1.3 Vascular Anatomy

Traction by these Þbers transmitted to the macular Muller cells may predispose them to swell. Plasmin, which cleaves these molecules and leads to posterior vitreous detachment, has been used to intentionally produce PVD in eyes with BRVO with the effect of reducing associated macular edema.31,32 Although vitreous traction on retinal veins has been suggested as a contributing factor in BRVO in certain cases, the idea is speculative in the cited cases.33

1.3 Vascular Anatomy

The key concepts in understanding ocular vascular anatomy are the dual blood supply to the eye and retinal vascular anastomoses. The dual sources of blood to the eye are the central retinal artery and the posterior ciliary arteries. Anastomoses between ocular vascular substructures are often of little importance under physiologic conditions but can become important if RVO develops.34

The blood supply to the eye comes from the ophthalmic artery, which derives from the internal carotid artery in 98% of cases and from the middle meningeal artery in 2% of cases.35 Just after the internal carotid artery passes through the cavernous sinus, the ophthalmic artery emerges and enters the orbit through the optic canal along the inferolateral aspect of the optic nerve (Figs. 1.5, 1.6, and 1.7).37 The ophthalmic artery

has a diameter of approximately 300 m.38 The ophthalmic artery then crosses from the lateral to medial orbit, in 80% of cases traveling above the nerve and in the other 20% below the nerve.35,36 The central retinal artery (CRA) and one to Þve posterior ciliary arteries (PCAs) issue from the ophthalmic artery. In most cases (77%), the central retinal artery emanates from the ophthalmic artery before the posterior ciliary arteries, but there are many exceptions.25,37 In 38% of cases, the central retinal artery is an independent branch of the ophthalmic artery, but in a greater fraction, it is a branch off of a common trunk that also supplies the medial or lateral posterior ciliary arteries or both.35 The variable distance between the origin of the central retinal artery and the origin of the cilioretinal artery is one hypothetical basis for the occasionally noted lower intravascular pressure of the posterior ciliary arteries compared to the central retinal artery.39,40

The posterior ciliary arteries divide into 10Ð20 short posterior ciliary arteries that enter the sclera close to the optic nerve (paraoptic short posterior ciliary arteries) or a short distance from the optic nerve laterally and medially (distal short posterior ciliary arteries) (Fig. 1.8). The short posterior ciliary arteries supply blood and oxygen to the optic nerve, the choroidal circulation up to the equator, the retinal pigment epithelium, and the outer 130 m of the retina.41 Eighty-Þve percent of the intraocular blood ßow is allocated to the choroidal circulation via the posterior ciliary arteries.42 Branches of

Fig. 1.5 Arterial supply of the right eye and orbit as viewed from the temporal side of the skull. The ophthalmic artery enters the orbit on the inferolateral side of the optic nerve and gives off the central retinal artery and posterior ciliary arteries near the orbital apex (Redrawn from Singh35)

Posterior ciliary arteries

Optic nerve

Internal carotid artery

Ophthalmic

artery

Central retinal artery

Fig. 1.6 The yellow structure represents the position of the optic nerve relative to the orbital arteries. OA ophthalmic artery, CRA central retinal artery, PC posterior ciliary arteries, Lac lacrimal artery, LP lateral palpebral artery, IO infraorbital artery, ZT zygomaticotemporal artery, ZF zymaticofacial artery, Mid men middle

meningeal artery, Rec meningeal recurrent meningeal artery, Ang angular artery, MP medial palpebral artery, DN dorsal nasal artery, ST supratrochlear artery, SO supraorbital artery, AE anterior ethmoidal artery, PE posterior ethmoidal artery (Redrawn from Rene36)

Fig. 1.7 The arterial supply to the right globe as seen from the top (Redrawn from Singh and Dass35)

the short posterior ciliary arteries form a variable circle, called the peripapillary arterial circle of ZinnÐHaller, around the optic disc (Fig. 1.9).42,46

The remaining 15% of intraocular blood ßow comes from the central retinal artery which supplies the retinal vasculature.42 The central retinal artery pierces the optic nerve from 5 to 16 mm behind the globe (Fig. 1.9).35,36,40,47 Within the optic nerve, the central retinal artery travels centrally enclosed in a Þbrous tissue envelope continuous with the Þbrous septa of the optic nerve (Fig. 1.10).47 This Þbrous sheath is relatively indistensible, and pulsations of the central retinal artery during the cardiac cycle produce in-phase venous pulsations in the adjacent central retinal vein, a phenomenon explained when it was not found in a patient who had a congenitally variant hemicentral retinal vein that directly entered the choroid outside of the optic nerve.48 There are many microanastomoses of the central retinal artery via its small pial branches with other branches of the ophthalmic artery, but no

Fig. 1.8 Diagram of the posterior ciliary arteries. (a) Top view

(b) Rear view (Redrawn from Singh and Dass35)

a

Long PCA

MPCA

A

ON

CZ

Fig. 1.9 Diagram of the optic nerve, optic disc, and peripapillary structures of the left eye. The temporal optic nerve is on the right side of the diagram so that the central retinal artery is nasal to the central retinal vein. CAR cen-

tral artery of the retina, CRV central retinal vein, PCA posterior ciliary artery, CZ circle of Zinn, ON optic nerve, D dura, A arachnoid, R retina, C choroid, S sclera (Redrawn from Hayreh45)

Fig. 1.10 Diagram of the arterial blood supply to the prelaminar optic nerve of the left eye. Choroidal arterioles supply centripetal arterioles that penetrate the prelaminar optic nerve, more densely temporally than nasally. In this diagram, temporal is to the right (Redrawn from Hayreh44)

Nasal

Choroidal

vessels

Central retinal artery

Central retinal vein

Temporal

Prelaminar region of optic disc

The blood supply to the optic disc can be divided into three parts: the surface layer of the optic disc, the prelaminar region, and the lamina cribrosa.44 The capillaries on the surface of the optic disc stem from arterioles of the peripapillary retina and the optic disc. These capillaries are continuous with the radial peripapillary capillaries and other capillaries of the peripapillary retina and the capillaries of the deeper layers of the optic nerve. The prelaminar optic nerve is supplied by centripetal arterioles from the peripapillary choroid and thus is dependent on posterior ciliary circulation (Fig. 1.10).42 These are sectoral end arterioles communicating little with adjacent vessels. Thus, the prelaminar optic nerve is not nourished by the central retinal artery but rather by the choroidal blood supply. The capillaries of the superÞcial and prelaminar optic disc are anastomotic, however. Therefore, in CRAO, there is a small amount of blood ßow emanating from the deeper optic nerve head that can perfuse the peripapillary retina.58 The lamina cribrosa derives its arteriolar blood supply from branches of the posterior ciliary arteries or from branches of the arterial circle of Zinn, which is itself supplied by the posterior ciliary arteries.42 The venous drainage of the optic disc is primarily the central retinal vein, although the prelaminar optic disc drains to choroidal veins as well through the aforementioned microanastomoses.

The arteries supply the retinal capillaries that dramatically increase the surface area for transfer of oxygen and other small molecules to the adjacent interstitium. Retinal capillaries reside within various lamina of the inner retina. During normal development, astrocytes in the retina produce vascular endothelial growth factor (VEGF) that induces development of the superÞcial capillary bed. Later, photoreceptor development in the outer retina causes hypoxia of the inner retina with upregulation of vascular endothelial growth factor (VEGF) from the inner nuclear layer and development of the deeper capillary bed within the inner retina.59 Astrocytes and retinal capillaries colocalize within the retina. Astrocytes and capillaries are absent from the foveal avascular zone and in the immediately postoral retina.34

A superÞcial network of capillaries called the radial peripapillary capillaries (RPCs) surround the optic nerve (Fig. 1.11).60 These capillaries lie in the superÞcial nerve Þber layer and preferentially nourish that layer but derive from arterioles located deeper at the levels of the outer nerve Þber layer and ganglion cell layer.11 The RPCs are arranged in parallel rows rather than in the anastomotic net typical of the deeper retinal capillaries. RPCs connect rarely with each other or with deeper retinal capillaries and run parallel to major retinal arteries, rarely crossing them.60 As their distribution parallels nerve Þber bundles and resembles the distribution of cotton wool spots in central retinal vein occlusion (CRVO), they may be important in the pathogenesis of Bjerrum scotomata in glaucoma and in cotton wool spots in RVO.11,60,62

Besides the RPCs, capillaries of the inner retina assume locations at four depths depending on the thickness of the ganglion cell layer.61 One lamina of capillaries is present in the nerve Þber layer and ganglion cell layer. Capillaries are regularly found at the outer and inner borders of the inner nuclear layer (which is approximately 40 m thick), are missing in the inner plexiform layer (approximately 30 m thick), and are found at the inner or outer boundaries of the ganglion cell layer for the parts where it is approximately 30 m thick and also within the ganglion cell layer where it is thicker (50Ð60 m in an annulus 0.7Ð1.8 mm from the fovea) (Fig. 1.12).61 The deepest lamina vanishes more proximally in the retinal midperiphery, the middle lamina vanishes more peripherally, and the most superÞcial lamina extends almost to the ora serrata which, like the fovea, is bordered by an avascular zone (Fig. 1.13). A capillary-free zone is also found adjacent to retinal arterioles (Fig. 1.14).11,34

The wall of a retinal capillary is made of endothelial cells, pericytes, and a basement membrane. The cytoplasmic thickness of a capillary endothelial cell is 0.4Ð0.7 m and is similar for retinal or choroidal capillaries.64 Capillary lumens are 3.5Ð6 mm in diameter and ~10 m2 in area depending on the species studied.64-67 Retinal capillary diameter is approximately half that of

Fig. 1.11 (a) Diagram of the distribution of the radial peripapillary capillaries.

(b) MagniÞed cutaway diagram showing the sparse anastomoses of the radial peripapillary capillaries with the deeper strata of retinal capillaries. (c) Schema of laminar distribution of retinal capillaries. Hatch up and right

Ð superÞcial capillaries are at the inner boundary of the inner nuclear layer. Hatch down and right Ð capillaries are at the outer boundary of the outer nuclear layer.

Cross-hatched area Ð capillaries are within the ganglion cell layer. Dotted area Ð capillaries touch both boundaries of the ganglion cell layer (Redrawn from Henkind60 and Iwasaki and Inomata61)

a

b

c

Optic disk

Radial peripapillary capillaries (RPC)

RPC in nerve fiber layer

Connection between capillary levels

Capillaries in ganglion cell layer

a b c

d

e

Foveola

Fovea

Central retina

choroidal capillaries. Capillary lumens are uneven due to inward bulging of endothelial nuclei. This requires that passing erythrocytes distort and mold. Capillary pericytes lie within the endothelial basement membrane. In vivo contraction of mammalian pericytes has not been demonstrated,

but pericytes contain contractile proteins and contract in vitro when exposed to endothelin, thromboxane A2, and angiotensin II.68-70 Loss of pericytes, as seen in ischemic retinopathies such as RVO, weakens the capillary walls and leads to microaneurysms and macroaneurysms.71

Fig. 1.12 Laminar arrangement of the capillary beds in the primate retina. (a) Posterior pole retina with the inner retina labeled 1Ð4. 1 Ð nerve Þber layer (NFL), 2 Ð ganglion cell layer, 3 Ð inner border of the inner nuclear layer (INL), 4 Ð outer border of the inner nuclear layer. The yellow arrow denotes a capillary within the deep nerve Þber layer. The turquoise arrow denotes a capillary at the inner border of the inner nuclear layer. The pink arrow denotes a capillary at the outer border of the inner nuclear layer which is the deepest level of the inner retina containing capillaries. The orange double-headed arrow spans the avascular outer retina comprised of the outer plexiform layer, outer nuclear layer, photoreceptor outer segments, and retinal pigment epithelium. (b) Sample of the

midperipheral retina showing the locus of termination of the outermost lamina of capillaries (arrowhead). To the right of the arrowhead, no capillaries are seen at the outer border of the inner nuclear layer, but capillaries are evident at the inner border of the inner nuclear layer and in the nerve Þber/ganglion cell layer. Slightly more peripherally, the capillary lamina at the inner border of the inner nuclear layer vanishes (not shown). (c) The peripheral retina/ora serrata junction showing that the innermost lamina of capillaries vanishes just proximal to the ora serrata (arrowhead). (d) Section of the retina from the perifovea (left side) to the fovea (right side). The foveal avascular zone begins at the arrowhead which denotes the border capillary (Reproduced with permission from Gariano et al.63)

Fig. 1.13 Image of retinal vessels stained for ADPase in the young human. (a) Just posterior to the ora serrata, the retina is avascular. The blue arrow denotes the most peripheral retinal capillary posterior to the ora serrata.

(b) The center of the macula is avascular (F) and is bordered by the single-layered perifoveal capillary arcade (blue arrow) (Reproduced with permission from Gariano et al.63)

Fig. 1.14 Trypsin digest of the retina showing the alternating arrangement of artery (red AÕs) and vein (blue V) with interposed capillaries. There is a paucicapillary zone adjacent to arteries (red ovals) but not veins (blue oval) (Reproduced with permission from Hogan et al.,11 [p. 510])

Normal retinal capillaries have low permeability, lacking fenestrations and possessing tight intercellular junctions that form the inner bloodÐ retina barrier.22 In contrast, normal choroidal capillaries have high permeability and possess fenestrations.42 The transfer of materials across retinal capillaries is therefore normally limited to diffusion through intercellular spaces and endothelial pinocytosis and is normally much more restricted than transfer of materials across choroidal capillaries. Vascular endothelial growth factor (VEGF) regulates fenestrations and the functional properties of the tight junctions.72 VEGF upregulation is associated with reduction of the protein occludin, a 65-kD transmembrane protein that is a component of vascular endothelial tight junctions.73 VEGF induces a rapid phosphorylation of tight junction proteins ZO-1 and occludin and leads to increased vascular permeability. VEGF is normally present in the retinal pigment

epithelium (RPE), and it is hypothesized that RPE-produced VEGF is critical for the choriocapillaris and is the factor responsible for its fenestrations and high permeability.74,75 In RVO, VEGF levels increase to pathological concentrations with resulting disruption of the endothelium and leakage of protein, lipid, and blood into the retina. At least initially, the leakage is reversible through the formation of new tight junctions and endothelial cell mitosis, but at a certain point of duration and severity, it seems that the possibility of repair of the bloodÐretina barrier is lost.25

The foveal avascular zone (FAZ) is approximately 400 m in diameter.34 Bordering the FAZ is a single level of capillaries that is found within the ganglion cell layer (Fig. 1.13). Moving further from the FAZ, the capillary network becomes trilaminar.61 Blood cell velocity in these capillaries as measured with the blue Þeld entoptic phenomenon is 0.5Ð1.0 mm/s.76 The outer retina (outer plexiform, outer nuclear, and photoreceptor layers) and the retinal pigment epithelium are avascular and receive oxygenation by diffusion from the deeper choriocapillaris and the deepest lamina of retinal capillaries in the inner retina.34 The maximum distance between capillaries in the inner retina is approximately 65Ð100 m, and the estimated maximal diffusion distance in the human macula consistent with normal function has been estimated to be approximately half this distance, or approximately 45 m.61 Retinal oxygen partial pressures are highest immediately adjacent to retinal arterioles and lowest adjacent to veins (see Chap. 2).

Retinal capillaries drain into terminal venules, the smallest branches of the venous tree. The smallest venules have a luminal diameter of 8Ð20 m and differ from capillaries only in size, not microstructure.11 As venules increase in size beyond 8 m, they begin to show collagen in the outer wall which distinguishes them from capillaries.11 The capillaries and terminal venules in adjacent sectors of the retina are not as separated from each other as are the end arterioles of the retina. The capillaries in one sector of the retina do have paths of communication to venules in an adjacent sector.77 This conÞguration is demonstrated in acute BRVO when extravasation of hemorrhage into the interstitium is evident in

Fig. 1.15 A 60-year-old hypertensive man was seen complaining of blurred vision on the left for 4 weeks. An inferotemporal BRVO of the left eye was found. Intraretinal hemorrhage extended far beyond the boundaries of the inferotemporal sector of retina. In the Þgure, the purple line indicates the horizontal raphe. The yellow oval indicates superotemporal retina with extensions of hemorrhage. There are anastomoses between superotemporal retinal capillaries and inferotemporal retinal veins. Thus, when intravenous pressure in the inferotemporal veins dramatically rises in the event of a BRVO, the increase in intravascular pressure is transmitted backward to some of the superotemporal capillaries with resultant extravasation of blood into the interstitium

adjacent retinal sectors (Fig. 1.15). Normal anastomoses between the venular end of adjacent sectors of the retinal microvasculature are shown in a complementary fashion by inspecting the phenomenon of backÞlling that occurs in branch retinal artery occlusion (Fig. 1.16). In this situation, there is no forward ßow to the superotemporal retinal capillaries from the completely obstructed superotemporal branch retinal artery, yet by virtue of anastomoses with the adjacent sectors of retinal venules, the veins of the superotemporal retina backÞll with ßuorescein from the inferotemporal retina.77 These underlying normal anastomoses dilate and become hemodynamically more important in the pathological situation of a BRVO, eventually becoming the mature, larger diameter collateral vessels associated with the chronic phase of BRVO.

Terminal venules converge and drain into higher-order branch retinal veins, which in turn converge and drain into one major (synonyms Ð

main or Þrst-order) retinal vein for each quadrant (Fig. 1.17). The major branch retinal veins converge to form the two hemicentral, or papillary, retinal veins, one for the superior retina and the other for the inferior retina. In 80% of eyes, the hemicentral retinal veins converge within the optic cup to form the central retinal vein, but in 20%, they converge within the deeper optic nerve as a congenital variant.79,80 Hemicentral retinal vein occlusion and central retinal vein occlusion are closely related in pathologic anatomy and more closely related than either of these to BRVO.79,81,82 Rarely, there may be a longer intraocular segment of the central retinal vein, and there are a myriad of other individual variations of this general scheme.78,82,83 When HCRVs are present, the area of the retina drained by each can range from 90 to 315¡.83 In an estimated 0.2% of eyes, there may be a cilioretinal vein that drains a portion of the retinal venous return directly into the choroid.84 Even rarer are cases of retinopial veins that drain retinal venous blood directly to veins of the pia mater.84 Retinal venous lumen diameter decreases in size from 122 to 180 mm adjacent to the disc to 20 mm at the equator, and smooth muscle cells are lost and replaced by pericytes, which are less able to contract.54,55,85 This allows luminal diameter to ßuctuate with intravenous pressure.

In the normal state, all retinal venous outßow passes out the central retinal vein which has a luminal diameter of 200 m.43 There is both histological and in vivo evidence from color Doppler imaging of the central retinal vein (CRV) that the CRV narrows in the region of the lamina crib- rosa.51,86-88 Such an anatomic situation allows the intraluminal pressure of the CRV to fall without venous collapse as it exits the higher pressure environment inside the eye to the lower pressure environment of the orbit. Without the constriction, the blood in the orbital CRV would accelerate, and the CRV would collapse. By decreasing the CRV diameter, the kinetic energy of the blood rises with its increasing venous velocity by an amount balanced by the decrease in intraluminal pressure. Thus, the central retinal venous pressure is hypothesized to drop by its greatest amount over the short distance where it traverses the lamina cribrosa.89 The intravascular pressure

Fig. 1.16 A 63-year-old woman with hypertension was seen with acute, painless visual loss of the left eye from a branch retinal artery occlusion. (a) Monochromatic fundus photograph of the left eye showing ischemic retinal whitening present in the sector of retina off the disc from 12 to 3 oÕclock. The ischemic zone abuts the fovea. (b) Frame from the arteriovenous phase of the ßuorescein angiogram shows absence of perfusion of the superotemporal retina because of the obstructed superotemporal branch retinal artery. The yellow arrows denote two intrinsic anastomotic veins that connect the inferotemporal quadrant circulation with the veins of the superotemporal quadrant. Some backÞlling of the superotemporal veins has begun. (c) A frame from a later stage of the arteriovenous phase of the ßuorescein angiogram shows that the entire superotemporal branch retinal vein (orange arrow) has Þlled from backßow via the anastomoses with the veins of the inferotemporal quad-

rant. The green arrow denotes a superotemporal branch retinal arteriole that is backÞlling from anastomoses with the inferotemporal microcirculation. We can infer that these anastomoses have higher resistance because this backÞlling occurs later than the backÞlling of the superotemporal veins. Venous backÞlling has also begun in the nasal macula (turquoise arrow). We can infer that venous anastomoses are hemodynamically less signiÞcant across the nasal macular portion of the horizontal raphe than across the temporal macular portion because of the delay in backÞlling in the nasal macular region relative to the temporal macular region. (d) Frame from the recirculation phase of the ßuorescein angiogram shows continuation of the arterial backÞlling of the superotemporal quadrant (green arrow). The ßow is so slow that the ßuorescein dye in the superotemporal branch retinal artery is pooled over a dependent layer of erythrocytes within the arterial lumen

of the intraocular central retinal vein is approximately equal to the intraocular pressure, that is, approximately 15 mmHg. Just posterior to the lamina cribrosa, the intravenous pressure is anywhere from a few mmHg when erect to 10 mmHg when recumbent.90,91 The lamina cribrosa thus acts as a throttle on the central retinal vein, and by the Bernoulli principle, the diameter

of the CRV must decrease in tandem with the reduction in intravenous pressure.90,91 The retinal veins as they enter the optic nerve are supported by the neural rim tissue.

When this neural rim is lost, as in glaucomatous optic atrophy, it has been hypothesized that the walls of the retinal veins could be stretched and injured, possibly accounting for the association of