Fundus Autoflu ores cence Findings Pre and Post Intravitreal Bevacizumab Injection in Patients with Diabetic Macular Edema

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1 Med. J. Cairo Univ., Vol. 84, No. 1, September: , Fundus Autoflu ores cence Findings Pre and Post Intravitreal Bevacizumab Injection in Patients with Diabetic Macular Edema LAMEECE MOUSTAFA, M.Sc.; SHERIF SHETA, M.D.; RANDA ABD EL-RAZEK, M.D.; GEHAN HELMY, M.D. and DINA EL-FAYOUMI, M.D. The Department of Ophthalmology, Faculty of Medicine, Cairo University 1093 Use of Spectral Domain Optical Coherence Tomography (SD OCT) is the gold standard for diagnosis and follow-up of DME in clinical practice. However, it has failed to become an indicator for visual function or prognosis, as it shows only moderate correlation with best-corrected visual acuity [3]. On the other-hand, the role of fluorescein angiography in diabetic macular edema remains mostly in the assessment of macular perfusion and not an indicator of macular function [4]. Fundus Autofluorescence (FAF) is a technique for in vivo imaging, which has been recently revolutionized allowing functional assessment of the retina. It reflects mainly the lipofuscin content in the retinal pigment epithelium [5]. Fundus autofluorescence of diabetic macular edema was shown to be associated with increased autofluorescence in the macular area, which could result from lateral displacement and reduction in the density of macular pigments, decreasing the blockage of the autofluorescence signal from the Retinal Pigment Epithelium (RPE) [6]. Fundus autofluorescence is a rapid and noninvasive technique yet to be routinely used in the evaluation of diabetic macular edema. It may allow correlation of structural and functional parameters and subsequently the identification of new DME patterns, which may be responsible for different responses to local treatments. Patients and Methods This study was designed to be a prospective interventional study assessing the changes in fundus autofluorescence patterns in forty cases with diabetic macular edema prior to and following intravitreal bevacizumab.

2 1094 FAF Findings Pre & Post Intravitreal Bevacizumab Injection in Patients Patient selection: The study was carried out between February 2014 and September All patients were obtained from the Kasr Al-Ainy Outpatient Clinic. The study included patients with diffuse nonischemic diabetic macular edema only. The exclusion criteria were applied in all steps of this study. The criteria included ischemic maculopathy or any other maculopathy, impeding visual improvement. Any patient with other significant ocular co-morbidities (i.e. advanced glaucoma, ambylopia, etc.) or media opacities preventing accurate imaging was excluded. Cases with vitreomacular traction or any form of prior treatment for macular edema warranted exclusion. Necessary ethical approvals for the study were obtained from the Ethical Committee at Kasr Al- Ainy School of Medicine, Cairo University. Patient evaluation: Each patient was subjected to an initial detailed ocular examination. This assessment the best spectacle corrected visual acuity, which was recorded in logmar notation. Examination included Goldmann applanation tonometry, slit lamp assessment of the anterior segment and posterior segment examination by use of both; indirect ophthalmoscopy and the 90-D Volk biomicroscopy lens. Fundus fluorescein angiography: The diagnosis of non-proliferative diabetic retinopathy with non-ischemic macular edema was confirmed by fundus fluorescein angiography and OCT. The angiography machine used was the Topcon TRC 50DX (Topcon Systems Inc., Oakland USA). The late phase revealed diffuse or cystoid pattern of leakage in all cases. Our study included cases with mild and moderate Non-Proliferative Diabetic Retinopathy (NPDR). Cases with multiple areas of peripheral capillary dropouts (severe NP- DR) or with neovascularization were excluded. Spectral domain optical coherence tomography: The SPECTRALIS HRA+OCT (Heidelberg Engineering, Heidelberg Germany), software version was used in this study. Volume scans of a 6x6mm 2 area of the macular region centered on the fovea were examined. Each image was composed of approximately B- scans each approximately 250µm apart. From the volume scans macular maps were produced composed of 3 circles 1, 3, 6mm (ETDRS circles) centered at the fovea. The Central Foveal Thickness (CFT) was calculated as the average thickness within the central 1mm of the ETDRS circle. All patients had CFTs greater than 250µm and less than 600µm. The presence of DME was confirmed by SD- OCT horizontal line scans as diffuse spongy retinal thickening with reduced intraretinal reflectivity or lacunae that are hyporeflective with highly reflective septae bridging the retinal layers and separating the cystoid cavities. Short wavelength fundus autofluorescence: The SPECTRALIS HRA+OCT (Heidelberg Engineering, Heidelberg Germany), is also equipped with a confocal scanning laser ophthalmoscope. A blue laser diode with wavelength 486± 3nm is used to excite the fluorescein or the intrinsic autofluorescence. Patients were fully dilated and the cslo system was used to capture images of the central 30 degrees of view upon blue laser excitation. Using the Spectralis software (version 6.0.8) the fovea was analyzed for any hyperautofluorescence. Normally the fovea on SW-FAF is hypoauotofluorescent and any hyperautofluorescence was considered as abnormal. The fovea was outlined using the ETDRs grid overlay option, with the central 1mm circle considered as the fovea. Any hyperautofluorescent spots were encircled using the spot overlay option on the spectralis software and their area was calculated. The number of spots and their total area was noted, as well as the presence of hemorrhages (hypoautofluorescent areas corresponding to those in color photos) within the fovea. Intervention: Each patient received 3 injections of 0.05cc of 1.25mg bevacizumab, four to six weeks apart. Four to six weeks following the third injection the OCT was repeated to document changes in macular thickness and configuration. The fundus autofluorescence was repeated to assess the change in the number or total area of hyperautofluorescent spots. Statistical analysis: Data was summarized using mean, standard deviation, median, minimum and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were done using the non-parametric Mann-Whitney test. For comparison of serial measurements before and after for each patient the non-parametric Wilcoxon signed rank test was used. p-values less than 0.05 were considered as statistically significant.

3 Lameece Moustafa, et al Results In our study 35 out of the forty cases (87.5%) had abnormal foveal hyperautofluorescence taking a circular, spot or cyst-like pattern. Out of these 35 cases, four showed a single spot of hyperautofluorescence (11.4%) and 31 showed multiple spots (88.6%). On analysis of the FAF, pre-injection the number of hyperautofluorescent spots in each patient ranged from 0-6 with a mean of 2.6 and the total area from 0-392µm 2 with a mean of µm 2. The post injection hyperautofluorescent spot number ranged from 0-5 with a mean of 2.68 and their total areas from 0-353µm 2 with a mean of µm 2 (Table 1). Table (1): Comparision between pre-injection and post-injection values in all patients (CFT in µm and total area of spots in µm 2 ). Mean SD Median Minimum Maximum p-value BCVA: Pre-injection <0.001 Post injection Number of hyper-autofluorescent spots: Pre-injection Post-injection Total area of hyperauotluorescent spots: Pre-injection Post-injection The pre and post injection OCT and FAF descriptive characteristics of the forty cases (before subdivision into three groups) were summarized in the (Table 2). Table (2): Descriptive characteristics in OCT and FAF. Number of patients % Pre-injection OCT: IS/OS junction: - Intact Interrupted Others: - Subfoveal exudates Neurosensory Detachment (NSD) Foveal exudates + NSD 4 10 Pre-injection FAF: Hemorrhages encroaching on the foveal avascular zone (FAZ): - Present Absent Post-injection OCT: IS/OS junction: - Intact Interrupted Others: - Subfoveal exudates Neurosensory detachment Foveal exudates + NSD Fovealexudates, NSD, epimacularmembrane Vitreomacular traction Post injection FAF: Hemorrhages encroaching on the FAZ: - Absent Less extensive More extensive 4 10

4 1096 FAF Findings Pre & Post Intravitreal Bevacizumab Injection in Patients Patients were subdivided into three groups according to the change in their best corrected visual acuity following the third intravitreal injection of bevacizumab (improved, stationary and worsened visual acuity). In 23 cases the visual acuity improved, while in 15 the acuity remained the same and 2 cases the vision deteriorated. Table (3): Comparison between pre and post injection values in Groups 1 and 2 (improved and stationary BCVA). Improved visual acuity (23) Stationary vision (15) Mean SD Median Mini. Maxi. Mean SD Median Mini. Maxi. CFT: Pre injection Post injection Numbers of autofluorescent spots pre injection: Pre injection Post injection Total area of hyperautofluorescent spots: Pre injection Post injection p- value Likewise on comparing between the two main groups the pre and post injection change in the mean values of the total area of hyperautofluorescent spots and the CFT, no statistical significance was found. In four cases, the FAF revealed no hyperautofluorescent spots, despite the presence of edema in both the angiography and OCT. In two cases prior to injection there were no hyperautofluorescent spots on FAF, but appeared in the post injection FAF. We also divided our patients according to FAF pattern into three groups: Multiple, single and no hyperautofluorescent spots (Table 4). There were 31 patients with multiple spots, 4 with one spot and 5 with no spots. The mean BCVA was best for those with no spots pre injection then the multiple then single spots, however this difference was not significant. Post injection, the BCVA was best for those with multiple spots then no spots then single spots, but the differences were also non significant. However, with regards to the total area of spots the difference between the three groups was significant pre and post injection (p= and p= respectively). The total area of hyperautofluorescent spots was greater for single than multiple spots both pre and post injection. We also compared the change in BCVA, CFT and total area of hyperautofluorescent spots between these groups (Table 4). The VA and the CFT improved in all three, while the area of hyperautofluorescent spots decreased in the multiple spots group and increased in the other two. The difference in all the changes was non significant. Table (4): Comparison between pre and post injection parameters in patients grouped according to FAF patten. Multiple spots Single spot No spots Mean SD Median Mean SD Median Mean SD Median Pre injection: BCVA Total area of spots CFT Post injection: BCVA Total area of spots CFT

subgroups: 1- Improved visual acuity group: Stationary group: (1A):

Post injection OCT CFT 329µm, interrupted IS/OS junction, Subfoveal

junction (1C): Pre-injection FAF 3 hyperautofluorescent spots, total

injection FAF 4 hyperautofluorescentspots, total area 169µm 2 (1D):

hemorrhages encroaching on the FAZ. Fig.

5 Lameece Moustafa, et al Examples of OCT and FAF images of patients in the three subgroups: 1- Improved visual acuity group: Stationary group: (1A): Pre injection OCT CFT 457µm, interrupted IS/OS, Subfoveal hard exudates. (2A): Pre Injection OCT CFT 380µm, Interrupted IS/OS junction (1B): Post injection OCT CFT 329µm, interrupted IS/OS junction, Subfoveal exudates (2B): Post injection OCT CFT 430µm, interrupted IS/OS junction (1C): Pre-injection FAF 3 hyperautofluorescent spots, total spot area 145µm 2 Hemorrhages encroaching on the FAZ (2E): Pre injection FAF 4 hyperautofluorescentspots, total area 169µm 2 (1D): Post-injection FAF 1 hyperautofluorescent spot, total area 57µm 2 No hemorrhages encroaching on the FAZ. Fig. (1): 54 years old, pre-injection VA 1 improving to 0.8 post injection, FFA revealed cystoid macular edema. (2F): Post injection FAF 4 hyperautofluorescent spots, total area 166µm 2 Fig. (2): 54 years old, FA shows cystoid edema, pre and post injection VA 1.

6 1098 FAF Findings Pre & Post Intravitreal Bevacizumab Injection in Patients Discussion Fundus autofluorescence is a rapid, non-invasive investigation that can give great insight into the function of the retina. However, its use in the diagnosis and follow-up of diabetic macular edema is debatable. The exact reason why hyperautofluorescence is seen in cases of macular edema on FAF is not known. Hyperautofluorescence in FAF is usually due to diseases of the RPE with accumulation of lipofuscin. McBain et al., [6] observed that this is a form of pseudo-fluorescence, with the fluid within the cysts reflecting light back. Bessho et al., [7] also referred to this hyperautofluorescence as a pseudo or relative autofluorescence due to stretching of the macula with lateral displacement of its pigment and consecutive reduction in the pigment density. Pece et al., [8] hypothesized that this phenomenon was due to increased visibility of the normal fluorescence of the RPE through a defect in the xanthophyll pigment. They also proposed that more of the excitatory light might pass through cysts within the foveal area such that the RPE under the cyst is more easily exposed to light and is more fluorescent. This exposure to light could cause additional RPE-photoreceptor damage and initiate a cycle of increasing damage. Vujosevic et al., [9] suggested an oxidative theory. The areas of increased FAF observed in DME are caused by the accumulation of oxidative products induced by activated microglia in which lipofuscin accumulates. According to their hypothesis, the residual FAF after an almost complete resolution of DME is related to the persistence of activated microglia or damaged cells. This was also found in our study, as persistent autofluorescence was seen in three cases post injection with almost complete resolution of macular edema by OCT (CFT less than 250µm, with absence of cystic spaces or diffuse edema). The above studies all offered hypothesis about the mechanism of increased autofluorescence in cystoid macular edema. In Kun et al., [10] they speculated that cases with only a single spot of increased autofluorescence and no cysts-like changes, the increased autofluorescence was due to disrupted retinal structure. The spot increased FAF was due to increased death of photoreceptor cells, with accumulation of photoreceptor outer segments and consequently lipofuscin. Thus, affecting the function of photoreceptor cells [10]. Similarly, in our study autofluorescence was seen in cases without cystic spaces on OCT or FA (diffuse macular edema). Additionally single spot autofluorescence was detected in 4 cases prior to injection and five following injection. Our study analyzed the presence of increased autofluorescence at the fovea only. At the fovea, FAF is almost absent in normal eyes because lutein and zeaxanthin are especially dense in the axons of the cone photoreceptors (Henle's fiber) and block the background autofluorescence of the RPE. Thus, increased FAF at the fovea could indicate significant damage to cone photoreceptor cells, which causes deterioration in vision. Following resolution of edema, the ability of photoreceptors and retinal cells to capture and stabilize lutein and zeaxanthin may indicate a good degree of physiologic and possible functional recovery [5]. In our study 35 out of the 40 cases (87.5%) diagnosed as macular edema by OCT and fluorescein angiography, had hyperautofluorescent spots in the fovea on FAF. This percentage was similar to that found in several studies. For instance, McBain et al., [6] reported 81% sensitivity and 69% specificity for FAF in diagnosing CME as compared to FA. In Pece et al., [8] 100% of their cases showed FAF abnormality in the center of the macula, corresponding to CME on FA and OCT. The study conducted by Vujosevic et al., [9] found increased autofluorescence in approximately 67% of cases. In Kun et al., [10] 86.7% of their cases of diabetic macular edema showed abnormal (increased) foveal autofluorescence. It was noticeable in our study that five cases with evident edema on OCT and FA did not have any hyperautofluorescence in the foveal area. Two of these cases did not have any detectable hyperautofluorescence pre and post injection, as they had mild diffuse edema on FA and CFT less than 300µm. Thus, in cases with non cystoid patterns of macular edema or with mild diffuse edema, FAF may not be as useful due to less dispersion of xanthophyll pigments in the fovea [11]. The other two cases, displayed hyperautofluorescence post injection. This is due to the resolution of hemorrhages, which were encroaching on the

7 Lameece Moustafa, et al FAZ and thus revealing the underlying hyperautofluorescent cysts. The abnormal foveal hyperautofluorescence found in our study took the form of a circular, spot or cystic pattern in 35 out of the forty cases (87.5%). Four cases showed a single spot of hyperautofluorescence (10% of total) and 31 showed multiple spots (77.5% of total). As aforementioned, five cases showed no autofluorescent spots (12%). Similar patterns were seen in Pece et al., autofluorescence patterns were classified into 3 subtypes: Multilobulated FAF (57%), single lobulated (12%) and mixed FAF (16%) [8]. Likewise in Kun et al., [10] 13.3% of their cases had normal FAF and those with abnormal FAF were subdivided into cystoid increased FAF (53.3%), spot increased FAF (20%), and irregular decreased FAF (13.3%). In Vujosevik et al., [9] the results were a little different. The distribution of FAF patterns was unlike ours, with a higher percentage with a normal FAF pattern (23.18%) and single spot pattern increased FAF (31.79%) and a lower percentage with a multiple spot pattern (45.03%). Central foveal thickness has been the parameter most commonly used to diagnose and manage macular edema in diabetics. Many studies have shown that the correlation between OCT measured macular thickness and visual acuity is variable. Furthermore, in some cases paradoxical changes in visual acuity occur in response to changes in OCT measured thickening [12]. The CFT in our patients was lowest in the group without hyperautofluorescent spots, than that with multiple spots and finally the highest in the single spot group, but without a statistically significant difference. When comparing the FAF findings in our two main groups (improved and stationary visual activity), we found that the pre and post injection number was lower but the total area of hyperautofluorescent spots was slightly higher for the improved group but without a significant difference. Likewise, on comparing the areas and numbers of spots within each group, the values decreased post injection but without a significance. In our study we also divided patients according to FAF pattern: Multiple, single and no hyperautofluorescent spots. The mean BCVA was best for those with no spots pre injection then the multiple then single spots. Post injection, the BCVA was best for those with multiple spots then no spots then single spots. It is contra-intuitive that those with multiple spots would have better vision. However, this goes hand in hand with the single spot group having higher CFTs. It is possible that multilobulated increased FAF may be a manifestation of a classic edematous disease, while those with a single, autofluorescent central space are due to chronic retinal thickening [8] or diffuse retinal disruption [10]. Conclusion: FAF is a rapid, non-invasive mode of imaging that may be useful in a wide spectrum of retinal disorders. In our study we attempted to determine whether this novel imaging technique could be used in diabetic macular edema, as a cheaper alternative to OCT in follow-up or as a prognostic factor for visual outcome. This study showed that the degree of hyperautofluorescence (number and total spot area) on FAF showed a positive correlation with the severity of the macular edema and changed correspondingly post injection. Interpreting FAF images is very subjective and quantifying changes manually is difficult. From our study, we can conclude that FAF should be reserved for RPE disorders and in cases of DME with fluorescein intolerance or financial restrictions preventing follow-up by OCT. References 1- Global status report on noncommunicable diseases Geneva, World Health Organization. Available at: Accessed December 23, GIRACH A. and LUND-ANDERSEN H.: Diabetic macular oedema: A clinical overview. Int. J. Clin. Pract., 61: 88-97, SAKAMOTO A., NISHIJIMA K., KITA M., OH H., TSUJIKAWA A. and YOSHIMURA N.: Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch. Clin. Exp. Ophthalmol., 247: , ADAMIS A.P., ALTAWEEL M., BRESSLER N.M., et al.: Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology, 113: 23-8, CHUNG H., PARK B., SHIN H.J. and KIM H.C.: Correlation of Fundus Autofluorescence with Spectral-Domain Optical Coherence Tomography and Vision in Diabetic Macular Edema. Ophthalmology, 119 (5): , 2012.

8 1100 FAF Findings Pre & Post Intravitreal Bevacizumab Injection in Patients 6- McBAIN V.A., FORRESTER J. and LOIS N.: Fundus autofluorescence in the diagnosis of cystoid macular oedema. Br. J. Ophthalmol., 92: , BESSHO K., GOMI F., HARINO S., et al.: Macular autofluorescence in eyes with cystoid macula edema, detected with 488 nm-excitation but not with 580 nmexcitation. Graefes. Arch. Clin. Exp. Ophthalmol., 247 (6): , PECE A., ISOLA V., HOLZ F., MILANI P. and BRAN- CATO R.: Autofluorescence imaging of cystoid macular edema in diabetic retinopathy. Ophthalmologica, 224: , MIDENA E. and VUJOSEVIC S.: Microperimetry in diabetic retinopathy. Saudi Journal of Ophthalmology, 25: 131-5, KUN L., YINCHEN S. and XUN X.: Fundus autofluorescence characteristics in patients with diabetic macular edema. Chinese Medical Journal, 127 (8): , EBRAHIMIADIB N. and RIAZI-ESFAHANI M.: Autofluorescence Imaging for Diagnosis and Follow-up of Cystoid Macular Edema. J. Ophthalmic. Vis. Res., 7 (3): 261-7, CHEW E.Y., FOROOGHIAN F., STETSON P.F., et al.: Relationship between Photoreceptor Outer Segment Length and Visual Acuity in Diabetic Macular Edema. Retina, 30 (1): 63-70, 2010.

Is OCT-A Needed As An Investigative Tool During The Management Of Diabetic Macular Edema

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