The vascular supply of the optic nerve head is complex and remains incompletely delineated. Over the past 50 years, various investigators have attempted to clarify the relative contributions of the choroid, the short posterior ciliary arteries and the central retinal artery to the vascular beds of the inner retinal, prelaminar, laminar and retrolaminar segments of the nerve head. Conflicting theories have evolved, in no small part due to differing techniques of study, involving both flow parameters and anatomical constructs. These have included studies, both in normal subjects and in those with optic nerve ischaemia, of histopathology, electron microscopic corrosion casting, orbital colour Doppler flow studies, fluorescein angiography, indocyanine green angiography, laser Doppler flow studies, laser speckle flowgraphy, microperfusion and labelling studies and optical coherence tomography angiography. The nature of the optic disc, peripapillary retina and choroid microvasculature has implications for the pathophysiology of ischaemic optic neuropathy.
- Optic Nerve
- Visual pathway
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Seminal studies between 1969 and 1976 highlighted the controversy regarding the contribution of the peripapillary choroid to the optic disc microvasculature. Henkind and Levitzky1 studied human and other primate eyes in serial cross-section, in some cases after intravascular injection of India ink. They concluded that the optic disc was supplied by branches of both choroidal and short posterior ciliary arterioles (SPCA) at the level of the choroid but they could not distinguish between the two origins. No contribution from the central retinal artery system (CRA) as detected. Hayreh,2 based on neoprene latex injection studies, histology and fluorescein angiography (FA), concluded that the laminar region was supplied by branches of the SPCA, the prelaminar segment from the peripapillary choroid, and the surface nerve fibre layer from the CRA, with no connection between the surface and the deeper vascular beds. Anderson and Braverman3 evaluated the vasculature of human and monkey specimens using light microscopy, with several monkeys also studied after injection of liquid silicone rubber. They concluded that the disc was supplied primarily by branches of the SPCA’s, some of which directly entered the disc, while others entered via the choroid. They emphasised that the choroidal circulation itself was not a significant supply to the optic nerve head and was a separate circulation system. Lieberman et al,4 based on serial sectioning of human autopsy eyes, came to a similar conclusion: that the vessels supplying the prelaminar and laminar regions of the disc are SPCA branches, some of which pass via the peripapillary choroid. A significant contribution from the CRA was not identified.
More recently, the technique of microperfusion and labelling has been applied to the study of the optic nerve head vascular supply. Yu et al 5 cannulated the CRA and SPCA’s in 18 human donor eyes, using fluorescent probes to perfuse through them, labelling the microvasculature of the retina, optic nerve head and choroid. In these studies, perfusion through both the CRA and the SPCA produced labelling of optic nerve head vessels, suggesting a component of CRA supply to this region.
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.
How have these techniques been applied to the study of ischaemic damage of the optic disc?
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.
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.
Colour Doppler flow studies
In the early 1990’s, Colour Doppler flow entered limited use as a method to measure vascular flow velocities and calculated resistance of the ophthalmic arteries, CRA and SPCA, using duplex ultrasonography. Flaharty et al 32 measured these variables in a series of patients with NAION, using fellow eyes as controls. Both CRA and SPCA velocities were lower in NAION than in control eyes, which was interpreted as showing initial flow impairment in NAION. The technique has limited value for this vascular system. First, it measures flow velocity rather than volume; increase in velocity may actually indicate a decrease in blood flow due to stenosis. Second, flow volume itself cannot be measured accurately because the diameter of the specific vessels measured is not known. Third, measuring the flow parameters in the orbit may not represent flow parameters within the eye.
Laser Doppler flow studies
Scanning laser Doppler imaging methods primarily measure surface blood flow derived from the retinal arterial circulation. Newer Laser Doppler flow (LDF) techniques may reach depths of up to 1000 µm, possibly including a component of SPCA-derived circulation, although specific contributions from various circulatory components are not measured. In evaluating LDF measurements of optic disc blood flow in rhesus monkey eyes after manipulation of ciliary and retinal circulations, Petrig et al 33 found that flow measurements were decreased with occlusion of the CRA, but not the PCAs. Collignon-Robe et al 34 reported that optic nerve head blood flow, as measured by LDF, was diminished in NAION compared with fellow eyes. The decrease in surface disc microvasculature during the oedematous phase correlates with findings noted previously on FA and currently on optical coherence tomography angiography (OCTA) (see below).
Laser speckle flowgraphy
Laser speckle flowgraphy allows for a measure of blood flow by analysing laser refraction by red blood cells, with the advantage that values for deeper tissues than by LDF may be obtained. Maekubo et al 35 used this technique to differentiate optic disc vasculature in NAION from that in papillitis, finding that a significant decrease in blood flow was present in NAION (compared with fellow eyes), but not in ON. The technique purportedly measured as deep as the lamina cribrosa, but also included calculations more superficially. The precise layers in which blood flow was diminished remain unclear, but the inclusion of superficial vascularity decrease parallels that seen by other techniques.
Optical coherence tomography angiography
OCTA compares the decorrelation signal between sequential OCT B-scans taken at a single cross section (motion contrast), within the region studied. The technique registers focal regions of flow, characterising the size and geometry of microvasculature based on a binary representation (present or absent) of flow at each point measured, rather than quantification of flow volume. While OCTA may allow study at greater depths of the optic disc than FA in non-oedematous discs, the presence of oedema creates significant artefact by blocking the signal from deeper tissues. Current techniques do not reliably eliminate this issue, but study of the superficial and laminar regions is possible. A number of small studies designed to differentiate ischaemic from non-ischaemic disc oedema have consistently shown a decreased vascular density, both qualitatively and quantitatively, in both the superficial disc and the superficial peripapillary retina in NAION when compared with non-ischaemic oedema such as papilloedema and papillitis.36–39 Our recent studies are consistent with these findings (figures 2 and 3); preliminary findings also suggest a decrease at the laminar level. One series documented superficial increase in some cases consistent with that seen focally on FA.40 It is of interest that macular vessel density decrease paralleling the optic disc and peripapillary retinal findings has been documented as well.41 OCTA, therefore, seems to corroborate other techniques in showing a decrease in disc vascularity in the oedematous phase of NAION. These findings in the superficial disc and peripapillary retina refocus us on this aspect of the pathophysiology of NAION: if the majority of the disc is supplied by the SPCA’s, and the documented infarctions seen in NAION are located in their territories, the retrolaminar and, less commonly, the laminar layers, what role do the abnormalities in the superficial layers play?
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.
Data availability statement
No data are available.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.