Marco Piccardi

Influence of short-term antioxidant supplementation on macular function in age-related maculopathy. A pilot study including electrophysiologic assessment

PURPOSE To evaluate the influence of short-term antioxidant supplementation on retinal function in age-related maculopathy (ARM) patients by recording focal electroretinograms (FERGs). DESIGN Nonrandomized, comparative clinical trial. PARTICIPANTS Thirty patients with early ARM and visual acuity >/=20/30, divided into two groups, similar for age and disease severity: antioxidant group (ARM-A, n = 17) and no treatment group (ARM-NT, n = 13). Eight age-matched normal subjects divided into antioxidant (N-A, n = 4) or no treatment (N-NT, n = 4) groups. METHODS ARM-A patients and N-A patients had oral supplementation of lutein, 15 mg; vitamin E, 20 mg; and nicotinamide, 18 mg, daily for 180 days, whereas ARM-NT patients and N-NT patients had no dietary supplementation during the same period. Eight of the 17 ARM-A patients took supplementation for an additional 180-day period. In all patients and normal subjects, FERG assessment was performed at the study entry (baseline) and after 180 days. Further testing was performed at 360 days for the eight ARM-A patients taking supplements and for one ARM-A patient who had discontinued supplementation after 180 days. FERGs were recorded in response to a 41-Hz sinusoidally modulated uniform field (93.5% modulation depth) presented to the macular region (18 degrees ) on a light-adapting background. In a subgroup of patients (11 ARM-A and 5 ARM-NT), whose responses had suitable signal-to-noise ratios, FERGs were also recorded at different stimulus modulation depths between 8.25% and 93.5%. MAIN OUTCOME AND MEASURES Amplitude (in micro V) and phase (in degrees) of the FERG fundamental harmonic component. FERG modulation thresholds, estimated from the value of log modulation depth yielding a criterion response. RESULTS At 180 days, FERGs of ARM-A patients and N-A patients were increased in amplitude (mean change, 0.11 and 0.15 log micro V, respectively, P </= 0.01) compared with baseline values, whereas no significant changes in FERG amplitudes of ARM-NT patients and N-NT patients were found (mean change, -0.004 and -0.023 log micro V, respectively). In all groups no changes in the FERG phase were found. FERG modulation thresholds decreased with respect to baseline values (mean change, -0.36 log units, P < 0.01) in ARM-A patients, whereas no significant change (mean change, 0.07 log units) in ARM-NT patients was seen. At 360 days, FERGs of ARM-A patients taking supplementation were still increased in amplitude with respect to baseline (P < 0.05) but did not differ from those recorded at 180 days. In the patient who had discontinued supplementation, FERG amplitude decreased from the 180 days value, approaching that recorded at baseline. CONCLUSIONS Although this study provides no evidence for the long-term benefit of antioxidants in ARM, the results suggest that increasing the level of retinal antioxidants might influence macular function early in the disease process, as well as in normal aging.

A Longitudinal Follow-Up Study of Saffron Supplementation in Early Age-Related Macular Degeneration: Sustained Benefits to Central Retinal Function

Objectives. In a previous randomized clinical trial (Falsini et al. (2010)), it was shown that short-term Saffron supplementation improves retinal flicker sensitivity in early age-related macular degeneration (AMD). The aim of this study was to evaluate whether the observed functional benefits from Saffron supplementation may extend over a longer follow-up duration. Design. Longitudinal, interventional open-label study. Setting. Outpatient ophthalmology setting. Participants. Twenty-nine early AMD patients (age range: 55–85 years) with a baseline visual acuity >0.3. Intervention. Saffron oral supplementation (20 mg/day) over an average period of treatment of 14 (±2) months. Measurements. Clinical examination and focal-electroretinogram-(fERG-) derived macular (18°) flicker sensitivity estimate (Falsini et al. (2010)) every three months over a followup of 14 (±2) months. Retinal sensitivity, the reciprocal value of the estimated fERG amplitude threshold, was the main outcome measure. Results. After three months of supplementation, mean fERG sensitivity improved by 0.3 log units compared to baseline values (P < 0.01), and mean visual acuity improved by two Snellen lines compared to baseline values (0.75 to 0.9, P < 0.01). These changes remained stable over the follow-up period. Conclusion. These results indicate that in early AMD Saffron supplementation induces macular function improvements from baseline that are extended over a long-term followup.

Macular dysfunction in multiple sclerosis revealed by steady-state flicker and pattern ERGs

Recent evidence indicates that the 2nd harmonics of steady-state (8 Hz) electroretinograms to either sinusoidal flicker (FERG) or to counterphased gratings (PERG) presented in the macular region (9 degrees) represent different subsets of generators in the inner retina. We evaluated the steady-state macular FERG and PERG 2nd harmonics (2F and 2P, respectively) in 19 normal subjects (19 eyes) and in 23 multiple sclerosis patients (44 eyes; 25 eyes with a history of clinical optic neuritis, and 19 eyes with no history of optic neuritis, subclinical eyes). The mean 2F and 2P amplitudes were significantly reduced, as compared to controls, in both subclinical and optic neuritis eyes. The 2P phase was significantly delayed, as compared to controls, in subclinical eyes, whereas 2F phase was delayed in eyes with optic neuritis. 2F was outside the 95% confidence limits (in amplitude or phase) in 11/19 subclinical eyes and in 25/25 optic neuritis eyes. 2P was outside the normal range in 12/19 subclinical eyes and in 24/25 optic neuritis eyes. These results show that FERG and PERG 2nd harmonics are significantly altered in multiple sclerosis eyes with or without a clinical history of optic neuritis. This finding suggests a dysfunction of inner macular layers which may result from direct retinal involvement or retrograde degeneration.

A fast visual evoked potential method for functional assessment and follow-up of childhood optic gliomas

OBJECTIVE To evaluate a fast technique of visual evoked potentials (VEPs) recording, in response to steady-state luminance stimuli (SS-LVEPs), for functional assessment and follow-up of childhood optic gliomas (OGs). METHODS Eighteen OG patients (age range: 3.5-18 years), with different degrees of optic pathway damage severity, were examined. Sixteen age-matched normal subjects served as controls. Ten of the 18 OG patients were re-tested 1-3 months after the first examination. SS-LVEPs were elicited by a sinusoidally-modulated flickering (8 Hz) uniform field, generated by a light emitting diode (LED)-array and presented monocularly in a mini-ganzfeld. Amplitude and phase of the Fourier-analyzed response fundamental (1F) and second harmonic (2F) were measured. The full VEP protocol had a median duration of 6 min (range: 4-12). RESULTS When compared to normal control values, median 1F and 2F SS-LVEP amplitudes of OG patients were reduced (P<0.01), with a borderline increase in 2F phase lag (P<0.05). In 11 OG patients with asymmetric optic pathway damage in between-eye comparisons, median 1F amplitude losses were greater (P<0.01) in fellow eyes with more severe damage. No significant interocular difference was observed in control subjects. Median test-retest changes of 1F and 2F component were <20% and 30 degrees for amplitude and phase, respectively. In individual OG patients, 1F and 2F amplitudes were positively correlated (P<0.01) with visual acuity. 1F amplitude losses were correlated (P=0.01) with the severity of optic disc atrophy. Considering both 1F and 2F abnormalities, diagnostic sensitivity of SS-LVEP in detecting OG-induced optic pathways damage was 83.3%. CONCLUSIONS The present findings support the use of this technique, as an alternative to pattern VEPs, for functional assessment and follow-up of OG in uncooperative children.

Functional effect of Saffron supplementation and risk genotypes in early age-related macular degeneration: a preliminary report.

BackgroundTo determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes.MethodsThirty-three early AMD patients, screened for CFH (rs1061170) and ARMS2 (rs10490924) polymorphisms and receiving Saffron oral supplementation (20 mg/day) over an average period of treatment of 11 months (range, 6–12), were longitudinally evaluated by clinical examination and focal electroretinogram (fERG)-derived macular (18°) flicker sensitivity estimate. fERG amplitude and macular sensitivity, the reciprocal value of the estimated fERG amplitude threshold, were the main outcome measures.ResultsAfter three months of supplementation, mean fERG amplitude and fERG sensitivity improved significantly when compared to baseline values (p < 0.01). These changes were stable throughout the follow-up period. No significant differences in clinical and fERG improvements were observed across different CFH or ARMS2 genotypes.ConclusionsThe present results indicate that the functional effect of Saffron supplementation in individual AMD patients is not related to the major risk genotypes of disease.

Topical nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology.

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.

Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response

PURPOSE To determine whether the Ganzfeld ERG photopic negative response (PhNR), an assay of inner retinal activity, is altered in childhood optic glioma (OPG). METHODS Seventeen pediatric patients with a diagnosis of OPG, established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria, were enrolled. The examination protocol included determination of visual acuity (VA), fundus examination, retinal nerve fiber layer (RNFL) measurement with spectral-domain optical coherence tomography (SD-OCT) and photopic ERG. Fifteen normal children served as control group. Ten of the 17 OPG patients were retested 1 to 3 months after the first examination. Photopic ERGs were recorded after 10 minutes of light adaptation in response to a Ganzfeld flash presented on a steady light-adapting background. Amplitude and peak-time of b-wave and PhNR were measured. RESULTS Compared with normal values, PhNR amplitude was significantly reduced (P < 0.0001) in the OPG group. Peak-time of PhNR as well as b-wave amplitude and peak-time were similar in both patients and controls. Losses of PhNR were found in patients with involvement of either anterior or retro-chiasmatic optic pathways. Linear regression analysis showed significant positive correlation between RNFL thickness and PhNR amplitude (r2 = 0.34, P = 0.008). Mean percentage test-retest difference for PhNR amplitude and peak-time was 12% and 6%, respectively. CONCLUSIONS These findings indicate that flash ERG PhNR can detect a loss of inner retinal function in childhood OPGs supporting the use of this technique, as an adjunct to standard psychophysical and electrophysiological tests, to monitor visual function in OPG.

Regional cone-mediated dysfunction in age-related maculopathy evaluated by focal electroretinograms: relationship with retinal morphology and perimetric sensitivity.

Purpose: To assess regional cone-mediated function in age-related maculopathy (ARM) by focal electroretinograms (FERGs), and to compare FERGs with morphologic changes and perimetric sensitivity at corresponding locations. Methods: Twenty-six ARM patients and 12 age-matched controls were evaluated. FERGs were elicited by either a central (0–2.25°, C) or a paracentral annular (2.25–9°, PC) flickering (41 Hz) field, presented on a light-adapting background. Morphological changes (soft drusen and/or retinal pigment epithelium defects) at matched locations were assessed by fundus photography and fluorescein angiography. Perimetric sensitivity was measured by Octopus 10° program (tM2). Results: When compared to controls, mean C and PC FERG amplitudes of patients were reduced (p < 0.01), and the mean PC FERG phase was delayed (p < 0.01). Both FERG delays and morphologic lesions tended to involve to a greater extent the PC compared to the C region. In the C region, perimetric losses were correlated with the extent of morphologic lesions (p < 0.05). In the PC region, perimetric losses were correlated with FERG amplitudes (p < 0.05). Conclusions: In ARM, FERG losses are eccentricity-dependent, not quantitatively linked to retinal morphology, and correlated with perimetric losses, suggesting a heterogeneous dysfunction with loss of both C and PC perimetric sensitivities.

Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial

Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double-blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas.

Long-term decline of central cone function in retinitis pigmentosa evaluated by focal electroretinogram

PURPOSE We evaluated long-term changes of central cone-mediated function in retinitis pigmentosa (RP) patients by recording focal electroretinograms (fERG). METHODS A cohort of 43 RP patients was followed from 4 to 16 years (average follow-up 9.3 years, average 10 examinations/patient) by recording the fERG response to a flickering uniform red field overlaying the central 18° of visual field (VF). Statistical censoring led to a reduced dataset of 32 patients (autosomal dominant 9, recessive 5, sporadic 5, x-linked 1, Usher II 12), from which long-term decay rates were estimated by global fitting of individual fERG amplitude time-curves. RESULTS Long-term follow-up of central cone FERG amplitude showed two main features: short-term variability and long-term decline. fERG short-term variability range was 0.14 to 0.2 log units. Mean yearly decay rate of central fERG was 5.6% (95% confidence interval [CI] 4%-7%). Yearly decline depended on inheritance pattern, being significantly greater in autosomal recessive and sporadic compared to autosomal dominant RP. The degree of central cone fERG decline was unrelated to the size of the residual VF. CONCLUSIONS The decline of central cone function is significantly slower than global cone function decline in RP. Central cone fERG loss is independent of residual VF.