Hereditary Retinal Artery Tortuosity

Recurrent macular hemorrhages occurring in family members with congenital arteriolar tortuosity constitute a recognized syndrome ( Figure 6.01A–C ). Visual loss in these patients may occur spontaneously or following relatively minor trauma (see the discussion on Valsalva maculopathy, p. p0315 in Chapter 8). Retinal arteriolar tortuosity may increase with age, particularly during adolescence. The tortuosity affects primarily the second- and third-order retinal arterioles in the macular area and the veins are spared. Fluorescein angiography has failed to disclose any primary alterations in the retinal vascular tree that would account for the predilection for hemorrhages. The pathogenesis is unknown. Despite recurrent bleeding, vision usually returns to normal. Retinal bleeding during scleral buckling procedure has been reported. There is no evidence that a systemic hemorrhagic diathesis is present in patients with this disease, which is inherited as an autosomal-dominant trait. Families with increased nail bed capillary tortuosities, carotid aneurysm, and microscopic hematuria have been described. Congenital retinal arteriolar tortuosity must be differentiated from other diseases associated with acquired retinal vascular tortuosity, including polycythemia, leukemia, dysproteinemia, sickle-cell disease, familial dysautonomia, mucopolysaccharidosis VI, and Fabry’s disease. Pulsatile three-dimensional arteriolar tortuosity, previously reported in patients with coarctation of the aorta, rarely occurs now because of early surgical intervention.

Spontaneous retinal hemorrhages may occur in multiple family members in the absence of related systemic disease or retinal arterial tortuosity.

Inherited Retinal Venous Beading

Meredith described five affected members in two generations with sausagelike beading of the major retinal veins and conjunctival venules, focal retinal infarctions, altered retinal vascular permeability, and in some cases abnormalities of arteriolar and venular distribution. Large venules crossed the horizontal raphe in some cases. Three members had retinal and/or optic disc neovascularization and vitreous hemorrhage. Some members had renal disease (Alport’s disease) and decreased leukocyte counts. Stewart and Gitter reported four affected members of two generations with retinal venous beading but no conjunctival vessel tortuosity. The affected members had low to normal neutrophil leukocyte counts that differed significantly from unaffected members.

Retinal Venous Tortuosity in Infants

Neonates born to mothers who smoke during pregnancy have a higher incidence of venous dilation and tortuosity, arteriolar straightening and narrowing, and intraretinal hemorrhages. This is likely the result of a combination of higher hematocrit and higher peripheral vascular resistance in these babies. All vascular changes correct by age 6 months. Infants with congenital heart diseases show a higher incidence of retinal vascular tortuosity (46%), more so those with cyanotic heart disease, low hematocrit, and low oxygen saturation.

Retinal vascular anomalies.

A–C : Congenital retinal arterial tortuosity and spontaneous macular hemorrhage in a 26-year-old man who developed loss of central vision in the right eye while weight-lifting. He had had a similar episode in both eyes previously. Each time the hemorrhages cleared and he regained 20/20 acuity. He was of Eastern European descent and had two paternal first cousins with the same ocular problem.

D–F : Congenital retinal arterial loop in an asymptomatic boy.

G–I : Congenital retinal arterial malformation in a young asymptomatic woman with 20/20 visual acuity.

J–L : Congenital venous loop in an asymptomatic young woman.

(A–C, courtesy of Dr. Donald J. D’Amico.)

Congenital Prepapillary Vascular Loops

Dilated loops involving either the veins or the arteries may occur in and around the optic nerve head ( Figure 6.01D–L ). Loops involving the retinal arteries are more common than those involving veins (4:1). Retinal arterial loops may arise on or near the optic disc from a major branch retinal artery, the central retinal artery, or a cilioretinal artery ( Figure 6.01D–F ). They extend anteriorly into the vitreous, are composed of one or more twists, and usually supply one of the retinal quadrants. The loops often exhibit movement within the vitreous and cast a shadow on the surrounding fundus. They may pulsate. They occasionally occur bilaterally, may be familial, and may be partly surrounded by glial or fibrous sheaths. Retinal circulation time in the affected quadrant may be slightly increased. There is a high incidence of cilioretinal arteries in these eyes, and they often supply much of the retinal circulation. A small percentage of these patients may lose vision secondary to occlusion of the arterial loop ( Figure 6.02A–G ), vitreous hemorrhage, amaurosis fugax, and hyphema. Thrombosis or twisting of the loop probably causes the obstruction ( Figure 6.02A–G ). Histologically the artery comprising the loop is of normal structure. The pathogenesis of the vitreous hemorrhage occurring in and around these loops is uncertain but probably is caused by rupture of small vessels near the base of the loop caused by its movement.

Congenital prepapillary venous loops ( Figure 6.01J–L ) and macroretinal vessels should be differentiated from acquired dilated venous collateral channels caused by retinal venous obstruction (see Figure 6.81J and K ) and meningioma of the optic nerve (see Figure 15.16 ).

Prepapillary loop with branch retinal artery occlusion.

A–G : This 17-year-old female developed a sudden temporal field defect in her left eye. She had a history of sickle-cell trait but was otherwise normal. Her visual acuity was 20/25 in each eye. A prepapillary loop emanated from the disc along with retinal opacification in the upper nasal quadrant secondary of a branch retinal artery to occlusion within the loop. The retinal color recovered in 4 weeks but the visual field defect remained. Thrombotic occlusion of the communication from the loop to the superonasal branch retinal artery was noted (arrow).

Congenital Macrovessel

H–J : A 34-year-old male presented with a 3-year history of type 2 diabetes. Visual acuity was 20/15 in both eyes. Dilated fundus examination of the right eye showed a large macrovessel coursing the macula. The macrovessel was a vein and the angiogram showed it draining into the superotemporal vein after crossing the horizontal raphe and lateral to the fovea and dipping back inferior to the fovea and recrossing nasal to the fovea.

(A–G, courtesy of Dr. Franco Recchia; H–J, from Jager et al., reprinted with permission from Retina . H, Also, Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p.384.)

Congenital Retinal Macrovessels and Arteriovenous Communications

A large aberrant retinal vessel, more often a vein than artery, may extend from the optic disc into the central macular area, where it typically sends tributaries across the horizontal raphe ( Figures 6.02H–J and 6.03A–I ). In some patients, both an artery and a vein are affected. Visual function is usually normal. Fluorescein angiography typically shows no permeability alterations but may show small areas of capillary nonperfusion and focal capillary dilations ( Figure 6.03C and D ). In some cases the capillary bed separating the dilated artery and vein may be normal ( Figure 6.02H–J ). In others there is a direct arteriovenous anastomosis ( Figure 6.03E–G ). Changes in blood flow or permeability within these communications may precipitate loss of visual function ( Figure 6.03A and B, and E–G ) and are reported following bungee jumping. These malformations typically occur unilaterally in single or multiple sites. There is a predilection for involvement of the papillomacular bundle area and the superotemporal quadrant. Both sexes are affected. Detection of the anomaly usually occurs on routine examination. Retinal macrovessels may occasionally be associated with similar vascular anomalies affecting the conjunctiva and mouth ( Figure 6.03J–L ). Macrovessels are isolated findings and should be differentiated from large-caliber retinal vessels (artery or vein) associated with anomalies such as Coats’ disease, retinal capillary hemangioma, familial exudative vitreoretinopathy (FEVR), incontinentia pigmenti, and other peripheral vascular occlusive diseases.

Retinal arteriovenous anomalies have been subdivided into groups, depending on the severity of the anomaly. Archer’s group 1 comprises patients with retinal macrovessels with interposition of an arteriolar or abnormal capillary plexus between the major communicating artery and vein. These well-compensated arteriovenous communications rarely extend to involve the papillary vasculature and are rarely associated with cerebrovascular malformations.

Congenital retinal macrovessels.

A and B : Macular hemorrhage occurring in a 50-year-old man who on awakening noted a central scotoma caused by a retinal hemorrhage associated with a congenital macroartery and vein. His visual acuity was 20/40.

C and D : Microaneurysms (arrows) associated with congenital macroartery and vein. There was minimal staining of the microaneurysms.

E–G : Blurred vision occurred in this healthy boy with macrovessels associated with angiographic evidence of arteriovenous shunting (arrow, F), and hypoperfusion of the juxtafoveal retinal capillary network (G).

H–L : Congenital retinal macroveins (arrows, H and I) associated with macrovessels of the conjunctiva (J) and the dorsal (K) and ventral side (L) of the tongue in an apparently healthy 51-year-old man. Computed tomography of the brain revealed multiple venous anomalies.

(C and D, courtesy of Dr. J. S. Cohen.)

Patients in group 2 demonstrate direct arteriovenous communications without the interposition of capillary or arteriolar elements ( Figure 6.04 ). These dilated arteriovenous communications, sometimes referred to as arteriovenous aneurysms or racemose aneurysms, may be single or multiple. Leaking macroaneurysms occasionally develop on these enlarged vessels ( Figure 6.04B ). Angiography demonstrates a short dye transit time but usually no evidence of extravascular leakage. The neighboring microvasculature may be altered, and there may be beading and multiple fusiform dilations of the large-vessel walls. Capillary nonperfusion or an absence of capillaries may be evident in the neighborhood of major vessels. These arteriovenous communications typically remain stationary. In some cases decompensation may occur and cause hemorrhages ( Figure 6.04F and G ), focal areas of extravascular exudation and perivascular scarring ( Figure 6.04B ), and neovascular glaucoma. Occlusion of a portion of or the entire malformation may occur ( Figure 6.04D and E, and H and I ).

Retinal arteriovenous malformation.

A–C : This 22-year-old asymptomatic woman had 20/20 visual acuity bilaterally. The left eye was normal. She had no evidence of extraocular vascular malformations. Note the arteriovenous communication in the macula (A) and focal vascular sheathing and scarring in the periphery (B). Angiography demonstrated the arteriovenous communication (C) and minimal staining only in the area of the perivascular scarring.

D and E : This 14-year-old girl had 20/20 visual acuity when first examined. Angiography at 14 seconds showed prompt filling of the superior arteriovenous anomaly (D). Two years later she experienced acute loss of vision in the eye. When seen 9 months later, her visual acuity was 20/300. The optic disc was swollen (E). Sheathing of some of the large retinal vessels and pigmentary abnormalities in the macula had occurred. Angiography revealed perfusion of the retinal arteries, increased retinal circulation time, and a window defect in the macula, all findings suggesting partial occlusion of the vascular anomaly and previous submacular exudation.

F and G : This teenage girl was asymptomatic and had normal visual function when the arteriovenous anomaly was discovered (F). She had no extraocular vascular malformations. Several years later she noted a paracentral scotoma in the right eye caused by spontaneous bleeding from the vascular anomaly nasal to the optic disc (G).

H and I : Arteriovenous malformations in the macula (H) and periphery of the right eye and the maxillary bone of this girl were discovered after she experienced severe bleeding during a dental extraction. Surgical ligation of the ipsilateral carotid artery was required to control the bleeding. Soon afterward there was spontaneous occlusion of the macular arteriovenous aneurysm (I).

J–L : Gross photograph and photomicrographs of an arteriovenous aneurysm with arteriovenous anastomosis (arrow, J) in a rhesus monkey. Fluorescein angiography showed no evidence of intraretinal staining. Note the enlarged retinal vessels that encroach on the surrounding retina (K and L). The dilated spaces in the inner nuclear and outer plexiform layer were free of proteinaceous exudate and apparently contained a serous transudate.

(D and E, courtesy of Dr. Robert Kalina; H, from LaDow et al. ; I from Gass ; © 1968, American Medical Association. All rights reserved. J–L from Horiuchi et al. ; published with permission from The American Journal of Ophthalmology; copyright by The Ophthalmic Publishing Co.)

In group 3 patients ( Figure 6.05 ) there are many anastomosing channels of large caliber that are so intertwined and convoluted that separation into their arterial and venous components may be difficult. Visual acuity is usually poor. Ophthalmoscopically and angiographically, the retina may show perivascular sheathing, exudation, and pigmentary degeneration. Some eyes may be blind from birth. Patients with severe retinal involvement are the most likely to have periorbital or cerebral involvement (Wyburn–Mason syndrome).

Complications of these vascular anomalies include intraretinal hemorrhage, aneurysm formation with intraretinal exudation, retinal artery occlusion, Valsalva retinopathy, central and peripheral retinal vein occlusions, neovascular glaucoma, vitreous hemorrhage, arterial macroaneurysm, and macular hole ( Figure 6.04B, E, G, and I ). Severe visual loss caused by occlusion of the malformation occurs infrequently ( Figure 6.04D and E ). Slow visual loss may occur because of mechanical compression of the optic nerve. Spontaneous regression of the lesions may occur occasionally. The histopathology of arteriovenous communications identical to those seen in humans has been described in rhesus monkeys ( Figure 6.04J–L ). Anomalous arteriovenous communications should be distinguished from those acquired secondary to peripheral vascular occlusive disease (see Figure 6.81J and K ).

Photocoagulation treatment may occasionally be warranted in those patients who develop exudative maculopathy.

For a discussion of congenital retinal telangiectasis and retinal vascular hamartomas, see p. p0660 in Chapter 6 and Chapter 13, respectively.

Retinal arteriovenous malformation.

A and B : Ths 16-year-old female was seen for intractable headaches and migraine with aura. Her vision was 20/15 in each eye. She had several anomalous vessels emanating from the disc and peripapillary area. Some of the larger-caliber vessels appeared to communicate with the choroidal circulation as they dipped into the substance of the retina while the others were part of a network of vessels seen on the disc and superficial peripapillary retina. She had had an inflammatory workup, which showed minimally elevated angiotensin-converting enzyme. Magnetic resonance imaging (MRI) of the head did not reveal other anomalous foci. She was treated medically for headaches and migraine.

C–F : This 28-year-old male with count-fingers vision in the right and 20/20 vision in the left eye complained of several episodes of headache for the past 2 years. He had a previous MRI that showed arteriovenous malformations in his brain. A large arteriovenous malformation simulating a bag of worms was seen in the right fundus involving the vessels on the disc and in the macula associated with dilated and tortuous retinal arteries and veins extending up to the periphery. One large vessel that dipped into the retina communicating with the choroid showed whitening of its wall (C and F). Fluorescein angiogram showed rapid filling of the malformation, making it difficult to determine if the majority of the vessels filled from the choroid or from the retinal side – they likely filled simultaneously from the choroid and retina (D and E). He was treated symptomatically for the migrainous headache.

Retinal capillary hamartoma.

G–K : This 34-year-old male noted metamorphopsia in his right eye for a few months. A 2×2 disc diameter subtle elevation (arrows) was noted in his right eye just temporal to the fovea associated with cystoid swelling of the temporal fovea (G). An angiogram revealed deep dilated plexus of vessels with several bulbous dilatations in the inner retina (I and J). The anomalous capillary plexus leaked with fluid accumulation into cystoid spaces (K). The malformation appears to be an isolated hamartoma of the retinal capillaries without an astrocytic component. There was no evidence of hamartomas elsewhere in the eye or body, thus ruling out tuberous sclerosis.

(A and B, courtesy of Dr. Patrick Lavin; G–K, courtesy of Dr. David Weinberg.)

Anomalous Foveal Avascular Zone

Controversy exists about the development of the foveal avascular zone (FAZ); one school believes the future FAZ is initially vascularized, and by a process similar to apoptosis the capillaries are lost to form a capillary-free zone. Absence of the FAZ and multilayered foveola seen in retinopathy of prematurity (ROP) is explained by this theory. The other school studied seven retinal whole mounts aged between 26 and 41 weeks’ gestation and found a blood vessel-free zone in all retinas, including at the 26-week gestational age. This ring was open temporally at age 26 weeks and closed by 37 weeks’ gestation to form a complete circle. It is believed that the superior and inferior blood vessels grow faster than the horizontal raphe and the nasal vessels grow faster than the temporal ones, resulting in the open temporal ring till about the 37-week gestational age. The diameter of the FAZ gradually decreased in size from 500 μm at 35 weeks to 300–350 μm at 40 weeks. After birth, the accelerated retinal growth stretches the foveal pit, making it wider and shallower; this remodeling of the FAZ continues to occur even up to 15 months to eventually yield an FAZ that is 500–750 μm in size.

It is likely various factors influence formation of the foveal vascular zone during development: astrocytes, macular pigment, ganglion cells, vasoendothelial growth factor (VEGF) levels and their alteration in hypoxia, to consider a few. Whatever the insult that allows blood vessels to invade the future foveal pit during development ( Figure 6.06 ), this in turn likely prevents normal foveal pit formation, resulting in a multilayered foveal center ( Figure 6.06E, F, K, and L ). Hypoplastic fovea with small or absent FAZ associated with multilayered foveal pit on OCT is a feature of albinism, chiasmal misrouting, ROP, and aniridia. It is likely we will discover more developmental vasculopathies and other disorders that harbor a multilayered foveal center.

Absent foveal avascular zone (FAZ) and foveal pit.

A–F : This 40-year-old male had a history of “jumping eyes” with subnormal vision since childhood. When his son was evaluated for nystagmus at age 6 months, he was sent in for a retina consultation to help find a diagnosis for the infant. He was best corrected to 20/60 in each eye with a moderately high myopic refractive error. He was not albinotic. The fundus had a blonde coloration with orange color at the posterior pole. A fluorescein angiogram showed no specific abnormality. Due to the myopia and light fundus background, a good perfusion of the fovea vascular pattern was not obtainable. Scanning through the entire macula, a foveal depression could not be found on optical coherence tomography (E and F), suggesting arrested foveal development as the cause of the subnormal vision and nystagmus.

G–L : This 16-year-old girl could only be corrected to 20/25 all through her refractive evaluations for the previous 10 years. Her color vision was full bilaterally and she had no nystagmus. The right eye had an anomalous architecture of the retinal arteries with two branches each supplying the superior and inferior posterior pole (G). The left eye’s architecture appeared within the normal variation (H). Careful examination of the fovea and its angiogram revealed possible small foveal avascular zone. Optical coherence tomography through the fovea could not localize the foveal pit in either eye (K and L), confirming the arrested foveolar development as a plausible cause of the subnormal vision.

(G–L, courtesy of Dr. Janice C. Law.)

Embolic Obstruction

Obstruction of the retinal circulation may be caused by emboli derived from within the human body (endogenous emboli) or from without (exogenous emboli).

Endogenous Embolization From the Major Arteries and Heart

Emboli derived from ulcerated atheromatous plaques in the carotid artery, occurring either spontaneously or during manipulation of the carotid artery during arteriography or surgery, are probably the most common cause of major retinal arterial occlusions ( Figures 6.07–6.10 ). Other important sources of emboli are diseased or anomalous heart valves. Embolization from the heart may occur spontaneously or during open-heart surgery or coronary artery angioplasty. Patients with embolic occlusion usually experience sudden monocular loss of vision. This loss may be antedated by episodes of transient loss of monocular vision lasting 1–2 minutes (amaurosis fugax) in 20–25% of cases, and transient ischemic attacks in approximately 5–10% of cases. The average age of onset of symptoms is approximately 60 years. Fewer than 10% of occlusions occur in persons under 30 years of age. Occlusion is more common in men than in women. In all, 50–75% of patients over 40 years of age with retinal artery occlusion will have clinical evidence of carotid artery disease. In younger patients the emboli are usually derived from heart valves damaged by rheumatic fever, congenital anomalies of the heart valves and great vessels, or prolapse of the mitral valve (Barlow’s syndrome) ( Figure 6.07E–I ). Most patients with central retinal artery occlusion (CRAO) will have a small area of preservation of light perception caused by the presence of small cilioretinal arteries ( Figure 6.08D and K , arrow). In patients with no light perception, the physician should look for evidence of abnormalities of choroidal and optic nerve head circulation.

Central retinal artery obstruction.

A–D : Central retinal artery obstruction occurred 1 week after replacement of an aortic and mitral valve for rheumatic heart disease in a 55-year-old man whose visual acuity consisted of light perception only. Note the cherry-red spot and “boxcar” formation of blood in the retinal vessels (A). Angiography shows marked retinal artery obstruction and retrograde filling of proximal retinal veins via the optic disc collateral circulation (B–D).

E and F : Central retinal artery obstruction in a 19-year-old woman. Angiography shows fluorescein leakage from perifoveal arterioles.

G–I : Central retinal artery obstruction and retinal hemorrhages in a 29-year-old man with rheumatic mitral valvular disease and subacute bacterial endocarditis. Note the cherry-red spot, “boxcar” formation, and angiographic evidence of marked increase in retinal circulation time.

J–L : Patchy retinal ischemia and delayed perfusion of both the retinal and choroidal circulation caused by ophthalmic artery obstruction in a 73-year-old hypertensive man with ultrasonographic evidence of thyroid ophthalmopathy. He experienced sudden almost complete loss of vision in the right eye several weeks before these photographs. He noted partial return of peripheral vision soon afterward. Angiography showed that dye appeared in the choroid at 21 seconds and in the central retinal artery at 25 seconds (K and L).

If retinal artery obstruction is incomplete and of short duration, only a slight gray haze may result, and little or no permanent damage to the retina may occur ( Figure 6.09G and H ). If the block is more complete, progressive whitening and swelling of the inner half of the retina develop ( Figure 6.07A and E ). These physical changes are caused by denaturation and breakdown of the normally transparent intracellular protein, an increase in the intracellular water, and, finally, complete cellular necrosis ( Figure 6.10I ). Acute ischemic whitening of the retina is a more accurate descriptive term for this change than retinal edema, which is best reserved for retinal thickening secondary to the accumulation of serous fluid escaping from retinal capillaries into the extracellular space, producing multiple cystoid changes in the outer retinal layers. Acute ischemic retinopathy may be localized (cotton-wool patch), as in small arteriolar obstruction, or more diffuse, as in obstruction of the central retinal artery or one of its major branches. Intensified retinal whitening along the peripheral edge of ischemic areas that cut across nerve fiber layers is related to the damming effect of the orthograde and retrograde axoplasmic flow.

Patients with visual loss caused by acute retinal artery obstruction usually seek treatment in the first week after obstruction and show a variety of clinical pictures, depending on the portion of the retinal arterial tree involved. In central retinal artery obstruction, widespread ischemic whitening of the retina occurs, except in the foveolar area (cherry-red spot), whose blood supply is derived from the choriocapillaris ( Figures 6.07A and 6.08G ), and except in some patients in whom focal peripapillary areas are supplied by a cilioretinal artery. Absence of the cherry-red spot in patients with CRAO should suggest the presence of choroidal vascular ischemia as well. In some patients, particularly those with chronic systemic hypertension, transient obstruction of the central retinal artery may produce a peculiar picture of multiple gray patches of retinal whitening simulating that seen in Purtscher’s retinopathy ( Figures 6.07J–L ; see Figures 6.23H, and 6.25J ). This pattern is probably the result of regional variations in arterial perfusion that occur normally or that are the result of formation of collateral pathways of retinal capillary flow caused by focal narrowing of the origin of the first-order arterioles in hypertensive patients. The visual prognosis in patients showing this pattern of retinal whitening is relatively good.

Branch artery obstruction may be overlooked or mistaken for other disease processes, particularly if the patient has a central scotoma caused by obstruction of a cilioretinal artery or other small arterioles supplying most of the macular area. Varying degrees of arterial narrowing occur. Segmentation of the blood column indicates marked slowing of arterial flow ( Figure 6.07A, H, and I ). Often one or more emboli are visible in the arterial tree, either as a large embolus at a bifurcation of the central retinal artery on the optic nerve head ( Figures 6.09 G and H and 6.10K and L ) or as one or more emboli lodged at distal bifurcations ( Figure 6.09D ).

Central retinal artery occlusion (CRAO) with neovascularization of disc.

A–F : This 68-year-old hypertensive diabetic woman with a history of end-stage renal disease presented with light perception vision in her right eye. The posterior pole was opacified and the blood column in all the retinal arterioles and some of the veins were fragmented (A). A tiny corkscrew vessel was present on the optic disc. A small zone of retina adjacent to the superotemporal edge of the disc appeared to be perfused by a cilioretinal artery. The left eye had scattered microaneurysms and dot hemorrhages from diabetes (B). Four weeks later she was found to have a vitreous hemorrhage, bleeding from the corkscrew-shaped vessel seen previously on the disc (C and D). An angiogram showed almost no perfusion of the retina except for a small zone from a cilioretinal artery (E and F). It is likely the ischemia secondary to the CRAO enhanced the pre-existing diabetic ischemia to cause the new vessel to bleed.

G–J : The right fundus of this male patient who presented with severe headache and sudden loss of vision in his right eye shows opacification of the retina with a cherry-red spot and boxcarring of the blood column in the retinal arterioles (G). An angiogram shows poor perfusion through the central retinal artery (H). Carotid angiogram shows dissection of the right internal carotid artery resulting in the CRAO (I and J). A few weeks later, the optic nerve turned pale. The boxcarring of the retinal arterioles continued with regaining of the orange color of the retina. The vision remained at light perception.

K and L : This 75-year-old male with hypercholesterolemia, hypertension, and previous history of bilateral carotid endarterectomies shows a retinal embolus in the superotemporal arteriole and opacification of the posterior pole secondary to a CRAO. There is a small patch of unopacified orange retina temporal to the disc from perfusion through a cilioretinal artery (arrow). Note three cotton-wool spots that likely predate the CRAO. Optical coherence tomography showed thickening and opacification of the inner retina and shadowing of the photoreceptor layer (L).

(G–J, courtesy of Dr. Robert Mittra. G and J, Also, Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p.387.)

Three major types of emboli occur. Platelet fibrin emboli are dull, gray-white, often elongated plugs that are subject to fragmentation and movement into more distal arterioles ( Figure 6.09J and K ). They may be either single or multiple and are most often lodged at a bifurcation. Cholesterol emboli are often multiple, yellow or copper-colored iridescent globules that are most often seen in the peripheral radicles on the temporal side of the fundus ( Figures 6.09D and 6.10C ). They are often unassociated with obstruction of blood flow. When causing obstruction, cholesterol emboli are usually located near the optic nerve head. Calcific emboli are usually single, solid, white, nonrefractile, ovoid or angulated emboli derived from the aortic or mitral valve ( Figure 6.10A, B, K, and L ). They are usually near the optic nerve head and, unlike cholesterol emboli, which often disappear in a few days, they may remain visible permanently. Occult calcified emboli may be detected ultrasonographically at the level of the lamina cribrosa in patients with CRAO and in some patients who present with ischemic optic neuropathy. The narrowest site of central retinal artery is where the artery perforates the dural sheath and enters the optic nerve; any of the three types of emboli can lodge here and not be visible. Occasionally a stream of emboli may be present, many behind the lamina cribrosa, hence not visible. Cholesterol emboli arise primarily from atheromatous disease affecting the proximal carotid artery. Calcific emboli arise primarily from the aortic valve and less often the aorta and carotid artery.

Focal areas of periarterial sheathing and focal accumulation of serum lipids within the artery wall at the site of embolic damage to the endothelium may be evident rather than the emboli themselves ( Figure 6.09J ).

Because both platelet fibrin and cholesterol emboli are soft and consequently become rapidly fragmented and cast into the distal radicles of the retinal circulation, fluorescein angiography often fails to demonstrate complete obstruction of either a branch or the central retinal artery by the time the patient reports for examination ( Figure 6.09J and K ). Likewise, the rapid development of collateral flow around an embolus obstructing the central retinal artery behind the level of the lamina cribrosa may restore intraocular blood flow to nearly normal levels soon after the occlusion. The best scenario for improvement in vision is with occlusion at the entry of the central retinal artery into the optic nerve, since several pial and intraneural collaterals vessels can contribute to filling the central retinal artery distal to its occlusion. In most cases, however, fluorescein angiography reveals a delayed appearance time and an increased retinal circulation time in the area of the occluded segment ( Figure 6.09B ). In complete occlusion of the central retinal artery, no dye enters the eye by the artery, but dye filling the optic nerve capillaries by way of the ciliary artery circulation may pass through collateral channels and fill the proximal branches of both the central retinal vein and artery ( Figure 6.07A–D ). In complete branch artery obstruction the arterial tree may be perfused in a retrograde fashion by neighboring collateral vessels. In most instances an embolus lodged in an arterial bifurcation either on the optic nerve head or in the periphery is only partly successful in impeding the flow of fluorescein into the artery distal to the site of obstruction. In some instances the dye seeps by the embolus, and in others it bypasses the embolus by way of collateral flow. A significant reduction in flow is usually demonstrated angiographically in either case ( Figure 6.07A–D ). Retinal flow remains depressed even after dissolution of the embolus because of the collapse of the capillary bed by the ischemic and swollen retinal tissue. Fragmented emboli may completely plug the paramacular arterioles. The dye column entering the partly blocked area may show a pattern of laminar flow. In other cases there may be alternating nonfluorescent zones caused by packets of erythrocytes and hyperfluorescent zones caused by stagnant plasma ( Figure 6.07D and H ). Focal fluorescein leakage may occur at the site of the obstructing emboli and less often at sites where emboli have previously impacted on the arterial wall ( Figures 6.07F and 6.09 ). Failure of fluorescein to leak from the blood vessels distal to the site of arterial obstruction, even when circulation has been partly restored, testifies to the resistance of the retinal vessel endothelium to the effects of ischemia. In rare instances massive embolization of the retinal circulation may cause marked damage to the endothelium of the major retinal artery segments and produce striking periarterial dye leakage. Small emboli frequently observed in the arterial tree beyond the site of obstruction and elsewhere in the fundus usually show little or no tendency to alter the flow of fluorescein. No staining occurs at the site of these nonobstructing emboli. Very few patients with endogenous retinal arterial embolization show angiographic evidence of embolic occlusion of the choroidal circulation.

Branch retinal artery obstruction.

A–C : Branch retinal artery obstruction of unknown cause in a 36-year-old man. Note the obscuration of the proximal part of the obstructed retinal artery that suggests the possibility of a focal area of retinitis and late staining at the site of obstruction.

D–F : This 61-year-old man developed sudden onset of central scotoma in his right eye secondary to embolic obstruction of a cilioretinal artery. Note the bright plaques in the cilioretinal artery and the superior branch of the central retinal artery (arrows, D). After 16 seconds there was delayed perfusion of the retina in the region of distribution of the cilioretinal artery (E). Several months later the scotoma persisted, but the retinal whitening had cleared (F). This patient had angiographic evidence of obstruction of his right carotid artery.

G–I : Transient embolic obstruction (arrow, G) of the inferior retinal artery. Note ischemic whitening of the retina inferiorly. The patient had an altitudinal field defect superiorly. Visual acuity was 20/20. Nineteen months later the retina had regained its transparency, and the patient had no field defect. He later developed loss of the inferior field of vision caused by embolization of the superior branches of the central retinal artery (arrow, H and I). Note that perivascular cuffing persists at the site of the previous embolus in the inferior artery (H).

J and K : Focal atheroma (arrows) of a retinal arterial bifurcation following resolution of an impacted cholesterol embolus. Note the slight narrowing of the arterial wall indicated in the angiogram (arrow, K).

L : Arterioarterial anastomosis in a 62-year-old woman distal to a previous atheromatous embolus in the main trunk of the arteriole. She had another tiny plaque at the foveal end of the arteriole not seen in fig. This patient had suffered a central retinal artery occlusion on the right side and subsequently developed another branch retinal artery occlusion in this eye with loss of a significant part of her visual field. She had a diseased aortic valve and an arrhythmia.

(D and E, from Gass. ; © 1968, American Medical Association. All rights reserved.)

Some patients with branch artery occlusion may subsequently develop another branch artery occlusion or central retinal artery obstruction ( Figure 6.09G–I ). Patients with recurrent episodes of multiple branch retinal artery occlusions are more likely to have a nonembolic cause for the obstruction. (See discussion of recurrent branch retinal artery occlusion (Susac syndrome), p. p0380 in Chapter 6.)

Electroretinography in eyes with central retinal artery obstruction reveals loss of the oscillatory potential and transient depression of the b-wave with either a normal or supernormal a-wave. The electro-oculogram is diminished or absent.

The intraocular pressure may be subnormal in both the affected and the opposite eye in some patients with both branch artery and CRAO. Relative hypotony in the affected eye suggests the presence of ciliary as well as retinal arterial obstruction. The reported incidence of neovascular glaucoma after CRAO varies from under 2.5% to 15% or more. Some authors suggest that it occurs most often in patients with chronic ocular ischemia associated with severe carotid or ophthalmic artery disease, whereas others have not found this association. Glaucoma usually develops within 2–3 months, often earlier than occurs with central retinal vein occlusion likely due to the rapid onset of retinal ischemia. Even rarer is the development of neovascularization of the disc and subsequent vitreous hemorrhage ( Figure 6.08D ).

During the first few days after retinal artery occlusion, light microscopy reveals swelling of the inner half of the retina. The swelling is caused by intracellular edema and cellular dissolution ( Figure 6.10I ). Histologic examination 3 or 4 weeks later reveals marked loss of the inner retinal layers and preservation of the outer retinal layers ( Figure 6.10J ).

The white inner retinal lesions caused by arterial obstruction should be differentiated from white lesions caused by: (1) retinitis (e.g., toxoplasmosis, acute multifocal inner retinitis ; see Behçet’s disease, Fig. 11.40 , Fig. 11.41 ); (2) inflammatory disease of the choroid and retinal pigment epithelium (RPE) (e.g., acute posterior multifocal placoid pigment epitheliopathy); (3) outer retinal whitening from choroidal ischemia caused by prolonged elevation of the intraocular pressure (see Figure 3.63 ); (4) retinal contusion (commotio retinae, Berlin’s edema); (5) neoplasia (e.g., reticulum cell sarcoma); and (6) opaque subretinal fibrin (e.g., idiopathic central serous chorioretinopathy; Figure 3.03J , Figure 3.04J and L ). Emboli may be simulated by atheromatous plaques developing within the arterial wall at a focal site of retinal artery endothelial defect, e.g., patients who are prone to develop arterial macroaneurysms (see p. p0515 in Chapter 6) or focal arterial wall damage caused by previous impact of an embolus, an immune complex, or inflammatory reaction, e.g., in patients with bilateral idiopathic recurrent branch retinal artery occlusion (see Figures 6.19–6.21 ); acute retinal necrosis caused by herpes zoster virus (see Chapter 10); toxoplasmosis (see Kyrieleis plaques, and Figure 10.22F–H ); chronic uveitis ; or neoplasia (see Figure 13.31H ).

Inner retinal infarction occurs experimentally after complete occlusion of the central retinal artery lasting beyond approximately 1 ¹ / ₂ hours. Only occasionally does the patient who develops an acute retinal arterial obstruction report for therapy within the first few hours. Treatment, therefore, is infrequently beneficial. Nevertheless, in some patients with incomplete arterial obstruction, obstruction due to spasm, or obstruction of short duration, the ischemic damage associated with the retinal whitening may be reversible ( Figure 6.09G and H ). Even the presence of biomicroscopic evidence of slow blood flow (rouleaux formation) does not exclude the possibility of visual recovery. Therefore, in any patient with a history of occlusion of 24 hours or less, therapy consisting of paracentesis, intermittent massage, breathing of 95% oxygen and 5% carbon dioxide, and administration of acetazolamide may be helpful. Other modes of therapy that have been employed include the intravenous administration of vasodilators such as papaverine, perfusion of the ocular circulation by cannulation of the supraorbital artery, hyperbaric oxygen, surgical removal of the embolus, and Nd-YAG laser disruption of the embolus. Experimental use of recombinant tissue plasminogen activator to lyse retinal arterial thrombi was first reported with retinal artery occlusion. Most recent, has been the interest in intra-arterial thrombolysis by cannulating the ophthalmic artery via the femoral artery and injecting tissue plasminogen activator. This treatment has a role if it can be performed within 4 hours of occlusion. When arrangements for intra-arterial cannulation are not possible, intravenous use of tissue plasminogen activator in the correct settings to manage any complications can be tried if the patient arrives within 4 hours of visual loss. Even without therapy some patients will experience a remarkable visual recovery.

Embolic retinal artery obstruction.

A : Calcified embolus from the aortic valve is lodged in a bifurcation of the retinal artery.

B : Histopathology of a calcified embolus (arrow).

C : Histopathology of a retinal artery embolus containing cholesterol crystals (arrow).

D–F : Obstruction of the central retinal artery (left arrow, D and arrow, E) and ciliary arteries (right arrows, D and arrows, F) caused by chondrosarcoma that metastasized from the hip in a 27-year-old man. His symptoms were acute onset of headache, left hemiplegia, and loss of vision in the right eye. E and F show a high magnification of tumor obstructing the central retinal artery and ciliary arteries, respectively.

G : Multiple cotton-wool patches in a patient with fat embolism associated with multiple bone fractures.

H : Fat embolus (arrow, I) in a retinal capillary.

I : Histopathology of acute retinal artery obstruction. Note the swelling of the inner half of the retina.

J : Histopathology showing atrophy of the inner half of the retina months after retinal artery occlusion.

K and L : Large calcific embolus in the main trunk of the inferior retinal artery coming off the disc, resulting in opacification of the inferior half of the retina in this man with a diseased aortic valve.

(B, courtesy of Dr. Andrew P. Ferry; C, courtesy of Dr. Louis Karp; D–F, from Burde et al. ; G, courtesy of Dr. Elaine L. Chuang; I, from Hogan and Zimmerman ; L, reprinted with permission from Fekrat S, Moshfeghi D, Elliott D (eds) Curbside consultation in retina. Thorofare, NJ: Slack, 2010, p. 38.)

In the absence of ophthalmoscopic evidence of emboli in patients over 65 years of age, a sedimentation rate should be obtained along with an exhaustive review of systems to exclude the possibility of cranial arteritis as the cause of the occlusion. Auscultation of the heart and carotid arteries and comparison of the pulsation of the carotid arteries with the ophthalmic artery pressures, either by ophthalmodynamometry or by finger pressure, are useful measures for determining the source of the emboli. Transesophageal echocardiography in addition to transthoracic echocardiography is necessary for detecting mitral valve prolapse or other cardiac abnormalities such as patent foramen ovale, endocardial vegetations, and noninfectious masses. All patients should have a medical evaluation. In patients who are reasonable surgical candidates and who have no other explanation for the emboli, the evaluation should include at least digital subtraction carotid arteriography, which may demonstrate evidence of carotid stenosis and/or atheromatous plaques ipsilaterally in approximately 50% of cases.

Normal retinal transparency usually returns 2–3 weeks after acute retinal artery obstruction, but the retinal flow through the involved area is only partly restored. This probably is primarily caused by collapse of the capillary bed accompanying the postnecrotic atrophy of the retina. In most cases following central artery obstruction and in many cases following branch artery obstruction, optic atrophy and some narrowing of the retinal arterial tree occur. In others with less ischemic retinal damage the retina may return to a relatively normal appearance. Some with persistent low-grade chronic retinal ischemia may show multiple peripheral retinal hemorrhages (venous stasis retinopathy) identical to that seen in patients with carotid artery obstruction. Although visual recovery is generally poor, as many as 35% of patients after central retinal artery obstruction regain 20/100 or better visual acuity. Only 1–5% of patients with CRAO will develop rubeosis and glaucoma, usually within 1–3 months. These latter patients are likely to have significant obstruction of the carotid artery on the ipsilateral side. Relatively few patients with embolic retinal artery obstruction in one eye develop a similar process in the second eye. Some authors have found that the life expectancy for patients with retinal artery obstruction is reduced, whereas others have not. Although there is an increased incidence of stroke, most patients die of atherosclerotic heart disease.

It is clinically relevant to classify CRAO into:

• 1.
  

  nonarteretic CRAO: most often due to embolism

  
  
• 2.
  

  arteretic CRAO: secondary to giant cell arteritis, almost all associated with ischemic optic neuropathy

  
  
• 3.
  

  transient CRAO: recovers almost complete vision within a few hours of occlusion.

Carotid maneuvering during internal carotid aneurysm embolization causing retinal embolization.

A–J : This 42-year-old woman underwent onyx embolization for an internal carotid aneurysm on the left side. Soon after the procedure she complained of a “film with spotty holes” with her left eye. Her vision was 20/20 on the right and 20/50 on the left with a relative afferent pupillary defect. She had numerous white intraarteriolar refractile emboli and patchy areas of retinal whitening, more so in the temporal periphery of the left eye (A–C, G). Angiogram revealed patchy choroidal and retinal arteriolar filling with late wedge-shaped hyperfluorescence of the temporal retina simulating Amalric’s triangles. The triangular areas of hyperfluorescence were secondary to choroidal ischemia from occlusion of large choroidal vessels. Her vision spontaneously improved to 20/25. Three months later she still had refractile emboli within her retinal arterioles (H–J), the peripheral retinal vessels were sheathed, and the previous areas of choroidal infarcts showed pigmentation (I and J). The emboli are believed to be cholesterol emboli originating in the carotid bulb due to manipulation of the hardware such as the guidewire and catheter, and not the onyx used for embolizing the intracranial aneurysm (which would be black in color).

(Courtesy of Dr. Karen Joos and Dr. Franco Recchia.)

Atheromatous Retinal Arterial Embolization Following Use of Onyx to Embolize Internal Carotid Aneurysm

Onyx is a liquid embolic agent used for occluding intracranial, renal, and peripheral aneurysms and arteriovenous malformations (AVMs). It comes in ready-to-use vials containing ethylene-vinylalcohol copolymer, dimethylsulfoxide, and tantalum. The polymer is dissolved in dimethylsulfoxide, and micronized tantalum powder, which is radiopaque, is added. Concentrations of 6, 6.5, and 8% are variably used. The higher the concentration, the more viscous is the agent. After injecting heparin, a microcatheter is threaded to the nidus of the aneurysm and dimethylsulfoxide is first injected to fill the dead space in the catheter, followed by the selected onyx concentration. The aneurysm is filled to its neck under fluoroscopic guidance. This material forms an acrylic cast occluding the aneurysm completely.

During the procedure, manipulation of the guidewire/catheter and other hardware near the carotid bulb can dislodge a stream of cholesterol plaques that can embolize the retinal and choroidal vessels. Two such cases are illustrated in Figures 6.11 and 6.12G–J . The overwhelming feature seems to be the multiple emboli affecting the retinal and/or the choroidal circulation. Since these two cases, attention is being paid by the interventional neuroradiologists to minimize manipulation of the guidewire and other hardware at the carotid root. Other complications include bleeding at the site of the AVM, bleeding at the percutaneous entry site, and anesthetic complications resulting in oxygen desaturation from dimethylsulfoxide, though small and transient most of the time.

Fat embolism.

A–B : This 15-year-old boy broke his collarbone while playing soccer. He noted a superior visual field loss the next morning. His visual acuity was 20/25 and the superior half of the macula was perfused via a cilioretinal artery while the rest of his retina was opacified from occlusion of his central retinal artery (A). Autofluorescence imaging showed altered fluorescence from the opacified retina (B). A transesophageal echo revealed a persistent foramen ovale, which led to the paradoxical fat embolus from the fractured clavicle.

Branch retinal artery occlusion in protein S deficiency.

C–F : This 40-year-old woman of African American ancestry woke up with a superior field loss in her right eye. In addition to the compact cuticular drusen in the fovea bilaterally, there was a right inferotemporal branch retinal artery occlusion (C). Angiogram revealed minimal perfusion of the involved arteriole and staining of the endothelium at the site of the thrombosis (D–F). She was otherwise healthy and had no known cardiac or vascular disease. There was no family history of strokes or other vascular diseases. Evaluation of her heart and carotids yielded no cause for the occlusion. A laboratory workup revealed protein S deficiency. She was placed on aspirin therapy and has had no further episodes. Her vision remains at 20/20 in each eye.

Choroidal vascular emboli during onyx embolization of internal carotid aneurysm.

G–J : This 51-year-old woman underwent onyx embolization of her right superior hypophyseal aneurysm. A few hours after the procedure she noticed a “veil” over her right eye with fluctuating vision. Her vision was 20/25 on the right and 20/20 on the left with a relative afferent pupillary defect on the right side. There was faint whitening of the inferior half of her right retina (G). No retinal arteriolar emboli were seen. Angiogram revealed delayed choroidal and retinal filling in the inferior half (H–J) secondary to choroidal embolic infarct and partial inferotemporal retinal trunk occlusion. Her vision eventually improved to 20/20 and subjectively the scotoma faded to become almost imperceivable.

(A and B, courtesy of Dr. Richard Spaide; A, Also, Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p.481. G–J, Dr. Karen Joos and Dr. Franco Recchia.)

Other Causes of Endogenous Embolization

Protein S Deficiency

Protein C and protein S are vitamin K-dependent proteins. Protein S is a cofactor for protein C. Protein C is activated to protein Ca, which inactivates factor Va and VIIIa, thus acting as an anticoagulant, and proteolytically inactivates the inhibitor to tissue plasminogen activator, thus increasing fibrinolytic activity. Deficiency of protein C and S can increase thrombus formation in both venous and arterial circulation. The deficiencies can be congenital (autosomal-dominant) or acquired. Homozygous deficiency results in life-threatening thrombotic disease in the neonatal period, whereas heterozygous deficiency may result in symptoms in early adulthood or later. Acquired deficiency occurs due to poor hepatic synthesis of proteins. The thrombus occurs at the site of the occlusion and has been reported in the central and branch retinal artery ( Figure 6.12C and D ), cerebral, common carotid, brachiocephalic, and as a cause of anterior ischemic optic neuropathy. Recurrent branch arterial occlusions may occur in some patients, simulating Susac syndrome. The absence of arterial wall staining on fluorescein angiography (see Figure 6.21C and E ) helps differentiate Susac sydrome from this. Any artery or vein can be affected. Other factors such as pregnancy, trauma, childbirth, or surgery can sometimes precipitate thrombosis in these patients. Treatment involves anticoagulation with heparin and warfarin.

Purtscher’s-like retinopathy.

A–C : Bilateral retinopathy associated with acute pancreatitis in an alcoholic patient complaining of bilateral loss of central vision. Angiogram (C) shows evidence of focal retinal arteriolar occlusions in the perifoveal area.

D–F : Retinopathy associated with acute pancreatitis (D) in a 32-year-old alcoholic patient who subsequently became comatose and died. Histopathologic examination of the eye revealed necrosis and swelling of the inner two-thirds of the retina (E) and thrombotic arteriolar occlusion (arrow, F).

G–K : Purtscher’s-like retinopathy in a 24-year-old woman who noted severe visual loss in both eyes on awaking after a cesarean section done because of toxemia of pregnancy (G and H). Her visual acuity was 20/200 bilaterally. Angiography showed evidence of capillary nonperfusion corresponding with the white lesions (I and J). She recovered 20/25 visual acuity in both eyes within several months but showed evidence of optic atrophy (K).

L : Purtscher’s-like retinopathy occurred in both eyes of this 39-year-old woman with hypereosinophilia, skin rash, chest pain, arthritis, and eosinophilic fasciitis. Visual acuity was 20/40 in both eyes.

(A–C, courtesy of Dr. Raul E. Valenzuela; D–F, from Kincaid et al. ; G–K, from Blodi et al. ; L, courtesy of Dr. Arun Patel.)

Leukoembolization (Purtscher’s and Purtscher’s-Like Retinopathy)

Intravascular aggregation of leukocytes in response to unusual activation of complement C5a has been incriminated as the possible cause of retinal arterial embolization that produces the ophthalmoscopic picture of Purtscher’s retinopathy. This response occurs after trauma (see Figure 8.06 ) and in patients with acute pancreatitis ( Figure 6.13A–F ). Similar findings have been reported in patients with collagen vascular diseases ( Figure 6.14 ) ; in patients receiving hemodialysis ; in patients with chronic renal failure or hemolytic–uremic syndrome ; during plasmapheresis for thrombotic thrombocytopenic purpura and thrombotic thrombocytopenic purpura per se, Still’s disease and ( Figure 6.15A–E ), in normotensive obstetric patients after a precipitous delivery induced with intravenous oxytocin (Pitocin), following delivery by cesarean section ( Figure 6.13G–K ); and in patients with amniotic fluid embolism, HELLP syndrome (see Figure 3.58 ), fat embolism, cardiac aneurysm, ophthalmic artery obstruction, hypereosinophilia syndrome ( Figure 6.15F–H ), post bone marrow transplant, cytotoxic drug therapy and retrobulbar anesthesia (see Figure 8.12J ). The frequent association of central nervous system symptoms in patients whose ophthalmoscopic picture resembles Purtscher’s retinopathy suggests that leukoembolization may affect the cerebral vessels as well.

Purtscher described multiple, superficial, white retinal patches, superficial retinal hemorrhages, and papillitis occurring in five patients with severe head trauma (see Figure 8.06 ). The pathogenesis of the fundus changes is not completely understood. The white lesions were attributed to lymphatic extravasations secondary to a sudden increase in intrathoracic pressure, fat embolism, reflux shock waves through the venous system, air embolism, and, later, granulocytic aggregation.

Chronic alcoholics hospitalized for treatment of acute pancreatitis, with or without signs of central nervous system involvement, may suddenly lose vision in both eyes secondary to a fundoscopic picture identical to that of Purtscher’s retinopathy ( Figure 6.13A–F ). Shapiro and Jacob studied blood samples of 12 consecutive alcoholic patients admitted for acute pancreatitis and were able to demonstrate marked granulocyte aggregation, reflecting the presence of activated complement C5a in eight patients. This lends some support to the concept that leukoembolization may be responsible for the fundus picture.

Complement, platelet, and neutrophil activation and endothelial dysfunction and inflammation characterize pre-eclampsia. These likely exert an effect similar to the mechanism of pancreatitis causing leukocyte and platelet aggregation and vascular thrombosis in Purtscher’s-like retinopathy occurring around childbirth.

Most patients with collagen vascular disease have normal fundi. Some patients, usually those who have hypertension, may develop retinal or choroidal changes (see pp. p0495-p0510 in Chapter 6, and s0390 in Chapter 3). A few patients, particularly those with an exacerbation of disseminated lupus erythematosus, lupuslike syndrome associated with autoantibodies to Sjögren’s syndrome A antigen, dermatomyositis, Still’s disease and scleroderma, may develop acute loss of vision in one or both eyes with a fundoscopic picture suggesting multifocal embolic retinal arterial occlusions simulating those seen in Purtscher’s retinopathy ( Figures 6.16 and 6.14 ). These patients often have central nervous system symptoms as well. The occlusive process may be confined to the posterior pole or may involve extensively the peripheral fundus ( Figures 6.16 and 6.14A–F ). The retinal arterioles and arteries may be partly filled with a milky white material. Those with involvement of the periphery may develop severe retinal neovascular proliferation and vitreous hemorrhage. The presence of antiphospholipid antibodies in patients with systemic lupus erythematosus also plays an important role in retinal vascular thrombosis. (See unusual causes for retinal artery and arteriolar thrombosis in subsequent sections.)

Purtscher’s-like retinopathy associated with collagen vascular diseases.

A–F : Ischemic retinopathy in a 26-year-old normotensive black woman with lupus erythematosus who noted acute bilateral loss of vision, lethargy, mental confusion, and hallucinations (A). Visual acuity was 3/200. Both eyes showed a similar appearance. Her blood pressure was 120/78. Angiography showed multiple branch retinal arteriolar occlusions and dye leakage from the retinal veins (B and C). Three years later visual acuity was 20/300 in the right eye and 20/200 in the left eye. Note in D and E the optic atrophy, large areas of retinal vascular nonperfusion, and optic disc new vessels (arrows, E). After panphotocoagulation, there were atrophy and occlusion of the disc new vessels (F).

G–K : Ischemic retinopathy associated with severe scleroderma and systemic hypertension in a 54-year-old woman who developed blurred vision in both eyes. Visual acuity was 20/200 in each eye. Note the multiple cotton-wool patches and incomplete macular star (G). The nonfluorescent areas (H and I) correspond to cotton-wool patches and dye leakage from the first-order arterioles (arrow, I) and capillaries adjacent to the cotton-wool patches. The patient developed pulmonary edema, became semicomatose, and died soon after these photographs were made. Histopathologic examination revealed multiple cytoid bodies (K) and retinal arteriolar occlusions as well as some areas of fibrinoid necrosis of choroidal arteries and the choriocapillaris (arrow, J).

The retinal whitening is referred to as a Purtscher “flecken” and it typically has a clear zone between its edge and an adjacent retinal arteriole ( Figure 6.13A, L ). Fluorescein angiography in all of these patients who have an ophthalmoscopic picture simulating Purtscher’s retinopathy is similar. It reveals multiple focal areas of retinal arteriolar and arterial obstruction, adjacent areas of capillary nonperfusion, and extensive leakage from the vessels in the areas of infarction ( Figures 6.13 and 6.14 ). This latter feature is uncommonly seen in branch arterial occlusion caused by emboli from the heart and great vessels. Resolution of the white peripapillary and macular ischemic areas may require several months. Varying degrees of narrowing and sheathing of the retinal arteries, optic atrophy, and retinal neovascularization may occur ( Figure 6.14D–F ). In some patients with collagen vascular disease, evidence of occlusive arterial disease may be confined to the peripheral fundus and be associated with evidence of vasculitis and venous stasis.

Histopathology of an eye studied 23 days after onset of Purtscher’s retinopathy in a patient secondary to pancreatitis, showed material occluding retinal and choroidal arterioles to be positive for fibrin. Focal areas of retinal edema, cystoid degeneration, and loss of inner retinal architecture with a sharp demarcation from an area of normal retina was noted.

Further research is required to determine the role of complement activation and leukocytic aggregation and embolization in all of these disorders resembling Purtscher’s retinopathy. By the time many of these patients consult the physician, the level of complement C5a may have returned to nearly normal. If elevation of complement proves to be important, then the use of systemic corticosteroids has some rationale.

Erythrocytic Aggregation

Although the role of erythrocytic aggregation in the pathogenesis of retinal vascular occlusion is uncertain in diseases such as diabetes mellitus and Eales’ disease, there is good evidence that it is important in the case of sickle-cell disease. Increased deformity of the erythrocytes caused by hypoxia in the peripheral fundus is probably responsible for occluding the small retinal arterioles, capillary nonperfusion, and reactive proliferation of new vessels into the vitreous (for further discussion, see 118 in Chapter 6).

Purtscher-like retinopathy associated with thrombotic thrombocytopenic purpura.

A–E : Right and left fundus appearance in a 27-year-old male who presented with acute blurry vision in both eyes for 3 days. His acuity was 20/40 on the right and 20/300 on the left. There were several cotton-wool spots and small retinal infarcts in both posterior poles (A and B). Angiogram showed occluded retinal arterioles and late staining of the vessel walls and breakdown of the blood–retinal barrier in both eyes (C–E). He had had a rash, fever, sore throat, myalgia, chest pain, shortness of breath, paresthesia, and weakness for the past month. His sedimentation rate was 93 mm/h, C-reactive protein 234 mg/dl, white count 27 cells/μl, hemoglobin 8.7 g/dl, and liver function tests were abnormal. He also had a pleural and pericardial effusion and hepatosplenomegaly. He was diagnosed with adult-onset Still’s disease and required plasma exchange, antimetabolites such as cytoxan, vincristine, and intravenous immunoglobulin after no response to ibuprofen and pulse steroids.

Purtscher-like retinopathy associated with hypereosinophilia syndrome.

F–H : This 25-year-old African American patient developed decrease in vision in both eyes associated with cough, rash, and muscle soreness. His white count was elevated to 51 000/mm with 60% eosinophils. Both retinas showed several retinal infarcts and cotton-wool spots simulating Purtscher’s retinopathy (F). The small retinal vessels showed leakage on angiography (G). Bone marrow biopsy showed several eosinophils with “spectacle-like nuclei” (H). Three days later he developed pleural and pericardial effusions, cardiomyopathy, uncontrolled hypertension, seizures, right middle cerebral and bilateral occipital infarcts.

(A–E, courtesy of Dr. Kourous Rezaei; A and B, Also, Yannuzzi, Lawrence J., The Retinal Atlas, Saunders 2010, 978-0-7020-3320-9, p.294. F–H, courtesy of Dr. Joseph Maguire.)

Exogenous Embolization

Talc Retinopathy

Drug users may prepare a suspension for injection by dissolving crushed tablets, most often methylphenidate (Ritalin), in boiling water. The suspension may be inadequately filtered and injected intravenously, causing showers of insoluble fillers, principally talc and cornstarch, to embolize the pulmonary vasculature. Large-caliber collateral vessels are created around areas of occluded pulmonary vasculature after repeated embolization. The trapped particles also produce pulmonary granulomatosis and pulmonary hypertension; particles that are 7 μm or smaller can traverse the intact pulmonary bed. Together with larger particles that pass through the pulmonary collateral vessels, they may be deposited as multiple, tiny, glistening, irregularly shaped particles in the retinal vasculature, particularly in the macular area ( Figure 6.17A, B, and D ). In most patients they produce no symptoms. In some patients deposits of this material in the peripheral retina may cause areas of retinal capillary nonperfusion and retinal neovascularization at the junction of perfused and nonperfused retina similar to that in sickle-cell disease. Angiography may show no evidence of obstruction or may show small areas of capillary nonperfusion, microaneurysmal changes, and widening and irregularities of the FAZ. Some such patients may have subnormal acuity. Optic disc neovascularization, vitreous hemorrhage, and traction retinal detachment have occurred. Only those patients with long-term drug use develop fundoscopic changes. The retinopathy has been produced experimentally in primates. In patients with a patent foramen ovale, that is prevalent in 29% of population, larger particles can occlude branch retinal arteries ( Figure 6.17C ). Biopsy of the pulmonary nodules showed material consistent with talc that was birefringent under polarizing microscope ( Figure 6.17F and G ). Other foreign materials may occasionally lodge in the retinal vessels of drug addicts. In those with retinal artery occlusion after use of cocaine, heroin, and methamphetamine, the mechanism of the retinal artery occlusion may be pharmacologic rather than embolic. (See Chapter 9). Very tiny talc particles in a chronic methamphetamine snorter using for more than 15 years has been reported. The mechanism may be from absorption of the particles into the nasal mucosal vessels eventually reaching the lungs and the retina.

Central retinal artery and vein occlusion associated with thrombotic thrombocytopenic purpura (TTP) and Still’s disease.

A–J : A previously healthy 50-year-old woman developed rash, fever, abdominal pain, and weakness over 1 week and was diagnosed as having adult-onset Still’s disease. She developed encephalopathy and secondary TTP, after which she noted bilateral loss of vision to counting fingers at 6 feet (2 meters). She had symmetric-appearing extensive retinal opacification and blot hemorrhages consistent with a combined central retinal artery occlusion/central retinal vein occlusion picture (A and B). Angiography revealed very poor perfusion of both retinal arteries (C–F). Her vision continued to decline and dropped to hand motions and light perception. Intravitreal triamcinolone (4 mg) did not help her retinal changes, and she developed neovascularization of the iris on the right side requiring intravitreal bevacizumab and panretinal photocoagulation. Both eyes ended with extreme atrophy of the retina and sclerosed vessels with no light perception vision (G–J).

(From Schwartz et al., with permission.)

Retinal Arterial Embolization Following Corticosteroid Suspension Injection

Injection of corticosteroid suspensions such as methylprednisolone acetate (Depo-Medrol) into the nasal mucosa, lips, face, scalp, tonsillar fossa, and orbit, as well as directly into periocular lesions (chalazion, hemangioma), may pass in a retrograde fashion into the ophthalmic, central retinal, and short ciliary arteries and produce visual loss caused by infarction of either the retina or the optic nerve. Both eyes may occasionally be affected. The presence of the drug in both the retinal and choroidal circulation may be evident over widespread areas in the fundus ( Figures 6.17I and J and 6.18A–C ). In some cases the patient may regain normal visual acuity. A similar picture has been produced experimentally in dogs.

Other causes of exogenous embolization include retrobulbar injection of silicone and fat ( Figure 6.18F–I ), ²²⁰⁵ surgical embolization of intracranial arteries with polyvinyl alcohol, platelet transfusion, fragments of artificial heart valves and arterial implants, and air. A picture suggesting multifocal retinal artery occlusions after local anesthesia for blepharoplasty was attributed to tissue substance released into the lacrimal artery.

Exogenous embolization of the central retinal artery.

A and B : Intra-arterial talc emboli in a patient who chronically injected methylphenidate (Ritalin) intravenously.

C–G : This 24-year-old woman was asked to be evaluated for positive fungal blood cultures during a hospital admission for osteomyelitis. She was visually asymptomatic and found to have a branch retinal artery occlusion on the right and several intra-arteriolar white particles (C and D). She admitted to having used recreational drugs intravenously for several years. A transesophageal echo revealed a patent foramen ovale, which allowed larger talc particles into her left circulation that resulted in the retinal emboli. A computed tomography angiogram of her chest revealed a diffuse nodular pattern and focal nodules (E, arrows). Lung biopsy showed foreign-body giant-cell reaction to polarizable material consistent with talc (F and G).

H : Retinal arterial embolization after intranasal injection of methylprednisolone acetate in a 24-year-old woman who complained of “champagne bubbles,” numbness of the upper lip, and transient blindness of the ipsilateral eye. Visual acuity returned to 20/20 30 minutes after injection.

I and J : Retinal (arrows) and widespread choroidal arteriolar embolization in a 35-year-old patient who experienced a positive scotoma, orbital pain, diplopia, and visual loss immediately after injection of methylprednisolone acetate into the ipsilateral nasal turbinates. Visual acuity initially was 20/80 but returned to 20/20. One day later most of the retinal emboli were no longer present. Note the intrachoroidal emboli were less apparent (J).

(A and B, courtesy of Dr. Mark J. Daily; C–G, from Tarantola et al., ; H–J, from Byers. ; © 1979, American Medical Association. All rights reserved.)

Obliterative Retinal Arterial Diseases

Unusual Causes of Retinal Artery and Arteriolar Thrombosis

Occlusion of the central retinal artery, presumably caused by thrombosis, may occur occasionally in association with systemic diseases including essential thrombocythemia, thrombotic thrombocytopenic purpura, homocystinuria, mild hyperhomocysteinemia in heterozygotes, antiphospholipid antibody syndrome (Snedden’s syndrome), protein S deficiency, ( Figure 6.16C–F ) protein C deficiency, and Lyme disease. Multifocal arteriolar occlusions associated with bone marrow transplantation may simulate Purtscher’s retinopathy. It is uncertain whether these arteriolar occlusions occur primarily as a complication of irradiation or some other mechanism such as leukoembolization. The administration of fibrinolytic agents, such as tranexamic acid, to reduce the chances of bleeding may occasionally promote spontaneous thrombosis and branch retinal artery occlusion.

Arteritis and Arteriolitis

A variety of inflammatory disorders, some infectious and some of unknown etiology, may cause acute obstruction of either or both the ophthalmic and retinal arterial circulation, e.g., cat-scratch disease, (see p. s0030 in Chapter 10), herpes zoster (see p. s0345), mucormycosis (see p. p0310 in Chapter 10), toxoplasmosis (see pp. p0325-p0395 in Chapter 10), giant cell arteritis (see figure 6.23 G-I ), hypereosinophilic syndrome, eosinophilic fasciitis ( Figure 6.13L and 6.15F–H ), Churg–Strauss syndrome (allergic angiitis and granulomatosis, Figure 11.51 ), Kawasaki disease, idiopathic multifocal retinitis (see p. 82 in Chapter 11), and acute multiple sclerosis (MS). Although the retinal occlusive disease seen in these patients, as well as in patients with collagen vascular disease, has been attributed by some authors to arteritis, the arterial obstruction may be caused by other mechanisms, including hypertensive arteriolar narrowing, immune complex vascular damage, thromboembolization or leukocytic aggregation, and embolization (see discussion under leukoembolization, pp. 28 in Chapter 6).

Exogenous embolization of the central retinal artery.

A–E : A 23-year-old girl received 1 ml of methyl prednisone acetate to a progressive hemangioma at the tip of her nose. She lost consciousness 15–20 seconds after the injection. On regaining consciousness she complained of visual loss in both eyes, to no light perception. Both retinas showed several intra-arterial embolic material and areas of retinal and choroidal whitening (A and B). Paracentesis of the anterior chamber in both eyes improved vision to count fingers bilaterally. The emboli had broken down 48 hours later and the vision had improved to 20/200 (C). Her vision gradually improved to 20/60 on the right and 20/30 on the left over 10 days when the retinal opacification had faded and all the emboli had disappeared (D and E) and eventually to 20/30 on the right and 20/20 on the left by 1 year.

F–I : Ischemic retinopathy and choroidopathy caused by embolization of silicone injected into the lid. The patient experienced sudden loss of vision immediately after the injection. Note the multiple blotchy retinal hemorrhages (G). Angiography revealed multifocal filling defects in the choroid (H) and focal retinal arteriolar leakage (I).

(A–E, courtesy of Dr. Vishali Gupta and Dr. Amod Gupta.)

Idiopathic Recurrent Branch Retinal Arterial Occlusion (Susac Syndrome)

Apparently healthy individuals may develop, in one or both eyes, visual loss caused by recurrent episodes of multiple branch retinal arterial and arteriolar occlusions that often spare central vision ( Figures 6.19–6.21 ). The scotomata may be accompanied by photopsia, typically characterized as irregular shimmering, geometric lines or shapes of light just preceding a new scotoma and confined to the area destined to become scotomatous (45%); vestibuloauditory symptoms (50%); other transient focal neurologic symptoms, often affecting the face and upper extremities (30%) ( Figure 6.19A–F ); and a history of migraine (40%), defined as recurrent episodes of scintillating scotoma (with or without headache) or severe one-sided headache with nausea. Memory and cognition disturbances with confusion and bizarre behavior with mood and personality changes may accompany, precede, or antecede the other symptoms. The disease affects 20–40-year-olds of both sexes with a slight preponderance in females.

It is considered to be an autoimmune endotheliopathy involving the arterioles of the brain, eye, and cochlea and is also referred to as retinocochleocerebral vasculopathy. The focal retinal arterial obstruction is unassociated with visible emboli, may occur in the midportion of an artery and at arterial bifurcations, and is frequently associated with focal periarterial whitening and fluorescein angiographic evidence of segmental arterial staining near the site of the obstruction and elsewhere in the fundus ( Figure 6.19A–F ). Sheathing and multiple periarterial yellow-white plaques often develop along the obstructed arterial segment and may remain permanently ( Figure 6.19G, H, K, and L ). Egan et al. named these Gass plaques ( Figure 6.19 K ). In some cases only a ghost remnant of the completely occluded arterial segment remains ( Figure 6.21A and G ). These patients are subject to recurrent retinal artery occlusive events that, in some cases, may extend over a period of 10 years or more. Retinal, optic disc, and iris neovascularization may develop in 25% of eyes and requires photocoagulation or in some cases vitrectomy ( Figure 6.19I and J ). These patients are frequently subjected to multiple extensive unrewarding medical evaluations. Standard screening tests for blood dyscrasia, dysproteinemias, and coagulopathies, including those for antiphospholipid antibodies and natural anticoagulant deficient states; imaging tests of the carotid arteries, heart, and brain; and screening tests (excluding magnetic resonance imaging: MRI) for systemic vasculitis are typically negative. Johnson et al. found multiple lesions compatible with focal brain infarcts in one of three patients studied with MRI. The angiographic and ophthalmoscopic findings suggest that focal retinal arteritis and arteriolitis, perhaps caused by precipitation of immune complexes along the arterial wall, are responsible for the occlusions. The occasional association with serologic evidence of cytomegalic infection and protein S and protein C deficiency disease in these patients may be coincidental.

Idiopathic, bilateral, recurrent, branch retinal arterial occlusion (Susac syndrome).

A–F : This 26-year-old woman noted tinnitus and multiple negative and scintillating scotomata in the left eye associated with multiple branch retinal arteriolar occlusions (A). Angiography revealed multiple focal areas of retinal artery and arteriolar staining and occlusion (B and C). She subsequently developed similar occlusions in the right eye (arrows, D–F) and had multiple other episodes of branch arterial occlusion over a 3-year period. Medical evaluation was negative. When last seen 5 years after the onset of symptoms, her visual acuity was 20/20 in both eyes.

G–J : This 48-year-old man had multiple branch retinal artery occlusions in both eyes over a 9-year period. Despite multiple extensive medical evaluations, no cause was found. Note the ghosting and sheathing of the retinal arteries, periarterial plaques, and focal area of retinal neovascularization (arrows, I and J). When last seen 13 years after the onset of symptoms, visual acuity was 20/20.

K and L : Periarterial plaque associated with bilateral, recurrent branch retinal artery occlusions of unknown cause in a 51-year-old man. The plaques became less prominent over a 4-year period (arrows).

Most patients with idiopathic recurrent branch retinal artery occlusion are part of the triad of the syndrome of multiple branch retinal arterial occlusions, hearing loss, and encephalopathy (Susac sydrome). The triad sometimes is not apparent for a few years and the diagnosis may be delayed. The encephalopathy usually develops subacutely and often includes psychiatric features, personality change, and bizarre and paranoid behavior. The hearing loss is usually bilateral, asymmetric, and is often associated with tinnitus, vertigo, and ataxia. Low and medium frequencies are affected, localizing the lesion to the apical portion of the cochlea. MRI of the inner ear fails to show microinfarcts in the inner ear. MRI typically shows numerous infarcts in white and gray matter, more often in the periventricular region and the central part of the corpus callosum, and may show leptomeningeal involvement. The lesions in the corpus callosum are small, multifocal, and enhance in the early stages of the diseases ( Figure 6.21J ). They are responsible for the behavioral manifestations. The lesions are hyperintense on T2 fluid-attenuated inversion recovery (FLAIR). Diffuse tensor imaging may be able to detect white-matter abnormalities in the early phase of the disease. The clinical findings and MRI changes are often attributed to MS or acute disseminated encephalomyelitis. The key differentiating features on MRI are central corpus callosum involvement in Susac’s but peripheral in MS and acute disseminated encephalomyelitis, leptomeningeal involvement is limited to Susac, and basal ganglial lesions are seen more often in Susac and are rare in MS. The cerebrospinal fluid examination usually reveals minimal pleocytosis. The clinical course in these patients with encephalopathy, hearing loss, and multiple branch retinal artery occlusion can be self-limited, ranging from 1 to 2 years, with a good prognosis. However, in some patients, the disorder may be progressive and result in severe visual loss and death ( Figure 6.11G–L ).

Pathogenesis of the disease is poorly understood. Endothelial deposition of C4d demonstration histologically (Magro CM, unpublished data), serum anti endothelial antibodies at a titre of 1:960, and indirect immunofluorescence demonstration of IgG ₁ subclass antibodies suggest the disorder to be autoimmune in nature. Elevated levels of factor VIII and von Willebrand factor antigen may be the result of endothelial damage. Response to steroids and immunosuppressives also lends strength to the autoimmune hypothesis.

Idiopathic recurrent branch retinal artery occlusion associated with cerebrovascular involvement.

A–F : In February 1986 this 48-year-old woman with a long history of migraine headaches experienced a sudden onset of a paracentral scotoma in the right eye associated with a small branch retinal artery occlusion. In the asymptomatic fellow eye she had evidence of a branch retinal artery obstruction (arrow, A) and multiple focal areas of retinal arterial wall permeability changes (C and D). Several days after initial examination she developed dizziness and difficulty swallowing and talking. The diagnosis was “brainstem migraine.” Over the next 2 years she experienced multiple branch retinal arterial occlusions (E, February 1986; F, August 1986). Extensive medical and neurologic investigations including assay for protein C, protein S, and lupus anticoagulant were normal. Over the next 5 years she had no further ocular or neurologic symptoms. Her visual acuity when last seen corrected to 20/15 bilaterally.

G–L : In December 1984 this 71-year-old man presented with a 3-month history of progressive loss of vision in the left eye and a 5-day history of headaches and loss of vision in the right eye. His past medical history was unremarkable except for well-controlled systemic hypertension. His visual acuity was 20/25 right eye and hand movements left eye. There were multiple branch retinal arteriolar occlusions, extensive atheromatous retinal arterial changes, and scattered retinal hemorrhages in both eyes (G–I). The left optic disc was pale. Fluorescein angiography revealed evidence of extensive retinal artery and arteriolar occlusion (J). The patient was hospitalized, and medical and neurologic evaluations, including temporal artery biopsy, cerebral arteriograms, and computerized scans of the brain, were negative. In January 1985 he developed new paracentral branch retinal artery occlusions in the right eye (K). In April 1985 he developed bilateral vitreous hemorrhage and proliferative retinopathy (L). His family noted that he had a change in personality. In June 1985 he developed signs of a right-sided stroke, and progressive mental deterioration; he died after cardiac arrest in September 1985.

A specific treatment is yet to be confirmed since the disease etiopathogenesis is not completely understood. Treatment has evolved over the years and currently is a combination of systemic corticosteroids, immunosuppressives, and immunomodulating drugs. For an acute severe presentation, intravenous immunoglobulin (IVIG, 2 g/kg divided over five doses) every other day along with a high dose of systemic steroids is begun. IVIG is given every month for the first year or so and then maintained at 2-monthly intervals indefinitely till the disease shows no flareups over a few years. Systemic steroid is maintained at a moderate dose for the first few months then at a low dose for a few years. Mycophenolate mofetil has been substituted as a steroid-sparing agent in some patients. Cyclophosphamide has also been used as a long-term immunosuppressant in place of IVIG. Most recently rituximab, a monoclonal antibody, is being tried. Some patients have a self-limiting disease that quietens in 1–2 years and do not require long-term maintenance therapy.

Young patients with branch retinal artery occlusion associated with idiopathic multifocal retinitis and neuroretinitis (cat-scratch disease) may simulate idiopathic recurrent branch retinal artery occlusion (see Chapter 10, Figure 10.04 ).

X-Ray Irradiation

Exposure of the retina to X-ray irradiation may cause retinal arteriolar narrowing, cotton-wool patches, capillary telangiectasia, and retinal arterial occlusion (see pp. 554–556).

Susac’s syndrome.

A–H : This 25-year-old woman presented with diplopia and ataxia in 1999. She was diagnosed with multiple sclerosis when magnetic resonance imaging (MRI) showed white-matter changes, and was treated with intravenous methyl prednisolone and placed on interferon-1-alpha. Two years later she developed a visual field defect in her right eye and hearing loss, when she received intravenous methyl prednisolone. Her visual loss improved but hearing remained impaired. A year later she noted a new field loss in her left eye when she was evaluated at Vanderbilt and diagnosed as having Susac’s syndrome. She had a fresh superotemporal branch retinal artery occlusion on the left with retinal whitening and evidence of old occlusion on the right (A and B). Angiogram showed typical finding of Susac syndrome with fusiform staining of the involved vessel wall (C) and other uninvolved vessels (E) and previously occluded vessels on the right (D). The retinal whitening faded somewhat by 2 weeks; over the course of several previous and further episodes her optic nerves became pale (G and H). She had patchy field loss, though her central vision remained at 20/25 in each eye. She was treated with intravenous immunoglobulin (IVIG) and systemic steroids and maintained on monthly IVIG injections. She continues to remain stable.

I–L : This 34-year-old woman in 1995, soon after the birth of her second child, was evaluated by her psychiatrist for personality changes and diagnosed with anxiety and depression. Over the next 10 years she developed episodic hearing loss, and visual field loss that was attributed to “multiple sclerosis.” In the meanwhile her cognition was impaired and she had become a “slow thinker.” She was treated with intravenous methyl prednisolone and started on interferon-1-alpha. In 2007 she presented to Vanderbilt with bilateral visual field defects attributable to fresh branch retinal artery occlusions (I). She was diagnosed as having Susac’s syndrome and started on IVIG, oral steroids, and methotrexate. An MRI of her brain showed several callosal (J), periventricular, cortical, cerebellar, and pontine hyperintense lesions on T2 fluid-attenuated inversion recovery (FLAIR) imaging. She developed a superotemporal artery occlusion in the right eye a few months later when she self-decreased her oral prednisone (K). Note the narrowing at the site of previous occlusion in the inferotemporal arteriole (arrow). An angiogram showed the typical fusiform staining of the affected and unaffected vessel walls (L, arrow heads). She also shows evidence of past occlusions in the inferonasal arteriole. She has remained without further retinal occlusions over the next 3 years and is on maintenance IVIG and a very low dose of prednisone.

(J, courtesy of Dr. Siddharama Pawate.)

Retinal Arterial Obstruction Caused by Spasm

Some degree of reflex spasm probably plays a role in retinal arterial obstruction from many causes. The ocular fundi of patients with amaurosis fugax have been observed numerous times during an attack. The characteristic picture described is pallor of the optic disc and marked narrowing of the retinal arteries. With restoration of circulation, vision promptly returns. In some cases this spasm may be associated with recognizable causes, such as ocular migraine, collagen vascular disease, sickle-cell disease (see Figure 6.60A–H ), inhalation of cocaine ( Figure 9.13 ) and amphetamines, and administration of propranolol. It is probable that some cases of ischemic infarction resulting from retinal artery occlusion are caused by prolonged spasm of the central retinal artery. In the review by Brown and associates of a series of 27 patients under the age of 30 years who had retinal artery occlusion, the only associated finding was migraine headaches. Wolter and Burchfield reported a 12-year history of recurrent episodes of total vision loss in one eye associated with a cherry-red spot and complete recovery of vision in a 20-year-old man with ocular migraine. It is of interest that the photographs in their case show narrowing of the retinal veins rather than the arteries. This same phenomenon was noted in another patient by Dr. Mark Daily ( Figure 6.22H and I ).

Retinal Migraine

Retinal migraine is a rare cause of transient monocular visual loss, first described by Galezowski in 1882. It is usually characterized by episodes of partial or complete reversible monocular visual loss ipsilateral to the headache and lasting less than an hour. Sometimes it can result in irreversible visual loss. The 2004 International Headache Society criteria for the diagnosis of retinal migraine are as follows :

• A.
  

  At least two attacks fulfilling criteria B and C

  
  
• B.
  

  Fully reversible monocular positive and/or negative visual phenomena confirmed by examination during an attack or by the patient’s drawing of a monocular field defect during an attack

  
  
• C.
  

  Headache fulfilling criteria – migraine without aura begins during the visual symptoms or follows them within 60 minutes

  
  
• D.
  

  Normal ophthalmological examinations between attacks

  
  
• E.
  

  Not attributed to another disorder.

The condition is more common in young women in their second and third decades. The field defect may not always be from the retina; the optic nerve or the choroid may be the site of spasm, hence “monocular migraine” may be a better term. When examined during an episode these patients may have an afferent pupillary defect, constricted retinal arterioles, pallor of the optic disc, retinal whitening, and occasionally retinal venous constriction. The documentation of a visual field defect that completely reverses in association with headache on the side of the visual loss is necessary to make the diagnosis. Treatment with propranolol can prevent future episodes and should be begun in a confirmed case. These patients should be differentiated from patients with recurrent branch retinal artery occlusion of Susac syndrome, amaurosis fugax from carotid embolic disease, retinal artery occlusions from collagen vascular disease such as lupus and antiphospholipid syndrome, protein C and S deficiency, and in older patients from giant cell arteritis, polyarteritis nodosa, and eosinophilic vasculitis.

Retinal Arterial Obstruction Caused by Diseases of Surrounding Structures

Acute closure of the retinal arterial circulation may be caused by diseases primarily affecting the surrounding tissues, including inflammatory diseases such as retinal toxoplasmosis ( Figure 10.22A–C ), neuroretinitis, Bartonella associated multifocal retinitis and neuroretinitis (see Figure 10.04 ), and orbital cellulitis; external pressure on the ophthalmic, central retinal, and cilioretinal arteries such as in orbital hemorrhage, cavernous sinus thrombosis, intersheath perioptic hemorrhage, papilledema, ischemic optic neuropathy, optic disc drusen, central retinal vein occlusion, and neoplastic diseases of the orbit, optic nerve, and retina ; carcinomatosis of the meninges of the brain and optic nerve ; and surgical manipulation such as retrobulbar procedures.

Episodic vasospastic central retinal artery occlusion.

A–G : This young black woman with lupus erythematosus and sickle-cell hemoglobin C disease experienced episodes of blindness, each lasting 1–3 minutes, in the right eye several times daily. During an episode the retinal arteries were narrowed (A). Angiography revealed total obstruction of the central retinal artery and slow filling of both retinal veins and arteries via optic disc collateral vessels (B, 12 seconds; C, 27 seconds; D, 40 seconds; E, 85 seconds after injection of the dye). As vision returned to normal, dilation of the retinal arteries and veins occurred (F) and angiography revealed normal retinal perfusion (G). Her signs and symptoms failed to respond to blood transfusions but did so after systemic corticosteroid treatment.

H and I : Focal constriction of retinal veins (E) occurring during an episode of ocular migraine. Compare H with asymptomatic state in I.

(A, E, F, and G from Shaw et al. ; H and I, courtesy of Dr. Mark J. Daily.)

Branch retinal or cilioretinal artery occlusion may accompany central retinal vein obstruction in the same eye. In some cases both may be the result of primary disease affecting the optic nerve head. In other patients, particularly those with cilioretinal artery obstruction, the central retinal vein obstruction may be the cause of decreased perfusion within the cilioretinal artery that normally has a lower perfusion pressure than the central retinal artery.

Retinal Arterial Hypoperfusion Caused by Systemic Hypotension and Ocular Hypertension

Reduction of retinal blood flow in patients during systemic hypotensive episodes rarely produces evidence of retinal ischemia unless it occurs in patients with pre-existing disease causing reduced retinal flow. Marked elevation of intraocular pressure may cause symptomatic optic nerve or retinal ischemia, particularly when it occurs in patients with other diseases, such as sickle-cell disease. Compression of the eye and orbital tissues during general anesthesia in the face-down position may occlude the ciliary and central retinal arterial blood supply to the eye. (See Figure 3.54K and L .) This can also cause posterior ischemic optic neuropathy.

Retinal Arterial Hypoperfusion Caused by Carotid and Ophthalmic Artery Obstruction

Reduction of retinal arterial blood flow may be caused by obstruction of either or both the ipsilateral carotid and ophthalmic arteries. Whereas this obstruction is usually caused by slow progressive narrowing associated with atheromatous disease, it may have a variety of other causes, including giant-cell arteritis, spontaneous dissection, fibromuscular dysplasia (FMD), surgical complication, Takayasu’s disease, and cavernous sinus thrombosis. Rapid obstruction such as may occur in cranial arteritis ( Figure 6.23G–L ), mucormycosis, or herpes zoster causes acute visual loss and ischemic retinal infarction. This is often accompanied by signs of ciliary artery obstruction, pallor of the optic disc, and hypotony ( Figure 6.23J and K ) In a few patients multifocal areas of ischemia simulating Purtscher’s retinopathy may occur ( Figure 6.16H ). If obstruction of the major arteries occurs more slowly from atheromatous disease or chronic inflammation of the large arteries (Takayasu’s disease), reduction in blood flow to the eye may or may not be sufficient to cause visual complaints ( Figure 6.23A–C ). A variety of fundus pictures may occur: (1) minimal or no ophthalmoscopic changes in patients complaining of transient loss of vision in one eye (amaurosis fugax) ; (2) few widely scattered blot and dot retinal hemorrhages and mild dilation of the retinal veins (venous stasis retinopathy), usually in patients with minimal visual complaints ( Figure 6.23A–C ) ; (3) dilation of the retinal arterial tree, dilation of the retina veins, and cotton-wool ischemic patches ( Figure 6.23H ); (4) retinal capillary changes, including microaneurysms, cystoid macular edema (CME), and angiographic evidence of areas of capillary nonperfusion that may be confined to the area along the horizontal raphe ( Figure 6.23A–C ) ; (5) larger areas of peripheral capillary nonperfusion, retinal neovascularization, and hemorrhage; (6) any degree of branch or central retinal vein or arterial obstruction ( Figure 6.23H ); (7) ischemic optic neuropathy ( Figure 6.23I ); and (8) any of the above associated with panuveitis, neovascular glaucoma, and a rapidly progressing cataract (ischemic ocular syndrome).

Carotid and ophthalmic artery obstruction.

A–C : Blotchy peripheral retinal hemorrhages and retinal capillary changes (arrows, A) in a 57-year-old man with a 4-month history of frequent 8–10-minute episodes of “fogging” of vision of the right eye. There was no other history of transient ischemic attacks. He had xanthelasma for 12 years. Visual acuity was 20/20. Ophthalmodynamometry was 35/20 in the right eye and 110/40 in the left eye. Angiography showed increased retinal circulation time, microaneurysms, and dilation of retinal capillaries (C). The left fundus was normal.

D–F : Loss of peripheral vision, hypotony, and a 360° serous detachment of the ciliary body and choroid developed in a 72-year-old aphakic man 8 weeks after medical evaluation detected ipsilateral carotid artery obstruction. Ciliochoroidal detachment nasally extended almost to the optic disc (D and E, arrows). Note the round retinal hemorrhages that were present throughout the midperiphery of the eye. There was ophthalmodynamometric evidence of marked reduction in the ophthalmic artery pressure.

G–I : This elderly woman noted the sudden loss of vision in the left eye. Her vision and the fundus of the right eye were normal (G). Visual acuity in the left eye was 20/200. Note in the left fundus the patchy dense whitening of the inner juxtapapillary retina (H) and the diffuse whitening of the retina superiorly. On the following day she awoke with no light perception in the right eye. The right optic disc showed swelling and pallor (I) typical of ischemic optic neuropathy associated with giant-cell arteritis, which was demonstrated histopathologically on temporal artery biopsy. Intensive corticosteroid therapy was given. Ten months later she remained blind in the right eye and retained 20/70 in the left eye.

J and K : Unilateral blindness caused by ophthalmic artery occlusion in an elderly patient with cranial arteritis. Note the pallor of the optic disc and narrowing of the retinal vessels caused by previous obstruction of circulation in the central retinal artery; also note the segmental atrophy of the retinal pigment epithelium caused by obstruction of the short ciliary arterial circulation (J and K).

L : Histopathology of the temporal artery in a patient with cranial arteritis. Note severe narrowing of the vessel lumen by granulomatous arteritis.

Dr. Gass has seen one aphakic patient with carotid artery obstruction develop loss of vision caused by acute exudative detachment of the choroid and ciliary body ( Figure 6.23D–F ). The detachment resolved rapidly after carotid endarterectomy. The ophthalmologist faced with any patient who has these ocular signs or symptoms should inquire about other signs or symptoms of transient ischemic attacks and should look for other evidence of ipsilateral carotid artery obstruction, such as reduction of carotid artery pulsation, a bruit over the carotid artery and orbit, and ease of collapse of the ipsilateral central retinal artery with finger pressure on the eye compared with that of the contralateral eye. Fluorescein angiography in all such cases should show a late appearance time of the dye in the central retinal artery and choroid and a prolonged retinal circulation time. In some cases a dramatic improvement in the fundus changes may occur after carotid endarterectomy.

Takayasu Retinopathy

Mikito Takayasu in 1908 described the ocular manifestations of this condition as “peculiar changes in the central retinal vessels and wreath of arertiovenous communication” around the optic disc. The retinal changes include dilatation of the retinal arteries and veins with beading ( Figure 6.24I and J ), microaneurysms at the capillary level and along the arterioles (very typical; Figure 6.24A–F, I–L ), vascular occlusion, large zones of nonperfusion, arteriovenous shunts, retinal and optic disc neovascularization ( Figure 6.24I and L ), and, occasionally, vitreous hemorrhages. The arm to retina time and the arteriovenous transit times are prolonged. Poor blood flow to the eye is the basis of the ocular findings and is seen in those patients with involvement of the common carotid arteries ( Figure 6.24G and H ). The left side is more commonly involved than the right. Since the intravascular hydrostatic pressure is low, these patients have very few retinal hemorrhages, and minimal leakage from the new vessels ( Figure 6.24L ) and microaneurysms. The poor endothelial oxygenation causes a break in the blood–retinal barrier and mild fluorescein leakage, but much less intensely than other conditions such as diabetic retinopathy. Intraocular pressure is low due to poor perfusion of the ciliary body; eventually rubeosis irides (but rarely neovascular glaucoma) and cataract develop. Traction retinal detachment and phthisis bulbi have been seen very occasionally. Those patients with renal artery stenosis without involvement of the carotids show features of hypertensive retinopathy in the form of arteriolar narrowing, retinal hemorrhages, and arteriovenous crossing changes.

Takayasu arteritis, also known as “aorta arteritis” and “pulseless disease,” is a form of chronic granulomatous panarteritis with possible autoimmune origin that affects the aorta and its branches. The coronary and pulmonary arteries can sometimes be involved. Why it is more common in Asia, Mexico, and other tropical countries is not fully understood. A link to poststreptococcus autoimmune change or to tuberculosis has been postulated. Intimal proliferation and fibrosis of the media with scarring, thrombus formation, and eventual stenosis of the affected artery occur.

A female preponderence of up to 9:1 is seen in Asia, and affects young adults who present with clinical features based on the vessels involved. Those with involvement of the branches of the aortic arch present with amaurosis fugax, dizziness, and syncope. Renal artery stenosis leads to hypertension and its manifestations.

Takayasu arteritis is classified based on vessel involvment using radiological imaging into six groups :

• •
  

  Type I: branches of aortic arch

  
  
• •
  

  Type IIa: ascending aorta, aortic arch, and its branches

  
  
• •
  

  Type IIb: descending thoracic aorta with or without ascending aorta, arch, and its branches

  
  

  
  

  
  

  

  
  

  
  

  Takayasu retinopathy.

  
  

  A–H : A 28-year-old East Indian woman had a 6-month history of diminution of vision in both eyes accompanied by giddiness, which recovered on lowering her head. Her visual acuity was 20/200 in each eye and intraocular pressure 6 and 7 mmHg respectively. There were no iris new vessels and pupils were sluggish. Multiple microaneurysms were seen in both eyes, which were significantly more common anterior to the equator, and several on the larger arterioles (arrows A and B). There was remarkable delay in dye appearance in both the choroidal and retinal circulation. Several microaneurysms as well as dilated capillary bed filled on angiography. The late frames showed diffuse vessel wall staining of all retinal vessels (C to F). Her physical exam was significant for absent radial and brachial pulses. She underwent computed tomography; angiogram of the arch of the aorta and its branches was suggestive of type 4 Takaysu arteritis involving the ascending arch and descending aorta, left pulmonary artery, bilateral common carotid artery, brachiocephalic trunk, bilateral subclavian and axillary arteries (G and H). She was treated with oral steroids.

  
  

  I–L : This 17-year-old Indian female was seen for episodic headaches and frequent blackouts. Her vision at initial evaluation was 20/30 both eyes, but subsequently declined over a year to count fingers in both eyes. Both eyes showed several microaneurysms, many of them on the arterioles (arrow), dilated and sausage-shaped veins (I and J). There were no retinal hemorrhages due to slow flow in the vessels. The left eye also had a large NVD (I). An angiogram picks up the numerous microaneurysms (K), and late frames show breakdown in the blood–retinal barrier due to endothelial hypoxia. Note the NVD does not leak early due to the very slow blood flow throughout the retina (L). Her blood pressure was unrecordable in the upper limbs and measured 160/80 mmHg in both lower limbs. Her carotid, radial, brachialis, and subclavian pulses were absent bilaterally, but the femoral, popliteal, posterior tibial, and dorsalis pedis were present. On an aortogram the right subclavian artery was absent, only stumps of the left common carotid and subclavian were seen, and there were rich collaterals between the intercostals and axillary vessels. She had type 2 Takayasu arteritis.

  
  

  (A–L, courtesy of Dr. Amod Gupta; I–L, courtesy of Dr. Vishali Gupta and Dr. Amod Gupta.)

  
  
  
  
• •
  

  Type III: descending thoracic aorta and abdominal aorta

  
  
• •
  

  Type IV: abdominal aorta only

  
  
• •
  

  Type V: aortic arch, descending thoracic aorta, and abdominal aorta.

Therapy depends on the stage of the disease. If the patient is seen early in the course of arteritis without significant occlusion, systemic steroids and immunosuppressives alone are indicated. Once occlusion or significant stenosis occurs, angioplasty and bypass grafts are needed in addition to the immunosuppressives. Medical management of hypertension, nephrectomy, and autotransplantation of the kidney may be necessary. Antituberculous drugs in those patients with highly positive Mantoux test is indicated.

Fibromuscular Dysplasia

FMD is a nonatheromatous, noninflammatory vascular disorder that commonly affects the renal and internal carotid arteries. It is known to cause choroidal hypoperfusion central retinal artery, and cilioretinal artery occlusion, though extremely rarely. Retinal hypoperfusion, and its various manifestations, leading to retinal neovascularization and traction retinal detachment, similar to Takayasu retinopathy, has been described in one patient. A fatal stroke and multiple retinal hemorrhages have been seen in an 11-month-old infant. When a young patient without cardiovascular risk factors presents with a CRAO, one should rule out FMD. These patients may have recurrent strokes, transient ischemic attacks, syncope, headache, tinnitus, and cranial nerve palsies. Unlike atherosclerosis that affects the proximal or origin of the caroid artery, FMD affects the middle or distal part and has a typical appearance on carotid Doppler/angiogram with the “pulled screw” configuration, focal tubular narrowing, or localized outpouching of the artery. These configurations occur specifically in the three types of FMD (1) pulled screw or multiple constrictions in the medial type; (2) focal tubular narrowing in the intimal type; and (3) outpouching in the adventitial type. Aneurysms and involvement of other medium-sized arteries can also occur. Genetic risk factors are being investigated, as the disease is known to occur in first-degree relatives.

Retinal Hypoperfusion Caused by Cardiac Anomalies

Young patients with congenital cyanotic heart disease commonly develop some dilation and tortuosity of the major retinal vessels often associated with polycythemia. Frank central retinal vein occlusion, atypical rubeosis iridis can be seen rarely. Patients with pulmonary hypertension and a reversed bidirectional shunt through an intracardiac defect (Eisenmenger’s syndrome) may develop retinal microvascular changes similar to that in patients with carotid artery obstruction. Paradoxical embolus due to a right-to-left shunt can cause retinal artery occlusion.

Retinal Arterial Hypoperfusion Caused by Occlusion of Retinal Venous Outflow

If severe and rapid obstruction of the central venous outflow occurs before collateral channels of venous outflow begin to function, severe ischemic whitening of the retina, in addition to widespread retinal hemorrhages, occurs, producing the ophthalmoscopic picture of combined central retinal arterial and venous occlusion. Obstruction of the central retinal vein may cause selective obstruction of a cilioretinal artery because of relatively low perfusion pressure of the cilioretinal arteries).

Hypertensive retinopathy.

A–C : This 32-year-old woman had a visual acuity of 20/80 secondary to severe hypertensive retinopathy. Note the macular star, cotton-wool patches, and hemorrhages. Early arteriovenous-stage angiograms showed narrowing of the first- and second-order arterioles (arrows) supplying the macula (B) and patchy staining of the retina corresponding to areas of dilated capillaries (C). Note the absence of fluorescein staining in the macula.

D–F : Foveal hemorrhage (D) caused by hypertensive microvascular changes evident in the angiogram (E). Note the white punctate flecks on the surface of the oval superficial retinal blood and the larger area of subretinal blood. Several months later the blood cleared (F) and the visual acuity returned to normal.

G–I : Ischemic optic neuropathy and branch retinal arterial occlusion in a patient with severe chronic hypertension. Note the sharp demarcation line (arrows, G) separating the ischemic retinal whitening from the nonischemic peripheral retina in the areas of distribution of the obstructed artery. The peripheral retina retained its transparency because of previously established collateral arterial channels (arrows) that became more apparent several months later in H and I.

J–L : Purtscher’s-like retinopathy in this 58-year-old man caused by central retinal artery obstruction in a patient with hypertension. He noted blurred central vision in the left eye that progressed over a period of 24 hours to include the entire visual field. His visual acuity was 1/200. Note the severe retinal whitening in the papillomacular bundle area and patchy retinal whitening in the macular area. Angiography revealed delay in perfusion of the retinal circulation. Echography revealed distension of the left optic nerve sheath with fluid. Carotid artery studies were negative. His serum triglyceride was 944.

Cystoid Macular Edema After Cataract Extraction

Approximately 50–70% of the patients who have an uneventful intracapsular cataract extraction will develop fluorescein angiographic evidence of leakage of fluorescein from the parafoveal retinal capillaries ( Figure 6.32 ). More than 90% of these patients will show no biomicroscopic evidence of CME, and they will not have any significant decrease in their visual acuity. The incidence of this subclinical CME is so high that it may be considered as a normal physiologic response to intracapsular cataract extraction. Approximately 5–15% of all patients will develop loss of visual acuity secondary to clinically significant CME after uneventful intracapsular cataract extraction. These patients will demonstrate the typical biomicroscopic and fluorescein angiographic changes caused by a polycystic pattern of expansion of the extracellular space by serous exudation ( Figures 6.32–6.34 ). These changes are described in detail in Chapter 2. The incidence is much lower after extracapsular cataract extraction and phacoemulsification surgery. Clinically significant CME usually occurs within 4–12 weeks postoperatively, but in some instances its onset may be delayed for months or many years after surgery. It infrequently occurs before the third postoperative week. Blurred vision is the usual complaint. Visual acuity is generally reduced to the range of 20/30–20/70. A few patients may complain of mild irritation of the eye and show some circumlimbal conjunctival injection. The anterior hyaloid face is ruptured in approximately 50% of patients after intracapsular cataract extraction or the posterior capsule is dehisced with or without anterior vitrectomy in eyes undergoing phacoemulsification. Some inflammatory cells may be present in the posterior vitreous, which typically shows evidence of extensive liquefaction. Vitreous attachment to the macula usually cannot be demonstrated. Mild and rarely severe degrees of papilledema may be present. Usually there is no ophthalmoscopically visible change in the structure of the capillary bed. An occasional small intraretinal hemorrhage or microaneurysm may be present. Approximately 10% of patients will show some evidence of epiretinal membrane formation, or so-called cellophane maculopathy (see Chapter 7). Over 50% of these patients will have either clinical evidence of systemic hypertension or fundoscopic evidence of focal retinal artery narrowing. The eyes are typically normotensive. CME after cataract extraction appears to be more common and more severe in patients with blue rather than brown irides. It occurs as a complication of cataract extraction less frequently in blacks than in whites and occurs infrequently after extracapsular cataract extraction in children. If lens extraction in infants is accompanied by an anterior vitrectomy, significant and persistent CME may occur.

Aphakic cystoid macular edema (CME).

A–D : Note thickening of the macular region and the presence of multiple cystoid spaces (A). An early angiogram showed evidence of perifoveal dye leakage from the retinal capillary bed (B). There was some evidence of dye leakage from the optic nerve head. The dye leaked into the cystoid spaces in the outer retinal layers and spread centrally and peripherally 1 hour after injection (C and D). The dye stained the fluid in the cystoid spaces. Note the dark stellate figure centrally, the feathery margins of the intraretinal dye peripherally, and the presence of retinal vessels that appear as dark lines overlying the fluorescein.

E and F : CME following cataract extraction. The vitreous haze partly obscured the cystoid spaces from view (E). The arrow indicates a small yellow deposit lying deep within the retina. Mild papilledema was present. A 1-hour angiogram (F) showed a typical angiographic pattern of CME.

G–L : This African American woman who underwent uneventful phacoemulsification and placement of posterior-chamber intraocular lens bilaterally developed CME and subretinal fluid in both eyes (G–J). After minimal response to topical steroids and nonsteroidals for nearly a year, she was started on oral acetazolamide 250 mg three times a day. She responded with resolution of subretinal and intraretinal fluid in approximately 3 months. The CME recurred in a mild fashion after discontinuation of acetazolamide, but resolved on its reinstitution (K and L). She was slowly tapered off the acetazolamide after another 3 months and remained stable with 20/20 vision in each eye.

(From Gass and Norton. , © 1966, American Medical Association. All rights reserved.)

Early phases of fluorescein angiography demonstrate dye leakage from the parafoveal retinal capillaries, and later phases show the characteristic picture of CME ( Figure 6.32 ). Angiography can be helpful in the diagnosis of CME in these patients, who often have hazy ocular media that prevent detailed biomicroscopic examination of the macula. Leakage of fluorescein often occurs from the capillaries of the optic nerve head and anterior uveal tract. The aqueous humor typically stains heavily with fluorescein. CME disappears spontaneously, and visual acuity returns to 20/30 or better within 3–12 months in two-thirds of these patients after intracapsular cataract extraction and no lens implant. Other patients will show clearing of the edema and return of good vision from 1 to 5 years following the onset of CME. The incidence of permanent visual loss caused by CME after extracapsular cataract extraction and posterior-chamber intraocular lens implantation is approximately 1–1.5%. The duration of CME is usually longer and recurrences are more frequent in patients with a history of vitreous loss at the time of extraction or in those who develop incarceration of vitreous in the wound postoperatively. Angiography of the opposite phakic eye shows no evidence of abnormal retinal or iris vessel permeability, except in the rare patient who has chronic bilateral vitritis of unknown cause before cataract extraction.

Vitreous fluorophotometry in patients with aphakic CME shows evidence of increased ocular vascular permeability that parallels the severity of the CME. Eyes with iris-supported implants that develop CME have a higher incidence of developing chronic CME and corneal edema.

Histopathologically, the extracellular space of the retina, particularly in the inner nuclear and outer plexiform layers, is expanded by serous fluid of low protein content ( Figures 6.34 and 6.35 ). Small numbers of chronic inflammatory cells have been found histologically in eyes with aphakic CME. Fine and Brucker’s electron microscopic findings suggested that the cystic spaces in CME might be caused by accumulation of intracellular fluid within expanded Müller cell processes. Gass et al., however, demonstrated that CME is caused by accumulation of serous exudate in the extracellular space, which is more in keeping with clinical, angiographic, and light microscopic findings in patients with CME.

The pathogenesis of aphakic and pseudophakic CME is unknown. Direct traction on the macula by the vitreous does not appear to be an important factor. The incidence of CME is higher in patients who have had vitreous loss during cataract extraction and patients who develop a peaked pupil with vitreous adherence to the wound following delayed rupture to the anterior hyaloid face. The typical findings of inflammatory cells in the posterior vitreous of most, but not all, patients suggest the possible importance of inflammation. It may however be that these cells are the result of, rather than the cause of, the retinal capillary abnormality. Comparable inflammatory reaction in the vitreous from other intraocular surgical procedures usually does not produce macular edema. Removal of the lens is undoubtedly a key factor in this disease, but the mechanism by which it leads to retinal edema is not clear. Diffusion of prostaglandins from the anterior segment to the retina, hyperosmolarity of the vitreous secondary to a ruptured anterior hyaloid face, smoldering low-grade cyclitis, and vitreous traction acting on the peripheral retina are suggested but unproved causes of CME. The frequent findings of narrowing of the retinal arterial tree and systemic hypertension suggest that underlying retinal vascular disease is also an important factor in the pathogenesis of CME. The incidence of CME occurring following cataract extraction in patients with background diabetic retinopathy is much higher than in healthy patients. In one study the incidence of clinically significant CME was 75% versus 6% of the control eyes, and the CME persisted for more than 1 year in 56% of diabetic eyes. The incidence of CME occurring in the second eye following an uneventful cataract extraction may be as high as 50%. It may occur soon after the subsequent opening of the posterior lens capsule. The incidence of CME after posterior-chamber lens implantation with simultaneous capsulotomy versus that after the same procedure without capsulotomy is probably slightly greater. The incidence of CME after delayed Nd:YAG laser capsulotomy is probably less than 1–2%.

Diagram illustrating the biomicroscopic appearance of the macula in the presence of cystoid macular edema. The anterior bowing of the inner retinal surface in the foveal region is caused by thickening of the retina. The cystic pockets of extracellular serous fluid are seen best with retroillumination .

(From Gass and Norton. , © 1966, American Medical Association. All rights reserved.)

The treatment of aphakic or pseudophakic CME with anti-inflammatory agents such as the antiprostaglandins and corticosteroids may result in some temporary improvement in visual acuity, yet there is no evidence that they significantly shorten the duration of clinically significant CME or reduce the incidence of the development of chronic CME. Topical nonsteroidal anti-inflammatory drops may be effective in reducing CME but probably are no more successful in this regard in most patients than topical corticosteroid drops. There is some evidence to suggest that in some patients the increase in the intraocular pressure induced by use of topical corticosteroids is partly responsible for its therapeutic effect. Excision of vitreous that is incarcerated in the wound is of value in some patients with persistent CME. Some patients with vitreous incarceration, particularly those with complaints of irritation and photophobia and those with many vitreous opacities, do obtain relief of symptoms and improvement in acuity following a vitrectomy. In the absence of chronic irritation, photophobia, or corneal edema, vitreous excision from the wound is not recommended for at least 1 year after the onset of edema because of the uncertainty of its value and the likelihood of spontaneous resolution. Carbonic anyhydrase inhibitors have been suggested for the treatment of aphakic and pseudophakic CME ( Figure 6.32G–L ).

In the aphakic or pseudophakic patient presenting with visual loss, contact lens examination usually is sufficient to determine the presence of CME as the cause. Fluorescein angiography and OCT are helpful in those cases where CME is not evident biomicroscopically, or in cases where an explanation of the visual loss is not evident. The physician should remember that CME identical to that complicating cataract extraction may be associated with many other disorders, some of which may have been unrecognized before, or have developed after, cataract extraction. Of particular importance is detection of the presence of a subtle rhegmatogenous retinal detachment, choroidal neovascularization in eyes with other evidence of age-related macular degeneration or vitreofoveal traction, that may play a role in causing the CME, or in producing a macular lesion that simulates CME biomicroscopically.

Cystoid Macular Edema Associated with Rhegmatogenous Retinal Detachment

A few patients may develop the biomicroscopic and fluorescein angiographic picture of CME secondary to a rhegmatogenous retinal detachment. CME may be present preoperatively or may appear initially during the postoperative course. Angiographic evidence of the edema has been described in 25% of phakic patients who have undergone a scleral buckling procedure and in 40–65% of aphakic eyes undergoing scleral buckling procedures. The incidence of CME appears to be higher in older patients, and in many instances it clears spontaneously. Late resolution of CME is responsible for the delayed improvement in visual acuity that sometimes occurs in patients 6 months or longer following successful repair of a retinal detachment. The general prognosis for spontaneous resolution of the CME is good. CME has been noted after cryotherapy of a retinal tear in the absence of rhegmatogenous detachment.

Cystoid Macular Edema Following Other Types of Intraocular Surgery

Transient CME also has been observed postoperatively in a few phakic patients who have had other intraocular procedures, such as glaucoma filtering operations and peripheral iridotomies. CME is a major complication after penetrating keratoplasty. Kramer found a 42% incidence of clinically significant CME in aphakic eyes in which penetrating keratoplasty and vitrectomy had been performed. He found an incidence of 19% of CME following combined cataract extraction and penetrating keratoplasty with a vitrectomy and only a 4% incidence following combined procedures without an anterior vitrectomy. In eyes with bullous keratopathy and CME with anterior-chamber and iris-supported lens, good visual recovery often occurs after penetrating keratoplasty and exchange of the intraocular lens for a posterior-chamber lens. CME has been noted following a laser iridotomy.

Histopathologic findings in a patient with aphakic cystoid macular edema.

A : Note the large cystic spaces containing serous exudate in the outer plexiform layer and the small spaces with exudate in the inner nuclear layer. Despite the marked thickening of the retina, there is little evidence of loss of neural tissue. Note the slight serous separation of the irregularly thinned underlying retinal pigment epithelium.

B : Photomicrograph of a section taken nearer to the center of the fovea than A. Note the artifactitious rupture (arrow) of the inner wall of the large central cyst.

(A from Gass and Norton. , © 1966, American Medical Association. All rights reserved.)

Complications Following Cystoid Macular Edema

Although visual acuity may return to 20/30 or better after 2 or more years of CME, some patients develop permanent retinal damage secondary to the prolonged edema. The spontaneous rupture of the inner wall of a large central cystoid space to form a lamellar hole is one of the complications of CME. When this occurs, it produces a characteristic biomicroscopic and a diagnostic angiographic change ( Figures 6.35 and 6.36 ). Biomicroscopically, a round or oval, one-third disc diameter, punched-out defect occurs in the center of the macula. The RPE in the base of the hole is undisturbed. A sheen or light reflex is usually evident on the surface of the remaining retina as a slit beam is moved across the hole. Yellow deposits within the hole and a halo of marginal retinal detachment typical of a full-thickness hole are not present. Small perifoveal cystoid spaces surrounding the inner lamellar hole may be difficult to visualize. Late-phase fluorescein angiography, however, demonstrates a polycystoid pattern of dye in the perifoveolar area surrounding a round or oval, nonfluorescent zone that corresponds with the inner lamellar hole ( Figure 6.36D ). Following rupture of the inner cyst wall, the fluorescein can no longer concentrate in the area of the lamellar hole ( Figures 6.35 and 6.36 ). Following resolution of the CME surrounding the lamellar hole, fluorescein angiography of the macula appears normal. Occasionally, multiple ruptures of the inner cyst walls produce a multifaceted lamellar macular hole, rather than a solitary oval or round hole.

In the aphakic patient with poor central vision and CME, failure to demonstrate the presence of central cysts during the late stages (10–60 minutes) of angiography suggests a poor prognosis caused by the presence of a lamellar hole, retinal atrophy, or a nonmacular cause for the visual loss.

Cellophane maculopathy and macular pucker caused by epiretinal membrane formation may be evident at the onset of CME, or they may occur as late complications of CME. When they occur, it is less likely that central acuity will return to normal following resolution of the CME. Occasionally, however, these membranes may peel spontaneously from the surface of the retina, and good acuity may be restored (see Figure 7.23 ).

Prolonged CME may occasionally produce atrophy of the outer retinal layers, and the macula may appear relatively normal except for the absence of a foveal reflex.

Infantile Cystoid Maculopathy

Infantile cystoid maculopathy that macroscopically resembled that seen in X-linked juvenile retinoschisis was observed on gross examination of the eyes of three premature infants of both sexes by Trese and Foos. Cystoid changes were noted at various retinal levels. Reduced numbers of ganglion cells were found in the retina and central nervous system of all patients.

Cystoid Macular Edema Associated with Choroidal Melanomas

Patients with peripherally located melanomas may develop the typical biomicroscopic and angiographic appearance of CME unassociated with serous detachment of the macula ( Figure 6.35 ). The cause of this edema may be the chronic inflammatory cell infiltration within the choroid adjacent to the melanoma and retinal vasculitis. It is important that patients with unilateral CME have a careful examination of the peripheral fundus to exclude the presence of a melanoma.

Cystoid Macular Edema and Topical Epinephrine and Prostaglandin Inhibitor Therapy

Either aphakic or phakic patients may develop the typical biomicroscopic and angiographic appearance of CME following the use of topical epinephrine-like and antiprostaglandin drops for glaucoma. If CME occurs and is caused by the drops, it can be reversed by discontinuing the medication.

Cystoid Macular Edema Associated with Ocular Inflammatory Diseases

CME may occur in a variety of recognized inflammatory diseases of the eye, such as pars planitis, Behçet’s disease, vitiliginous chorioretinitis, sarcoidosis, idiopathic vitritis, and scleritis.

Electron microscopic findings in phakic woman with cystoid macular edema and a choroidal melanoma.

A–E : Before enucleation, angiography revealed evidence of cystoid macular edema (A and B). Epoxy resin-embedded section of the eye (C) revealed cystic expansion of the extracellular space in the inner nuclear and outer plexiform layers (×40). Electron microscopic section through the edge of one of the smaller cystoid spaces (D) showed the extracellular space filled with homogeneous material between healthy well-preserved cells. Glycogen granules (arrow) indicate prompt fixation (×15 000). There was thickening of the retinal capillary basement membrane (E, ×7200).

(From Gass et al. )

Cystoid Macular Edema From Other Causes

Discussions of CME associated with tapetoretinal dystrophies, carotid artery occlusion, congenital juxtafoveolar capillary telangiectasia, overlying occult choroidal neovascularization, and occurring after occult central retinal vein occlusion are found on pp. 330, 522, 570, and 588, respectively.

Idiopathic Cystoid Macular Edema

CME of uncertain cause occasionally occurs in one or both eyes of patients ( Figures 6.37 and 6.38A–H ). The CME may be associated with a typical pattern of fluorescein leakage, or with no evidence of fluorescein staining. Some of these patients may eventually develop evidence of a tapetoretinal dystrophy.

Pseudocystoid Macular Edema

Superficial changes in the retina occurring in patients with sex-linked juvenile retinoschisis (see Figure 5.59A, C, and E , Figure 5.58 ), Goldmann–Favre syndrome (see Figure 5.57A, D, and H ), infantile cystoid maculopathy, and rhegmatogenous retinal detachment, lightning maculopathy (see Figure 8.16 ), and following spontaneous vitreoretinal separation (see Figure 7.14J–L ) may be mistaken for CME. Fluorescein angiography is helpful in this differential diagnosis. In patients with suspected CME and a negative angiogram, care must be taken to exclude the possibility of a tapetoretinal dystrophy (see Figure 5.42 ) and nicotinic acid maculopathy ( Figure 6.38I–L ).

Lamellar macular hole developing in a patient with prolonged cystoid macular edema (CME) after cataract extraction.

A–D : Note the yellow pigment centrally lying within the retina (arrow, A). Visual acuity was 20/40. A 1-hour angiogram (B) shows a typical picture of CME. Note that the dye fills the central cystoid spaces. Four years later (C), the patient has developed a circumscribed defect involving the inner layers of the retina centrally. There was biomicroscopic evidence of an epiretinal membrane and cystoid edema of the retina around the lamellar hole (C). The visual acuity was 20/70. Angiography demonstrated evidence of CME surrounding the lamellar hole (D). There was no pooling of the dye centrally because it was free to diffuse into the vitreous through the defect in the inner retinal layer. The patient died soon after the photographs in C and D were taken.

E : Histopathologic examination revealed a lamellar hole (1), epiretinal membrane (2), the slit-like areas of retinal edema in the outer plexiform layer (3), and small pockets of exudate in the inner nuclear layer. There was some loss of the receptor elements (4) in the vicinity of the lamellar macular hole where because of postmortem artifact the receptor cell layer is folded back on itself.

F and G : Schematic diagram showing the development of a lamellar macular hole in a patient with CME.

F : CME before rupture of the internal limiting membrane.

G : Lamellar macular hole with surrounding epiretinal membrane.

(From Gass. )

Nicotinic Acid Maculopathy

A small percentage of patients (probably under 1%) receiving high oral doses of nicotinic acid (1.5–5 g/day) for the treatment of hypercholesterolemia will develop bilateral blurring of vision caused by CME ( Figure 6.38I–L ). Although the biomicroscopic appearance of CME is identical to that seen in patients after cataract extraction, it is unaccompanied by vitritis, other retinal vascular changes, and fluorescein angiographic evidence of retinal capillary permeability alterations ( Figure 6.38K ). Cystic spaces are seen in the outer plexiform and inner nuclear layer on OCT. The reason for the absence of fluorescein leakage is speculative. Whether the permeability change in the retinal capillaries is so mild that fluorescein particles do not leak out or Müller cell edema is the cause of the cystic spaces is still debated. Prompt recovery of normal vision and complete resolution of macular edema occur after nicotinic acid therapy is stopped ( Figure 6.38L ). Reinstitution of the therapy results in recurrence of the CME.

Dominantly Inherited Cystoid Macular Edema

Deutman et al. described an autosomally dominant macular dystrophy characterized by CME, fluorescein leakage from the retinal capillaries throughout the posterior pole, normal electroretinographic findings, subnormal electrooculographic findings, and hyperopia. Atrophic pigment epithelial changes with a “beaten bronze” appearance may eventually develop. Histopathologic examination reveals large retinal schisis spaces in the macula, marked disorganization of the inner retinal layers, and advanced degeneration of Müller cells. Treatment with oral acetazolamide has not been successful. However a somatostatin analog, octreotide acetate, stabilized visual acuity and decreased fluorescein leakage in seven out of eight eyes.

Idiopathic cystoid macular edema (CME).

A : Idiopathic unilateral CME in the left eye of this man who was complaining of blurred vision. There were no vitreous cells or biomicroscopic evidence of vitreomacular traction. Stereoscopic angiograms showed thickening of the retina centrally but no fluorescein staining. One month later the CME had disappeared and there was evidence of posterior vitreous detachment.

B–D : Idiopathic self-limited bilateral CME in this 37-year-old woman with a 4-month history of visual loss in both eyes. Soon after the onset of symptoms examination revealed marked bilateral CME and only a few vitreous cells. Except for multiple allergies her past medical history was negative. The CME failed to respond to long-acting prednisolone orbital injections and oral prednisone. When seen in Miami her visual acuity was 20/70 both eyes. There were no vitreous cells. Prominent CME in the absence of any other abnormalities was present bilaterally (B and C). Angiography (D) showed no staining. Her family history was negative. An electroretinogram was normal. Approximately 1 month later she had surgery for abdominal scarring caused by endometriosis. Three months later the CME had cleared spontaneously.

E–G : Idiopathic, possibly congenital, nonstaining CME in a 34-year-old woman with pendular nystagmus, poor vision all her life, and no history of nyctalopia or hemeralopia. Her visual acuity was 20/60 right eye and 20/200 left eye. Fluorescein angiography revealed evidence of slight mottled depigmentation of the RPE paracentrally (G). Color vision by Ishihara color plates was normal. An electroretinogram revealed mild decrease in cone and rod amplitudes with the b-wave much more affected than the a-wave.

H–L : This 55-year-old phakic woman complained of blurred vision in her right eye for 6 months. Biomicroscopic examination revealed cysts in the right fovea (H) that did not accumulate dye on angiography (I). There were no vitreous cells, vitreofoveal traction, or other ocular pathology. She was on no medications. Observation over 4 months did not change her ocular status. Optical coherence tomography (OCT) confirmed persistence of cysts and revealed a pre-existing posterior vitreous separation. She was treated with oral acetazolamide 250 mg three times daily, the cysts resolved, and vision returned to 20/20 (K) by 3 months. Acetazolamide was tapered over 2 months and repeat OCT 2 further months later (L) revealed no recurrence of CME.

Idiopathic cystoid macular edema (CME).

A–D : Idiopathic bilateral CME (A and B) occurring 1 week after a mild viral-like gastrointestinal illness, in an otherwise healthy woman, who on awakening noted marked loss of central vision bilaterally. Examination revealed 20/200 acuity, prominent CME in both eyes (A and B), and no signs of intraocular inflammation. There was a poorly defined equatorial zone of leopard-spot hyperpigmentation in both eyes (C). Angiography revealed a prominent staining pattern typical for CME (D). An electroretinogram and peripheral visual fields were normal. Within 6 weeks she was asymptomatic and her visual acuity returned to 20/25 right eye and 20/20 left eye.

E and F : Bilateral postpartum CME and mild vitreous cellular infiltration in a 22-year-old woman who noted blurred vision 3 days after a normal delivery of a full-term healthy infant. Visual acuity was 20/50 in the right eye and 20/25 in the left eye. Two months later the visual acuity was 20/40 in the right eye and 20/20 in the left eye. There was an epiretinal membrane in the right eye but no macular edema or vitreous cells in either eye.

G and H : Idiopathic unilateral CME in a 52-year-old healthy man with a 4-month history of blurred vision. His visual acuity was 20/30 in the right eye and 20/20 in the left eye. There were no vitreous cells. His past medical and family history was negative. His findings were unchanged 5.5 years later.

Nicotinic acid maculopathy.

I–L : This 50-year-old man experienced progressive loss of central vision bilaterally. He was receiving 3–5 grams of nicotinic acid a day for the treatment of hypercholesterolemia. Visual acuity in the right eye was 20/70, and in the left eye was 20/50. The fundi were normal except for typical CME (I and J). Fluorescein angiography showed no evidence of capillary permeability in the macula (K). Six months after cessation of nicotinic acid therapy, his visual acuity returned to 20/20, and the CME had resolved (L) bilaterally.

(F–I, from Gass. ; © 1968, American Medical Association. All rights reserved.)

Facioscapulohumeral Muscular Dystrophy and Coats’ Syndrome

FSHD is an autosomal-dominant disorder with a variable age of onset from childhood to old age, and severity from mild weakness to severe disability. A family history may be difficult to elicit because expression of the gene is variable and penetrance is incomplete. The characteristic clinical features include wasting of the shoulder girdle, upper deltoid, pectoralis, biceps, and triceps muscles, with relative preservation of the lower deltoid and prominence of the upper trapezius muscles. Muscle weakness can progress to the trunk and lower limbs over time and 20% can become confined to the wheelchair. Loss of tone of the abdominal musles leads to a protruding belly, and of the facial muscles to a drool and protruding tongue. Leg muscle involvement can lead to tiptoe walking and foot drop, resulting in an unstable gait. Loss of vision caused by retinal telangiectasis and deafness (high-frequency hearing loss) occur in some of these patients and rarely may be the initial manifestation of FSHD ( Figure 6.40A–F ). Early onset of symptoms and deafness herald more severe cases. Myoclonus and temporal-lobe absence attacks can occur. Unlike congenital retinal telangiectasis, both eyes are affected and both sexes are affected equally. The onset of visual loss is variable and may occur in early childhood. Asymptomatic family members with minimal evidence of FSHD may show evidence of retinal telangiectasis without evidence of exudation. The patients and family members should be screened for evidence of retinal telangiectasis since early treatment with photocoagulation may prevent visual loss. A young girl’s presentation with neovascular glaucoma at age 2 led to the detection of bilateral Coats’ disease; further onset of seizures led to the diagnosis of FSHD. Coats’ syndrome has also been reported in a scapulohumeral muscular dystrophy that is probably is a variant of FSHD.

Deletion in the long arm of chromosome 4 (4q35) is the locus for the gene for FSHD; however the exact gene has not been found.

Coats’ disease.

A–E : This 36-year-old male noted trouble with his vision on the right 3 months previously. His vision was 3/200 on the right and 2/20 on the left. In the superotemporal quadrant 3–4 disc areas of retinal telangiectasia with hemorrhages surrounded by dense circinate lipid exudates and retinal thickening were seen (A–C). Another patch was present nasally. Angiogram showed the bulbous vessels, capillary nonperfusion, surrounding dilated capillary bed, and leakage from the telangiectatic vessels (D and E). He underwent laser treatment and moved to Texas.

Coats’ disease with retinal degeneration.

F–H : A 72-year-old man, followed since 1980 from age 45 for retinitis pigmentosa, initially presented with retinal and vitreous hemorrhage in the right eye, requiring pars plana vitrectomy ×3 and phacoemulsification cataract surgery. That eye turned phthisical. The left eye has had several episodes of vitreous hemorrhage and received laser treatment (F–H).

(F–H, courtesy of Dr. Laurence W. Arend.)

Group 1A: Unilateral Congenital Macular Telangiectasia

Patients with unilateral congenital foveal and parafoveolar telangiectasis probably suffer from a localized mild form of congenital retinal telangiectasis, a nonfamilial disorder affecting predominantly one eye of males without other evidence of systemic disease (see previous discussion of congenital retinal telangiectasis and Coats’ syndrome). The localized form of congenital retinal telangiectasis is typically confined to an area between 1½ and 2 disc diameters in the temporal half of the macula, where it straddles the horizontal raphe ( Figures 6.43 and 6.44 ). Approximately one-third of patients will have some focal telangiectasis in the extramacular area, usually temporally. Yellow, lipid-rich exudation is usually present at the outer margins of the area of telangiectasis, often in a ring configuration ( Figures 6.43I, and 6.44A and E ). The mean age of onset of symptoms is approximately 35 years. Polycystic macular edema and exudation are the cause of the loss of acuity, which usually ranges from 20/25 to 20/40. Telangiectatic capillaries are easily visualized with biomicroscopy and fluorescein angiography. Blunted right-angle venules, superficial retinal crystals, intraretinal pigment plaques, and subretinal neovascularization, features of group 2 juxtafoveal capillary telangiectasis, are not found in these patients. Early-phase stereoscopic fluorescein angiography shows prompt filling of the telangiectatic vessels, affecting both the superficial and the deep capillary network, and late intraretinal staining. The natural course of this disorder is variable. Some patients may retain excellent visual acuity for many years in spite of chronic waxing and waning CME ( Figure 6.43A–I ). Those with yellow lipid exudate in or near the center of the macula are probably at greatest risk of developing progressive loss of visual acuity. Focal applications of laser photocoagulation of the telangiectatic vessels may be helpful in restoring and preserving central acuity ( Figure 6.44A–H ). Congenital telangiectasis confined to the capillary bed in the region of the macular area should be differentiated from idiopathic bilateral acquired juxtafoveal capillary telangiectasis ( Figures 6.45–6.48 ), and telangiectasis caused by branch vein obstruction (see Figure 6.79D–F ), diabetic retinopathy ( Figure 6.52A–C ), X-ray irradiation retinopathy ( Figure 6.57 ), Eales’ disease, sickle-cell maculopathy, tuberous sclerosis ( Figure 6.40G and H ), and carotid artery obstruction. Group 1A patients should be clearly differentiated from patients with dilated perifoveal capillaries and evidence of vitreous cellular infiltration, whether it is caused by acquired inflammatory disease or is part of a tapetoretinal dystrophy.

Natural course of congenital juxtafoveolar retinal telangiectasis, group 1A.

A–D : This 52-year-old man noted blurred vision in the left eye. His visual acuity in the left eye was 20/30. The right eye was normal. Note the localized zone of capillary telangiectasis, which was confined to the juxtafoveolar region temporally (arrows, A). Angiography demonstrated the telangiectasis (B) and showed evidence of cystoid macular edema (C). No treatment was given. Twelve years later he had developed some lipid exudation (D) and his visual acuity was 20/40.

E–I : Spontaneous resolution of circinate maculopathy caused by juxtafoveolar retinal telangiectasis occurred in a 16-year-old boy, who when he was seen initially in 1958 had marked exudative maculopathy (E); his visual acuity was approximately 20/100. Six years later the exudate had cleared, he was asymptomatic, and his visual acuity was 20/20 (F and G). Angiography demonstrated that the telangiectasis extended into the peripheral fundus temporally (H). At age 38 years he noted decreased vision in the right eye. His visual acuity was 20/50. Note the recurrence of the lipid exudation (I).

J–L : This 57-year-old man presented with a 6-year history of blurred vision in the left eye and a 2-week history of blurred vision in the right eye. His visual acuity was 20/20, right eye, and 20/30, left eye. He had bilateral juxtafoveolar telangiectasis associated with mild cystoid edema but no lipid exudation in both eyes (J). Ten years later his visual acuity was 20/30, right eye, and 20/40, left eye. Note the temporal location of the telangiectatic capillaries and the lipid exudate (K and L).

Group 1B: Unilateral, Idiopathic, Focal Macular Telangiectasis

Most patients with unilateral idiopathic focal juxtafoveolar telangiectasis are middle-aged men who have mild metamorphopsia or blurring caused by exudation from a minute area of capillary telangiectasis that is usually confined to 2 hours of the clock or less at the edge of the capillary-free zone ( Figure 6.44I–L ). It may or may not be associated with a small amount of yellow exudate. The visual acuity is usually 20/25 or better. Angiography shows the focal capillary telangiectasis and minimal staining. Photocoagulation is usually not advisable because of the proximity of the leakage to the capillary-free zone and the good visual prognosis without treatment. It is uncertain whether this is an acquired lesion or merely represents a minute focus of congenital telangiectasis.

Congenital juxtafoveolar retinal telangiectasis, group 1A.

A–D : Retinal telangiectasis involving the capillary bed temporal to the macula associated with a localized serous detachment of the retina, retinal edema, and circinate retinopathy in a 27-year-old man (A). Note the sheathed capillaries just temporal to the macula (arrow). The elevation of the lesion was caused primarily by thickening of the retina secondary to edema. Angiography revealed extensive telangiectatic involvement of the capillary bed temporal to the macula (B and C). There was marked leakage of dye from the capillary bed in the area surrounded by circinate retinopathy (G). Note the partial dark figure in the macula (arrow). Twelve months after xenon photocoagulation, the exudate had cleared (D) and visual acuity was 20/20.

E–H : Unilateral congenital juxtafoveolar telangiectasis in the right eye (E and F) of this 49-year-old man, whose visual acuity was 20/50. Following focal argon laser photocoagulation his visual acuity improved to 20/20 and the exudation resolved (H).

Congenital monocular focal juxtafoveolar retinal telangiectasis, group 1B.

I and J : This 40-year-old man noted blurred vision in the right eye caused by exudation from a focal area of capillary telangiectasis (arrows, I and J) at the edge of the capillary-free zone at 1 o’clock.

K and L : This healthy 28-year-old man noted metamorphopsia in the left eye caused by yellow exudation from focal retinal telangiectasis confined to a small area at the edge of the capillary-free zone.

Group 2A: Bilateral, Idiopathic, Acquired Macular (Juxtafoveolar) Telangiectasia

Most of these patients are in the fifth or sixth decade of life (mean age 55 years) when they seek treatment for mild blurring of vision in one or both eyes. Both sexes are equally affected. Patients with group 2A telangiectasis typically demonstrate bilateral, symmetrically small areas, usually 1 disc diameter or less, of occult capillary telangiectasis that involves and may be confined to the temporal half of the foveolar areas or may include part or all of the nasal parafoveolar areas ( Figures 6.45 and 6.46 ). This form of telangiectasis is associated with minimal intraretinal serous exudation and no evidence of lipid exudation. Visual acuity is typically 20/30 or better when persons initially seek treatment. Biomicroscopically, the development of this disorder can be subdivided into five stages. In stage 1, usually found in the fellow asymptomatic eye, biomicroscopy demonstrates no abnormality. The early phases of stereoangiography show minimal or no evidence of capillary dilation, and late phases show mild staining at the level of the outer parafoveolar retina temporally. In stage 2 there are slight graying and loss of transparency of the parafoveolar retina and minimal or no telangiectatic vessels ( Figure 6.45A and D ). Early-phase angiography reveals evidence of mild capillary telangiectasis affecting primarily the outer capillary network temporally ( Figure 6.45B and C ). In stage 3 there is biomicroscopic evidence of one or several slightly dilated and blunted retinal venules that extend at right angles into the depth of the parafoveolar retina. These are usually first evident temporally. Stereoscopic angiography often shows unusual capillary dilation and permeability change in the outer retina beneath one or more of these venules ( Figure 6.45D–F ). A peculiar linear branching pattern of these capillaries occurs in some patients ( Figure 6.46B–D ). In stage 4, one or several stellate foci of intraretinal black hyperplastic RPE envelops the posterior extension of the right-angle venules ( Figures 6.45J–L, and 6.46A and E ). These intraretinal pigmented plaques have a characteristic appearance that should suggest the correct diagnosis, even when the telangiectasis cannot be visualized biomicroscopically. In stage 5, biomicroscopic and fluorescein angiographic evidence of type 2A subretinal neovascularization occurs in the parafoveolar area, often in the vicinity of the intraretinal pigment epithelial migration ( Figure 6.46G and I–L ). Multiple, tiny, golden, crystalline deposits develop near the inner surface of the parafoveolar retina in approximately one-half of the eyes in stages 2–5 ( Figure 6.46A, E, and G–I ). Approximately 5% of patients may develop a round, yellow, intraretinal spot 100–300 μm in diameter in the center of the foveola in one or both eyes ( Figure 6.45G ). This is usually associated with minimal loss of the foveolar depression.

Bilateral acquired juxtafoveolar telangiectasis, group 2A.

A–C : Bilateral, acquired, parafoveolar capillary telangiectasis in a 59-year-old man with a 3-year history of mild blurring of vision in both eyes. His past medical history and family history were negative. Visual acuity in the right eye was 20/20; the left eye was 20/30. He had nasal paracentral scotomata in both eyes on Amsler grid testing. There was slight graying of the juxtafoveal retina temporally in both eyes (A). No dilated capillaries were visible. Angiography revealed early leakage of dye from the retinal capillaries on the temporal side of the macula bilaterally (C).

D–F : Acquired juxtafoveolar telangiectasis and foveolar atrophy in a 42-year-old woman with a 2-month history of painless progressive loss of vision in both eyes. A general medical examination was within normal limits. The family history was negative. Visual acuity in the right eye was 20/100 and in the left eye was 20/35. There was a faint gray halo in both maculae (D). Angiography revealed evidence of mild perifoveolar capillary telangiectasis (E and F) and paracentral fluorescein staining bilaterally. There was no evidence of cystoid macular edema (CME) centrally.

G–I : Acquired, bilateral, juxtafoveolar telangiectasis and CME in a 54-year-old surgeon with a 10-year history of mild blurring of vision and metamorphopsia that were worse in the right eye than in the left eye. His visual acuity was 20/25 in both eyes. Note the halo of gray discoloration of the perifoveolar retina and the yellow spot centrally (G). The appearance of the left macula was similar, except there was no central yellow deposit. His past medical history and family history were negative. Angiography showed bilateral juxtafoveolar telangiectasis and evidence of perifoveolar retinal staining that did not extend into the central macular area (H and I).

J–L : Acquired, bilateral juxtafoveolar telangiectasis in a 65-year-old woman who had a history of telangiectasis for 6 years at the time of the photograph in J when she had superficial retinal crystals and one small stellate retinal pigment epithelium lesion (arrow, J). Over a period of 4 years, she developed multiple areas of stellate pigment migration into the retina (arrows) around the right-angled venules draining the telangiectatic capillaries in both eyes (K and L). Note the small superficial punctate white retinal crystalline deposits. Her visual acuity when last measured was 20/50 in the right eye and 20/80 in the left eye.

(A–C, from Gass and Oyakawa. , © 1982, American Medical Association. All rights reserved.)

OCT shows one or more cysts or lacunae in the inner or outer retina in all stages of the disease ( Figure 6.47H and I ). These cysts or lacunae may be the result of breakdown and loss of the Müller cell bodies in the Müller cell cone and the rest of the fovea.

Visual acuity is usually normal in stages 1 and 2. Most patients become symptomatic at stage 3, and some maintain good acuity after developing stage 4. Loss of central vision in these patients typically occurs slowly over many years and is associated with atrophy of the foveolar retina that develops in the absence of typical CME. This atrophy may produce a picture simulating a lamellar macular hole ( Figure 6.46E and F ). Fluorescein angiography in stages 1–4 fails to show late staining extending into the center of the fovea in all but a few eyes that develop angiographic evidence of capillary ingrowth into the FAZ ( Figure 6.45H and I ). OCT demonstrates some degree of thinning in almost all patients and is extremely useful in confirming this observation, made by Gass. Cystoid edema, yellow exudate, and loss of the foveolar depression develop only in those patients who develop subretinal neovascularization ( Figure 6.46G–L ). This complication may be associated with rapid loss of vision, subretinal hemorrhage, disciform scarring, and retinochoroidal anastomosis ( Figure 6.46G–L ).

The yellow foveal lesions in these patients may be mistaken for those seen in the adult form of vitelliform foveomacular dystrophy (see Figure 5.08 , Figure 5.09 ) or Best’s disease (see Figure 5.01 , Figure 5.02 ). Those with stellate pigment plaques or with choroidal neovascularization may be misdiagnosed as having senile macular degeneration or chorioretinal scars secondary to focal choroiditis.

Histopathologic examination in one patient with group 2A telangiectasis reported by Green and coworkers showed focal thickening of the sensory retina in the parafoveolar region, thickening of the retinal vessel walls, evidence of capillary endothelial abnormalities, but minimal or no evidence of capillary telangiectasis ( Figure 6.48 ). In a review of histopathologic sections of the eye previously reported by Green and coworkers, Gass found evidence of retinal capillary invasion of the retinal receptor layer and minimal evidence of cystic accumulation of extracellular fluid ( Figure 6.48F–H ).

Bilateral acquired juxtafoveolar telangiectasis, group 2A.

A–E : This woman first noted loss of central vision at age 50 years. At that time her visual acuity was 20/25 bilaterally. There was mild loss of retinal transparency and superficial retinal crystals in the juxtafoveolar region temporally in both eyes (A). Stereoscopic angiograms revealed evidence of juxtafoveal telangiectasis in both eyes temporally and evidence of a peculiar remodeling of dilated blood vessels in the outer retina in the left eye (B–D). When she returned 13 years later, visual acuity was 20/200, right eye, and 20/30, left eye. She had developed stellate foci of intraretinal retinal pigment epithelium hyperplasia temporally in both eyes (E). Note the multiple, superficial, pale yellow crystalline deposits, and the focal atrophy of the retina centrally simulating an inner lamellar hole.

F : This woman had bilateral acquired juxtafoveolar retinal telangiectasis. Note the sharply delineated foveolar atrophy simulating a macular hole.

G–L : This 36-year-old man was being observed because of mild blurring of vision caused by acquired, bilateral, perifoveolar telangiectasis, before developing marked metamorphopsia in the right eye caused by subretinal neovascularization (G). He was asymptomatic in the left eye (H). Note the prominent superficial crystalline retinal opacities in both eyes (G and H). Six years later in the left eye he developed subretinal neovascularization (I–K) that resulted in a large disciform scar (L).

(G–L, from Gass and Oyakawa. , © 1982, American Medical Association. All rights reserved.)

How do we account for the retinal staining and the absence of evidence of migration of extracellular fluid into the central macular region to form cystoid edema in patients with group 2A juxtafoveolar telangiectasis? The following sequence of events appears to occur ( Figure 6.47J ). Early fluorescein staining of the thickened capillary walls, particularly those in the deeper plexus, is responsible for the early-phase angiographic appearance of “telangiectatic” vessels. The altered structure of the capillary wall is associated with decreased metabolic exchange and minimal increased endothelial permeability. These changes result in low-grade chronic nutritional damage to the retinal cells, particularly those at the level of the inner nuclear layer that includes the Müller cells. The late diffuse staining that stereoscopically appears to occur at the middle and outer retina is probably caused by staining of minimal amounts of extracellular matrix and intracellular diffusion of fluorescein into damaged retinal cells. Further changes in the outer capillary bed, which may include capillary proliferation and invasion of the outer retina and occasionally the foveolar retina, are accompanied by alteration of the pattern of venous outflow and formation of dilated right-angled venules ( Figure 6.47J , stage 3). Nutritional deprivation of the retinal cells in the middle retina, particularly the Müller cells, leads to degeneration and atrophy of these cells and the connecting photoreceptor cells. This loss of photoreceptor cells is responsible for the gradual loss of visual acuity and biomicroscopic picture that may simulate a lamellar macular hole. Loss of photoreceptor cells permits RPE cells to migrate into the overlying retina, particularly along the right-angle venules, to form black stellate plaques ( Figure 6.47J , stage 4). Stage 5 disease results when loss of retinal cells induces proliferative changes in the deep capillary network that may eventually gain entrance into the subsensory retinal space, where a type II pattern of subretinal neovascular growth and reactive proliferation of the RPE occurs ( Figure 6.47J , stage 5). Although it is probable that this neovascularization is primarily derived from the retinal vessels, evidence of chorioretinal vascular anastomosis may eventually occur. The cause of the golden refractile structures at the inner retinal surface in the juxtafoveolar area is unknown. Their appearance suggests that they are lipid. Their location in the region of the internal limiting membrane of the retina suggests that they may be a product of degenerating Müller cells whose nuclei are located in the inner nuclear layer at the site of the altered deep retinal capillary plexus, and whose foot plates form the internal limiting membrane.

Bilateral acquired juxtafoveolar telangiectasis, group 2A with good vision and lacunae.

A–I : This 67-year-old woman noted a change in her vision in her right eye in 2004 to 20/40. She saw 20/20 with her left eye. Both foveas had fine telangiectatic vessels, no pigmentation, crystals or hemorrhages (A and B). Angiogram was consistent with bitemporal hyperfluorescence and staining of tissue (C and D). Four years later her vision continues to remains at 20/40 right and 20/25 left eye. She now has a few pigment figures in the left fovea (F and G). Optical coherence tomography shws the typical lacunae seen in this condition likely from changes in the Müller cell cone (H and I).

J : Diagram of presumed anatomic changes accompanying stages 3, 4, and 5 of development of acquired juxtafoveolar telangiectasis involving the deep retinal plexus.

Stage 3, Incompetent retinal capillaries, swelling of the retina on the left side of the fovea, development of dilated right-angle venules (RaV) draining the deep capillary plexus (DCP), and early proliferation of capillaries into the outer retinal layers. Arrow indicates superficial retinal crystals.

Stage 4, Atrophy of outer retinal layers, hyperplasia of the retinal pigment epithelium (RPE), intraretinal migration of RPE cells alongside the RaV, further proliferation and remodeling of the DCP.

Stage 5, Type 2 subretinal neovascularization, subretinal bleeding, and exudation. The subretinal new vessels may or may not anastomose with the choroidal vessels.

The cause for group 2A telangiectasis, which is the most common form of idiopathic juxtafoveolar telangiectasis, is unknown. Chronic venous stasis caused by obstruction of the retinal veins as they cross the retinal arteries on both sides of the horizontal raphe may be a factor. More recently, study of the FAZ using whole mounts at 26–41-week gestational age has shown that the vessels making up the temporal FAZ are the last to close in to complete the ring. The temporal juxtafoveolar vessels are the earliest vessels to be affected in type 2 juxtafoveolar telangiectasis. Whether there is a relationship between these two features is interesting and needs further exploration. Although approximately 15% of these patients may have evidence of systemic diseases including systemic hypertension, borderline diabetes, coronary artery disease, and renal failure associated with Alport’s disease, long-term follow-up studies have failed to link group 2A telangiectasis to systemic disease in the majority of patients. Familial cases of group 2A telangiectasis occur occasionally.

Patients with group 2A telangiectasis should be differentiated from cases of bilateral retinal telangiectasis with other causes, including bilateral group 1A congenital juxtafoveal telangiectasis ( Figure 6.43J–L ), juxtafoveal telangiectasis associated with Eales’ disease (see Figure 6.62A–H ), diabetes mellitus, and irradiation retinopathy.

There is limited information available concerning the results of photocoagulation treatment of group 2A telangiectasis. It is probable that photocoagulation is ineffective in restoring visual function in these patients before the development of subretinal neovascularization because loss of function is associated with retinal atrophy rather than intraretinal exudation, as in the case of group 1 telangiectasis. It is also unlikely that prophylactic photocoagulation of the paracentral retinal capillaries will either slow or prevent the loss of visual acuity. In most instances the close proximity of subretinal neovascular networks to the center of the fovea precludes photocoagulation as a means of restoring or preventing loss of central vision.

Group 2B: Juvenile Occult Familial Idiopathic Juxtafoveolar Retinal Telangiectasis

Juxtafoveolar retinal telangiectasis similar to group 2A, but without evidence of right-angle venules, superficial retinal refractile deposits, or stellate pigmented plaques, has been reported in two siblings, 9 and 12 years of age.

Group 3A: Occlusive Idiopathic Juxtafoveolar Retinal Telangiectasis

Group 3A patients experience variable degrees of loss of central vision in both eyes associated with juxtafoveolar retinal telangiectasis and progressive loss of the juxtapapillary capillary network in later life associated with a variety of systemic diseases, including polycythemia, hypoglycemia, ulcerative colitis, multiple myeloma, and chronic lymphatic leukemia ( Figure 6.49A–F ). The macular changes in this group are similar to those that occasionally occur in patients with sickle-cell retinopathy, diabetic retinopathy ( Figure 6.52 ), and X-ray radiation retinopathy ( Figure 6.57B and D ). The loss of central vision may be abrupt and be associated with ischemic whitening of the retina centrally, occlusion of the perifoveolar retinal capillaries, and minimal evidence of telangiectasis, which develops only later ( Figure 6.51A ). In others the loss of parafoveolar retinal capillaries may occur slowly and be associated with telangiectasis of the adjacent capillaries, probably as the result of development of collateral pathways of flow.

Spontaneous retinal hemorrhage in bilateral acquired juxtafoveolar telangiectasis, group 2A.

A–D : This 65-year-old asymptomatic woman with vision of 20/30 in each eye when seen for a routine exam was found to have bilateral foveal telangiectasia with fine intraretinal pigment, and a fleck of blood in the superficial retina in her left eye. An angiogram revealed the typical pattern of staining of the intraretinal tissue, but no late pooling of dye. Optical coherence tomography did not reveal intra- or subretinal thickening or fluid (D). No treatment was given and the retinal hemorrhage disappeared by 3 months. Examination 15 months later revealed no change in vision, or signs of subretinal neovascular membrane (D).

Clinicopathologic correlation of bilateral juxtafoveolar retinal telangiectasis, group 2A.

E–H : This 58-year-old woman, whose visual acuity was 20/25 in both eyes, had angiographic evidence of intraretinal fluorescein staining in the temporal juxtafoveolar region bilaterally (E). Light microscopy revealed focal thickening of the retina in the juxtafoveolar area (F). Compare the normal retina on the right side of the arrow in B with the affected retina on the left side of the arrow. The ganglion cells appear vacuolated and swollen. There is minimal evidence of focal accumulation of extracellular fluid in the inner nuclear and outer plexiform layers. Higher-power views of the affected retina showed evidence of focal invasion of the nerve fiber layer of Henle and the receptor cell layer with fine capillaries (arrows, G and H). The retinal pigment epithelium and choroid were normal.

(E and F, from Green et al. )

Group 3B: Occlusive Idiopathic Juxtafoveolar Retinal Telangiectasis Associated with Central Nervous System Vasculopathy

Group 3B patients have a hereditary oculocerebral syndrome characterized by the onset in middle or later life of progressive loss of central vision in both eyes caused by progressive obliteration and telangiectasis of the perifoveolar capillary network, which in some patients is associated with optic atrophy, abnormal deep tendon reflexes, and other evidence of central nervous system involvement ( Figure 6.49 ). Loss of the juxtafoveolar capillaries, marked aneurysmal dilation of the terminal capillary network, and relatively little fluorescein leakage from the affected capillary bed are features that differentiate these patients from those in groups 1 and 2. In one family the retinal telangiectasis was associated with frontoparietal-lobe pseudotumors, comprised of small blood vessel damage and fibrinoid necrosis of white matter in the absence of evidence of vasculitis. Van Effenterre et al. described three sisters with similar retinal findings involving retinal telangiectasis and capillary occlusion in the peripheral retina and posterior pole, associated with poikiloderma, graying of the hair, and idiopathic nonarteriosclerotic cerebral calcifications. Pathology studies revealed small-vessel hyalinosis caused by basement membrane thickening involving the digestive tract, kidney, and calcified areas in the brain. In another family with evidence of autosomal-dominant inheritance of both central and peripheral retinal obliterative vasculopathy, there was associated Raynaud’s phenomena and mental changes, mainly forgetfulness, aggression, and depression. Ehlers and Jensen reported similar macular lesions in three family members of two successive generations. These patients did not have optic atrophy or neurologic disease.