Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

(d)

Conventional

Ribbon

Postnatal days

Cone photoreceptor

the earliest bipolar synapses appear to be monads, that is, there is only one postsynaptic process, whereas with maturation, bipolar cells synapses occur at junctions with two processes, forming a dyad synapse. The postsynaptic processes may comprise processes from two amacrine cells, an amacrine and a ganglion cell, or two ganglion cells. That bipolar synapses are already present on ganglion cell dendrites prior to the appearance of ribbons is supported by electrophysiological recordings from immature retinal ganglion cells. As discussed in more depth later, spontaneous excitatory postsynaptic currents (sEPSCs) can be recorded from ganglion cells in mammals prior to when ribbons appear. Electron microscope observations of developing mouse retina also suggest that bipolar synapses are present in the outer half (OFF) of the inner plexiform layer prior to their appearance in the inner half (ON) of the inner plexiform layer. There is support for the relatively earlier differentiation of synaptic connections, or at least their structures, in the OFF sublamina of the inner plelxiform layer. For example, in mice, VGluT1 (vesicular

glutamate transporter) immunolableing is first observed in the OFF sublamina prior to its appearance in the ON sublamina (Figure 5). The significance of this sequence in maturation of the ON and OFF vertical pathways is unclear because light-evoked activity does not emerge until several days later.

Reconstructions of bipolar cell synapses at the ultrastructural level, however, cannot provide a view of the spatial distribution of such inputs on individual ganglion cell dendritic arbors unless extensive serial reconstructions are performed on immature ganglion cells. Using transient transfection methods, recent studies have successfully explored the spatial distribution of bipolar cell inputs on the dendritic arbors of retinal ganglion cells using light microscopy. Expression of fluorescently tagged postsynaptic density protein 95 (PSD95), a scaffolding protein found at glutamatergic postsynaptic sites, revealed the distribution of bipolar cell contacts across the dendritic arbors of ganglion cells in the mouse retina. Quantification of the spatial maps of these synaptic puncta

indicated that in mice, there is a rapid acquisition of glutamatergic postsynaptic sites from postnatal day 5 until eyeopening (Figure 7). Synaptogenesis between bipolar cells and retinal ganglion cells thus appears to proceed mostly prior to eye-opening (around 2 weeks after birth). Interestingly, the density of connections across the dendritic territory of the ganglion cells appears to be fairly invariant with age, even though there is significant structural remodeling (largely reduced dendritic branching density) of the dendritic arbors with maturation. This may reflect the developmental increase in the number of contact sites along the dendrites as dendritic density decreases with age.

Electron microscopy studies clearly indicate that cones form synaptic connections prior to rods. However, to date, there is little information concerning how bipolar cells and photoreceptors establish the specificity in their connectivity patterns during synaptogenesis. Retinas in which rod or cone populations are perturbed provide important insight into the specificity of wiring between rod and cone photoreceptors and their target bipolar cell types. In nrl-knockout mice in which rods fail to form and all photoreceptors become cones, rod bipolar cells are contacted by cones. Conversely, in in cyclic nucleotide gated channel A3 (CNGA3) knock-out mice in which cones are present but nonfunctional, cone bipolar cells form synaptic connections with rods. Thus, rod and cone bipolar cells can be targeted nonspecifically by cones and rods in the absence of proper interactions between these preand postsynaptic cell types. However, it is not yet clear

whether specificity in the wiring between rods and cones and their target bipolar cells is obtained during development after a period of rewiring, or whether there is target selectivity during synaptogenesis. One way to address this question is to follow the development of photoreceptorbipolar synaptogenesis over time in vivo. This can be readily achieved in zebrafish but is more difficult to perform for mammalian retinas. Furthermore, experiments that will determine how the different color cones wire up to the appropriate bipolar cells during development will be important in determining how color circuits are established in cone-dominated retinas.

Assembly of Lateral Circuits

Compared to the vertical pathway, the assembly of circuits that modulate transmission in the inner and outer retina are not as well understood. However, recent studies in which amacrine cells and horizontal cells can be identified early in development have shed new insight into the cellular behaviors of these cells as they form circuits.

Inner Retina – Amacrine Cells

Amacrine cells migrate freely toward the inner retina and appear to stratify shortly upon reaching the border with the forming ganglion cell layer (Figure 2). Serial electron microscopy suggested this pattern of amacrine cell migration and neurite development, which has

# Puncta/μm dendritic

5 x

length(P/D)

0.5

0.4

0.3

0.2

0.1

0.0

10 μm

5X

subsequently been visualized in real time by in vivo imaging of these neurons in the zebrafish retina. Zebrafish amacrine cells very quickly stratify their neurites within the inner or outer half of the IPL as soon as their cell bodies reach their final locations. Thus, amacrine cell neurites do not appear to undergo a period of indiscriminate occupation of the IPL. Whether this pattern of neurite growth also occurs for mammalian amacrine cells, however, is not known although in rodents, cholinergic amacrine cells appear to form their mirror-sym- metric laminations at two distinct depths in the IPL early in IPL formation.

The cues that influence the neuritic stratification of amacrine cells are not completely known, but it is evident that ganglion cells are not necessary for this process to occur. In mouse atonal 5 (Math5) knock-out mice and in the zebrafish mutant, lakritz, both lacking retinal ganglion cells, amacrine cells form stratified arbors. Because bipolar cells differentiate later than amacrine cells, these interneurons are unlikely to provide lamination cues for amacrine cells. The influence of adhesion molecules in the stratification of amacrine cell neurites has, however, been shown in the chick retina. The immunoglobulin superfamily of adhesion molecules, Down syndrome cell adhesion molecule (DsCam), DsCam-like, Sidekick-1 and Sidekick-2 are expressed in nonoverlapping strata in the chick inner plexiform layer. Manipulating the expression of these adhesion molecules in ovo suggests that they are involved in specifying the laminae within which amacrine cells and their target retinal ganglion cells stratify.

As yet, it is unknown what factors regulate synapse density between the amacrine cells and their target retinal ganglion cells. This issue can potentially be investigated by serial reconstructions of the IPL but because there are at least two dozen types of amacrine cells in the mammalian retina, and perhaps an even greater variety in the fish retina, mapping the inputs of specific subtypes of amacrine cells on the dendrites of their postsynaptic ganglion cells is extremely challenging. No doubt, future studies using transgenic approaches to visualize specific amacrine subtypes will be invaluable. Amacrine cells also provide feedback inhibition onto bipolar axon terminals. These feedback synapses have largely been studied in the rod bipolar cell pathway where A17 amacrine cells are known to contact the large axon terminals of rod bipolar cells (see Figure 6

(a)). The development of this highly localized reciprocal synapse has yet to be examined in detail but its well-char- acterized function makes this synapse a good model for studying the development of feedback circuits in general.

Outer Retina – Horizontal Cells

In the outer retina, modulation of transmission along the vertical pathway is provided by horizontal cells. In rodents, horizontal cell dendrites attain a laminated arbor

after a period of reorganization (Figure 2). Cajal described immature horizontal cells as having a radial rather than lateral arbor. Since then, horizontal cells in rodents have been identified by immunolabeling for the GABA synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), and by calbindin immunoreactivity. Such labeling confirmed Cajal’s early observations and also showed that horizontal cell dendritic stratification occurs as photoreceptors form synaptic connections onto the horizontal cells. Dendritic stratification of horizontal cells does not appear to rely on neurotransmission from photoreceptors because this process occurs even when cone photoreceptors are ablated during development. However, long-term loss of photoreceptor transmission does lead to elaboration of horizontal cell dendrites into the outer nuclear layer where they can receive ectopic contact.

Horizontal cells form contacts with cone photoreceptor terminals prior to the elaboration of bipolar cell dendrites that later invaginate into the cone terminal to form a synaptic triad (Figure 6(c) and 6(d)). The triad comprises a single bipolar cell dendritic tip flanked by two horizontal cell processes at a location opposite to the ribbon in the cone terminal. The assembly of this triad structure has been described by elegant ultrastructural studies in the past but the cues that coordinate the assembly of each component of this synapse are still unknown. Figure 5 summarizes the time-line of synaptogenesis between the various cell elements contributing to the OPL.

Emergence of Function – Spontaneous

and Light-Evoked Activity

Visually evoked signals in the mammalian retina emerge shortly before eye-opening when photoreceptors have formed synaptic connections with the bipolar cells. However, the retina generates its own pattern of activity prior to photoreceptor transmission. In many mammalian species studied thus far, retinal ganglion cells have been found to exhibit bursts of action potentials that occur rhythmically and are synchronized among neighboring cells (Figure 8). This synchronized activity takes on the form of propagating waves that spread across the retina in different directions. The wave-like activity pattern has been linked to the refinement of the axonal projection patterns of the retinal ganglion cells to their subcortical targets, but as yet waves have not been found to influence the development of intraretinal circuits in mammals.

Changes in the properties of retinal waves, however, have been informative with regard to the organization and development of retinal circuits. For example, studies of retinal activity in chick, mice, ferret, and rabbit all suggest that early synchronized activity is mediated by gap junctions, then by cholinergic drive and later by glutamatergic transmission. Moreover, ON and OFF retinal

ganglion cells are synchronized in their bursting activity during the period when cholinergic drive is necessary for the wave activity. However, as glutamatergic drive takes over, the spontaneous bursting activity of ON and OFF mouse ganglion cells becomes desynchronized: ON ganglion cells burst before OFF ganglion cells. This asynchrony is generated by cross-over inhibition between these parallel pathways. Thus, prior to eye-opening, retinal circuits undergo changes in spontaneous activity patterns of the ganglion cells largely due to alterations in the type of excitatory drive (cholinergic then glutamatergic) and the maturation of inhibitory circuits. At the level of synapses, measurements of synaptic currents from individual retinal ganglion cells show that the amplitudes and frequency of sEPSCs increase with age, even after eye-opening.

Few studies have directly measured the early visual response properties of retinal ganglion cells. Such studies have been difficult to carry out in vivo because of the poor optics of the immature eye. As soon as it is possible to record light responses from the retina ex vivo, generally a few days before eye-opening, the characteristic center-surround organization of ganglion cell receptive fields can be identified in cat and rabbit. Although the antagonistic surround, mediated by inner and/or outer retinal inhibition, is present when the receptive field centers are first detected, the response properties of the early surrounds appear to be species dependent. The early light responses are weak and adapt rapidly but become robust several days later. However, ON and OFF responses are evident and there is no significant developmental change in the percentage of cells with ONand OFF-center receptive fields in the cat. In contrast, in ferret and mice, there is a higher proportion of ganglion cells that receives converging ON and OFF input during development. The reduction in the incidence of ON–OFF cells in the ferret has been attributed to dendritic pruning, whereas in mice this reduction is considered to be the result of a decrease in the number of cells with dendritic arbors located at the

border of the ON and OFF sublaminae of the IPL. However, in mice, direct correlation between structure and function of individual ganglion cells that have converging ON and OFF input has yet to be obtained. Directionselective ganglion cells can be found in rabbit retina before eye-opening and the development of the circuitry underlying this visual response property in mouse retinal ganglion cells does not depend on spontaneous retinal wave activity or visual experience. In contrast, the spatial receptive fields of turtle retinal ganglion cells appear to reorganize with maturation. Direction selectivity, orientation preference, and receptive field sizes of turtle ganglion cells are shaped by spontaneous and light-driven activity. Thus, the influence of neurotransmission, especially visual experience, in establishing the precision in wiring of intraretinal circuits appears to vary across species, perhaps due to different developmental constraints that are species specific. Alternatively, such differences may be due to how neurotransmission is altered in vivo and the consequence of each manipulation in the transmission of signals between specific cell types.

Conclusions

Much remains to be done in order to elucidate the molecular and cellular mechanisms that are responsible for establishing the many circuits within the vertebrate retina dedicated to the processing of light information. In recent years there have been significant technological advances that allow probing the structural and functional development of retinal circuits. However, cell-type specific markers that will enable tracking the same cell type throughout development are necessary for many future studies. With the increasing availability of transgenic models, it should be possible to directly address the mechanisms that are essential to circuit assembly in vivo. Investigating the development of intraretinal circuits is certainly well aided by the immense knowledge of the structure and function of the

adult vertebrate retina, and the comparative anatomy and physiology of its circuits across many species.

See also: GABA Receptors in the Retina; Ganglion Cell Development: Early Steps/Fate; Histogenesis: Cell Fate: Signaling Factors; Information Processing: Amacrine Cells; Information Processing: Bipolar Cells; Information Processing: Ganglion Cells; Information Processing: Horizontal Cells; Information Processing in the Retina; Photoreceptor Development: Early Steps/Fate; Retinal Histogenesis.

Further Reading

Cajal, R. Y. (1960). Studies on Vertebrate Neurogenesis. Springfield, IL: Thomas.

Eglen, S. J., Sernagor, E., and Wong, R. O. (eds.) (2006). Mechanisms of Retinal Development. Cambridge: Cambridge University Press.

Elstrott, J., Anishchenko, A., Greschner, M., et al. (2008). Direction selectivity in the retina is established independent of visual experience and cholinergic retinal waves. Neuron 58: 499–506.

Fisher, L. J. (1979). Development of synaptic arrays in the inner plexiform layer of neonatal mouse retina. Journal of Comparative Neurology 187: 359–372.

Fuerst, P. G., Koizumi, A., Masland, R. H., and Burgess, R. W. (2008). Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature 451: 470–474.

Galli-Resta, L., Leone, P., Bottari, D., et al. (2008). The genesis of retinal architecture: An emerging role for mechanical interactions? Progress in Retinal and Eye Research 27: 260–283.

Godinho, L., Mumm, J. S., Williams, P. R., et al. (2005). Targeting of amacrine cell neurites to appropriate synaptic

laminae in the developing zebrafish retina. Development 132: 5069–5079.

Haverkamp, S., Michalakis, S., Claes, E., et al. (2006). Synaptic plasticity in CNGA3( / ) mice: Cone bipolar cells react on the missing cone input and form ectopic synapses with rods. Journal of Neuroscience 26: 5248–5255.

Kay, J. N., Roeser, T., Mumm, J. S., et al. (2004). Transient requirement for ganglion cells during assembly of retinal synaptic layers. Development 131: 1331–1342.

Morest, D. K. (1970). The pattern of neurogenesis in the retina of the rat. Zeitschrift fu¨r Anatomie und Entwicklungsgeschichte 131: 45–67.

Morgan, J. L., Schubert, T., and Wong, R. O. (2008). Developmental patterning of glutamatergic synapses onto retinal ganglion cells.

Neural Development 3: 8.

Mumm, J. S., Williams, P. R., Godinho, L., et al. (2006). In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells. Neuron 52: 609–621.

Nishimura, Y. and Rakic, P. (1987). Development of the rhesus monkey retina: II. A three-dimensional analysis of the sequences of synaptic combinations in the inner plexiform layer. Journal of Comparative Neurology 262: 290–313.

Schmitt, E. A. and Dowling, J. E. (1999). Early retinal development in the zebrafish, Danio rerio: Light and electron microscopic analyses.

Journal of Comparative Neurology 404: 515–536.

Sernagor, E., Eglen, S. J., Harrris, W., and Wong, R. O. L. (eds.) (2006). Retinal Development. Cambridge: Cambridge University Press.

Sernagor, E., Eglen, S. J., and Wong, R. O. (2001). Development of retinal ganglion cell structure and function. Progress in Retinal and Eye Research 20: 139–174.

Strettoi, E., Mears, A. J., and Swaroop, A. (2004). Recruitment of the rod pathway by cones in the absence of rods. Journal of Neuroscience 24: 7576–7582.

Yamagata, M. and Sanes, J. R. (2008). Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 451: 465–469.

Ischemic Optic Neuropathy

S S Hayreh, University of Iowa, Iowa City, IA, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

Afferent pupillary defect – Reduction in the response of the pupil to direct light.

Giant cell arteritis – An inflammation of the arterial wall, affecting medium and large size arteries.

Ischemic optic neuropathy constitutes one of the major causes of blindness or seriously impaired vision among the middle-aged and elderly population, although no age is immune. Its pathogenesis, clinical features, and management are discussed in this article.

Classification

Ischemic optic neuropathy is an acute ischemic disorder of the optic nerve. Based on the blood-supply pattern, the optic nerve can be divided into two very distinct parts:

(1)the anterior part (called the optic nerve head) and

(2)the rest of the optic nerve (Figure 1). Ischemic optic neuropathy is of two distinct types.

1.Anterior ischemic optic neuropathy (AION). This is due to ischemia of the anterior part of the optic nerve, which is supplied by the posterior ciliary artery (PCA) circulation. Etiologically and pathogenetically, AION is of the following two types: (a) arteritic AION (A-AION), which is due to giant cell arteritis (GCA), and (b) nonarteritic AION (NA-AION), which is due to all other causes and not GCA.

2.Posterior ischemic optic neuropathy (PION). This is due to ischemia of a segment of the rest of the optic nerve, which is supplied by multiple sources but not the PCA (Figure 1).

Nonarteritic Anterior Ischemic Optic

Neuropathy

This is the most common type of ischemic optic neuropathy and has attracted the most controversy about its pathogenesis and management.

Pathogenesis

Nonarteritic anterior ischemic optic neuropathy (NAAION) is caused by acute ischemia of the optic nerve head, whose main source of blood supply is from the PCA

circulation (Figure 1). Marked interindividual variations in the blood supply of the optic nerve head and its bloodflow patterns profoundly influence the pathogenesis and clinical features of NA-AION.

Etiologically and pathogenetically, NA-AION is of two types:

1.Transient nonperfusion or hypoperfusion of the optic nerve head circulation. This is by far the most common cause of NA-AION. All the available evidence indicates that NA-AION is not a thromboembolic disorder. The mechanism causing transient nonperfusion or hypoperfusion of the optic nerve head circulation in NA-AION is multifactorial in nature. In the vast majority of cases, it is a transient fall of blood pressure, most commonly during sleep (nocturnal arterial hypotension – Figure 2) or a nap during the day. Any kind of shock also can cause a transient marked fall of blood pressure. A sharp rise in the intraocular pressure to high levels, as in neovascular glaucoma associated with ocular ischemia, or angle closure glaucoma, can also cause a transient fall in perfusion pressure in the optic nerve head, where perfusion pressure is equal to mean blood pressure minus the intraocular pressure.

A transient fall of perfusion pressure in the optic nerve head vessels below the critical autoregulatory range level in susceptible persons results in ischemia of the optic nerve head and development of NA-AION. The severity of the ischemia may vary from mild to marked, depending upon the severity and duration of the transient ischemia, and upon other factors influencing the blood flow in the optic nerve head.

2.Embolic lesions of the arteries/arterioles feeding the optic nerve head. This is a rare cause of NA-AION. Compared to the hypotensive type of NA-AION, the extent of optic nerve head damage in this type is usually massive, severe, and permanent.

Risk Factors for Development of NA-AION

All available evidence indicates that NA-AION is multifactorial in nature. The risk factors fall into two main categories:

1.Predisposing risk factors:

(a)Systemic. These include arterial hypertension, nocturnal arterial hypotension, diabetes mellitus, ischemic heart disease, hyperlipidemia, atherosclerosis

Blood pressure (mmHg)

280

260

240

220

200

180

160

140

120

100

80

60

40

20

Time (h)

and arteriosclerosis, sleep apnea, arterial hypotension due to any cause, and migraine.

(b)Risk factors in the eye and/or the optic nerve head. These include absent or small cup in the optic disk, marked optic disk edema, raised intraocular pressure, and optic disk drusen. There is a misconception in the ophthalmic community that a small or absent cup is actually the primary factor in the development of the disease; this has resulted in catchy terms like ‘‘disk at risk’’. However, in the multifactorial scenario of the pathogenesis of NA-AION, an absent or small cup is simply a secondary contributing factor once the process of NA-AION has started.

2.Precipitating risk factor(s): in a person with predisposing risk factors present, a precipitating risk factor acts as the final insult (last straw), resulting in ischemia of the optic nerve head and NA-AION. Nocturnal arterial hypotension (Figure 2) is the most important factor in this category. Studies have shown that patients with NA-AION typically discover visual loss on waking in the morning, indicating that NA-AION developed during sleep when there is invariably a fall of blood pressure.

Conclusion

A host of systemic and local factors, acting in different combinations and to different extents, may derange the optic nerve head circulation, with some increasing optic nerve head susceptibility to ischemia and others acting as the final insult. Nocturnal arterial hypotension seems to be an important precipitating factor in the susceptible patient. Thus, the pathogenesis of NA-AION is complex but, not, as often stated, unknown.

There is a common perception among ophthalmologists and neurologists that NA-AION and cerebral stroke are similar in nature pathogenetically and in management. It is well established that stroke is a thromboembolic disorder. However, available evidence indicates that NA-AION is pathogenetically a hypotensive disorder, not a thromboembolic disorder. In NA-AION, unlike stroke, (1) there is no association between smoking and NA-AION; (2) aspirin has no beneficial effects in NA-AION; (3) no significant association has been found between NA-AION and thrombophilic risk factors; (4) fluorescein fundus angiography during the early stages of onset of visual loss invariably shows no evidence of complete occlusion of the vessels supplying the optic nerve head (Figures 3(a) and 3(b)); and (5) 41% of NA-AION eyes show spontaneous visual improvement, which is rare in a thromboembolic disorder.

Clinical Features of NA-AION

NA-AION is the most common type of ischemic optic neuropathy. It usually has classical symptoms and signs. NA-AION is mostly a disease of the middle-aged and

(a)

(b)

Figure 3 Fluorescein fundus angiograms of eyes with NA-AION. (a) Shows non-filling of temporal part of the peripapillary choroid (oblique arrow) and adjacent optic disk and the choroidal watershed zone (horizontal arrow). (b) Shows non-filling of the choroidal watershed zone (vertical dark band: arrows) between the lateral and medial PCAs and of the temporal part of optic disk. Reproduced from Hayreh, S. S. (1985). Interindividual variation in blood supply of the optic nerve head. Its importance in various ischemic disorders of the optic nerve head, and glaucoma, low-tension glaucoma and allied disorders.

Documenta Ophthalmologica 59: 217–246.

elderly population, although no age is immune. It has been reported in twenty-three percent of patients with NA-AION are under the age of 50 years. It is far more common among the white population than in other racial groups.

1.Symptoms. In the vast majority of patients, there is a sudden and painless deterioration of vision, usually

discovered on waking in the morning. NA-AION patients often complain of loss of vision toward the nose and less often in the lower part. Later on,

photophobia is a common complaint. Simultaneous bilateral onset of NA-AION is extremely rare.

2.Signs. Initial visual acuity may vary from 20/20 (better than 20/40 in 33%) to marked loss. Therefore, a normal visual acuity does not rule out NA-AION. An inferior nasal visual field defect is the most common, followed by an inferior altitudinal defect; a combination of a relative inferior altitudinal defect with absolute inferior nasal defect is the most common pattern in NA-AION (Figures 4(a) and 4(b)). The eye shows the presence of a relative afferent pupillary defect in unilateral NA-AION cases, and in some there may be raised intraocular pressure.

Figure 4 Visual-field defects in NA-AION, plotted with Goldmann perimeter using I-2e, I-4e, and V-4e targets, where the Roman numeral indicates target size, the Arabic numeral indicates relative intensity, and the lowercase letter indicates minor filter adjustment of the light intensity. (a) Shows an inferior altitudinal defect with I-2e and an inferior nasal defect with I-4e and V-4e. (b) Shows an absolute inferior altitudinal defect with I-2e, I-4e, and V-4e. The visual acuity in both eyes was 20/20. Reproduced from Hayreh et al. (2005) Archives of Ophthalmology 123:1554–1562.

misconceptions about optic disk edema in NA-AION. The most common one is that in NA-AION the optic disk edema is always pale, which is not at all true initially because the color of optic disk edema in NA-ION initially does not differ from that due to other causes; in some cases there may even be hyperemia of the optic disk (Figures 5 and 6(a)). A splinter hemorrhage at the disk margin is common (Figure 7). The optic disk edema resolves spontaneously in about 8 weeks, and the disk develops segmental or generalized pallor (Figure 6(b)). In the normal fellow eye, the optic disk usually shows either no cup or a small cup, which can be a helpful clue in the diagnosis of NA-AION in doubtful cases.

In diabetics, optic disk changes in NA-AION may have some characteristic diagnostic features. During the initial stages, the optic disk edema is usually, but not always, associated with characteristic prominent, dilated, and frequently telangiectatic vessels over the disk and many more peripapillary retinal hemorrhages than in nondiabetics (Figures 8(a) and 8(c)). Because of these disk changes, NA-AION in diabetics has been mistakenly diagnosed as diabetic papillopathy. With the resolution of optic disk edema, vascular changes and hemorrhages also resolve spontaneously (Figures 8(b) and 8(d)).

Fluorescein fundus angiography, at the onset of NAAION, during the very early phase of dye filling in the fundus almost invariably shows delayed filling of the prelaminar region and the peripapillary choroid (Figure 3(a)) and/or choroidal watershed zone (Figure 3(b)).

Bilateral NA-AION

The cumulative probability of the fellow eye developing NA-AION has varied among different studies: 25%

Figure 5 Left fundus photograph showing optic disk edema and hyperemia during the acute phase of NA-AION.

(a)

(b)

Figure 6 Fundus photographs of left eye of a 53-year-old man.

(a)With optic disk edema during the active phase of NA-AION.

(b)After resolution of optic disk edema and development of optic disk pallor – more marked in the temporal part than in the nasal part.

within 3 years, 17% in 5 years, and 15% over 5 years. Diabetics have a significantly (p ¼ 0.003) greater risk than non-diabetics of NA-AION in the second eye as well as earlier involvement. Simultaneous bilateral onset of NA-AION is extremely rare, except in patients who develop sudden, severe arterial hypotension, for example during hemodialysis or surgical shock.

Recurrence of NA-AION in the same eye

In a study of 829 NA-AION eyes, the overall cumulative percentage of recurrence of NA-AION in the same eye at 2 years was 5.8%. The only significant association for recurrence of NA-AION was with nocturnal arterial hypotension.

NA-AION and phosphodiesterase-5 inhibitors

These agents are currently popular for erectile dysfunction. A critical review of all the reported cases usually shows a good temporal relationship between the ingestion

Figure 7 Right fundus photograph showing optic disk edema and hyperemia, with a splinter hemorrhage (arrow) during the acute phase of NA-AION.

of Viagra and other phosphodiesterase-5 inhibitors and the development of NA-AION, in persons who already have predisposing risk factors.

Amiodarone and NA-AION

There is a universal belief that amiodarone causes optic neuropathy, called ‘‘amiodarone-induced optic neuropathy’’. However, it is NA-AION produced in the multifactorial scenario by the systemic cardiovascular risk factors for which the drug is given rather than amiodarone per se causing it.

Familial NA-AION

There are five reports in the literature representing 10 unrelated families in which more than one member developed NA-AION. It is clinically similar to the classical nonfamilial NA-AION, with the exception that familial NA-AION occurs in younger patients and has much higher involvement of both eyes than the classical NA-AION. The role of genetic factors in familial NA-AION is not known.

Management of NA-AION

The outcome of all advocated treatments has to be compared with the natural history of a disease, so that natural recovery is not attributed to the beneficial effect of a mode of treatment. Therefore, it is essential to first consider the natural history of visual outcome in NA-AION. This has been investigated by two prospective studies in patients seen within 2 weeks of onset of visual loss and initial visual acuity of 20/70 or worse. Both showed spontaneous visual acuity improvement in 41–43% of the patients and worsening in 15–19% at 6 months. Evaluation of visual fields