Using Fluorescein Angiography To Assess Retinal Disease

Fluorescein angiography can be a very useful procedure for assessing retinal disease by delineating areas of involvement, guiding treatment, and formulating a prognosis for changes in the patient's vision.

In this course, retinal anatomy and physiology will be reviewed; angiographic equipment and procedures will be discussed; and cases will be presented to illustrate the value of fluorescein angiography in assessing retinal disease.

The course provides a clinical overview of angiography and retinal disease assessment. It does not present a detailed discussion of fundus/angiography camera mechanics or a step-by-step procedural technique for fluorescein angiography.

To interpret fluorescein angiographic images, knowledge of retinal/choroidal anatomy and circulation is essential. Arterial and venous circulation differences, as well as the retina’s barriers against the passage of sodium fluorescein (NaFl) dye including the retinal pigment epithelium or RPE (outer blood-retinal barrier) and the retinal vascular endothelium (inner blood-retinal barrier), must be understood.(3) Knowledge of fundus pathophysiology and anatomy has been greatly enhanced by research using fluorescein angiography.(4,5)

To facilitate a meaningful interpretation of angiographic findings, a brief review of retinal structures will be beneficial.

Vitreous

The vitreous of a normal eye is non-fluorescent and relatively clear. However, in conditions such as asteroid hyalosis, the accumulated calcium soaps can be an obstacle to obtaining a good view of the fundus. The asteroid bodies reflect a considerable portion of white camera light, but, because they do not stain with NaFl, they are left relatively undetectable on angiogram images.(6)

The vitreous can, however, be studied with angiography especially when neovascularization or inflammatory conditions exist. If leakage of fluids into the vitreous occurs, cloud-type fluorescence can be noted as NaFl diffuses out of the retinal circulation and into the vitreous.

Dense hemorrhages or other opacities in the vitreous can block the view of retinal and choroidal structures causing the angiogram to be termed hypofluorescent.

Retinal Layers

For purposes of angiogram interpretation, the sensory retina can be divided into vascular and avascular portions.(1) The vascular portion is composed of the internal limiting membrane (ILM), nerve fiber layer (NFL), ganglion cell layer (GC), inner plexiform layer (IPL), and the inner nuclear layer (INL). These portions of the retina receive direct metabolic support from retinal blood vessels.

The sensory retina's avascular portion consists of the outer plexiform layer (OPL), the outer nuclear layer (ONL), and rod and cone photoreceptor cells. These structures receive metabolic support from the choroidal vessels via the pigment epithelial cells.

Several distinguishing features of the inner vascular portion of the sensory retina can be noted. The nerve fiber layer contains large retinal veins and arteries (this is where flame-shaped hemorrhages occur), whereas retinal capillaries are found in the inner nuclear layer.

The outer plexiform layer resides in the avascular outer portion of the sensory retina. With an edematous retina, the OPL gathers excessive fluid and widens causing cystoid spaces –a honeycomb appearance. Within the macula, the OPL is oblique in orientation creating a stellate appearing cystoid edema presentation on a fluorescein angiogram (cystoid macular edema). The OPL will also collect hard exudates and can be the site of deep retinal hemorrhages.

Bruch’s membrane separates the retinal pigment epithelium from the choriocapillaris and the choroid. Interestingly, NaFl dye will diffuse through Bruch’s membrane but will not penetrate normal pigment epithelial cells because of the tight junctions between the cells.

Photoreceptors have a rather weak attachment to the pigment epithelial cells. Junctions between the epithelial cells and the photoreceptors facilitate phagocytosis and recycling of the photoreceptor outer segments, as well as metabolic support. Therefore, when the pigment epithelium becomes diseased and/or non-functional, the photoreceptors are in grave danger of extinction.(7)

Fluorescein Angiography and Filter Basics

Most angiograms involve injecting sodium fluorescein into a vein and using a fundus camera to observe the dye as it passes through the retinal vasculature. Photographic images are acquired at various times during dye passage and studied for perfusion abnormalities.

NaFl dye is a biologically inert substance that absorbs blue light with wavelengths between 485 and 500 nm and emits (or fluoresces) a green-yellow light with wavelengths between 520 and 530 nm. In a typical fundus camera set up for angiography, white light is passed through an excitation filter that transmits only that portion of the white light with a wavelength of about 490 nm. Some of this blue light strikes the retina and is reflected, and some is absorbed by the NaFl causing it to emit green light. Because only the green light emitted by the dye is useful in angiography, a second filter, the barrier filter (peak transmission of 525 nm), is used. The barrier filter transmits the green light emitted by the NaFl and absorbs the reflected blue light.

Barrier filters can be placed in front of the eyepiece or the film plane of the fundus camera. When placed in front of the eyepiece, early filling of the retinal vessels may be difficult to detect because the retina appears black, and alignment of the fundus camera can be a problem. Solenoid-activated barrier filters are favored today due to automatic activation of the filter with a switch or the shutter release. By manually removing the barrier filter, the retina can be viewed with blue light from the excitation filter only. This provides an excellent opportunity to photodocument the nerve fiber layer using reflected blue light.(11)

Annual replacement set of fluorescein filters is recommended for busy offices, especially in warm, humid climates. Filter degradation is generally due to light exposure, humid conditions, and simple aging of the filter. Noting significant pseudoautofluorescence (i.e., the retina appears to glow even before the NaFl is injected) is a strong indication that filters need to be changed.(1)

Traditionally, fluorescein images are acquired on black and white film so that on a positive print the parts of the retina containing the dye are seen as white against a black background.

Most fundus cameras also allow use of a red-free (i.e., monochromatic green) filter that transmits light with wavelengths between 540 and 575 nm. This light can be used to photograph the patient's nametag information as well as to provide initial red-free fundus photographs. A red-free filter enhances retinal vessels and hemorrhages by intensifying the contrast between blood (dark) and the background retina (light). A red-free view provides an excellent comparative baseline photograph for angiographic images, as illustrated in the retinal embolus image shown below.

Digital Versus Film-Based Images

Digital fluorescein angiography in which images are acquired and stored electronically as opposed to on photographic film has recently become the standard in the ophthalmic community. Enhanced image resolution; reduced processing time; and ease of image duplication, manipulation, and transmission are definite advantages of a digital system.(10) Although digital angiography is the standard, many clinicians still rely on traditional film-based angiography systems.(1)

Preparation for angiography is best achieved in a methodical manner. Before the patient arrives in the angiography room, the camera or digital system is readied (operative controls set at midpoint, film loaded, illumination settings adjusted, dioptric compensation control set, etc.). To obtain consistent, sharp photography, setting the focus reticule in the eyepiece is of supreme importance. Accommodation and spherical refractive error of the photographer can hinder the process of obtaining the best focus, so always bring the reticule setting out of plus power until sharp focus in first perceived.

After reviewing the patient's chart and angiography request form, establish a mental game plan appropriate for documenting the suspected pathology.

When the patient is present, the angiography procedure is described; any prior angiogram experiences, side-effects, adverse reactions, or medical interventions are discussed; all questions are answered; and the informed consent document is reviewed and signed.

Next dilating drops are instilled, the chair position is adjusted for patient comfort, the intravenous site is reviewed, and reassurance is provided.

Dye Preparation and Injection

With present day ocular angiography, two primary dyes are utilized: fluorescein sodium and indocyanine green (ICG).

ICG absorbs and fluoresces in the near-infrared range so it is typically used for imaging the choroid and the choroidal vasculature.(12,13) This is because the long wavelength light that excites ICG penetrates the retinal layers and reaches the underlying choroid. However, for this course, the discussion of ocular angiography will be limited to the use of NaFl dye.

Fluorescein sodium is a hydrocarbon that effectively fluoresces at normal blood pH (7.37 to 7.45) and readily diffuses through most of the body fluids and the choriocapillaris. It does not, however, diffuse through the retinal endothelial or pigment epithelial barriers.

Dye concentration influences the intensity of NaFl fluorescence, but a 5 cc bolus of 10% NaFl or a 2 cc bolus of 25% NaFl is typically adequate to achieve an effective retinal evaluation. For intravenous injection of NaFl, a needle/catheter combination is inserted into the selected vein.

The needle and catheter penetrate the vein as one, then the needle is retracted into a holder and the flexible catheter is left in place. Using this system, there is no needle stick hazard. In addition, the catheter is easier on the vein and more comfortable for the patient. When the needle has been withdrawn, the vein is flushed with saline through the catheter in preparation for NaFl dye injection.

Next, the patient is positioned at the fundus camera, a visual fixation point is established to facilitate alignment, and preliminary colored, red-free, and time-zero angiographic pictures are taken. A bolus of NaFl is then injected, and retinal images are acquired at pre-specified times.

Injection Safety Precautions and Concerns

As with any venipuncture and intravenous procedure, universal blood borne-pathogen precautions must be taken. Proper disposal of needles, gloves, and other potentially infectious materials is required by law, and each clinic should have a specific, written protocol to follow. In 1991, the Occupational Safety and Health Act (OSHA) delineated specific precautions to be followed by employers to aid employees in avoiding an occupational exposure.(20)

Recent technological advances in needless systems, recessed needle systems, and needles with engineered sharps injury protection (esip) have made great strides in reducing the risk of needle stick injuries. Recessed needle systems should include: 1) a fixed safety feature to provide a barrier between the hands and the needle after use (this safety feature should allow or require the worker’s hands to remain behind the needle at all times); (2) the safety feature should be an integral part of the device, and not an accessory; (3) the safety feature should be in effect before disassembly and remain in effect after disposal to protect users and trash handlers; and (4) the safety feature should be as simple as possible and require little or no training to use it effectively.(21-23)

All clinics and private physician offices must have written policies and procedures that follow OSHA mandates regarding blood-borne pathogens.(20) Intravenous injection protocols should be part of the written office policies and procedures manual. The needle system utilized in ocular fluorescein angiography should not be a vector for disease transmission!

Potential Complications and Contraindications for NaFl Angiography

When lack of retinal fluorescence is noted after bolus injection, obstructed circulation is possible. Check for a physical barricade at the injection site by having the patient straighten his or her arm. Infiltration or extravasation at the injection site and carotid insufficiency are also possible causes of poor fluorescence.(14)

Systemic complications following the use of intravenous NaFl dye are relatively rare but can range from mild and transient to severe if they do occur.(14-18) In an effort to avert potential complications, fluorescein angiography should be performed with caution (or should be avoided altogether) with patients having severe renal impairment, anginal instability, severe asthma, confirmed history of iodine or shellfish allergy (because of a possible cross-reaction allergy), or a recent history of myocardial infarction or stroke.(15,17,18)

A history of heart disease, cardiac arrhythmia, or cardiac pacemaker use does not seem to be an absolute contraindication to fluorescein dye injection.(15,17)

Pregnant women, especially those in the first trimester, should not undergo fluorescein angiography. Although no cases of fetal injury due to NaFl dye injection are known, the standard of care is to avoid NaFl injection for pregnant patients when ever possible.(16)

Mild side-effects of angiography include transiently jaundiced skin tone and urine discoloration. Two to four percent of patients experience nausea (sometimes including vomiting) within a few minutes after dye injection.(14,18) Patients with a history of nausea during previous angiography procedures can be given an anti-emetic of 25 to 50 mg of Phenergan® prior to procedure.

A small number of patients (0.5%) will have an allergic reaction to NaFl that includes hives, itching, and/or angioedema within 15 minutes after injection.

More serious allergic and other reactions can include bronchospasm, syncopal events, and/or an obstructed airway (laryngeal edema) that require prompt attention. Occurrence of true anaphylaxis (hypotension, tachycardia, bronchospasm, hives, and itching) requires emergency medical care, which should be initiated by calling 911 or summoning on-site assistance. Typically, anaphylactic treatment includes administering epinephrine (0.4 cc of 1:1000 intramuscularly, repeated 3 to 4 times at 15 min intervals, as needed) and oxygen.

The Fluorescein Angiography Complication Survey has reported that one death occurs for every 222,000 ocular angiograms.(14) It is therefore imperative that all personnel involved with angiography are trained in the most current Health Care Provider CPR techniques, including use of an automated external defibrillator.

Extravasation of blood (i.e., leakage of blood into the tissues around a vessel) can occur as the result of the venipuncture required to inject NaFl. It can be caused by using too large a needle, penetrating the vein completely during insertion, or failure to provide adequate compression at the injection site following needle removal. The extravasation can result in a hematoma.

Extravasation of dye into tissues surrounding the injection site can cause skin necrosis (18), pain, and discoloration.

If extravasation occurs, ice the affected area for pain relief and administer an analgesic, e.g., Tyenol® (aspirin and related drugs can reduce clotting time). Some patients may need Benadryl® and a local anesthetic applied to the affected area.

Although rare, accidental intra-arterial injection is another complication of a failed injection. If dye is injected into an artery, it circulates away from the heart, i.e., toward the fingers. (Interestingly, about 10 percent of the population has the ulnar arteries placed superficially next to the basilic vein, which makes this type of accident somewhat more likely.(19)) Patients who receive an intra-arterial injection often describe a pressure sensation with pain, and the area below the injection site can develop bright yellow splotches.

Proper intravenous injection technique is imperative to prevent failed injections. After the intravenous needle is in place, withdraw a small amount of blood into the flash chamber, and check for blood color and ease of flow. Note that arterial blood is bright red due to its oxygen level, whereas venous blood is darker.

A fluorescein angiogram typically involves acquiring images during each of the following stages:

1. Name tag, red-free and colored photographs.
2. Baseline Photographs with barrier and exciter fillters in place. Check for autofluorescence and pseudofluorescence.
3. Injection of NaFl dye [0.0 seconds]
4. Photograph of posterior ciliary arteries filling with dye [7 to 9 seconds].
5. Photograph of choriocapillaris filling with dye causing a choroidal flush [9 to 10 seconds].
6. Photograph of retinal arteries filling [10 to 12 seconds].
7. Photograph of complete filling of the arteries and capillaries and the beginning of laminar flow in the veins [13 to 15 seconds]. NaFl initially flows along the outer edges of the vein and then fills the entire lumen.
8. Photograph of veins filling [16 to 20 seconds].
9. NaFl contained in blood vessels leaves the eye. NaFl that has leaked or pooled remains.
10. Recirculation of NaFl occurs after is has passed through the heart and re-entered the eye [up to 5 minutes].

Sequence for Acquiring Images

Upon initiating the angiography sequence, acquire nametag and red-free photographs of the fundi. Generally, the eye of interest will be designated as the primary eye. Imaging the primary eye last during red-free photographs allows for the camera to be ready and in position for the early angiography images. In addition, the focus will be set for the angiogram.

Next, the control photograph with the fluorescein filters in place is acquired. Following injection, pictures are taken – usually one image every two to three seconds - even if nothing is seen. The object of these early images is to record the progress of dye as it enters and fills the choroid.

As dye flows into the retinal blood vessels, the pace is increased to an image every one to two seconds until the 30 second mark. Then the primary eye’s macula is imaged, and a switch is made to the secondary eye for a macula shot and several images of the full fundus.

Late images typically document the primary eye then the secondary eye at three, five, and ten minutes after injection, depending on the suspected pathology. Usually, the retinal and choroidal vessels are relatively empty of dye in approximately ten minutes with a late stage grayish appearance.

Consistent, precise timing is essential for achieving excellence in fluorescein angiography. The early photographs between zero and 30 seconds are vital to the diagnostic value of an angiogram; timing is everything! Leaking dye as it enters the eye is truly an important clinical finding. Regular timing of late phases for comparison with prior as well as future angiograms is also critical.(9) For example, cystoid macular edema (CME) or central serous retinopathy (CSR) are best visualized in the late frames, and management of these problems rely on a comparative study of sequential angiograms.

Viewing Angiogram Images

A standard fluorescein angiography analysis also requires consistency in viewing the angiogram images.(5) Reading images follows a somewhat unusual convention: images are always scanned from right to left.

When viewing fluorescein angiograms as a positive image, the fluorescing NaFl dye appears white (or lit up), and non-fluorescent areas appear black. A negative image shows fluorescent areas as black. Original negatives often offer more information than prints because a positive print will lose resolution and acquire artifacts during processing and printing.(1)

Circulation Of Fluorescein Dye In The Retina

The normal fluorescein angiogram clearly documents the dual nature of retinal circulation.(1) Following injection, filling of the larger choroidal vessels (outermost vessels) is noted; then, immediately, the dye flows to the choriocapillaris (the innermost layer).(8) The dye permeates the choroid and partially infuses the sclera.

Because the choriocapillaris is fenestrated, these capillaries normally leak fluorescein freely; this produces what is termed the "choroidal flush" or background fluorescence. A choroidal flush is not always uniform; one may see patchy or variable filling, even with normal patients.

The "watershed zone," a vertical zone with delayed filling that is located through the papillomacular region including the disc can appear patchy as well. In some instances, patchy, delayed choroidal filling is indicative of ocular disease, such as giant cell arteritis.

Within the macula, choroidal fluorescence is obscured due to the macular pigments of lutein and zeaxanthin found in Henle's fiber layer (OPL). Thus, a normal macula should remain dark throughout the angiogram.

If a ciloretinal artery is present, it will fluoresce as the choroid fluoresces.

Dye from the choriocapillaris diffuses through Bruch’s membrane, but is blocked by a healthy, intact retinal pigment epithelium (RPE). Again, the darker the pigmentation of the RPE, the less observable will be the choroidal fluorescence; however, contrast for retinal vessels will be enhanced.

Subsequently, the retinal circulation fills with dye. The retinal vessels with their tight junctions, the zonulae occludentes in the vascular endothelium, create a barricade to stop the passage of dye into the extracellular spaces of the retina.(3) In a normal retina, vessels should not leak fluorescein and no pooling should be seen.

With the intact retinal vessels visible, the retinal circulation, especially the single capillary layer framing the foveal avascular zone, is particularly well defined. The center of the fovea has no retinal capillaries; its metabolic support is provided by the choroid. The macula is darker appearing than the adjacent retina due to the yellow macular pigments absorbing the exciting blue light from the angiographic system.

The optic nerve head has abundant circulation from both the central retinal artery and the posterior ciliary arteries that supply the choroid, so it is an important structure to observe during angiography. The rim of scleral tissue surrounding the optic nerve typically retains dye. This normal hyperfluorescent staining remains fairly constant throughout most of the early angiogram but fades in the late phase.

The capillaries of the optic nerve head are vulnerable to insult. For example, in papilledema and optic neuritis the capillaries become enlarged and leak dye.(1,2) In ischemic optic neuropathy, and other ischemic diseases of the disc, the capillary network also shows fluorescein leakage. The archaic term, "hot disc" implies abnormal hyperfluorescence of the optic nerve head due to ischemia or inflammation. Typical presentation is an increased hyperfluorescence and leakage seen throughout the anigogram and late staining with an uneven border of fluorescence surrounding the optic nerve.

An unusual optic nerve head presentation involves an optic nerve head pit. Initially, the pit is hypofluorescent, at mid-phase the pit fills with dye, and during the late phase of the angiogram leakage is noted.

For adult patients who simply cannot tolerate an injection or for children requiring angiography, oral fluorescein administration may be the only alternative available. The rule-of-thumb for a normal size adult is to double the IV dose and dissolve the NaFl in tomato, vegetable, or orange juice. The child or small adult (100 lbs or less) dose is weight dependent; follow the manufacturer’s recommendations as provided on the package insert.

Retinal photographs are taken 5, 10, 20, and 30 minutes after drinking the dye mixture. Transient side-effects including skin and urine discoloration may be noted.

Oral fluorescein angiography provides images that are of lower contrast than those acquired with injected NaFl, and allow visualizing only the late stages of the angiogram. Late leakage can, however, be clinically significant in assessing macular edema.

Recently oral NaFl has been used in conjunction with diabetic screenings and may provide a useful method for diabetic retinopathy detection, especially for detecting diabetic maculopathy.(24) Other pilot studies have utilized computer technology to enhance the low-contrast oral fluorescein angiograms.(25)

Abnormal fluorescein dye perfusion can be categorized as hypofluorescence (dye blockage or lack of filling) or hyperfluorescence (dye observed as leakage, staining, or pooling).(1,2) Recognition of the fluorescein dye’s retinal presentation as normal or abnormal is essential when interpreting fluorescein angiograms.

Hypofluorescence

To determine the cause of hypofluorescence, it is important to review the fundus appearance prior to injection of the dye and note any opacity or material that corresponds to the area of hypofluorescence. The location of the material blocking fluorescence is either in front of the retina (hypofluorescence of the retinal and choroidal circulation will be noted), or beneath the retinal circulation but in front of the choroid (hypofluorescence of only choroidal circulation will be noted).

If no opacity is blocking the fluorescence, it is reasonable to assume that the patient with hypofluorescence has a vascular filling defect - fluorescein dye did not perfuse the vessels. However, with an ischemic, pallorous retina such as might result from an artery occlusion, the filling defect and the opaqueness of the retina resulting from the patient's occlusion both contribute to the appearance of hypofluorescence. The blockage of choroidal fluorescence is due to the opaque retina, which, in turn, is caused by retinal nonperfusion.

When assessing areas of hypofluorescence, a common technique involves comparing the angiogram to the corresponding white light fundus photograph, ophthalmoscopy, or a 90 diopter slit lamp view. The object is to determine whether the hypofluorescence is due to a vascular filling defect or an opacity (e.g., hemorrhage, exudate, or pigment) that blocks the retinal view.

With vein occlusions, the angiogram pattern reveals a normal fill of arteries and non-occluded veins. The occluded veins display delayed filling and leaky stained vessel walls, partly due to retinal ischemia. This is illustrated in the image below.

Dot and blot hemorrhages that do not block fluorescence from large retinal vessels are situated deep in the retinal layers as shown on the images below.

If retinal capillary fluorescence is visible, the hemorrhages are located deeper than the INL. A hemorrhage under the sensory retina blocks the view of the choroidal fluorescing circulation, yet actually enhances the contrast and visibility of the retinal circulation (sometimes called a dark hemorrhage backdrop).

Hazy media caused by some type of partial opacification (e.g., corneal haze or scaring, cataractous lens, intraocular inflammation) will contribute to hypofluorescence and/or poor resolution of the angiogram photographs.

Hyperfluorescence

A second abnormality found in angiograms is hyperfluorescence - excessive fluorescence relative to a normal angiogram. Any area of the retina, macula, or optic nerve demonstrating hyperfluorescence should be investigated as pathology. Areas of hyperfluorescence can be caused by the presence of abnormal vessels, immediate leakage of dye from the NaFl bolus as it passes the leakage site, or by slow leakage and pooling into retinal tissues.

Structures and tissues that naturally fluoresce prior to dye injection are termed autofluorescent, and their appearance can sometimes be confused with hyperfluorescence. These structures include optic nerve head drusen, astrocytic harmatoma, and some forms of cataract.(26,27)

Superficial optic disc drusen often show a very bright nodular autofluorescence, whereas buried drusen may show diffuse, less intense autofluorescence.(27) Hidden drusen can be "uncovered" if autofluorescence can be demonstrated. Mustonen and Nieminen note that fluorescein angiography may also reveal buried drusen that do not show autofluorescence and may be of help in the differential diagnosis of pseudopapilledema from true papilledema. Optic nerve head drusen do not show dye leakage, but late staining does occur along with dye retention.(27) Hence, the appearance of these drusen does not appear to change throughout the angiogram.

The ability to detect autofluorescence of the retina, especially the retinal pigment epithelium, has recently been investigated. A relatively new imaging technique, fundus autofluorescence, can detect lipofuscin deposits and provide information on retinal pigment epithelium metabolic status.(10,18) Use of fundus autofluorescence imaging may also aid in detecting changes in retinal pigment epithelium fluorescence after thermal laser photocoagulation.(29)

Mismatched and/or aged fundus camera system barrier and exciter filters can cause pseudoautofluorescence detectable before dye injection(11) and this will decrease overall contrast of the angiogram. Highly reflective areas of retina (e.g., scar tissue, myelinated nerve fibers, or scleral exposure) can also create pseudoautofluorescence.

Hyperfluorescence can occur with leakage, vascular abnormality, or transmission increase.(1) When a buildup of fluorescein is noted that increases over time, it is referred to leakage, such as might occur with subretinal (choroidal) neovascularization.

Dye can also pool in an anatomic space, e.g., the space created by a sensory retinal detachment, central serous retinopathy, or a retinal pigment epithelial detachment.

NaFl staining can occur with hard drusen, scar tissue, at the optic nerve head, in ischemic blood vessels, and in the sclera (especially with blonde fundi or myopes).

Dragging of blood vessels in the macula due to tangential traction of an epiretinal membrane can affect the vessels’ integrity and can create leakage. A variety of epiretinal membrane presentations can also be demonstrated by angiography. Typically, some type of retinal vascular pattern distortion is noted in the macula. Straightening of some blood vessels can occur, whereas others might appear tortuous.

Abnormal retinal and/or choroidal vasculature can also be demonstrated using fluorescein angiography. Abnormal vessels (e.g., vein occlusions or tumor feeder vessels) can display hyperfluorescence.

Relatively common vascular abnormalities include retinal or disc neovascularization or choroidal neovascularization (e.g., in wet age-related macular degeneration). Abnormal vessels produced in these conditions may be detected in the early angiogram images and typically will show leakage in later frames.(9)

Visualizing hyperfluorescence that would be blocked from view in a normal eye can be caused by a "transmission increase." In a normal eye, the retinal pigment epithelium blocks NaFl fluorescence in the choroid to some degree, but a transmission increase can occur if there is a loss of RPE, e.g., with an atrophic window defect.

To evaluate hyperfluorescence produced by a transmission increase, note that the hyperfluorescence presents during the early phases of angiography (i.e., as the choroid fills), increases in intensity during the filling process, stays relatively the same size and shape throughout the angiogram, and fades as the choroid empties.(30)

Hyperfluorescence can also be seen as a transmission increase and leakage around a macular hole. Early fluorescence in the central macula that remains throughout the angiogram and that is accompanied by additional leakage with a subretinal cuff of fluid suggests this diagnosis.

Practical interpretation of fluorescein angiography images requires diligence and continual training of the clinician’s eye. Sequential assessment of angiograms based on an understanding of retinal physiology proves to be the clinician’s best aid for utilizing fluorescein angiography as a diagnostic tool.

Presumed Ocular Toxoplasmosis

Ocular Toxoplasomosis is an acquired infection with a protozoan parasite. The causative organism is typically acquired from contact with infected cat feces. It is capable of crossing the placenta and producing a fetal infection. The organism has a predilection for neural tissue and can encyst in the retina. At some future time, the organism can become active, dividing and destroying retinal tissue producing a typical toxo scar.

The fundi show unilateral or bilateral chorioretinal scarring, usually circumscribed and pigmented, in the posterior pole. With reactivation of the organism, an anterior uveitis erupts and a whitish, fluffy infiltrate appears adjacent the chorioretinal scar.

In the 48 yoWM whose images are shown below, toxo scars were noted bilaterally and there was a reduction in vision to 20/80 OS with the vision in the fellow eye of 20/30.

NaFl angiography produced a somewhat surprising finding. Although the patient had toxoplasmosis, it was not the direct cause of his acuity loss. Instead, the angiography revealed subretinal neovascularization in the macula, which produced the acuity reduction.

Hypertensive Retinopathy

Systemic hypertension is associated with an increased risk of retinal arterial and venous occlusions.(31) Generally, mild hypertensive changes in the retina do not cause a compromise of the blood-retinal barriers,(3,31) but chronic decompensation of the barriers due to arteriolosclerotic changes can cause problems. Hyperlipidemia is another cause of retinal arteriolar changes.

Retinal hemorrhages, microaneurysms, cotton wool spots, capillary nonperfusion, retinal edema, and lipid exudate (e.g., a macular star exudate) are common findings with hypertensive retinopathy.

The images shown below are from a 36 yoHM with systemic hypertension and a branch retinal vein occlusion. His blood pressure was 190/110 sitting, and his cholesterol level was 320. Best acuities were 20/25 OD, 20/200 OS.

Exudative Age-Related Macular Degeneration

Early stage age-related macular degeneration can sometimes be difficult to distinguish from the normal photoreceptor and RPE cell changes in that result from aging. However, late stage, wet ARMD is more easily detected using angiography.

In early stage ARMD, the macula can show clinically pathologic changes such as drusen formation. Hard and soft drusen have distinctive angiographic features. Hard drusen fluoresce brightly in early images, maintain their fluorescence through the angiogram, and stain in the late phases. Soft drusen also tend to fluoresce early, but with a softer, more indistinct, fluorescence.

RPE or serous detachments with pooling of dye can sometimes be part of the macular degenerative process. If RPE integrity is compromised, hemorrhage due to neovascularization is a prominent risk. New blood vessel growth coming from the choroidal system can be detected in early images because these vessels will leak producing areas of increased dye intensity with fuzzy, indistinct borders.

The images shown below are from a 82 yoWF with history of ARMD. He reported Amsler grid distortion and a best acuity of 20/200.

ARMD with RPE Tear

The images below are from a legally blind 86 yoWF with a long-standing history of exudative ARMD. Vision is counting fingers OU. The patient’s history includes smoking 2 packs of cigarettes daily for 40 years.

With a serous detachment of the retinal pigment epithelium and an increase of subretinal fluid, exudate and new blood vessel growth predisposes the retina for a tear in the macular region.

The fluorescein angiographic pictures below show hypofluorescence demarcating the edge of the ‘rolled’ RPE against the bright fluorescence of the exposed choroid.

Notice a hemorrhage shadow on the red-free photograph and partially blocked fluorescence on the angiograms as dye highlights exposed areas of the choroid.

Best’s Disease

Best’s disease (vitelliform dystrophy) is a bilateral inherited macular dystrophy that can produce accelerated unilateral retinal pigment epithelium changes. Macular changes can resemble age-related macular degeneration, central serous choroidopathy, or RPE serous detachments. To aid in the differential diagnosis, retinal function tests including electroretinography (ERG) and electro-oculography (EOG) can be valuable. A normal ERG and an abnormal EOG provide a definitive diagnosis of Best’s disease.

The images below come from a 48 yoWF who received a confirmed diagnosis of Best’s at age 15 years. Her left eye has decreased acuity with an egg appearance of the fundus and subsequent subretinal neovascularization. Her right eye showed atrophic changes in the retinal pigment epithelium.

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