Anatomic studies: electron microscopic corrosion casting

These findings were supported by electron microscopic corrosion cast studies performed in primates by Risco et al 6 and by two landmark studies in human cadaver eyes. Risco et al concluded that the prelaminar optic disc received its blood supply from both direct branches of the SPCA’s entering the disc and indirect branches flowing through the choroid to the disc. The choriocapillaris was not seen to supply the disc. Both Olver et al 7 and Onda et al 8 studied human autopsy eyes by similar techniques and focused on the presence of partial or complete forms of the ‘circle of Zinn’ as the ‘arteriolar intrascleral anastomosis between branches of the medial and lateral paraoptic SPCA’s.’ Olver et al not only confirmed that it was these direct (paraoptic) branches rather than the choroidal branches of the SPCA’s that supplied the disc, but also that, in contrast to earlier studies, these vessels supplied the retrolaminar disc, in addition to the prelaminar portion. The findings are significant not only in focusing on the retrolaminar region which is most frequently the site of infarction in non-arteritic arteritic anterior ischaemic optic neuropathy (NAION), but on the semicircular components of the full circle as a potential correlation with the altitudinal nature of visual field loss in NAION. The CRA was not shown to contribute significantly to the supply of this region in either study.

Optic nerve head blood flow studies: FA

While the anatomic studies provide one essential aspect of the disc microcirculation, they do not assess dynamic blood flow characteristics.

Hill9 and O’Day et al 10 described FA characteristics of optic disc filling patterns suggesting two separate systems with no significant interconnection: the early ‘deep glow’ felt to represent the microvascularity of the prelaminar/laminar region, with onset synchronous with onset of choroidal fluorescence; and the later superficial radial vessels, filling with the earliest appearance of dye in the CRA. Hayreh,2 along with Shimizu,11 and Piermarocchi,12 interpreted the simultaneous choroidal and prelaminar optic disc filling to indicate direct supply of this region by the choroid rather than by direct SPCA branches. Later studies by Ernest and Archer,13 and cineangiography by Evans et al, 14 however, showed that it was not the choroid directly but SPCA paraoptic branches filling simultaneously with it, that supplied this layer of the disc. There was general agreement by these investigators that the surface layer of the disc was supplied by the CRA branches and that there was no interconnection with deeper layers.

Studies of choroidal angiography generally show segmental filling throughout the fundus, with a so-called ‘watershed zone,’ representing relatively delayed filling in the region between the territories supplied by the medial and lateral posterior ciliary arteries, not infrequently seen. The optic disc is located within this zone (encompassing at least 1/2 of the optic disc border) in a significant minority of patients; Arnold and Hepler15 documented this feature in 42% of 43 normal subjects, while Giuffre16 and Oto et al 17 recorded 24% and 22%, respectively. In contrast, Hayreh18 reported a figure of 86%. The significance of this feature with regard to optic disc vascular supply has been debated.

Histopathology

What is the histopathological evidence that there is occlusive vasculopathy within the optic disc microcirculation in NAION and that the optic nerve damage is truly ischaemic? In arteritic anterior ischaemic optic neuropathy (AAION), there is extensive histopathologic documentation of infarction in the paralaminar regions of the optic nerve head along with inflammation, thrombosis and occlusion within the SPCA’s.19 20 While these findings confirm that SPCA occlusion can and does produce optic disc infarction, the corresponding evidence that this takes place in NAION is lacking. Isolated clinical case reports of NAION, none of them typical clinically, have documented the presence of infarcts. Knox et al 21 documented histopathological evidence of infarction in a large study of autopsy eyes, but clinical data were largely unreported, precluding the clinical diagnosis of idiopathic NAION. No confirmation of lipohyalinosis or other occlusive process within the disc vascular supply has been documented in these or other cases; the location of vascular compromise in NAION remains undocumented by histopathology. A key feature is evident from histopathological studies of both AAION and NAION: infarction is primarily located in the retrolaminar region of the optic nerve head, with occasional extension to the laminar and prelaminar layers. This pattern speaks against a primary role for the choroidal circulation in pathogenesis. Although the proportion of the optic disc vasculature supplied by the peripapillary choroid has been controversial, researchers agree that the choroidal contribution is primarily to the prelaminar, not laminar or postlaminar layers. Infarction originating more posteriorly implicates the SPCA branches directly supplying the optic disc.

FA/indocyanine green angiography

Fluorescein angiographic studies in AAION consistently show severely impaired filling of the optic disc and the peripapillary choroid.22–25 In NAION, studies show similarly delayed filling of at least a segment of the optic disc (but not the peripapillary choroid, see below) in the oedematous phase, prior to the development of the impaired filling that eventually comes with any form of atrophy (due to loss of supporting vasculature). This in vivo evidence of optic disc circulatory impairment in NAION was clearly documented by Hayreh and by Eagling et al.22 26 Later studies by Arnold et al 15 27 28 confirmed that delayed prelaminar optic disc filling (>5 s later than choroid and retinal vasculature) was noted in 76% of subjects with acute NAION, compared with no delay in normal controls or in subjects with non-ischaemic optic disc oedema. This suggests that the delayed filling is a primary process rather than one secondary to disc oedema. In their studies, the overlying disc surface vasculature, presumed derived from the retinal arterial circulation, showed variable filling patterns. In all cases, a substantial portion filled poorly, delayed until the late leakage occurred (figures 1 and 2). In 54% of cases, a segment of the disc surface demonstrated early hyperfluorescence. It has been postulated that this vascular dilation, most often sectoral, may be analogous to the ‘luxury perfusion’ seen at the junction of perfused and nonperfused regions in cerebral infarctions, perhaps a manifestation of shunting to relatively spared regions of the disc in NAION.15 29 These segments did not correlate with the sectors of visual field loss documented. The significance of the poorly filling superficial disc vasculature segments in the pathogenesis of NAION remains unclear.

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Figure 1

Top: Fluorescein angiography in NAION, arteriovenous phase. Early optic disc filling of both laminar and superficial optic disc layers is markedly delayed. The peripapillary choroid has filled normally. Bottom: Fluorescein angiography in NAION, arteriovenous phase. Similar picture of filling delay in both layers, with a focal region of preserved filling of superficial layer temporally. The peripapillary choroid has filled normally. NAION, non-arteritic anterior ischaemic optic neuropathy.

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Figure 2

Swept source en face OCTA images in NAION, superficial layer (segmentation below). Top left: Qualitative image of disc and peripapillary retina. Bottom left: Quantitative image of disc with vascular density calculation, 23.48%. Top right: Quantitative image of peripapillary retina with vascular density calculation, 33.40%. Vascular density calculations exclude major vessels. Bottom right: B-scan image demonstrating segmentation at superficial level. NAION, non-arteritic anterior ischaemic optic neuropathy, OCTA, optical coherence tomography angiography.

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Figure 3

Swept source en face OCTA images in idiopathic intracranial hypertension with papilloedema, superficial layer (segmentation below). Top left: Qualitative image of disc and peripapillary retina. Bottom left: Quantitative image of disc with vascular density calculation, 38.23%. Top right: Quantitative image of peripapillary retina with vascular density calculation, 38.20%. Vascular density calculations exclude major vessels. Bottom right: B-scan image demonstrating segmentation at superficial level. OCTA, optical coherence tomography angiography.

Whether the location of the optic disc within a watershed zone between territories supplied by the PCA branches is a major factor in the development of optic nerve ischaemia has been controversial. Hayreh26 postulated that impaired perfusion pressure within such a region predisposes the optic disc to infarction, reporting that a majority of cases demonstrated this feature. In the study of Arnold and Hepler,15 however, significantly delayed filling (>5 s) of a vertical watershed zone encompassing at least one half of the optic disc border was recorded more often in normal subjects (42%) than in patients with NAION (27%) . Filling of the disc located within these zones, either in normal subjects or in NAION, did not correlate with adjacent choroidal filling. Normal regions of optic disc filling were seen adjacent to delayed filling choroidal segments in 39% in NAION and 58% of normal. The lack of correlation of disc and choroidal filling would mitigate against watershed ischaemia as a cause of NAION, as disc and parapapillary choroidal flow would be expected to slow together. Moreover, the choriocapillaris, which is the layer visualised on FA and whose absence is interpreted as a watershed zone, does not materially contribute to the laminar region optic disc vascular supply. While the location of the optic disc at the limit of the distribution of a PCA may predispose it to ischaemic damage if there is significantly decreased PCA flow, as evidenced by the delayed flow in the PCA and choroid seen in some cases, this is not consistently documented. Fluorescein angiographic findings are more consistent with impaired flow in the direct paraoptic branches to the disc rather than a watershed phenomenon. Similar findings regarding the peripapillary choroid have been reported with indocyanine green (ICG) studies, which show substantial filling abnormalities in AAION but not in NAION.17 30 31

Non-invasive vascular imaging

Other techniques to assess vascular flow to the optic disc, either macroscopically or microscopically, have primarily been used for comparisons of ischaemic conditions to normal, rather than delineating origins of various disc layers.

Implications for optic disc ischaemia

The studies in aggregate confirm both delayed flow and decreased vascular density in the laminar region of the optic disc without corresponding changes in the peripapillary choroid, consistent with the assumptions that NAION is associated with impaired perfusion in the territory of the paraoptic branches of the SPCA’s. The additional correlated findings of delayed flow and decreased vascular density on the surface of the optic disc, primarily supplied by CRA branches, have not previously been emphasised; moreover, the relatively spared regions of this surface flow and the correlation with sparing of ischaemic damage, have not been explored. In addition, decreased vascular density in the peripapillary retina, also supplied via the CRA branches, is unexplained in NAION. Regions of spared disc surface microvasculature in NAION have been proposed to represent ‘luxury perfusion’ adjacent to ischaemic sectors. An alternative explanation might be that the collateral supply provided by the longitudinal connections between CRA and SPCA branches in the optic disc may allow for ischaemia without infarction; this might be either segmental (in typical NAION), or for the entire optic disc (in cases such as diabetic papillopathy). The possibility exists that for infarction to occur, impairment of both SPCA and CRA supplies must be present.