Lasers in Surgery and Medicine 47:549–558 (2015)
A Light-Emitting Diode (LED)-Based Multispectral Imaging System in Evaluating Retinal Vein Occlusion Yupeng Xu, PhD, MBBS, Xiaoxiao Liu, PhD, MBBS, Lu Cheng, MD, Li Su, PhD, MD, and Xun Xu, MD, MS Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P. R. China
Background and Objective: Retinal vein occlusion (RVO), the second most common retinal vascular disorder worldwide, is considered to be a critical cause of visual loss. The aim of this study was to describe the characteristics of eyes with RVO using a light-emitting diode (LED)-based multispectral imaging (MSI) system and to compare its performance in terms of reliability and diagnostic power with those of fundus fluorescein angiography (FFA), optical coherence tomography (OCT), and fundus photography (FP). Materials and Methods: Fifty-six eyes of 28 patients with RVO disease were evaluated by MSI, FP, FFA, and spectral domain OCT. All images were analyzed by an experienced reading center grader. Nonperfusion area, occlusion area, and intraretinal edema from occlusions and FP abnormalities (presence of cotton-wool spots, epiretinal membrane, hard exudates, and retinal hemorrhage) were documented. The diagnostic power of MSI was evaluated by the area under receiver operating characteristic (ROC) curve (AUC). Results: Of the 56 eyes, 15 had branch RVO (BRVO), 13 had central RVO (CRVO), and 28 were normal. The ROC curve analysis showed that MSI was a better discriminator of RVO than FP (AUC ¼ 0.911 vs. 0.768, P ¼ 0.0318). The sensitivity (and 95% confidence intervals) of MSI for nonperfusion area was 42.3% (18.8–70.4), 80.0% (51.4–94.7) for retinal hemorrhage, 90.0% (54.1–99.5) for cotton-wool spots, 90.9% (57.1–99.5) for hard exudates, and 21.1% (7.0–46.1) for intraretinal edema. MSI was capable of finding abnormalities such as nonperfusion area, retinal hemorrhage, cotton-wool spots, hard exudates, and epiretinal membrane. MSI oxy–deoxy maps showed low oxygen levels in the affected vein, especially in CRVOs, and could be used in detecting the nonperfusion area. Conclusion: MSI reveals highly defined vascular abnormalities in shortwave images and oxy–deoxy maps, which is compatible with FP, FFA, and OCT findings and indicates, preliminarily, the advantages of the noninvasiveness, simplicity, and effectiveness of MSI in evaluating RVO diseases. Lasers Surg. Med. 47:549–558, 2015. ß 2015 Wiley Periodicals, Inc. Key words: branch retinal vein occlusion; central retinal vein occlusion; optical imaging; spectroscopy ß 2015 Wiley Periodicals, Inc.
INTRODUCTION Retinal vein occlusion (RVO), classified as either branch RVO (BRVO) or central RVO (CRVO), is the second most common cause of retinal vascular disease, after diabetic retinopathy [1]. The standardized prevalence of age and sex has been reported as 5.20 per 1,000 for any RVO worldwide, 4.42 per 1000 for BRVO, and 0.80 per 1000 for CRVO [2]. It can lead to severe vision loss [3] and cause vitreous hemorrhage and neovascular glaucoma [1,4,5]. Therefore, early diagnosis and treatment of this disease is significant in the health care system. In most cases, RVO is caused by a combination of factors, including arterial stiffness compressing the neighboring veins, degenerative vessel wall changes, and hypercoagulability [4,6]. After an occlusion occurs, the retina undergoes hemorrhage with venous dilation or tortuosity, capillary nonperfusion, and edema, which might be asymptomatic [7]. Both BRVO and CRVO can be detected by indirect ophthalmoscopy, by which flame hemorrhage, along with retinal edema, dilated or tortuous vein, and cotton-wool spots in the affected portion of retina can be observed [4,7]. Accessory examinations are also helpful in diagnosing RVO. Fundus fluorescein angiography (FFA) has traditionally been the gold standard for evaluating retinal occlusion and finding the ischemia area [8]. Clinical features of the disease, such as cotton-wool spots, hard exudates, and retinal edema can be detected by fundus photography (FP) and optical coherence tomography (OCT) [4,6,9]. However, these methods have some limitations. For example, FP can only show the superior layers
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Contract grant sponsor: National Natural Science Foundation of China; Contract grant numbers: 81302683, 81273424, 81170862; Contract grant sponsor: Shanghai Natural Science Foundation; Contract grant number: 13ZR1459700. Correspondence to: Li Su, PhD, MD, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P. R. China. E-mail: [email protected] Accepted 19 June 2015 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/lsm.22392
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TABLE 1. Summary Data of Patients With Retinal Vein Occlusion Patient no.
Sex Age
Study eye
BCVA (ETDRS score, study eye)
BCVA (ETDRS score, fellow eye)
Diagnosis
Other eye diseases
Systemic diseases NA NA HTN HTN HTN HTN HTN HTN NA HTN Hyperlipidemia HTN HTN hyperlipidemia HTN HTN DM NA HTN, DM NA Hyperlipidemia DM, HTN DM NA HTN HTN Hyperlipidemia Thyroidectomy HTN
1 2 3 4 5 6 7 8 9 10 11 12 13
F F F F F M M F M F F M F
59 56 61 66 59 64 62 54 44 58 57 44 63
OS OD OS OD OD OD OD OS OD OD OD OD OS
62 78 67 77 65 58 82 56 75 72 77 53 75
75 88 78 86 86 80 85 73 96 84 88 70 82
BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO
NA NA NA NA NA Cataract NA NA NA NA NA NA NA
14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
F M M M M F F M F F F M M M M
76 61 82 60 62 48 71 61 76 53 80 53 54 58 43
OS OD OS OS OD OS OS OD OS OS OS OS OS OS OS
64 82 62 71 51 80 71 70 32 49 30 82 72 75 78
80 89 79 81 79 95 81 82 84 84 73 80 80 84 98
BRVO BRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO
NA NA Cataract NA NA NA NA NA Cataract NA NA NA NA PM NA
BCVA, best-corrected visual acuity; OD, right eye; OS, left eye; ETDRS, Early Treatment in Diabetic Retinopathy Study; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; HTN, hypertension; DM, diabetes mellitus; PM, pathological myopia.
of the retina, FFA is an invasive examination and some patients are allergic to fluorescein, and OCT mainly provides horizontal cross-sectional images not en Face images [8,10]. Multispectral imaging (MSI) is an improved technique using different light wavelengths from light-emitting diodes (LEDs), ranging from 550 (green) to 850 nm (infrared), to examine the layers of the retina and choroid progressively [11–14]. Image formation in the machine depends on the wavelength of the incident light and the amount of each wavelength reflected. Because the pigments in the different layers of the retina and different tissues in the same layer differ, MSI can show a clear vision from the retina to the choroid [11,14]. In addition to our RVO study, MSI has been used in other eye diseases, such as polypoidal choroidal vasculopathy [13], Stargardt disease [15], and hydroxychloroquine toxicity of the eye [16]. The main aim of this study was to test a grading model using MSI, to compare its patterns with those of FFA, OCT, and FP, and to test its reliability and diagnostic power.
Fig. 1. Receiver operating characteristic curve analysis for evaluating the diagnostic performance of the MSI. Comparison of the diagnostic performance of MSI and FP in this study. ROC curve shows that MSI findings (blue line) seemed to be statistically more often than FP (red dash line) (AUC ¼ 0.911vs 0.768, P ¼ 0.0318).
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TABLE 2. Frequency Table Showing Specificity and Sensitivity of Multispectral Imaging (MSI) Findings Compared to Fundus Photography (FP) Findings of Vascular Abnormalities Detected by Fundus Fluorescein Angiography (FFA) in Patients Diagnosed With Retinal Vein Occlusion MSI findings
Abnormalities by FFA (n ¼ 28) Normal by FFA (n ¼ 28)
FP findings
Yes
No
Yes
No
23 (82.1%) 0
5 (17.9%) 28 (100%)
15 (53.6%) 0
13 (46.4%) 28 (100%)
MATERIALS AND METHODS This study was approved by the institutional review board of Shanghai General Hospital, Shanghai, China, adhered to the tenets of the Declaration of Helsinki, and was conducted in accordance with regulations set forth by the Health Insurance Portability and Accountability Act. Patients with the diagnosis of RVO based on clinical findings and ancillary testing were included in the study. All patients underwent comprehensive ophthalmic assessment, including best-corrected visual acuity (based on the chart used in the Early Treatment in Diabetic Retinopathy Study), slit-lamp biomicroscopy, indirect ophthalmoscopy, FP, FFA, spectral domain (SD)-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and MSI (RHA; Annidis, Ottawa, Canada). RVO disease was categorized into CRVO and BRVO based on FFA and compared with FP and MSI. Nonperfusion area images were compared between FFA and MSI, and intraretinal macular edema images were compared between SD-OCT and MSI. Clinical features such as cotton-wool spots, hard exudates, and retinal hemorrhage were compared between FP and MSI. MSI data were acquired with an RHA instrument, using a modified fundus camera with 12 monochromatic, discrete LEDs ranging 550–850 nm in wavelength. It takes less than 5 minutes to do the standard scanning mode to adjust the focus and acquire data from both eyes. The RHA report is a set of monochromatic en face sequential retinal images that are acquired and arranged in order of wavelength [14]. Longer wavelengths reveal deeper retinal structures; red and infrared wavelength
TABLE 3. ROC Curves for the Capacity of MSI to Discriminate Clinical Features of Retinal Vein Occlusion Clinical features
AUC
95%CI
Vascular abnormality (FFA) Nonperfusion area (FFA) Retinal hemorrhage (FP) Cotton-wool spots (FP) Hard exudates (FP) Intraretinal macular edema (OCT)
0.911 0.714 0.888 0.939 0.943 0.605
0.824–0.998 0.533–0.895 0.763–1.000 0.827–1.000 0.841–1.000 0.439–0.771
ROC, receiver operating characteristic; AUC, area under the curve; 95%CI, 95% confidence interval.
images correspond approximately to the retinal pigment epithelium and choroid, respectively. The retinal structures and tissues observed in images depend on the excitation peak and reflectivity characteristics of the fundus tissues being examined, which in turn depend on the distribution, quantities, and characteristic optical absorption properties of hemoglobin, melanin, and macular pigments [12–14]. Images obtained using a 580 nm light source, tailored for monitoring the anterior to mid retina, were used mainly to identify hemorrhage, cotton-wool spots, edema, and hard exudates. MSI oxy–deoxy maps (including retinal and choroidal maps), which are the combination of two wavelength images, reflect oxyhemoglobin in the retinal and choroidal vasculatures, thus enhancing the differential contrast of the retinal vasculature [12,14]. Retinal oxy–deoxy maps combining 580 and 590 nm wavelength image mimic nonperfusion area in FFA images, based on different absorption pattern of hemoglobin oxygenation level in the vessels and the retina. Areas of oxygenated blood are hyperreflective (white in appearance), while areas of deoxygenated blood are hyporeflective (dark in appearance) and considered to be either nonperfused or hypoperfused [11,14]. This map is used to detect the nonperfusion area and vascular health affected by retinal blood flow in the RVO to compare with FFA findings. All images were analyzed by one well-trained reading center grader (SL). Statistical analysis was performed using SPSS Software Version 21.0 (IBM Corporation, New York, NY) and MedCalc 10.4.7.0 (MedCalc Software BVBA, Ostend, Belgium). Depending on whether or not the variables conformed to a normal law, parametric or nonparametric tests were applied. Qualitative variables were tested using the x2 or Fisher’s exact test, as appropriate. Sensitivity, specificity, and positive and negative predictive values were calculated for MSI, using FFA, OCT, or FP as the standard reference, with 95% confidence intervals (CIs). Diagnostic power was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). ROC curves of MSI versus FP were compared using FFA as the gold standard. P-values < 0.05 were considered statistically significant. RESULTS A total of 56 eyes of 28 patients with RVO diseases were included in the study. There were 13 male patients and 15 female patients, with a mean age of 60.2 10.1 years
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TABLE 4. Frequency Table Showing Specificity and Sensitivity of MSI Findings Compared to Gold Standard Findings of Clinical Features of Retinal Vein Occlusion Clinical feature (gold standard) Nonperfusion area (FFA)
Retinal hemorrhage (FP)
Cotton-wool spots (FP)
Hard exudates (FP)
Intraretinal macular edema (OCT)
Gold standard Yes 14 No 42 Yes 15 No 41 Yes 10 No 46 Yes 11 No 45 Yes 19 No 37
MSI findings Yes 6 (42.9%) Yes 0 Yes 12 (80.0%) Yes 1 (7.0%) Yes 9 (90%) Yes 1 (2.2%) Yes 10 (90.9%) Yes 1 (2.2%) Yes 4 (21.1%) Yes 0
No 8 (57.1%) No 42 (100%) No 3 (7.7%) No 40 (93.0%) No 1 (10%) No 45 (97.8%) No 1 (9.1%) No 44 (97.8%) No 15 (78.9%) No 37 (100%)
Positive predict value Negative predict value 100.0% (51.7–100.0)
84.0% (70.3–92.4)
92.3% (62.1–99.6)
93.0% (79.9–98.2)
90.0% (54.1–99.5)
97.8% (87.0–99.9)
90.9% (57.1–99.5)
97.8% (86.8–99.9)
100.0% (39.6–100.0)
71.2% (56.7–82.5)
Fig. 2. MSI images from RHA arranged in order of wavelength (Case 1).
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Fig. 3. Case 1: MSI, FP, and FFA images of a 64-year-old man with branch retinal vein occlusion in his right eye. MSI oxy–deoxy map shows poor oxygen supply to the inferotemporal branch (short arrow, top row, left). FFA shows dilated, tortuous vein in the inferotemporal branch (short arrow, top row, middle). FFA shows nonperfusion area in the peripheral inferotemporal quadrant (white stars, top row, right). MSI 580 nm (yellow) image shows hard exudates (arrowheads) and dot hemorrhage (long arrow, bottom row, left). FP image shows hard exudates (arrowheads) but blurred dot hemorrhage (long arrow, bottom row, right).
(range, 43–82 years). The mean best corrected visual acuity (BCVA) of the study eyes was 66.6 13.8 letters, while the mean BCVA of the fellow eyes was 82.8 6.6 letters. Of the 56 eyes, 15 had BRVO, 13 had CRVO, and 28 were normal. Twenty-two (78.6%) of the 28 patients had pre-existing systemic diseases, of which 16/22 (72.7%) could be attributed to hypertension. Table 1 summarizes the patient demographics and systemic diseases. In the absence of RVO, there was no obvious difference between MSI and FP findings. In the presence of RVO with vascular abnormalities detected by FFA, the ROC curve showed that MSI findings were more often statistically significant than FP findings (AUC ¼ 0.911 vs. 0.768, P ¼ 0.0318) (Fig. 1). The sensitivity of MSI to detect abnormalities in the presence of FFA abnormalities was 82.1% (62.4–93.2), with a specificity of 100.0% (84.9–100.0), while the sensitivity of FP was 53.6% (34.2–72.0), with a specificity of 100.0% (84.9–100.0) (Table 2). The ROC curve also showed that MSI had good discriminative value for detecting clinical features such
as retinal hemorrhage, cotton-wool spots, and hard exudates (AUC ¼ 0.888, 0.939, and 0.943, respectively; 95%CI ¼ 0.763–1.000, 0.827–1.000, and 0.841–1.000, respectively) (Table 3). The sensitivity of detecting nonperfusion area by MSI compared with that of FFA was 42.3% (18.8–70.4) with a specificity of 100.0% (89.5–100.0). The sensitivity of detecting retinal hemorrhage by MSI compared with FP was 80.0% (51.4–94.7) with a specificity of 97.6% (85.6–99.9); for cotton-wool spots, sensitivity was 90.0% (54.1–99.5) with a specificity of 97.8% (87.0–99.9); and for hard exudates, sensitivity was 90.9% (57.1–99.5) with a specificity of 97.8% (86.8–99.9). The sensitivity of detecting intraretinal macular edema by MSI compared with OCT was 21.1% (7.0–46.1) with a specificity of 100.0% (88.3–100.0). The positive and negative predictive values are shown in Table 4. The following representative cases are presented to illustrate the MSI findings in RVO disease. Case 1 (Patient #6) was a 64-year-old man with systemic hypertension, diagnosed with BRVO in his
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Fig. 4. Case 2: MSI, FP, and FFA images of a 61-year-old man with branch retinal vein occlusion in his right eye. FP image (top row, left) shows hard exudates (arrowhead), cotton-wool spots (yellow arrow), and blot hemorrhage (white arrow), which caused the masking of fluorescence on the FFA images (top row, right) and was difficult to differentiate. MSI 580 nm (yellow) image (bottom row, left) shows the same features as the FP image. MSI oxy–deoxy map (bottom row, right) shows cotton-wool spots (yellow arrow) and blot hemorrhages (white arrow) along the inferotemporal branch and poor oxygen supply in the same area (short arrow).
right eye for a year with a BCVA of 58 letters. The patient also had cataracts. Clinical examination showed BRVO with dilated, tortuous vein in the inferotemporal branch. There were scattered laser spots in the peripheral inferotemporal area, and some hard exudates were found temporal to the macula. MSI with a short wavelength of 580 nm (yellow) clearly showed the retinal hemorrhage and hard exudates. In addition, the retinal oxy–deoxy map showed poor oxygen supply in the inferotemporal quadrant. FFA showed a nonperfusion area in the inferotemporal quadrant in the early phase. In summary, this case of BRVO showed evidence of bad oxygen supply in the inferotemporal quadrant, and MSI was more
helpful in detecting retinal hemorrhage than FP in some patients (Figs. 2 and 3). Case 2 (Patient #15) was a 61-year-old man with systemic hypertension, diagnosed with BRVO in his right eye for half a year with a BCVA of 82 letters. Clinical examination showed BRVO with RVO in the inferotemporal branch. Masking of fluorescence could be found on the FFA images. MSI 580 nm (yellow) and the retinal oxy–deoxy map showed cotton-wool spots and blot hemorrhages along the inferotemporal branch. The MSI oxy–deoxy map also showed poor oxygen supply in the same area. This case showed the ability of MSI to distinguish between cotton-wool spots and dot hemorrhage (Fig. 4).
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Fig. 5. Case 3: MSI, FP, and FFA images of a 54-year-old man with central retinal vein occlusion in his left eye. Hard exudates can be detected by FP (top row, left) and MSI 580 nm (yellow) image (bottom row, left). FFA images of the left eye show some leakage and small nonperfusion areas in the superotemporal branch (top row, middle) and that the diameters of the veins are nearly the same as those of the fellow eye (short arrow, top row, right). MSI oxy–deoxy map shows poor oxygen supply to the vein in the left eye (short arrows, bottom row, middle) compared to the fellow eye (short arrows, bottom row, right).
Case 3 (Patient #26) was a 54-year-old man with hyperlipidemia, diagnosed with CRVO in his left eye for 10 months with a BCVA of 72 letters. Hard exudates could be detected with FP and MSI. Some leakages and small nonperfusion areas in the superotemporal branch could be seen in the FFA images. The retinal oxy–deoxy map showed that the oxygen supply to the vein was still poor in the left eye compared with the fellow eye, and FFA showed that the diameters of the veins were the same, which could be a potential biomarker (Fig. 5). Case 4 (Patient #3) was a 61-year-old woman with systemic hypertension, diagnosed with BRVO in her left eye for 1 year with a BCVA of 67 letters. Clinical examination showed BRVO with RVO in the superotemporal branch. Hard exudates could be found on the FP and MSI images. SD-OCT images showed a small cystoid edema that was in the same position on the MSI 580 nm (yellow) image. Nonperfusion areas could be found on the retinal oxy–deoxy map, as well as on the FFA images. This case showed the potential ability of the MSI retinal oxy–deoxy map to diagnose nonperfusion areas (Fig. 6).
Case 5 (Patient #14) was a 76-year-old woman with systemic hypertension, diagnosed with BRVO in her left eye for a year and a half with a BCVA of 64 letters. Clinical examination showed BRVO with RVO in the superotemporal branch. FA showed a small piece of nonperfusion area that was not obvious on the MSI retinal oxy–deoxy map. However, a vascular abnormality was shown in the same area in the MSI 580 nm (yellow) image. An epiretinal membrane was obvious in the OCT and MSI images (580 nm, yellow), but not in FP. This case showed that MSI was a better way to diagnose epiretinal membrane; however, its ability to distinguish a small nonperfusion area by oxy–deoxy map was limited (Fig. 7). DISCUSSION The diagnosis of retinal vein diseases is mainly established on the basis of funduscopic examination and intravenous angiography. Clinical features such as retinal hemorrhage, cotton-wool spots, hard exudates, retinal edema, and dilated, tortuous veins can be observed by fundoscopy [4,6]. Areas of ischemia can be evaluated using
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Fig. 6. Case 4: MSI, FP, FFA, and OCT images of a 61-year-old woman with branch retinal vein occlusion in her left eye. FP shows hard exudates (arrowhead, top row, left). SD-OCT images show a small cystoid edema (circle, top row, middle, and right). MSI 580 nm (yellow) image (bottom row, left) shows both features. MSI oxy–deoxy map shows nonperfusion areas (white stars, bottom row, middle) as proved by the FFA images (white stars, bottom row, right).
FFA [17], and OCT is helpful in monitoring response to treatment and detecting edema [18]. Although these examinations are widely used in clinical routines, they have some limitations. FFA using 488 nm solid state laser is an invasive procedure [8], and the fluorescein used can cause some allergic reactions and even anaphylaxis. In a recent retrospective study, the incidence of anaphylaxis caused by fluorescein was found to be 0.083% [10], which could not be ignored, as this examination is widely used in ophthalmology clinics. Some of the anaphylaxis cases were accompanied by hypotension, occurred in less than 3 minutes, and required special attention [10,19]. Conventional FP uses light in a limited range (480–600 nm) and is thus unable to show the inferior layers of the retina, while OCT uses laser centered at a wavelength of 830 nm, but provides horizontal crosssectional images [20]. MSI was introduced to detect RVO with a light source ranging 550–850 nm, covering the wavelength of FP and OCT, and showing en face images [14]. In this study, we focused mainly on shortwave images (580 nm, yellow), which enhance anterior and mid-retina specular
reflections (the visibility of the retinal vasculature and nerve fiber layer) and improve the visualization of hemorrhage, cotton-wool spots, and hard exudates (AUC ¼ 0.888, 0.939, 0.943, respectively). Disorders in this layer that are not obvious in FP images can be detected by MSI (e.g., Case 3), which improves the diagnostic power. Epiretinal membrane, which occurs in the anterior-retinal layers and is almost transparent when viewed with a conventional white light source (used by FP), is also more obvious in this wavelength (e.g., Case 5) [12,14]. The high oxygen demands of the retina and the relatively sparse nature of the retinal vasculature are thought to contribute to the retina’s vulnerability to vascular disease, including RVO [21]. In our study, the retinal oxy–deoxy map showed an obvious difference in the study eye of CRVO patients compared to the fellow eye (e.g., Case 3). This map can also be used to find the nonperfusion area (AUC ¼ 0.714) and can partly replace the FFA examination. Small nonperfusion areas in FFA images that are not shown in MSI oxy–deoxy maps might appear as vascular abnormalities around the area in MSI 580 nm (yellow) images. Oxy–deoxy maps and MSI
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Fig. 7. Case 5: MSI, FP, OCT, and FFA images of a 76-year-old woman with branch retinal vein occlusion in her left eye. FP image shows hard exudates (arrowhead) and cotton-wool spots (yellow arrow). SD-OCT shows epiretinal membrane (top row, right) inferior to the macula (green line, top row, middle). MSI 580 nm (yellow) image shows the features on the FP as well as epiretinal membrane (yellow stars, bottom row, left). FA shows a small piece of nonperfusion area (white star, bottom row, right), which is not obvious on the MSI oxy–deoxy map (bottom row, middle); however, the vascular abnormality was found on the MSI 580 nm (yellow) image (white star, bottom row, left).
580 nm (yellow) images can be used to diagnose the nonperfusion area, especially in patients who are allergic to fluorescein [12,13]. Limitations of this study include limited precision of the results, given the small number patients evaluated. Future prospective and larger consecutive case studies might be able to show diagnostic power better than this study. Furthermore, nonperfusion areas located outside the MSI capture zoom contributed to low sensitivity. Only obvious edemas were detectable in the MSI images showing that it is not as sensitive as OCT. In addition, MSI was unable to observe exudative lesions dynamically compared with FFA. Viewed from this aspect, FFA is still irreplaceable. In conclusion, MSI revealed the full spectrum of changes caused by RVO disease including nonperfusion area, retinal hemorrhage, cotton-wool spots, and hard exudates. MSI is capable of detecting hemorrhage and cotton-wool spots in cases where the fluorescein masking of FA images causes confusion. MSI also has the ability to map retinal vasculature oxygen levels and find nonperfusion areas by detecting oxygenation of the blood. In addition, comparing
MSI oxy–deoxy maps from the same patient could easily identify differences in oxygen supply, even if the vascular diameters are the same. Because MSI is basically an injection-free angiography, using it avoids potentially lifethreatening complications due to anaphylaxis to fluorescein [10,12]. Despite some limitations, MSI is a promising tool for diagnosing and screening RVO. ACKNOWLEDGMENTS Financial support for this study was provided by National Natural Science Foundation of China (nos. 81302683, 81273424, and 81170862), and Shanghai Natural Science Foundation (13ZR1459700). REFERENCES 1. Thach AB,Yau L, Hoang C, Tuomi L. Time to clinically significant visual acuity gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials. Ophthalmology 2014;121(5):1059–1066. 2. Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY. International Eye Disease C. The prevalence of retinal vein occlusion: Pooled
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14. Zimmer C, Kahn D, Clayton R, Dugel P, Freund KB. Innovation in diagnostic retinal imaging: Multispectral imaging. Retina Today 2014 October:94–99. 15. Pang CE, Suqin Y, Sherman J, Freund KB. New insights into Stargardt disease with multimodal imaging. Ophthalmic Surg Lasers Imaging Retina 2015;46(2):257–261. 16. Bhavsar KV, Mukkamala LK, Freund KB. Multimodal imaging in a severe case of hydroxychloroquine toxicity. Ophthalmic Surg Lasers Imaging Retina 2015;46(3): 377–379. 17. Hvarfner C, Andreasson S, Larsson J. Multifocal electroretinography and fluorescein angiography in retinal vein occlusion. Retina 2006;26(3):292–296. 18. Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio RG. Predictive value in retinal vein occlusions of early versus late or incomplete ranibizumab response defined by optical coherence tomography. Ophthalmology 2013;120(5):1057–1063. 19. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, Brown SG, Camargo CA, Jr., Cydulka R, Galli SJ, Gidudu J, Gruchalla RS, Harlor AD, Jr., Hepner DL, Lewis LM, Lieberman PL, Metcalfe DD, O’Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons FE, Thomas S, Wood JP, Decker WW. Second symposium on the definition and management of anaphylaxis: Summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391–397. 20. Wojtkowski M, Bajraszewski T, Gorczynska I, Targowski P, Kowalczyk A, Wasilewski W, Radzewicz C. Ophthalmic imaging by spectral optical coherence tomography. Am J Ophthalmol 2004;138(3):412–419. 21. Yu DY, Cringle SJ. Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 2001;20(2):175–208.
A Light-Emitting Diode (LED)-Based Multispectral Imaging System in Evaluating Retinal Vein Occlusion Yupeng Xu, PhD, MBBS, Xiaoxiao Liu, PhD, MBBS, Lu Cheng, MD, Li Su, PhD, MD, and Xun Xu, MD, MS Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P. R. China
Background and Objective: Retinal vein occlusion (RVO), the second most common retinal vascular disorder worldwide, is considered to be a critical cause of visual loss. The aim of this study was to describe the characteristics of eyes with RVO using a light-emitting diode (LED)-based multispectral imaging (MSI) system and to compare its performance in terms of reliability and diagnostic power with those of fundus fluorescein angiography (FFA), optical coherence tomography (OCT), and fundus photography (FP). Materials and Methods: Fifty-six eyes of 28 patients with RVO disease were evaluated by MSI, FP, FFA, and spectral domain OCT. All images were analyzed by an experienced reading center grader. Nonperfusion area, occlusion area, and intraretinal edema from occlusions and FP abnormalities (presence of cotton-wool spots, epiretinal membrane, hard exudates, and retinal hemorrhage) were documented. The diagnostic power of MSI was evaluated by the area under receiver operating characteristic (ROC) curve (AUC). Results: Of the 56 eyes, 15 had branch RVO (BRVO), 13 had central RVO (CRVO), and 28 were normal. The ROC curve analysis showed that MSI was a better discriminator of RVO than FP (AUC ¼ 0.911 vs. 0.768, P ¼ 0.0318). The sensitivity (and 95% confidence intervals) of MSI for nonperfusion area was 42.3% (18.8–70.4), 80.0% (51.4–94.7) for retinal hemorrhage, 90.0% (54.1–99.5) for cotton-wool spots, 90.9% (57.1–99.5) for hard exudates, and 21.1% (7.0–46.1) for intraretinal edema. MSI was capable of finding abnormalities such as nonperfusion area, retinal hemorrhage, cotton-wool spots, hard exudates, and epiretinal membrane. MSI oxy–deoxy maps showed low oxygen levels in the affected vein, especially in CRVOs, and could be used in detecting the nonperfusion area. Conclusion: MSI reveals highly defined vascular abnormalities in shortwave images and oxy–deoxy maps, which is compatible with FP, FFA, and OCT findings and indicates, preliminarily, the advantages of the noninvasiveness, simplicity, and effectiveness of MSI in evaluating RVO diseases. Lasers Surg. Med. 47:549–558, 2015. ß 2015 Wiley Periodicals, Inc. Key words: branch retinal vein occlusion; central retinal vein occlusion; optical imaging; spectroscopy ß 2015 Wiley Periodicals, Inc.
INTRODUCTION Retinal vein occlusion (RVO), classified as either branch RVO (BRVO) or central RVO (CRVO), is the second most common cause of retinal vascular disease, after diabetic retinopathy [1]. The standardized prevalence of age and sex has been reported as 5.20 per 1,000 for any RVO worldwide, 4.42 per 1000 for BRVO, and 0.80 per 1000 for CRVO [2]. It can lead to severe vision loss [3] and cause vitreous hemorrhage and neovascular glaucoma [1,4,5]. Therefore, early diagnosis and treatment of this disease is significant in the health care system. In most cases, RVO is caused by a combination of factors, including arterial stiffness compressing the neighboring veins, degenerative vessel wall changes, and hypercoagulability [4,6]. After an occlusion occurs, the retina undergoes hemorrhage with venous dilation or tortuosity, capillary nonperfusion, and edema, which might be asymptomatic [7]. Both BRVO and CRVO can be detected by indirect ophthalmoscopy, by which flame hemorrhage, along with retinal edema, dilated or tortuous vein, and cotton-wool spots in the affected portion of retina can be observed [4,7]. Accessory examinations are also helpful in diagnosing RVO. Fundus fluorescein angiography (FFA) has traditionally been the gold standard for evaluating retinal occlusion and finding the ischemia area [8]. Clinical features of the disease, such as cotton-wool spots, hard exudates, and retinal edema can be detected by fundus photography (FP) and optical coherence tomography (OCT) [4,6,9]. However, these methods have some limitations. For example, FP can only show the superior layers
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Contract grant sponsor: National Natural Science Foundation of China; Contract grant numbers: 81302683, 81273424, 81170862; Contract grant sponsor: Shanghai Natural Science Foundation; Contract grant number: 13ZR1459700. Correspondence to: Li Su, PhD, MD, Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P. R. China. E-mail: [email protected] Accepted 19 June 2015 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/lsm.22392
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TABLE 1. Summary Data of Patients With Retinal Vein Occlusion Patient no.
Sex Age
Study eye
BCVA (ETDRS score, study eye)
BCVA (ETDRS score, fellow eye)
Diagnosis
Other eye diseases
Systemic diseases NA NA HTN HTN HTN HTN HTN HTN NA HTN Hyperlipidemia HTN HTN hyperlipidemia HTN HTN DM NA HTN, DM NA Hyperlipidemia DM, HTN DM NA HTN HTN Hyperlipidemia Thyroidectomy HTN
1 2 3 4 5 6 7 8 9 10 11 12 13
F F F F F M M F M F F M F
59 56 61 66 59 64 62 54 44 58 57 44 63
OS OD OS OD OD OD OD OS OD OD OD OD OS
62 78 67 77 65 58 82 56 75 72 77 53 75
75 88 78 86 86 80 85 73 96 84 88 70 82
BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO BRVO
NA NA NA NA NA Cataract NA NA NA NA NA NA NA
14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
F M M M M F F M F F F M M M M
76 61 82 60 62 48 71 61 76 53 80 53 54 58 43
OS OD OS OS OD OS OS OD OS OS OS OS OS OS OS
64 82 62 71 51 80 71 70 32 49 30 82 72 75 78
80 89 79 81 79 95 81 82 84 84 73 80 80 84 98
BRVO BRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO CRVO
NA NA Cataract NA NA NA NA NA Cataract NA NA NA NA PM NA
BCVA, best-corrected visual acuity; OD, right eye; OS, left eye; ETDRS, Early Treatment in Diabetic Retinopathy Study; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; HTN, hypertension; DM, diabetes mellitus; PM, pathological myopia.
of the retina, FFA is an invasive examination and some patients are allergic to fluorescein, and OCT mainly provides horizontal cross-sectional images not en Face images [8,10]. Multispectral imaging (MSI) is an improved technique using different light wavelengths from light-emitting diodes (LEDs), ranging from 550 (green) to 850 nm (infrared), to examine the layers of the retina and choroid progressively [11–14]. Image formation in the machine depends on the wavelength of the incident light and the amount of each wavelength reflected. Because the pigments in the different layers of the retina and different tissues in the same layer differ, MSI can show a clear vision from the retina to the choroid [11,14]. In addition to our RVO study, MSI has been used in other eye diseases, such as polypoidal choroidal vasculopathy [13], Stargardt disease [15], and hydroxychloroquine toxicity of the eye [16]. The main aim of this study was to test a grading model using MSI, to compare its patterns with those of FFA, OCT, and FP, and to test its reliability and diagnostic power.
Fig. 1. Receiver operating characteristic curve analysis for evaluating the diagnostic performance of the MSI. Comparison of the diagnostic performance of MSI and FP in this study. ROC curve shows that MSI findings (blue line) seemed to be statistically more often than FP (red dash line) (AUC ¼ 0.911vs 0.768, P ¼ 0.0318).
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TABLE 2. Frequency Table Showing Specificity and Sensitivity of Multispectral Imaging (MSI) Findings Compared to Fundus Photography (FP) Findings of Vascular Abnormalities Detected by Fundus Fluorescein Angiography (FFA) in Patients Diagnosed With Retinal Vein Occlusion MSI findings
Abnormalities by FFA (n ¼ 28) Normal by FFA (n ¼ 28)
FP findings
Yes
No
Yes
No
23 (82.1%) 0
5 (17.9%) 28 (100%)
15 (53.6%) 0
13 (46.4%) 28 (100%)
MATERIALS AND METHODS This study was approved by the institutional review board of Shanghai General Hospital, Shanghai, China, adhered to the tenets of the Declaration of Helsinki, and was conducted in accordance with regulations set forth by the Health Insurance Portability and Accountability Act. Patients with the diagnosis of RVO based on clinical findings and ancillary testing were included in the study. All patients underwent comprehensive ophthalmic assessment, including best-corrected visual acuity (based on the chart used in the Early Treatment in Diabetic Retinopathy Study), slit-lamp biomicroscopy, indirect ophthalmoscopy, FP, FFA, spectral domain (SD)-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and MSI (RHA; Annidis, Ottawa, Canada). RVO disease was categorized into CRVO and BRVO based on FFA and compared with FP and MSI. Nonperfusion area images were compared between FFA and MSI, and intraretinal macular edema images were compared between SD-OCT and MSI. Clinical features such as cotton-wool spots, hard exudates, and retinal hemorrhage were compared between FP and MSI. MSI data were acquired with an RHA instrument, using a modified fundus camera with 12 monochromatic, discrete LEDs ranging 550–850 nm in wavelength. It takes less than 5 minutes to do the standard scanning mode to adjust the focus and acquire data from both eyes. The RHA report is a set of monochromatic en face sequential retinal images that are acquired and arranged in order of wavelength [14]. Longer wavelengths reveal deeper retinal structures; red and infrared wavelength
TABLE 3. ROC Curves for the Capacity of MSI to Discriminate Clinical Features of Retinal Vein Occlusion Clinical features
AUC
95%CI
Vascular abnormality (FFA) Nonperfusion area (FFA) Retinal hemorrhage (FP) Cotton-wool spots (FP) Hard exudates (FP) Intraretinal macular edema (OCT)
0.911 0.714 0.888 0.939 0.943 0.605
0.824–0.998 0.533–0.895 0.763–1.000 0.827–1.000 0.841–1.000 0.439–0.771
ROC, receiver operating characteristic; AUC, area under the curve; 95%CI, 95% confidence interval.
images correspond approximately to the retinal pigment epithelium and choroid, respectively. The retinal structures and tissues observed in images depend on the excitation peak and reflectivity characteristics of the fundus tissues being examined, which in turn depend on the distribution, quantities, and characteristic optical absorption properties of hemoglobin, melanin, and macular pigments [12–14]. Images obtained using a 580 nm light source, tailored for monitoring the anterior to mid retina, were used mainly to identify hemorrhage, cotton-wool spots, edema, and hard exudates. MSI oxy–deoxy maps (including retinal and choroidal maps), which are the combination of two wavelength images, reflect oxyhemoglobin in the retinal and choroidal vasculatures, thus enhancing the differential contrast of the retinal vasculature [12,14]. Retinal oxy–deoxy maps combining 580 and 590 nm wavelength image mimic nonperfusion area in FFA images, based on different absorption pattern of hemoglobin oxygenation level in the vessels and the retina. Areas of oxygenated blood are hyperreflective (white in appearance), while areas of deoxygenated blood are hyporeflective (dark in appearance) and considered to be either nonperfused or hypoperfused [11,14]. This map is used to detect the nonperfusion area and vascular health affected by retinal blood flow in the RVO to compare with FFA findings. All images were analyzed by one well-trained reading center grader (SL). Statistical analysis was performed using SPSS Software Version 21.0 (IBM Corporation, New York, NY) and MedCalc 10.4.7.0 (MedCalc Software BVBA, Ostend, Belgium). Depending on whether or not the variables conformed to a normal law, parametric or nonparametric tests were applied. Qualitative variables were tested using the x2 or Fisher’s exact test, as appropriate. Sensitivity, specificity, and positive and negative predictive values were calculated for MSI, using FFA, OCT, or FP as the standard reference, with 95% confidence intervals (CIs). Diagnostic power was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC). ROC curves of MSI versus FP were compared using FFA as the gold standard. P-values < 0.05 were considered statistically significant. RESULTS A total of 56 eyes of 28 patients with RVO diseases were included in the study. There were 13 male patients and 15 female patients, with a mean age of 60.2 10.1 years
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TABLE 4. Frequency Table Showing Specificity and Sensitivity of MSI Findings Compared to Gold Standard Findings of Clinical Features of Retinal Vein Occlusion Clinical feature (gold standard) Nonperfusion area (FFA)
Retinal hemorrhage (FP)
Cotton-wool spots (FP)
Hard exudates (FP)
Intraretinal macular edema (OCT)
Gold standard Yes 14 No 42 Yes 15 No 41 Yes 10 No 46 Yes 11 No 45 Yes 19 No 37
MSI findings Yes 6 (42.9%) Yes 0 Yes 12 (80.0%) Yes 1 (7.0%) Yes 9 (90%) Yes 1 (2.2%) Yes 10 (90.9%) Yes 1 (2.2%) Yes 4 (21.1%) Yes 0
No 8 (57.1%) No 42 (100%) No 3 (7.7%) No 40 (93.0%) No 1 (10%) No 45 (97.8%) No 1 (9.1%) No 44 (97.8%) No 15 (78.9%) No 37 (100%)
Positive predict value Negative predict value 100.0% (51.7–100.0)
84.0% (70.3–92.4)
92.3% (62.1–99.6)
93.0% (79.9–98.2)
90.0% (54.1–99.5)
97.8% (87.0–99.9)
90.9% (57.1–99.5)
97.8% (86.8–99.9)
100.0% (39.6–100.0)
71.2% (56.7–82.5)
Fig. 2. MSI images from RHA arranged in order of wavelength (Case 1).
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Fig. 3. Case 1: MSI, FP, and FFA images of a 64-year-old man with branch retinal vein occlusion in his right eye. MSI oxy–deoxy map shows poor oxygen supply to the inferotemporal branch (short arrow, top row, left). FFA shows dilated, tortuous vein in the inferotemporal branch (short arrow, top row, middle). FFA shows nonperfusion area in the peripheral inferotemporal quadrant (white stars, top row, right). MSI 580 nm (yellow) image shows hard exudates (arrowheads) and dot hemorrhage (long arrow, bottom row, left). FP image shows hard exudates (arrowheads) but blurred dot hemorrhage (long arrow, bottom row, right).
(range, 43–82 years). The mean best corrected visual acuity (BCVA) of the study eyes was 66.6 13.8 letters, while the mean BCVA of the fellow eyes was 82.8 6.6 letters. Of the 56 eyes, 15 had BRVO, 13 had CRVO, and 28 were normal. Twenty-two (78.6%) of the 28 patients had pre-existing systemic diseases, of which 16/22 (72.7%) could be attributed to hypertension. Table 1 summarizes the patient demographics and systemic diseases. In the absence of RVO, there was no obvious difference between MSI and FP findings. In the presence of RVO with vascular abnormalities detected by FFA, the ROC curve showed that MSI findings were more often statistically significant than FP findings (AUC ¼ 0.911 vs. 0.768, P ¼ 0.0318) (Fig. 1). The sensitivity of MSI to detect abnormalities in the presence of FFA abnormalities was 82.1% (62.4–93.2), with a specificity of 100.0% (84.9–100.0), while the sensitivity of FP was 53.6% (34.2–72.0), with a specificity of 100.0% (84.9–100.0) (Table 2). The ROC curve also showed that MSI had good discriminative value for detecting clinical features such
as retinal hemorrhage, cotton-wool spots, and hard exudates (AUC ¼ 0.888, 0.939, and 0.943, respectively; 95%CI ¼ 0.763–1.000, 0.827–1.000, and 0.841–1.000, respectively) (Table 3). The sensitivity of detecting nonperfusion area by MSI compared with that of FFA was 42.3% (18.8–70.4) with a specificity of 100.0% (89.5–100.0). The sensitivity of detecting retinal hemorrhage by MSI compared with FP was 80.0% (51.4–94.7) with a specificity of 97.6% (85.6–99.9); for cotton-wool spots, sensitivity was 90.0% (54.1–99.5) with a specificity of 97.8% (87.0–99.9); and for hard exudates, sensitivity was 90.9% (57.1–99.5) with a specificity of 97.8% (86.8–99.9). The sensitivity of detecting intraretinal macular edema by MSI compared with OCT was 21.1% (7.0–46.1) with a specificity of 100.0% (88.3–100.0). The positive and negative predictive values are shown in Table 4. The following representative cases are presented to illustrate the MSI findings in RVO disease. Case 1 (Patient #6) was a 64-year-old man with systemic hypertension, diagnosed with BRVO in his
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Fig. 4. Case 2: MSI, FP, and FFA images of a 61-year-old man with branch retinal vein occlusion in his right eye. FP image (top row, left) shows hard exudates (arrowhead), cotton-wool spots (yellow arrow), and blot hemorrhage (white arrow), which caused the masking of fluorescence on the FFA images (top row, right) and was difficult to differentiate. MSI 580 nm (yellow) image (bottom row, left) shows the same features as the FP image. MSI oxy–deoxy map (bottom row, right) shows cotton-wool spots (yellow arrow) and blot hemorrhages (white arrow) along the inferotemporal branch and poor oxygen supply in the same area (short arrow).
right eye for a year with a BCVA of 58 letters. The patient also had cataracts. Clinical examination showed BRVO with dilated, tortuous vein in the inferotemporal branch. There were scattered laser spots in the peripheral inferotemporal area, and some hard exudates were found temporal to the macula. MSI with a short wavelength of 580 nm (yellow) clearly showed the retinal hemorrhage and hard exudates. In addition, the retinal oxy–deoxy map showed poor oxygen supply in the inferotemporal quadrant. FFA showed a nonperfusion area in the inferotemporal quadrant in the early phase. In summary, this case of BRVO showed evidence of bad oxygen supply in the inferotemporal quadrant, and MSI was more
helpful in detecting retinal hemorrhage than FP in some patients (Figs. 2 and 3). Case 2 (Patient #15) was a 61-year-old man with systemic hypertension, diagnosed with BRVO in his right eye for half a year with a BCVA of 82 letters. Clinical examination showed BRVO with RVO in the inferotemporal branch. Masking of fluorescence could be found on the FFA images. MSI 580 nm (yellow) and the retinal oxy–deoxy map showed cotton-wool spots and blot hemorrhages along the inferotemporal branch. The MSI oxy–deoxy map also showed poor oxygen supply in the same area. This case showed the ability of MSI to distinguish between cotton-wool spots and dot hemorrhage (Fig. 4).
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Fig. 5. Case 3: MSI, FP, and FFA images of a 54-year-old man with central retinal vein occlusion in his left eye. Hard exudates can be detected by FP (top row, left) and MSI 580 nm (yellow) image (bottom row, left). FFA images of the left eye show some leakage and small nonperfusion areas in the superotemporal branch (top row, middle) and that the diameters of the veins are nearly the same as those of the fellow eye (short arrow, top row, right). MSI oxy–deoxy map shows poor oxygen supply to the vein in the left eye (short arrows, bottom row, middle) compared to the fellow eye (short arrows, bottom row, right).
Case 3 (Patient #26) was a 54-year-old man with hyperlipidemia, diagnosed with CRVO in his left eye for 10 months with a BCVA of 72 letters. Hard exudates could be detected with FP and MSI. Some leakages and small nonperfusion areas in the superotemporal branch could be seen in the FFA images. The retinal oxy–deoxy map showed that the oxygen supply to the vein was still poor in the left eye compared with the fellow eye, and FFA showed that the diameters of the veins were the same, which could be a potential biomarker (Fig. 5). Case 4 (Patient #3) was a 61-year-old woman with systemic hypertension, diagnosed with BRVO in her left eye for 1 year with a BCVA of 67 letters. Clinical examination showed BRVO with RVO in the superotemporal branch. Hard exudates could be found on the FP and MSI images. SD-OCT images showed a small cystoid edema that was in the same position on the MSI 580 nm (yellow) image. Nonperfusion areas could be found on the retinal oxy–deoxy map, as well as on the FFA images. This case showed the potential ability of the MSI retinal oxy–deoxy map to diagnose nonperfusion areas (Fig. 6).
Case 5 (Patient #14) was a 76-year-old woman with systemic hypertension, diagnosed with BRVO in her left eye for a year and a half with a BCVA of 64 letters. Clinical examination showed BRVO with RVO in the superotemporal branch. FA showed a small piece of nonperfusion area that was not obvious on the MSI retinal oxy–deoxy map. However, a vascular abnormality was shown in the same area in the MSI 580 nm (yellow) image. An epiretinal membrane was obvious in the OCT and MSI images (580 nm, yellow), but not in FP. This case showed that MSI was a better way to diagnose epiretinal membrane; however, its ability to distinguish a small nonperfusion area by oxy–deoxy map was limited (Fig. 7). DISCUSSION The diagnosis of retinal vein diseases is mainly established on the basis of funduscopic examination and intravenous angiography. Clinical features such as retinal hemorrhage, cotton-wool spots, hard exudates, retinal edema, and dilated, tortuous veins can be observed by fundoscopy [4,6]. Areas of ischemia can be evaluated using
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Fig. 6. Case 4: MSI, FP, FFA, and OCT images of a 61-year-old woman with branch retinal vein occlusion in her left eye. FP shows hard exudates (arrowhead, top row, left). SD-OCT images show a small cystoid edema (circle, top row, middle, and right). MSI 580 nm (yellow) image (bottom row, left) shows both features. MSI oxy–deoxy map shows nonperfusion areas (white stars, bottom row, middle) as proved by the FFA images (white stars, bottom row, right).
FFA [17], and OCT is helpful in monitoring response to treatment and detecting edema [18]. Although these examinations are widely used in clinical routines, they have some limitations. FFA using 488 nm solid state laser is an invasive procedure [8], and the fluorescein used can cause some allergic reactions and even anaphylaxis. In a recent retrospective study, the incidence of anaphylaxis caused by fluorescein was found to be 0.083% [10], which could not be ignored, as this examination is widely used in ophthalmology clinics. Some of the anaphylaxis cases were accompanied by hypotension, occurred in less than 3 minutes, and required special attention [10,19]. Conventional FP uses light in a limited range (480–600 nm) and is thus unable to show the inferior layers of the retina, while OCT uses laser centered at a wavelength of 830 nm, but provides horizontal crosssectional images [20]. MSI was introduced to detect RVO with a light source ranging 550–850 nm, covering the wavelength of FP and OCT, and showing en face images [14]. In this study, we focused mainly on shortwave images (580 nm, yellow), which enhance anterior and mid-retina specular
reflections (the visibility of the retinal vasculature and nerve fiber layer) and improve the visualization of hemorrhage, cotton-wool spots, and hard exudates (AUC ¼ 0.888, 0.939, 0.943, respectively). Disorders in this layer that are not obvious in FP images can be detected by MSI (e.g., Case 3), which improves the diagnostic power. Epiretinal membrane, which occurs in the anterior-retinal layers and is almost transparent when viewed with a conventional white light source (used by FP), is also more obvious in this wavelength (e.g., Case 5) [12,14]. The high oxygen demands of the retina and the relatively sparse nature of the retinal vasculature are thought to contribute to the retina’s vulnerability to vascular disease, including RVO [21]. In our study, the retinal oxy–deoxy map showed an obvious difference in the study eye of CRVO patients compared to the fellow eye (e.g., Case 3). This map can also be used to find the nonperfusion area (AUC ¼ 0.714) and can partly replace the FFA examination. Small nonperfusion areas in FFA images that are not shown in MSI oxy–deoxy maps might appear as vascular abnormalities around the area in MSI 580 nm (yellow) images. Oxy–deoxy maps and MSI
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Fig. 7. Case 5: MSI, FP, OCT, and FFA images of a 76-year-old woman with branch retinal vein occlusion in her left eye. FP image shows hard exudates (arrowhead) and cotton-wool spots (yellow arrow). SD-OCT shows epiretinal membrane (top row, right) inferior to the macula (green line, top row, middle). MSI 580 nm (yellow) image shows the features on the FP as well as epiretinal membrane (yellow stars, bottom row, left). FA shows a small piece of nonperfusion area (white star, bottom row, right), which is not obvious on the MSI oxy–deoxy map (bottom row, middle); however, the vascular abnormality was found on the MSI 580 nm (yellow) image (white star, bottom row, left).
580 nm (yellow) images can be used to diagnose the nonperfusion area, especially in patients who are allergic to fluorescein [12,13]. Limitations of this study include limited precision of the results, given the small number patients evaluated. Future prospective and larger consecutive case studies might be able to show diagnostic power better than this study. Furthermore, nonperfusion areas located outside the MSI capture zoom contributed to low sensitivity. Only obvious edemas were detectable in the MSI images showing that it is not as sensitive as OCT. In addition, MSI was unable to observe exudative lesions dynamically compared with FFA. Viewed from this aspect, FFA is still irreplaceable. In conclusion, MSI revealed the full spectrum of changes caused by RVO disease including nonperfusion area, retinal hemorrhage, cotton-wool spots, and hard exudates. MSI is capable of detecting hemorrhage and cotton-wool spots in cases where the fluorescein masking of FA images causes confusion. MSI also has the ability to map retinal vasculature oxygen levels and find nonperfusion areas by detecting oxygenation of the blood. In addition, comparing
MSI oxy–deoxy maps from the same patient could easily identify differences in oxygen supply, even if the vascular diameters are the same. Because MSI is basically an injection-free angiography, using it avoids potentially lifethreatening complications due to anaphylaxis to fluorescein [10,12]. Despite some limitations, MSI is a promising tool for diagnosing and screening RVO. ACKNOWLEDGMENTS Financial support for this study was provided by National Natural Science Foundation of China (nos. 81302683, 81273424, and 81170862), and Shanghai Natural Science Foundation (13ZR1459700). REFERENCES 1. Thach AB,Yau L, Hoang C, Tuomi L. Time to clinically significant visual acuity gains after ranibizumab treatment for retinal vein occlusion: BRAVO and CRUISE trials. Ophthalmology 2014;121(5):1059–1066. 2. Rogers S, McIntosh RL, Cheung N, Lim L, Wang JJ, Mitchell P, Kowalski JW, Nguyen H, Wong TY. International Eye Disease C. The prevalence of retinal vein occlusion: Pooled
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