Fluorescein and Indocyanine Green Angiography in Infectious and Inflammatory Diseases of the Retina and Choroid
STEVEN R. SANISLO, MARK S. BLUMENKRANZ and THIERRY C. VERSTRAETEN
Table Of Contents
PRINCIPLES OF FLUORESCEIN|
PRINCIPLES OF INDOCYANINE GREEN (ICG)
METHOD FOR ASSESSING MECHANISM OF VISUAL LOSS AND RESPONSE TO TREATMENT
QUANTITATION OF DISEASE SEVERITY
INFLAMMATORY RETINAL PIGMENT
|In many instances, angiography can serve as a useful guide to the clinician in the diagnosis and management of infectious and inflammatory diseases of the retina and choroid. Sodium fluorescein is the most common angiographic dye used for this purpose, but indocyanine green (ICG) dye is also useful in certain cases. Because angiography yields a high-contrast image for the permanent medical record, the potential exists for overuse of this modality, when more simple and inexpensive methods will suffice. In instances where clinical history and ophthalmoscopy alone are not sufficient to either establish a working diagnosis or develop and monitor a treatment plan, fluorescein or ICG angiography in conjunction with other serologic studies may play an important role. Because of restrictions on the length of this chapter, as well as the availability of excellent reviews on specific diseases, both in other portions of this series as well as elsewhere,1–4 an encyclopedic listing of the angiographic features of all major inflammatory and infectious conditions is not provided. Our intent is to establish basic guidelines for the indications and interpretation of fluorescein and ICG angiography in this broad category of diseases.|
|PRINCIPLES OF FLUORESCEIN|
The rationale for the use of sodium fluorescein for diagnostic imaging of the fundus is covered more completely in other chapters. By absorbing photic energy in the wavelength range of 465 to 490 nm and emitting at a different wavelength range of 520 to 530 nm, sodium fluorescein yields a dynamic high-contrast image of the retinal structures, emphasizing the discrete intravascular compartments silhouetted against their adjacent structures, when photographed with appropriate barrier and excitation filters in place. In some instances, the presence of the monochromatic filters alone is sufficient to decrease light scattering and consequently improve resolution of fine detail in eyes with hazy intraocular media. In most instances, however, the luminescence provided by the excited fluorescein molecule is responsible for the apparent image enhancement available by this technique. With the recent availability of more sophisticated video and digital signal processing techniques, the capacity for image enhancement has been further increased. Because of its relatively low molecular weight of 376 Daltons, sodium fluorescein freely traverses the fenestrated capillaries and larger vessels comprising the choroid. However, the tight junctions between adjacent retinal pigment epithelial cells and healthy mature retinal capillary endothelial cells effectively block the ingress of fluorescein from the choroid to the subretinal space, or from the retinal vessels into the neurosensory retina or vitreous, respectively, under normal conditions. The loss of this selective barrier effect as a result of disease underlies the value of fluorescein angiography as an imaging modality. In addition to ischemia, mechanical or thermal trauma and inflammation result in breakdown of the barrier effect of tight junctions and allow passage of fluorescein, generally in proportion to the degree of the inflammation.1–4 Because the inflammation may be either generalized or localized to a specific region of the chorioretinal complex, depending on the nature of the disease process, the fluorescein angiogram may yield valuable information not only with regard to severity of the breakdown of the barrier such as fluorophotometry but also with regard to localization of the site of inflammation. In instances in which inflammation coexists with ischemia or neovascularization, fluorescein angiography can be particularly valuable in distinguishing between these elements. Additionally, fluorescein angiography can show alterations to the retinal pigment epithelium during acute inflammatory phases and also show chronic changes in the pigment epithelium that often remain after the inflammation has subsided.
|PRINCIPLES OF INDOCYANINE GREEN (ICG)|
Indocyanine green angiography differs from fluorescein angiography in several ways. Indocyanine green dye is more highly bound to protein than sodium fluorescein and has peak absorption and emission wavelengths in the infrared spectrum, outside of the visible range. Because the fluorescence efficiency of the ICG molecule is only 4% of that of sodium fluorescein, photographic film is too insensitive to record this weak fluorescence. To detect ICG fluorescence, charge coupled device (CCD) cameras with a digital acquisition process are necessary. Indocyanine green angiography can image the choroidal vasculature better than fluorescein angiography because the larger and more highly protein bound ICG molecule is unable to diffuse out of the fenestrated choroidal vessels. In addition, the infrared emission spectrum of ICG dye is not blocked by the overlying retinal pigment epithelium. Thus ICG angiography is an excellent technique for evaluating choroidal hypoperfusion or choroidal leakage.
Indocyanine green angiography can be helpful in the diagnosis and management of various infectious and inflammatory diseases. ICG patterns of hypofluorescence and hyperfluorescence have been described for many inflammatory diseases including: multiple evanescent white dot syndrome (MEWDS), 5–7 acute multifocal placoid pigment epitheliopathy (AMPPE),8 multi-focal choroiditis,9 Vogt-Koyanagi-Harada disease (VKH),10–12 ocular sarcoidosis,13 and Behcet disease.14,15 ICG angiography often shows discreet or patchy areas of hypofluorescence in the active inflammatory phases of these diseases indicative of choroidal alterations, often much more extensive than is clinically apparent with ophthalmoscopy or fluorescein angiography. In some of these disorders such as MEWDS the ICG, abnormalities resolve completely with resolution of the patient's symptoms, whereas in others ICG abnormalities may persist. Hyperfluorescence may also be seen with ICG angiography, as in VKH disease where diffuse choroidal leakage can be prominent in late phases of the study. By better-visualizing the condition of the choroidal circulation, ICG angiography is helping us to better-understand the pathophysiology and possible mechanisms involved in infectious and inflammatory diseases of the retina and choroid. Currently, the clinical usefulness of ICG angiography for infectious and inflammatory diseases remains somewhat limited. However, with increasing familiarity of the angiographic findings in these diseases, ICG angiography is likely to play a greater role in their diagnosis and management.
|METHOD FOR ASSESSING MECHANISM OF VISUAL LOSS AND RESPONSE TO TREATMENT|
|As indicated earlier, in the large majority of cases, the combination of
the clinical history and ocular examination including binocular slit
lamp biomicroscopy are generally sufficient to establish a working diagnosis
and formulate a treatment plan. In selected instances, including
the peculiar leopard spot appearance of luetic neuroretinitis16–21 or the classic brush-fire appearance of serpiginous choroiditis (see Figs. 1, 2, and 3),22–30 the diagnosis may be established on the basis of the angiographic findings
alone. More often, the angiography is used to answer specific questions
about the individual case, relating either to the mechanism of
visual loss or to the measurement of the response to treatment. The following
is a partial list of complications of inflammations and infections
of the posterior segment that result in visual loss that can be better
defined by angiography:|
As an example, patients with posterior segment involvement by the spirochete Treponema pallidum may manifest visual loss on the basis of a large number of different mechanisms.16–21 These include perioptic neuritis, retinal periphlebitis or periarteritis, diffuse neuroretinitis, cystoid macular edema, or choroidal neovascularization. Fluorescein angiography may be helpful not only in establishing the causative agent but also in determining the predominant mechanism of visual loss (see Figs. 4 and 5).
|QUANTITATION OF DISEASE SEVERITY|
One of the most useful applications of fluorescein angiography in infections and inflammations of the posterior segment is the delineation and quantization of cystoid macular edema. Although it is generally possible to ascertain the presence or absence of gross cystoid macular edema in eyes with clear media, this is often not the case in eyes with intraocular inflammation. The presence of intraocular inflammation, such as the vitreous cells accompanying pars planitis31–33 or sarcoidosis, 34–40 may prevent clear viewing of the macula. The tell-tale hyperfluorescence seen in the normally hypofluorescent macula after dye injection is an important indicator. The presence of cystoid macular edema by angiography may lead the clinician to take a more aggressive posture in the treatment of these diseases, especially in younger patients in whom some uncertainty exists regarding the relative contribution of the media opacity versus the macular function to the reduced vision (see Figs. 6 and 7).
Once a treatment regimen has been instituted, the follow-up fluorescein angiogram can serve as a marker for treatment response in addition to other clinical variables, including visual acuity and severity of intraocular inflammation (see Fig. 8).
OPTIC NERVE DISEASE
The fluorescein angiogram can provide useful information with regard to inflammatory involvement of the optic nerve in association with retinal inflammation either in eyes with clear or opaque media. In eyes with clear media, excessive staining of the optic nerve in the late frames of the angiogram may signify sub clinical inflammation, even in the absence of any obvious disc swelling or engorgement. Patients with Vogt-Koyanagi-Harada disease, 41 sympathetic ophthalmia42–46 and luetic neuroretinitis frequently have occult inflammation of the optic nerve, which may signify the clinical stage of the intraocular inflammation more accurately than the retinal findings, particularly in long-standing cases with extensive atrophic retinal abnormalities in which it is difficult to monitor change (see Fig. 9).
Another circumstance in which fluorescein angiography is helpful in defining the cause and extent of inflammatory disease is in the context of a patient who has a coexisting disease process. Patients with diabetes mellitus who are found to have cystoid macular edema after cataract extraction represent a difficult management problem. Although diffuse leakage may occur from the perifoveal capillary net, in response to hyperglycemia or low-grade intraocular inflammation such as that which follows cataract surgery, the presence of late staining of the optic nerve in a fluorescein angiogram in such a patient suggests that at least a portion of the edema may be related to postsurgical inflammation.
A third instance in which fluorescein angiography concentrating on the optic nerve may be helpful is in eyes with vascular engorgement of the optic nerve, especially with media opacities. Fluorescein angiography may help the clinician distinguish abnormally leaking capillaries from neovascularization. In acute multifocal hemorrhagic retinal vasculitis, optic nerve involvement is common in the early stages of the disease, 47 with optic nerve disc neovascularization seen later (see Figs. 10, 11, 12, and 13). Another fluorescein angiographic clue to the distinction between optic disc vessel engorgement and true neovascularization is the presence of associated large zones of retinal capillary nonperfusion such as those seen in sarcoidosis (see Figs. 14 and 15),34–40 acute multifocal hemorrhagic retinal vasculitis (see Figs. 10 and 11),47 or Eale disease (see Figs. 16 and 17).48–52
Ultimately, the diagnosis of optic nerve head neovascularization should be made on the angiographic characteristics of the optic nerve head vessels rather than on the presence of retinal capillary nonperfusion, because some patients, including those with severe forms of pars planitis or sarcoid, may develop “inflammatory” neovascularization in the absence of ischemia that responds to antiinflammatory therapy rather than scatter photocoagulation (see Fig. 18).
RETINAL VASCULAR INVOLVEMENT
Fluorescein angiography may be helpful in distinguishing between different forms of retinal vasculitis. Diseases such as sarcoidosis (see Figs. 14 and 15), Eales disease (see Figs. 16 and 17), pars planitis, and acute multifocal hemorrhagic retinal vasculitis (see Figs. 10, 11, 12, and 13) primarily produce inflammation of the veins (phlebitis), whereas other inflammations and infections, including acute retinal necrosis (see Figs. 19, 20, and 21),53–71 Behçet disease,46,72–74 and occasionally toxoplasmosis,1,75 preferentially involve the arterial side with secondary phlebitis not uncommon.
One way in which angiography can be particularly helpful in cases of secondary retinal vasculitis is in evaluating the severity of inflammation initially and in response to treatment. Even occult foci of periphlebitis seen in sarcoidosis and Eale disease can be dramatically illustrated angiographically by fluorescein staining of the vessel walls in the late frames of the study (see Figs. 16 and 17).
Fluorescein angiography study also yields valuable information about the presence of retinal capillary nonperfusion76–78 often associated with periphlebitis or periarteritis that may lead to retinal neovascularization and vitreous hemorrhage. Early identification of such patients permits prophylactic photocoagulation to be judiciously applied in selected patients. Occasionally, perivasculitis induced at an arteriovenous crossing by underlying choroiditis may result in a branch vein occlusion and distal nonperfusion or neovascularization.
A minority of patients with the ocular ischemic syndrome secondary to carotid stenosis may present with anterior segment pseudoinflammatory changes such as severe flare and fibrin response in addition to iris neovascularization. Fluorescein angiography may be helpful in demonstrating delayed filling of the choroidal and retinal vasculature in such patients.
|INFLAMMATORY RETINAL PIGMENT|
A number of inflammatory diseases of the posterior segment produce changes in the retinal pigment epithelium, which may range from the relatively subtle alterations in multiple evanescent white dot syndrome (see Figs. 22 and 23)79 to the striking opacification and pigment spotting of acute multifocal placoid pigment epitheliopathy (see Figs. 24 and 25),80–85 serpiginous choroiditis(see Figs. 26, 27, 28, and 29),22–30 and luetic neuroretinitis (see Fig. 9).16–21 In fact, there has been some controversy in the interpretation of the angiographic features of these diseases based on the distinction between hypofluorescence of the choroidal vasculature because of presumed vasculitic nonperfusion and simply optical blockage because of primary inflammation and opacification of the overlying retinal pigment epithelium. ICG angiographic findings in these disorders would favor choroidal hypoperfusion in many of these instances since ICG fluorescence is unlikely to be blocked by subtle changes in the overlying pigment epithelium.
In addition to exudative detachment of the neurosensory retina and papillitis, patients with Vogt-Koyanagi-Harada disease as well as sympathetic ophthalmia may also develop serous detachment of the retinal pigment epithelium. This differs from the usual form of retinal pigment epithelium detachment that occurs in age-related macular degeneration by the absence of adjacent soft drusen and the presence of multiple pinpoint leak sites and disc staining characteristic of Vogt-Koyanagi-Harada disease (see Figs. 30, 31, 32, 33, and 34) and sympathetic ophthalmia (see Figs. 35 and 36).41–46 In cases of Vogt-Koyanagi-Harada disease with serous retinal detachment or detachment of the retinal pigment epithelium, some authors have reported hyperfluorescence of the large choroidal vessels in early stages of the angiogram, followed by dye leakage in the late phase of the study, whereas others report leakage from the choroidal vessels throughout the study (see Figs. 33 and 34).11,12
The syndrome of diffuse unilateral subacute neuroretinitis (DUSN) is now believed to be caused by a migratory filarial worm interposed between the neurosensory retina and retinal pigment epithelium.1 The two most likely candidates are Baylisascas procyonis and Ankylostoma braziliensis. The late stages of the disease are characterized by diffuse mottling of the retinal pigment epithelium, optic atrophy, and narrowing of the retinal vessels mimicking retinitis pigmentosa. When the disease is discovered in the early stages while the worm is still actively migrating, ophthalmoscopy reveals the presence of evanescent white dots in the outer retina; these dots are relatively nondescript in the early phases of angiography but stain in the later phases. Although fluorescein angiography is not characteristic in this disorder, nor required for diagnosis, it may provide some insight into the degree of retinal and retinal vascular inflammation that is amenable to pharmacologic therapy.
CHOROIDAL VASCULAR DISEASE
Angiography is especially useful in delineating the presence and extent of choroidal inflammation and secondary vascular alterations. In certain instances, fluorescein and indocyanine green angiography may be the most sensitive indicators of subclinical or occult choroiditis. Hypofluorescent spots seen with ICG angiography in several inflammatory diseases such as MEWDS suggest that choroidal vascular alterations play a role in the pathogenesis of these diseases. In diseases such as the presumed ocular histoplasmosis syndrome,1,86 the presence of a focus of choroiditis or subtle choroidal atrophic scar enhanced by the fluorescein or ICG contrast medium may presage the later development of choroidal neovascularization.
Fluorescein and ICG angiography may yield unsuspected clues as to the pathophysiology of certain infectious syndromes. The first descriptions of acute retinal necrosis reported confluent necrotizing peripheral retinitis, arteritis, and vitreitis.53–71 This leads many investigators to assume that the herpes virus, believed to be responsible, invaded through the retinal circulation. In fact, angiography performed on the minority of patients seen early enough in the disease with clear media disclosed multifocal nummular zones of choroidal nonperfusion in the posterior pole, indicative of widespread choroidal vasculitis that may precede the development of retinitis. This may not be the case in the related disorder of cytomegalovirus retinitis, which is more frequent in immunosuppressed persons, in which periphlebitis rather than choroidal vasculitis appears to precede the development of necrotizing retinitis.87,88
A variety of inflammations and infections, most notably presumed ocular histoplasmosis syndrome (see Figs. 37 and 38), serpiginous choroiditis, and multifocal choroiditis (see Figs. 39, 40, 41, and 42),1,89,90 are associated with the late complication of choroidal neovascularization. Probably the single most important application of fluorescein angiography in infectious and inflammatory diseases of the posterior segment is for the evaluation and potential treatment of this complication. In some instances, fluorescein angiography may be the single best method to determine whether visual loss seen late in the course of such disease as paramacular toxoplasmosis or serpiginous choroiditis is the result of secondary choroidal neovascularization or inflammatory disease recrudescence. In other diseases, such as presumed ocular histoplasmosis syndrome or multifocal choroiditis, choroidal neovascularization may occur early and be suspected on the basis of associated hemorrhage or lipid exudation. In some instances, even with the benefit of high-quality fluorescein angiography it may be difficult to distinguish between choroidal vasculitis and choroidal neovascularization superimposed on underlying choroiditis. We have recently identified a subgroup of young female patients, frequently darkly pigmented, who develop solitary zones of elevated choroiditis that have features of choroidal neovascularization. These appear to have a more indolent course than either idiopathic choroidal neovascularization or that associated with atypical multifocal choroiditis.
|Fluorescein and IGC angiography are useful diagnostic tools in the evaluation of certain infections and inflammations of the posterior segment. Because of its biophysical properties, fluorescein acts as an image enhancer and also provides valuable information about the dynamic state of the blood-ocular barriers. Rarely, fluorescein or ICG angiography may result in a pathognomonic picture that convincingly establishes a diagnosis. More frequently, however, angiography provides useful information regarding the delineation of disease severity, mechanism of visual loss, and response to treatment. It enhances the ability of the ophthalmologist to distinguish between optic nerve, retinal, retinal vascular, pigment epithelial, and choroidal disease. It is especially useful in corroborating the presence of retinal or choroidal neovascularization or cystoid macular edema amenable to treatment, particularly in eyes with partially opacified media as a result of the intraocular inflammation.|
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