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Background and purpose: Our work evaluates visual function before and after treatment with cytidine-5-diphosphocholine (Citicoline) in patients with non-arteritic ischaemic optic neuropathy (NION). Methods: Twenty-six patients in which at least 6 months elapsed from NION, were randomly divided into two age-similar groups: 14 patients had Citicoline (Cebrolux-Tubilux, Italy, 1600 mg/diem for 60 days, followed by a 120-day period of wash out, days 60–180) (T-NION); 12 patients had no treatment during the same period (NT-NION). At day 180, in T-NION a second period of treatment (days 181–240) followed by a wash-out (days 241–360) was performed. Fourteen age-matched healthy subjects provided normative data. In all patients, pattern-electroretinogram (PERG), visual evoked potentials (VEPs) and visual acuity (VA) measurements were performed at baseline and at days 60 and 180. In T-NION, further measurements were achieved at days 240 and 360. Results: At baseline, NT-NION and T-NION patients showed abnormal PERGs and VEPs, and reduced VA, compared to controls. At the end of treatment (days 60 and 240), T-NION patients showed improvement (P

The aim of this study was to evaluate longitudinally functional and neuro-radiologic findings in childhood optic gliomas (OG), by comparing flicker visual evoked potentials (F-VEPs) with brain magnetic resonance imaging (MRI) changes. Fourteen children (age range: 1-13 years) with OGs underwent serial F-VEP, MRI and neuro-ophthalmic examinations over a 38 month (median, range: 6-76) follow-up. F-VEPs were elicited by 8 Hz sine-wave flicker stimuli presented in a mini-Ganzfeld. Contrast-enhanced MRI examinations were performed. Results of both tests were blindly assessed by independent evaluators. F-VEPs were judged to be improved, stable or worsened if changes in the amplitude and/or phase angle of the response exceeded the limits of test-retest variability (+/-90th percentile) established for the same patients. MRI results were judged to show regression, stabilization or progression of OG based on its changes in size (+/-20%) or extension. Two to seven pairs of F-VEP/MRI examinations per patient (median: 4) were collected. Based on a total of 38 pairs of F-VEP/MRI examinations, both tests agreed in showing worsening (progression), stabilization and improvement (regression) in 5, 15 and 10 cases, respectively. In 3 cases, F-VEPs showed a worsening and MRI a stabilization, while in 5 cases F-VEPs showed an improvement and MRI a stabilization. Agreement between F-VEP and MRI changes was 78.9% (95% CI: +/- 37%, K statistics = 0.67, P0.001). The results indicate that longitudinal F-VEP changes can predict changes in MRI-assessed OG size and extension, providing a non-invasive functional assay, complementary to neuro-imaging, for OG follow-up.

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.

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.

We have initiated a clinical trial for an ocular condition that has prominent synaptic dysfunction caused by mutations in an extracellular matrix protein, RS1 (retinoschisin). This report describes our findings on dissection of the molecular pathology at the synapse and reversal of the structural and functional defects when RS1 is introduced into mature Rs1-KO mouse retina using an AAV8 vector. We have started a human trial (NCT02317887) using the same vector, which will probe the synaptic plasticity in XLRS patients. RS1 mutations result in XLRS, a rare but recognized ocular condition that causes splitting of the neural retinal layers and results in intraretinal cysts. Medical attention generally was focused on the structural abnormalities of XLRS. However, visual function testing shows a selective depression of the electroretinogram (ERG) b-wave despite a normal a-wave, indicating intact photoreceptor responses but deficient post-synaptic signaling.The AAV8-RS1 vector for the murine studies and the clinical trial contains a self-complementary vector genome with the human RS1 promoter and the RS1 cDNA. For synaptic structural studies in adult Rs1-KO retina, 2.5e9 viral vector genomes (vg)/eye were administered by intravitreal injection at postnatal day 30. Retinal morphology, function and pathology were evaluated 2 months post injection, with contralateral untreated eyes as controls.The photoreceptor-depolarizing bipolar cell (DBC) synapse initially develops normally in Rs1 -KO mice, but the mGluR6-TRPM1 signaling cascade elements in the post-synaptic structure are progressively delocalized to the dendritic shaft and soma of the DBC. Concomitantly, the DBC resting membrane potential is altered. This molecular pattern of post-synaptic disruption is different from several other murine night-blindness models which share a “negative-going” ERG response that characterizes murine and human XLRS. Following AAV8-RS1 gene transfer to the XLRS mouse eye, TRPM1 and the signaling molecules return to their proper location at the dendritic tips, and the proper DBC resting membrane potential is restored, along with the ERG b-wave.The clinical trial utilizing the same vector is a prospective, dose-escalation, single-center study conducted at the National Eye Institute. One eye of each participant receives the RS1 gene vector given by intravitreal injection. While the primary outcome is safety, the dose range is scaled to probe possible efficacy.Invoking synaptic plasticity for therapeutic repair would be a desirable treatment strategy for a number of neurological conditions. These findings in Rs1 -KO mice provide insight into the molecular pathology of XLRS disease and demonstrate remarkable plasticity of a critical synapse in the visual system. Reversal of synaptic pathology by an AAV8-RS1 gene construct demonstrates novel possible therapeutic avenues for this and other diseases involving synaptic pathology.

To assess short-term changes in macular function after transpupillary thermotherapy (TTT) in patients with occult subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), using focal electroretinography (FERG).Twenty-five patients with occult subfoveal CNV due to AMD were treated with TTT delivered using an infrared (810 nm) diode laser (spot size 3.0 mm, laser power 400-600 mW, duration 60 seconds). All patients were clinically evaluated before, 1 and 6 weeks after treatment. Snellen visual acuity (VA) was measured at each visit. Fluorescein angiography (FA) was performed at baseline and 6 weeks after TTT. Focal ERGs were recorded in all patients immediately before and 1 week after TTT in response to an 18-degree diameter, 41 Hz flickering spot (630 nm) centred on the fovea, presented on a steady background in Maxwellian view. A subgroup of 12 patients was also re-tested by FERG at 6-weeks post-TTT.No significant changes in mean FERG amplitude and phase were observed across the different recording sessions before and after TTT. One week after TTT, four patients had significant (2 SD from baseline variability) increases in FERG amplitude and/or phase advances, one had a decrease in amplitude and four had phase delays, compared to baseline. The remaining 15 patients had stable FERGs. Six weeks after TTT, four patients had significant increases in FERG amplitude and/or phase advances, four had decreases in amplitude and/or phase delays, and four had stable FERGs, compared to baseline. Improvement in FERG parameters after TTT was always associated with an improvement in VA and a decrease in exudation. Patients with post-TTT FERG deterioration had stable or deteriorated clinical pictures. At either 1 or 6 weeks post-TTT, the FERG amplitude increase was inversely correlated (p0.05) with the baseline FERG amplitude and VA.Three major conclusions can be drawn: in a short-term follow-up, TTT was not found to be associated with significant changes in macular function; FERG improvement was associated with VA improvement, and the increase in FERG amplitude was greatest in patients with the worst baseline acuity.

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.

PURPOSE To evaluate the influence of aging and age-related maculopathy (ARM) on the temporal frequency response function (TFR) of macular focal electroretinography. METHODS Macular (18 degrees ) focal electroretinograms (FERGs) in response to sinusoidal flicker, modulated at TFs between 3.7 and 52 Hz, were recorded from 13 young (age range, 14-29 years) and 9 old (age range, 55-80 years) healthy subjects and from 18 patients with ARM (stage 2 disease; age range, 55-80 years; visual acuity >/=0.4). Amplitude and phase of the Fourier-analyzed response fundamental (1F) and seconnd harmonic (2F) were measured. RESULTS In young healthy subjects, mean 1F TFR showed a maximum amplitude at 41 Hz, a secondary peak at 3.7 Hz, a minimum at 8 Hz, and a high TF (32-52 Hz) roll-off. Mean 1F TFR of old, compared with young, healthy subjects showed amplitude enhancement at 10 to 14 Hz and a small loss at high TF. Mean 2F TFR of young and old healthy subjects had a maximum at 5.7 to 8 Hz and an attenuation beyond 10 Hz. Mean 1F and 2F TFRs of ARM patients were similar to those of old healthy subjects but were depressed in mean amplitude. FERG TFR changes of old healthy subjects and ARM patients were not mimicked by reducing stimulus retinal illuminance or modulation depth in young healthy subjects. CONCLUSIONS FERG temporal properties are affected by normal aging and ARM. Because FERG TFR is shaped mainly by postreceptoral activity, the findings suggest that photoreceptor and postsynaptic dysfunction underlie aging- and ARM-related FERG changes.

2087 Background: To evaluate longitudinally the relationship between brain imaging and functional findings in childhood optic gliomas (OG) by comparing over time magnetic resonance imaging (MRI) with flicker visual evoked potential (FVEP) changes. Methods: Fourteen children (median age 3 yrs, range: 2–7) suffering from OGs involving chiasm and retro-chiasmatic visual pathways underwent serial MRI and FVEP examinations over a median follow-up time of 38 months (range 12–76). FVEPs were monocularly recorded in response to 8 Hz sine-wave flicker stimuli presented in a mini-Ganzfeld according to a published technique (Trisciuzzi et al., Clin. Neurophysiol., 2004). MRI examinations were performed according to standard procedures. Longitudinal results of both tests were examined in a blind fashion by independent evaluators. FVEPs were judged to be improved, stable or worsened if changes in the amplitude and/or phase of the fundamental response component exceeded the limits of test-retest variability (±90th percentile) established in the same patients. MRI results were judged to show regression, stabilization or progression of OG based on its changes in size (±20%) or extension. Two to seven pairs (< one month apart) of FVEP/MRI examinations per patient (median: 4, range 2–7) were collected. Agreement between test changes over time were evaluated by K-statistics. Results: Based on a total of 38 pairs of longitudinal FVEP/MRI examinations, both tests agreeed in showing worsening (progression), stabilization and improvement (regression) in 5, 10 and 15 cases, respectively. In 3 cases, FVEPs showed a worsening and MRI a stabilization, while in 5 cases FVEPs showed an improvement and MRI a stabilization. Agreement between FVEP and MRI changes was 78.9% (95% CI: ± 37%, K = 0.67, p < 0.001). Conclusions: The results indicate that changes over time in FVEPs, an objective and non-invasive test of visual function, can accurately predict associated changes in OG size and extension as assessed by MRI, and suggest that the latter changes may have a significant impact on visual function during developmental age. No significant financial relationships to disclose.