Journal of Neuro-Ophthalmology, December 2013, Volume 33, Issue 4

Optic Nerve Cupping and the Neuro-Ophthalmologist

While glaucoma is the most common cause of optic disc cupping, it can also be seen in a number of congenital and acquired optic neuropathies. It behooves both glaucoma and neuro-ophthalmic specialists to be able to differentiate glaucoma from neurological conditions, which give a similar ophthalmoscopic appearance to the optic disc. This review is a combination of the authors' clinical experience from tertiary glaucoma and neuro-ophthalmology referral centers, combined with a literature review using PubMed. Even for experienced observers, differentiation between glaucomatous and nonglaucomatous cupping can be difficult. In the majority of cases, this distinction can be made following a careful clinical examination combined with a variety of imaging techniques. Possible mechanisms, which lead to changes in optic disc morphology, are reviewed. Differentiating glaucomatous from nonglaucomatous optic disc cupping can be a formidable challenge for the clinician. Examination of the patient combined with imaging of e retinal nerve fiber layer and optic disc topography provides a basis to resolve this clinical conundrum.

Optic Nerve Cupping and the Neuro-Ophthalmologist Clare L. Fraser, MBBS, MMed, FRANZCO, Andrew J. R. White, MBBS, PhD, FRANZCO, Gordon T. Plant, MD, FRCP, FRCOphth, Keith R. Martin, DM, MRCP, FRCOphth Background: While glaucoma is the most common cause of optic disc cupping, it can also be seen in a number of congenital and acquired optic neuropathies. It behooves both glaucoma and neuro-ophthalmic specialists to be able to differentiate glaucoma from neurological conditions, which give a similar ophthalmoscopic appearance to the optic disc. Evidence Acquisition: This review is a combination of the authors' clinical experience from tertiary glaucoma and neuro-ophthalmology referral centers, combined with a literature review using PubMed. Results: Even for experienced observers, differentiation between glaucomatous and nonglaucomatous cupping can be difficult. In the majority of cases, this distinction can be made following a careful clinical examination combined with a variety of imaging techniques. Possible mechanisms, which lead to changes in optic disc morphology, are reviewed. Conclusions: Differentiating glaucomatous from nonglau-comatous optic disc cupping can be a formidable challenge for the clinician. Examination of the patient combined with imaging of the retinal nerve fiber layer and optic disc topog-raphy provides a basis to resolve this clinical conundrum. Journal of Neuro-Ophthalmology 2013;33:377-389 doi: 10.1097/WON.0000000000000080 © 2013 by North American Neuro-Ophthalmology Society While pathological optic disc cupping ismost commonly associated with glaucoma, it is not pathognomonic. Trobe et al (1) reported a tendency to overdiagnose glaucoma in the presence of optic disc cupping based on fundus photographs. The Optic Disc Assessment Project found that differentiating glaucoma from genetic optic neuropathies based on disc assessment alone is difficult, concluding that a careful history and clinical examination are required for accurate diagnosis (2). Differentiating glaucomatous from nonglaucomatous optic disc cupping is the focus of this review. This requires an understanding of the normal anatomical relationships of the optic nerve head (ONH) and potential pathophysiological mechanisms that lead to configurational changes of the optic disc. OPTIC DISC CUPPING The ONH consists of 3 layers (3). The first is a continuation of the retinal nerve fiber layer (RNFL) (Fig. 1A). The second is the prelaminar layer, with loose trabecular glial tissue con-taining capillaries and retinal nerve fibers. Progressive loss of prelaminar neural tissues results in increased optic cup depth and width, classified as "prelaminar cupping" (Fig. 1B). The third layer lies within the scleral portion of the lamina cribrosa. Axon bundles pass though a meshwork of connective tissue covered in astrocytes and containing capillaries (4). The short posterior ciliary arteries are the sole vascular supply via a capil-lary network and the peripapillary choroid. The laminar extra-cellular matrix provides structural support and allows passage of nutritional support for the axons (5). Loss of support of deeper structures leads to posterior displacement of the lamina cribrosa and excavation beneath the anterior scleral canal (4). This has been designated "laminar cupping" (Fig. 1C). There-fore, cupping is the result not only of axonal loss but also of supportive glial tissue. Extensive axonal loss with preservation of glial structures results in a pale optic disc without cupping. Normal Reference Values Normal reference ranges for optic disc morphological param-eters have been established in different ethnic groups (6). On clinical examination and using optical coherence tomography (OCT), the horizontal disc diameter and the disc area are significantly smaller in Caucasians and Hispanics compared to populations from South Asia, Southeast Asia, and Africa (7,8). South Asian and Hispanic participants have the thick-est global RNFL measurements. Statistically significant differ-ences have been demonstrated among racial groups for all OCT ONH and RNFL parameters except rim area (9). Save Sight Institute (CLF, AJRW), University of Sydney, Sydney, Australia; Westmead Millennium Institute (AJRW), University of Sydney, Sydney, Australia; Moorfields Eye Hospital (GTP), London, United Kingdom; and Cambridge University Teaching Hospitals NHS Foundation Trust (KRM), Cambridge, United Kingdom. Address correspondence to Clare L. Fraser, MBBS, MMed, FRANZCO, Save Sight Institute, 8 Macquarie Street, Sydney, NSW 2010, Australia; E-mail: [e-mail] Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 377 State-of-the-Art Review Section Editors: Grant T. Liu, MD Randy H. Kardon, MD, PhD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. The mean horizontal cup-to-disc ratio (CDR) in the Caucasian North American population is 0.25-0.49, compared to 0.35-0.66 in African-Americans (10,11). In a predominantly Caucasian European population, mean vertical CDR was 0.49 and horizontal CDR was 0.4 (12). Asymmetry of the optic disc cup diameter is ,0.1 in 92% of a normal North American population (13). CLINICAL ASSESSMENT Congenital Optic Disc Cupping There are a variety of optic disc anomalies that are char-acterized by significant cupping. They are summarized in Table 1 and Figure 2. Acquired Optic Disc Cupping While glaucoma is the most frequent cause of acquired optic disc cupping, a variety of ischemic, toxic, compressive, and genetic causes can lead to optic disc excavation. Differentiating glaucomatous optic neuropathy (GON) and nonglaucomatous cupping (NGC) requires careful clinical examination and use of various imaging techniques. Visual Acuity and Color Vision Loss of visual acuity and color vision will occur in advanced glaucoma but usually occur early in other optic neuro-pathies. However, both acuity and color vision can be affected at any stage in GON if the patient develops a temporal RNFL bundle defect with a corresponding macular arcuate scotoma splitting fixation across the FIG. 1. Anatomical changes of optic disc cupping. Dashed line indicates original location of internal limiting membrane (ILM). Solid black line indicates altered location of ILM. Orange area indicates prelaminar neural and vascular tissue. Blue line indicates anterior laminar surface. Green lines indicate Bruch's membrane opening. A. Normal optic nerve head. B. Prel-aminar or shallow cupping. Black arrows indicate the movement towards the altered position of the ILM. C. Laminar or deep cupping. White arrows indicate posterior movement of anterior laminate surface. Note there is also prelaminar cupping (black arrows). Modified from Burgoyne and Downs (3). 378 Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. horizontal meridian (14). The Amsler grid and automated visual fields of the central 10° can help detect macular involvement. A particularly confusing situation for the cli-nician is preserved acuity with poor performance on Ishihara plates in early glaucoma. Such patients are often referred to neuro-ophthalmology. With a preserved central island of visual field, visual acuity is retained, but the paramacular field required to read Ishihara plates is lost as a result of macular arcuate defects. Decreased visual acuity in NGC is caused by a scotoma centered on the fovea or splitting the central visual field vertically. Anterior ischemic optic neuropathy (AION) can split fixation horizontally. The altitudinal visual field defect (VFD) in AION typically involves a number of RNFL bundles subserving more than an isolated arcuate area (15). Loss of acuity out of proportion to disc cupping has been reported in NGC (16), with a reduction in acuity ,20/40 having a 77% sensitivity for NGC (17). Color vision loss in optic neuropathy classically causes a red-green deficiency, as described by Kollner in 1912 (18). Performance on Ishihara plates is a useful screening test in discriminating early glaucoma from other causes of optic neuropathy. However, if visual acuity is preserved, as is often the case in glaucoma, the color vision defect is predominantly blue yellow (18,19). Deficiencies in color vision testing (pseudoisochromatic plates, Hardy- Rand-Rittler, Farnsworth-Munsell) greater than expected from acuity or visual field loss should lead to suspicion of NGC (Table 2). Macular and cone dystrophies can present with color vision deficits and temporal optic disc pallor and are best diagnosed with a full-field, multifocal, and pattern electroretinography (20). Pupillary Findings Estimates of the presence of a relative afferent pupillary defect (RAPD) in GON range between 9% and 82% (21). The magnitude of a RAPD is proportionate to the differ-ence in visual field loss between the 2 eyes (22). A RAPD is detectable when RNFL thickness is decreased to 83% of TABLE 1. Congenital causes of optic nerve cupping and associated features Name Cause Appearance Associations Morning glory (Fig. 2A) Abnormal closure of embryonic fissure Funnel-shaped excavation Mid face anomalies Elevated pigment epithelium Basal encephalocele Abnormal development of the optic disc stalk Increased blood vessels at edges of disc Moya-moya disease Glial tissue in place of optic disc cup Coloboma (Fig. 2B) Failure of closure of embryonic fissure Can resemble deep cupping CHARGE syndrome: coloboma, heart defects, choanal atresia, mental retardation, genitourinary and ear abnormalities May be part of complete chorioretinal coloboma Usually extend inferonasally Tilted optic disc (Fig. 2C) Oblique insertion of optic nerve through scleral canal Elevated superior pole, with posterior displacement of inferonasal disc Myopia Oval disc with oblique elongation X-linked congenital stationary night blindness Inferior scleral crescent Megalopapilla (Fig. 2D) Unknown Abnormally large optic disc diameter with increased cup-to-disc ratio Optic nerve glioma Optic nerve hypoplasia (Fig. 2E) First trimester insult Disc is pale and small with a surrounding scleral crescent "double ring sign" Absent septum pellucidum Abnormal vascular pattern or tortuosity Agenesis of corpus callosum Hypothalamic and pituitary dysfunction Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 379 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. that in the fellow eye (23). Discovery of a RAPD has been shown to be highly specific (.90%) for detecting glaucoma within a normal population (21). Although a RAPD cannot differentiate among optic neuropathies, the degree of RAPD may be important. The simple rule is that optic neuropathies that tend to be symmetrical will not show a RAPD: these are principally glaucoma, papilledema, nutritional, toxic, and genetically determined optic neuropathies. Neuroimaging should be considered if a large RAPD is present, unless there is highly asymmetric field loss, which is clearly glaucomatous (Table 2). Glaucomatous Optic Disc Assessment Focal loss of the neuroretinal rim (NRR) is reported to be 87% specific for glaucoma (1,24) and is associated with progressive disease (25,26). Other GON characteristics include normal color of the remaining NRR, vertical cup elongation, splinter hemorrhages (27), and positional changes of the optic disc vasculature (Fig. 3). A greater proportion of glaucomatous optic disc cupping is classified as "deep" compared to NGC (2). Conformational changes within the neural canal and posterior bowing of the lamina cribrosa explain this appearance of deep cups (28) (Fig. 1C). In an ocular hypertensive cohort, the strongest predictors of glaucomatous visual field loss were vertical CDR cor-rected for disc size, total NRR area, rim-to-disc area ratio, and CDR corrected for disc size (29). Tatham et al (30) showed a nonlinear relationship between estimates of retinal ganglion cell (RGC) number and CDR. Therefore, in glaucoma patients with a physiologically large CDR, even a relatively small change in CDR may be associated with a large loss of RGCs. Peripapillary atrophy (PPA) is divided into a central (beta) zone with sclera and large choroidal vessels visible on ophthalmoscopy, and a peripheral (alpha) zone with irreg-ular pigmentation. The size, shape, and frequency of alpha and beta PPA do not differ significantly between normal FIG. 2. Congenital optic neuropathies associated with optic disc cupping. A. Morning glory syndrome. B. Optic disc coloboma. C. Tilted optic disc. D. Megalopapilla. E. Optic nerve hypoplasia. Figures A, B, C, and E are reproduced with permission from Kline LB, Foroozan R. Optic Nerve Disorders. New York, NY: Oxford University Press, 2007. Figure D courtesy of Randy Kardon, MD, PhD. TABLE 2. When to consider neuroimaging of a patient with a cupped optic disc Definite Indications Potential Indications Vertically aligned field defects Relative afferent pupillary defect Pallor of the neuroretinal rim ,50 years old Hypothalamic pituitary dysfunction Asymmetrical loss of color vision Other neurological abnormalities Visual acuity , 20/40 380 Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. eyes and those with optic atrophy (31). However, in glaucoma, PPA is thought to be caused by ischemia (32), as the posterior ciliary arteries supply the optic disc and this region as well. While beta zone atrophy is often enlarged in glaucoma (33-35) and predictive of progression (36,37), it is not thought as essential in establishing the diagnosis of GON. However, on recent histological studies in cadaveric eyes, it was found that a more rigidly defined beta zone was strongly correlated with glaucoma (38). Progressive enlarge-ment of beta zone atrophy is not seen in NGC (39). The PPA seen in myopia, tilted discs, and optic disc hypoplasia does not have a region of choroid interposed between the retina and the sclera, as in GON (40). Features that do not help distinguish GON from NGC are the intraocular pressure (IOP), presence of laminar dots, and thinning of the NRR without complete obliteration (1). Nonglaucomatous Optic Disc Assessment Indicators and specificity (shown in brackets) of NGC reported in the literature are reduction in acuity ,20/40 (77%), pallor of remaining rim (94%), patients presenting age ,50 years (93%), and visual fields obeying vertical meridian (81%) (1,17). Other features typical of NGC include visual field loss with minimal cupping and retinal vasculature changes (41) (Fig. 3). In addition, a normal disc in the fellow eye with an abnormal visual field should raise concerns of chiasmal or retrochiasmal pathology. NGC has been reported in a variety of optic neuropathies including compressive (16,42-44), ischemic (45), inflammatory, and traumatic (46) neuropathies. Compressive lesions include meningioma (42), pituitary adenoma (47), craniopharyngioma (48), and internal carotid artery aneurysm (48). Compression of the intracranial portions of the optic nerves by the supraclinoid internal carotid artery has also been reported to cause NGC (49). In compressive NGC, the median CDR asymmetry in patients was only 0.13 but significantly higher than controls who had 0.04 asymmetry (48). Optic disc cupping may be the result of arteritic anterior ischemic optic neuropathy (A-AION) secondary to giant cell arteritis (45,50). NRR thinning and enlargement of the CDR in A-AION is similar to glaucoma, supporting the vascular theory of GON (50-53). However, other reports in patients with GON have demonstrated more marked posterior excavation and large cups with less rim volume than in those with AION (both A-AION and nonarteritic AION [NA-AION]), after adjusting for the amount of RGC loss (15). Methanol poisoning produces profound RGC loss leading to blindness with pale, cupped optic discs (54) (Fig. 4). Loss of NRR and ONH excavation have been FIG. 3. Optic disc cupping. Glaucomatous cupping. A. There is focal loss of superior neuroretinal rim (NRR) (arrow), normal color of remaining NRR, vertical elongation of the cup, deep cup, mild peripapillary atrophy, and positional changes of blood vessels. B. Automated visual fields show an inferior arcuate defect with prominent nasal field involvement, corresponding to the superior loss of NRR (gray scale, numeric decibel graphs, total deviation, and pattern deviation). Nonglaucomatous cupping. C. Autosomal dominant optic atrophy with pallor of the NRR (arrow), shallow cupping with no focal loss of NRR, and no change in blood vessel position. D. Automated visual fields demonstrate a central scotoma with nasal sparing (gray scale, numeric decibel graphs, total deviation, and pattern deviation). Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 381 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. described in long-standing autosomal dominant optic atrophy (ADOA) (55) and Leber hereditary optic neu-ropathy (LHON) (2,56). Cases have been misdiagnosed as glaucoma (57). In one study, 48%-89% of ADOA patients were found to have significant NRR thinning and CDR .0.5 (58), but another found all to have NRR pallor, either temporally (52%) or globally (48%) (59). Clinical features, which should lead to genetic testing, are outlined in Table 3. ANCILLARY TESTING Visual Fields 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 rela-tionship 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 FIG. 4. Methanol poisoning. A. Acute findings include optic disc edema with opacification of the peripapillary retinal nerve fiber layer. B. Chronic changes show optic atrophy with cupping. Courtesy of Lanning Kline, MD. TABLE 3. When to consider ordering genetic tests for patients with optic disc cupping Leber hereditary optic neuropathy Sudden loss of central vision Bilateral or sequential profound vision loss Maternal family history of vision loss Relative preservation of pupil responses Autosomal dominant optic atrophy Very slowly progressive visual loss over decades despite normal intraocular pressures Family history of poor vision Color vision deficit Pallor of the remaining neuroretinal rim Disc changes seen in younger family members 382 Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 pathol-ogy. An algorithm has been proposed to discriminate vertical neurological visual field abnormalities from horizontal glau-coma 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 essen-tial 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. Retinal Nerve Fiber Layer Imaging 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 spec-tral- 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. Glaucoma Optic nerve and RNFL imaging have allowed earlier detec-tion of glaucoma (71). When a sloping cup is present, OCT can quantify the disc changes better than clinical observation alone. This is particularly true for comprehensive ophthal-mologists; however, optic disc assessment by a glaucoma specialist is still more reliable than either (72). Neither OCT nor GDx is useful in distinguishing GON from NGC in highly myopic individuals (73). Thinning of the lamina cribrosa is present in myopic eyes with no other pathology, and refractive error leads to high artifact levels in image acquisition. 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. Nonglaucomatous Optic Disc Cupping Gupta et al (75) used OCT to evaluate GON vs NGC (optic neuritis and NA-AION). In cases matched for CDR or average RNFL thickness, it was found that patients with NGC had a lower mean RNFL in the nasal and temporal quadrants (76). The pattern of RNFL thinning in ischemic optic neuropathy and ONH drusen is more likely to mimic the pattern of glaucomatous change caused by the predilection for the superior and inferior quadrants (77). 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. With HRT, 73% of LHON patients were misclassified as having glaucoma (79). In the acute phase of LHON, RNFL thickness initially increases in the temporal and inferior quadrants, progressing to involve superior and nasal quadrants within 3 months (80). By 9 months, there is a significant reduction in RNFL thickness in all but the nasal quadrants. These changes were of greater magnitude in patients with the 11,778 mutations than the 14,484 mutations (81). 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 epi-sode (89). In neuromyelitis optica, the superior and inferior quadrants typically are more severely affected (90). Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 383 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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). Macular Imaging 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 anal-ysis 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 asso-ciated with a narrow region of RNFL thinning at the border of temporal and inferior disc quadrants. Normal tension glau-coma (NTG) patients are the more likely to be referred to neuro-ophthalmology with central VFDs than those with ele-vated IOP, making these macular scans invaluable (95). In patients with A-AION who have outer retinal ischemia sec-ondary to occlusion of posterior ciliary arteries, there is disruption of the inner-outer photoreceptor segment line on SD-OCT (96). Multifocal Visual Evoked Potentials Although multifocal visual evoked potential (mfVEP) testing has been described for many years (97,98), it is not com-monly 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 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 demye-lination 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). POTENTIAL COMMON PATHOPHYSIOLOGICAL MECHANISMS OF OPTIC DISC CUPPING Anatomical and experimental research regarding the basis of optic disc cupping is primarily found in the glaucoma literature. These theories involve a pathophysiological mech-anism at the level of the lamina cribrosa. Mechanical 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 384 Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 biomechan-ical stress is determined by posterior scleral compliance and rigidity (120). However, it is difficult to separate the mechan-ical 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 predis-position to GON (122). Vascular The vascular theory (123) emphasizes the potential impor-tance of IOP elevation on blood flow at the ONH (124). Autoregulation is a process whereby blood flow is kept relatively constant, despite changes in the ocular perfusion pressure. However, induced levels of high IOP affect autor-egulation mechanisms in the choroid (125). Whether this also is true for ONH blood flow remains controversial. There is evidence that glaucoma patients show abnormal au-toregulation, although the reasons for this remain largely unknown (126). A reduction in IOP may improve the regu-latory capacity of the optic disc vasculature, thereby reducing the likelihood of ischemic periods and progressive GON (125). Cerebrospinal Fluid Pressure Gradient The intraocular to intracranial pressure (ICP) gradient may cause changes in ONH structure and function (127). Cere-brospinal fluid (CSF) surrounds the optic nerve to the level of the lamina cribrosa, thereby directly influencing the translami-nar pressure difference and laminar position. The average pos-terior force from IOP on the lamina is 1 mm Hg per 100 mm (assuming a mean IOP of 16 mm Hg, mean ICP of 12 mm Hg, and a lamina cribrosa thickness of 450 mm) (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). Mean lumbar CSF opening pressure in NTG is 3-4 mm Hg lower than in controls (130-132). Interestingly, in large population studies, the difference between IOP measurement in controls and progressive primary open angle glaucoma is 4 mm Hg higher. In both situations, the difference in translaminar pressure gradient between the normal and glaucoma patients is the same. Even this small difference in CSF pressure may be significant in the pathogenesis of GON. In addition, Ren et al (133) found a statistically significant difference in CSF pressure in 17 ocular hyper-tensive patients (16.0 ± 2.5 mm Hg) compared to 71 control subjects (12.9 ± 1.9 mm Hg). The authors speculate that this finding might explain why ocular hypertension pa-tients do not develop progressive optic disc changes. A COMMON METABOLIC PATHWAY: MITOCHONDRIAL DYSFUNCTION AND OPTIC NEUROPATHIES 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). ADOA is the most common inherited nonglaucomatous optic neuropathy (59) and has been linked to the OPA1 gene on chromosome 3q (136). This gene encodes a mitochondrial dynamin-related protein and plays a role in the maintenance of mitochondrial cristae (134). Interestingly, OPA1 polymor-phisms have been found in patients with NTG (137). Although results are controversial, a recent meta-analysis showed that some OPA1 variants may affect individual sus-ceptibility (138). Data suggest that OPA1 deficiency impairs oxidative phosphorylation efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial adenosine triphosphate (ATP) production in patients who maintain normal vision (139). This raises the possibility that NTG is also an inherited optic neuropathy with similar mitochondrial dysfunction to ADOA but a different phenotypic expression (137,140). 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). CONCLUSIONS In evaluating a patient with optic disc cupping, neuro-ophthalmic pathology should be considered when: 1) color Fraser et al: J Neuro-Ophthalmol 2013; 33: 377-389 385 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. 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