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Using Optical Coherence Tomography to Monitor Photodynamic Therapy in Age Related Macular Degeneration
Using Optical Coherence Tomography to Monitor Photodynamic Therapy in Age Related Macular Degeneration ANGEL SALINAS-ALAMÁN, MD, PHD, ALFREDO GARCÍA-LAYANA, MD, PHD, MIGUEL J. MALDONADO, MD, PHD, CARMEN SAINZ-GÓMEZ, MD, PHD, AND AURORA ALVÁREZ-VIDAL, MS
● PURPOSE: To evaluate the role of optical coherence tomography (OCT) in determining choroidal neovascularization (CNV) activity before and after photodynamic therapy (PDT) in patients with age-related macular degeneration (ARMD). ● DESIGN: Prospective observational case series. ● METHODS: SETTING: Institutional study. PATIENT POPULATION: Fifty-three patients (62 eyes) with ARMD. OBSERVATION PROCEDURE: Prospective observational case study. MAIN OUTCOME MEASURES: Presence or absence of leakage on fluorescein angiography, presence of intraretinal or sub-retinal fluid on OCT, and macular and choroidal neovascular complex thickness on OCT. ● RESULTS: The macular thickness decreased significantly after PDT (P ⴝ .001). However, no significant changes in CNV thickness were measured after PDT (P ⴝ .567). Once the diagnosis of ARMD was established before treatment, OCT had a sensitivity of 96.77% for detecting CNV activity. After treatment, OCT had a good sensitivity (95.65%) and a moderate specificity (59.01%) in determining CNV activity, which resulted in a diagnostic efficiency (proportion of correct results) of 82.95%. ● CONCLUSIONS: OCT appears to be useful for indicating CNV activity. Therefore, it may serve as a complementary technique for deciding the need for PDT and re-treatment in patients with ARMD. (Am J Ophthalmol 2005;140:23–28. © 2005 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 25, 2005. From the Department of Ophthalmology, University Clinic, University of Navarra, Pamplona, Spain. Inquiries to Angel Salinas-Alamán, MD, PhD, Departament of Ophthalmology, Clínica Universitaria de Navarra, Avda. Pío XII, 36, 31080 Pamplona, Spain; fax: 00-34-948-296500; e-mail: asalinas@ unav.es 0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.01.044
©
2005 BY
C
HOROIDAL NEOVASCULARIZATION (CNV) IN AGE-
related macular degeneration (ARMD) is the leading cause of severe vision loss in people age 60 years and older in Western countries.1,2 Photodynamic therapy (PDT) is an effective treatment for some of these patients.3–5 Based on the results of the Treatment of Age-Related Macular Degeneration with Verteporfin Study and the Verteporfin in Photodynamic Therapy Study,3–5 PDT has been shown to be a beneficial treatment for subfoveal CNV related to ARMD, except when lesions are minimally classic on fluorescein angiography (FA). Currently, the presence or absence of fluorescein leakage and the angiographic appearance of neovascular ARMD are the main criteria in the decision to treat and re-treat using PDT.6 Optical coherence tomography (OCT) is a medical diagnostic imaging technique that can obtain cross-sectional or tomographic images in biologic tissues.7 OCT is a good imaging system for evaluating macular pathology.8 –10 For ARMD, OCT appears to be useful for evaluating the responses of the retina and retinal pigment epithelium to PDT.11 OCT permits direct visualization of a cross-section of the CNV and the possibility of measuring the lesions.7 OCT is useful for quantitatively evaluating sub-retinal and intraretinal fluid, assessing possible sub-foveal involvement of neovascularization, and monitoring CNV before and after laser photocoagulation.12 However, OCT cannot detect other features including blood, lipid, and vascular patterns. The aim of this study was to assess the sensitivity and specificity of OCT in detecting the presence of sub-retinal or intraretinal fluid for determining CNV activity before and after PDT. We also evaluated the role of OCT in detecting changes associated with PDT.
PATIENTS AND METHODS A TOTAL OF 53 CONSECUTIVE PATIENTS (62 EYES) WHO
presented with signs of exudative ARMD with predomi-
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nantly classic CNV were included in this prospective observational case study. In nine patients, both eyes had CNV caused by ARMD. A total of 62 eyes were then analyzed, and 42 of them were evaluated at the 12-month follow-up examination; the other 20 were evaluated at least at the 6-month follow-up visit. All patients provided written informed consent, and the study was approved by the university clinic research committee. All patients underwent a complete ophthalmic evaluation every 3 months. Additionally, FA and OCT images were obtained with dilated pupils. The best-corrected visual acuity (BCVA) was evaluated with a Snellen chart. The same certified optometrist measured the BCVA in each case. Visual acuity (VA) was determined using the Snellen chart. During the evolution of ARMD, when the BCVA reached 20/400, Early Treatment of Diabetic Retinopathy at 2 m was used; in this case, the VA was expressed as the Snellen equivalent. The VA was considered stable when it increased or decreased less than 2 lines on the Snellen chart. If the change in VA was 2 or more lines on the Snellen chart, the change was considered to be an increase or decrease in BCVA. FA images were captured after intravenous injection of 3 ml of sodium fluorescein 20%. The same two independent observers determined the presence or absence of leakage on the angiograms in every case. If no agreement was reached between the two observers, the criteria of the same senior retina specialist were accepted as valid. Optical coherence tomograms were obtained with a commercially available unit (OCT 2000 scanner, Humphrey Instruments, San Leandro, California), using the previously reported methodology.8,9 For this study, the same experienced technician performed all OCT evaluations. When the experienced OCT technician was ill, a less experienced technician performed the OCT examinations. The scans not acquired by the experienced OCT technician were not included in the statistical analysis. Another independent observer, who was masked to the patient status, evaluated the OCT scans on each occasion. The following data were recorded: retinal thickness at the fovea, choroidal neovascular complex thickness, and presence or absence of sub-retinal and intraretinal fluid. Measurements of the retinal thickness at the fovea were performed using a manually assisted technique in the system software (A-5; Zeiss-Humphrey Instruments, San Segundo, California, USA). Foveal fixation and landmark functions were used to perform every scan in the same region of the macula. In cases in which well-defined thickness and fragmentation of the retinal pigment epithelium/choriocapillaris reflection were observed, it was assumed that these represented CNV.12 Only the well-defined CNV on the OCT scans were manually measured to determine thickening. If sub-retinal or intraretinal fluid was present on the OCT scan, that remark was considered positive. FA leakage was considered the standard reference for these two findings in 23.e2
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OCT and was considered positive when leakage was present. Sensitivity, specificity, diagnostic efficiency, and the likelihood ratio for a positive and a negative test were calculated for OCT, with FA as the standard reference. However, FA does not provide information about macular and CNV thickness. For that reason, OCT thickness measurements could not be correlated with FA. The Student t test was used to assess differences between paired means (macular and CNV thickness change). P values less than .05 were considered significant. The association between the pre-treatment macular thickness and the pre-treatment CNV thickness with BCVA evolution (post-treatment minus pre-treatment BCVA) was calculated with Pearson correlation coefficient.
RESULTS FIFTY-THREE CONSECUTIVE WHITE PATIENTS (26 MEN, 27
women) were included in this study. The average age was 76.50 ⫾ 7.5 SD years. A total of 62 eyes were analyzed; 32 were right eyes and 30 were left eyes. The mean number of treatments was 2.5 ⫾ 1.2 SD (range, 1 to 3) in the group of eyes (n ⫽ 62) followed for 6 months, and 2.9 ⫾ 1.1 SD (range, 1 to 5) in the group followed for 12 months (n ⫽ 42). All sets of FA and OCT scans (n ⫽ 62) were obtained before treatment. However, after the first treatment of the 208 sets of FA and OCT that were expected, 176 (84.6%) were obtained as the result of intolerance to FA in 12 cases (5.8%), and in 20 cases (9.6%) the OCT technician was unavailable at that particular visit for the examination. The median BCVA before treatment was 20/80 (interquartile range, 20/140 to 20/50). In the 62 eyes followed for 6 months, 40 (64.5%) of the eyes maintained the BCVA after treatment, seven (11.3%) of the eyes improved 2 or more lines in vision after treatment, and 15 (24.2%) of the eyes had a worse BCVA despite treatment. The respective percentages in the group followed for 12 months were 59.5% (25 eyes), 11.9% (five eyes), and 28.6% (12 eyes). Macular thickness was measured with OCT at the pre-treatment examination and at the 6-month follow-up visit in 62 eyes. At the 12-month follow-up examination, the macular thickness was measured in 42 eyes. Table 1 shows the data regarding macular thickness and CNV thickness. Statistically significant differences were observed between the macular thickness at 6 months (329.82 ⫾ 95.22 m) and the pre-treatment macular thickness (400.05 ⫾ 119.14 m, paired t test; P ⫽ .001). Significant differences also were found between the macular thickness at the 12-month follow-up visit (304.53 ⫾ 91.89 m) and the initial macular thickness (400.05 ⫾ 119.14 m, paired t test, P ⫽ .001). OF
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TABLE 1. Change in Macular and Choroidal Neovascularization Thickness After Photodynamic Therapy Pre-treatment (n ⫽ 62)
6 Months (n ⫽ 62)
12 Months (n ⫽ 42)
Retinal thickness at 400 (119 SD) 329 (95 SD)* 304 (91 SD)† fovea (m) CNV thickness (m) 191 (63 SD) 198 (59 SD) 209 (69 SD) CNV ⫽ Choroidal neovascularization. *Statistically significant difference with respect to the pretreatment measure (P ⫽ .001). † Statistically significant difference with respect to the pretreatment measure (P ⫽ .001).
FIGURE 1. Pre-treatment of the left eye of a patient with exudative age related macular degeneration (ARMD). (Top left) Fundus photograph shows microhemorrhage and signs of choroidal neovascularization (CNV). (Top right) Optical coherence tomography (OCT) shows intraretinal and sub-retinal fluids (white stars). The CNV complex also is identifiable in OCT scan (white arrows). (Bottom left) Early phase of angiogram shows a predominantly classic CNV membrane. (Bottom right) Leakage on a late-phase angiogram.
The thickness of the CNV complex was also obtained at the same examinations. At pre-treatment and the 6-month follow-up visits, well-defined CNV on the OCT scans was identified and measured in 38 (61.29%) of 62 eyes. At the 12-month follow-up visit, well-defined CNV on the OCT scans was measured in 24 (57.14%) of 42 eyes. In the rest of the scans, the CNV could not be clearly identified. No statistically significant changes in CNV thickness were observed at the 6-month follow-up examination (198.92 ⫾ 59.66 m) with respect to the initial CNV thickness (191.02 ⫾ 63.55 m) (paired t test, P ⫽ .567) (Table 1). Likewise, differences in CNV thickness at the 12-month follow-up visit (209.40 ⫾ 69.24 m) and before treatment VOL. 140, NO. 1
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(191.02 ⫾ 63.55 m) were not statistically significant (paired t test, P ⫽ .357). No significant correlation was found between the pretreatment macular thickness and changes in BCVA after 6 (r ⫽ .02; P ⫽ .85) or 12 months (r ⫽ .03; P ⫽ .84). Likewise, no significant correlation was found between the pre-treatment CNV thickness and changes in BCVA after 6 (r ⫽ .02; P ⫽ .92) or 12 months (r ⫽ .28; P ⫽ .29). Before treatment, leakage on the FA was found in all eyes and OCT detected the presence of either intraretinal or sub-retinal fluid (Figure 1) in 60 (96.77%) of 62 eyes. Therefore, with FA as the reference standard, OCT had a sensitivity of nearly 97% in detecting CNV activity. Only two cases (3.22%) in which leakage was present on pre-treatment FA were considered negative on OCT. After treatment, there was a total of 115 remarks in which leakage was observed on FA; in 110 (95.65%) of them OCT showed intraretinal or sub-retinal fluid (Figure 2). Nevertheless, of a total of 61 angiograms in which no leakage was observed, only 36 (59.01%) had no intraretinal or sub-retinal fluid (Figure 3). In the group with no leakage on FA but with fluid on OCT (n ⫽ 25), 19 cases (76%) presented with cystoid macular edema. With FA as the standard, OCT achieved a sensitivity of 95.65% in determining CNV activity after treatment. However, OCT obtained a moderate specificity of 59.01%. The likelihood ratio for a positive test was 2.31, and the likelihood ratio for a negative test was 0.08. A diagnostic efficiency of 82.95% was calculated for the presence of intraretinal or sub-retinal fluid in OCT to detect post-treatment CNV activity.
DISCUSSION IN THE PRESENT STUDY, WE DEMONSTRATED THAT THE
total macular thickness decreased after PDT. Additionally, once CNV caused by ARMD was diagnosed, intraretinal and sub-retinal fluid detected on OCT appeared to have excellent sensitivity and moderate specificity in detecting CNV activity with FA leakage as the standard test. The macular thickness could be measured before and after treatment in all cases. Our results indicated that the macular thickness decreased significantly at the 6- and 12-month follow-up visits. According to the stage II and V classification of Rogers and associates,11 sub-retinal fluid diminishes after PDT in a notable proportion of eyes. We hypothesize, therefore, that the significant reduction in macular thickness in our series resulted from partial or total resolution of the sub-retinal fluid, intraretinal fluid, or both. We identified, according to the description of Hee and the CNV complex in nearly 60% of eyes pre-treatment and at the 6-month follow-up visit and in a slightly lower percentage (57.14%) at the 12-month follow-up visit. A difficulty identifying the CNV complex by OCT was
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used alone to detect the presence of CNV. Currently, posterior pole biomicroscopy and FA are needed to correctly establish a diagnosis of CNV associated with ARMD. PDT was reported to have a vaso-occlusive mechanism that affects both the CNV and the normal choroid.13 However, compared with other treatment modalities such as laser photocoagulation, CNV does not completely resolve after PDT as examined by indocyanine green angiography.14 Some authors reported the clinicopathologic findings of CNV specimens obtained after PDT. Schnurrbusch and associates15 reported two CNV specimens removed from patients with ARMD after PDT; one was removed 14 weeks after ocular PDT and the second, 14 months after PDT. The findings in that report were diffuse endothelial damage, evidence of vascular occlusion, patent vessels within the CNV complex, and diffuse inflammatory infiltrates. Other authors, who described CNV specimens obtained from 3 to 152 days after PDT,16 reported evidence of vascular occlusion on histopathologic examination only at the earliest time point, and no specimens removed more than 3 days after PDT had thrombus formation. Those authors reported that the vessels were temporarily or partially occluded after PDT and then re-perfused, or that they were never occluded. In the current study, using OCT, we did not find significant changes in CNV thickness after PDT. Although we used foveal fixation and landmark functions to attempt to achieve good image registration, it is possible that the difficulty of precisely replicating the scan location could have introduced errors in the interpretation of the changes in lesion thickness over time. In fact, a nonstatistically significant increment in CNV thickness was verified at the 6- and 12-month follow-up visits. This might be related to the merging of the fibrosis with the retinal epithelial layer that Rogers and associates described in their classification as stages IIIb and V.11 We did not find a significant correlation between BCVA changes and pre-treatment macular thickness or pre-treatment CNV thickness, which may indicate that pre-treatment macular thickness is not associated with the final success of PDT. Likewise, it may be that CNV extent17 but not the pre-treatment CNV thickness has an impact on the outcome after PDT. We reached the decision to re-treat patients based on BCVA and FA. The presence of fluorescein leakage from CNV was the main criterion for deciding to re-treat patients during follow-up, as indicated by previous studies.3–5 Nevertheless, we found that FA is sometimes difficult to interpret. Other authors have reported substantial variations in the agreement between both observers and the individual reader in classifying the type of CNV in eyes with ARMD.18 –20 In our study, agreement about the presence of leakage between the two observers was achieved in 216 (90.75%) of 238 angiograms. When both
FIGURE 2. The right eye of a patient 3 months after the first photodynamic therapy (PDT) session. (Top left) Fundus photograph shows ophthalmoscopic signs of CNV. (Top right) Intraretinal fluid (white stars) and hyperreflective intraretinal structure (white arrows), related to the fibrosis, blood, and CNV complex observed during a fundus examination are present on the OCT scan. (Bottom left) Early-phase angiogram shows predominantly classic sub-foveal CNV. (Bottom right) Late-phase angiogram shows fluorescein leakage.
FIGURE 3. The right eye of a patient after three PDT sessions. (Top left) Fundus photograph does not show ophthalmoscopic signs of lesion activity. (Top right) Hyperreflective lesion related to the CNV complex identified on fluorescein angiography is identifiable on OCT (white arrows), but no intraretinal or sub-retinal fluid is seen. (Bottom left and right) Early and late phases of angiogram, respectively, show staining of the lesion but no leakage.
previously described; Hee and colleagues12 reported that seven (77.7%) of nine classic CNV lesions were considered well defined by OCT. However, only one (20%) of five in classic and occult CNV lesions was well defined by OCT in their series. Nevertheless, because OCT cannot differentiate blood and fibrosis from CNV, OCT cannot be 23.e4
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observers did not agree, the criteria of the senior of the two prevailed. In retrospect, we found that in cases in which FA was inconclusive, OCT could have provided useful information regarding treatment or re-treatment, considering the remarkable sensitivity of OCT (96.77% and 95.65%, respectively). OCT was considered as positive (presence of sub-retinal fluid and/or intraretinal fluid) in 25 (14.2%) of the cases in which FA did not show clear leakage. In our series, 76% of the cases with positive OCT findings and no leakage on FA (false positives) had a disciform scar with persistent cystic cavities on OCT. We, therefore, suggest that in cases in which fluid is seen on OCT and no leakage is seen on FA, a disciform scar should be ruled out in the fundus examination, because in these cases no treatment is indicated.6 We also hypothesize that if there is no disciform scar visible during the fundus examination, the presence of remaining fluid on the OCT scan may indicate residual CNV activity that could be misdiagnosed on FA. It is also valid to assume that a hyperreflective structure on OCT could be misinterpreted without a fundus examination. Therefore, we believe that OCT, FA, and a fundus examination are complementary examinations that should be interpreted together. OCT was reported to be as effective in detecting macular edema as FA in patients with uveitis21 and patients with non-diabetic macular edema.22 Recently, a significant correlation was reported between the features of OCT and FA in diabetic macular edema, and that both OCT and FA provide information that may be useful to optimize the treatment for each type of edema.23 Other prospective studies may be warranted to determine whether interpretation of OCT scans has good intraobserver and interobserver agreement for the presence of intraretinal and sub-retinal fluid in CNV related to ARMD. In conclusion, OCT may be a good complementary imaging technique in the decision-making process regarding treatment or re-treatment of CNV in ARMD with PDT. Using FA as the standard reference, OCT has high sensitivity but only moderate specificity in detecting CNV activity before and after PDT. In view of the high sensitivity of OCT in detecting CNV activity, if no intraretinal or sub-retinal fluid is observed in OCT, it is unlikely that CNV activity exists. This may be especially useful when FA is inconclusive,6,18 or the general condition of the patient does not allow frequent FA examinations.24
REFERENCES 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933–943.
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2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–210. 3. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin. One-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol 1999;117:1329 –1345. 4. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin. Two year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol 2001;119:198 –207. 5. Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001;131:541– 560. 6. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) and Verteporfin in Photodynamic Therapy (VIP) Study Groups. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin. Fluorescein angiographic guidelines for evaluation and treatment—TAP and VIP Report No. 2. Arch Ophthalmol 2003;121:1253–1268. 7. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178 –1181. 8. Sánchez-Tocino H, Álvarez-Vidal A, Maldonado MJ, et al. Retinal thickness study with optical coherence tomography in patients with diabetes. Invest Ophthalmol Vis Sci 2002; 43(5):1588 –1594. 9. Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995;113:1019 –1029. 10. Puliafito CA, Hee MR, Lin CP, et al. Imaging of macular disease with optical coherence tomography. Ophthalmology 1995;102:217–229. 11. Rogers AH, Martidis A, Greenberg PB, et al. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol 2002;134(4):566 – 576. 12. Hee MR, Baumal CR, Puliafito CA, et al. Optical coherence tomography of age-related macular degeneration and choroidal neovascularization. Ophthalmology 1996;103:1260 –1270. 13. Costa RA, Farah ME, Cardillo JA, et al. Immediate indocyanine green angiography and optical coherence tomography evaluation after photodynamic therapy for subfoveal choroidal neovascularization. Retina 2003;23:159 –165. 14. Schmidt-Erfurth U, Michels S, Barbazetto I, et al. Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 2002;43(3):830 – 841. 15. Schnurrbusch UEK, Welt K, Horn LC, Wiedemann P, Wolf S. Histological findings of surgical excised choroidal neovascular membranes after photodynamic therapy. Br J Ophthalmol 2001;85:1086 –1091.
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20. Friedman SM, Margo CE. Choroidal neovascular membranes: reproducibility of angiographic interpretation. Am J Ophthalmol 2000;130:839 – 841. 21. Antcliff RJ, Stanford MR, Chauhan DS, et al. Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis. Ophthalmology 2000;107: 593–599. 22. Schneeberg AE, Gobel W. Diagnosis and follow-up of non-diabetic macular edema with optical coherence tomography. Ophthalmologe 2003;100:960 –966. 23. Kang SW, Park CY, Ham DI. The correlation between fluorescein angiographic and optical coherence tomographic features in clinically significant diabetic macular edema. Am J Ophthalmol 2004;137:313–322. 24. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986;93: 611– 617.
16. Moshfeghi DM, Kaiser PK, Grossniklaus HE, et al. Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy. Am J Ophthalmol 2003;135:343–350. 17. Blinder KJ, Bradley S, Bressler NM, et al. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003;136:407– 418. 18. Holz FG, Jorzik J, Schutt F, et al. Agreement among ophthalmologists in evaluating fluorescein angiograms in patients with neovascular age-related macular degeneration for photodynamic therapy eligibility (FLAPStudy). Ophthalmology 2003;110:400 – 405. 19. Kaiser RS, Berger JW, Williams GA, et al. Variability in fluorescein angiography interpretation for photodynamic therapy in age-related macular degeneration. Retina 2002; 22:683– 690.
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Biosketch Angel Salinas-Alaman, MD, PhD, is associate professor of ophthalmology at the Department of Ophthalmology, University Clinic of Navarra, Pamplona, Spain. Dr. Salinas-Alaman earned his MD and PhD from the Facultdad de Medicina, University of Navarra and completed his residency at the Department of Ophthalmology, Hospital of Zaragoza, Spain. His research interest is age-related macular degeneration and his specialties are diabetic retinopathy, macular degeneration, macular diseases, and vitreoretinal diseases and surgery.
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● PURPOSE: To evaluate the role of optical coherence tomography (OCT) in determining choroidal neovascularization (CNV) activity before and after photodynamic therapy (PDT) in patients with age-related macular degeneration (ARMD). ● DESIGN: Prospective observational case series. ● METHODS: SETTING: Institutional study. PATIENT POPULATION: Fifty-three patients (62 eyes) with ARMD. OBSERVATION PROCEDURE: Prospective observational case study. MAIN OUTCOME MEASURES: Presence or absence of leakage on fluorescein angiography, presence of intraretinal or sub-retinal fluid on OCT, and macular and choroidal neovascular complex thickness on OCT. ● RESULTS: The macular thickness decreased significantly after PDT (P ⴝ .001). However, no significant changes in CNV thickness were measured after PDT (P ⴝ .567). Once the diagnosis of ARMD was established before treatment, OCT had a sensitivity of 96.77% for detecting CNV activity. After treatment, OCT had a good sensitivity (95.65%) and a moderate specificity (59.01%) in determining CNV activity, which resulted in a diagnostic efficiency (proportion of correct results) of 82.95%. ● CONCLUSIONS: OCT appears to be useful for indicating CNV activity. Therefore, it may serve as a complementary technique for deciding the need for PDT and re-treatment in patients with ARMD. (Am J Ophthalmol 2005;140:23–28. © 2005 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 25, 2005. From the Department of Ophthalmology, University Clinic, University of Navarra, Pamplona, Spain. Inquiries to Angel Salinas-Alamán, MD, PhD, Departament of Ophthalmology, Clínica Universitaria de Navarra, Avda. Pío XII, 36, 31080 Pamplona, Spain; fax: 00-34-948-296500; e-mail: asalinas@ unav.es 0002-9394/05/$30.00 doi:10.1016/j.ajo.2005.01.044
©
2005 BY
C
HOROIDAL NEOVASCULARIZATION (CNV) IN AGE-
related macular degeneration (ARMD) is the leading cause of severe vision loss in people age 60 years and older in Western countries.1,2 Photodynamic therapy (PDT) is an effective treatment for some of these patients.3–5 Based on the results of the Treatment of Age-Related Macular Degeneration with Verteporfin Study and the Verteporfin in Photodynamic Therapy Study,3–5 PDT has been shown to be a beneficial treatment for subfoveal CNV related to ARMD, except when lesions are minimally classic on fluorescein angiography (FA). Currently, the presence or absence of fluorescein leakage and the angiographic appearance of neovascular ARMD are the main criteria in the decision to treat and re-treat using PDT.6 Optical coherence tomography (OCT) is a medical diagnostic imaging technique that can obtain cross-sectional or tomographic images in biologic tissues.7 OCT is a good imaging system for evaluating macular pathology.8 –10 For ARMD, OCT appears to be useful for evaluating the responses of the retina and retinal pigment epithelium to PDT.11 OCT permits direct visualization of a cross-section of the CNV and the possibility of measuring the lesions.7 OCT is useful for quantitatively evaluating sub-retinal and intraretinal fluid, assessing possible sub-foveal involvement of neovascularization, and monitoring CNV before and after laser photocoagulation.12 However, OCT cannot detect other features including blood, lipid, and vascular patterns. The aim of this study was to assess the sensitivity and specificity of OCT in detecting the presence of sub-retinal or intraretinal fluid for determining CNV activity before and after PDT. We also evaluated the role of OCT in detecting changes associated with PDT.
PATIENTS AND METHODS A TOTAL OF 53 CONSECUTIVE PATIENTS (62 EYES) WHO
presented with signs of exudative ARMD with predomi-
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nantly classic CNV were included in this prospective observational case study. In nine patients, both eyes had CNV caused by ARMD. A total of 62 eyes were then analyzed, and 42 of them were evaluated at the 12-month follow-up examination; the other 20 were evaluated at least at the 6-month follow-up visit. All patients provided written informed consent, and the study was approved by the university clinic research committee. All patients underwent a complete ophthalmic evaluation every 3 months. Additionally, FA and OCT images were obtained with dilated pupils. The best-corrected visual acuity (BCVA) was evaluated with a Snellen chart. The same certified optometrist measured the BCVA in each case. Visual acuity (VA) was determined using the Snellen chart. During the evolution of ARMD, when the BCVA reached 20/400, Early Treatment of Diabetic Retinopathy at 2 m was used; in this case, the VA was expressed as the Snellen equivalent. The VA was considered stable when it increased or decreased less than 2 lines on the Snellen chart. If the change in VA was 2 or more lines on the Snellen chart, the change was considered to be an increase or decrease in BCVA. FA images were captured after intravenous injection of 3 ml of sodium fluorescein 20%. The same two independent observers determined the presence or absence of leakage on the angiograms in every case. If no agreement was reached between the two observers, the criteria of the same senior retina specialist were accepted as valid. Optical coherence tomograms were obtained with a commercially available unit (OCT 2000 scanner, Humphrey Instruments, San Leandro, California), using the previously reported methodology.8,9 For this study, the same experienced technician performed all OCT evaluations. When the experienced OCT technician was ill, a less experienced technician performed the OCT examinations. The scans not acquired by the experienced OCT technician were not included in the statistical analysis. Another independent observer, who was masked to the patient status, evaluated the OCT scans on each occasion. The following data were recorded: retinal thickness at the fovea, choroidal neovascular complex thickness, and presence or absence of sub-retinal and intraretinal fluid. Measurements of the retinal thickness at the fovea were performed using a manually assisted technique in the system software (A-5; Zeiss-Humphrey Instruments, San Segundo, California, USA). Foveal fixation and landmark functions were used to perform every scan in the same region of the macula. In cases in which well-defined thickness and fragmentation of the retinal pigment epithelium/choriocapillaris reflection were observed, it was assumed that these represented CNV.12 Only the well-defined CNV on the OCT scans were manually measured to determine thickening. If sub-retinal or intraretinal fluid was present on the OCT scan, that remark was considered positive. FA leakage was considered the standard reference for these two findings in 23.e2
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OCT and was considered positive when leakage was present. Sensitivity, specificity, diagnostic efficiency, and the likelihood ratio for a positive and a negative test were calculated for OCT, with FA as the standard reference. However, FA does not provide information about macular and CNV thickness. For that reason, OCT thickness measurements could not be correlated with FA. The Student t test was used to assess differences between paired means (macular and CNV thickness change). P values less than .05 were considered significant. The association between the pre-treatment macular thickness and the pre-treatment CNV thickness with BCVA evolution (post-treatment minus pre-treatment BCVA) was calculated with Pearson correlation coefficient.
RESULTS FIFTY-THREE CONSECUTIVE WHITE PATIENTS (26 MEN, 27
women) were included in this study. The average age was 76.50 ⫾ 7.5 SD years. A total of 62 eyes were analyzed; 32 were right eyes and 30 were left eyes. The mean number of treatments was 2.5 ⫾ 1.2 SD (range, 1 to 3) in the group of eyes (n ⫽ 62) followed for 6 months, and 2.9 ⫾ 1.1 SD (range, 1 to 5) in the group followed for 12 months (n ⫽ 42). All sets of FA and OCT scans (n ⫽ 62) were obtained before treatment. However, after the first treatment of the 208 sets of FA and OCT that were expected, 176 (84.6%) were obtained as the result of intolerance to FA in 12 cases (5.8%), and in 20 cases (9.6%) the OCT technician was unavailable at that particular visit for the examination. The median BCVA before treatment was 20/80 (interquartile range, 20/140 to 20/50). In the 62 eyes followed for 6 months, 40 (64.5%) of the eyes maintained the BCVA after treatment, seven (11.3%) of the eyes improved 2 or more lines in vision after treatment, and 15 (24.2%) of the eyes had a worse BCVA despite treatment. The respective percentages in the group followed for 12 months were 59.5% (25 eyes), 11.9% (five eyes), and 28.6% (12 eyes). Macular thickness was measured with OCT at the pre-treatment examination and at the 6-month follow-up visit in 62 eyes. At the 12-month follow-up examination, the macular thickness was measured in 42 eyes. Table 1 shows the data regarding macular thickness and CNV thickness. Statistically significant differences were observed between the macular thickness at 6 months (329.82 ⫾ 95.22 m) and the pre-treatment macular thickness (400.05 ⫾ 119.14 m, paired t test; P ⫽ .001). Significant differences also were found between the macular thickness at the 12-month follow-up visit (304.53 ⫾ 91.89 m) and the initial macular thickness (400.05 ⫾ 119.14 m, paired t test, P ⫽ .001). OF
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TABLE 1. Change in Macular and Choroidal Neovascularization Thickness After Photodynamic Therapy Pre-treatment (n ⫽ 62)
6 Months (n ⫽ 62)
12 Months (n ⫽ 42)
Retinal thickness at 400 (119 SD) 329 (95 SD)* 304 (91 SD)† fovea (m) CNV thickness (m) 191 (63 SD) 198 (59 SD) 209 (69 SD) CNV ⫽ Choroidal neovascularization. *Statistically significant difference with respect to the pretreatment measure (P ⫽ .001). † Statistically significant difference with respect to the pretreatment measure (P ⫽ .001).
FIGURE 1. Pre-treatment of the left eye of a patient with exudative age related macular degeneration (ARMD). (Top left) Fundus photograph shows microhemorrhage and signs of choroidal neovascularization (CNV). (Top right) Optical coherence tomography (OCT) shows intraretinal and sub-retinal fluids (white stars). The CNV complex also is identifiable in OCT scan (white arrows). (Bottom left) Early phase of angiogram shows a predominantly classic CNV membrane. (Bottom right) Leakage on a late-phase angiogram.
The thickness of the CNV complex was also obtained at the same examinations. At pre-treatment and the 6-month follow-up visits, well-defined CNV on the OCT scans was identified and measured in 38 (61.29%) of 62 eyes. At the 12-month follow-up visit, well-defined CNV on the OCT scans was measured in 24 (57.14%) of 42 eyes. In the rest of the scans, the CNV could not be clearly identified. No statistically significant changes in CNV thickness were observed at the 6-month follow-up examination (198.92 ⫾ 59.66 m) with respect to the initial CNV thickness (191.02 ⫾ 63.55 m) (paired t test, P ⫽ .567) (Table 1). Likewise, differences in CNV thickness at the 12-month follow-up visit (209.40 ⫾ 69.24 m) and before treatment VOL. 140, NO. 1
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(191.02 ⫾ 63.55 m) were not statistically significant (paired t test, P ⫽ .357). No significant correlation was found between the pretreatment macular thickness and changes in BCVA after 6 (r ⫽ .02; P ⫽ .85) or 12 months (r ⫽ .03; P ⫽ .84). Likewise, no significant correlation was found between the pre-treatment CNV thickness and changes in BCVA after 6 (r ⫽ .02; P ⫽ .92) or 12 months (r ⫽ .28; P ⫽ .29). Before treatment, leakage on the FA was found in all eyes and OCT detected the presence of either intraretinal or sub-retinal fluid (Figure 1) in 60 (96.77%) of 62 eyes. Therefore, with FA as the reference standard, OCT had a sensitivity of nearly 97% in detecting CNV activity. Only two cases (3.22%) in which leakage was present on pre-treatment FA were considered negative on OCT. After treatment, there was a total of 115 remarks in which leakage was observed on FA; in 110 (95.65%) of them OCT showed intraretinal or sub-retinal fluid (Figure 2). Nevertheless, of a total of 61 angiograms in which no leakage was observed, only 36 (59.01%) had no intraretinal or sub-retinal fluid (Figure 3). In the group with no leakage on FA but with fluid on OCT (n ⫽ 25), 19 cases (76%) presented with cystoid macular edema. With FA as the standard, OCT achieved a sensitivity of 95.65% in determining CNV activity after treatment. However, OCT obtained a moderate specificity of 59.01%. The likelihood ratio for a positive test was 2.31, and the likelihood ratio for a negative test was 0.08. A diagnostic efficiency of 82.95% was calculated for the presence of intraretinal or sub-retinal fluid in OCT to detect post-treatment CNV activity.
DISCUSSION IN THE PRESENT STUDY, WE DEMONSTRATED THAT THE
total macular thickness decreased after PDT. Additionally, once CNV caused by ARMD was diagnosed, intraretinal and sub-retinal fluid detected on OCT appeared to have excellent sensitivity and moderate specificity in detecting CNV activity with FA leakage as the standard test. The macular thickness could be measured before and after treatment in all cases. Our results indicated that the macular thickness decreased significantly at the 6- and 12-month follow-up visits. According to the stage II and V classification of Rogers and associates,11 sub-retinal fluid diminishes after PDT in a notable proportion of eyes. We hypothesize, therefore, that the significant reduction in macular thickness in our series resulted from partial or total resolution of the sub-retinal fluid, intraretinal fluid, or both. We identified, according to the description of Hee and the CNV complex in nearly 60% of eyes pre-treatment and at the 6-month follow-up visit and in a slightly lower percentage (57.14%) at the 12-month follow-up visit. A difficulty identifying the CNV complex by OCT was
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used alone to detect the presence of CNV. Currently, posterior pole biomicroscopy and FA are needed to correctly establish a diagnosis of CNV associated with ARMD. PDT was reported to have a vaso-occlusive mechanism that affects both the CNV and the normal choroid.13 However, compared with other treatment modalities such as laser photocoagulation, CNV does not completely resolve after PDT as examined by indocyanine green angiography.14 Some authors reported the clinicopathologic findings of CNV specimens obtained after PDT. Schnurrbusch and associates15 reported two CNV specimens removed from patients with ARMD after PDT; one was removed 14 weeks after ocular PDT and the second, 14 months after PDT. The findings in that report were diffuse endothelial damage, evidence of vascular occlusion, patent vessels within the CNV complex, and diffuse inflammatory infiltrates. Other authors, who described CNV specimens obtained from 3 to 152 days after PDT,16 reported evidence of vascular occlusion on histopathologic examination only at the earliest time point, and no specimens removed more than 3 days after PDT had thrombus formation. Those authors reported that the vessels were temporarily or partially occluded after PDT and then re-perfused, or that they were never occluded. In the current study, using OCT, we did not find significant changes in CNV thickness after PDT. Although we used foveal fixation and landmark functions to attempt to achieve good image registration, it is possible that the difficulty of precisely replicating the scan location could have introduced errors in the interpretation of the changes in lesion thickness over time. In fact, a nonstatistically significant increment in CNV thickness was verified at the 6- and 12-month follow-up visits. This might be related to the merging of the fibrosis with the retinal epithelial layer that Rogers and associates described in their classification as stages IIIb and V.11 We did not find a significant correlation between BCVA changes and pre-treatment macular thickness or pre-treatment CNV thickness, which may indicate that pre-treatment macular thickness is not associated with the final success of PDT. Likewise, it may be that CNV extent17 but not the pre-treatment CNV thickness has an impact on the outcome after PDT. We reached the decision to re-treat patients based on BCVA and FA. The presence of fluorescein leakage from CNV was the main criterion for deciding to re-treat patients during follow-up, as indicated by previous studies.3–5 Nevertheless, we found that FA is sometimes difficult to interpret. Other authors have reported substantial variations in the agreement between both observers and the individual reader in classifying the type of CNV in eyes with ARMD.18 –20 In our study, agreement about the presence of leakage between the two observers was achieved in 216 (90.75%) of 238 angiograms. When both
FIGURE 2. The right eye of a patient 3 months after the first photodynamic therapy (PDT) session. (Top left) Fundus photograph shows ophthalmoscopic signs of CNV. (Top right) Intraretinal fluid (white stars) and hyperreflective intraretinal structure (white arrows), related to the fibrosis, blood, and CNV complex observed during a fundus examination are present on the OCT scan. (Bottom left) Early-phase angiogram shows predominantly classic sub-foveal CNV. (Bottom right) Late-phase angiogram shows fluorescein leakage.
FIGURE 3. The right eye of a patient after three PDT sessions. (Top left) Fundus photograph does not show ophthalmoscopic signs of lesion activity. (Top right) Hyperreflective lesion related to the CNV complex identified on fluorescein angiography is identifiable on OCT (white arrows), but no intraretinal or sub-retinal fluid is seen. (Bottom left and right) Early and late phases of angiogram, respectively, show staining of the lesion but no leakage.
previously described; Hee and colleagues12 reported that seven (77.7%) of nine classic CNV lesions were considered well defined by OCT. However, only one (20%) of five in classic and occult CNV lesions was well defined by OCT in their series. Nevertheless, because OCT cannot differentiate blood and fibrosis from CNV, OCT cannot be 23.e4
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observers did not agree, the criteria of the senior of the two prevailed. In retrospect, we found that in cases in which FA was inconclusive, OCT could have provided useful information regarding treatment or re-treatment, considering the remarkable sensitivity of OCT (96.77% and 95.65%, respectively). OCT was considered as positive (presence of sub-retinal fluid and/or intraretinal fluid) in 25 (14.2%) of the cases in which FA did not show clear leakage. In our series, 76% of the cases with positive OCT findings and no leakage on FA (false positives) had a disciform scar with persistent cystic cavities on OCT. We, therefore, suggest that in cases in which fluid is seen on OCT and no leakage is seen on FA, a disciform scar should be ruled out in the fundus examination, because in these cases no treatment is indicated.6 We also hypothesize that if there is no disciform scar visible during the fundus examination, the presence of remaining fluid on the OCT scan may indicate residual CNV activity that could be misdiagnosed on FA. It is also valid to assume that a hyperreflective structure on OCT could be misinterpreted without a fundus examination. Therefore, we believe that OCT, FA, and a fundus examination are complementary examinations that should be interpreted together. OCT was reported to be as effective in detecting macular edema as FA in patients with uveitis21 and patients with non-diabetic macular edema.22 Recently, a significant correlation was reported between the features of OCT and FA in diabetic macular edema, and that both OCT and FA provide information that may be useful to optimize the treatment for each type of edema.23 Other prospective studies may be warranted to determine whether interpretation of OCT scans has good intraobserver and interobserver agreement for the presence of intraretinal and sub-retinal fluid in CNV related to ARMD. In conclusion, OCT may be a good complementary imaging technique in the decision-making process regarding treatment or re-treatment of CNV in ARMD with PDT. Using FA as the standard reference, OCT has high sensitivity but only moderate specificity in detecting CNV activity before and after PDT. In view of the high sensitivity of OCT in detecting CNV activity, if no intraretinal or sub-retinal fluid is observed in OCT, it is unlikely that CNV activity exists. This may be especially useful when FA is inconclusive,6,18 or the general condition of the patient does not allow frequent FA examinations.24
REFERENCES 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933–943.
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2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–210. 3. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin. One-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol 1999;117:1329 –1345. 4. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin. Two year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol 2001;119:198 –207. 5. Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001;131:541– 560. 6. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) and Verteporfin in Photodynamic Therapy (VIP) Study Groups. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin. Fluorescein angiographic guidelines for evaluation and treatment—TAP and VIP Report No. 2. Arch Ophthalmol 2003;121:1253–1268. 7. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178 –1181. 8. Sánchez-Tocino H, Álvarez-Vidal A, Maldonado MJ, et al. Retinal thickness study with optical coherence tomography in patients with diabetes. Invest Ophthalmol Vis Sci 2002; 43(5):1588 –1594. 9. Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995;113:1019 –1029. 10. Puliafito CA, Hee MR, Lin CP, et al. Imaging of macular disease with optical coherence tomography. Ophthalmology 1995;102:217–229. 11. Rogers AH, Martidis A, Greenberg PB, et al. Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol 2002;134(4):566 – 576. 12. Hee MR, Baumal CR, Puliafito CA, et al. Optical coherence tomography of age-related macular degeneration and choroidal neovascularization. Ophthalmology 1996;103:1260 –1270. 13. Costa RA, Farah ME, Cardillo JA, et al. Immediate indocyanine green angiography and optical coherence tomography evaluation after photodynamic therapy for subfoveal choroidal neovascularization. Retina 2003;23:159 –165. 14. Schmidt-Erfurth U, Michels S, Barbazetto I, et al. Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 2002;43(3):830 – 841. 15. Schnurrbusch UEK, Welt K, Horn LC, Wiedemann P, Wolf S. Histological findings of surgical excised choroidal neovascular membranes after photodynamic therapy. Br J Ophthalmol 2001;85:1086 –1091.
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20. Friedman SM, Margo CE. Choroidal neovascular membranes: reproducibility of angiographic interpretation. Am J Ophthalmol 2000;130:839 – 841. 21. Antcliff RJ, Stanford MR, Chauhan DS, et al. Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis. Ophthalmology 2000;107: 593–599. 22. Schneeberg AE, Gobel W. Diagnosis and follow-up of non-diabetic macular edema with optical coherence tomography. Ophthalmologe 2003;100:960 –966. 23. Kang SW, Park CY, Ham DI. The correlation between fluorescein angiographic and optical coherence tomographic features in clinically significant diabetic macular edema. Am J Ophthalmol 2004;137:313–322. 24. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Ophthalmology 1986;93: 611– 617.
16. Moshfeghi DM, Kaiser PK, Grossniklaus HE, et al. Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy. Am J Ophthalmol 2003;135:343–350. 17. Blinder KJ, Bradley S, Bressler NM, et al. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003;136:407– 418. 18. Holz FG, Jorzik J, Schutt F, et al. Agreement among ophthalmologists in evaluating fluorescein angiograms in patients with neovascular age-related macular degeneration for photodynamic therapy eligibility (FLAPStudy). Ophthalmology 2003;110:400 – 405. 19. Kaiser RS, Berger JW, Williams GA, et al. Variability in fluorescein angiography interpretation for photodynamic therapy in age-related macular degeneration. Retina 2002; 22:683– 690.
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Biosketch Angel Salinas-Alaman, MD, PhD, is associate professor of ophthalmology at the Department of Ophthalmology, University Clinic of Navarra, Pamplona, Spain. Dr. Salinas-Alaman earned his MD and PhD from the Facultdad de Medicina, University of Navarra and completed his residency at the Department of Ophthalmology, Hospital of Zaragoza, Spain. His research interest is age-related macular degeneration and his specialties are diabetic retinopathy, macular degeneration, macular diseases, and vitreoretinal diseases and surgery.
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