Tim) and dorzolamide 2%/timolol 0.5% solution (Dorz/Tim), in patients with open-angle glaucoma or ocular hypertension who required a change in therapy due to elevated IOP while receiving IOP-lowering medication. MethodsThis was a one-year, multicenter, randomized, double-masked, active-controlled, parallel-group trial of Brinz/Tim and Dorz/Tim. IOP assessments were taken at 8 and 10 AM at week 2 and months 3 and 9, and at 8 AM, 10 AM, and 4 PM at months 6 and 12. Primary efficacy was a noninferiority comparison of mean IOP at the three month 6 time points. ResultsOf the 437 patients enrolled, 220 dosed Brinz/Tim whereas 217 dosed Dorz/Tim twice daily. Brinz/Tim produced IOP-lowering efficacy comparable to Dorz/Tim, with the upper 95% confidence limits for the differences between groups within +1.5 mm Hg at all assessment times, including the month 6 primary efficacy time points, establishing noninferiority. Differences in means numerically favored Brinz/Tim at 9 of 12 study visits and times. The IOP reductions ranged from 7.2 to 9.2 mm Hg for Brinz/Tim and from 7.4 to 8.9 mm Hg for Dorz/Tim. Although a similar overall safety profile was observed between the 2 treatment groups, Brinz/Tim showed significantly less ocular irritation (2.7% vs. 10.6%; P=0.0009) than Dorz/Tim. ConclusionsBrinz/Tim suspension provides statistically significant and clinically relevant IOP-lowering efficacy that is noninferior to Dorz/Tim. Additionally, Brinz/Tim affords an ocular comfort advantage compared with Dorz/Tim.

Do sex and hormonal status influence choroidal circulation

AIMS To investigate the relation between pulse amplitude (PA), pulsatile ocular blood flow (POBF), and sex and hormonal status. METHODS Measurements of POBF and PA were obtained by ocular blood flow tonography in 76 healthy subjects: 32 males and 44 females (age range 17–77 years). Females were divided into two age groups: group 1 (premenopausal) 17–42 years, and group 2 (post-menopausal) 55 years old and over. Two groups of age matched males served as controls. RESULTS Premenopausal females demonstrated a significantly higher rate of POBF and PA than age matched males and post-menopausal females. CONCLUSION Sex and hormonal status were shown to influence choroidal circulation.

The effect of increased intraocular pressure on pulsatile ocular blood flow in low tension glaucoma

In the present study the relationship between intraocular pressure (IOP) and pulsatile ocular blood flow (POBF) in low tension glaucoma (LTG) has been investigated. The POBF was measured using the Ocular Blood Flow system of Langham in undisturbed eyes and repeated at IOP increments of about 5 and 10 mmHg in 20 patients affected with bilateral LTG and in 25 healthy subjects matched for age, IOP, refractive error, arterial blood pressure and heart rate. The POBFs were 740.1 (SD 58.83) and 667 (SD 108) microliters/minute (microliter/min) in the control and LTG groups, respectively and statistically significantly different. The POBFs at an IOP increased by 5 mmHg were 658.1 (SD 60.2) and 457.3 (SD 74.8) microliter/min in the control and LTG groups, respectively; in the control group the mean POBF at an IOP increment of 10 mmHg was 552.1 microliters/min (SD 66.9), and in the LTG group was 317.7 microliters/min (SD 85.2). Statistical analysis of the data showed a significant difference of POBFs in the two groups either at an IOP increment of 5 or 10 mmHg (p < 0.0001). The substantial decrease of POBF with increased IOP in LTG eyes compared with normals shows an altered response of the vascular system in LTG. These findings are probably consistent with a lack of the myogenic autoregulation in reply to IOP-induced modifications of the perfusion pressure.

Influence of Disc Size on Optic Nerve Head versus Retinal Nerve Fiber Layer Assessment for Diagnosing Glaucoma

PURPOSE To explore and compare the influence of optic disc size on the diagnostic accuracy of retinal nerve fiber layer (RNFL) thickness and optic nerve head (ONH) quantitative assessment. DESIGN Observational, cross-sectional evaluation of diagnostic tests. PARTICIPANTS We included 120 eyes from 50 normal subjects and 70 glaucomatous patients classified by the presence of a repeatable visual field defect for the analysis. TESTING The RNFL thickness was measured by scanning laser polarimetry with variable corneal compensator (GDx-VCC, Carl-Zeiss Meditec, Dublin, CA) and spectral-domain optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec, Inc). We obtained ONH imaging by means of confocal scanning laser ophthalmoscopy (HRT3; Heidelberg Engineering, GmbH, Dossenheim, Germany). MAIN OUTCOME MEASURES Sensitivity and specificity for normative classifications, sensitivity at fixed specificity and area under the receiver operating characteristics curve (AUC) for continuous parameters. A logistic marginal regression model and coefficients of variation (CoV) have been used to test and quantify the influence of optic disc size on the diagnostic accuracy of the 3 technologies under investigation. RESULTS Among continuous parameters average RNFL thickness for Cirrus HD-OCT, nerve fiber indicator for GDx-VCC and cup shape measure for the HRT3 showed the best diagnostic accuracy with an AUC of 0.97, 0.94, and 0.94, respectively. Among normative classifications, the highest sensitivity and specificity were found for OCT average RNFL thickness (75.8% and 94.7%), for GDx superior thickness (77.1% and 97.5%), for HRT3 Moorfields regression analysis result (89.4% and 73.7%) and for HRT3 GPS global (92.3% and 76.5%). The diagnostic performance of HRT3 parameters seemed to be significantly influenced by optic disc size, although the same was not true for Cirrus HD-OCT and GDx VCC. The most steady performers for each imaging device across disc size groups were Cirrus HD-OCT average thickness (CoV, 1.6%), GDx-VCC inferior thickness (CoV, 2.5%), and HRT3 GPS temporal and nasal (CoV, 21.4%). CONCLUSIONS The diagnostic accuracy of quantitative RNFL assessment as performed by Cirrus HD-OCT and GDx-VCC is high and virtually unaffected or only minimally affected by the size of the optic disc and may provide more consistent diagnostic outcomes across small and large discs than ONH assessment as performed by HRT3.

Electrophysiological assessment of visual function in IDDM patients.

Various electrophysiological tests have been employed to reveal functional abnormalities at different levels of the visual system in insulin-dependent diabetic (IDDM) patients. The aim of our work was to assess, with a comprehensive neurophysiological protocol evaluating the retinal, macular and visual pathways functions, whether and when such electrophysiological abnormalities do appear in IDDM patients free of any fluorangiographic sign of retinopathy with various disease duration. Flash-electroretinogram (ERG), oscillatory potentials (OPs), pattern-electroretinogram (PERG), and visual evoked potentials (VEPs) in basal condition and after photostress were assessed in 12 control subjects (C) and 42 aged-matched IDDM patients without clinical retinopathy (DR-) divided, on the basis of the disease duration, into 4 groups (1-5, 6-10, 11-15, 16-20 years). In addition another age-matched group of IDDM patients with a background retinopathy (DR+; n = 12; duration of disease 18 +/- 49 years) was evaluated. In all IDDM DR-patients PERG and VEP were significantly impaired. In addition, groups 11-15 and 16-20 years displayed impaired OPs. All electrophysiological parameters were further impaired in DR+ patients. In conclusion, retinal, macular and visual pathways functions are differently impaired in IDDM (DR-) patients with different disease duration. Electrophysiological impairment starts in the nervous conduction of the visual pathways with an early involvement, goes on in the innermost retinal layers and in the macula and ends in the middle and outer retinal layers.

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.

Sector-Based Analysis with the Heidelberg Retinal Tomograph 3 Across Disc Sizes and Glaucoma Stages: A Multicenter Study

PURPOSE To investigate the ability of sectorial analysis using the Heidelberg Retinal Tomograph 3 (HRT3) to discriminate between healthy and glaucomatous eyes and to determine whether this is affected by disc size and glaucoma severity. DESIGN Multicenter, cross-sectional evaluation of diagnostic tests. PARTICIPANTS Two hundred thirty-three eyes from 137 normal subjects and 96 glaucoma patients classified by the presence of a repeatable visual field defect. TESTING Participants underwent imaging with the HRT3, and the diagnostic accuracy of stereometric parameters, Moorfields regression analysis (MRA), and glaucoma probability score (GPS) were analyzed sectorially by glaucoma stage and optic disc size. MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristics curve (AUC). RESULTS Of stereometric parameters, the cup-to-disc area ratio of the inferotemporal sector had the largest AUC (AUC, 0.74). Both MRA and GPS algorithms showed the best diagnostic accuracy in the inferotemporal sector, with a sensitivity and specificity of 63% and 88% for MRA and 80% and 62% for GPS, respectively. In small discs, sectorial MRA analysis had higher diagnostic accuracy than the global optic nerve head (ONH) analysis (sensitivity of 70% and specificity of 82% in the inferonasal sector), and these findings were confirmed in very large discs (sensitivity of 74% and specificity of 85% in the inferotemporal sector). Similarly, stereometric parameters discriminated better sectorially rather than globally, with different parameters giving the best results in different optic disc size subgroups. MRA sensitivity was weak in the early-glaucoma stage, with slightly higher figures if considered sectorially rather than globally. GPS diagnostic accuracy was very consistent across ONH sectors in each disc size and glaucoma stage subgroup, with no single sector demonstrating better diagnostic accuracy than the global analysis. CONCLUSIONS Heidelberg Retinal Tomograph 3 sectorial analysis showed moderate diagnostic performance and may offer potential advantages over global analysis in the clinical diagnostic process. Small discs are classified more accurately by examining the inferonasal sector, whereas larger discs are classified more accurately by examining the inferotemporal sector. Neither HRT parameters nor classification algorithms seem to be good at the earlier stage of the disease. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

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.