Alessio Martucci

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.

Differences between Proximal versus Distal Intraorbital Optic Nerve Diffusion Tensor Magnetic Resonance Imaging Properties in Glaucoma Patients

PURPOSE To analyze in vivo the diffusion tensor magnetic resonance imaging (DT-MRI) properties of the intraorbital optic nerve at two different levels: Proximal to the optic nerve head (ONH) and distal to the ONH at the level of the orbital apex in glaucoma patients. METHODS Twenty-four patients with primary open-angle glaucoma were examined. The categorization into early and severe glaucoma was performed by Hodapps classification. Fifteen healthy individuals served as controls. DT-MRI was performed with a 3T-MR unit. RESULTS At early stage mean diffusivity (MD) values were higher at the proximal site with respect to the distal site. On the contrary, a decrease in fractional anisotropy (FA) was observed only relative to patient stage, independent of optic nerve site. Moreover, at early disease stage an increase in overall diffusivities, was evident at the proximal site, whereas at the distal site a decrease of the largest diffusivity and an increase in both the intermediate and smallest diffusivities were observed. FA and MD measured at the proximal site, had, respectively, the highest sensitivity and specificity in discriminating between healthy and glaucomatous eyes. CONCLUSIONS Our study represents the first attempt to evaluate in vivo fiber integrity changes along the optic nerve with DT-MRI. Optic nerve degeneration appears to be a process that affects differently the proximal and the distal segments of the optic nerve. The complementary high sensitivity of FA with the high specificity of MD at the proximal site may provide reliable indexes for the identification of glaucomatous patients at early stages.

Glaucoma progression associated with altered cerebral spinal fluid levels of amyloid beta and tau proteins

Several studies have revealed links between Alzheimer’s disease (AD) and glaucoma. This report describes a glaucoma patient with medically controlled intraocular pressure (IOP) who experienced disease progression concomitantly with the onset of mild cognitive impairment (MCI) and positivity for cerebral spinal fluid (CSF) markers of AD. In 2005 a 69-year-old man presented with reduced visual acuity in the left eye. He had no history of hypertension, diabetes, cerebrovascular problems or cognitive impairment, but the family history was positive for glaucoma. Best-corrected visual acuity in the right eye was 0.1 logMAR; the left eye could barely perceive light. IOPs were 25 mmHg (right eye) and 28 mmHg (left eye). Exam of the anterior chamber with the gonioscopic lens revealed an open irodocorneal angle. Visual field testing (Humphrey sita standard 30–2) of the right eye revealed stage 4 glaucoma (Brusini Glaucoma Staging System 2, GSS2) (Fig. 1). The optic nerve head of the right eye presented advanced cupping with total loss of superior, inferior and temporal disc tissue and with nasal displacement of the blood vessels (Fig. 2a). In the left eye, all the neural rim was destroyed, and the optic nerve head appeared white and deeply excavated (Fig. 2b). Advanced open-angle glaucoma was diagnosed and treatment started with timolol 0.5% BID and travoprost (both eyes). Follow-up visits every 6 months for 4 years revealed IOPs < 16 mmHg and no change in the visual fields. Between February and October 2009, he developed progressive visual loss in the right eye (0.7 logMAR), and worsening of the visual field to GSS2 stage 5 (Fig. 1) although the IOP was 14 mmHg. Because his wife reported concomitant onset of memory deficits, the Mental Deterioration Battery was performed and MCI was diagnosed. Routine blood work including B12 and folate levels, screening for vasculitis (erythrocyte sedimentation rate (ESR), C-reactive protein, antinuclear antibodies, rheumatoid factor) and syphilis serology were normal. Blood pressure monitoring for episodes of systemic hypotension, electrocardiogram and epiaortic ultrasonography were also unremarcable. Magnetic resonance imaging with gadolinium found normal-appearing visual pathways. CSF markers of neurodegenerative dementia were assessed with commercial ELISAs (Innogenetics, Ghent, Belgium). The results were consistent with AD: decreased amyloid beta (Ab)1–42 (226 pg/mL) and elevated levels of total and phosphorylated tau (t-tau and p-tau) (655 and 105 pg/mL, respectively). An increased incidence of primary open-angle glaucoma has been reported among AD patients, and a Japanese population study found that almost all such cases are the normal-tension form, which suggests the involvement of causative factors unrelated to IOP. Glaucoma also seems to progress more rapidly in AD patients than in other groups. In addition, in rats with experimental ocular hypertension, activation of caspase 3 in the retinal ganglion cells has been shown to cause cleavages of the amyloid precursor protein that generate Ab and other neurotoxic species. This is consistent with reports that blocking the effects of Ab prevents retinal ganglion cell apoptosis. Recent evidence indicates that altered CSF circulatory dynamics can reduce the clearance of both Ab and tau, and decreased Ab and increased tand p-tau levels in the CSF have been shown to predict progression from cognitive normality to MCI or AD-type dementia and from MCI to AD. Cut-off values were 550 (95% CI 531–570) ng/L for Ab, 375 (325–405) ng/L for t-tau and 52 (48–56) ng/L for p-tau. Our experience with the patient described here suggests that in advanced glaucoma, the onset of cognitive impairment may be associated with progression to end-stage glaucoma, regardless of IOP levels. Apart from predicting imminent dementia, the altered CSF levels of Ab and tau proteins observed in this case might also reflect increased risk for progression of glaucoma to the stage of visual loss. It is also possible that altered CSF circulatory dynamics in this case reduced neurotoxin clearance along optic nerves in the subarachnoid space and that deposits/aggregates of tau and/or other toxic molecules may have contributed to the glaucoma progression (see Killer et al. 2008). This seems to be the first report of severe glaucoma progression associated with CSF alterations indicative of AD, and it requires confirmation in large studies.

Links among glaucoma, neurodegenerative, and vascular diseases of the central nervous system.

Glaucoma is the leading cause of irreversible blindness worldwide. Although the intraocular pressure (IOP) has been considered for long time the key point and the only treatable risk factor of the disease, there are cases in which glaucoma continues to progress despite normal IOP values. Vision loss in glaucoma is related to a selective decrease in the number of retinal ganglion cells by apoptosis that is associated to alterations of the central visual pathways. Interestingly, similar events have been also described in disorders of the central nervous system (CNS), such as Alzheimers disease, Parkinsons disease, Lebers hereditary optic neuropathy, and cerebrovascular diseases. In this review, we discuss recent evidence supporting pathological links between glaucoma and disorders of the CNS.

Association Between Alzheimer's Disease and Glaucoma: A Study Based on Heidelberg Retinal Tomography and Frequency Doubling Technology Perimetry

Aim: To assess the frequency of glaucoma-like alterations in Alzheimers disease (AD) patients using Heidelberg Retinal Tomograph III (HRT-3) and Frequency Doubling Technology (FDT) perimetry. Methods: The study included 51 eyes of 51 AD subjects and 67 eyes of 67 age- and sex-matched controls. Subjects underwent an ophthalmological examination including measurements of intraocular pressure (IOP), Matrix FDT visual field testing, optic nerve head morphology and retinal nerve fiber layer thickness (RNFLt) assessment by slit-lamp biomicroscopy and HRT-3. Results: The frequency of alterations was significantly higher in the AD group (27.5 vs. 7.5%; p = 0.003; OR = 4.69). AD patients showed lower IOP (p = 0.000) despite not significantly different values of central corneal thickness (CCT) between the groups (p = 0.336). Of all the stereometric parameters measured by HRT-3, RNFLt was significantly lower in AD patients (p = 0.013). This group also had significantly worse results in terms of Moorfields Regression Analysis (p = 0.027). Matrix showed significantly worse Mean Deviation (MD) (p = 0.000) and Pattern Standard Deviation (PSD) (p = 0.000) values and more altered Glaucoma Hemifield Test (p = 0.006) in AD patients. Pearsons R correlation test showed that Mini Mental State Examination is directly correlated with MD (R = 0.349; p = 0.034) and inversely correlated with PSD (R = −0.357; p = 0.030). Conclusion: Patients with AD have a higher frequency of glaucoma-like alterations, as detected by the use of HRT-3. These alterations were not associated with elevated IOP or abnormal CCT values.

Glaucoma progression associated with Leber’s hereditary optic neuropathy

The purpose of this article is to describe a case of open-angle glaucoma progression associated with Leber’s hereditary optic neuropathy. Single case analysis method is used. A 53-year-old woman with a previous diagnosis of glaucoma presented with progressive visual field loss. Complete ophthalmological examination and blood tests were negative for other concomitant diseases. Genetic counseling revealed mitochondrial DNA mutation compatible with the diagnosis of Leber’s hereditary optic neuropathy. In conclusion, the case describes the concomitant occurrence of open-angle glaucoma and Leber’s optic neuropathy. We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment. Screening for mitochondrial DNA mutations may be requested in patients with glaucoma who, despite pharmacologically controlled intraocular pressure, show rapid progression of the disease.

New strategies for neuroprotection in glaucoma,a disease that affects the central nervous system

Glaucoma is a disease where retinal ganglion cells (RGC) are specifically affected though a number of evidences endorse the hypothesis that glaucoma is a neuro-degenerative disorder of the central nervous system and suggest a possible connection between glaucomatous damage and cerebrovascular alterations. The mechanisms underlying RGC loss are not yet fully known but alterations of the autophagy machinery have been recently proposed as a potential contributing factor as for Alzheimers disease. Here we review the current literature on new strategies for neuroprotection in glaucoma, focusing on pharmacologic strategies to minimize RGC damage.

Evaluation of pupillary response to light in patients with glaucoma: a study using computerized pupillometry

The aim of this study was to evaluate pupillary response to light stimulation in patients with different stages of glaucoma using computerized pupillometry. We conducted a retrospective study on a group of 44 glaucoma patients who had undergone complete ophthalmological examination, visual field test (Humphrey SITA Standard 24-2) and monocular dynamic pupillometry (MonCV3 Metrovision). Eyes were classified into stages of glaucoma according to visual field damage using the Glaucoma Staging System 2. A group of 18 healthy subjects, homogeneous for age and sex with glaucoma patients, was used as a control. The following parameters were considered—latency and duration of contraction and dilatation; initial, minimum, maximum, and mean pupil diameter; amplitude of contraction; contraction and dilatation speed; and percent pupil contraction (PPC). PPC and pupil contraction speed and minimum diameter showed covariate correlation with the stages of glaucoma. The control group significantly differed from the stage 3 group in terms of PPC and from the stage 4 group in terms of minimum diameter. There were significant differences between the stage 5 group and stage 1, 2, 3 and control groups. Ordinal logistic regression showed a correlation between pupil contraction speed, minimum diameter, PPC, initial diameter and the stage of glaucoma. The study showed that glaucoma damage is associated with altered values of pupillary response to light. This event may be the consequence of the progressive loss of retinal ganglion cells and their axons induced by glaucoma.

Assessment of the retinal posterior pole in dominant optic atrophy by spectral-domain optical coherence tomography and microperimetry.

Background To assess posterior pole (PP) retinal structure in patients with genetically confirmed autosomal dominant optic atrophy (ADOA) using new spectral domain optical coherence tomography (SD-OCT) segmentation technology. To analyze retinal PP thickness in relation to retinal sensitivity data from microperimetry (MP) in ADOA patients. Methods and findings This prospective cross-sectional study included 11 patients with ADOA and 11 age-matched healthy subjects. All participants underwent both a “Posterior Pole” and “peripapillary RNFL (pRNFL)” scanning protocol using SD-OCT. Functional mapping of the PP was also performed using MP. A customized program was implemented in order to achieve accurate superimposition of MP sensitivity map onto SD-OCT map. The thickness of the PP different retinal layers and pRNFL was obtained and measured for each eye. Mean retinal sensitivity values and fixation stability were obtained and compared between ADOA patients and healthy subjects. Correlation analysis was performed on a point-to-point basis to evaluate the association between mean thickness and retinal sensitivity of each retinal layer. Total retinal thickness (TRT), Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL), Inner Nuclear Layer (INL) and Inner Retinal Layers (IRL) at the posterior pole as well as pRNFL were significantly thinner in ADOA patients (P < 0.0001). On the contrary, the Outer Plexiform Layer (OPL) and the Outer Nuclear Layer (ONL) were significantly thicker in the ADOA group (P < 0.001). No significant differences were found in Retinal Pigment Epithelium (RPE) and Outer Retinal Layers (ORL) thickness between ADOA and controls. The average PP retinal sensitivity was significantly reduced in ADOA patients compared with controls (P < 0.001), as measured by microperimeter Nidek MP-1 (MP1). Fixation stability was significantly worse in the ADOA group (P = 0.01). The most severe sensitivity defects in ADOA patients were found at the level of the papillo-macular bundle (PMB). Conclusions Inner retinal layers showed pathological changes in ADOA patients. In addition, the whole retinal PP (not only the PMB) was significantly altered in ADOA, both in terms of retinal thickness and sensitivity.

Automatic Segmentation of Posterior Pole Retinal Layers In Patients with Early Stage Glaucoma Using Spectral Domain Optical Coherence Tomography

Purpose: To measure Ganglion Cell Layer (GCL) and Retinal Nerve Fiber Layer (RNFL) thickness of the retinal posterior pole in patients with early stage primary open-angle glaucoma (POAG) using the new automatic segmentation technology of spectral domain optical coherence tomograph (SD-OCT). Methods: 37 clinical records of patients with early glaucoma (grade 1 to 2 according to the Glaucoma Staging System 2) and 40 age and sex-matched controls were considered in this case-control observational retrospective study. Automated segmentation of GCL and RNFL was performed in one randomly selected eye from the electronic OCT records of each participant using the new Spectralis SD-OCT segmentation technology (Heidelberg Engineering, Inc., Heidelberg, Germany). Thickness of different retinal layers was obtained from each Posterior Pole volumetric scan. Measurements of the peripapillary RNFL thickness (pRNFLt) were also obtained and then compared with those of posterior pole RNFL thickness (ppRNFLt). Results: Both GCL and RNFL were significantly thinner at the retinal posterior pole in the POAG group as compared to the control group (p<0,0001). Furthermore, pRNFLt was significantly thinner in the glaucoma group as opposed to the control group (p<0,0001). Measurements of pRNFLt were significantly correlated with those of the ppRNFLt (Pearson’s coefficient r=0.863). Conclusions: The new Spectralis SD-OCT automatic segmentation tool may be useful in evaluating structural damage in patients with early glaucoma, by providing complementary measurements to the clinical assessment of glaucoma that could be used in conjunction with other relevant parameters in the diagnosis and the evaluation of the progression of the disease.