Normal Anatomy & Physiology
The blood supply to the eye is from the ophthalmic artery, which is the first branch of the internal carotid artery (see Chapter 1). The first branches of the ophthalmic artery are the central retinal artery and the long posterior ciliary arteries. The retina is perfused by retinal and choroidal vessels that provide contrasting anatomic and physiologic circulations. The retinal arteries correspond to arterioles in the systemic circulation. They function as end arteries and feed a capillary bed consisting of small capillaries (7 μm) with tight endothelial junctions. Dependent on this anatomic arrangement is the maintenance of the blood-retina barrier, and this system is autoregulated, there being no autonomic nerve fibers. Most of the blood within the eye, however, is in the choroidal circulation, which is characterized by a high flow rate, autonomic regulation, and an anatomic arrangement with collateral branching and large capillaries (30 μm), all of which have fenestrations in juxtaposition to Bruch's membrane. Examination of the retinal vessels is facilitated by the use of red-free light and fluorescein angiography, whereas indocyanine green angiography gives further information about the choroidal vessels.
The sources of fundal hemorrhages may be arteries, capillaries, or veins, and their configurations depend on the site and severity of the disruption of vascular integrity (Figure 15–1). They usually indicate some abnormality of the retinal or choroidal vascular system but they may be caused by any condition that alters the efficacy of the endothelial barrier. The contribution of systemic factors should be considered in relation to (1) vessel wall disease (eg, hypertension, diabetes), (2) blood disorders (eg, thrombocytopenia, anemia, leukemia), and (3) reduced perfusion (eg, carotid artery–cavernous sinus fistula, acute blood loss).
A: Large preretinal hemorrhage due to severe straining. B: Flame-shaped retinal hemorrhages in the nerve fiber layer radiating out from the optic disk. Three days before the photograph was taken, the patient experienced sudden loss of vision, which left him with light perception only.
These result from damage to superficial disk or retinal vessels, which commonly are the consequence of retinal neovascularization, and are usually large with a crescentic shape, a gravity-dependent fluid level forming the superior border, and the extent of posterior vitreous detachment determining the lower border.
These lie in the superficial nerve fiber layer and their shape, often so-called flame-shaped, reflects the orientation of the retinal ganglion cell axons in the affected area of the fundus.
These are situated deeper in the substance of the retina, their source being capillaries and smaller venules. Their circular appearance reflects the compact arrangement of the deeper retinal tissues.
Normally there are no blood vessels between the retina and the choroid, but these may arise due to optic disk abnormalities or whenever there is subretinal neovascularization. They are large and red, with a well-defined margin and no fluid level.
Hemorrhages under the Retinal Pigment Epithelium
Hemorrhages situated under the retinal pigment epithelium are usually dark and large, their source being choroidal vessels. They need to be differentiated from choroidal melanomas and hemangiomas.
White Centered Hemorrhages (Roth's Spots)
Although commonly thought to be peculiar to subacute bacterial endocarditis, superficial retinal hemorrhages with pale or white centers are not pathognomonic of any disease process. They may be due to (1) a cotton-wool spot (see later in the chapter) with surrounding hemorrhage; (2) retinal hemorrhage in combination with extravasation of white blood cells (eg, leukemia); or (3) retinal hemorrhage with central resolution.
Optic Disk Infarction (Anterior Ischemic Optic Neuropathy)
Impairment of the blood supply to the optic disk produces sudden visual loss, usually with an altitudinal field defect, and sectoral pallid swelling of the optic disk. The primary abnormality is complete or partial interruption of the choroidal blood supply to the disk, while the retinal capillaries on the surface of the disk appear dilated. Fluorescein angiography confirms the circulatory alterations (Figure 15–2). Pathologic studies show infarction of the retrolaminar region of the optic nerve. The explanation for the vulnerability of the short posterior ciliary vessels supplying this region is unclear.
Ischemic optic neuropathy. Sudden visual loss in a 48-year-old man produced a complete inferior altitudinal field loss. A: Fluorescein angiogram shows impaired filling of the upper part of the disk with dilation of retinal capillaries at the lower part of the disk. B: Photograph taken 10 minutes after injection shows leakage of dye mainly at the lower part of the disk.
The most common cause is non-arteritic anterior ischemic optic neuropathy (NAION), in which the optic disk is small, the so-called “disk at risk,” and hypertension and arteriosclerotic disease are the commonly identified additional factors in middle age, although it is uncertain whether vascular occlusion or a perfusion deficit is the precipitating event. With increasing likelihood with increasing age over 50 years, optic disk infarction may be caused by giant cell arteritis. Other systemic vasculitides (such as ANCA-associated vasculitis) may also present with anterior ischemic optic neuropathy. The visual loss is usually less severe than in GCA and the disc may not be small as in NAION. Bilateral optic disk infarction can be seen after sudden hypotension following acute blood loss, but posterior (retrobulbar) optic nerve infarction without optic disc changes in the acute stage is more typical.
This is extremely rare, although certain clinical appearances have been attributed to ciliary vessel occlusion. These include small pale areas in the equatorial region that resolve to leave mottled pigmentary areas (Elschnig's spots) due to necrosis of the pigment epithelium. Larger infarcts may occur and may be triangular (Amalric's sign) or linear (Siegrist streaks) (Figure 15–3).
Anti-phospholipid antibody syndrome. Fluorescein angiogram demonstrates choroidal infarcts in a patient who presented with multiple strokes.
Retinal Infarction or Ischemia
The funduscopic appearance of arteriolar occlusion depends on the size of the vessel occluded, the duration of occlusion, and the time course. Occlusion of major arterioles (retinal arteries) produces total, hemispheric, or segmental pallid swelling of the retina, with corresponding visual loss (Figure 15–4) (see Chapter 10). Central retinal artery occlusion is usually due to atherosclerosis but can result from embolic disease. It can also be a manifestation of giant cell arteritis in the elderly. Branch retinal artery occlusion is more commonly due to emboli (see later in the chapter).
Central retinal artery occlusion, with pallid retinal swelling and a “cherry red spot” at the fovea (arrow) in a patient with hypertension.
A cotton-wool spot (Figure 15–5), representing interruption of axoplasmic transport in the axons of the retinal nerve fiber layer due to superficial retinal ischemia, is usually due to occlusion of a precapillary retinal arteriole but occasionally may result from more proximal impairment of retinal blood flow. It consists of pale, slightly elevated swelling usually one-fourth to one-half the size of the optic disk. Pathologic examination shows distention of neurons, with cytoid bodies (Figure 15–6); electron microscopy shows accumulation of axoplasm and organelles.
Cotton-wool spots. Numerous cotton-wool spots are seen in the posterior poles in three patients. (A) A young woman with acute systemic lupus erythematosus and neurologic disease. (B) A young man with pancreatitis (Purtscher's retinopathy). (C) A patient with HIV infection. Cotton-wool spots resolve over 6 weeks regardless of their cause.
Cotton-wool spot. Histologic examination shows cytoid bodies and distended neurons in the superficial retinal layers. Deeper retinal layers are normal. (Courtesy of N Ashton.)
Transient Retinal Ischemia Due to Emboli (Amaurosis Fugax)
Episodes of complete monocular visual loss with full recovery after 5–10 minutes, the beginning and end often being described as a curtain passing vertically across the vision, are characteristic of transient retinal ischemia due to transit of platelet-fibrin emboli through the retinal circulation (amaurosis fugax). Paresthesias or weakness in the contralateral limbs confirm involvement of the vascular territory of the internal carotid artery, with embolization into the ophthalmic and middle cerebral arteries.
Retinal emboli most commonly arise from carotid artery disease (see Chapter 14). A cardiac cause such as atrial fibrillation, mitral or aortic valve disease, or subacute infective endocarditis needs to be considered, particularly in patients under 40 years of age or those with a history of cardiac disease. It is important for the ophthalmologist to search the fundus for emboli, although frequently they are not seen; auscultate for carotid bruits and cardiac murmurs; check the pulse for atrial fibrillation; and arrange investigations for disease of the carotids, including for underlying risk factors, and cardiac disease as appropriate. Retinal emboli, whether or not associated with retinal dysfunction, indicate a risk of stroke and the incidental discovery of usually cholesterol emboli should prompt similar assessment.
The three main types of retinal emboli are:
Cholesterol emboli—These so-called Hollenhorst plaques usually arise from an atheromatous plaque in the carotid artery. They initially lodge at the bifurcation of retinal arterioles, are refractile, and may appear larger than the vessel that contains them but may not obstruct the blood flow (Figure 15–7). Passage of a cholesterol embolus may result in permanent focal arteriolar whitening.
Platelet-fibrin emboli—These are usually broken up as they traverse the retinal circulation, and hence are rarely seen, although occasionally they produce retinal infarction. Usually arising from abnormalities of the great vessels or heart, they may be reduced by drugs that reduce platelet aggregation (eg, aspirin).
Calcific emboli—Originating from damaged cardiac valves, these solid emboli usually lodge permanently within a retinal arteriole, producing complete occlusion and infarction of the distal retina.
Cholesterol embolus (Hollenhorst plaque). Top: A cholesterol embolus at the optic disk, which is refractile and appears larger than the vessel that contains it. A collateral vessel is seen at the lower border of the disk. Bottom: Surgical specimen from a patient with a similar embolus shows an atheromatous ulcer at the bifurcation of the common carotid artery.
There are several other causes of transient visual loss, including cerebral emboli, arterial occlusive disease, including giant cell arteritis, hematologic disease, systemic hypertension, systemic hypotension that may be due to various entities, migraine, raised intraocular pressure, and raised intracranial pressure (Table 15–1).
Table 15–1. Causes of Transient Visual Loss ||Download (.pdf)
Table 15–1. Causes of Transient Visual Loss
|Retinal emboli (amaurosis fugax) or cerebral emboli|
|Carotid artery stenosis, ulceration, or dissection|
|Basilar or vertebral artery disease (cerebral not retinal emboli)|
|Cardiac dysrhythmia (eg, atrial fibrillation)|
|Cardiac valvular disease (eg, mitral leaflet prolapse)|
|Left ventricular aneurysm with mural thrombus secondary to myocardial infarction|
|Arterial occlusive disease|
|Internal carotid artery occlusion|
|Basilar or vertebral artery occlusion|
|Arteritis (eg, giant cell arteritis)|
|Sickle cell disease|
|Impaired left ventricular function|
|Autonomic dysfunction (eg, diabetes mellitus)|
|Endocrine dysfunction (eg, Addison's disease)|
|Migraine, including retinal (choroidal) migraine|
|Raised intraocular pressure|
|Raised intracranial pressure|
Central Retinal Vein Occlusion (Figure 15–8)
Central retinal vein occlusion is an important cause of visual morbidity in elderly people, particularly those with hypertension or glaucoma.
Central retinal vein occlusion. A: Photograph shows linear hemorrhages in the nerve fiber layer and punctate hemorrhages in the deeper retinal layers. B: Fluorescein angiogram shows dilation of the veins.
Fundus examination shows dilated tortuous veins with retinal and macular edema, hemorrhages all over the posterior pole, and cotton-wool spots. The arterioles are usually attenuated, indicating generalized microvascular disease.
Fluorescein angiography demonstrates two types of response: a nonischemic type, with dilation of retinal vessels and edema; and an ischemic type, with large areas of capillary nonperfusion or evidence of retinal or anterior segment neovascularization. In less than 10% of ischemic but over 80% of nonischemic central retinal vein occlusions, the ultimate visual acuity is better than 20/200.
Central retinal vein occlusion has an increased incidence in certain systemic conditions such as hypertension, hyperlipidemia, diabetes mellitus, collagen-vascular diseases, chronic renal failure, and hyperviscosity syndromes (eg, myeloma, Waldenström's macroglobulinemia). Smoking is also a risk factor. Central retinal vein occlusion is associated with increased mortality from ischemic heart disease, including myocardial infarction. Investigations include measurement of serum lipids, plasma proteins, plasma glucose, and assessment of blood viscosity by hemoglobin, hematocrit, and fibrinogen estimations. In young patients, the antiphospholipid antibody syndrome should be excluded, and protein C, protein S, factor V Leiden, homocysteine, and antithrombin III levels should be measured to exclude abnormalities of the thrombolytic system. If hypertension is present, simple renal function tests, including urea and electrolytes, estimation of creatinine clearance, microscopic examination of the urine, and renal ultrasound are indicated.
Treatment of retinal vein occlusion is unsatisfactory. Randomized controlled trials treating patients with hemodilution have reported variable results. Trials with anticoagulants and fibrinolytic agents have not been successful. Intravitreal vascular endothelial growth factor (VEGF) inhibitors or steroid may be indicated, and surgical procedures are being investigated (see Chapter 10). In ischemic central retinal vein occlusion, pan-retinal laser photocoagulation is effective in preventing and treating secondary neovascular glaucoma.
Occasionally, central retinal vein occlusion occurs in young people and may be associated with cells in the vitreous. Rheologic investigations are usually negative, and the prognosis for vision is good.
Retinal Branch Vein Occlusion (Figure 15–9)
Occlusion of a branch vein should be viewed as part of the spectrum of central retinal vein occlusion. Investigations are similar in the two conditions, but arterial disease—particularly hypertension—is common. Branch retinal vein occlusion occurs more frequently in the superotemporal and inferotemporal regions and particularly at sites where arteries cross over veins, and only rarely where veins cross over arteries.
The roles of laser treatment, intravitreal anti-VEGF agents or steroid, and surgery in the management of branch retinal vein occlusion are discussed in Chapters 10 and 24.
Retinal branch vein occlusion. The affected segment of retina shows changes of reduced perfusion. This results in irregularity of the arterioles and veins, areas of capillary closure, and dilated capillaries with microaneurysms.
Atherosclerosis & Arteriosclerosis
The process of atherosclerosis occurs in larger arteries and is due to fatty infiltration of a patchy nature occurring in the intima and associated with fibrosis. Involvement of smaller vessels (ie, < 300 μm) by diffuse fibrosis and hyalinization is termed arteriosclerosis. The retinal vessels beyond the disk are less than 300 μm; therefore, involvement of the retinal arterioles should be termed arteriosclerosis, whereas involvement of the central retinal artery is properly termed atherosclerosis.
Atherosclerosis is a progressive change developing in the second decade, with lipid streaks in larger vessels, progressing to a fibrous plaque in the third decade. In the fourth and fifth decades, ulceration, hemorrhages, and thrombosis occur, and the lesion may be calcified. Destruction of the elastic and muscular elements of the media produces ectasia and rupture of the large vessels, although in smaller vessels obstruction is usually seen. The clinical results of atherosclerosis are seen several decades after the onset of the process. Factors contributing to atheroma include hyperlipidemia, hypertension, and obesity.
Arteriosclerosis is characterized by an enhanced light reflection, focal attenuation, and irregularity of caliber. These signs may also be seen in the arterioles of normotensive individuals in middle age. In elderly individuals with arteriosclerosis and associated mild hypertension, it is difficult to differentiate the changes of arteriosclerosis from those due to hypertension.
Appearance of Retinal Vessels
A normal arteriolar wall is transparent, so that what is actually seen is the column of blood within the vessel. A thin, central light reflection in the center of the blood column appears as a yellow refractile line about one-fifth the width of the column. As the walls of the arterioles become infiltrated with lipids and cholesterol, the vessels become sclerotic. As this process continues, the vessel wall gradually loses its transparency and becomes visible; the blood column appears wider than normal, and the thin light reflection becomes broader. The grayish yellow fat products in the vessel wall blend with the red of the blood column to produce a typical “copper wire” appearance. This indicates moderate arteriosclerosis. As sclerosis proceeds, the blood column-vessel wall light reflection resembles “silver wire,” which indicates severe arteriosclerosis; at times, even occlusion of an arteriolar branch may occur.
Red-free light (a white light with a green filter) allows details of hemorrhages, focal irregularity of blood vessels, and nerve fibers to be seen more clearly (Figure 15–10).
Acute retinal infarction. Red-free photograph shows acute arterial occlusion in a congenitally anomalous vessel at the disk. The inferior retina is infarcted, but axoplasm has accumulated beneath the fovea in an irregular pattern owing to preserved neuronal function of the distal ganglion cells.
The appearance of the fundus in hypertensive retinochoroidopathy is determined by the degree of elevation of the blood pressure and the state of the retinal arterioles. In mild to moderate systemic hypertension, the retinal signs may be subtle. Focal attenuation of a major retinal arteriole is one of the earliest signs. Diffuse arteriolar attenuation, broadening of the arteriolar light reflex, and arteriovenous crossing changes also occur. However, in young patients with accelerated malignant hypertension, an extensive retinopathy is seen, with hemorrhages, retinal infarcts (cotton-wool spots), choroidal infarcts, and occasionally serous detachment of the retina. Severe disk edema is a prominent feature and may be accompanied by a macular star of hard exudates (Figure 15–11). Vision may be impaired and may deteriorate further if blood pressure is reduced too quickly.
Accelerated hypertension in a young woman manifesting as marked optic disk edema, macular star of hard exudates, serous retinal detachment, and retinal hemorrhages and cotton-wool spots.
In contrast, elderly patients with arteriosclerotic vessels are unable to respond in this manner, and their vessels are thus protected by the arteriosclerosis. It is for this reason that elderly patients seldom exhibit florid hypertensive retinochoroidopathy (Figure 15–12).
Accelerated hypertension. Fluorescein angiogram in an elderly woman showing marked arteriolar constriction and irregularity but few signs of florid retinopathy.
In young patients with hypertension, fluorescein angiography demonstrates arteriolar attenuation and occlusion and capillary nonperfusion in relation to a cotton-wool spot, which is surrounded by abnormal dilated capillaries and microaneurysms with increased permeability. Resolution of the cotton-wool spots and the arteriolar changes occurs with successful hypotensive therapy. In elderly patients, the underlying arterio-sclerotic changes are irreversible.
Other Forms of Hypertensive Retinochoroidopathy
A severe retinochoroidopathy may be seen in advanced renal disease, in patients with pheochromocytoma, and in preeclampsia–eclampsia. All such patients should receive a complete medical workup to establish the nature of the hypertension.
Reduction in the retinal arteriovenous pressure gradient may produce acute signs of ocular ischemia (see preceding pages) or the less frequently recognized chronic changes.
Carotid Occlusive Disease
Carotid occlusive disease usually presents in middle-aged and elderly patients and is due to involvement of both the carotid artery and its smaller branches. Contributory factors include hypertension, smoking, and hyperlipidemia.
In anterior segment ischemia, patients develop iritis, intraocular pressure changes, and pupillary abnormalities. In retinal ischemia (Figure 15–13A), patients show evidence of capillary dilation and hemorrhages, capillary occlusion, new vessels at the optic disk, and cotton-wool spots.
A: Fluorescein angiogram of left fundus in a patient with chronic ocular ischemia secondary to Takayasu's disease. Note capillary dilation, leakage of dye, retinal hemorrhages, cotton-wool spots, and neovascularization of the optic nerve head. B: Fluorescein angiogram, showing leakage at optic disk and macula in a patient with chronic ocular ischemia secondary to dural arteriovenous fistula.
Carotid Artery–Cavernous Sinus Fistula
Carotid artery–cavernous sinus fistula results from a communication between the carotid artery or its branches and the cavernous sinus. Direct fistulas occur as a consequence of rupture of the intracavernous internal carotid artery, due to aneurysm, weakened vessel wall (eg, collagen vascular disease and Ehler's Danlos syndrome), or trauma. They usually have an acute, florid presentation and commonly require closure. Indirect (dural) fistulas are chronic and mild. They are associated with diabetes and systemic hypertension and may be a consequence of thrombosis of dural veins. Frequently they resolve spontaneously. Clinical features of carotid artery–cavernous sinus fistulas include dilated conjunctival and episcleral vessels, elevated intraocular pressure, dilated retinal vessels with hemorrhages and fluorescein leakage (Figure 15–13B), ophthalmoplegia (usually lateral rectus), and bruit. Computed tomography (CT) and magnetic resonance imaging (MRI) show thickened ocular muscles and a dilated superior ophthalmic vein, the latter being a differentiating feature from thyroid eye disease. Reversal of flow (“arterializations”) in the superior ophthalmic vein is a characteristic finding on orbital ultrasound blood flow studies. When required, closure of carotid artery–cavernous sinus fistulas is usually achieved by interventional radiological techniques.
Idiopathic (Benign) Intracranial Hypertension (Pseudotumor Cerebri)
Idiopathic intracranial hypertension is characterized by raised intracranial pressure with normal cerebrospinal fluid constituents and normal radiologic studies, particularly no evidence of cerebral venous sinus occlusion. The cause of the increased intracranial pressure is unknown, although diminished absorption of cerebrospinal fluid due to impaired venous sinus drainage is suspected. Usually patients are young overweight women and present with headache; transient visual obscurations, blurred vision, and diplopia are the ophthalmologic features. Etiologic factors that need to be excluded include (1) drug therapy, particularly tetracyclines, retinoids including vitamin A, prolonged steroid therapy or in children steroid withdrawal, and possibly hormonal contraceptives; (2) endocrine abnormalities; and (3) sleep apnea syndrome. Idiopathic intracranial hypertension is very rare in adult men.
Initially visual fields are normal apart from enlarged blind spots due to papilledema. Generalized field constriction and inferonasal and arcuate defects may occur. CT or MRI usually shows distended optic nerve sheaths, flattened globes, and an empty pituitary sella. The aims of treatment are to minimize permanent visual loss, which occurs in up to 50% of patients, and relieve symptoms. Treatment options include weight loss, oral acetazolamide or other diuretics, cerebrospinal fluid shunt, and optic nerve sheath fenestration (see also Chapter 14).
Subacute Infective Endocarditis
Inflammatory changes on the cardiac valves may produce multiple embolization with frequent ocular manifestations that range from retinal and choroidal infarction to a mild infective vitritis. The emboli may be composed of platelet-fibrin aggregates or calcified endocardial vegetations (Figure 15–14).
Subacute bacterial endocarditis. Calcific embolus impacted in arteriole below the disk, producing a distal area of retinal infarction.