Carlo Nucci

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe

Background: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. Methods: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. Results: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated €86 for each incremental step ranging from €455 per person year for stage 0 to €969 per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. Conclusions: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Optic Nerve and Optic Radiation Neurodegeneration in Patients with Glaucoma: In Vivo Analysis with 3-T Diffusion-Tensor MR Imaging

PURPOSE To evaluate, with high-field-strength diffusion-tensor (DT) magnetic resonance (MR) imaging, the axonal architecture of the optic nerves and optic radiations in patients with glaucoma and determine whether DT MR imaging-derived parameters correlate with disease severity. MATERIALS AND METHODS The study was approved by the institutional review board. All participants provided written informed consent. Sixteen patients with primary open-angle glaucoma were examined. Glaucoma severity was clinically assessed with use of a six-stage system based on static threshold visual field parameters. Ten healthy individuals served as control subjects. DT MR imaging was performed with a 3-T MR unit. Mean diffusivity (MD) and fractional anisotropy (FA) maps were automatically created. Regions of interest were positioned on the MD and FA maps, and mean MD and mean FA values were calculated for each optic nerve and each optic radiation. RESULTS The optic radiations and optic nerves of patients with glaucoma, as compared with control subjects, had significantly higher MD and significantly lower FA. The mean MD values for the optic nerves and the glaucoma stages varied consistently (r = 0.8087, P < .0001). A negative correlation between mean FA for the optic nerves and glaucoma stage (r = -0.7464, P < .0001) was observed. CONCLUSION Glaucoma is a complex neurologic disease that affects optic nerves and optic radiations. The finding that DT MR imaging-derived MD and FA in the optic nerves correlate with glaucoma severity suggests that these parameters could serve as complementary indicators of disease severity.

Calpain-mediated cleavage of Beclin-1 and autophagy deregulation following retinal ischemic injury in vivo

Autophagy is the major intracellular degradation pathway that regulates long-lived proteins and organelles turnover. This process occurs at basal levels in all cells but it is rapidly upregulated in response to starvation and cellular stress. Although being recently implicated in neurodegeneration, it remains still unclear whether autophagy has a detrimental or protective role. In this study, we investigated the dynamics of the autophagic process in retinal tissue that has undergone transient ischemia, an experimental model that recapitulates features of ocular pathologies, including glaucoma, anterior ischemic optic neuropathy and retinal vessels occlusion. Retinal ischemia, induced in adult rats by increasing the intraocular pressure, was characterized by a reduction in the phosphatidylethanolamine-modified form of LC3 (LC3II) and by a significant decrease in Beclin-1. The latter event was associated with a proteolytic cleavage of Beclin-1, leading to the accumulation of a 50-kDa fragment. This event was prevented by intravitreal treatment with the non-competitive N-methyl-D-aspartate antagonist MK801 and calpain inhibitors or by calpain knockdown. Blockade of autophagy by pharmacological inhibition or Beclin-1 silencing in RGC-5 increased cell death, suggesting a pro-survival role of the autophagic process in this neuronal cell type. Altogether, our results provide original evidence for calpain-mediated cleavage of Beclin-1 and deregulation of basal autophagy in the rat retina that has undergone ocular ischemia/reperfusion injury.

Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects.

Certain general conclusions can be drawn from a series of 56 studies on glaucoma prevalence. Even in the most recently published studies the rate of undiagnosed glaucoma is particularly high. Another fairly constant finding is the discrepancy between the clinical and epidemiologic diagnoses of glaucoma. The prevalence of primary open-angle glaucoma (POAG) has been increasing, and this trend is undoubtedly due at least in part to advances in diagnostic technology. The decreasing prevalence of primary angle-closure glaucoma (PACG) is due to the adoption of more stringent criteria for the diagnosis of this form of glaucoma. Prevalence increases proportionately with age for each racial group. African or African origin populations had the highest POAG prevalence at all ages but the increase in prevalence of POAG is steeper for white populations. PACG is commonest in Asian ethnic groups, with the exception of the Japanese. Low-tension glaucoma (LTG) is quite common in the Japanese population. Over 80% of those with PACG live in Asia, while POAG disproportionately affects those of African derivation. Women are more affected by glaucoma. Very few incidence studies have been completed, because the cost of examining large samples is high. There are only two recent studies conducted on persons of African descent in Barbados (West Indies) and on white inhabitants of Rotterdam (Netherlands). Risk of incident glaucoma was highest among persons classified as having suspect POAG at baseline, followed by those with ocular hypertension. No difference in incidence of POAG between men and women was found. The more recent studies which included routine visual-field testing reveal rates of blinding glaucoma <10% in many countries, including those that are developing.

Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat.

Recent studies support a role for excitotoxicity in the development of retinal ganglion cell (RGC) damage in subjects suffering from glaucoma. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, has been reported to afford neuroprotection, preventing the formation of the mitochondrial permeability transition pore. Using an established animal model of retinal ischemia/reperfusion here, we show that synaptic glutamate increases at 130min from beginning of reperfusion and delayed apoptosis in the RGC layer is seen at 24h. Intraocular administration of CoQ10 minimizes glutamate increase and affords neuroprotection, suggesting that oxidative stress and energy failure might be implicated in the mechanisms of RGC death.

PREVALENCE OF BLINDNESS AND LOW VISION IN AN ITALIAN POPULATION: A COMPARISON WITH OTHER EUROPEAN STUDIES

AimThe scientific literature contains recent data on the prevalence of blindness and low vision for a few European countries, but most of these studies have been focused exclusively on the elderly sector of the populations. The purpose of the present study was to provide age-specific estimates of the prevalence and causes of visual loss in an Italian population aged 40 years and over.MethodsIn total, 847 of the 1200 citizens >40 years of age (70.6%) in the island community of Ponza underwent complete standardized ophthalmological examinations. Visual acuity (VA) was measured using a standard logarithmic chart. World health organization (WHO) definitions of blindness and low vision were adopted (respectively, VA>1.3 logMAR or a visual field <10° around central fixation, and VA >0.5 to 1.3 logMAR or a visual field <20° around central fixation). Prevalence rates based on presenting VAs were also calculated.ResultsThe overall best-corrected prevalence rates were 0.6% (presenting, 0.8%) for better eye blindness, 2.1% (presenting, 6.7%) for better eye low vision, 1.8% (presenting, 2.6%) for monocular blindness, 5.0% (presenting, 11.2%) for monocular low vision. Cataract, glaucoma, degenerative myopia, and AMD were the main causes of better eye visual loss.ConclusionAge-specific prevalence rates in Ponza are fairly consistent with those for other European countries with similar socio-economic conditions and public healthcare systems. A substantial percentage of visual losses remains uncorrected despite the availability of potentially curative therapy. Greater emphasis needs to be placed on educating the public regarding the importance of good vision.

Incidence of blindness and low vision in a sample population ☆: The Priverno Eye Study, Italy

PURPOSE To study the incidence of blindness and low vision over a 7-year period. DESIGN Population-based cohort study. PARTICIPANTS The survivors of the original cohort of 860 persons from Priverno, Italy, aged 45 to 69 years, were reexamined. Of the 760 eligible survivors, 619 (81.4%) had a 7-year follow-up visit. METHODS Baseline and follow-up examinations included the collection of anamnestic and ophthalmologic data by the same observers using the same methods and classification criteria to minimize sources of variability. MAIN OUTCOME MEASURES Best-corrected visual acuity (VA) measured at 4 m by standardized logarithmic chart was expressed as the logarithm of the minimum angle of resolution (logMAR). World Health Organization definitions of blindness and low vision were adopted (respectively, VA > 1.3 logMar and VA > 0.6 to 1.3 logMar in the better eye or in either eye). Participants at risk for visual impairment were those without blindness or low vision in one or both eyes at baseline; participants at risk for one-eye visual impairment were those without blindness or low vision in both eyes at baseline. RESULTS A total of 33 participants were defined as incident cases of visual impairment. The overall incidence figures for blindness, low vision, one-eye blindness, and one-eye low vision were respectively 0.2% (95% confidence interval [CI], 0.0-0.9), 1.3% (95% CI, 0.7-2.6), 1.2% (95% CI, 0.6-2.4), and 2.9% (95% CI, 1.8-4.6). CONCLUSIONS This study provides population-based estimates of the incidence of visual impairment in an adult, free-living European population. With respect to the younger participants, older subjects at baseline were at higher risk for incident visual impairment, the main causes of which were cataract, myopia, and diabetic retinopathy. The incidence of visual impairment in the subgroup aged 55 to 64 years at baseline was significantly higher than that found in Beaver Dam 5-year study and similar to that found in Beaver Dam 10-year Study, when the same definitions were adopted. This difference may be partially explained by social and cultural habits of the female samples, but many other factors may play a role.

17β-Estradiol prevents retinal ganglion cell loss induced by acute rise of intraocular pressure in rat

Glaucoma, is a progressive optic neuropathy often associated with increased intraocular pressure (IOP) and characterized by progressive death of retinal ganglion cells (RGCs). High acute rise of IOP is a model for retinal ischemia and may represent a model of acute angle closure glaucoma. Here we have used this experimental model in combination with a neurochemical and neuropathological approach to gain more insight in the neuroprotective profile of 17beta-estradiol (E2), a steroid hormone, which has been shown to increase the viability, survival, and differentiation of primary neuronal cultures from different brain areas including amygdala, hypothalamus, and neocortex. Our data demonstrate that systemic administration of E2 significantly reduces RGC loss induced by high IOP in rat. In addition, pretreatment with E2, 30 min before ischemia, minimizes the elevation of glutamate observed during the reperfusion period. These effects seem to be in part mediated by the activation of the estrogen receptor, since a pretreatment with ICI 182-780, a specific estrogen receptor antagonist, partially counteracts the neuroprotection afforded by the estrogen.

3-T Diffusion tensor imaging of the optic nerve in subjects with glaucoma: correlation with GDx-VCC, HRT-III and Stratus optical coherence tomography findings

Objectives To correlate diffusion-tensor imaging (DTI) of the optic nerve with morphological indices obtained by scanning laser polarimetry (GDx-VCC); confocal scanning laser ophthalmoscopy (Heidelberg III retinal tomograph; HRT-III) and optical coherence tomography (Stratus OCT). Methods Thirty-six subjects (12 with no eye disease and 24 with perimetrically diagnosed glaucoma) were examined. One eye for each participant was studied with 3-Tesla DTI (with automatic generation of mean diffusivity (MD) and fractional anisotropy (FA) values); GDx-VCC, HRT-III and OCT. Single and multiple regression analyses of all variables studied were performed. Results MD displayed the strongest correlation with linear cup/disc ratio (LCDR) from HTR-III (r=0.662), retinal nerve fibre layer (RNFL) thickness (avThickn) from OCT (r=−0.644), and nerve fibre index (NFI) from GDx (r=0.642); FA was strongly correlated with the LCDR (r=−0.499). In multiple regression analyses, MD correlated with LCDR (p=0.02) when all variables were considered; with avThickn (p<0.01) (analysis of all RNFL parameters); with NFI (p<0.01) (analysis of all GDx parameters); with avThickn (p<0.01) (analysis of OCT parameters); with LCDR (p=0.01) (analysis of HRT-III morphometric parameters) and with linear discriminant function (RB) (p=0.02) (analysis of HRT-III indices). As for FA, it correlated with avThickn (p=0.02) when we analysed the OCT parameters and with RB (p=0.01) (analysis of HRT-III indices). Conclusions DTI parameters of the axonal architecture of the optic nerve show good correlation with morphological features of the optic nerve head and RNFL documented with GDx-VCC, HRT-III and OCT.

Potential roles of (endo)cannabinoids in the treatment of glaucoma: from intraocular pressure control to neuroprotection

Recent evidence shows that the endocannabinoid system is involved in the pathogenesis of numerous neurodegenerative diseases of the central nervous system. Pharmacologic modulation of cannabinoid receptors or the enzymes involved in the synthesis, transport, or breakdown of endogenous cannabinoids has proved to be a valid alternative to conventional treatment of these diseases. In this review, we will examine recent findings that demonstrate the involvement of the endocannabinoid system in glaucoma, a major neurodegenerative disease of the eye that is a frequent cause of blindness. Experimental findings indicate that the endocannabinoid system contributes to the control of intraocular pressure (IOP), by modulating both production and drainage of aqueous humor. There is also a growing body of evidence of the involvement of this system in mechanisms leading to the death of retinal ganglion cells, which is the end result of glaucoma. Molecules capable of interfering with the ocular endocannabinoid system could offer valid alternatives to the treatment of this disease, based not only on the reduction of IOP but also on neuroprotection.