Glaucomatous Neuropathy Research Articles

Automated alternation flicker for the detection of optic disc haemorrhages

Optic disc haemorrhages are associated with active glaucomatous neurodegeneration and ongoing visual field loss. We sought to determine whether automated alternation flicker enhances the detection of disc haemorrhages in serial images from patients with glaucoma when compared to side-by-side photographic evaluation and single-image display. Serial sets of optic nerve photographs of 394 eyes from 234 patients followed for glaucoma at the authors' institutions were included in this study. Eyes with disc haemorrhages were graded for difficulty level and randomized along with nondisc haemorrhage control images into one of three presentation groups (automated alternation flicker, side-by-side or single image). Seven graders viewed all images and assessed for the presence or absence of disc haemorrhages. The sensitivity of automated alternation flicker for disc haemorrhage detection (0.878) was higher than side-by-side (0.705; p = 0.002) and single photographs (0.757; p = 0.01). There was no specificity difference between pairs of presentation groups (all p ≥ 0.7). Automated alternation flicker was a more sensitive method for disc haemorrhage detection than the current clinical standards and may have an important role in the management of glaucoma.

HRT III: Its Role in the Diagnosis and Follow-up of Optic Glaucomatous Neuropathy

HRT III: Its Role in the Diagnosis and Follow-up of Optic Glaucomatous Neuropathy

Primary open angle glaucoma and snoring: Prevalence of OSAS

Obstructive sleep apnea syndrome (OSAS) may be suspected at interview, notably in case of snoring. Various studies suggested a link between primary open angle glaucoma (POAG) and OSAS. The present study sought to determine OSAS prevalence in POAG associated with snoring. Thirty-one snoring glaucomatous patients prospectively underwent simplified polysomnography. Ophthalmologic examination ruled out secondary glaucoma and assessed the glaucomatous neuropathy. 49% of the patients included were diagnosed with OSAS. Ophthalmologically, glaucoma showed no specific characteristics. Given the high-prevalence of OSAS in patients with POAG, presence of snoring should be explored at interview. Conversely, patients who snore should be asked whether they have POAG, and if so, should undergo all-night sleep recording to explore for OSAS.

The case for autoimmunity in glaucoma

Although the majority of patients with glaucoma have elevated intraocular pressure as the presumed etiology for their resultant neuropathy, it is well known that approximately 25% of patients with glaucoma have intraocular pressure within the normal range for their race. These patients may have conditions that facilitate non-pressure related stress to the retina and optic nerve that might directly contribute to their glaucomatous neuropathy and include chronic or intermittent ischemia (i.e atherosclerosis, heart disease, vasospasm, migraine, sleep apnea), altered scleral/optic nerve head morphology that predisposes to glaucomatous stress (i.e myopia); genetic mutations that predispose to glaucoma damage at normal IOP (OPA-1,optineurin, myocilin) and evidence of aberrant immunity that suggests that their glaucoma might be a form of an autoimmune neuropathy (i.e. presumed autoimmune glaucoma). This review provides a critical assessment of the potential role for autoimmunity as an initiating or exacerbating etiology in some patients with glaucoma.

Congenital iris ectropion associated with juvenile glaucoma

Congenital iris ectropion is an uncommon malformation of the anterior segment of the eye. The authors describe a case of bilateral congenital iris ectropion associated with juvenile glaucoma in an otherwise healthy 9-year-old girl. Intra-ocular pressure (IOP) measured by Goldmann applanation tonometry was 40 mmHg in the right eye and 32 mmHg in the left eye. Despite maximum IOP lowering therapy, the desired IOP levels needed to prevent further progression of the glaucoma could not be achieved. Visual field testing and confocal scanning laser tomography showed glaucomatous neuropathy. Trabeculectomy with antimetabolites (mitomycin C 0.2 mg/ml) was performed in both eyes and IOP was normalized without IOP lowering medications during a follow-up of 4 years. The authors point out the importance of recognizing congenital iris ectropion early to prevent blindness in young patients and improve their prognosis.

Serum Cytokine Alteration is Associated With Optic Neuropathy in Human Primary Open Angle Glaucoma

The purpose of this study is to compare human serum levels of TH1 and TH2 cytokines between 2 stages of primary open-angle glaucoma (POAG) and nonglaucomatous controls. Thirty-two patients with primary POAG and 26 normal control subjects were enrolled into this study. The 32 patients with POAG were divided into 2 subgroups according to their mean defect (MD) with MD better than -12 dB and worse than -12 dB on the visual field. Enzyme-linked immunosorbent assay was used to assay for the levels of TH1 cytokines serum soluble interleukin-2 receptor (sIL-2R), interleukin (IL)-2, IL-12p40, IL-12p70, IL-23, tumor necrosis factor (TNF)-alpha, interferon-gamma, and TH2 cytokines IL-4, IL-6 in the peripheral serum. Patients with mild glaucomatous neuropathy exhibited significant elevations in IL-4 (P<0.0001) and IL-6 (P=0.0302) compared with the controls, whereas higher concentrations of IL-4 (P<0.0001) and IL-6 (P=0.0084) were found in patients with severe glaucomatous neuropathy. The level of IL-12p70 was significantly increased in both the MD >/=12 dB (P<0.0001) and MD <12 dB (P<0.0001) groups. A significant decrease in TNF-alpha levels were observed in MD <12 dB group compared with the controls (P=0.0464), and TNF-alpha levels in MD <12 dB group were lower than MD >/=12 dB group (P=0.0328). No significant differences in serum concentrations of IL-2, sIL-2R IL-12p40, IL-23 and interferon-gamma were found between MD <12 dB group, MD >or=12 dB group, and control group. Significant alterations of serum TH1 and TH2 cytokines are associated with glaucoma, suggesting the possibility that abnormal immune environments contribute to the glaucomatous neuropathy of POAG.

Targeted preventive measures and advanced approaches in personalised treatment of glaucoma neuropathy

Glaucoma is a major cause of vision loss worldwide with nearly 8 million people bilaterally blind from the disease. This number is estimated to increase over the next 10 years. The key to preventing blindness from glaucoma is effective diagnosis and treatment. The classical glaucoma treatment focuses on intraocular pressure (IOP) reduction. Better knowledge of the pathogenesis has opened up additional therapeutical approaches often called non-IOP lowering treatment. Whilst most of these new avenues of treatment are still in the experimental phase, others are already used by some physicians. These new therapeutic approaches allow a more personalised patient treatment. Non-IOP lowering treatment includes improvements of ocular blood flow, particularly blood flow regulation. This can be achieved by improving the regulation of ocular blood flow (improving autoregulation) by drugs such as carbonic anhydrase inhibitors, magnesium or calcium channel blockers. It can also be improved by decreasing blood pressure over-dips. Blood pressure can be increased by an increase in salt intake or in rare cases by treatment with fludrocortisone. Experimentally, glaucomatous optic neuropathy can be prevented by inhibition of astrocyte activation, either by blockage of epidermal growth factor receptor or by counteracting Endothelin. Glaucomatous optic neuropathy can also be prevented by nitric oxide-2 synthase inhibition. Suppression of matrix metalloproteinase-9 inhibits apoptosis of retinal ganglion cells and tissue remodelling. Upregulation of heat shock proteins protects the retinal ganglion cells and the optic nerve head. Reduction of oxidative stress especially at the level of mitochondria also seems to be protective. This can be achieved by gingko, dark chocolate, polyphenolic flavonoids occurring in tea, coffee or red wine and anthocyanosides found in bilberries as well as by ubiquinone and melatonin. This review describes the individual mechanisms which may be targeted by non-IOP lowering treatment based on our pathogenic scheme.

Usefulness of Frequency-Doubling Technology for Perimetrically Normal Eyes of Open-Angle Glaucoma Patients with Unilateral Field Loss

To determine whether frequency-doubling technology (FDT) perimetry detects visual field loss in perimetrically normal eyes of patients with open-angle glaucoma (OAG) and whether these visual field defects subsequently are detected by standard automated perimetry (SAP), and to explore the relating factors of the progression from abnormalities based on FDT to visual field loss based on SAP. Prospective cohort study. Sixty-eight OAG patients with unilateral field loss detected by SAP (Octopus, G2 program; Interzeig, Schlieren, Switzerland). Perimetrically normal eyes of participants were examined with the FDT N-30 threshold program (Humphrey Instruments, Welch-Allyn, Skaneateles, NY). The visual field examination was followed by a series of SAP examinations administered over 3 years. The relationship between FDT and subsequent SAP results in perimetrically normal eyes was analyzed. Glaucomatous optic neuropathy (GON), visual field indices, intraocular pressure (IOP), and central corneal thickness (CCT) were compared between converters (eyes with subsequent SAP abnormality) and nonconverters within perimetrically normal eyes with abnormal FDT results. Finally, the SAP test points were matched to the abnormal FDT sectors. The relative risk (RR) of subsequent SAP abnormality corresponding to FDT abnormal sectors was calculated. Sixty perimetrically normal eyes of 60 participants had complete data and a qualifying follow-up. Baseline FDT results were abnormal in 65%. Of the eyes with abnormal FDT results, 51% developed abnormal SAP results after 4 to 27 months, whereas none of the eyes with normal FDT results developed abnormal SAP results (P<0.05). In perimetrically normal eyes with abnormal FDT results, converters had a greater cup-to-disc ratio, more eyes with GON, larger and deeper cups, and worse FDT mean deviation than nonconverters (P<0.05). The IOP and CCT did not differ between the 2 groups. The RR of subsequent SAP abnormality corresponding to abnormal FDT sectors was 5.38 (95% confidence interval, 3.61-8.04; P<0.05). In perimetrically normal eyes of OAG patients, FDT detected visual field loss in almost 2 of every 3 of these eyes and also predicted to some extent future visual field loss on SAP. Severity of glaucomatous neuropathy at baseline was related to conversion of abnormalities on FDT to visual field loss on SAP.

Melatonin: a novel neuroprotectant for the treatment of glaucoma

Glaucoma is a leading cause of blindness. Although ocular hypertension is the most important risk factor, several concomitant factors such as elevation of glutamate and decrease in gamma-aminobutyric acid (GABA) levels, disorganized NO metabolism, and oxidative damage could significantly contribute to the neurodegeneration. The aim of this report was to analyze the effect of melatonin on retinal glutamate clearance, GABA concentrations, NO synthesis, and retinal redox status, as well as on functional and histological alterations provoked by chronic ocular hypertension induced by intracameral injections of hyaluronic acid (HA) in the rat eye. In normal retinas, melatonin increased glutamate uptake, glutamine synthase activity, GABA turnover rate, glutamic acid decarboxylase activity, superoxide dismutase activity, and reduced glutathione (GSH) levels, whereas it decreased NOS activity, L-arginine uptake, and lipid peroxidation. To assess the effect of melatonin on glaucomatous neuropathy, weekly injections of HA were performed in the eye anterior chamber. A pellet of melatonin was implanted subcutaneously 24 hr before the first injection or after six weekly injections of HA. Melatonin, which did not affect intraocular pressure (IOP), prevented and reversed the effect of ocular hypertension on retinal function (assessed by electroretinography) and diminished the vulnerability of retinal ganglion cells to the deleterious effects of ocular hypertension. These results indicate that melatonin could be a promissory resource in the management of glaucoma.

Functional MRI Signal Changes in Primary Visual Cortex Corresponding to the Central Normal Visual Field of Patients with Primary Open-Angle Glaucoma

To investigate, by functional magnetic resonance imaging (fMRI), the impact of glaucomatous neuropathy of primary open-angle glaucoma (POAG) on neuronal activity in the primary visual cortex, which corresponds to the central normal visual field. Six POAG patients with asymmetric visual field damage and spared central vision were enrolled in the study. All patients underwent detailed ophthalmic examinations, including visual acuity, intraocular pressure, refraction, gonioscopy, and fundus examination. Scanning laser polarimetry with variable corneal compensation, confocal scanning laser ophthalmoscopy, posterior segment optical coherence tomography (OCT), and SITA-standard 30-2 and 10-2 visual field perimetry were also performed on each patient. Block-design fMRI was then performed. The stimulus was a hemifield checkerboard contrast, reversing at 8 Hz and viewed by the examined eye monocularly during fMRI scanning, with the fellow eye occluded. The blood oxygen level-dependent (BOLD) fMRI signal change in the primary visual cortex corresponding to central visual input from the more severely affected eye was less than that of the fellow eye. Such a difference in fMRI response did not correlate with interocular differences in measurements of scanning laser polarimetry, OCT, and scanning laser ophthalmoscopy, but showed a negative correlation with interocular pattern SD (PSD) difference of visual field analysis. Glaucomatous neuropathy from POAG may lead to decreased cortical activity in the primary visual cortex, which corresponds to the central normal visual field. The resultant cortical depression is not related to interocular differences in results of polarimetry, OCT, and ophthalmoscopy, but is negatively correlated with PSD of visual field analysis.

Que faire si la mesure de la pression intraoculaire semble peu fiable ?

Among the various intraocular pressure (IOP) measurement methods available today, Goldmann applanation tonometry (GAT) remains the gold standard for in-office routine IOP measurement. However, numerous factors may affect IOP measurement with GAT, namely corneal features. Before any interpretation of an IOP value, the measurement conditions should be checked and the central corneal thickness evaluated, since GAT overestimates IOP in thick corneas and underestimates IOP in thin ones. When GAT is not applicable, other IOP measurement devices, which have their own limits, are available. For example, the ocular response analyzer (ORA) and dynamic contour tonometry (DCT) provide IOP readings that are less influenced by corneal properties and may be useful after refractive surgery. Regardless of the choice of tonometer, the IOP value must not be considered alone but from a clinical point of view, including, namely, multiple IOP measurements over a day since the IOP fluctuates over a 24-h time period. A complete clinical examination is necessary in each case to search for glaucomatous neuropathy.

Is neuroglobin (Ngb) a perspective for glaucoma?

Abstract Purpose To further explore the mechanisms of Ngb function in the retina, and investigate the possible neuroprotective potency of this O2‐binding protein in glaucoma. Our project will potentially open exciting perspectives for the treatment and prognosis of the blinding condition of glaucoma. Methods 1) In vitro: We will set up cultures for primary RGCs. The cultured RGCs will be subjected to hypoxia by incubation in a controlled‐atmosphere incubator. Cell survival and apoptosis will be assessed using MTT method and TUNEL staining. Ngb expression in normoxic and hypoxic cells will be compared. Additionally, the RGCs will be transfected with plasmids expressing Ngb mRNA to evaluate the neuroprotective effect of Ngb. 2) In vivo: The ischemia/reperfusion model and the staurosporine intravitreal injection model cause acute RGC loss. We will also use a laser model to induce chronic elevated IOP by obstructing the aqueous outflow pathway. We will first analyze upregulated Ngb expression in these models. The localization of both Ngb mRNA and protein will be assessed. Ngb‐Tg mice will be subjected to the glaucoma models. We will measure cell density or retinal thickness and perform electroretinography to evaluate the physiological function of retina. We will also analyse the possible contribution of oxidative stress via immunostainings for ROS and determine possible effects on NO scavenging by evaluating the expression of NOS. Furthermore, we will transfect RGCs in vivo using intravitreal injections of a Ngb expressing adeno‐associated virus (AAV) to test the therapeutic potential of Ngb. Conclusion Our project will not only provide us with an improved understanding of neuroglobin, but also open a new perspective for the treatment of retinal ganglion cell apoptosis and glaucomatous neuropathy.

Disease mechanisms leading to impaired blood flow in glaucoma

Abstract Purpose SIS lecture Methods Literature search Results Although primary open‐angle glaucoma (POAG), is associated more closely with elevated intraocular pressure (IOP), other risk factors already implicated in the aetiology of this disease and especially in the aetiology of normal‐tension glaucoma are: abnormal ocular circulation, ocular and systemic vascular dysregulation, as well as systemic blood pressure (BP) alterations. Oxidative stress, which occurs as a result of an imbalance between generation of reactive oxygen species (ROS) and antioxidant defence mechanisms and is implicated in the pathogenesis of disorders ranging from atherosclerosis to neurodegenerative disorders, diabetes and aging, may also contribute to the general vascular disturbances observed in glaucoma. Moreover, increasing evidence shoes that oxidative stress plays a role in promoting endothelial dysfunction, which is a key factor in progression of vascular diseases. Indeed, glaucomatous optic nerve damage has been related to endothelial damage/dysfunction. This presentation explores the role of various ocular and systemic circulatory factors in the pathogenesis of glaucomatous neuropathy.

Progress of chronic ocular hypertensive glaucoma in rodents

Glaucoma is characterized by progressive loss of retinal ganglion cell (RGCs), optic nerve atrophy, cupping of the optic disc, and specific visual field deficits. Elevated intraocular pressure (IOP) is considered to be a major risk factor associated with the development of this neuropathy, therefore, elevated IOP has been induced in animals to simulate key aspects of human glaucoma, in order to unlock the mechanism of this disease and seek out new therapeutic strategies. In the following review: (1) models used for the study of hypertensive glaucomatous neuropathy in rodents, (2) assessment of these animal models and (3) their usage will be described.

APPLICATION OF HYPERBARIC OXYGENATION IN GLAUCOMA OPTIC NEUROPATHY THERAPY

We assed the Hyperbaric Oxygenation neuroprotection effect of treatment in patient with primary open-angle glaucoma. Аge range (45-75 years) patients with primary open-angle glaucoma with normal intraocular pressure were treated with Hyperbaric Oxygenation as monotherapy. Complete ophthalmologic examination, including visual acuity, tonometry, electronic tonography, kinetic perimetry, campimetry, analysis of blood flow was performed. As a results of dynamic functional inspection of patient with primary open-angle glaucoma with normal intraocular pressure marks improvement of basic parameters reflecting a ganglion cells condition that testifies to good efficiency of a Hyperbaric Oxygenation in neuroprotection therapy glaucoma neuropathy. Hyperbaric Oxygenation can be recommended for out - patient treatment.

Congenital Iris Ectropion Associated With Juvenile Glaucoma

Congenital iris ectropion is an uncommon malformation and no reports exist about the use of modern technologies in this pathology. The authors describe a case of unilateral and isolated congenital iris ectropion associated with juvenile glaucoma in a healthy and completely asymptomatic 6-year-old girl with an unusual form of anisocoria. Optical coherence tomography and confocal scanning laser tomography showed a progressive glaucomatous neuropathy. A trabeculectomy without antimetabolites was performed and intraocular pressure normalized without other medications during a follow-up of 2 years. The authors assert the utility of various diagnostic technologies to recognize congenital iris ectropion early to prevent blindness in young patients and improve their prognosis.

Gene expression and functional studies of the optic nerve head astrocyte transcriptome from normal African Americans and Caucasian Americans donors.

PurposeTo determine whether optic nerve head (ONH) astrocytes, a key cellular component of glaucomatous neuropathy, exhibit differential gene expression in primary cultures of astrocytes from normal African American (AA) donors compared to astrocytes from normal Caucasian American (CA) donors.MethodsWe used oligonucleotide Affymetrix microarray (HG U133A & HG U133A 2.0 chips) to compare gene expression levels in cultured ONH astrocytes from twelve CA and twelve AA normal age matched donor eyes. Chips were normalized with Robust Microarray Analysis (RMA) in R using Bioconductor. Significant differential gene expression levels were detected using mixed effects modeling and Statistical Analysis of Microarray (SAM). Functional analysis and Gene Ontology were used to classify differentially expressed genes. Differential gene expression was validated by quantitative real time RT-PCR. Protein levels were detected by Western blots and ELISA. Cell adhesion and migration assays tested physiological responses. Glutathione (GSH) assay detected levels of intracellular GSH.ResultsMultiple analyses selected 87 genes differentially expressed between normal AA and CA (P<0.01). The most relevant genes expressed in AA were categorized by function, including: signal transduction, response to stress, ECM genes, migration and cell adhesion.ConclusionsThese data show that normal astrocytes from AA and CA normal donors display distinct expression profiles that impact astrocyte functions in the ONH. Our data suggests that differences in gene expression in ONH astrocytes may be specific to the development and/or progression of glaucoma in AA.

Premise and Prediction???How Optic Nerve Head Biomechanics Underlies the Susceptibility and Clinical Behavior of the Aged Optic Nerve Head

We propose that age-related alterations in optic nerve head (ONH) biomechanics underlie the clinical behavior and increased susceptibility of the aged ONH to glaucomatous damage. The literature which suggests that the aged ONH is more susceptible to glaucomatous damage at all levels of intraocular pressure is reviewed. The relevant biomechanics of the aged ONH are discussed and a biomechanical explanation for why, on average, the stiffened peripapillary scleral and lamina cribrosa connective tissues of the aged eye should lead to a shallow (senile sclerotic) form of cupping is proposed. A logic for why age-related axon loss and the optic neuropathy of glaucoma in the aged eye may overlap is discussed. Finally, we argue for a need to characterize all forms of clinical cupping into prelaminar and laminar components so as to add precision to the discussion of clinical cupping which does not currently exist. Such characterization may lead to the early detection of ONH axonal and connective tissue pathology in ocular hypertension and eventually aid in the assessment of etiology in all forms of optic neuropathy including those that may be purely age-related.

A Great Ocean of Truth Lay Undiscovered

A Great Ocean of Truth Lay Undiscovered

Charles F. Prentice Award Lecture 2006: A Neuron Doctrine for Glaucoma

The glaucomas are a group of potentially blinding optic neuropathies that are characterized by progressive pathological losses of the retinal ganglion cells (RGCs) and their axons that form the optic nerve. The causes are unknown and, therefore, the diagnosis and assessment of progression of disease depends on ophthalmic testing to identify and quantify clinical characteristics of glaucomatous neuropathy, such as the pattern of visual field defects and/or thinning of the retinal nerve fiber layer. To relate these clinical measurements to the basic pathology of glaucoma, a neuron doctrine for glaucoma has been proposed to correlate data from standard tests (standard automated perimetry and optical coherence tomography) to the loss of RGCs. The doctrine was derived through initial laboratory studies of experimental glaucoma in macaque monkeys and, then, modified and refined though patient-based clinical investigations. The final formulation of the doctrine produced concordance between subjective and objective measurements when the results were translated to their common parameter of RGCs, for both normal vision and defective vision from glaucoma. Thus, it was concluded that for individual patients, alterations in structure-function relationships usually should be in agreement for the degree and location of visual field defects caused by glaucoma.