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INDOCYANINE GREEN ANGIOGRAPHY IN AGE-RELATED MACULAR DEGENERATION
ATUL KUMAR, SANJEEV NAINIWAL, GUNJAN PRAKASH
Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029 India.
Age-related macular degeneration is one of the leading causes of bilateral irreversible severe visual loss in individuals over 60 years of age. Imaging of the posterior segment in cases of age-related macular degeneration has evolved rapidly in the past two decades. Infrared light is now routinely used to visualize features not seen by other methods. With digitalization, our ability to acquire, store and retrieve images has greatly improved. We can diagnose lesions consistently and manage the same with much more confidence that was not possible before.
The development of choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD), as well as other macular disorders, is a cause of significant visual morbidity. While laser photocoagulation has been shown to be effective in reducing severe visual loss, many patients are ineligible for treatment because their neovascular membranes are poorly defined or occult when imaged with fluorescein angiography due to overlying subretinal exudate, haemorrhage, or turbid fluid, or because of an associated pigment epithelial detachment.
PHARMACOKINETICS
Indocyanine green (ICG) is a tricarbocyanine dye that absorbs light at 790 to 805 nm and has a peak emission at 835 nm.[1-3] These spectral properties allow ICG to be visualized through the ocular pigments, blood, and serous fluids. ICG is almost 98% plasma protein bound. This high degree of protein binding results in the tendency for ICG to remain intravascular, which facilitates visualization of the choroidal vessels and, in certain cases, choroidal pathologic processes. Circulating ICG is almost exclusively removed by the liver and not by the kidney due to its strong protein binding.
ICG is supplied as sterile water-soluble lyophilized powder (25 mg, ICG Pulsion®) with the empirical formula of C43H47N2O6S2Na.[4] It is an anhydro-3,3,3’,3’-tetramethyl-1,1’-di-(4-sulphobutyl)-4,5,4’,5’,-dibenzoindotricarbocyanine hydroxide sodium salt with molecular weight of 775 Daltons. It is supplied with distilled water (5 ml) and its pH is between 5.5 and 6.5 in dissolved state. Under direct exposure to bright light, the aqueous dye solution decays approximately 10% in ten hours. Hence, the dye should be used within 10 hours of reconstitution.
ICG is safe for general use and less toxic than sodium fluorescein. The dye does not produce the nausea caused by sodium fluorescein after intravenous injection, but it can cause vasovagal reactions. Extravasation of injected ICG is well tolerated and resolves without complication. Because it contains approximately 5% iodine by weight, it should not be given to patients with a history of iodine allergy. In addition, patients who are uraemic[6] or who have liver disease should not be given the dye. As with fluorescein angiography, appropriate emergency equipment must be available. The incidence of death after fluorescein injection is 1 in 222000; for ICG it has been estimated as 1 per 333000.[7,8] ICG is not detected in the cerebrospinal fluid.[9,10] The dye does not cross the placenta.[11] No studies on foetal toxicity have been performed.
EQUIPMENT AND TECHNIQUE
Although it was recognized that ICG could in theory provide better definition of choroidal abnormalities than fluorescein, its clinical usefulness was limited by its low fluorescence and the consequent poor quality of photographic images. Two different types of fundus camera systems are available for performing ICG angiography.
One type is a digital charged coupled device (CCD) video camera for image recording. The digital CCD cameras usually have higher spatial resolutions (1024 x 1024 pixels), while the temporal resolutions are less as it records only 1-2 frames per second. The CCD camera employs filtered light from a Xenon flashlamp to excite ICG dye.
The Scanning Laser Ophthalmoscope (SLO) is extremely light efficient, however has a low spatial resolution (256 x 256 pixels) while it takes 20 to 30 images per second, thus providing high temporal resolution. The SLO uses very low-power laser diode that is brought to extremely sharp focus (approximately 10 microns) onto the surface of the retina. The laser beam is scanned across the retina at the same rate and in the same pattern that an electron beam moves across a television screen. The reflected light is not brought back to sharp focus but, rather, is presented to a very sensitive light detector, where the light energy is transduced and amplified. Measuring the reflectance of the retina, as the laser beam scans across it, assembles a picture of the retina.
A computer controls the position of the laser beam and is used to add appropriate synchronization signals to the output of the amplifier so that a regular video signal is produced, which can be shown on any television screen. The brightness at any point on the television screen indicates the reflectance of the corresponding point on the retina. Thus the advent of infrared SLO and high-resolution digital angiographic systems has improved the image quality and thereby enhanced the effectiveness of ICG as a tool for diagnosis and management of choroidal vascular disorders, particularly neovascular membranes.[5]
The blue wavelength is used for fluorescein angiography, the infrared wavelength for indocyanine green angiography, and the green wavelength for "red-free" photographs prior to angiography. We use the red wavelength to provide a fixation target during indocyanine green angiography and to obtain pre-injection photographs through nuclear sclerotic cataracts that excessively scatter the green light. The field varies from 10 to 30 degrees. Digital Angiography (Fig. 1) and SLO systems have the added advantage of acquiring simultaneous ICG and Fluorescein angiograms (FA).
As an ophthalmologic agent, ICG is used as 25 mg in 2-ml of distilled water. Intravenous injection should be immediately followed by a 5-ml normal saline flush. Rapid photographs are taken. Subsequent photographs are taken at about 3 minutes, 10 minutes and 30 minutes. If necessary, it is possible to perform ICG angiography simultaneously with or sequentially to FA.
PHASES OF NORMAL ICG ANGIOGRAM
The approach for ICG angiogram interpretation is similar to that of FA.
* Early phase-Rapid filling of choroidal arteries, choriocapillaries and choroidal veins (first 2 to 5 seconds), early filling of retinal arteries
-Retinal veins are not visible
-Gradual fading of choroidal arterial filling and watershed zone gets filled (five seconds to 3 minutes)
* Middle phase-Fading of choroidal vasculature (3 to 15 minutes)
-Overall diffuse fluorescence that is evident is due to diffuse perfusion of dye in the chorio- capillaries
-Retinal vessels are still visible
* Late phase-Relative hypofluorescence of choroidal vasculature against background hyperfluorescence resulting from staining of extrachoroidal tissue (15 to 60 minutes)
-Retinal vessels are not visible
CLINICAL APPLICATIONS
Clinically, Indocyanine Green and Fluorescein provide different, but complementary information regarding choroidal vascular diseases. ICG has been applied as an adjunctive study in patients with neovascular membranes poorly defined by fluorescein angiography (Figs. 2-4).
* Occult choroidal neovascularization
Leakage from CNV with ICG is slow compared to the rapid leakage of fluorescein. Careful evaluation of ICG angiograms in patients of AMD with occult CNV has revealed that two main forms[12] of neovascular lesions may exist. These involve localized, intensely hyperfluorescent leaking areas (no more than one disc diameter in size) of neovascularization known as hotspots (incidence 29%). Other more subtle and larger areas (one disc diameter in size) of hyperfluorescence with less evident leakage are known as plaques (incidence 61%). Plaque is classified as ill defined if the margins are indistinct or if there is blockage of any portion of the neovascularization by blood. Combination (incidence 8%) of these lesions may occur that are subdivided into marginal spots, overlying spots and remote spots. Other 2% is constituted by multiple spots.
ICG angiography is an important adjunctive study to FA in the detection of CNV. The medium and larger proliferating choroidal vessels may be better imaged by ICG angiography. If more than one well-defined areas of occult CNV is seen, this is termed as multifocal. FA may image well-defined CNV better than ICG angiography in some cases; however, in many patients ICG angiography can convert occult CNV shown by FA into classic CNV. It appears that the best imaging strategy for detecting CNV is to perform both FA and ICG angiography.
ICG dye-enhanced diode laser photocoagulation[13] is a potential therapeutic application especially for the feeder vessel treatment. The high speed ICG-video angiography may pick up these vessels in about 70-80% eyes. The affected eye could also have more than one feeder vessel, which are imaged simultaneously. Intraretinal dye leakage[14] is seen in approximately 11% of the patients with occult CNV. The peak absorption of ICG is at a similar frequency as the peak emission of the diode laser. This may allow selective ablation of the ICG-containing CNV with relative sparing of the normal neighbouring retina. In age-related macular degeneration, ICG videoangiography can successfully guide laser photocoagulation of occult CNV. It is especially useful in the diagnosis of occult CNV with overlying haemorrhage and recurrent CNV.[15] It is extremely useful in converting occult CNV into classic, well-defined CNV.
* Idiopathic polypoidal choroidal vasculopathy
IPCV is often seen in middle-aged women of Asian-African ancestry and is also known as the posterior uveal bleeding syndrome. It is a primary abnormality of the choroidal circulation in which a network of vessels terminate in polypoidal or aneurysmal excrescences at the level of the choroid. This is visible clinically as a reddish orange mass. ICG angiography is sensitive and specific in the accurate detection and characterization of this abnormality. The initial phase reveals a distinct network of vessels within the choroid that start to fill before the retinal vessels, fill more slowly than the retinal vessels, but this area is hypofluorescent as compared to the surrounding choroid. The hyperfluorescent "polyps" that become visible within the choroid correspond to the clinically visible reddish orange choroidal excrescences. These lesions leak slowly and in the later phases there is a uniform disappearance of the dye from these. The late ICG staining that characterizes occult CNV in AMD is absent in the IPCV. Thus, ICG angiography is also able to differentiate between the aneurysm-like and secondary choroidal neovascularization, a known complication of this chronic disease. In cases with juxtapapillary involvement, the vascular network extends in a radial, arching pattern and is interconnected with small spanning branches that are distinct and more numerous at the edge of the IPCV lesion. Vitreous haemorrhage may occur with significantly higher incidence in these lesions than in exudative ARMD.
* Maculorhexis
ICG enhanced removal of the internal limiting membrane (ILM) is a useful surgical approach to close an idiopathic macular hole. We are following a technique, called as maculorhexis, in which we stain the ILM with a solution of ICG to facilitate the removal of ILM in eyes with an idiopathic macular hole. The goal of this technique is to produce the least possible foveal traction during the complete removal of macular ILM. There is a significant visual recovery at 6 months with the surgical technique[17] as compared to the natural history of the stage 2 macular holes (Gass classification).
The surgical technique includes a standard three-port pars plana vitrectomy. Complete posterior cortical vitrectomy is followed by careful identification, engagement, elevation and removal of the posterior cortical vitreous layer. Sterile 0.5% ICG (approximately 0.1 ml of 5 mg per ml of distilled water) is squirted over the macula. The vitrectomy ports are temporarily plugged for about 2 minutes. This much time is usually required for ILM to take the stain (personal experience). The excess ICG is aspirated from the vitreous cavity with the vitrector. The media clarity improves and then we proceed with the maculorhexis, as described.
An optimal starting point for ILM-peel is chosen within the arcade vessels but remote from the fovea at approximately 5 o’clock, for surgical convenience. The site is chosen to lie outside the maculopapular bundle. Tano’s Diamond Dusted Membrane Scraper (Synergetics, Inc., USA) is used to raise a small ILM flap. In this way, engaging the neurosensory retina is avoided.
The ILM flap is grasped with end-opening forceps (Grieshaber, Alcon Laboratories, Inc. 6201 South Freeway, Fort Worth, TX 76134, USA) and a "rhexis" (smooth-edged continuous tear) is created by slowly tearing the ILM in a circular motion, concentric with the fovea, keeping the direction of force always following the natural course of the nerve fibers. Most of the times, the ILM can be removed as a single piece; but if the tear is incomplete, the ILM can be simply re-grasped at the new edge, and the rhexis resumed.
If the fovea is noted to be under traction during this procedure, the peeling force vector is redirected slightly toward the fovea until the traction resolves, and the tearing is then continued in a similar fashion. When working close to the fovea, we keep the hole under constant observation. The ILM is peeled so as to cover as much of the area of the macula as possible (minimum size of two-disc diameter, 3000 microns).
The small circle of ILM (operculum), if still remaining over the foveola is not disturbed. The vitreous cavity is filled with a 14% non-expansile volume of perfluropropane (C3F8) and the sclerotomies are closed with 6-0 Vicryl suture. The gas bubble, which is placed inside the eye, provides a long-acting splint to the macular hole (this is known to increase the chance of successful surgery). The gas bubble spontaneously disappears from the eye slowly over six weeks post-surgery. The patient is advised to follow strict facedown positioning for 1 week. Such positioning is advised not only during the day, but during the night also. The intraocular pressure (IOP) should be noted with an applanation tonometer at 8 hours postoperatively.
Electron microscopy and immunofluorescent assays have confirmed that the ILM can be predictably removed without the risk of attachment of nerve fibre layer fragments. Since a minimal surface traction has been increasingly implicated in certain forms of maculopathy, and the long term macular functions appear to be stable or improved even without the ILM, removal should be a familiar technique to the surgeon treating traction maculopathy.
CONCLUSION
Fluorescein angiography revolutionized the diagnosis and treatment of CNV. However, our ability to treat many patients with occult or poorly defined CNV was limited. ICG angiography allows enhanced, high-resolution imaging of CNV that is useful in many eyes with occult CNV shown by FA. The use of a combination of FA and ICG angiography allows us to potentially treat many more patients with CNV than would be possible by performing FA alone. We presently recommend performing ICG angiography along with FA in all patients with CNV.
Advancement of angiographic techniques such as high speed ICG video angiography for feeder vessel identification in CNV and wide-field angiography, which provides a field of view of up to 160°, and digital subtraction ICG angiography, which allows visualization of the filling of separate elements in the vascular circuit, may increase the ability to diagnose and treat retinal and choroidal abnormalities.
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