V. Parisi

Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma

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 μg/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 μg/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/mm2) 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.

Visual electrophysiological responses in persons with type 1 diabetes

Persons with type 1 diabetes show electrophysiological abnormalities of the visual system which are revealed by methods such as flash electroretinogram (FERG), oscillatory potentials (OPs), pattern electroretinogram (PERG), focal electroretinogram (focal ERG), visual evoked potentials (VEP) in basal condition and after photostress. This review reports the changes in electrophysiological responses of the different structures composing the visual system observed in persons with type 1 diabetes before the development of the overt clinical retinopathy. In persons with type 1 diabetes without retinopathy (IDD), the earlier abnormal electrophysiological responses are recorded from the innermost retinal layers and postretinal visual pathways, as suggested by impaired PERGs and delayed retinocortical time (RCT). These are observed in IDD persons with a disease duration shorter than 6 months. Further electrophysiological changes are recorded from the macula (abnormal focal ERG and VEP after photostress) in IDD persons with disease duration greater than 1 year. Additional electrophysiological changes are recorded from the middle and outer retinal layers (impaired FERG and OPs) in IDD persons with a disease duration greater than 10 years. All the electrophysiological tests show a greater degree of abnormal responses in persons with type 1 diabetes when a background retinopathy is present. Copyright

Ocular application of nerve growth factor protects degenerating retinal ganglion cells in a rat model of glaucoma

PurposeElevated 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. MethodsGL 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. ResultsThe 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. ConclusionsThese 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.

Neural conduction in the visual pathways in ocular hypertension and glaucoma

Abstract• Background: The aim of our work was to evaluate neural conduction in visual pathways in subjects with ocular hypertension and glaucoma. • Methods: We assessed simultaneous recordings of pattern electroretinograms (PERG) and visual evoked potentials (VEP) in 16 subjects with ocular hypertension (OHT), in 16 subjects with primary open-angle glaucoma (POAG) and in 15 age-matched controls. The visual stimuli were checkerboard patterns (the check edges subtend 15 min of visual arc; contrast 70%) reversed at the rate of 2 reversals/s.• Results: In OHT and POAG patients we found PERG and VEP latencies signficantly longer than in controls. The P50-N95 PERG amplitudes were significantly reduced in OHT and POAG eyes. VEP amplitudes were significantly reduced in POAG eyes, while in OHT they were similar to controls. The retinocortical time (RCT; difference between VEP P100 latency and PERG P50 latency) was longer in POAG patients than in controls; no differences between patients with OHT and controls were observed. Moreover, we observed that in POAG the longer RCT was inversely related to the PERG amplitude. • Conclusion: Our results suggest that involvement of the innermost retinal layers in POAG is accompanied by slowed neural conduction in the visual pathways.

Electrophysiological assessment of visual function in IDDM patients.

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

Visual evoked potentials after photostress in insulin-dependent diabetic patients with or without retinopathy

Visual evoked potentials (VEPs) were assessed under basal conditions and after photostress in normal control subjects, in insulin-dependent diabetic patients with retinopathy (IDDPWR) and in insulin-dependent diabetic patients without retinopathy (IDDP). The VEPs recorded under basal conditions showed a P100 latency significantly higher in IDDP and IDDPWR eyes than in control eyes and in IDDPWR than in IDDP eyes (P<0.01). N75-P100 amplitude was significantly lower in IDDP and IDDPWR eyes than in control eyes (P<0.01). No difference was recorded in the N75-P100 amplitudes between IDDP and IDDPWR eyes. In all eyes, the VEPs recorded after photostress showed an increase in latency and a decrease in amplitude. In both IDDPWR eyes and IDDP eyes VEPs recorded at 20, 40 and 60 s after photostress showed higher mean increments in P100 latency than in C control eyes, and IDDPWR eyes showed higher mean increments in P100 latency than IDDP eyes (IDDP vs control P<0.01, IDDPWR vs control P<0.01, IDDPWR vs IDDP P<0.017). The mean reductions in amplitude observed at 20, 40 and 60 s after photostress in IDDP and IDDPWR eyes were lower than in control eyes (IDDP vs control P=0.01, IDDPWR vs control P<0.01, IDDPWR vs IDDP P<0.01). VEPs were superimposable on the basal VEP (recovery time) at 73.9 s in control eyes, at 88.17 s in IDDP eyes and at 113.3 s in IDDPWR eyes. VEPs after photostress in IDDP patients with normal visual acuity and no fluorangiographic signs of retinopathy may show multiple modifications. This may indicate the presence of an early functional deficiency of the central retinal layers.

Neural conduction in visual pathways in newly-diagnosed IDDM patients

OBJECTIVES Visual evoked potentials (VEPs) show abnormal responses in newly-diagnosed insulin-dependent diabetic (IDDM) patients. Electrophysiological methods allow one to dissect and explore different structures contributing to neural conduction in the visual pathways. The aim of our work was to assess whether the VEP abnormalities are due to impaired function of the retinal layers and/or a delayed conduction in the postretinal visual pathways. METHODS Simultaneous recordings of VEP and pattern-electroretinogram (PERG) were performed at two intervals (at entry of the study and after 3 months) in 14 newly-diagnosed IDDM patients (age: 24.8+/-6.8 years; duration of disease: 3+/-1.5 months), and in 14 age-matched control subjects. RESULTS In comparison with control subjects, IDDM patients showed: VEP P100 latencies significantly delayed (P < 0.01), a significant impairment of all PERG parameters (P < 0.01) and retinocortical time (RCT, difference between VEP P100 and PERG P50 latencies) and latency window (LW, difference between VEP N75 and PERG P50 latencies) also significantly increased (P < 0.01). All electrophysiological parameters were not significantly changed when retested after 3 months. No correlations were found between VEP P100 latency, RCT, LW and PERG parameters. CONCLUSIONS Impaired PERG indicates an involvement of the innermost retinal layers; increased values of RCT and LW represent an index of delayed neural conduction in the postretinal visual pathways. Therefore two sources, one retinal (impaired PERG) and one postretinal (delayed RCT and LW), may independently contribute in to the abnormal responses of VEP observed in newly-diagnosed IDDM patients. Three months of relatively-stable metabolic control have not normalized the VEP and PERG impairment.

Glaucoma alters the expression of NGF and NGF receptors in visual cortex and geniculate nucleus of rats: Effect of eye NGF application

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.

Impact of regional retinal responses on cortical visually evoked responses: Multifocal ERGs and VEPs in the retinitis pigmentosa model

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.

Effects of Coenzyme Q10 in Conjunction With Vitamin E on Retinal-evoked and Cortical-evoked Responses in Patients With Open-angle Glaucoma

Purpose:To evaluate pattern-evoked retinal and cortical responses [pattern electroretinogram (PERG) and visual-evoked potential (VEP), respectively] after treatment with coenzyme Q10 in conjunction with vitamin E in open-angle glaucoma (OAG) patients. Methods:Forty-three OAG patients (mean age, 52.5±5.29 y; intraocular pressure <18 mm Hg with &bgr;-blocker monoterapy only) were enrolled. At baseline and after 6 and 12 months, simultaneous recordings of PERG and VEPs were obtained from 22 OAG patients who underwent treatment consisting of coenzyme Q10 and vitamin E (Coqun, 2 drops/d) in addition to &bgr;-blocker monoterapy (GC group), and from 21 OAG patients who were only treated with &bgr;-blockers (GP group). Results:At baseline, intraocular pressure, PERG, and VEP parameters were similar in both GC and GP groups (analysis of variance, P>0.05). After 6 and 12 months, PERG and VEP response parameters of GP patients were unchanged when compared to baseline. In GC patients, PERG P50 and VEP P100 implicit times were decreased, whereas PERG P50-N95 and VEP N75-P100 amplitudes were increased (P<0.01) when compared to baseline. In the GC group, the differences in implicit times and amplitudes with respect to baseline were significantly larger (P<0.01) than those recorded in the GP group. The improvement (12 mo minus baseline) of VEP implicit time was significantly correlated with the changes of PERG P50-N95 amplitude (r=−0.66171, P=0.0008) and P50 implicit time (r=0.68364, P=0.00045) over a period of 12 months. Conclusions:Coenzyme Q10 associated with vitamin E administration in OAG shows a beneficial effect on the inner retinal function (PERG improvement) with consequent enhancement of the visual cortical responses (VEP improvement).