Is primary open‐angle glaucoma part of a generalized sensory neurodegeneration? A review of the evidence

Open‐angle glaucoma is an optic neuropathy that has a multifarious aetiological profile. Emerging theories suggest that a group of factors induce optic nerve injury in innately susceptible aging optic nerves. These factors have the potential to impact on the function of other vulnerable neurons within the central nervous system of older patients. Although changes within the visual pathways due to retinal ganglion cell dysfunction and death are well established, research exploring the behaviour of other sensory systems in individuals with glaucoma is limited. This review summarizes what is known about these other non‐visual sensory changes, explores whether glaucoma is in fact part of a global neurodegenerative condition, and suggests areas for future research direction.     

Is the corneal degradation in keratoconus caused by matrix‐metalloproteinases?

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP‐2 and MMP‐9. Matrix metalloproteinase‐2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP‐9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, α‐1‐proteinase inhibitor and α‐2‐macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP‐1) and gelatinases (MMP‐2 and MMP‐9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane‐bound MT1‐MMP (MMP‐14), which activates latent MMP‐2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP‐3 and MMP‐10, were not.     

Is the nasal optic disc sector important for morphometric glaucoma diagnosis?

BACKGROUND/AIM: Since the central retinal vessel trunk usually located in the nasal optic disc sector can render difficult the delineation of the neuroretinal rim and optic disc, the aim of this study was to evaluate whether the nasal region of the optic nerve head is important, or can be left out, for the morphometric glaucoma diagnosis. METHODS: The clinical observational study included 1337 patients with primary or secondary open angle glaucoma and 649 normal subjects. The glaucoma group was divided into 1187 patients with glaucomatous visual field defects ("perimetric glaucoma"), and into 150 patients with optic nerve head changes and normal visual fields ("preperimetric glaucoma"). Colour stereo optic disc photographs were morphometrically evaluated. RESULTS: Highest diagnostic power for the separation between the normal group and the perimetric glaucoma group, and for the differentiation between the normal group and the preperimetric glaucoma group, had the sum of inferotemporal rim area plus superotemporal rim area, the sum of inferotemporal rim area plus superotemporal rim area plus temporal rim area, and the inferotemporal rim area as single parameter. The lowest diagnostic precision had the nasal rim area as single parameter or in combination with rim measurements in other disc sectors. CONCLUSION: Excluding the nasal optic disc sector does not markedly decrease the diagnostic power of morphometric optic disc analysis in glaucoma diagnosis. It may have importance for an automated computerised morphometric detection of glaucomatous optic nerve damage.     

Is silicone oil optic neuropathy caused by high intraocular pressure alone? A semi-biological model

BACKGROUND: Silicone oil endotamponade is used for the repair of complicated retinal detachments. Cataract, glaucoma and corneal endothelial dysfunction are the most frequent complications of silicone oil tamponade. Clinical and histopathological studies have revealed that silicone oil can penetrate into the optic nerve and into the brain. The mechanism by which silicone oil moves from intraocular into the optic nerve is still under debate. To investigate the effect of intraocular pressure only, a post-mortem experimental histological study was performed to determine whether silicone oil penetration from the globe into the optic nerve after vitrectomy and silicone oil instillation is a purely pressure-related phenomenon. Although a post-mortem study excludes physiological processes, it serves as a model for the study of pure physical forces onto biological structures. METHODS: The study was carried out on 20 human eyes with their optic nerves attached. All specimens had been harvested from patients without known eye disease. The vitreous body was removed with a syringe and the globe was filled with silicone oil. A lipophil fluorescence marker (Bodipy) was added in 8 eyes. The mean intraocular pressure after silicone oil filling measured 40 mm Hg and the globes stayed under pressure for up to 16 weeks. The eyes and optic nerves were stained with H&E and examined with light, phase-contrast and fluorescence microscopy. RESULTS: None of the 20 specimens examined showed silicone oil in the retrolaminar portion of the optic nerve. CONCLUSIONS: Migration of silicone oil into the optic nerve was not demonstrated in this human post-mortem study. Therefore other factors, such as pre-existing glaucomatous damage to the disc region and/or active transport mechanisms must be involved in the development of silicone oil-associated optic neuropathy.     

Imaging of the optic disc in glaucoma: which way to go?

Less than 10 years ago, fundus photography was believed to be the only method to document optic disc changes in glaucoma. Since then, many sophisticated electronic devices have been developed to supersede conventional photography. At the moment, confocal laser scanning tomography, nerve fiber layer polarimetry, and optical coherence tomography are the most popular techniques. The current status of optic disc imaging in glaucoma can (in our very subjective opinion) be summarized as follows. Confocal laser scanning tomography is the most comprehensively tested electronic modality. It is perhaps the method of choice in major glaucoma centers. Nerve fiber layer polarimetry has forged ahead during the past 2 years and may become an alternative to confocal laser scanning tomography in the future. Optical coherence tomography is a fascinating technique, which may also become important in the future. Right now, however, it is still in the experimental stage. Conventional disc photography--despite all those new techniques--still has its place. Perhaps it is the method of choice in routine glaucoma practice, except those clinics that can afford one of the "high tech" machines.     

Is poor life expectancy a predictive factor in the progression of primary open angle glaucoma?

AIM: To investigate the disease progression and final visual outcome of glaucoma patients with poor life expectancy, compared to matched patients with a longer life expectancy. METHOD: Visual fields at diagnosis and at the last ophthalmic appointment before death were analysed for glaucoma patients referred between 1991 and 1995, and deceased before the end of 2001. These patients were matched to the patients living beyond 2001. Functional vision was also assessed, and classified as better than the NHS partial sighted criteria. RESULTS: A total of 61 deceased patients were identified, resulting in 40 matched pairs. In all, 6.5% of the patients with poor life expectancy progressed from functional vision to beyond partial sighted criteria, and none of the matched patients progressed to this extent. At final assessment an association between poor life expectancy and progression beyond functional vision was found existing (P = 0.02), with a lesser association at diagnosis (P = 0.06). Visual field scores of the matched pairs who had test results available for both initial and final assessment (n = 23 pairs) showed no statistically significant difference between the two groups at diagnosis (P = 0.52); However, a significant difference at final the assessment did exist (P = 0.042). No difference between the initial (off medication) intraocular pressures (IOPs) was found (P = 0.82). At the final assessment a significant difference existed (P = 0.025), with the surviving group having a higher final mean pressure (15.9 mmHg, SD 2.8, vs 18.3 mmHg, SD 4.9). CONCLUSION: Patients with poor life expectancy progressed more than the matched surviving patients, when measured from an initially similar position, despite better IOP control.     

Myocilin and glaucoma: A TIGR by the tail?

In 1997, Stone and 14 colleagues from 7 laboratories reported the identification of a gene (TIGR) associated with juvenile open-angle glaucoma (JOAG). Screening of adults with primary open-angle glaucoma (POAG) revealed that about 4% also carried a mutation of the coding region of this gene. The mutations were found through genetic linkage analysis of families with JOAG. Juvenile open-angle glaucoma was a logical starting point in the search for genetic causes of open-angle glaucoma: it shows a strong autosomal-dominant inheritance pattern, occurs at an early age, demonstrates obvious phenotypic signs (dramatic elevation of intraocular pressure and subsequent optic nerve damage), and is likely to be found in multiple generations as parents of affected children are still living. These factors, however, also serve to distinguish it from adult-onset POAG, which generally has a lower intraocular pressure and a less severe course. The discovery of the actual gene represented a true advance over previous studies that had mapped the gene to a segment of a chromosome but did not identify the specific gene. How the mutant gene causes glaucoma is unknown and is the subject of intense research. To date, 26 mutations in the TIGR gene sequence (the term TIGR has been replaced by the term myocilin, abbreviated MYOC) have been described, all associated with either JOAG or adult-onset POAG. A correlation between specific mutations in MYOC and the clinical course of glaucoma has been found. Not all cases of JOAG or POAG have mutations in the MYOC gene, however, indicating that more discoveries of other genes are yet to come. Arch Ophthalmol. 2000;118:974-978