REVIEW URRENT C OPINION
Ultra-wide-field fluorescein angiography in retinal disease Mrinali Patel and Szilard Kiss
Purpose of review Ultra-wide-field fluorescein angiography (UWFA), which captures up to 2008 of retina in a single image, now affords us the ability to angiographically examine the parts of the retina previously not photographable. Here, we review the role of UWFA in the management of retinal disease. Recent findings UWFA effectively images the abnormality in a variety of retinal conditions, including diabetic retinopathy, retinal vein occlusion, sickle cell retinopathy, uveitis, and pediatric retinal disease, in turn guiding both diagnosis and management of these conditions. Summary UWFA is a useful imaging modality that is expected to become increasingly incorporated into the practice of retina. This will likely fuel the studies to determine how to reconcile the findings from UWFA with practice guidelines based on the studies conducted prior to the development of UWFA. Keywords angiography, Optos, ultra-wide-field, wide-field
INTRODUCTION Since its introduction in the l960s, fluorescein angiography has been an essential tool in the diagnosis and management of retinal diseases, often offering insights into the presence, activity, and severity of disease not appreciable through clinical examination alone. As many retinal diseases manifest with peripheral abnormality, there has been an ever increasing pressure to better image the retinal periphery. Traditional fundus cameras offered a field of view ranging from 308 to 608 in one exposure. Examination of more peripheral retina required technical skill by the photographer as well as redirection of gaze by the patient, and even then, the far periphery was not imaged. The seven standard fields (7SF) imaging involved capturing seven photos in a montage comprising 758 of the retina, whereas other montaging techniques could portray up to 1408 at once [1 ]. Even so, the far periphery was not imaged. Moreover, these montage techniques posed certain constraints for fluorescein angiography in particular, as it is a time-sensitive test and different parts of the retina could not be imaged at one time. Wide-angle angiography with the use of contact lens, such as the Staurenghi lens, expanded the view to 150–1608 but was technically more challenging and required patient cooperation with the contact
lens system [2]. The Optos Optomap Panoramic 200A imaging system (Optos, PLC, Scotland) further widened the viewing field to 2008 [3]. The Optos Optomap Panoramic system uses a scanning laser ophthalmoscope technology with an ellipsoid mirror, forming a virtual scanning head within the patient’s eye, covering approximately 82% of the retina in a single image [1 ]. More recently, Heidelberg (Heidelberg Engineering, Germany) introduced a noncontact lens that attaches to the Heidelberg Spectralis and Retina Angiograph systems to allow ultra-wide-field photography and angiography. Ultra-wide-field fluorescein angiography (UWFA), first described in 2004 by Friberg and Forrester for the Optos, not only captures a wide field of retina at once, allowing visualization of many different areas of the retina at the same timepoint during angiography and reducing the amount &
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Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA Correspondence to Szilard Kiss, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY 10021, USA. Tel: +1 646-962-2020; fax: +1 646-962-0602; e-mail: [email protected] Curr Opin Ophthalmol 2014, 25:213–220 DOI:10.1097/ICU.0000000000000042
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KEY POINTS Ultra-wide-field fluorescein angiography (UWFA) captures up to 2008 of retina in a single image and has been shown to image up to twice as much retinal area as conventional fluorescein angiography. UWFA has been shown to demonstrate abnormality in a variety of retinal conditions, including diabetic retinopathy, retinal vein occlusion, sickle cell retinopathy, uveitis, and pediatric retinal disease. Early studies suggest that findings on UWFA, compared with examination and standard fluorescein angiography, have the potential to significantly alter the management of these conditions. As UWFA becomes increasingly incorporated into the practice of retina, further studies will be necessary to reconcile the findings from UWFA with practice guidelines based on the studies conducted prior to the development of UWFA.
of patient cooperation and technical expertise required for photography, but also visualizes the peripheral retina that was previously not photographed [4]. Compared with conventional digital acquisition systems, UWFA using the Optos system captures twice as much retina area [5]. A comparison of UWFA with the Optos system versus the Heidelberg noncontact system demonstrated that the Optos captured a significant wider total retinal area, especially nasally and temporally. The Heidelberg system imaged slightly more area superiorly and inferiorly, though this was not statistically significant. The Optos, however, exhibited more peripheral distortion as well as greater variability in image quality, due largely to lid and lash artifacts. Overall, both systems offered a dramatic improvement over traditional noncontact imaging systems in the area of retina imaged, with more retinal area photographed by the Optos, albeit at the expense of image quality [6]. Approximately 5–10% of Optos UWFA has been found to be of poor quality or ungradable in several studies of different retinal conditions [7–9]. In almost a decade since its conception, UWFA has demonstrated great utility in the diagnosis and management of a range of retinal conditions. Here, we review the applications of UWFA in a range of retinal conditions, including diabetic retinopathy, vein occlusion, uveitis, and pediatric retinal disease (Table 1 [5,8,9,10 ,11–15,16 ,17 ,18,19]). &&
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DIABETIC RETINOPATHY Fluorescein angiography is integral to the management of diabetic retinopathy, in which it can reveal 214
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microaneurysms, nonperfusion, macular edema, and neovascularization. As much of the abnormality in diabetic retinopathy, especially nonperfusion, can occur in the midperiphery and periphery [20], ultra-wide-field imaging may be particularly useful in the evaluation of this condition. By overlaying a 7SF template on the UWFA of 218 eyes with diabetic retinopathy, Wessel et al. [10 ] found that UWFA showed 3.2 times the amount of retinal area, 3.9 times the amount of retinal nonperfusion, 1.9 times the area of neovascularization, and 3.8 times the area of panretinal photocoagulation (PRP), compared with the simulated 7SF image. A prior study looking at a smaller number of patients with diabetic retinopathy similarly showed that UWFA imaged significantly more retinal area and revealed more ischemia than fluorescein angiography using conventional digital acquisition systems [5]. Figure 1 is a representative UWFA of a 36-year-old patient with diabetic retinopathy and prior PRP who on UWFA was noted to have a large frond of neovascularization superiorly, smaller neovascular fronds inferiorly, and a wide swath of peripheral ischemic retina temporally OS, only part of which had previous laser treatment. Almost all of this abnormality – except for a small area of neovascularization at the posterior edge of the frond superiorly – was located outside the 7SF (Fig. 1a and b). On the basis of UWFA, this patient underwent targeted PRP to the untreated inferotemporal and partially treated superotemporal areas of peripheral ischemia OS noted on UWFA, with regression of the neovascularization (Fig. 1c and d). A small but significant proportion of patients (10%) in the study by Wessel et al. [10 ] had normal simulated 7SF fluorescein angiography with positive findings on UWFA, suggesting that UWFA may allow us to diagnose patients previously missed by standard fluorescein angiography. As the study was a retrospective review of all patients who had underwent UWFA imaging, there may be a selection bias for patients more likely to exhibit peripheral abnormality, such that the true rate of missing abnormality with standard imaging may be lower in practice. Nevertheless, the study highlighted that UWFA demonstrates more abnormality than 7SF imaging, and that the added retina visualized with UWFA can significantly change the qualitative assessment of the degree of retinopathy. The study suggested that UWFA expands our view of the periphery without significantly compromising the imaging of central abnormality, as only 5.4% of patients with clinically significant macular edema exhibited no macular edema on UWFA [10 ]. Prior studies suggest that midperipheral nonperfusion, as noted on standard fluorescein &&
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CRVO
Sickle cell disease
Uveitic conditions: sarcoidosis, pars planitis
Uveitic conditions: lupus vasculitis, CMV retinitis, idiopathic intermediate uveitis, acute multifocal placoid posterior pigment epitheliopathy
Noninfectious uveitis
Noninfectious retinal vasculitis
Tsui et al. [12]
Cho et al. [13]
Tsui et al. [14]
Kaines et al. [15]
Campbell et al. [16 ]
Leder et al. [17 ]
1040-8738 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins UWFA can reveal abnormality in lupus vasculitis, CMV retinitis, idiopathic intermediate uveitis, acute multifocal placoid posterior pigment epitheliopathy
UWFA captures phlebitis and macular edema in patients with sarcoidosis and pars planitis
UWFA images abnormality in sickle cell retinopathy well, and captured the abnormality missed on examination and simulated 7SF photographs
Leakage on UWFA correlated to edema on OCT and abnormalities in the foveal avascular zone on UWFA correlated to atrophy on OCT
Targeted PRP to areas of ischemia on UWFA can cause NV regression
UWFA shows more retinal area, nonperfusion, NV, and PRP compared with simulated 7SF FA imaging; in 10% of cases, UWFA captured abnormality in which 7SF imaging is normal
Untreated peripheral nonperfusion on UWFA is associated with macular edema and NV
Peripheral nonperfusion on UWFA is associated with NV and macular ischemia, but not macular edema. Late peripheral vascular leakage on UWFA was associated with nonperfusion and NV
UWFA shows more retinal area and reveals more ischemia compared with conventional FA, though image quality was better with standard systems
Major findings
Pediatric retinal diseases (FEVR and Coats’ disease)
Kang et al. [19]
UWFA can aid the diagnosis and management of FEVR and Coats’ disease in children, and can enable UWFA-guided targeted PRP
UWFA can be performed successfully in children (mean age 9.3, range 5–12 years), though earlier phases were less likely to be captured or to capture a wide field than later phases
7SF, seven standard fields; BRVO, branch retinal vein occlusion; CMV, cytomegalovirus; CRVO, central retinal vein occlusion; FA, fluorescein angiography; FEVR, familial exudative vitreoretinopathy; HRVO, hemiretinal vein occlusion; NV, neovascularization; OCT, optical coherence tomography; PRP, panretinal photocoagulation; UWFA, ultra-wide-field fluorescein angiography.
Retrospective case series study
Pediatric retinal disease Retrospective case (uveitis, Coats’ disease, series study retinopathy of prematurity, X-linked retinoschisis, Best’s disease, Stargardt disease, inactive toxoplasmosis, history of intraocular foreign body, retinal detachment, and choroidal melanoma)
Prospective observational UWFA changes the assessment of disease activity, compared with examination case series study and examination and simulated standard FA); UWFA changes the management compared with examination and examination and simulated standard FA
Prospective observational UWFA changes the assessment of disease activity, compared with examination case series study (but not compared with examination and simulated standard FA); UWFA changes the management compared with examination and examination and simulated standard FA
Case series
Case series
Retrospective case series study
Retrospective case series study
Case series
Tsui et al. [18]
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Diabetic retinopathy
Reddy et al. [11]
Retrospective case series study
Diabetic retinopathy
Wessel et al. [10 ]
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Retrospective case series study
BRVO, HRVO
Prasad et al. [9]
Prospective study Retrospective case series study
Diabetic retinopathy
Friberg et al. [5]
Study type
Oliver and Schwartz [8] Diabetic retinopathy
Diseases
Study
Table 1. Literature on ultra-wide-field fluorescein angiography and major findings
Retinal disease Patel and Kiss
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(a)
34s
(b)
6m 7s
(c)
27s
(d)
3min 11s
FIGURE 1. UWFA in diabetic retinopathy. UWFA in a patient with a history of proliferative diabetic retinopathy status after panretinal photocoagulation revealed a large superotemporal neovascular frond as well as smaller neovascular fronds OS, which were not well captured on simulated seven standard fields fluorescein angiography (red circles, a and b). There was also a large area of ischemia temporally, only partially treated superotemporally and untreated inferotemporally (a and b). After targeted photocoagulation in this area of ischemia, regression of the neovascularization was noted (c and d). UWFA, ultra-wide-field fluorescein angiography.
angiography, is associated with neovascularization [21]. This is consistent with our current conception that hypoxia generates vascular endothelial growth factor and other substances that stimulate neovascularization and edema. More recently, Oliver and Schwartz[8] demonstrated that peripheral nonperfusion, which was present in 54% of diabetic retinopathy cases imaged by UWFA, was associated with increased risk of neovascularization, including neovascularization anterior to the equator and neovascularization posterior to the equator. Peripheral nonperfusion on UWFA was also associated with macular ischemia, though not macular edema. The group also noted a finding of late peripheral vascular leakage, which was associated both with peripheral nonperfusion and with neovascularization, especially posterior neovascularization. Given that UWFA better demonstrates peripheral nonperfusion than standard fluorescein angiography [11] and that this finding, as well as the newer finding of peripheral vascular leakage, correlates to visually significant and treatable complications such as neovascularization [8], UWFA has 216
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the potential to significantly impact the clinical management. UWFA may be useful in identifying patients who have not yet developed neovascularization or macular edema but are at increased risk to do so, based on the presence of extensive peripheral nonperfusion or vascular leakage. These patients may, in turn, warrant more frequent follow-up than might have been recommended using traditional fluorescein angiography imaging modalities. UWFA may also directly guide the treatment of patients undergoing PRP. The Diabetic Retinopathy Study (DRS) showed that 10% of patients suffer a decrease in vision after PRP and 5% develop constriction of their visual field. Complications of PRP included macular edema, hemorrhage, choroidal detachment, angle closure glaucoma, and decrease in color vision and contrast [22]. By targeting PRP directly to the areas of ischemia, rather than broadly throughout the retina, we may be able to spare healthy retinal tissue and reduce the side-effects of PRP, while directly treating those areas most likely contributing to the hypoxic drive. A case series of UWFA-guided targeted PRP in proliferative diabetic Volume 25 Number 3 May 2014
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retinopathy described successful regression of neovascularization and no adverse effects [11]. Diabetic retinopathy remains one of the most evidence-guided diseases in the field of retina. As such, it is important to note that seminal studies in diabetic retinopathy such as the DRS and the Early Treatment of Diabetic Retinopathy Study (ETDRS) were conducted well before the advent of UWFA. This raises important questions regarding how and when we can apply older studies toward the management of patients in an age where we are able to visualize and image far more retinal abnormality than was previously possible. For example, PRP is generally not indicated for patients with retinopathy in the absence of neovascularization. However, our newfound ability to visualize specific areas of peripheral nonperfusion as well as to apply targeted PRP through UWFA may shift the scales regarding the risk–benefit ratio of prophylactic PRP prior to the development of neovascularization or macular edema; this remains to be investigated. Moreover, as ischemia likely drives macular edema, targeted PRP to areas of peripheral nonperfusion may also prove useful as an adjunctive therapy for macular edema; studies investigating this modality are currently underway. In general, studies comparing targeted PRP to true ‘pan-retinal’ photocoagulation are necessary.
In vein occlusions, it appears that UWFA expands our ability to image the periphery without compromising imaging of central abnormality. In a study of 68 patients with CRVO with UWFA, macular edema on UWFA correlated to edema on optical coherence tomography (OCT), and there were no cases in which edema was noted on OCT but not on UWFA. Moreover, nine patients exhibited edema on UWFA but not on OCT, suggesting that UWFA may capture early edema before it is visible on OCT. Abnormalities in the foveal avascular zone on UWFA suggestive of ischemia also correlated with ganglion cell layer atrophy on OCT [12].
RETINAL VEIN OCCLUSION
UVEITIS
Retinal vein occlusion, which shares several features with diabetic retinopathy including its vascular basis and the development of complications such as nonperfusion, macular edema, and neovascularization, has also shown promise in UWFA [9,12]. A retrospective study by Prasad et al. [9] examining all UWFA for patients with branch retinal vein occlusion or hemiretinal vein occlusion demonstrated that untreated peripheral nonperfusion on UWFA was associated with both macular edema and neovascularization. Macular edema was specifically associated with untreated peripheral nonperfusion anterior to the equator, but not to untreated nonperfusion posterior to the equator – that is, that which is captured by standard fluorescein angiography. Thus, as in diabetic retinopathy, findings of peripheral nonperfusion on UWFA have clinical relevance and may prompt closer follow-up for complications in patients who do not yet exhibit neovascularization or macular edema. Moreover, as with diabetic retinopathy, areas of peripheral ischemia may generate VEGF and other factors that promote macular edema. As such, targeted PRP treatment of peripheral nonperfusion may be a useful adjunct in the management of macular edema. This remains to be demonstrated in clinical trials.
UWFA has been demonstrated in a case series to facilitate the documentation, diagnosis, and management of uveitis [14,15], offering evidence of activity not visible clinically and in some cases, enabling targeted PRP to areas of nonperfusion or neovascularization [15]. In a prospective study of 43 patients with noninfectious posterior uveitis, Campbell et al. [16 ] employed a questionnaire to determine how simulated 308 or 608 fluorescein angiography or UWFA changed the clinician’s assessment of disease activity or management. Leder et al. [17 ] performed a similar study for 23 patients with retinal vasculitis. Campbell et al. [16 ] report that UWFA changed the assessment of disease activity compared with examination, but not compared to examination and standard fluorescein angiography. Leder et al. [17 ] found that disease activity was more commonly noted with UWFA compared with examination and examination with standard fluorescein angiography. Both studies found that UWFA changed the management compared with examination and examination with standard fluorescein angiography [16 ,17 ]. These studies suggest the value of UWFA over standard fluorescein angiography in determining
SICKLE CELL RETINOPATHY Sickle cell retinopathy is a vascular disease exhibiting abnormality in the retinal periphery. As such, it, too, may be particularly amenable to UWFA. A retrospective review of 12 eyes of 6 patients with sickle cell retinopathy demonstrated a role for UWFA in both diagnosis and management. In 25% of eyes, UWFA revealed peripheral vascular findings not identified by the trainee or attending on clinical exam. In all except one eye with macular ischemia, simulated 7SF fluorescein angiography did not capture the abnormality seen on UWFA [13].
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the disease activity and management in patients with posterior uveitis [16 ] and posterior vasculitis [17 ]. As the entire UWFA imaging was visible when the graders were asked to look only at the more central, simulated standard fluorescein angiography [16 ,17 ], there may have been bias in the interpretation of the standard fluorescein angiography. If so, the true value of UWFA imaging may be even greater than that suggested by these studies. Figure 2 is representative of the utility of UWFA in the management of patients with uveitis. This patient was a 32-year-old woman who presented with decreased vision in the left eye. Visual acuities were 20/20 OD and count fingers OS. Examination was unremarkable OD and revealed disc hyperemia, &&
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cystoid macular edema, and vasculitis OS. UWFA OS revealed disc leakage and marked vasculitis (Fig. 2a and b). Systemic therapy was considered, but because of her normal UWFA OD (Fig. 2c) and lack of systemic manifestations, she instead underwent implantation of a 0.7 mg dexamethasone implant (Ozurdex, Allergan Inc.) OS, with subsequent improvement in the vasculitis on UWFA (Fig. 2d and e). Vision also improved to 20/40 OS. Four months later, UWFA revealed leakage consistent with secondary retinal neovascularization OS (Fig. 2f and g). She underwent a second 0.7 mg dexamethasone implant placement, followed by intravitreal administration of 1.25 mg bevacizumab, and then sector PRP OS. UWFA 1 month after laser
(a)
20s
(b)
3m
(c)
5m 3s
(d)
22s
(e)
3m 11s
(f)
18s
(g)
2m 57s
(h)
27s
(i)
3m 8s
FIGURE 2. UWFA in uveitis. UWFA in a patient with decreased vision in the left eye revealed disc leakage and significant vasculitis OS (a and b), with normal UWFA OD (c). After implantation of a 0.7 mg dexamethasone implant (Ozurdex, Allergan Inc.) OS, there was improvement in the vasculitis on UWFA (d and e). Four months later, UWFA revealed leakage consistent with secondary retinal neovascularization OS (f and g). After placement of a second 0.7 mg dexamethasone implant placement, intravitreal bevacizumab 1.25 mg, and sector panretinal photocoagulation, UWFA revealed continued improvement of vasculitis and regression of the neovascularization OS (h and i). UWFA, ultra-wide-field fluorescein angiography. 218
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revealed continued improvement of vasculitis and regression of the neovascularization OS (Fig. 2h and i). Her visual acuity continued to improve, eventually reaching 20/25þ OS.
PEDIATRIC CONDITIONS Children pose a unique challenge to imaging. Imaging in children is usually accomplished through the RetCam technology, with very young infants swaddled and older children examined under anesthesia. Standard imaging in the office requires significant compliance from the patient, especially if the abnormality is peripheral and requires the patient to direct their gaze in the necessary directions. UWFA offers advantages over standard imaging in that it captures a broad area of retina with less cooperation required from the patient. In a retrospective review of 16 patients under age 12 years undergoing UWFA imaging in one practice, Tsui et al. [18] noted an average age of 9.3 years, with the youngest child being 5 years old. The study found that imaging of the choroidal phase was difficult, with only 1 of 16 patients having photos from this phase, whereas venous and recirculation and late phases were imaged in all patients. Similarly, 2.9 quadrants were imaged in the arterial phase versus 3.6 in the late phases. The difficulty in adequately imaging the earlier phases was felt to be related to the time it takes to console the patient after intravenous injection and reposition the head. UWFA may, therefore, be limited in children if visualization of early phases is critical for diagnosis. However, cases in which later phases are sufficient may derive great utility from UWFA, allowing the patient to potentially avert a trip to the operating room for examination under anesthesia. To date, UWFA has been demonstrated to be useful in the diagnosis and management of pediatric patients with uveitis (pars planitis), Coats’ disease, ROP, schisis, Stargardt’s disease, Best disease, history of IOFB, inactive toxoplasmosis, melanoma, and familial exudative vitreoretinopathy (FEVR) [18,19]. In some cases, simulated 7SF missed the abnormality visible by UWFA in these pediatric patients. In addition, UWFA-guided PRP produced improvement in subretinal and intraretinal fluid exudation in Coat’s disease and regression of neovascularization in FEVR [19].
CONCLUSION Having already demonstrated utility in retinal vascular disease, uveitis, and pediatric retinal condition, UWFA possesses great potential for the diagnosis and management of retinal conditions
(Table 1). As UWFA has expanded our ability to angiographically evaluate the far periphery of the retina, we are identifying abnormality more frequently and earlier than we previously did. This is, in turn, changing our conception of the disease processes and how best to diagnosis, follow, and treat them. With these gains, however, also comes the challenge of how to apply the findings on UWFA toward clinical practice. Diabetic retinopathy, for example, remains one of the most evidence-driven diseases in the field of retina. Much of the studies regarding the risks for vision loss or progression as well as response to therapy were established in seminal trials such as DRS and ETDRS, which were based on clinical examination and 7SF imaging. As our ability to examine the far periphery angiographically has grown, it is becoming increasingly difficult to apply data from the prior studies to the current management. UWFA has led to many questions: Is targeted PRP more effective than conventional PRP? Can prophylactic PRP to areas of ischemia reduce the risk of macular edema and neovascularization? Is targeted PRP to areas of ischemia an effective adjunct therapy for the treatment of macular edema? The use of UWFA in vein occlusions raises similar questions. For example, if targeted photocoagulation was applied directly to the areas of ischemia rather than via in a panretinal fashion in the Central Vein Occlusion Study, would there still have been no benefit to prophylactic PRP? More generally, how do we better categorize vein occlusions, now that the disc area of nonperfusion criteria used in the Central Vein Occlusion and Branch Vein Occlusion Studies are rendered obsolete by UWFA, which markedly increases the amount of angiographic nonperfusion visible overall. As with diabetic retinopathy, might there be a role for targeted PRP as adjunctive therapy for macular edema? As we increasingly turn to UWFA to diagnose and manage the retinal conditions, we will likewise have to increasingly reconcile the practice guidelines based on the older studies with the arsenal of new information now available through UWFA. Further clinical trials will be necessary to incorporate UWFA into evidence-based practice guidelines for the diagnosis and management of retinal disease. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Witmer MT, Kiss S. Wide-field imaging of the retina. Surv Ophthalmol 2013; & 58:143–154. This study is a review of wide-field imaging, including fundus photography and fluorescein angiography. It provides a history of wide-field imaging, imaging capabilities of various systems, and clinical applications. 2. Staurenghi G, Viola F, Mainster MA, et al. Scanning laser ophthalmoscopy and angiography with a wide-field contact lens system. Arch Ophthalmol 2005; 123:244–252. 3. Manivannan A, Plskova J, Farrow A, et al. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol 2005; 140:525–527. 4. Fiberg TR, Forrester JV. Ultrawide angle (200þ) fluorescein angiography using a modified Optos Panoramic200TM Imaging System. Invest Ophthalmol Vis Sci 2004; 45:; ARVO E-Abstract 3001. 5. Friberg TR, Gupta A, Yu J, et al. Ultrawide angle fluorescein angiographic imaging: a comparison to conventional digital acquisition systems. Ophthalmic Surg Lasers Imaging 2008; 39:304–311. 6. Witmer MT, Parlitsis G, Patel S, et al. Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis noncontact ultra-widefield module versus the Optos Optomap. Clin Ophthalmol 2013; 7:389–394. 7. Neubauer AS, Kernt M, Haritoglou C, et al. Nonmydriatic screening for diabetic retinopathy by ultra-widefield scanning laser ophthalmoscopy (Optomap). Graefes Arch Clin Exp Ophthalmol 2008; 246:229–235. 8. Oliver SCN, Schwartz SD. Peripheral vessel leakage (PVL): a new angiographic finding in diabetic retinopathy identified with ultra wide-field fluorescein angiography. Semin Ophthalmol 2010; 25:27–33. 9. Prasad PS, Oliver SCN, Coffee RE, et al. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology 2010; 117:780–784. 10. Wessel MW, Aaker GD, Parlitsis G, et al. Ultra-wide-field angiography && improves the detection and classification of diabetic retinopathy. Retina 2012; 32:785–791. This retrospective case series study evaluates the utility of UWFA in diabetic retinopathy, comparing it with simulated seven standard fields fluorescein angiography in ability to demonstrate various pathological changes of diabetic retinopathy.
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11. Reddy S, Shwartz SD. Ultra wide field fluorescein angiography guided targeted retinal photocoagulation. Semin Ophthalmol 2009; 29:9–14. 12. Tsui I, Franco-Cardenas V, Hubschman J-P, et al. Ultra wide field fluorescein angiography can detect macular pathology in central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2012; 43:257–262. 13. Cho M, Kiss S. Detection and monitoring of sickle cell retinopathy using ultra wide-field color photography and fluorescein angiography. Retina 2011; 31:738–747. 14. Tsui I, Kaines A, Schwartz S. Patterns of periphlebitis in intermediate uveitis using ultra wide field fluorescein angiography. Semin Ophthalmol 2009; 24:29–33. 15. Kaines A, Tsui I, Sarraf D, et al. The use of ultra wide field fluorescein angiography in evaluation and management of uveitis. Semin Ophthalmol 2009; 24:19–24. 16. Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the && management of noninfectious posterior uveitis. Am J Ophthalmol 2013; 154:908–911. This prospective case series study evaluates the utility of UWFA in noninfectious posterior uveitis to determine whether findings on UWFA, compared with examination or examination and simulated standard fluorescein angiography, changed the assessment of disease activity or management. 17. Leder HA, Campbell JP, Sepah YJ, et al. Ultra-wide-field retinal imaging in the && management of noninfectious retinal vasculitis. J Ophthalmic Inflamm Infect 2013; 3:1–6. This prospective case series study evaluates the utility of UWFA in noninfectious retinal vasculitis to determine whether findings on UWFA, compared with examination or examination and simulated standard fluorescein angiography, changed the assessment of disease activity or management. 18. Tsui I, Franco-Cardenas V, Hubschman J-P, et al. Pediatric retinal conditions imaged by ultra wide field fluorescein angiography. Ophthalmic Surg Lasers Imaging 2013; 44:59–67. 19. Kang KB, Wessel MM, Tong J, et al. Ultra-widefield imaging for the management of pediatric retinal diseases. J Pediatr Ophthalmol Strabismus 2013; 50:282–288. 20. Shimizu K, Kobayashi Y, Muraoka K. Mid-peripheral fundus involvement in diabetic retinopathy. Ophthalmology 1981; 88:601–612. 21. Shimizu K, Muraoka K. Diabetic retinopathy. Is it a maculopathy? A super-wide fluorescein angiographic evaluation. Dev Ophthalmol 1981; 2:235–242. 22. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981; 88:583–600.
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Ultra-wide-field fluorescein angiography in retinal disease Mrinali Patel and Szilard Kiss
Purpose of review Ultra-wide-field fluorescein angiography (UWFA), which captures up to 2008 of retina in a single image, now affords us the ability to angiographically examine the parts of the retina previously not photographable. Here, we review the role of UWFA in the management of retinal disease. Recent findings UWFA effectively images the abnormality in a variety of retinal conditions, including diabetic retinopathy, retinal vein occlusion, sickle cell retinopathy, uveitis, and pediatric retinal disease, in turn guiding both diagnosis and management of these conditions. Summary UWFA is a useful imaging modality that is expected to become increasingly incorporated into the practice of retina. This will likely fuel the studies to determine how to reconcile the findings from UWFA with practice guidelines based on the studies conducted prior to the development of UWFA. Keywords angiography, Optos, ultra-wide-field, wide-field
INTRODUCTION Since its introduction in the l960s, fluorescein angiography has been an essential tool in the diagnosis and management of retinal diseases, often offering insights into the presence, activity, and severity of disease not appreciable through clinical examination alone. As many retinal diseases manifest with peripheral abnormality, there has been an ever increasing pressure to better image the retinal periphery. Traditional fundus cameras offered a field of view ranging from 308 to 608 in one exposure. Examination of more peripheral retina required technical skill by the photographer as well as redirection of gaze by the patient, and even then, the far periphery was not imaged. The seven standard fields (7SF) imaging involved capturing seven photos in a montage comprising 758 of the retina, whereas other montaging techniques could portray up to 1408 at once [1 ]. Even so, the far periphery was not imaged. Moreover, these montage techniques posed certain constraints for fluorescein angiography in particular, as it is a time-sensitive test and different parts of the retina could not be imaged at one time. Wide-angle angiography with the use of contact lens, such as the Staurenghi lens, expanded the view to 150–1608 but was technically more challenging and required patient cooperation with the contact
lens system [2]. The Optos Optomap Panoramic 200A imaging system (Optos, PLC, Scotland) further widened the viewing field to 2008 [3]. The Optos Optomap Panoramic system uses a scanning laser ophthalmoscope technology with an ellipsoid mirror, forming a virtual scanning head within the patient’s eye, covering approximately 82% of the retina in a single image [1 ]. More recently, Heidelberg (Heidelberg Engineering, Germany) introduced a noncontact lens that attaches to the Heidelberg Spectralis and Retina Angiograph systems to allow ultra-wide-field photography and angiography. Ultra-wide-field fluorescein angiography (UWFA), first described in 2004 by Friberg and Forrester for the Optos, not only captures a wide field of retina at once, allowing visualization of many different areas of the retina at the same timepoint during angiography and reducing the amount &
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Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA Correspondence to Szilard Kiss, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY 10021, USA. Tel: +1 646-962-2020; fax: +1 646-962-0602; e-mail: [email protected] Curr Opin Ophthalmol 2014, 25:213–220 DOI:10.1097/ICU.0000000000000042
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KEY POINTS Ultra-wide-field fluorescein angiography (UWFA) captures up to 2008 of retina in a single image and has been shown to image up to twice as much retinal area as conventional fluorescein angiography. UWFA has been shown to demonstrate abnormality in a variety of retinal conditions, including diabetic retinopathy, retinal vein occlusion, sickle cell retinopathy, uveitis, and pediatric retinal disease. Early studies suggest that findings on UWFA, compared with examination and standard fluorescein angiography, have the potential to significantly alter the management of these conditions. As UWFA becomes increasingly incorporated into the practice of retina, further studies will be necessary to reconcile the findings from UWFA with practice guidelines based on the studies conducted prior to the development of UWFA.
of patient cooperation and technical expertise required for photography, but also visualizes the peripheral retina that was previously not photographed [4]. Compared with conventional digital acquisition systems, UWFA using the Optos system captures twice as much retina area [5]. A comparison of UWFA with the Optos system versus the Heidelberg noncontact system demonstrated that the Optos captured a significant wider total retinal area, especially nasally and temporally. The Heidelberg system imaged slightly more area superiorly and inferiorly, though this was not statistically significant. The Optos, however, exhibited more peripheral distortion as well as greater variability in image quality, due largely to lid and lash artifacts. Overall, both systems offered a dramatic improvement over traditional noncontact imaging systems in the area of retina imaged, with more retinal area photographed by the Optos, albeit at the expense of image quality [6]. Approximately 5–10% of Optos UWFA has been found to be of poor quality or ungradable in several studies of different retinal conditions [7–9]. In almost a decade since its conception, UWFA has demonstrated great utility in the diagnosis and management of a range of retinal conditions. Here, we review the applications of UWFA in a range of retinal conditions, including diabetic retinopathy, vein occlusion, uveitis, and pediatric retinal disease (Table 1 [5,8,9,10 ,11–15,16 ,17 ,18,19]). &&
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DIABETIC RETINOPATHY Fluorescein angiography is integral to the management of diabetic retinopathy, in which it can reveal 214
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microaneurysms, nonperfusion, macular edema, and neovascularization. As much of the abnormality in diabetic retinopathy, especially nonperfusion, can occur in the midperiphery and periphery [20], ultra-wide-field imaging may be particularly useful in the evaluation of this condition. By overlaying a 7SF template on the UWFA of 218 eyes with diabetic retinopathy, Wessel et al. [10 ] found that UWFA showed 3.2 times the amount of retinal area, 3.9 times the amount of retinal nonperfusion, 1.9 times the area of neovascularization, and 3.8 times the area of panretinal photocoagulation (PRP), compared with the simulated 7SF image. A prior study looking at a smaller number of patients with diabetic retinopathy similarly showed that UWFA imaged significantly more retinal area and revealed more ischemia than fluorescein angiography using conventional digital acquisition systems [5]. Figure 1 is a representative UWFA of a 36-year-old patient with diabetic retinopathy and prior PRP who on UWFA was noted to have a large frond of neovascularization superiorly, smaller neovascular fronds inferiorly, and a wide swath of peripheral ischemic retina temporally OS, only part of which had previous laser treatment. Almost all of this abnormality – except for a small area of neovascularization at the posterior edge of the frond superiorly – was located outside the 7SF (Fig. 1a and b). On the basis of UWFA, this patient underwent targeted PRP to the untreated inferotemporal and partially treated superotemporal areas of peripheral ischemia OS noted on UWFA, with regression of the neovascularization (Fig. 1c and d). A small but significant proportion of patients (10%) in the study by Wessel et al. [10 ] had normal simulated 7SF fluorescein angiography with positive findings on UWFA, suggesting that UWFA may allow us to diagnose patients previously missed by standard fluorescein angiography. As the study was a retrospective review of all patients who had underwent UWFA imaging, there may be a selection bias for patients more likely to exhibit peripheral abnormality, such that the true rate of missing abnormality with standard imaging may be lower in practice. Nevertheless, the study highlighted that UWFA demonstrates more abnormality than 7SF imaging, and that the added retina visualized with UWFA can significantly change the qualitative assessment of the degree of retinopathy. The study suggested that UWFA expands our view of the periphery without significantly compromising the imaging of central abnormality, as only 5.4% of patients with clinically significant macular edema exhibited no macular edema on UWFA [10 ]. Prior studies suggest that midperipheral nonperfusion, as noted on standard fluorescein &&
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CRVO
Sickle cell disease
Uveitic conditions: sarcoidosis, pars planitis
Uveitic conditions: lupus vasculitis, CMV retinitis, idiopathic intermediate uveitis, acute multifocal placoid posterior pigment epitheliopathy
Noninfectious uveitis
Noninfectious retinal vasculitis
Tsui et al. [12]
Cho et al. [13]
Tsui et al. [14]
Kaines et al. [15]
Campbell et al. [16 ]
Leder et al. [17 ]
1040-8738 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins UWFA can reveal abnormality in lupus vasculitis, CMV retinitis, idiopathic intermediate uveitis, acute multifocal placoid posterior pigment epitheliopathy
UWFA captures phlebitis and macular edema in patients with sarcoidosis and pars planitis
UWFA images abnormality in sickle cell retinopathy well, and captured the abnormality missed on examination and simulated 7SF photographs
Leakage on UWFA correlated to edema on OCT and abnormalities in the foveal avascular zone on UWFA correlated to atrophy on OCT
Targeted PRP to areas of ischemia on UWFA can cause NV regression
UWFA shows more retinal area, nonperfusion, NV, and PRP compared with simulated 7SF FA imaging; in 10% of cases, UWFA captured abnormality in which 7SF imaging is normal
Untreated peripheral nonperfusion on UWFA is associated with macular edema and NV
Peripheral nonperfusion on UWFA is associated with NV and macular ischemia, but not macular edema. Late peripheral vascular leakage on UWFA was associated with nonperfusion and NV
UWFA shows more retinal area and reveals more ischemia compared with conventional FA, though image quality was better with standard systems
Major findings
Pediatric retinal diseases (FEVR and Coats’ disease)
Kang et al. [19]
UWFA can aid the diagnosis and management of FEVR and Coats’ disease in children, and can enable UWFA-guided targeted PRP
UWFA can be performed successfully in children (mean age 9.3, range 5–12 years), though earlier phases were less likely to be captured or to capture a wide field than later phases
7SF, seven standard fields; BRVO, branch retinal vein occlusion; CMV, cytomegalovirus; CRVO, central retinal vein occlusion; FA, fluorescein angiography; FEVR, familial exudative vitreoretinopathy; HRVO, hemiretinal vein occlusion; NV, neovascularization; OCT, optical coherence tomography; PRP, panretinal photocoagulation; UWFA, ultra-wide-field fluorescein angiography.
Retrospective case series study
Pediatric retinal disease Retrospective case (uveitis, Coats’ disease, series study retinopathy of prematurity, X-linked retinoschisis, Best’s disease, Stargardt disease, inactive toxoplasmosis, history of intraocular foreign body, retinal detachment, and choroidal melanoma)
Prospective observational UWFA changes the assessment of disease activity, compared with examination case series study and examination and simulated standard FA); UWFA changes the management compared with examination and examination and simulated standard FA
Prospective observational UWFA changes the assessment of disease activity, compared with examination case series study (but not compared with examination and simulated standard FA); UWFA changes the management compared with examination and examination and simulated standard FA
Case series
Case series
Retrospective case series study
Retrospective case series study
Case series
Tsui et al. [18]
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Diabetic retinopathy
Reddy et al. [11]
Retrospective case series study
Diabetic retinopathy
Wessel et al. [10 ]
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Retrospective case series study
BRVO, HRVO
Prasad et al. [9]
Prospective study Retrospective case series study
Diabetic retinopathy
Friberg et al. [5]
Study type
Oliver and Schwartz [8] Diabetic retinopathy
Diseases
Study
Table 1. Literature on ultra-wide-field fluorescein angiography and major findings
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(a)
34s
(b)
6m 7s
(c)
27s
(d)
3min 11s
FIGURE 1. UWFA in diabetic retinopathy. UWFA in a patient with a history of proliferative diabetic retinopathy status after panretinal photocoagulation revealed a large superotemporal neovascular frond as well as smaller neovascular fronds OS, which were not well captured on simulated seven standard fields fluorescein angiography (red circles, a and b). There was also a large area of ischemia temporally, only partially treated superotemporally and untreated inferotemporally (a and b). After targeted photocoagulation in this area of ischemia, regression of the neovascularization was noted (c and d). UWFA, ultra-wide-field fluorescein angiography.
angiography, is associated with neovascularization [21]. This is consistent with our current conception that hypoxia generates vascular endothelial growth factor and other substances that stimulate neovascularization and edema. More recently, Oliver and Schwartz[8] demonstrated that peripheral nonperfusion, which was present in 54% of diabetic retinopathy cases imaged by UWFA, was associated with increased risk of neovascularization, including neovascularization anterior to the equator and neovascularization posterior to the equator. Peripheral nonperfusion on UWFA was also associated with macular ischemia, though not macular edema. The group also noted a finding of late peripheral vascular leakage, which was associated both with peripheral nonperfusion and with neovascularization, especially posterior neovascularization. Given that UWFA better demonstrates peripheral nonperfusion than standard fluorescein angiography [11] and that this finding, as well as the newer finding of peripheral vascular leakage, correlates to visually significant and treatable complications such as neovascularization [8], UWFA has 216
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the potential to significantly impact the clinical management. UWFA may be useful in identifying patients who have not yet developed neovascularization or macular edema but are at increased risk to do so, based on the presence of extensive peripheral nonperfusion or vascular leakage. These patients may, in turn, warrant more frequent follow-up than might have been recommended using traditional fluorescein angiography imaging modalities. UWFA may also directly guide the treatment of patients undergoing PRP. The Diabetic Retinopathy Study (DRS) showed that 10% of patients suffer a decrease in vision after PRP and 5% develop constriction of their visual field. Complications of PRP included macular edema, hemorrhage, choroidal detachment, angle closure glaucoma, and decrease in color vision and contrast [22]. By targeting PRP directly to the areas of ischemia, rather than broadly throughout the retina, we may be able to spare healthy retinal tissue and reduce the side-effects of PRP, while directly treating those areas most likely contributing to the hypoxic drive. A case series of UWFA-guided targeted PRP in proliferative diabetic Volume 25 Number 3 May 2014
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retinopathy described successful regression of neovascularization and no adverse effects [11]. Diabetic retinopathy remains one of the most evidence-guided diseases in the field of retina. As such, it is important to note that seminal studies in diabetic retinopathy such as the DRS and the Early Treatment of Diabetic Retinopathy Study (ETDRS) were conducted well before the advent of UWFA. This raises important questions regarding how and when we can apply older studies toward the management of patients in an age where we are able to visualize and image far more retinal abnormality than was previously possible. For example, PRP is generally not indicated for patients with retinopathy in the absence of neovascularization. However, our newfound ability to visualize specific areas of peripheral nonperfusion as well as to apply targeted PRP through UWFA may shift the scales regarding the risk–benefit ratio of prophylactic PRP prior to the development of neovascularization or macular edema; this remains to be investigated. Moreover, as ischemia likely drives macular edema, targeted PRP to areas of peripheral nonperfusion may also prove useful as an adjunctive therapy for macular edema; studies investigating this modality are currently underway. In general, studies comparing targeted PRP to true ‘pan-retinal’ photocoagulation are necessary.
In vein occlusions, it appears that UWFA expands our ability to image the periphery without compromising imaging of central abnormality. In a study of 68 patients with CRVO with UWFA, macular edema on UWFA correlated to edema on optical coherence tomography (OCT), and there were no cases in which edema was noted on OCT but not on UWFA. Moreover, nine patients exhibited edema on UWFA but not on OCT, suggesting that UWFA may capture early edema before it is visible on OCT. Abnormalities in the foveal avascular zone on UWFA suggestive of ischemia also correlated with ganglion cell layer atrophy on OCT [12].
RETINAL VEIN OCCLUSION
UVEITIS
Retinal vein occlusion, which shares several features with diabetic retinopathy including its vascular basis and the development of complications such as nonperfusion, macular edema, and neovascularization, has also shown promise in UWFA [9,12]. A retrospective study by Prasad et al. [9] examining all UWFA for patients with branch retinal vein occlusion or hemiretinal vein occlusion demonstrated that untreated peripheral nonperfusion on UWFA was associated with both macular edema and neovascularization. Macular edema was specifically associated with untreated peripheral nonperfusion anterior to the equator, but not to untreated nonperfusion posterior to the equator – that is, that which is captured by standard fluorescein angiography. Thus, as in diabetic retinopathy, findings of peripheral nonperfusion on UWFA have clinical relevance and may prompt closer follow-up for complications in patients who do not yet exhibit neovascularization or macular edema. Moreover, as with diabetic retinopathy, areas of peripheral ischemia may generate VEGF and other factors that promote macular edema. As such, targeted PRP treatment of peripheral nonperfusion may be a useful adjunct in the management of macular edema. This remains to be demonstrated in clinical trials.
UWFA has been demonstrated in a case series to facilitate the documentation, diagnosis, and management of uveitis [14,15], offering evidence of activity not visible clinically and in some cases, enabling targeted PRP to areas of nonperfusion or neovascularization [15]. In a prospective study of 43 patients with noninfectious posterior uveitis, Campbell et al. [16 ] employed a questionnaire to determine how simulated 308 or 608 fluorescein angiography or UWFA changed the clinician’s assessment of disease activity or management. Leder et al. [17 ] performed a similar study for 23 patients with retinal vasculitis. Campbell et al. [16 ] report that UWFA changed the assessment of disease activity compared with examination, but not compared to examination and standard fluorescein angiography. Leder et al. [17 ] found that disease activity was more commonly noted with UWFA compared with examination and examination with standard fluorescein angiography. Both studies found that UWFA changed the management compared with examination and examination with standard fluorescein angiography [16 ,17 ]. These studies suggest the value of UWFA over standard fluorescein angiography in determining
SICKLE CELL RETINOPATHY Sickle cell retinopathy is a vascular disease exhibiting abnormality in the retinal periphery. As such, it, too, may be particularly amenable to UWFA. A retrospective review of 12 eyes of 6 patients with sickle cell retinopathy demonstrated a role for UWFA in both diagnosis and management. In 25% of eyes, UWFA revealed peripheral vascular findings not identified by the trainee or attending on clinical exam. In all except one eye with macular ischemia, simulated 7SF fluorescein angiography did not capture the abnormality seen on UWFA [13].
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the disease activity and management in patients with posterior uveitis [16 ] and posterior vasculitis [17 ]. As the entire UWFA imaging was visible when the graders were asked to look only at the more central, simulated standard fluorescein angiography [16 ,17 ], there may have been bias in the interpretation of the standard fluorescein angiography. If so, the true value of UWFA imaging may be even greater than that suggested by these studies. Figure 2 is representative of the utility of UWFA in the management of patients with uveitis. This patient was a 32-year-old woman who presented with decreased vision in the left eye. Visual acuities were 20/20 OD and count fingers OS. Examination was unremarkable OD and revealed disc hyperemia, &&
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cystoid macular edema, and vasculitis OS. UWFA OS revealed disc leakage and marked vasculitis (Fig. 2a and b). Systemic therapy was considered, but because of her normal UWFA OD (Fig. 2c) and lack of systemic manifestations, she instead underwent implantation of a 0.7 mg dexamethasone implant (Ozurdex, Allergan Inc.) OS, with subsequent improvement in the vasculitis on UWFA (Fig. 2d and e). Vision also improved to 20/40 OS. Four months later, UWFA revealed leakage consistent with secondary retinal neovascularization OS (Fig. 2f and g). She underwent a second 0.7 mg dexamethasone implant placement, followed by intravitreal administration of 1.25 mg bevacizumab, and then sector PRP OS. UWFA 1 month after laser
(a)
20s
(b)
3m
(c)
5m 3s
(d)
22s
(e)
3m 11s
(f)
18s
(g)
2m 57s
(h)
27s
(i)
3m 8s
FIGURE 2. UWFA in uveitis. UWFA in a patient with decreased vision in the left eye revealed disc leakage and significant vasculitis OS (a and b), with normal UWFA OD (c). After implantation of a 0.7 mg dexamethasone implant (Ozurdex, Allergan Inc.) OS, there was improvement in the vasculitis on UWFA (d and e). Four months later, UWFA revealed leakage consistent with secondary retinal neovascularization OS (f and g). After placement of a second 0.7 mg dexamethasone implant placement, intravitreal bevacizumab 1.25 mg, and sector panretinal photocoagulation, UWFA revealed continued improvement of vasculitis and regression of the neovascularization OS (h and i). UWFA, ultra-wide-field fluorescein angiography. 218
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revealed continued improvement of vasculitis and regression of the neovascularization OS (Fig. 2h and i). Her visual acuity continued to improve, eventually reaching 20/25þ OS.
PEDIATRIC CONDITIONS Children pose a unique challenge to imaging. Imaging in children is usually accomplished through the RetCam technology, with very young infants swaddled and older children examined under anesthesia. Standard imaging in the office requires significant compliance from the patient, especially if the abnormality is peripheral and requires the patient to direct their gaze in the necessary directions. UWFA offers advantages over standard imaging in that it captures a broad area of retina with less cooperation required from the patient. In a retrospective review of 16 patients under age 12 years undergoing UWFA imaging in one practice, Tsui et al. [18] noted an average age of 9.3 years, with the youngest child being 5 years old. The study found that imaging of the choroidal phase was difficult, with only 1 of 16 patients having photos from this phase, whereas venous and recirculation and late phases were imaged in all patients. Similarly, 2.9 quadrants were imaged in the arterial phase versus 3.6 in the late phases. The difficulty in adequately imaging the earlier phases was felt to be related to the time it takes to console the patient after intravenous injection and reposition the head. UWFA may, therefore, be limited in children if visualization of early phases is critical for diagnosis. However, cases in which later phases are sufficient may derive great utility from UWFA, allowing the patient to potentially avert a trip to the operating room for examination under anesthesia. To date, UWFA has been demonstrated to be useful in the diagnosis and management of pediatric patients with uveitis (pars planitis), Coats’ disease, ROP, schisis, Stargardt’s disease, Best disease, history of IOFB, inactive toxoplasmosis, melanoma, and familial exudative vitreoretinopathy (FEVR) [18,19]. In some cases, simulated 7SF missed the abnormality visible by UWFA in these pediatric patients. In addition, UWFA-guided PRP produced improvement in subretinal and intraretinal fluid exudation in Coat’s disease and regression of neovascularization in FEVR [19].
CONCLUSION Having already demonstrated utility in retinal vascular disease, uveitis, and pediatric retinal condition, UWFA possesses great potential for the diagnosis and management of retinal conditions
(Table 1). As UWFA has expanded our ability to angiographically evaluate the far periphery of the retina, we are identifying abnormality more frequently and earlier than we previously did. This is, in turn, changing our conception of the disease processes and how best to diagnosis, follow, and treat them. With these gains, however, also comes the challenge of how to apply the findings on UWFA toward clinical practice. Diabetic retinopathy, for example, remains one of the most evidence-driven diseases in the field of retina. Much of the studies regarding the risks for vision loss or progression as well as response to therapy were established in seminal trials such as DRS and ETDRS, which were based on clinical examination and 7SF imaging. As our ability to examine the far periphery angiographically has grown, it is becoming increasingly difficult to apply data from the prior studies to the current management. UWFA has led to many questions: Is targeted PRP more effective than conventional PRP? Can prophylactic PRP to areas of ischemia reduce the risk of macular edema and neovascularization? Is targeted PRP to areas of ischemia an effective adjunct therapy for the treatment of macular edema? The use of UWFA in vein occlusions raises similar questions. For example, if targeted photocoagulation was applied directly to the areas of ischemia rather than via in a panretinal fashion in the Central Vein Occlusion Study, would there still have been no benefit to prophylactic PRP? More generally, how do we better categorize vein occlusions, now that the disc area of nonperfusion criteria used in the Central Vein Occlusion and Branch Vein Occlusion Studies are rendered obsolete by UWFA, which markedly increases the amount of angiographic nonperfusion visible overall. As with diabetic retinopathy, might there be a role for targeted PRP as adjunctive therapy for macular edema? As we increasingly turn to UWFA to diagnose and manage the retinal conditions, we will likewise have to increasingly reconcile the practice guidelines based on the older studies with the arsenal of new information now available through UWFA. Further clinical trials will be necessary to incorporate UWFA into evidence-based practice guidelines for the diagnosis and management of retinal disease. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Witmer MT, Kiss S. Wide-field imaging of the retina. Surv Ophthalmol 2013; & 58:143–154. This study is a review of wide-field imaging, including fundus photography and fluorescein angiography. It provides a history of wide-field imaging, imaging capabilities of various systems, and clinical applications. 2. Staurenghi G, Viola F, Mainster MA, et al. Scanning laser ophthalmoscopy and angiography with a wide-field contact lens system. Arch Ophthalmol 2005; 123:244–252. 3. Manivannan A, Plskova J, Farrow A, et al. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol 2005; 140:525–527. 4. Fiberg TR, Forrester JV. Ultrawide angle (200þ) fluorescein angiography using a modified Optos Panoramic200TM Imaging System. Invest Ophthalmol Vis Sci 2004; 45:; ARVO E-Abstract 3001. 5. Friberg TR, Gupta A, Yu J, et al. Ultrawide angle fluorescein angiographic imaging: a comparison to conventional digital acquisition systems. Ophthalmic Surg Lasers Imaging 2008; 39:304–311. 6. Witmer MT, Parlitsis G, Patel S, et al. Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis noncontact ultra-widefield module versus the Optos Optomap. Clin Ophthalmol 2013; 7:389–394. 7. Neubauer AS, Kernt M, Haritoglou C, et al. Nonmydriatic screening for diabetic retinopathy by ultra-widefield scanning laser ophthalmoscopy (Optomap). Graefes Arch Clin Exp Ophthalmol 2008; 246:229–235. 8. Oliver SCN, Schwartz SD. Peripheral vessel leakage (PVL): a new angiographic finding in diabetic retinopathy identified with ultra wide-field fluorescein angiography. Semin Ophthalmol 2010; 25:27–33. 9. Prasad PS, Oliver SCN, Coffee RE, et al. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology 2010; 117:780–784. 10. Wessel MW, Aaker GD, Parlitsis G, et al. Ultra-wide-field angiography && improves the detection and classification of diabetic retinopathy. Retina 2012; 32:785–791. This retrospective case series study evaluates the utility of UWFA in diabetic retinopathy, comparing it with simulated seven standard fields fluorescein angiography in ability to demonstrate various pathological changes of diabetic retinopathy.
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11. Reddy S, Shwartz SD. Ultra wide field fluorescein angiography guided targeted retinal photocoagulation. Semin Ophthalmol 2009; 29:9–14. 12. Tsui I, Franco-Cardenas V, Hubschman J-P, et al. Ultra wide field fluorescein angiography can detect macular pathology in central retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2012; 43:257–262. 13. Cho M, Kiss S. Detection and monitoring of sickle cell retinopathy using ultra wide-field color photography and fluorescein angiography. Retina 2011; 31:738–747. 14. Tsui I, Kaines A, Schwartz S. Patterns of periphlebitis in intermediate uveitis using ultra wide field fluorescein angiography. Semin Ophthalmol 2009; 24:29–33. 15. Kaines A, Tsui I, Sarraf D, et al. The use of ultra wide field fluorescein angiography in evaluation and management of uveitis. Semin Ophthalmol 2009; 24:19–24. 16. Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the && management of noninfectious posterior uveitis. Am J Ophthalmol 2013; 154:908–911. This prospective case series study evaluates the utility of UWFA in noninfectious posterior uveitis to determine whether findings on UWFA, compared with examination or examination and simulated standard fluorescein angiography, changed the assessment of disease activity or management. 17. Leder HA, Campbell JP, Sepah YJ, et al. Ultra-wide-field retinal imaging in the && management of noninfectious retinal vasculitis. J Ophthalmic Inflamm Infect 2013; 3:1–6. This prospective case series study evaluates the utility of UWFA in noninfectious retinal vasculitis to determine whether findings on UWFA, compared with examination or examination and simulated standard fluorescein angiography, changed the assessment of disease activity or management. 18. Tsui I, Franco-Cardenas V, Hubschman J-P, et al. Pediatric retinal conditions imaged by ultra wide field fluorescein angiography. Ophthalmic Surg Lasers Imaging 2013; 44:59–67. 19. Kang KB, Wessel MM, Tong J, et al. Ultra-widefield imaging for the management of pediatric retinal diseases. J Pediatr Ophthalmol Strabismus 2013; 50:282–288. 20. Shimizu K, Kobayashi Y, Muraoka K. Mid-peripheral fundus involvement in diabetic retinopathy. Ophthalmology 1981; 88:601–612. 21. Shimizu K, Muraoka K. Diabetic retinopathy. Is it a maculopathy? A super-wide fluorescein angiographic evaluation. Dev Ophthalmol 1981; 2:235–242. 22. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. Ophthalmology 1981; 88:583–600.
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