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Purpose: To study the neuroprotective effect of topical citicoline., Materials and Methods: Experimental phase to evaluate the ability of citicoline eye drops to reach the vitreous and the retina: The right eyes of 5 mice CD1 were treated with two drops per day for three days of citicoline 1% and 2% (OMK1, Omikron Italia s.r.l.), and then the vitreous was analyzed with the liquid chromatography and spectrometry mass (LC-MS/MS). Clinical phase to determine if topical citicoline is able to delay glaucoma progression, considering perimetric parameters and electro functional tests. Patients were randomized in two groups, OMK1 and OAG. The first group was treated with OMK1 three times per day, plus hypotensive therapy for two months and one month of wash out. The second group was treated only with hypotensive treatment for three months., Results: LC-MS/MS detected the molecule very well, and only OMK1 showed systemic absorption. Thirty-four patients were enrolled, 16 in the OMK1 and 18 in the OAG group. Perimetric parameters showed a positive trend in individual eyes of patients in OMK1 group, but these values were not statistically significant in the whole group. Retinal ganglion cells function improved as shown by reduced P50 latency (P = 0.04) and increased P50-N95 amplitude (P < 0.0001) of pattern electroretinogram, up to 30 days after the washout (P = 0.01; P = 0.002). Visual evoked potential and retino-cortical time improvement regressed after 30 days of washout. In OAG group, there was any change during the follow-up. No adverse reactions were reported in both groups., Conclusions: Topical citicoline seems to have a neuroprotective action.

We studied whether patients affected by Temporo-Mandibular Disorder (TMD), showing asymmetric electromyographic (EMG) activity of masticatory muscles also display asymmetries in pupil size. In 30 pain free TMD patients a highly significant, positive correlation was found between left-right differences in EMG and pupil size. The asymmetry in pupil size was induced by the asymmetric sensorimotor signals arising from the orofacial region, since pupils became of about the same size following orthotic correction, which greatly reduced the EMG asymmetry. Moreover, bite wearing bilaterally increased the mydriasis induced by performing haptic tasks. Finally, unbalancing the occlusion by a precontact increased the diameter of the ipsilateral pupil and abolished the mydriasis induced by haptic tasks. In conclusion, trigeminal sensorimotor signals may exert a tonic control on autonomic structures regulating pupil size at rest and during sensorimotor tasks. Since task-associated mydriasis is correlated with task performance and is strictly proportional to the phasic release of noradrenaline at cerebral cortical level, the present findings may suggest an impact of unbalanced trigeminal activity on brain processing not directly related to the orofacial region.

Background: Parkinson disease (PD) is a neurodegenerative process that leads to a selective loss of dopaminergic neurons, mainly in the basal ganglia of the brain. Numerous studies have analyzed the ability of optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) thickness abnormalities and changes in PD, but the results have not always been consistent. Therefore, we carried out a meta-analysis to evaluate the RNFL thickness measured with OCT in PD., Methods and Findings: Case-control studies were selected through an electronic search of the Cochrane Controlled Trials Register, PUBMED and EMBASE. For the continuous outcomes, we calculated the weighted mean difference (WMD) and 95% confidence interval (CI). The statistical analysis was performed by RevMan 5.0 software. Thirteen case-control studies were included in the present meta-analysis, containing a total of 644 eyes in PD patients and 604 eyes in healthy controls. The results of our study showed that there was a significant reduction in average RNFL thickness in patients with PD compared to healthy controls (WMD = -5.76, 95% CI: -8.99 to -2.53, P = 0.0005). Additionally, differences of RNFL thickness in superior quadrant (WMD = -4.44, 95% CI: -6.93 to -1.94, P = 0.0005), inferior quadrant (WMD = -7.56, 95% CI: -11.33 to -3.78, P<0.0001), nasal quadrant (WMD = -3.12, 95% CI: -5.63 to -0.61, P = 0.01) and temporal quadrant (WMD = -4.63, 95% CI: -7.20 to -2.06, P = 0.0004) were all significant between the two groups., Conclusion: In view of these results and the noninvasive nature of OCT technology, we surmise that OCT could be a useful tool for evaluating the progression of the Parkinson disease., Trial Registration: ClinicalTrials.gov NCT01928212.

Purpose: To explore functional retinal changes in neovascular AMD patients (nAMD) treated with ranibizumab 0.5 mg combined with photodynamic therapy (PDT) 3 days after the first injection in the long term., Methods: Patients with no prior treatment for nAMD were treated with 3 injections of ranibizumab 0.5 mg 1 month apart and a single session of standard PDT 3 days after the first injection. Best-corrected visual acuity and time-domain OCT at baseline and every 28 ± 2 days were performed; microperimetry at 3, 6, and 12 months and multifocal electroretinogramm (mfERG) at 3 and 12 months were repeated. Fluorescein angiography and vision-related quality-of-life questionnaire were performed at baseline and 12 months., Results: 12/15 nAMD patients completed the 12 months study and received an average of 3.4 ± 0.7 injections. Mean VA changed from 54.67 ± 15.72 to 59.0 ± 24.77 letters (p = 0.371), while mean retinal sensitivity from 5.5 ± 4.8 to 6.6 ± 6.0 dB (p = 0.216). MfERG N1-P1 response amplitude densities (RADs) were significantly different from baseline (p < 0.01) in the central 0°-2.5°, whereas in the peripheral retinal areas (2.5°-20°), not significant (p > 0.01) changes in N1-P1 RADs were detected. The "general vision" VFQ-25 subscale showed a statistically significant improvement at 3 and 12 months., Conclusions: Ranibizumab 0.5 mg combined with standard PDT 3 days after the first injection determines an improvement of mfERG values in the retinal central area in nAMD patients in long-term follow-up.

Purpose: We assessed retinal ganglion cell (RGC) function, and established a correlation between the neural conduction along the visual pathways and the retinal involvement in Leber's hereditary optic neuropathy (LHON)., Methods: A total of 39 individuals carrying a LHON mutation (mean age, 33.35 ± 8.4 years), LHON-unaffected (LU, 22 eyes) or LHON-affected (LA, 17 eyes), underwent visual acuity and visual field examinations. A total of 22 age-similar normal subjects (mean age, 38.2 ± 6.0 years) served as controls. In all subjects, simultaneous pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded in response to 60-minute (60') and 15-minute (15') checkerboard stimuli., Results: When compared to controls, LU eyes did not show any statistically significant difference in 60' and 15' VEP P100 implicit times (ITs), VEP N75-P100 amplitudes, and 60' PERG P50 ITs, whereas 15' PERG P50-N95 amplitudes were significantly (P < 0.01) reduced. When compared to control and LU eyes, LA eyes showed significant differences in PERG and VEP ITs, and amplitudes with both stimulations (60' and 15' checks). No significant correlations between PERG and VEP parameters were found in LU eyes, while in LA eyes, PERG P50 and VEP P100 ITs correlated significantly only when using 60' checks., Conclusions: The LHON-unaffected eyes showed a retinal dysfunction detected by abnormal PERG responses that was not associated with changes along the visual pathways assessed by normal VEP responses. In LA eyes, the impaired neural conduction recorded by VEPs in response to larger (60' VEP responses) and smaller (15' VEP responses) checks were associated and not associated, respectively, with the detected retinal dysfunction.

Objective: Sustained pattern stimulation in normal subjects induces adaptive changes in pattern electroretinogram (PERG), an effect that has been interpreted as a response of glial cells and retinal ganglion cells (RGC). The aim of this study was to compare the effect in normal subjects and in multiple sclerosis patients without previous optic neuritis., Methods: PERGs were elicited by a 7.5 Hz pattern stimulus, presented continuously over 152 s. Response cycles were averaged in 20 packets of 60 events each and amplitude and phase of the 2nd harmonic response was measured. Adaptive changes are expressed as amplitude reduction over the full examination time., Results: In normal subjects PERG amplitude declined progressively to a plateau (dA=-0.46 μV, SE=0.09 μV); in patients the effect size was severely reduced (dA=-0.20 μV, SE=0.04 μV). No significant difference was found in mean amplitude., Conclusions: The results show reduced RGC habituation in patients, suggesting an abnormal gain and sensitivity control in the inner retina, even in absence of clinical optic neuritis. Recent findings in astrocyte biology and indications drawn from a mathematical model point to a key role of glial cells in this process., Significance: The proposed methodology may have implications in the assessment of MS patients and in understanding the pathophysiology of neurological and retinal disorders., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Purpose: To compare the measurements of the optic nerve head (ONH) parameters provided by time-domain (TD) and spectral-domain (SD) optical coherence tomography (OCT)., Methods: Four ONH parameters were analyzed: optic disc area, rim area, cup-to-disc area ratio (CDR), and vertical cup-to-disc ratio (VCDR). Stratus OCT and Cirrus HD-OCT were used to obtain measurements by TD-OCT and SD-OCT, respectively. Stratus OCT measurements were collected before and after manual correction of the ONH edges., Results: Twenty healthy participants and 20 patients with glaucomatous eyes were enrolled. Although manual correction of Stratus OCT measurements reduced the differences compared with Cirrus HD-OCT, the latter measured a smaller mean disc area than Stratus OCT in healthy (2.02±0.31 vs. 2.18±0.29 mm2, P=0.0003) and glaucomatous eyes (1.92±0.35 vs. 2.19±0.38 mm2, P<0.0001). Cirrus HD-OCT measured a smaller rim area than Stratus OCT in healthy (1.31±0.30 vs. 1.56±0.32 mm2, P<0.0001) and glaucomatous eyes (0.80±0.25 vs. 0.97±0.36 mm2, P=0.0052), a higher CDR (0.55±0.11 vs. 0.49±0.11, P<0.0001) and VCDR in healthy eyes (0.55±0.11 vs. 0.49±0.11, P<0.0001), and a higher CDR in glaucomatous eyes (0.74±0.10 vs. 0.58±0.18, P<0.0001). No statistically significant differences were detected for VCDR in glaucomatous eyes. All measured values showed good correlation (r≥0.70). Large 95% limits of agreement between the 2 devices were found for most parameters., Conclusions: ONH parameter measurements provided by TD-OCT and SD-OCT show significant differences and cannot be considered interchangeable.

Background: The interictal deficit of habituation to repetitive visual stimuli in migraine patients could be due to deficient intracortical inhibition and/or to low cortical pre-activation levels. Which of these abnormalities contributes more to the habituation deficit cannot be determined with the common methods used to record transient visual responses.We investigated lateral inhibition in the visual cortex during the migraine cycle and in healthy subjects by using differential temporal modulations of radial windmill-dartboard (WD) or partial-windmill (PW) visual patterns., Methods: Transient (TR-VEP) and steady-state visual-evoked potentials (SS-VEP) were recorded in 65 migraine patients (21 without and 22 with aura between attacks; 22 patients during an attack) and in 21 healthy volunteers (HV). Three stimulations were used in each subject: classic checkerboard pattern (contrast-reversion 3.1 Hz), WD and PW (contrast-reversion ~4 Hz). For each randomly presented stimulation protocol, 600 sweeps were acquired and off-line partitioned in 6 blocks of 100. Fourier analysis allowed data to extract in SS-VEP the fundamental (1H) and the second harmonic (2H) components that reflect respectively short-(WD) and long- range lateral inhibition (attenuation of 2H in WD compared to PW)., Results: Compared to HV, migraineurs recorded interictally had significantly less habituation of the N1-P1 TR-VEP component over subsequent blocks and they tended to have a smaller 1st block amplitude. 1H amplitude in the 1st block of WD SS-VEP was significantly greater than in HV and habituated in successive blocks, contrasting with an amplitude increase in HV. Both the interictal TR-VEP and SS-VEP abnormalities normalized during an attack. There was no significant between group difference in the PW 2H amplitude and its attenuation. When data of HV and migraine patients were combined, the habituation slope of WD-VEP 1H was negatively correlated with that of TR-VEP N1-P1 and with number of days since the last migraine attack., Conclusion: These results are in favour of a migraine cycle-dependent imbalance between excitation and inhibition in the visual cortex. We hypothesize that an interictal hypoactivity of monaminergic pathways may cause a functional disconnection of the thalamus in migraine leading to an abnormal intracortical short-range lateral inhibition that could contribute to the habituation deficit observed during stimulus repetition.

Purpose: Recent investigations suggested that unaffected carriers of Leber hereditary optic neuropathy (LHON) may show subclinical visual alterations. Structural changes have also been detected by optical coherence tomography (OCT), which revealed a temporal thickening of the retinal nerve fiber layer (RNFL). These changes may reflect compensatory effects such as mitochondria accumulation within the RNFL axons. This study aimed to investigate whether the RNFL of LHON carriers shows greater than expected thickness variations, which may reflect transient subclinical changes, over the course of years., Methods: Using Stratus OCT, the RNFL thickness was measured yearly from 2005 to 2008 in 24 Brazilian LHON carriers, all with homoplasmic 11778/ND4 mtDNA mutation. An Italian sample of 20 healthy subjects served as a control. Data were compared also to a previously published sample (n=59) of glaucomatous eyes., Results: The LHON carriers showed test-retest standard deviations that were larger than normal controls in the temporal (p=0.004), superior (p&lt;0.0001), and inferior quadrants (p=0.019). Compared to the glaucoma cases, no statistical differences were observed., Conclusions: The RNFL thickness in LHON carriers, when measured at different time points, has higher variability than in normal subjects. Transitory RNFL swelling may be caused either by compensatory mechanisms (increased mitochondrial biogenesis) or by axonal stasis preceding decompensation of retinal ganglion cells. In both situations, these changes may represent the origin of the visual alterations previously detected in LHON carriers. Alternatively, increased variability of RNFL thickness may be influenced by the LHON microangiopathy, as retinal blood vessels contribute to the OCT RNFL thickness measurements.

Purpose: To evaluate macular function in patients with open-angle glaucoma (OAG) by means of multifocal electroretinogram (mfERG)., Methods: Twenty-four OAG patients (mean age 54.6 ± 9.1 years) and 14 age-similar controls were enrolled. OAG patients had intraocular pressure (IOP) less than 18 mm Hg with topical medical treatment, 24-2 visual field (Humphrey Field Analyzer [HFA]) with mean deviation (MD) between -2 and -12 dB, and corrected pattern standard deviation (CPSD) between +2 and +10 dB and no history or presence of cataract and/or macular disease. MfERGs in response to 61 M-stimuli presented to the central 20° of the visual field were assessed in OAG patients (24 eyes) and in controls (14 eyes). Ring (R) analysis was performed every five retinal eccentricities in areas between the fovea and midperiphery: 0° to 2.5° (R1), 2.5° to 5° (R2), 5° to 10° (R3), 10° to 15° (R4), and 15° to 20° (R5). MfERG response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg(2)) and P1 implicit time (P1 IT, ms) of the first-order binary kernel were measured for each ring., Results: OAG patients showed a significant (P < 0.01) decrease in N1-P1 RADs and an increase in P1 IT in both R1 and R2 with respect to controls. The reduction in N1-P1 RADs was significantly (P < 0.01) correlated with HFA MD and CPSD. No other significant differences between OAG and controls were found., Conclusions: OAG patients show macular dysfunction detectable by the mfERG technique. Since the mfERG N1-P1 component is thought to be generated by preganglionic elements (photoreceptors and OFF bipolar cells), our data support the functional impairment of the neural generators of the macular region in patients with glaucoma.

Purpose: To review prevalence, long-term progression, and prognosis of vitreoretinal interface modifications in pathologic myopia with posterior staphyloma and investigate foveal sensitivity and fixation stability., Methods: Retrospective single-institution series of 214 eyes (116 patients) with pathologic myopia, axial length >30 mm, and posterior staphyloma. Exclusion criteria included follow-up less than five years, incomplete records, and/or less than three optical coherence tomography or microperimetry. Patients were divided into 5 groups according to optical coherence tomography: 1) epiretinal membrane without schisis (ERM); 2) macular retinal schisis (Schisis); 3) partial thickness macular hole (PTMH); 4) full-thickness macular hole (FTMH); and 5) posterior retinal detachment (PRD) with or without macular hole. Disease progression was defined as a visual acuity decrease of two or more lines associated to objective worsening of the optical coherence tomography and/or microperimetry., Results: Vitreoretinal abnormalities at baseline were present in 116 of 204 patients (56.8%) and 214 of 408 eyes (52.4%); 98 of 116 patients (84.4%) showed bilateral involvement. Baseline visual acuity and foveal sensitivity varied significantly with ERM performing better and PRD worse than others; PTMH and FTMH did not differ. During the 66 months of average follow-up, 33 of 214 eyes (15.4%) required surgery and 13 of 33 eyes (39.3%) needed reintervention. Surgery rate significantly differed among groups: 2% for ERM, 20% to 25% for Schisis, PTMH, and FTMH, and up to 50% for PRD. Progression rate of Schisis and FTMH was the same, regardless of symptoms, while macula-off PRD always required surgery. Decrease of fixation stability and foveal sensitivity correlated to need for surgery, while baseline foveal sensitivity and fixation did not., Conclusion: Vitreoretinal interface pathology in pathologic myopia with posterior staphyloma encompasses a spectrum of conditions whose baseline functionality, prognosis, rate, and amount of progression vary significantly. Customized treatment for each different condition should be considered.

Purpose: The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to age-related macular degeneration (AMD) and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent AMD. The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD., Methods: In this multicenter, prospective open-label randomized study, 145 patients were randomly assigned to 2 different treatment groups. Interventions were lutein (10 mg), zeaxanthin (1 mg), astaxanthin (4 mg; AZYR SIFI, Catania, Italy), and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years. Primary outcome was mean changes in visual acuity (VA) at 12 and 24 months. Other measures included contrast sensitivity (CS) and National Eye Institute visual function questionnaire (NEI VFQ-25) scores at 12 and 24 months., Results: Patients in the treated group showed stabilization of VA with significantly (p=0.003) better VA scores (81.4 ± 7.2) compared to the nontreated group (76.8 ± 8.9) at 24-month follow-up. An improvement in CS (p=0.001) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown (p<0.001)., Conclusions: Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinically meaningful stabilization/improvements in VA, CS, and visual function through 24 months compared with nontreated subjects. Further studies are needed with more patients and for longer periods of time.

Background: To evaluate the influence of axial length on measurements of the retinal nerve fibre layer (RNFL) thickness and optic nerve head (ONH) parameters in healthy subjects., Methods: Using Cirrus HD-OCT, RNFL thickness and ONH parameters (disc and rim area) were measured in 15 short (<22.5 mm), 15 medium (22.51-25.5 mm) and 15 long (>25.51 mm) eyes., Results: The mean axial length was 21.5 ± 0.5 mm in short eyes, 24.1 ± 0.8 mm in medium eyes and 26.6 ± 1.0 mm in long eyes. The RNFL thickness decreased with longer axial lengths in the superior (r=-0.52, r(2)=0.27, p=0.0003), inferior (r=-0.72, r(2)=0.52, p<0.0001), nasal (r=-0.60, r(2)=0.37, p<0.0001) and temporal (r=-0.30, r(2)=0.09, p=0.0485) quadrants, as well as in the 360° mean measurement (r=-0.69, r(2)=0.48, p<0.0001). The optic-disc area (r=-0.74, r(2)=0.54, p<0.0001) and rim area (r=-0.41, r(2)=0.17, p=0.0051) decreased with longer axial lengths. Correcting for axial length-induced ocular magnification by means of the Littmann formula resolved the relationship between axial length and both RNFL thickness and ONH area., Discussion: Axial length influences measurements of RNFL thickness and ONH parameters in healthy subjects. Caution is recommended when comparing the measured values of myopic and hyperopic eyes with the normative database of the instrument.

Purpose: To measure the retinal nerve fiber layer (RNFL) thickness by means of optical coherence tomography (OCT) in patients with dominant optic atrophy (DOA)., Design: Cross-sectional study., Participants: Thirty-three patients from 15 pedigrees with DOA harboring heterozygous mutations in the OPA1 gene and 43 healthy subjects were enrolled., Methods: The RNFLs of DOA patients were studied by OCT and compared with those of 43 healthy subjects matched for age and optic nerve head (ONH) size., Main Outcome Measures: Retinal nerve fiber layer thickness., Results: Dominant optic atrophy patients revealed a significant RNFL thickness reduction in all quadrants, with a preferential involvement of the temporal and inferior sectors. The progressive decline of RNFL thickness with age was similar to that observed in healthy subjects and was more evident in the 2 quadrants with higher residual amounts of fibers, that is, the superior and the inferior. The temporal quadrant was profoundly depleted of fiber so that the further rate of loss of microns per year is close to zero, whereas the nasal quadrant was spared the most by neurodegeneration., Conclusions: The present findings, taken in conjunction with the authors' previous description of small ONH size in DOA, strongly suggest that patients with this disease are born with fewer optic nerve axons and support the hypothesis that subsequent visual loss depends on further age-related loss of fibers, which also occurs in controls., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: To date, no specific therapy is available for optic glioma (OG)-induced visual loss., Objective: To evaluate the effects on visual function of murine nerve growth factor (NGF) eye drop administration in children with severe visual impairment due to low-grade OGs., Methods: Five patients with OGs and advanced optic nerve atrophy were assessed before and after a single 10-day course of 1 mg murine NGF topical administration by clinical evaluation, visual evoked potentials (VEPs), and brain magnetic resonance imaging (MRI). VEPs, the main functional outcome measure, were recorded at baseline and 1, 30, 45, 90, and 180 days posttreatment. MRI examinations were performed at baseline and at 180 days after NGF treatment. Six untreated control patients with OGs also underwent serial VEPs, clinical testing, and MRI assessments., Results: After NGF treatment, median VEPs amplitude showed a progressive increase from the baseline values (P < .01). VEPs reached a maximum amplitude at 90 days (170% increase) and declined at 180 days, still remaining above the baseline level. Perception of spontaneous visual phosphenes was noted in all patients after NGF administration. MRI showed stable tumor size. In controls, clinical findings and VEPs did not show any significant change over the observation period., Conclusions: The findings from the study show that NGF administration may be an effective and safe adjunct therapy in children with optic atrophy due to OGs. The beneficial effect on optic nerve function suggests a visual rescuing mechanism exerted by murine NGF on the residual viable optic pathways.

Background and Objective: To evaluate the repeatability of optic nerve head (ONH) measurements by spectral-domain optical coherence tomography., Patients and Methods: Three scans were acquired in 32 healthy subjects during one session. Using Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), the cup-to-disc ratio (CDR), disc area, rim area, cup volume, and horizontal and vertical CDRs were investigated. Repeatability was assessed by the coefficient of variation (COV), the test-retest intrasession variability, and the intraclass correlation coefficient (ICC)., Results: Good repeatability was achieved for all parameters, with a COV of 4.23% or less and ICCs of 0.98 or greater for all measurements. Test-retest intrasession variability was 0.024 for CDR, 0.121 mm(2) for disc area, 0.087 mm(2) for rim area, 0.017 mm(3) for cup volume, and 0.048 for horizontal and vertical CDR., Conclusion: In healthy eyes, Cirrus HD-OCT provides repeatable measurements of ONH parameters., (Copyright 2011, SLACK Incorporated.)

Background: Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ)., Methods: Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement., Results: FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 ± 2.41 dB vs 0.21 ± 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 ± 2.88 dB vs 0.15 ± 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 ± 0.65 dB vs 2.41 ± 0.31 dB, p < 0.01 and in the 10-2 program (2.86 ± 0.48 dB vs 2.48 ± 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5°-10° RAD and the 0°-2.5° RAD (0.31 ± 0.08 vs 0.36 ± 0.07 respectively, p < 0.05) was found between groups., Conclusion: Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine.

Purpose: Elevated intraocular pressure is a crucial pathologic event for the development of glaucoma (GL). We have reported that nerve growth factor (NGF) reaches retinal cells and the optic nerve (ON) when applied to the eye. Whether ocular application of NGF prevents or reduces damage to retinal ganglion cell (RGC) is not known., Methods: GL was induced in adult rats by the injection of hypertonic saline into the episcleral vein of the right eye and the left eye used as control. Rats were then treated daily with ocular application of NGF or vehicle solution for 7 weeks. Retinal and ON tissues were then used for structural, immunohistochemical, and biochemical studies., Results: The injection of hypertonic saline into the episcleral vein led to progressive degeneration of RGCs, with the loss of nearly 40% of these cells after 7 weeks of treatment. This cellular loss is associated with the downregulation of NGF and NGF-receptor expression in the retina and ON of the glaucomatous eye and ocular treatment with NGF significantly reduced the deficit induced by GL., Conclusions: These findings indicate that NGF can exert protective action on RGC degeneration occurring in glaucomatous retina. We suggest that ocular NGF treatment might be a suitable pharmacologic approach to investigate protective mechanisms of degenerating RGCs.

Background: Medication-overuse headache (MOH) is a frequent, disabling disorder. Despite a controversial pathophysiology convincing evidence attributes a pivotal role to central sensitization. Most patients with MOH initially have episodic migraine without aura (MOA) characterized interictally by an absent amplitude decrease in cortical evoked potentials to repetitive stimuli (habituation deficit), despite a normal initial amplitude (lack of sensitization). Whether central sensitization alters this electrophysiological profile is unknown. We therefore sought differences in somatosensory evoked potential (SEP) sensitization and habituation in patients with MOH and episodic MOA., Methods: We recorded median-nerve SEPs (3 blocks of 100 sweeps) in 29 patients with MOH, 64 with MOA and 42 controls. Episodic migraineurs were studied during and between attacks. We measured N20-P25 amplitudes from 3 blocks of 100 sweeps, and assessed sensitization from block 1 amplitude, and habituation from amplitude changes between the 3 sequential blocks., Results: In episodic migraineurs, interictal SEP amplitudes were normal in block 1, but thereafter failed to habituate. Ictal SEP amplitudes increased in block 1, then habituated normally. Patients with MOH had larger-amplitude block 1 SEPs than controls, and also lacked SEP habituation. SEP amplitudes were smaller in triptan overusers than in patients overusing nonsteroidal anti-inflammatory drugs (NSAIDs) or both medications combined, lowest in patients with the longest migraine history, and highest in those with the longest-lasting headache chronification., Conclusions: In patients with MOH, especially those overusing NSAIDs, the somatosensory cortex becomes increasingly sensitized. Sensory sensitization might add to the behavioral sensitization that favors compulsive drug intake, and may reflect drug-induced changes in central serotoninergic transmission.

Hyperventilation is often associated with stress, an established trigger factor for migraine. Between attacks, migraine is associated with a deficit in habituation to visual-evoked potentials (VEP) that worsens just before the attack. Hyperventilation slows electroencephalographic (EEG) activity and decreases the functional response in the occipital cortex during visual stimulation. The neural mechanisms underlying deficient-evoked potential habituation in migraineurs remain unclear. To find out whether hyperventilation alters VEP habituation, we recorded VEPs before and after experimentally induced hyperventilation lasting 3 min in 18 healthy subjects and 18 migraine patients between attacks. We measured VEP P100 amplitudes in six sequential blocks of 100 sweeps and habituation as the change in amplitude over the six blocks. In healthy subjects, hyperventilation decreased VEP amplitude in block 1 and abolished the normal VEP habituation. In migraine patients, hyperventilation further decreased the already low block 1 amplitude and worsened the interictal habituation deficit. Hyperventilation worsens the habituation deficit in migraineurs possibly by increasing dysrhythmia in the brainstem-thalamo-cortical network.

Purpose: To evaluate macular function and neural conduction along postretinal visual pathways in amblyopic patients., Methods: Twenty-five anisometropic amblyopic patients (mean age, 7 ± 1.9 years; visual acuity [VA]: 0.44 ± 0.27 logMAR in amblyopic [AM] eyes and 0.023 ± 0.067 logMAR in sound [SE] eyes) and 25 age-similar control subject ([CE] eyes, VA of 0.0 ± 0.0 logMAR in both eyes) were enrolled. In AM, SE, and CE eyes, simultaneous pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded in response to checks reversed at the rate of two reversals/second stimulating macular or extramacular areas (the check edge subtended 15 minutes and 60 minutes of visual arc, respectively)., Results: Nonsignificant differences (ANOVA, P > 0.005) were observed in PERG, in VEP responses to the 60-minute stimulus, and in retinocortical time with the 60-minute stimulus (RCT; the difference between VEP P100 and PERG P50 implicit times) between AM, SE, and CE eyes. AM eyes showed a significant (P < 0.005) increase in VEP P100 implicit time and in RCT in response to the 15-minute stimulus, compared with the values observed in SE and CE eyes. In AM patients, the interocular difference in VA was significantly (Pearson's test, P < 0.005) related to the interocular difference VEP P100 latencies and RCT with the 15-minute stimulus., Conclusions: Amblyopic eyes showed abnormal visual cortical responses only when the macular area was stimulated (increase in VEP P100 implicit times with the 15-minute stimulus). This functional impairment, in the presence of normal macular function (PERG responses similar to control eyes) may be attributable to a delay in postretinal neural conduction (increase in RCT).

Purpose: To analyze the influence of OPA1 gene mutations on the optic nerve head (ONH) morphology in patients with dominant optic atrophy (DOA)., Design: Cross-sectional study., Participants: Twenty-eight patients with DOA from 11 pedigrees, which were positive for the presence of OPA1 gene mutations, and 56 age-matched control subjects, were enrolled., Methods: The ONH of DOA patients was studied by optical coherence tomography and compared with an age-matched control group of 56 individuals., Main Outcome Measures: ONH area, and vertical and horizontal diameters., Results: The ONH analysis of DOA patients showed a significantly smaller optic disc area (P<0.0001), vertical (P = 0.018), and horizontal (P<0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal ONH area with 2 mutations, whereas the only missense mutation linked to a "DOA plus" phenotype had the smallest ONH measurements., Conclusions: The DOA patients carrying OPA1 gene mutations present, as a group, a significantly smaller ONH compared with the range of size observed in a control population; this feature may be mutation specific. This observation suggests that OPA1 is involved in shaping the anatomic conformation of the ONH in patients with DOA. The relevance of OPA1 in regulating apoptosis and modeling the eye development has been recently shown by others. Thus, mutations in the OPA1 gene may determine the previously unrecognized feature of a smaller optic disc size and this in turn may have relevance for DOA pathogenesis. Furthermore, OPA1 gene polymorphic variants may contribute to the normal variability of ONH size in the general population., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In patients with migraine, the various sensory stimulation modalities, including visual stimuli, invariably fail to elicit the normal response habituation. Whether this lack of habituation depends on abnormal activity in the sub-cortical structures responsible for processing incoming information as well as nociception and antinociception or on abnormal cortical excitability per se remains debateable. To find out whether inducing tonic pain in the hand by cold pressure test (CPT) alters the lack of visual-evoked potential (VEP) habituation in migraineurs without aura studied between attacks we recorded VEPs in 19 healthy subjects and in 12 migraine patients during four experimental conditions: baseline; no-pain (hand held in warm water, 25 degrees C); pain (hand held in cold water, 2-4 degrees C); and after-effects. We measured P100 amplitudes from six blocks of 100 sweeps, and assessed habituation from amplitude changes between the six sequential blocks. In healthy subjects, the CPT decreased block 1 VEP amplitude and abolished the normal VEP habituation (amplitude decrease to repeated stimulation) in patients with migraine studied between attacks; it left block 1 VEP amplitude and abnormal VEP habituation unchanged. These findings suggest that the interictal cortical dysfunction induced by migraine prevents the cortical changes induced by tonic painful stimulation both during pain and after pain ends. Because such cortical changes presumably reflect plasticity mechanisms in the stimulated cortex, our study suggests altered plasticity of sensory cortices in migraine. Whether this abnormality reflects abnormal functional activity in the subcortical structures subserving tonic pain activation remains conjectural.

Unlabelled: We investigated changes in visual cortex excitability by analyzing visual evoked potential (VEP) habituation in healthy subjects during tonic pain evoked by the cold-pressor test (CPT). We tested VEP amplitude habituation (slope of the linear regression line for N1-P1 amplitude from the 1st to 6th block of 100 sweeps) in 19 healthy volunteers during 4 experimental conditions: baseline; no-pain (hand held in warm water, 25 degrees C); pain (hand held in cold water, 2-4 degrees C); and the after-effects of tonic pain. During baseline and no-pain sessions, VEPs habituated normally across the 6 consecutive blocks (mean slope -.28 and -.18%), whereas during pain and its after-effects they failed to decrease (0%, and -.11%). Tonic pain induced by the CPT abolishes normal VEP habituation and the lack of habituation persists after the CPT is stopped. Tonic pain probably abolishes VEP habituation by acting on brainstem neural structures which modulate thalamo-cortical activation thereby changing visual cortex excitability., Perspective: This study shows that tonic pain alters visual cortex excitability, a brain region unrelated to pain processing. These changes probably reflect defensive strategies against pain. Extending the study from healthy volunteers to patients with migraine between attacks would offer the opportunity to investigate visual cortical excitability under conditions when baseline habituation is absent., (Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the impact of the regional retinal responses on cortical visually evoked responses, by evaluating the relationship between multifocal ERG (mfERG) and multifocal VEP (mfVEP), in the retinitis pigmentosa (RP) model., Methods: MfERGs and mfVEPs were recorded from 20 typical RP patients. Response amplitude density (RAD, nV/deg(2)) and implicit time (ms) of the mfERG 1st order binary kernel (N1-P1) and mfVEP 2nd order binary kernel (P1) components were measured. Ring analysis, matched for mfERG and mfVEP stimuli, was performed between fovea and mid-periphery (0-2.5, 2.5-5, 5-10, 10-15 and 15-20deg)., Results: At central and pericentral retinal regions (four eccentricities between 0 and 15deg), mfERG N1 RADs were positively correlated (r0.68, p<0.01) with corresponding mfVEP P1 RADs. Similarly, mfERG P1 implicit times were positively correlated (r>or=0.65, p<0.01) with corresponding mfVEP N1 implicit times., Conclusions: There are quantitative correlations between mfERG and mfVEP components in RP., Significance: The data suggest that regional responses of the photoreceptors and off-bipolar cells, the main generators of mfERG N1, have a major impact on the corresponding cortical activity.

Objective: Sustained pattern stimulation (SPS) induces habituation in the normal pattern electroretinogram (PERG). In this study, the authors evaluated whether sustained flicker stimulation (SFS) induces habituation in the normal flicker ERG (FERG)., Methods: FERGs were elicited in normal volunteers by an 8Hz flicker stimulus, presented continuously over 3 min after 20 min of light adaptation. One stimulus temporal period was sampled and averaged in packets (n=20) of 60 events, each of 8s duration. Amplitudes and phases of the response 1st and 2nd harmonics (1F and 2F, respectively) were measured. FERG results were compared with those obtained by recording PERGs with a similar SPS paradigm., Results: During SFS, FERG 2F showed a modest increase in amplitude (about 25%, p<0.05). No changes were observed for the 1F amplitude and for the phase of both components. In contrast, PERG amplitude showed SPS-induced habituation, described by an exponential decay with a time constant of approximately 20s., Conclusions: The normal FERG, unlike PERG, does not show habituation, suggesting that the adaptive changes of retinal neurons underlying FERG are different from those of PERG generators., Significance: Our findings may have implications for diagnosis and/or pathophysiology of retinal disorders involving the inner retina.

Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 mug/mL) were tested on 24 rats, and the higher dose was found to be more effective. Glaucoma was then induced in an additional 36 rats: half untreated and half treated with 200 mug/mL NGF QID for 7 weeks. Apoptosis/survival of RGCs was evaluated by histological, biochemical, and molecular analysis. Three patients with advanced glaucoma underwent psychofunctional and electrofunctional tests at baseline, after 3 months of NGF eye drops, and after 3 months of follow-up. Seven weeks of elevated IOP caused RGC degeneration resulting in 40% cell death. Significantly less RGC loss was observed with NGF treatment (2,530 +/- 121 vs. 1,850 +/- 156 RGCs/mm(2)) associated with inhibition of cell death by apoptosis. Patients treated with NGF demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity. NGF exerted neuroprotective effects, inhibiting apoptosis of RGCs in animals with glaucoma. In 3 patients with advanced glaucoma, treatment with topical NGF improved all parameters of visual function. These results may open therapeutic perspectives for glaucoma and other neurodegenerative diseases.

We investigated the effect of glaucoma (GL) on nerve growth factor (NGF) presence in two brain visual areas. Rats with elevated intraocular pressure (EIOP), induced by hypertonic saline injection in the episcleral vein, were treated with eye topical application of saline or NGF. Rats were subsequently sacrificed, and brain tissues were used for immunohistochemical, biochemical, and molecular analyses. We found that GL alters the basal level of NGF and NGF receptors in brain visual centers and that NGF eye application normalized these deficits. These findings demonstrate that the reduced presence of NGF can arise due to degenerative events in retinal and brain visual areas.

Purpose: To identity anatomic risk factors involved in the onset of retinal complications causing decrease of visual acuity (VA) in the fellow eyes of highly myopic patients operated for retinal detachment with macular hole (RDMH)., Design: Cohort study., Participants: Ninety-eight patients (mean age, 51.5+/-8.0 years) with bilateral high myopia (mean myopia of the fellow eye, 20.4+/-5.5 diopters) affected by RDMH in the other eye at baseline., Methods: Evaluation of the anatomic features at baseline and during 84+/-2.7 months of follow-up by biomicroscopic examination, indirect binocular ophthalmoscopy, B-scan ultrasonography, and optical coherence tomography., Main Outcome Measures: Detection of anatomic features associated with onset of retinal complications causing decrease of VA during the follow-up period., Results: The fellow eyes were divided into 2 groups according to the clinical features of the RDMH eyes: Group 1, presence of posterior vitreous detachment (PVD); and Group 2, presence of posterior vitreous schisis (PVS). At baseline, the incidence of PVD in group 1 was 31 of 47 eyes (65.9%) and the incidence of PVS in Group 2 was 42 of 51 eyes (82.3%). At the end of follow-up, group 1 eyes had a lower incidence of retinal complications causing visual decrease than group 2 eyes (group 1, 2/47 eyes; group 2, 9/51 eyes)., Conclusions: Fellow eyes of RDMH cases with higher degree of myopia and peculiar vitreoretinal features including PVS, posterior epiretinal membrane, severe posterior staphyloma, and chorioretinal atrophy are more likely to develop retinal complications causing decrease of VA.

Objective: To evaluate the influence of short-term carotenoid and antioxidant supplementation on retinal function in nonadvanced age-related macular degeneration (AMD)., Design: Randomized controlled trial., Participants: Twenty-seven patients with nonadvanced AMD and visual acuity > or =0.2 logarithm of the minimum angle of resolution were enrolled and randomly divided into 2 age-similar groups: 15 patients had oral supplementation of vitamin C (180 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), lutein (10 mg), zeaxanthin (1 mg), and astaxanthin (4 mg) (AZYR SIFI, Catania, Italy) daily for 12 months (treated AMD [T-AMD] group; mean age, 69.4+/-4.31 years; 15 eyes); 12 patients had no dietary supplementation during the same period (nontreated AMD [NT-AMD] group; mean age, 69.7+/-6.23 years; 12 eyes). At baseline, they were compared with 15 age-similar healthy controls., Methods: Multifocal electroretinograms in response to 61 M-stimuli presented to the central 20 degrees of the visual field were assessed in pretreatment (baseline) conditions and, in nonadvanced AMD patients, after 6 and 12 months., Main Outcome Measures: Multifocal electroretinogram response amplitude densities (RAD, nanovolt/deg(2)) of the N1-P1 component of first-order binary kernels measured from 5 retinal eccentricity areas between the fovea and midperiphery: 0 degrees to 2.5 degrees (R1), 2.5 degrees to 5 degrees (R2), 5 degrees to 10 degrees (R3), 10 degrees to 15 degrees (R4), and 15 degrees to 20 degrees (R5)., Results: At baseline, we observed highly significant reductions of N1-P1 RADs of R1 and R2 in T-AMD and NT-AMD patients when compared with healthy controls (1-way analysis of variance P<0.01). N1-P1 RADs of R3-R5 observed in T-AMD and NT-AMD were not significantly different (P>0.05) from controls. No significant differences (P>0.05) were observed in N1-P1 RADs of R1-R5 between T-AMD and NT-AMD at baseline. After 6 and 12 months of treatment, T-AMD eyes showed highly significant increases in N1-P1 RADs of R1 and R2 (P<0.01), whereas no significant (P>0.05) change was observed in N1-P1 RADs of R3-R5. No significant (P>0.05) changes were found in N1-P1 RADs of R1-R5 in NT-AMD eyes., Conclusions: In nonadvanced AMD eyes, a selective dysfunction in the central retina (0 degrees -5 degrees ) can be improved by the supplementation with carotenoids and antioxidants. No functional changes are present in the more peripheral (5 degrees -20 degrees ) retinal areas.

From the results of the Ocular Hypertension Treatment Study emerged the conclusion that ocular hypertensive subjects with thinner central corneal thickness (CCT) are at increased risk of developing glaucoma. Although possible underlying biases that could have led to this conclusion are still under investigation, there is an increasing interest in the scientific community to understand the potential mechanisms of this increased risk profile. It has been proposed that interindividual differences in CCT might be purely responsible for inaccuracies of the tonometric readings with potential underestimation of the true IOP in subjects with thinner CCT although it is becoming progressively clearer that the true IOP is unpredictable with linear correction formulas for CCT, and it is likely that other material properties of the cornea contribute, together with CCT, to the tonometric artifact. Recently, it has become possible to measure the biomechanical properties of the cornea in vivo and it has been suggested that differences in corneal biomechanics may be the expression of interindividual structural differences of the ocular tissues (including lamina cribrosa), with potential consequences on the interindividual susceptibility to the glaucomatous damage under the same IOP level. A possible underlying biological risk related to thinner CCTs, independent of the influence on tonometric reading, has been proposed and largely studied after the results of the OHTS were published. Besides the understanding of the mechanism underlying the role of CCT as a risk factor for the development of glaucoma, it is important to understand how the information about CCT should be integrated in the clinical management of both ocular hypertension (OHT) and glaucoma and whether other ocular properties should be measured to better understand the individual risk profile.

The glaucomatous disease is currently considered a disease involving ocular and visual brain structures. This new approach to glaucoma introduces the possibility of inducing an improvement by means of a pharmacological approach similar to that used in different degenerative brain disorders. In line with this hypothesis, we studied the effects of oral (1600 mg/die, Cebrolux, Tubilux Pharma, Pomezia, Rome, Italy) or intramuscular (1000 mg/die, Cebroton, Tubilux Pharma) cytidine-5'-diphosphocholine (citicoline) treatment on retinal function and neural conduction in the visual pathways of glaucoma patients with moderate visual defects. Improvement of retinal function (objectively evaluated by pattern electroretinogram recordings) and of neural conduction along visual pathways (objectively evaluated by visual evoked potential recordings) were observed in glaucoma patients after two 60-day periods of oral or intramuscular treatment with citicoline. However, partial regression of this improvement was detected after two 120-day periods of washout. This suggests that the beneficial effects observed are in part treatment-dependent. The extension of citicoline treatment up to a period of 8 years lead to the stabilization or improvement of the glaucomatous visual dysfunction. These results suggest potential neuroprotective effects of citicoline in the glaucomatous disease.

Purpose: To evaluate psychophysical and electrophysiologic responses in eyes with early age-related macular degeneration (AMD) without a decrease in visual acuity and with or without late AMD in the fellow eye., Methods: Fifteen patients (mean age: 67.9 +/- 7.20 years) with early AMD in both eyes (AMD1 group, 15 eyes) and 15 patients (mean age: 71.40 +/- 7.06 years) with early AMD in one eye and late AMD in the fellow eye (AMD2 group, 15 eyes) were enrolled. They were compared to 15 age-similar normal control subjects. LogMAR visual acuity (VA), macular sensitivity by MP-1 microperimetry, and multifocal electroretinograms (mfERG) were assessed in control, AMD1, and AMD2 eyes. mfERG response amplitude density (RAD, nV/deg2) of the N1-P1 component of first order binary kernels was measured., Results: When compared to controls, AMD1 and AMD2 eyes showed a significant (analysis of variance, P < 0.01) decrease in MP-1 microperimetry assessed in the 0-2.5 and 2.5-5 degrees of the macula, significantly correlated (Pearson test, P < 0.01) to the corresponding significant decrease (P < 0.01) in mfERG N1-P1 RADs assessed in the 0-2.5 and 2.5-5 degrees. In AMD1 and AMD2 eyes, VA and mfERG N1-P1 RADs assessed in the 5-20 degrees were similar (P > 0.01) to controls. VA, MP-1, and mfERG values were not significantly different in AMD1 and AMD2 eyes., Conclusion: In eyes with early AMD there is a dysfunction of preganglionic elements in the central 0-5 retinal degrees detectable by mfERG or MP-1 microperimetry. This impairment is not further influenced by the presence of late AMD in the fellow eye.

Elevated intraocular pressure may lead to retinal ganglion cell injury and consequent visual deficits. Chronic intraocular pressure increase is a major risk factor for glaucoma, a leading blinding disease, and permanent visual deficits can also occur following acute pressure increments due to trauma, acute glaucoma or refractive surgery. How pressure affects retinal neurons is not firmly established. Mechanical damage at the optic nerve head, reduced blood supply, inflammation and cytotoxic factors have all been called into play. Reasoning that the analysis of retinal neurons soon after pressure elevation would provide useful cues, we imaged individual ganglion cells in isolated rat retinas before and after short hydrostatic pressure increments. We found that slowly rising pressure to peaks observed in trauma, acute glaucoma or refractive surgery (50-90 mmHg) did not damage ganglion cells, whereas a rapid 1 min pulse to 50 mmHg injured 30% of these cells within 1 h. The severity of damage and the number of affected cells increased with stronger or repeated insults. Degrading extracellular ATP or blocking the P2X receptors for ATP prevented acute pressure-induced damage in ganglion cells. Similar effects were observed in vivo. A short intraocular pressure transient increased extracellular ATP levels in the eye fluids and damaged ganglion cells within 1 h. Reducing extracellular ATP in the eye prevented damage to ganglion cells and accelerated recovery of their response to light. These data show that rapid pressure transients induce acute ganglion cell injury and unveil the causal role of extracellular ATP elevation in such injury.

Objective: To evaluate possible changes of vitreous status in emmetropic eyes after uneventful phacoemulsification surgery, and possible related complications such as the onset of retinal detachment (RD)., Design: Retrospective case series., Participants: Four hundred fifty-three emmetropic eyes from 453 patients (mean age, 62.03+/-5.57 years) subjected to uneventful phacoemulsification with intraocular lens implantation in the capsular bag were considered in the study. They had a refractive error within +/-0.5 diopters (mean, -0.21+/-0.08). Eyes with peripheral retinal lattice degeneration were included only if asymptomatic and only if the degeneration involved one retinal quadrant. After cataract surgery, the 453 eyes were evaluated preoperatively at days 1, 15, and 30 and months 3, 6, 12, 18, 24, 36, 48, and 60. The whole period of follow-up was 5 years., Methods: Evaluation of vitreous status by biomicroscopic examination, indirect binocular ophthalmoscopy, and B-scan ultrasonography., Main Outcome Measures: Postoperative onset of posterior vitreous detachment (PVD) and RD., Results: After cataract surgery, a PVD occurred in 107 of 141 (75.88%) eyes without preoperative PVD or lattice degeneration. Posterior vitreous detachment occurred in 41 of 47 eyes (87.23%) with preoperative lattice degeneration and no PVD. Eyes with preoperative lattice degeneration and postoperative PVD showed a higher incidence of RD after cataract surgery (21.27%) than eyes without preoperative PVD or lattice degeneration (0.70%). In all patients with lattice degeneration, RD originated from horseshoe retinal tears on lattice areas located on the superior quadrants. No correlation was observed between the development of RD and age., Conclusions: Our results suggest that the onset of postoperative PVD should be considered an important risk factor for the development of RD after cataract surgery, particularly in eyes with lattice areas.

Purpose: To evaluate macular function before and after surgical peeling of idiopathic epimacular membrane (EMM)., Methods: Logarithm of the minimal angle of resolution visual acuity and results of focal (central 9 x 9 degrees) electroretinogram (fERG), pattern electroretinogram (pERG), and optical coherence tomography (OCT) assessment of macular volume were evaluated for 22 eyes of 22 patients (mean age +/- SD, 63.20 +/- 10.0 years) with EMM preoperatively (baseline) and 6 months after surgical peeling. Preoperative visual acuity and fERG and pERG amplitudes observed in EMM eyes were compared with those in 15 age-matched control eyes., Results: In the preoperative evaluation, EMM eyes had a significant (P < 0.01; one-way analysis of variance) reduction in visual acuity and fERG and pERG amplitudes and an increase in OCT macular volume when compared with controls. In EMM eyes, the decrease in visual acuity was significantly correlated (P < 0.01, Pearson test) to the reduction in fERG and pERG amplitudes. At the postoperative evaluation, EMM eyes had a correlated significant (P < 0.01) increase in visual acuity, fERG amplitude, and pERG amplitude with respect to the preoperative values. All EMM eyes had a significant (P <0.01) reduction in macular volume, and retinal microanatomy was restored to normal conditions., Conclusion: In EMM eyes, the decrease in visual acuity is related to dysfunction of both preganglionic (abnormal fERG) and ganglionic (abnormal pERG) macular elements. Surgical removal of EMM may induce improvement of the function of both outer and innermost macular retinal layers, leading to a related increase in visual acuity.

Objective: To assess the presence of normal or abnormal pattern electroretinogram (PERG) and visual evoked potential (VEP) responses in patients with ocular hypertension or open-angle glaucoma (OAG)., Design: Retrospective, cross-sectional, case-control study., Participants: Eighty normal control subjects (mean age, 51.77+/-6.04 years; 80 eyes), 68 ocular hypertension patients (mean age, 51.58+/-7.12; 68 eyes; intraocular pressure [IOP] < 18 mmHg under pharmacological treatment; Humphrey field analysis [HFA] 24/2 mean deviation [MD] > -2 decibels [dB]), and 84 OAG patients (mean age, 52.77+/-5.28; 84 eyes; IOP < 18 mmHg under pharmacological treatment; HFA 24/2 mean deviation between -2 and -23 dB) were enrolled., Methods: Simultaneous recording of PERGs and VEPs using high-contrast (80%) 15' checkerboard stimuli reversed at the rate of 2 reversals per second., Main Outcome Measures: Pattern electroretinogram P50 and VEP P100 implicit times were considered delayed when exceeding the limit of mean values of controls plus 2 standard deviations (SDs). Pattern electroretinogram P50 to N95 and VEP N75 to P100 amplitudes were considered reduced when exceeding the limit of mean values of controls minus 2 SDs., Results: Pattern electroretinogram: P50 implicit times were delayed in 58 of 68 (85.30%) ocular hypertension eyes and 83 of 84 (98.80%) OAG eyes; P50 to N95 amplitudes were reduced in 47 (69.12%) ocular hypertension eyes and 84 (100%) OAG eyes. Visual evoked potential: P100 implicit times were delayed in 58 (85.30%) ocular hypertension eyes and 84 (100%) OAG eyes; reduced N75 to P100 amplitudes were observed in 39 (57.35%) ocular hypertension eyes and 73 (86.90%) OAG eyes. Ocular hypertension eyes showed no significant correlations (Pearson test, P>0.01) between electrophysiological parameters and age, IOP before or under medical treatment, HFA, and corneal thickness values. Significant correlations (P<0.01) were observed in OAG eyes between electrophysiological results and HFA values. Pattern electroretinogram and VEP responses were normal in all control eyes., Conclusions: Combined PERG/VEP recordings identified a large percentage of ocular hypertension eyes with impairment of the innermost retinal layers, notwithstanding normal optic disc morphology and normal HFA. In OAG eyes, PERG P50 to N95 amplitude and VEP P100 implicit time showed the highest sensitivity/specificity for the detection of a visual dysfunction. The presence of abnormal PERG and/or VEP responses did not allow a clearcut separation between ocular hypertension and OAG eyes.

Objective: To evaluate the presence of macular holes (MHs) in very highly myopic eyes in the absence of visual symptoms., Design: Retrospective case series., Participants: Three hundred eighty-three eyes from 383 patients (mean age, 51.70+/-12.73 years) affected by very high myopia (between -14 and -32 diopters [D]), with no visual disturbance such as metamorphopsia and with visual acuity (VA) of >0.2 logarithm of the minimum angle of resolution, were considered in the study. They were evaluated at baseline and every 6 months during a mean total period of 30.2+/-0.5 months (range, 28.3-32.1)., Methods: Evaluation of macular morphology by optical coherence tomography (OCT)., Main Outcome Measures: Changes in OCT macular morphology ascribed to the presence of an MH., Results: Macular holes were detected by OCT in 24 of 383 (6.26%) myopic eyes. These MHs were defined as asymptomatic (AMHs). The presence of AMHs was more prevalent (although not significantly when compared with the overall study population) in myopic patients younger than 50 years and with concomitant myopia of >-20 D. Posterior vitreous schisis was the most frequent vitreous modification associated with AMH (18/24 eyes [75.0%]). During follow-up, a decrease in VA was observed in 5 of 24 (20.8%) AMH eyes due to the enlargement of the lesion or to posterior retinal detachment, leading to the development of a symptomatic MH. Greater degree of myopia and younger age were associated with the evolution of the macular disease, consisting of an enlargement of the MH and/or the onset of a macular detachment., Conclusions: A small percentage (6.26%) of highly myopic eyes may develop an MH in the absence of visual symptoms. The absence of symptoms could be related to the localization of the hole in a juxtafoveal area. Its evolution in a symptomatic MH seems to be related to the presence of epiretinal tissue, younger age, and the degree of myopia.

Purpose: To evaluate the effects of photodynamic therapy (PDT) on macular function in myopic subfoveal choroidal neovascularization (CNV)., Methods: Fourteen eyes of 14 patients (mean age, 48.1 +/- 13.3 years) with myopic CNV (myopia ranging from -6.50 to -20 D) were enrolled. In each eye, at baseline and at 15 and 90 days after PDT with verteporfin, logMAR visual acuity (logarithm of the minimum angle of resolution VA), macular sensitivity by scanning laser ophthalmoscope microperimetry, and focal (central 9 x 9 degrees ) ERGs (FERGs) and pattern ERGs (PERGs) were assessed., Results: At 15 days after PDT, myopic CNV eyes showed, in relation to baseline values, a significant (ANOVA, P < 0.01) reduction in the diameter of the lesion that correlated (Pearson test, P < 0.01) with the significant (ANOVA, P < 0.01) increase in FERG and PERG amplitudes, VA, and scanning laser ophthalmoscopy (SLO) microperimetry results obtained from the central 1 degrees to 2 degrees of the macular area (SLO-CM). At 90 days after PDT, myopic CNV eyes showed, in comparison with baseline values, a nonsignificant (ANOVA, P > 0.01) reduction in the diameter of the lesion, a nonsignificant increase in VA and SLO-CM, and a still significant increase in FERG and PERG amplitudes., Conclusions: In myopic CNV eyes, PDT induces an increase, though not significant, in VA and macular sensitivity. These changes may be related to a reduction in the diameter of the lesion, with an improvement in the function of both ganglionic and preganglionic elements of the macular region, as suggested by the improvement in FERG and PERG responses.

In this study we assessed, by simultaneous recordings of visual evoked potentials (VEPs) and pattern-electroretinograms (PERGs), the effects cytidine-5'-diphosphocholine (citicoline) on retinal function and/or visual cortical responses in glaucoma patients. Thirty glaucoma patients were randomly divided into two age-matched groups: patients in group GC (15 patients) were treated with citicoline (1,000 mg/die intramuscularly) for 2 months; patients in group GP (15 patients) were treated with placebo for 2 months. After 4 months of wash-out (month 6), GC patients underwent a further 2-month period of citicoline treatment (months 7-8) followed by another 4-month period of wash-out (months 9-12). In GP patients the wash-out was extended for a further 6 months (months 7-12). During the following 13-96 months, GC patients received additional 2-month periods of treatment with citicoline (each period followed by 4 months of wash-out) for a total of 16 periods in 8 years. GP patients were also examined at months 24, 26, 48, 60, 72, 84 and 96. In GC patients the first two treatments with citicoline induced a significant (p <0.01) improvement of VEP and PERG parameters with respect to pre-treatment conditions. VEPs and PERGs recorded in GC patients after the first wash-out revealed that, although there was a worsening trend, the electrophysiological improvement was still maintained with respect to baseline conditions. The additional periods of citicoline treatment in GC patients during the subsequent 13-96 months induced a greater (p <0.01) improvement of VEP and PERG parameters with respect to pre-treatment conditions and when compared to GP patients. Thus, we observed that citicoline significantly improves retinal and cortical bioelectrical responses in glaucoma patients, suggesting a potential use of this substance in the medical treatment of glaucoma, as a complement to hypotensive therapy.

Purpose: To evaluate the efficacy of different surgical strategies on the postoperative outcomes of retinal detachments (RDs) associated with macular holes (MHs) in high myopia., Design: Prospective, noncomparative case series., Participants: The study included 120 phakic, highly myopic eyes (mean degree of myopia, -22.2+/-4.80 diopters) with RDs and MHs that underwent surgical repair. The patients were divided into 2 groups. Group 1 consisted of 60 eyes with a posterior vitreous detachment (PVD). Mean preoperative visual acuity (VA) was 20/200+/-20/500. Group 2 consisted of 60 eyes with posterior vitreous schisis (PVS). The mean preoperative VA was 20/152+/-20/333. The minimum follow-up was 6 months., Intervention: The surgical approach was chosen on the basis of the clinical characteristics. Twenty-five eyes of group 1 underwent pneumoretinopexy (group 1A), whereas 35 eyes of group 1 were repaired with vitrectomy (group 1B). Forty-nine eyes of group 2 underwent pars plana vitrectomy (group 2A), whereas 11 eyes of group 2 underwent scleral buckling of the macula (group 2B)., Main Outcome Measures: Anatomic attachment of the retina and VA., Results: Retinal reattachment at 6 months was achieved in 23 of 25 (92%) eyes of group 1A, 31 of 35 (88.5%) eyes of group 1B, 45 of 49 (91.8%) eyes of group 2A, and 8 of 11 (72.7%) eyes of group 2B. A significant (P<0.01) improvement of postoperative VA with respect to the preoperative values was observed in all groups. The greatest percentage improvement in postoperative VA was observed in groups 1A and 1B eyes., Conclusions: Different surgical approaches can be used to repair myopic RD associated with an MH. The choice between different surgical techniques may depend on vitreoretinal relationships, the extent of chorioretinal atrophic areas, and presence of posterior staphyloma. In our study, eyes with a PVD had significantly better visual outcomes than detachments in eyes with PVS.

Purpose: To evaluate the incidence of retinal detachment (RD) after cataract surgery performed by phacoemulsification in very highly myopic eyes., Design: Retrospective, paired-eye, case-control trial., Participants and Intervention: We assessed the development of RD in 930 eyes from 930 subjects (mean age = 62.5 +/- 8.5 years) affected by very high myopia (between -15 and -30 diopters) undergoing cataract surgery after uncomplicated phacoemulsification (cataract-subjected [CS] eyes). Fellow eyes served as controls. Follow-up was 36 months., Main Outcome Measure: Detachment of the retina., Results: Retinal detachment was observed in 8.0% of CS eyes compared with 1.2% of control eyes (P<0.01, chi-square test). In CS eyes, posterior RD was most common (52.7% of eyes with RD). In control eyes, peripheral detachments with or without macular involvement were most common (47.3% of eyes with RD)., Conclusion: Cataract surgery, despite the use of a safe technique such as phacoemulsification, increases the risk of RD development in very highly myopic eyes.

In this article the correlations between the morphological evaluation of the nerve fiber layer (NFL) thickness (by OCT) and retinal functional assessment (by Pattern ERG recordings) performed in patients affected by ocular hypertension (OHT), glaucoma (OAG), demyelinating optic neuritis (MSON), and Alzheimer's disease (AD) are reported. In OHT eyes with ocular hypertension we observed that the inter-individual variation in NFL thickness is correlated with the variability of the PERG responses (the thinner the layer, the worse the visual function). In our OAG, MSON and AD eyes we observed a significant reduction in NFL thickness when compared with controls. In OHT, OAG, MSON and AD eyes abnormal PERG responses with delayed implicit times and reduced amplitudes were found. The impairment in the PERG parameters was significantly correlated to the reduction in NFL thickness. Our results suggest that in patients affected by ocular hypertension, glaucoma, demyelinating optic neuritis, and Alzheimer's Disease there is a reduction of NFL thickness evaluated "in vivo" by OCT, and this morphological involvement is correlated with electrophysiological responses assumed to be originating from the innermost retinal layers.

Purpose: To evaluate recovery of pattern visual evoked potentials (VEPs) after macular bleaching in patients with Stargardt's disease-fundus flavimaculatus (STD/FF)., Methods: Sixteen unrelated patients with STD/FF (age, 26-52 years; visual acuity, 0.2-1.0; phenotype I, n = 6; phenotype II, n = 8; or phenotype III, n = 2) and 15 age-matched control subjects were evaluated. VEPs were recorded in response to counterphased (two reversals per second) checkerboards (check size, 15 minutes; mean luminance, 80 cd/m(2); contrast, 80%; stimulus field size, 18 degrees ) in baseline condition and at 20, 40, and 60 seconds after a 30-second exposure to a bleaching light (3.58 log photopic trolands), presented to the central (6 degrees field) retina. In all patients, macular focal electroretinograms (FERGs) to an 18 degrees uniform field, flickering at 41 Hz, were also recorded in separate sessions., Results: At every postbleaching time, VEPs were delayed and suppressed in amplitude, compared with prebleaching values, in both patients and control subjects. However, the amount of delay and suppression was, on average, more pronounced (P < 0.001) in patients than in control subjects. This difference was not accounted for by eccentric fixation in patients (n = 8) with central scotoma and was still substantial when only patients (n = 8) with normal visual field and acuity were considered. In individual patients, baseline FERG amplitudes correlated (r = -0.6, P < 0.01) with the suppression of VEP amplitude at 40-seconds after bleaching., Conclusions: The results indicate an altered recovery of pattern VEPs after macular bleaching in STD/FF and suggest adaptation abnormalities in macular cone photoreceptors, occurring at disease stages with relatively preserved central visual field and acuity.

Purpose: To assess the changes in visual acuity and macular sensitivity and the possible evolution into a full-thickness macular hole in patients with macular pseudoholes during a 3-year follow-up period., Methods: Twenty-seven eyes (mean age, 61.0 +/- 8.9 years) with macular pseudoholes were enrolled. They were compared with 16 eyes from 16 age-matched control eyes. In each eye with a macular pseudohole, we assessed the Snellen visual acuity and macular sensitivity by scanning laser ophthalmoscopic central (1-2 degrees of the macula, SLO-CM) and paracentral (annular area from 2-7 degrees from the macula, SLO-PM) microperimetry at the time of diagnosis (baseline condition) and every 6 months for 3 years., Results: Eyes with macular pseudoholes at baseline had a significant (P < 0.05) reduction in visual acuity, SLO-CM, and SLO-PM when compared with control eyes. After 12 months of follow-up, no changes in VA, SLO-CM, or SLO-PM were observed in eyes with macular pseudoholes with respect to the baseline values. After 36 months of follow-up, further significant (P < 0.05) decreases in visual acuity, SLO-CM, and SLO-PM were observed. One third of eyes with macular pseudoholes showed an evolution into a full-thickness macular hole. In these eyes, the lowest SLO-CM had been observed at the baseline condition., Conclusion: This study suggests that in the 36-month follow-up period in eyes with macular pseudoholes, there is the possibility of a worsening trend, leading to the development of a full-thickness macular hole. A useful role of the functional assessment by SLO-CM and SLO-PM can be suggested for the clinical diagnosis and the follow-up of macular pseudoholes.