Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009
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ophthalmology [2,3]. The first color fundus photographs appeared in 1929. Today, ophthalmologists are fortunate to have wide-angle fundus cameras, nonmydriatic cameras, and digital imaging at their disposal.
Clinical Indications. Fundus photography is an invaluable tool with which diabetic retinopathy can be followed up [4]. Photographs can be used to monitor progression of disease, particularly when following subtle changes in the posterior pole. The use of fundus photography to screen for diabetic retinopathy is also becoming more common [5,6].
It is critical to employ standardized photographic technique and parameters when using photographs to follow up any disease process. Accurate comparisons can only be made through photographs that reflect the same exposure and field of view. Color fundus photos can be taken in stereoscopic or nonstereoscopic mode and can be performed in the traditional seven stereoscopic 30° fields or wide angle 60° fields. Both 30° and 60° have advantages and disadvantages, but generally the seven stereoscopic 30° fields provide the most complete coverage.
As the prevalence of diabetes rises, the challenge of screening large patient populations for diabetic retinopathy also increases, particularly in underserved areas. Direct ophthalmoscopy, either by primary care physicians or ophthalmologists, has a sensitivity as low as 65% for the detection of sight-threatening disease [7]. Digital retinal photography has therefore become an important method of screening diabetic patients. Photos provide a permanent image of the retina that can be easily stored, enhanced, and transferred electronically for remote interpretation. Multiple studies have confirmed that digital photos can be an excellent screening tool when evaluated by a trained clinician [8–10]. Nonmydriatic cameras and automated screening systems to analyze digital retinal photographs have been used successfully in screening for diabetic retinopathy and will allow for more rapid evaluation of large patient populations in the future [11–13].
FLUORESCEIN ANGIOGRAPHY
Background. In 1955, MacClean and Maumenee first used intravenous fluorescein in humans to assist in diagnosing choroidal hemangiomas and choroidal melanomas [14]. In 1961, Novotny and Alvis described the current technique for retinal angiography [15].
Sodium fluorescein is a hydrocarbon that is 80% bound to albumin in the circulation. The unbound molecule diffuses freely through the choriocapillaris, Bruch’s membrane, optic nerve, and sclera. However, it does not diffuse through the tight junctions of the retinal endothelial cells, the retinal pigment epithelium, or the larger choroidal vessels. A physiologic inner blood–retina barrier exists at the level of the retinal capillaries because of the tight junctions within these vessels. When there is a disruption of this inner blood–retina barrier, dye leakage occurs. The outer blood–retina barrier is formed by tight junctions between the retinal pigment epithelial cells and is also normally impermeable to fluorescein. Understanding these vascular barriers is critical to interpreting fluorescein angiograms.
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Fluorescence occurs when light of a specific wavelength excites the electrons of a substance to a higher level of energy. When these electrons return to their original energy level, a longer wavelength is emitted. Sodium fluorescein is excited by blue light with wavelengths between 465 and 490 nm and fluoresces green-yellow light at wavelengths of 520 to 530 nm. The blue flash of the fundus camera excites both the 20% of fluorescein molecules that are unbound to albumin and any fluorescein that has leaked out of the vessels. A blue filter blocks all other light entering the eye. Reflected back into the camera is the green-yellow light emitted from the fluorescein molecules and reflected blue light. Another filter blocks the unwanted blue light and transmits the green-yellow light. “Autofluorescence” refers to areas of hyperfluorescence seen in preinjection fundus photographs when using the filters. It is produced by highly reflective structures such as optic disc drusen, astrocytic hamartomas, or exudates.
Image quality is dependent on technique, filters, film or digital processing equipment, ocular media, and patient cooperation. Intravenously administered fluorescein allows for high resolution images and standardized circulation times, although orally administered fluorescein is still occasionally used in limited clinical settings.
Although sodium fluorescein is generally safe, adverse reactions such as itching, nausea, or vomiting may occur. Severe anaphylactic reactions can rarely occur (1 in 200,000) [16,17]. All angiography facilities should have a clear protocol for managing such emergencies.
Clinical Indications. Fluorescein angiography plays an important role in the diagnosis and treatment of retinal and choroidal vascular pathology. It is particularly useful in identifying areas of nonperfusion, increased vascular permeability, and neovascularization. These characteristics make fluorescein angiography a valuable tool in managing the vascular complications commonly associated with diabetic retinopathy.
Nonproliferative Diabetic Retinopathy. The earliest detectable clinical change in diabetic retinopathy is the presence of microaneurysms (MAs). Histologic studies have demonstrated that the blood–retinal barrier is compromised within MAs because of loss of tight junction anchor proteins in the capillary endothelial cells. This breakdown results in leakage of fluid and retinal edema [18,19]. MAs therefore typically leak fluorescein and are easy to detect with angiography (Fig. 7.1). Angiography often shows more MAs than are seen either clinically or with color stereoscopic photographs. One study estimated that fluorescein angiogram could detect four times as many MAs than can be seen on fundus photos [20]. Other retinal vascular changes, such as altered caliber of vessels and focal areas of capillary nonperfusion, are also better seen angiographically than on clinical exam. Despite this high sensitivity in detecting the earliest changes in diabetic retinopathy, fluorescein angiography is not typically indicated for management at this early stage as the presence of these lesions is not in itself an indication for treatment [21].
As diabetic retinopathy progresses, intraretinal hemorrhages, cotton wool spots, and hard exudates may be seen. These lesions may produce blocking defects
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Figure 7.1. Early fluorescein angiogram demonstrates multiple microaneurysms scattered throughout the macula.
on fluorescein angiogram. Fluorescein angiography is usually not indicated for patients with moderate nonproliferative diabetic retinopathy (NPDR), unless the level of visual loss seems to surpass the degree of diabetic retinopathy seen clinically. In these cases, ischemic diabetic maculopathy that may be present can be identified angiographically (Fig. 7.2).
Severe NPDR is characterized by numerous hemorrhages and MAs in four quadrants, venous beading in two or more quadrants, or intraretinal microvascular abnormalities (IRMA) in at least one quadrant (Figs. 7.3 and 7.4). The risk of progression from severe NPDR to high risk proliferative diabetic retinopathy (PDR) is 15% within 1 year and 56% within 5 years. The risk of progression to PDR from very severe NPDR, defined by the presence of any two of the above features, is 45% within 1 year and 71% within 5 years [22]. Although fluorescein angiography well delineates the defining vascular abnormalities of severe NPDR, the presence of these features alone is not an indication for testing. At this advanced stage of NPDR, however, it may be helpful to follow disease progression with color fundus photographs [23].
Wide-angle fluorescein angiography can be directed to detect peripheral capillary nonperfusion, a feature that has been shown to be associated with progression of PDR (Fig. 7.5A and 7.5B). Investigators from Japan demonstrated that the peripheral retina was much more likely to undergo capillary nonperfusion than the posterior retina [24]. The same group later found a positive correlation between the initial site of capillary nonperfusion and progression of retinopathy. Progression was more rapid when nonperfused areas were, in ascending order: peripheral, midperipheral, central, and generalized [25].
Proliferative Diabetic Retinopathy. While fluorescein angiography is not typically necessary to make the diagnosis of PDR, the angiographic characteristics of
Figure 7.2. Fluorescein angiogram reveals extensive capillary nonperfusion within the macula.
Figure 7.3. Color photograph of severe nonproliferative diabetic retinopathy with intraretinal microvascular abnormalities and extensive intraretinal hemorrhages. (Source: Courtesy of ETDRS.)
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Figure 7.4. Fluorescein angiogram demonstrates characteristics of severe nonproliferative diabetic retinopathy including blocking defects from extensive intraretinal hemorrhages and intraretinal microvascular abnormalities (arrowhead), as well as diffuse microaneurysms.
neovascularization are accentuated on angiography. Fronds of neovascularization, often occurring at the junction of perfused and nonperfused retina, leak fluorescein dye abundantly (Fig. 7.6). They sometimes have a propensity to fill before the normal retinal arteries, suggesting a choroidal blood source for these vessels. After panretinal photocoagulation, a decrease in the leakage from the fronds is noted.
The decision to treat PDR with scatter photocoagulation is also typically based on clinical findings rather than fluorescein findings. The “high risk” characteristics for severe visual loss in PDR as defined by the Diabetic Retinopathy Study are based on clinical ophthalmic examination [26]. One study, however, has found
A B
Figure 7.5. (A) Color photograph displaying numerous hemorrhages, microaneurysms, cotton wool spots, and intraretinal microvascular abnormalities. (B) Wide-angle fluorescein angiogram of the same patient reveals significant capillary nonperfusion centrally and in the periphery.
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Figure 7.6. Pronounced fluorescein leakage from neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) in proliferative diabetic retinopathy.
that peripheral angiography may be useful in identifying patients likely to develop anterior segment neovascularization [27].
Macular Edema. The most common indication for fluorescein angiography in diabetic retinopathy is in the management of macular edema. The incidence of macular edema in diabetic retinopathy is between 13.9% and 25.4% [28]. The Early Treatment Diabetic Retinopathy Study (ETDRS) defined edema characteristics that are associated with more pronounced treatment effect [29]:
1.Thickening of the retina at or within 500 microns of the center of the macula
2.Hard exudates at or within 500 microns of the center of the macula if associated with thickening of the adjacent retina
3.A zone or zones of retinal thickening one disc area or larger in size, any part of which is within one disc diameter of the center of the macula
Diabetic macular edema that meets any one of the above criteria is termed “clinically significant macular edema” (CSME). The incidence of CSME in diabetic retinopathy is between 9.2% and 17.6% [22]. It is important to note that the diagnosis of CSME is made on the basis of clinical exam rather than on fluorescein angiogram findings. Eyes with macular edema that is not clinically significant are usually not treated with laser photocoagulation and, therefore, are primarily followed by clinical examination.
In eyes with CSME, the fluorescein angiogram is useful in guiding focal or grid laser treatment [22,30,31]. Although some clinicians feel that fluorescein angiography is not necessary prior to laser treatment, a study found that preoperative imaging improves the accuracy and probably the effectiveness of laser treatment
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A B
Figure 7.7. (A) Circinate lipid and thickening consistent with focal clinically significant macular edema. (B) Extensive fluorescein leakage is present in the area of macular edema seen clinically.
[32]. Focal diabetic maculopathy is characterized by areas of discrete leakage with sufficient macular perfusion (Fig. 7.7A and 7.7B). These areas can be treated with focal laser directed at individual lesions. Diffuse diabetic maculopathy, however, results from hyperpermeability of the entire perimacular capillary bed secondary to breakdown of the inner blood–retina barrier (Fig. 7.8A and 7.8B) [33]. Areas of diffuse leakage are typically treated with grid laser, although treatment outcome may be less favorable [34]. Fluorescein angiography is also helpful in guiding laser treatment by demonstrating the border of the foveal avascular zone. When considering retreatment, fluorescein angiogram is useful in identifying areas of persistent leakage, capillary nonperfusion, and previous laser treatment.
Angiography is also useful for evaluating macular edema in patients with some degree of diabetic retinopathy after cataract extraction, where differentiating diabetic CSME from post-cataract extraction cystoid macular edema (the Irvine-Gass Syndrome) may be difficult based on clinical exam alone. The leakage pattern in Irvine-Gass syndrome is typically “petalloid” in appearance as opposed to the
A B
Figure 7.8. (A) Extensive hard exudates with associated clinically significant macular edema.
(B) Fluorescein angiogram of the same patient demonstrates diffuse leakage in the macula.
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Figure 7.9. A “petalloid” pattern of leakage reflecting fluid accumulation in Henle’s layer is seen angiographically in cystoid macular edema. Note that the disc is hyperfluorescent.
focal or diffuse leakage seen in diabetic macular edema (Fig. 7.9). Reports have also noted that the disc is more likely to hyperfluoresce in Irvine-Gass Syndrome and less likely in exacerbation of CSME [35]. Differentiating these two entities is important in guiding treatment. In some cases, however, both forms of leakage may be present.
FLUORESCEIN ANGIOSCOPY
In fluorescein angioscopy, indirect ophthalmoscopy rather than photography is used in conjunction with fluorescein injection to directly evaluate retinal vascular abnormalities. This technique may allow for better visualization of the fundus as compared to standard angiography in eyes with hazy media. Peripheral retinal lesions may also be better visualized with fluorescein angioscopy. In the operating room, angioscopy may be used if standard angiography equipment is not available. The main disadvantage of fluorescein angioscopy, however, is that no permanent record of the exam is created.
INDOCYANINE GREEN ANGIOGRAPHY
Indocyanine green (ICG) fluorescence angiography was first introduced in 1973 by Robert Flower and Bernard Hochheimer [36]. The technique did not become widely used, however, until the 1990s with the advent of sensitive infrared video imaging and high resolution digital equipment. The ICG molecule is 98% proteinbound and, unlike sodium fluorescein, does not extravasate from the fenestrated choriocapillaris. The excitation and emission wavelengths at the near-infrared
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region allow penetration to deeper fundus structures as well as through overlying hemorrhage. Owing to these characteristics, visualization of the choroidal circulation is better with ICG angiography as compared to fluorescein angiography.
While ICG is not commonly used in diabetic retinopathy, studies have suggested that ICG could be a complementary test to fluorescein angiography in NPDR. One study showed that NPDR exhibits lobular spotty (“salt and pepper”) hyperfluorescence and hypofluorescence, diffuse late-phase hyperfluorescence in areas of retinal thickening and edema, and MAs not seen on fluorescein angiogram [37]. This suggests that the degree of diabetic retinopathy seen clinically and by fluorescein angiography may reveal only part of the pathology in the chorioretinal vasculature. ICG may better highlight these abnormalities. Currently, the clinical utility of this information is unclear.
ULTRASONOGRAPHY
Background. The use of ultrasonography in ophthalmology has become a critical tool to enable evaluation of intraocular pathology when ophthalmoscopic examination is limited by media opacity. Ultrasound waves have frequencies greater than 20 kHz. Ophthalmic ultrasonography utilizes frequencies in the range of 8–10 MHz. The sound wave is emitted from a probe that can be positioned on the globe or eyelid. The velocity of the emitted sound wave in the eye is dependent on the density of the medium through which it passes. When the sound wave strikes an interface of two media with different densities, part of the wave is reflected back to the probe where it is reacquired and the acoustic energy is converted to electrical energy that is depicted on an oscilloscope. B-scan ultrasound is a brightnessmodulated display in which echoes are represented by pixels on the monitor that form a two-dimensional image, whereas A-scan ultrasound is a one dimensional representation of the amplitude of the reflected sound waves. The amplification of the signal may be increased or decreased by adjusting the gain setting on the instrument.
Clinical Indications. Ultrasound is most commonly indicated when media opacity, such as cataract or vitreous hemorrhage, prevents an adequate view of the fundus. In these cases, ultrasound can be used to monitor progression of posterior segment disease and assist in deciding when surgical intervention is appropriate. The major pathologic processes that should be differentiated include: vitreous hemorrhage, posterior vitreous detachment (PVD), fibrovascular proliferation, blood layered on the retina, and retinal detachment [38].
Vitreous hemorrhage is a common complication of diabetic retinopathy. Blood can be positioned in the subhyaloid space or within the vitreous gel itself. While vitreous hemorrhage usually results from primary disease in diabetic patients, the possibility of other causes, such as a retinal tear or detachment should be considered. Therefore, any patient who presents with a vitreous hemorrhage should be evaluated with ultrasonography if an adequate view of the retina is not sufficient to rule out these processes. On ultrasound, vitreous hemorrhage is usually represented by diffuse, mobile, minimally reflective opacities in the vitreous cavity
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Figure 7.10. Vitreous hemorrhage is seen on ultrasound as a diffuse, minimally reflective opacity in the vitreous cavity.
(Fig. 7.10). Serial exams should be performed until the hemorrhage has sufficiently cleared to allow ophthalmoscopic evaluation.
Ultrasound is also useful in detecting fibrovascular membranes on the retinal surface [39,40]. Such membranes can cause fibrous contraction resulting in tangential traction or exaggerated adhesions between the vitreous and retina. Fibrovascular tissue can also cause splitting of the cortical vitreous (posterior vitreoschisis) that may simulate PVD on ultrasound [41,42].
Ultrasound plays an important role in managing tractional retinal detachment. These detachments are usually located in the peripapillary area or along the arcades. Common patterns of traction detachment include “tent-like” or “tabletop.” A tent-like detachment has a concave appearance and results from vitreoretinal adherence at a focal point Fig. 7.11). This elevation of the retina is immobile
Figure 7.11. With ultrasonography, the posterior hyaloid is seen attaching to the retina at a focal point, resulting in a “tent-like” tractional retinal detachment.