Nonglaucomatous Cupping of the Optic Disc. Balamurali K. Ambati, M.D. Joseph F. Rizzo III M.D.

Transcription

1 Nonglaucomatous Cupping of the Optic Disc Balamurali K. Ambati, M.D. Joseph F. Rizzo III M.D. Visual field loss in the setting of optic neuropathy can be attributed to a host of diseases. Pathological optic disc cupping (ODC) is most often caused by glaucoma but may be seen in many less common neuroophthalmic conditions. This chapter surveys the realm of entities causing ODC, presents key differentiating characteristics and pathophysiologies, and outlines diagnostic approaches. Historical Overview In 1855, Weber 1 described ODC in glaucoma and, 2 years later, von Graëfe 2 described a case of ODC in a patient with normal intraocular pressure (IOP), which he termed amaurosis with excavation. Controversy arose over the clinical significance of ODC, and most authorities sided with Donders, 3 who believed that all cupping was glaucomatous. This view prevailed until the introduction of the Schiøtz tonometer, which for the first time permitted reliable measurement of IOP, and ODC then was recognized in many patients with normal pressure. Many explanations of ODC were offered, including congenital variations, optic atrophy, underdevelopment of the lamina cribrosa, lacunar degeneration in the brain, dissolution of nerve fibers, toxins, and compression by the carotid arteries. 4 6 Seminal histopathological studies on the optic disc beginning in the 1960s laid the foundation for our more complete understanding of the pathogenesis of ODC. 7,8 Still, our knowledge about the cause of cupping even in the relatively common disease of open-angle glaucoma remains obscure. Optic Disc Anatomy and Physiology Attempts to understand the mechanisms of pathologic ODC must be grounded in consideration of the normal anatomy of this region. The 139

2 140 Ambati and Rizzo optic disc, or nerve head, consists of three layers: the superficial nerve fiber layer (which continues as the nerve fiber layer of the retina), the intermediate prelaminar layer (composed principally of nerve fibers and glial septa), and the deeper lamina cribrosa (constituted by dense connective tissue septa through which nerve fibers pass on their way to the brain). The nerve fiber layer contains compact nerve fibers as they converge from across the retina and is covered by the internal limiting membrane of Elschnig, which is made of astrocytes and separates this layer from the vitreous. The prelaminar layer is composed of nerve fibers in bundles surrounded by loose trabecular glial tissue, within the septa of which are capillaries. The lamina cribrosa is made of lamellae of connective tissue alternating with glial sheets having pores through which the nerve fiber bundles and central retinal vessels pass. The connective tissue of the lamina cribrosa is made of specialized fibroblasts and an extracellular matrix, which support neural tissue. 9 The sole vascular supply of the optic nerve head is derived from the short posterior ciliary arteries, branches of the ophthalmic artery, which send centripetal branches to form a dense capillary plexus in the septa of the lamina. The prelaminar layer is supplied by centripetal branches of the peripapillary choroid (also derived from the short posterior ciliary arteries), which are arranged sectorially. The temporal region of the prelaminar layer is more vascular and receives more blood supply from the peripapillary choroid. The most superficial nerve fiber layer is supplied primarily by retinal arterioles; its temporal portion receives some supply from the short posterior ciliary arteries as well. The retrolaminar portion of the optic nerve is supplied mostly from pial vessels derived from the peripapillary choroid; however, in up to 75% of people, some branches in the retrolaminar region originate from the central retinal artery. 10 Thus, the short posterior ciliary arteries, via direct branches and the peripapillary choroid, are the major vascular supply to the optic nerve and most of the optic disc. In humans, the median value of the cup-to-disc (C/D) ratio is 0.25 to In Armaly s study, 11 the difference in the C/D ratio between fellow eyes was less than 0.2 in 99% of subjects and less than 0.1 in 92%. Fishman 15 also found that disc asymmetry was unusual in normal subjects: Of normal patients, 5.6% had one disc that measured one and a half times larger than their other disc; this was the case also in 30% of patients with elevated IOP without field defects and in 36% of patients with established glaucoma. Kirsch and Anderson 16 found large physiological cups to be usually round, horizontally oval, or eccentric in position. The depth of the cups was highly variable in normal subjects, ranging from no visibility to complete visibility of the lamina. 12,17 Britton and colleagues 18 found that larger cups occurred in larger discs and that the C/D ratio was proportional to disc size. Quigley and associates 19 found that the mean vertical and horizontal disc diameters were 1.88 and 1.77 mm, respectively. Their

3 Nonglaucomatous Cupping 141 study also noted that blacks had larger discs and more vertical cups than did whites (vertical-horizontal disc diameter ratio in blacks, 1.1; in whites, 1.05). Beck and coworkers 20 observed that the mean C/D ratio in blacks was 0.35, as compared to 0.24 in whites. Differential Diagnosis and Mechanisms of Cupping Optic cupping is not solely the sequela of glaucoma. ODC in the absence of elevated IOP has been observed with physiological ( congenital ) cupping; low-tension glaucoma; congenital optic disc anomalies (e.g., coloboma, pits, or hypoplasia); anterior (AION) or posterior ischemic optic neuropathy (PION) (rarely); shock optic neuropathy; traumatic optic neuropathy; hereditary (Leber s and autosomal dominant) optic neuropathies; compression from fusiform aneurysms of the intracranial carotid arteries or tumors compressing the anterior visual pathway; syphilis; radiation optic neuropathy; and methanol poisoning Cups also may seem large in patients with myopia or oblique insertion of the optic nerve, as the sloping margins of the disc make difficult definition of the cup s borders. Physiological cupping (presumed congenital variants with no untoward visual effects) has already been discussed. Optic disc anomalies that may produce focal depressions of the normal surface topography include pits and colobomas. Coloboma confined to the disc is rare and is due to an abnormality in the distal extremity of the embryonic fissure; most authorities agree that the defect lies in excessive proliferation of the inner layer of the cup. 21 In these cases, amblyopia may be present at an early age, and the cupping is deepest inferiorly, with a corresponding nonprogressive visual field defect. Coloboma is an irregularly inherited dominant trait with variable expressivity and 30% penetrance. Optic pits can be congenital or acquired and can be of varying size and colors; 70% are temporal. One-half of patients with pits have some visual field defect. Javitt and colleagues 22 found that whereas only 15% of patients with glaucoma and high IOP had acquired optic pits, 74% of patients with normaltension glaucoma exhibited such pits. Pits did not correlate with severity of field loss. On the basis of this finding, several investigators proposed that ODC in normal-tension glaucoma was due to decreased resistance of the disc or lamina to IOP Another anomaly that can produce cupping is a variant of optic nerve hypoplasia in children with periventricular leukomalacia. 26 In preterm babies with anoxic brain damage, axonal disruption in the optic radiations may occur (with corresponding visual field defects), leading to transsynaptic retrograde degeneration across the geniculate body. The resulting loss of optic nerve axons may give rise to cupping. Cupping in this situation occurs only if the anoxic insult occurs at between 29 and 34 weeks of gestation, prior to full development of the

4 142 Ambati and Rizzo optic nerve and after the time when scleral plasticity leads to a small disc in cases of optic nerve hypoplasia. The mechanism of cupping in glaucoma is not clear. One theory is that increased IOP may compress the posterior ciliary artery and its branches. The prelaminar vessels and peripapillary choroid are the most susceptible to elevated IOP, whereas the choroidal and retinal circulations are much more resistant to elevated IOP. That the temporal portion of the disc is more dependent on the peripapillary choroid may also explain why temporal loss of axons with nasal field defects is frequently seen in glaucoma. Thus, hypoperfusion of optic disc tissue, along with mechanical impairment of axonal transport and metabolism (due to elevated IOP), may be the underlying factors producing ODC. Cupping is likely a consequence both of death of axonal tissue passing through the disc and of the connective and glial tissue elements of the disc. Radius and Maumenee 27 studied C/D ratios in patients with nonglaucomatous optic atrophy (NGOA) and found nonglaucomatous cupping to be almost invariably associated with large physiological cupping in the fellow eye. However, their study was biased by the observers prior knowledge of the correct diagnosis. Trobe and colleagues 28,29 showed that glaucoma and nonglaucomatous cupping were difficult to distinguish in a significant proportion of cases, even by experienced observers. Whether ischemia and compression of the optic nerve could cause ODC were points of contention for a long time. Drance and coworkers 30 reported that 10 of 38 patients with normal-tension glaucoma had a previous episode of shock that produced nonprogressive visual field loss. Hayreh 8 reported cupping was present in 11 of 13 eyes with arteritic AION but not in any of 7 eyes with nonarteritic AION. Quigley and Anderson 31 found that 10% of eyes (6 of 61) with nonarteritic AION developed cupping. They also reported that 5 of 10 eyes with arteritic AION and ODC had confounding factors (2 had elevated IOP, and 3 had large physiological cups in the fellow eye). Sebag and associated 32 presented a definitive series of patients with arteritic AION who had cupping without glaucoma or physiological cupping. Sonty and Schwartz 33 presented a case of PION that led to ODC weeks later. Hayreh 8 has stated that arteritic AION provides a telescoped natural course of cupping that closely resembles that of glaucoma and normaltension glaucoma, owing to similarities in underlying pathogeneses. He believes that acute arteritic AION produces acute hypoperfusion of the optic nerve, whereas glaucoma produces a chronic hypoperfusion state. Infarction of the anterior optic nerve in arteritic AION destroys neural tissue and connective tissue. The vessels supplying the optic disc s nerve fiber layer, arising from the retinal circulation, can also damaged by the edema of the optic disc. Further, in arteritic AION, the retrolaminar optic nerve infarcts and may become fibrotic, which can lead to backward traction on the lamina cribrosa as all retrolaminar fibrous septa attach to the

5 Nonglaucomatous Cupping 143 posterior surface of the lamina, inciting maximal cupping at approximately 4 months. The loss of neural tissue and ischemic insults to the lamina also may contribute to its weakening. Thus, Hayreh 8 posits that destruction of neural tissue and backward bowing of the lamina (due to loss of support from connective and neural tissue and backward traction from retrolaminar fibrosis) are the key factors contributing to ODC in AION. Glaucomatous damage may occur more slowly than that seen with acute ischemia, because the retrolaminar optic nerve is supplied by peripapillary choroid, which is vulnerable to high IOPs. Pathophysiological parallels between glaucoma and AION are supported by findings that peripapillary vasoconstriction is common to both diseases and correlates with disease severity and degree of ODC. 56,57 Central retinal artery occlusion, like PION, only occasionally produces ODC and then only long after the event. Cupping with central retinal artery occlusion is likely due to death of just ganglion cells in the retina (with delayed death of their axons) without necrosis of the optic disc s glial and connective tissue (as opposed to glaucoma and AION). The role of compression in the development of cupping also took decades to define. Walsh and Hoyt 34 mentioned that suprasellar lesions could produce glaucoma. Portney and Roth 35 provided the first case report of an intracranial aneurysm compressing the optic nerve and being associated with ODC. Radius and Maumenee 27 did not find cupping in their large series of 170 eyes with NGOA, which included 12 eyes with compression of the optic nerve. Kupersmith and Krohn 36 presented the first significant series of 16 patients with lesions compressing the anterior visual pathway who developed glaucoma like cupping. In Gutman and colleagues series 37 of 62 patients with a diagnosis of normal-tension glaucoma, 45% had asymmetrical cupping, which was correlated with the severity of carotid calcification, dilation, and ectasia into the optic canal; the authors hypothesized that many cases of normal-tension glaucoma represent compression of the nerve in the optic canal by an ectatic carotid artery. Bianchi-Marzoli and coworkers 38 performed the first quantitative and masked retrospective review of compressive optic neuropathies, confirming that they can produce ODC. Using planimetry, these researchers found that the median C/D ratio was 0.37 in compressive neuropathies as compared with 0.10 in control subjects (p <.001) They also found that the intereye difference in compressive optic neuropathy patients was 0.13, as compared with 0.04 for controls (p <.001), confirming that the cupping was an acquired feature. Hereditary optic neuropathies also produce ODC. Leber s optic neuropathy, a maternally inherited disease characterized by slow central visual loss secondary to bilateral optic degeneration, has been shown in several series to cause ODC Ortiz and associates 39 stated that ODC in this disorder was due to loss of unmyelinated axons (which have more mitochondria than myelinated axons), which may contribute to making the

6 144 Ambati and Rizzo retinal nerve fiber layer a vulnerable site. Dominant optic atrophy, the other major hereditary disorder to cause ODC, is diagnosed on the basis of several criteria, often including autosomal dominant inheritance, insidious onset in the first two decades of life, and symmetrical visual loss that is mild to moderate. It is associated with dyschromatopsia, temporal disc pallor, and a peculiar triangular cupping of the temporal portion of the optic disc. 40 Clinical Distinction Between Glaucomatous and Nonglaucomatous Cupping The characteristics of glaucomatous cupping are listed in Table 1. Traditionally, findings favoring a glaucomatous etiology of ODC are vertical extension of the cup, excavation of the cup, and lack of pallor of the residual neuroretinal rim. Jonas and Xu 42 also found that peripapillary atrophy was a parameter that occurred in glaucoma but not in nonarteritic ischemic optic neuropathy. The clinical differentiation of glaucomatous from nonglaucomatous ODC can be difficult. In two retrospective reviews of disc photographs, ODC was found in 20% of eyes with NGOA (roughly one-third of which were mistaken to be glaucomatous by eight experienced observers). 28,29 Cupping was more profound in eyes with glaucoma, whereas nonglaucomatous eyes with cupping had greater degrees of neuroretinal rim pallor (which was 94% specific for nonglaucomatous causes of ODC). Rim thinning was only 47% specific for glaucoma, although obliteration of the rim was 87% specific for glaucoma. Laminar dots were present in both glaucomatous and nonglaucomatous disorders, indicating that they likely occur in any condition that causes loss of disc substance. Compressive lesions produced both segmental and generalized disc pallor. CRAO was distinguished from ischemic optic neuropathy by the former s greater severity of optic pallor and arteriolar attenuation and by retinal vascular sheathing and dilated venous collaterals. Both ischemic optic neuropathy and papillitis frequently produced posterior pole exudates and glial overgrowth Table 1. Funduscopic Features of Glaucoma Vertical extension of the cup Total cupping Asymmetrical cupping Thinning of the neuroretinal rim Backward bowing of the lamina cribrosa Residual neuroretinal rim that is not pale Disc hemorrhage (as seen in normal-tension glaucoma) Excavation of the cup Peripapillary atrophy

7 Nonglaucomatous Cupping 145 on the disc surface. Thus, the authors concluded that inflammatory and ischemic neuropathies were difficult to distinguish once they became quiescent. Disc pallor was present in 16% of normal eyes, and ODC was present in 10% of normal eyes, revealing that pallor is a clinical judgment that depends substantially on optical factors. Pallor may be evident despite normal afferent visual function. Table 2 lists funduscopic features that favor NGOA. No characteristic optic nerve head findings are described for compressive lesions. To exclude occult intracranial masses, neuroimaging often is performed in patients with pathologic ODC without ocular hypertension. Neuroimaging in such instances has a very low yield, though certain clinical features mandate neuroimaging. Greenfield and colleagues 43 undertook a retrospective case-controlled study to determine the yield of these examinations and to discern any underlying characteristics that might indicate a higher risk of intracranial masses. Of 29 consecutive patients with a diagnosis of normal-tension glaucoma who underwent neuroimaging (with presumably a selection bias toward detecting mass lesions based on atypical clinical presentations), none had occult lesions of the visual pathways. These results are limited by the small scope of the study and the unclear selection of the control group: Did the patients with the known mass lesions have cupping before or after they received a diagnosis of a mass lesion? Other workers reported incidences of 3.8% and 5.7% of occult compressive lesions in this patient population. 44,45 These studies indicate that routine neuroimaging is not indicated in patients with nonglaucomatous cupping. However, the finding of Gutman and associates 39 that many patients with normal-tension glaucoma have carotid abnormalities that might be amenable to decompression has not been supported by the rest of the literature. Carotid disease Table 2. Funduscopic Features Favoring Nonglaucomatous Cupping Finding Conditions Generalized disc pallor Optic neuritis; ION Sectorial pallor ION Retinal arteriolar narrowing CRAO; ION; trauma; radiation optic neuropathy Bilateral, symmetrical, temporal, segmental Hereditary optic neuropathy disc pallor Unilateral, segmental temporal pallor Optic neuritis Severe optic pallor with arteriolar CRAO attenuation Retinal vascular sheathing; dilated venous CRAO collateral vessels Posterior pole exudates ION (rare) CRAO = central retinal artery occlusion; ION = ischemic optic neuropathy.

8 146 Ambati and Rizzo is not widely believed to cause ODC. Stroman and coworkers 46 did not find an increased frequency of gross carotid abnormalities in a group of 20 patients. Reviewing a control group of patients with ODC due to known intracranial lesions, Greenfield and colleagues 43 found several risk factors that predicted nonglaucomatous causes of ODC. Age younger than 50 years was 93% specific for NGOA. Optic pallor greater than cupping, vertically aligned visual field defects, and visual acuity of less than 20/40 were 90%, 81%, and 77% specific for nonglaucomatous cupping, respectively. Although rim pallor was 90% specific for NGOA, it was only 46% sensitive. Glaucomatous patients had larger C/D ratios, greater vertical elongation of the cup, horizontal visual field defects, a family history of glaucoma, and more frequent peripapillary atrophy and disc hemorrhages. No patients with NGOA had disc hemorrhages. In glaucoma, fiber loss is usually symmetrical; hence, asymmetrical color vision deficits and relative afferent pupillary defects are rare). Such symmetrical fiber loss tends to spare the papillomacular bundle (hence the rarity of central visual field loss). For evaluating the patient with cupping, normal IOP, and visual field loss, we recommend that neuroimaging be performed in those with risk factors associated with NGOA, including age younger than 50 years, visual acuity of less than 20/40, vertically aligned visual field defects, pallor of the residual neuroretinal rim, field defects approaching the vertical meridian, asymmetrical loss of color vision, an afferent pupillary defect, cranial pain, and symptoms of hypothalamic-pituitary dysfunction. Computed tomography and magnetic resonance imaging are the two main neuroimaging modalities in this context. Both have certain advantages and disadvantages. In general, magnetic resonance imaging is superior for intracranial masses owing to its finer resolution and its ability to ascertain the composition of the imaged tissue. Contrast generally is helpful in the evaluation of possible intracranial masses. Computed tomography may be the superior modality for imaging meningiomas. Summary Optic disc cupping is a consequence of myriad disorders. The anatomy and vasculature of the disc provide great insight into why, how, and when ODC occurs in various conditions. Approaches to distinguish glaucomatous from nonglaucomatous causes of ODC should rely on patient history, visual fields assessment, and funduscopic findings, as described. Cupping can be seen with neurological processes, including benign tumors, that are treatable. The clinician must remain vigilant to detect uncommon but potentially threatening forms of nonglaucomatous optic disc cupping.

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