Glaucomatous VFDs follow 4 major patterns: an isolated scotoma, an arcuate scotoma, nasal step (if there are both superior and inferior arcuate defects), and generalized depression (60). VFDs of NGC are more often central. Progressive glaucomatous field loss will be reflected in the changes seen at the ONH and RNFL measurements. The anatomical correlation between visual fields, RNFL trajectory, and position on the optic disc has been well described (61–63). Several groups have mapped OCT optic disc sectors with VFDs on standard automated perimetry (SAP) (64,65). There is a simple linear relationship between RNFL in superior and inferior disc sectors and corresponding arcuate SAP function (decibel units) in GON, as there is in AION (61).
Glaucoma patients are almost always tested on SAP 24-2 protocols, with central test points spaced 6° apart, thereby underestimating any macular arcuate changes. In patients with normal-tension glaucoma, VFDs often are more localized, closer to fixation, and in the superior hemifield (inferior macula) (66). The optic disc region, the most vulnerable to glaucoma damage, is the border between the temporal and inferior quadrants (67), producing macular field defects that are typically described as an arcuate “comma” or a “pistol barrel scotoma” (67,68).
The least vulnerable macular region to GON is the papillomacular bundle between the nasal fovea and the temporal optic disc (69). In contrast, the papillomacular bundle is particularly susceptible in other optic neuropathies, although the explanation for this vulnerability is unknown. Therefore, the involvement of the “central isle” of the visual field on Amsler, 10-2 SAP, or kinetic perimetry should raise the suspicion of a neurological process.
VFDs that respect the vertical meridian should be considered neurological until proven otherwise. Bitemporal visual field changes place the pathology at the optic chiasm. Homonymous defects (complete, incomplete, incongruous, and sectoral defects) are all seen with retrochiasmal pathology. An algorithm has been proposed to discriminate vertical neurological visual field abnormalities from horizontal glaucoma defects (70). However, SAP protocols can give the false appearance of VFDs respecting a vertical (or horizontal) meridian because of the sparsity of the points tested. Common mimics are temporal wedge defects extending from the blind spot as seen in optic nerve hypoplasia and acute zonal occult outer retinopathy. Kinetic visual fields are essential to more accurately assess the relationship to the horizontal and vertical meridians and to show the peripheral extent of a scotoma. SAP protocols for central fields have an extension nasally to facilitate the identification of a nasal step, but coverage temporal to the blind spot is minimal.
The confocal scanning laser ophthalmoscope (Heidelberg Retinal Tomograph [HRT]; Heidelberg Engineering, Heidelberg, Germany) provides quantitative measures of optic disc topography with reconstruction of a 3-dimensional image of the optic disc. OCT provides cross-sectional measures of RNFL thickness with the use of interferometry, using time-domain (TD-OCT) or spectral-domain (SD-OCT) methodology. Scanning laser polarimetry technology (GDx; Carl Zeiss Meditec, Dublin, CA) also provides a quantitative measure of the RNFL thickness. Using these instruments, there is a substantial overlap in structural measurements of the normal optic disc and the optic disc in GON and in NGC. This limits their diagnostic capability.
Enhanced depth imaging OCT can been used to evaluate the types of PPA to help differentiate GON and NGC. The beta-zone atrophy, located next to the optic disc, is associated with GON (74). However, gamma-zone atrophy, defined as the region between the temporal disc margin to the beginning of Bruch's membrane, was not associated with GON and more likely a sign of NGC.
Using HRT, glaucoma patients have been shown to have less disc rim tissue, a greater cup volume, and a deeper optic cup than AION (arteritic and nonarteritic) (15). However, only in glaucoma were the laminar connective tissues damaged, resulting in retroplacement of the cup. These findings were confirmed on OCT (78) with glaucoma patients having greater RNFL thinning overall. However, in the affected hemifields, RNFL thickness was not significantly different.
Ninety percent of a group of ADOA patients had a statistically significant reduction in temporal RNFL thickness (82). Other studies showed a reduction in all quadrants with preferential involvement of temporal and inferior sectors (76) and relative sparing of the nasal region (83). Patients with a severe disease OPA1 variant mutation, having additional symptoms such as deafness, ataxia, and myopathy, had more pronounced RNFL thinning. Other causes of NGC also have a predilection for temporal RNFL loss, including ethambutol (84,85), syphilis (86), and toxic optic neuropathies (87). Eyes affected by demyelinating optic neuritis also have a reduction in RNFL thickness predominantly in the temporal quadrant involving the papillomacular bundle (88). These changes become evident 3–6 months after the acute episode (89). In neuromyelitis optica, the superior and inferior quadrants typically are more severely affected (90).
Caution is needed when diagnosing GON on OCT in patients following cerebral infarction or other damage to the postchiasmal visual pathways. This causes RNFL thinning in a “band” pattern in the eye with the temporal hemianopia and thinning of the superior and inferior arcuate bundles in the eye with the nasal hemianopia (91). The degree of change depends on the time since stroke, location of the damage (e.g., optic tract involvement will give greater loss), and the extent of the VFD (92).
Since a large portion of macular thickness is composed of RGCs and the inner plexiform layer, the macula also loses volume as glaucomatous damage progresses. Previous studies concluded that macular segmentation to measure these layers was less accurate than RNFL thickness measured by TD-OCT (93,94). However, with newer algorithms (67), macular analysis may become more important in diagnostic decisions.
Using frequency-domain OCT to examine the macular RGC layer plus the inner plexiform layer (RGC+), GON can be differentiated from nonglaucomatous changes (67). In GON, there is arcuate thinning of the inferior retina associated with a narrow region of RNFL thinning at the border of temporal and inferior disc quadrants. Normal tension glaucoma (NTG) patients are the more likely to be referred to neuro-ophthalmology with central VFDs than those with elevated IOP, making these macular scans invaluable (95). In patients with A-AION who have outer retinal ischemia secondary to occlusion of posterior ciliary arteries, there is disruption of the inner-outer photoreceptor segment line on SD-OCT (96).
Although multifocal visual evoked potential (mfVEP) testing has been described for many years (97,98), it is not commonly used in clinical practice. Caprioli et al (95) described the use of mfVEP to demonstrate objective VFDs in patients with disc changes but no abnormalities on SAP. In addition, the mfVEP was able to confirm central arcuate scotoma in normotensive glaucoma patients in 44% of eyes with normal SAP. This finding is because of the mfVEP protocols having greater representation of the central field than the 24-2 SAP.
The mfVEP can give additional information about visual pathways, with latency analysis showing abnormalities in compressive and inflammatory optic neuropathies (99,100). In comparison, relatively few glaucomatous eyes have latency delays (101). The domination of the “full-field” visual evoked potential by the macula severely limits its use in the diagnosis of glaucoma.
Magnetic resonance imaging (MRI) studies have shown morphological changes in the visual pathways of glaucoma patients, including loss of chiasmal height and reduced optic nerve cross-sectional area, which correlate with OCT RNFL thickness and VFDs (102–104). However, MRI optic nerve changes are seen with increasing age and are not specific for glaucoma (104). Glaucoma-related changes are seen in the lateral geniculate nucleus, visual cortex, and optic radiations (105,106). By analyzing the diffusion tensor imaging (DTI) features of the optic radiation, distinction between primary open angle glaucoma, NTG and controls, can be made with >90% accuracy (107). Optic nerve DTI measures correlate with changes in RNFL on HRT and glaucoma staging (108). However, reduced optic nerve volume and anisotropy on DTI also have been reported in patients with optic neuritis (109) and LHON (110). Whether MRI is more suitable diagnostically than OCT or SAP in some patients and whether these techniques can distinguish between different causes of ONH cupping remain to be seen. In NTG, diffuse cerebral ischemic changes are detectable on MRI, indicating that GON may be a manifestation of more widespread cerebrovascular disease (111,112).
Using standard MRI protocols, the optic nerve usually has a normal appearance in the acute phase of ischemic optic neuropathy. However, there are increasing reports of the detection of optic nerve ischemia with diffusion-weighted imaging (113). In comparison to optic neuritis, only 16% of NA-AION had abnormal MRIs, with increased short T1 inversion recovery or T2 signal and nerve enhancement (114). The acute T2 changes with increased intensity within the optic nerve are the result of the breakdown of the blood-brain barrier in optic neuritis. The chronic T2 hyperintensity in the affected portion of the anterior visual pathway occurs in all forms of optic neuropathy with Walleran degeneration (optic neuritis, LHON, and AION) (115). These T2 changes have not been reported in GON, which may be because the axonal loss in GON is gradual and incremental. In ADOA, there is significant thinning of the optic nerves on MRI (116). However, even in ADOA patients with extraocular neurological features, no evidence of demyelination or structural abnormalities has been documented on MRI (117). In contrast, white matter changes with a multiple-sclerosis-like phenotype are seen in some cases of LHON (118,119).
Anatomical and experimental research regarding the basis of optic disc cupping is primarily found in the glaucoma literature. These theories involve a pathophysiological mechanism at the level of the lamina cribrosa.
The biomechanical paradigm of glaucomatous ONH damage provides an explanation as to how the pressure-related stress of increased IOP and the local deforming strain within the load-bearing tissues of ONH influence the physiology of all tissues within the ONH. This theory assumes that the ONH astrocytes and glia support both the lamina cribrosa extracellular matrix and RGC axons (4).
How the ONH connective tissues respond to biomechanical stress is determined by posterior scleral compliance and rigidity (120). However, it is difficult to separate the mechanical forces leading to laminar deformation from other ONH effects caused by IOP-related stress (4). Differences in collagen genes alter the mechanical behavior of the sclera, reducing the RGC loss following chronic IOP elevation experimentally (121). However, regional differences in peripapillary fiber anisotropy seen between nonglaucoma and glaucoma eyes may represent either adaptive change in response to elevated IOP or baseline structural properties associated with predisposition to GON (122).
The intraocular to intracranial pressure (ICP) gradient may cause changes in ONH structure and function (127). Cerebrospinal fluid (CSF) surrounds the optic nerve to the level of the lamina cribrosa, thereby directly influencing the translaminar pressure difference and laminar position. The average posterior force from IOP on the lamina is 1 mm Hg per 100 μm (assuming a mean IOP of 16 mm Hg, mean ICP of 12 mm Hg, and a lamina cribrosa thickness of 450 μm) (128). As the lamina becomes increasingly weakened and thinned with glaucoma, this posterior force is spread across a smaller tissue volume, and this may explain why continued optic nerve damage occurs even with IOP at “normal” levels (129).
RGCs are particularly sensitive to mitochondrial dysfunction, which is recognized as the underlying cause of optic neuropathy in LHON and ADOA (134). LHON is caused by mitochondrial DNA mutations (135), and increasingly, mitochondrial changes are thought to contribute primary open angle glaucoma pathogenesis. This could explain the morphological similarities in the optic discs of LHON and GON (2).
An increase in free radical production is an early event related to increased IOP in experimental models of glaucoma (141,142). Generation of reactive oxygen species appears to be a NADPH related event that can be modulated to reduce cell death in experimental models of glaucoma (143,144).
Further analysis of mitochondrial dysfunction in glaucoma patients compared to controls has confirmed a specific reduction in ATP synthesis from mitochondrial oxidative phosphorylation (145). The RGCs are particularly vulnerable to stressors (i.e., elevated IOP) because of the very high bioenergetic demand created propagating action potentials and driving axoplasmic flow within unmyelinated axons found in the retina.
Superoxide generation is associated with axonal injury in other experimental models of optic neuropathy and can likewise be modulated (146–148). Recent attempts at neuroprotective therapies for glaucoma have, at least in part, focused on altering mitochondrial oxidative phosphorylation with some success in vitro (142,149).
In evaluating a patient with optic disc cupping, neuro-ophthalmic pathology should be considered when: 1) color vision loss is disproportionate to reduction in visual acuity and cannot be explained by the presence of macular arcuates; 2) VFDs do not correlate with optic disc changes; 3) vertically aligned VFDs are present; 4) there is a marked RAPD; and 5) the surviving neural rim of the optic disc shows pallor. Fundus imaging techniques can provide additional information in making the clinical decision between glaucomatous cupping and NGC, while neuroimaging provides information regarding the cerebral changes seen with GON and other optic neuropathies.
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