HYPERREFLECTIVE FOCI IN OUTER RETINA PREDICTIVE OF PHOTORECEPTOR DAMAGE AND POOR VISION AFTER VITRECTOMY FOR DIABETIC MACULAR EDEMA KAZUAKI NISHIJIMA, MD, PHD, TOMOAKI MURAKAMI, MD, PHD, TAKAKO HIRASHIMA, MD, AKIHITO UJI, MD, PHD, TADAMICHI AKAGI, MD, PHD, TAKAHIRO HORII, MD, NAOKO UEDA-ARAKAWA, MD, YUKI MURAOKA, MD, NAGAHISA YOSHIMURA, MD, PHD Purpose: To investigate the correlation between visual outcomes and preoperative hyperreflective foci in the outer retinal layers seen on spectral domain optical coherence tomography images in eyes that underwent vitrectomy for diabetic macular edema. Methods: We retrospectively reviewed 32 consecutive eyes that underwent vitrectomy for diabetic macular edema. Ten eyes had accumulated or many hyperreflective foci in the outer retinal layers preoperatively; 22 eyes did not have the pathology. The logarithm of the minimum angle of resolution and the junction between inner and outer segments were studied in the groups. Results: Logarithm of the minimum angle of resolution was significantly better in eyes without hyperreflective foci than in those with hyperreflective foci at 3 months and 6 months, and the last visit (P = 0.029, 0.010, and ,0.001, respectively) compared with no differences at the baseline. Visual improvement was greater in eyes with no hyperreflective foci at the same time points. Seven eyes with hyperreflective foci had no junction between inner and outer segments at the final visit, whereas only 4 eyes with no foci had no junction between inner and outer segments (P = 0.004). However, the foveal thickness did not differ between the groups at any time. Conclusion: Preoperative hyperreflective foci in the outer retinal layers detected by spectral domain optical coherence tomography might predict the photoreceptor damage and a poorer prognosis after vitrectomy for diabetic macular edema. RETINA 34:732–740, 2014
D
iabetic macular edema (DME) remains a leading cause of severe visual loss in diabetic retinopathy.1–3 The proven effective therapy for DME is focal/ grid laser photocoagulation as performed in the Early Treatment Diabetic Retinopathy Study.4 Anti–vascular
endothelial growth factor treatment also leads to better visual prognosis in patients with DME, whether combined with photocoagulation or not.5,6 However, some eyes have persistent macular edema and visual loss despite these interventions. Lewis et al7 first reported that vitrectomy improved DME in 8 of 10 eyes after the biomicroscopically taut premacular hyaloids were separated from the retina. Since then, vitrectomy has been evaluated as an alternative treatment modality to focal or grid laser photocoagulation. Thereafter, various authors have reported the favorable effects of vitrectomy for treating DME with or without obvious abnormalities of the vitreoretinal interface.8–12 However, despite complete resolution of DME by vitrectomy, the visual outcomes occasionally remain poor in some
From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. None of the authors have any financial/conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Tomoaki Murakami, MD, PhD, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaracho, Sakyo, Kyoto 6068507, Japan; e-mail: [email protected]
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cases, and macular ischemia,9,10 photoreceptor dysfunction,13,14 and accumulated subfoveal hard exudates15–17 may be the causes. Spectral domain optical coherence tomography (SD-OCT), with substantially faster image acquisition compared with previous generations, axial resolution of ,5 mm, and multiple B-scan averaging to reduce speckle noise, identifies individual retinal layers and provides much needed clinicopathologic information, even in the presence of an intraretinal cystoid space or diffuse retinal edema. The technology has contributed greatly in clarifying the mechanisms of DME. Recently, Bolz et al18 used SD-OCT and reported distinct hyperreflective foci associated with DME scattered throughout all retinal layers; in contrast, color fundus photography or biomicroscopy did not detect any apparent changes. The investigators suggested that these hyperreflective foci might represent subclinical initial steps in the development of intraretinal hard exudates.18 This finding is of great clinical interest because the presence of clinically detectable hard exudates is associated closely with pronounced neurosensory destruction and severe functional loss.19,20 In this study, we used SD-OCT to investigate how preoperative hyperreflective foci in the outer retinal layers in the macular region were associated with foveal photoreceptor status and visual acuity after vitrectomy for DME.
Methods Patients We retrospectively reviewed the medical records of 69 consecutive patients (76 eyes) with type 2 diabetes mellitus who underwent vitrectomy to treat DME between October 2007 and September 2009 at Kyoto University Hospital. The macular areas were scanned using SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) preoperatively and followed for a minimum of 6 months postoperatively. The mean periods of follow-up were 15.3 ± 6.2 months. The exclusion criteria included the presence of vitreomacular traction, subfoveal hard exudates, optic disk atrophy, glaucoma, epiretinal membrane, vitreous hemorrhage, ischemic maculopathy, ophthalmic disorders associated with macular edema such as uveitis, and retinal vein occlusion before vitrectomy. We also excluded eyes that had undergone macular grid or focal photocoagulation or received intravitreal injections of steroids or anti–vascular endothelial growth factor drugs within 3 months before surgery, those with a cataract that exceeded the Emery classification Level 2 or
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with a cortex opacity, and those with any postoperative complications, including vitreous hemorrhage and neovascular glaucoma. After excluding these cases, 32 eyes of 28 patients were included in this study. All the research and measurements adhered to the tenets of the Declaration of Helsinki. The Institutional Review Board at Kyoto University Graduate School of Medicine approved the study protocol. Optical Coherence Tomography All patients had undergone comprehensive ophthalmologic examinations, including measurement of the best-corrected visual acuity, slit-lamp biomicroscopy, indirect fundus ophthalmoscopy, color fundus photography, and fluorescein angiography after the medical history was obtained. The visual acuity was measured with a Landolt chart and converted into the logarithm of the minimal angle of resolution visual acuity. At the initial visit, all patients underwent fluorescein angiography using a confocal laser scanning system (HRA-2; Heidelberg Engineering). In all patients, an SD-OCT examination was performed to assess the morphologic changes in the outer retinal layers including hyperreflective foci and to evaluate the effectiveness of the treatment of DME before and after surgery. In all eyes, we obtained 6 radial cross-sectional images centered on the fovea and a series of horizontal and vertical scans, in which speckle noise was reduced by averaging 20 and 30 scans, respectively. Spectralis HRA+OCT is equipped with an automatic recognition system, which enables scanning of precisely the same location during follow-up examinations as during the original examination. After analysis of 6 radial crosssectional SD-OCT images, the study eyes were divided into 2 groups based on the finding of hyperreflective foci in the outer retinal layers (from the external-limiting membrane [ELM] to the retinal pigment epithelium) within the central 1 mm after determination of the presumed foveal center according to the modified methods.17,21,22 When the ELM line was interrupted or absent, imaginary ELM lines were drawn connecting the terminals of the ELM.21 The eyes with no or ,10 hyperreflective foci in the outer layers were classified into the no hyperreflective foci group and those with .10 hyperreflective foci or with large accumulated hyperreflective foci were in the hyperreflective foci group whether or not a serous retinal detachment (SRD) was present. The ELM was described previously as intact or disrupted.23 The junction between the photoreceptor inner and outer segments (IS/OS) was classified as one of three morphologic patterns, that is, intact, discontinuous, or absent, as described previously.21,24 The clinical differences and
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characteristics between these two groups were studied. Using SD-OCT, two experienced and masked ophthalmologists subjectively evaluated the hyperreflective foci and in case of disagreement, the third higher specialist participated. The foveal thickness was measured automatically by the OCT software. Intervention A standard 23-gauge 3-port vitrectomy was performed under local anesthesia. After the vitreous gel was removed, if a posterior vitreous detachment was not present, it was induced by suction with a backflush needle or a vitreous cutter; thereafter, residual posterior hyaloid on the retina also was removed. Triamcinolone acetonide was used to improve visualization of the posterior hyaloid membrane in all cases. In 22 phakic eyes, phacoemulsification with intraocular lens implantation was performed. The internal limiting membrane was peeled using indocyanine green and internallimiting membrane forceps in 25 of 32 eyes. Subconjunctival injections of dexamethasone (2 mg) were administered at the end of surgery. Additional treatments, including macular grid, focal photocoagulation, or intravitreal injection of triamcinolone, were applied in such cases without the tendency for macular edema to recur 3 months after vitrectomy. Statistical Analysis Statistical analysis was performed using StatView software, version 5.0 (SAS Institute, Cary, NC). All values are expressed as mean ± standard deviation. Student’s t-test was used to compare quantitative data populations with normal distributions and equal variance. Data were analyzed using the Mann–Whitney U test for populations with nonnormal distributions or unequal variance. Significant differences in the sampling distributions were determined using the Fisher exact test. Multiple linear regression analysis with a stepwise forward approach was used to evaluate the
association of postoperative logarithm of the minimal angle of resolution with preoperative ocular parameters, including logarithm of the minimal angle of resolution, central thickness, the presence of hyperreflective foci, and ELM status as well as systemic factors, including age, gender, HbA1c, hypertension, and hyperlipidemia. A value of P , 0.05 was considered significant.
Results We evaluated the status of hyperreflective foci in the outer retinal layers at baseline and found that 10 eyes had an accumulated or large number of hyperreflective foci (hyperreflective foci group), and 22 eyes had no or few hyperreflective foci (no hyperreflective foci group). When we compared the visual outcomes and foveal thickness after vitrectomy was performed to treat DME in these groups, we found that the logarithm of the minimal angle of resolution visual acuity in the hyperreflective foci group was significantly poorer than that in the group without hyperreflective foci at 3 months and 6 months postoperatively and at the last visit (P = 0.029, 0.010, and ,0.001, respectively), although there were no significant (P = 0.720) differences in the preoperative visual acuity between these groups (Table 1). In addition, the visual acuity improved significantly in the eyes with no hyperreflective foci at the same time points, whereas the postoperative visual acuity was almost the same as the preoperative visual acuity in eyes with hyperreflective foci (Table 1). These data suggested that hyperreflective foci in the outer retinal layers are predictive of a poorer visual prognosis and less efficacious vitrectomy for DME. Among 22 eyes of no hyperreflective foci group, the foci were emerged at the final visit in 10 eyes. Twelve eyes with no hyperreflective foci at either baseline or final visit had better final visual acuity than 10 eyes in which the foci developed (0.252 ± 0.215 vs. 0.477 ± 0.287; P , 0.001) compared with no
Table 1. Hyperreflective Foci in the Outer Retinal Layers Predict Poor Visual Prognosis and Refractoriness to Vitrectomy in DME
LogMAR VA hyperreflective foci at baseline No hyperreflective foci at baseline P VA improvement hyperreflective foci at baseline No hyperreflective foci at baseline P
Baseline
1 Month
3 Months
6 Months
Final Visit
0.719 ± 0.268
0.706 ± 0.324
0.804 ± 0.407
0.780 ± 0.341
0.755 ± 0.260
0.678 ± 0.304
0.571 ± 0.290
0.495 ± 0.326
0.455 ± 0.293
0.364 ± 0.273
0.720
0.248 0.013 ± 0.274
0.029 −0.085 ± 0.316
0.010 −0.061 ± 0.312
,0.001 −0.036 ± 0.189
0.108 ± 0.257 0.352
0.183 ± 0.301 0.028
0.224 ± 0.333 0.030
0.314 ± 0.333 0.004
Hyperreflective foci, hyperreflective foci in the outer retinal layers; logMAR VA, logarithm of minimal angle of resolution visual acuity.
HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
differences in preoperative visual acuity (0.624 ± 0.329 vs. 0.733 ± 0.281; P = 0.411). Many publications have reported a relationship between visual function and macular thickness in DME,25 which prompted us to investigate the course of the foveal thickness. Compared with the changes in visual function, the foveal thickness did not differ between eyes with and without hyperreflective foci at any time points, and there were no differences in the foveal thickness changes (Table 2). This result suggested that the poor prognosis in the eyes with hyperreflective foci depends on factors other than the magnitude of the edematous changes in the macula. Recent studies have reported the clinical relevance of the status of the photoreceptors visualized by OCT as another marker of visual function in macular
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edema,23,24,26,27 which prompted us to investigate the association between the hyperreflective foci and the ELM (or IS/OS) status. Eight of 10 eyes (80.0%) with hyperreflective foci at baseline had a disrupted ELM at the final visit, whereas only 10 of 22 eyes (45.5%) without hyperreflective foci had a disrupted ELM, which was not significantly different (P = 0.068; Table 3; Figures 1–3). Interestingly, the ELM changed from intact to disrupted in 3 of 5 eyes (60.0%) with hyperreflective foci, and the ELM became disrupted in only 2 of 14 eyes (14.3%) without hyperreflective foci (P = 0.046) (see Table 1, Supplemental Digital Content, http://links.lww.com/IAE/A198). When we studied the relationship between the hyperreflective foci and the IS/OS status, we found that at the final visit the IS/OS was absent in 7 of 10 eyes (70.0%) with
Fig. 1. A representative case of DME without hyperreflective foci in the outer retinal layers. A 60-year-old woman with visual impairment from DME had a significant improvement in the decimal best-corrected visual acuity from 0.2 to 1.0 after vitrectomy. Color fundus photographs at baseline (A) and 10 months postoperatively (B) show the absence of hard exudates around the fovea. E. Preoperative optical coherence tomographic images show cystoid spaces and SRD but no hyperreflective foci in the outer retinal layers at the fovea. F. Two photoreceptor markers, the ELM and the junction between the IS/OS, are visible after surgery, whereas no hyperreflective foci are present in the outer layers. (C) and (D) are magnified versions of the inset in (E) and (F).
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Table 2. Course of Foveal Thickness After Vitrectomy for DME in Eyes With and Without Hyperreflective Foci in the Outer Retinal Layers
FT, mm Hyperreflective foci at baseline No hyperreflective foci at baseline P FT change, mm Hyperreflective foci at baseline No hyperreflective foci at baseline P
Baseline
1 Month
3 Months
6 Months
Final Visit
548 ± 118 545 ± 138 0.951
391 ± 185 405 ± 178 0.843
368 ± 193 394 ± 179 0.716
406 ± 225 312 ± 160 0.190
294 ± 53 297 ± 79 0.908
158 ± 152 141 ± 176 0.795
180 ± 151 151 ± 191 0.677
143 ± 172 233 ± 190 0.211
255 ± 126 248 ± 136 0.901
FT, foveal thickness; hyperreflective foci, hyperreflective foci in the outer retinal layers.
hyperreflective foci at baseline, and the IS/OS was absent in only 4 of 22 eyes (18.2%) without hyperreflective foci at baseline, which was a significant difference (P = 0.004; Table 4).
To elucidate the preoperative prognostic factors, we then used the multivariate analyses and found that hyperreflective foci in the outer retinal layers (P , 0.001) and disrupted ELM (P = 0.001) predicted poor
Fig. 2. A representative case of DME with hyperreflective foci in the outer retinal layers. A 59-year-old man underwent vitrectomy for DME. A. A color fundus photograph shows fine hard exudates around the fovea before vitrectomy, and the decimal best-corrected visual acuity is 0.15. B. The hard exudates are almost absorbed completely 17 months postoperatively, and the visual acuity is 0.3. E. Preoperative optical coherence tomographic images show cystoid spaces accompanied by hyperreflective foci in the outer retinal layers, whereas the ELM and the junction between the IS/OS are not seen in the fovea. F. The macular edema had resolved after vitrectomy, although the ELM or IS/OS are absent at the fovea. Hyperreflective foci are diffused from the inner to the outer layers. C and D. Magnified versions of the inset in (E) and (F). The arrowheads indicate hyperreflective foci in the outer layers.
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HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
Table 3. Relationship Between the Disrupted ELM and Hyperreflective Foci in the Outer Retinal Layers Before and After Vitrectomy
Hyperreflective foci at baseline Present (10 eyes) Absent (22 eyes) Hyperreflective foci at final visit Present (20 eyes) Absent (12 eyes)
Disrupted ELM at Baseline
Intact ELM at Baseline
P*
Disrupted ELM at Final Visit
Intact ELM at Final Visit
5 8
5 14
0.467
8 10
2 12
0.068
11 2
9 10
0.033
18 0
2 12
,0.001
P*
*P values for Fisher exact test. Hyperreflective foci, hyperreflective foci in the outer retinal layers.
visual outcome independently. As to the additional treatments, neither the combination with internal limiting membrane peeling nor postoperative administration of triamcinolone or photocoagulation was correlated to hyperreflective foci in outer layers, ELM status, and visual prognosis.
Discussion This study showed for the first time the clinical relevance of hyperreflective foci in the outer retinal layers in eyes treated with vitrectomy for DME. Eyes with hyperreflective foci had a poorer prognosis than those without hyperreflective foci compared with no differences in the preoperative visual acuity. This finding also predicted the efficacy of vitrectomy. Although we did not find differences in the foveal thickness between eyes with and without hyperreflective foci at any time point, damage to the IS/OS at the last visit was associated with preoperative hyperre-
flective foci in the outer retinal layers. Many studies have reported a significant association between visual function and photoreceptor damage represented by disruption of the ELM or IS/OS on OCT images in eyes with macular edema associated with retinal and choroidal vascular diseases.13,24,26–28 Because of this, we hypothesized that the hyperreflective foci affect visual outcomes through the photoreceptor dysfunction at the fovea but not through the magnitude of edematous changes in eyes treated with vitrectomy for DME. However, because hyperreflective foci are a subjective finding, and this study was retrospective with a few cases, further studies should be undertaken. Recent publications have proposed several possibilities regarding hyperreflective foci in the outer retinal layers, that is, deposition of extravasated lipoproteins (the precursor of hard exudates), lipidladen macrophages, photoreceptor degeneration, and activated or over-phagocytosed retinal pigment epithelium cells, or retinal pigment epithelium metaplasia.18,21,29,30 The course of ELM disruption and
Table 4. Junction Between Inner and Outer Segments at Final Visit Associated With Preoperative Hyperreflective Foci in the Outer Retinal Layers After Vitrectomy for DME Absent IS/OS at Final Visit Discontinuous or Intact IS/OS at Final Visit LogMAR VA at the last visit Hyperreflective foci at the final visit Present (20 eyes) Absent (12 eyes) ELM status at the final visit Intact (14 eyes) Disrupted (18 eyes) Hyperreflective foci at the baseline Present (10 eyes) Absent (22 eyes) ELM status at the baseline Intact (13 eyes) Disrupted (19 eyes)
P ,0.001*
0.771 ± 0.304
0.337 ± 0.216
11 0
9 12
0.002†
0 11
14 7
,0.001†
7 4
3 18
0.004†
7 4
6 15
0.055†
*P values for Student’s t-test. †P values for Fisher exact test. Hyperreflective foci, hyperreflective foci in the outer retinal layers; logMAR VA, logarithm of minimal angle of resolution visual acuity.
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Fig. 3. A representative case of DME with hyperreflective foci in the subretinal spaces. A 59-year-old man with DME underwent vitrectomy. A. A color fundus photograph shows fine hard exudates in the parafoveal areas before vitrectomy, which was absorbed 12 months after surgery (B). The decimal best-corrected visual acuity changed from 0.15 to 0.1. Serous retinal detachment is seen on a preoperative optical coherence tomographic image (E) and its magnified image (C), with hyperreflective foci floating in the subretinal fluid (arrowheads). After vitrectomy, the disrupted ELM and absent IS/OS are accompanied by an irregular retinal pigment epithelium (D and F).
hyperreflective foci in the outer retinal layers suggested the reciprocal effects in this study. Preoperative hyperreflective foci in the outer layers were associated with progression in ELM disruption (from intact to disrupted); and vice versa, a disrupted ELM at baseline also was related to exacerbation of the hyperreflective foci (see Tables 1 and 2, Supplemental Digital Content, http://links.lww.com/IAE/A198; Figures 1 and 2, Supplemental Digital Content, http://links.lww.com/IAE/A198). The ELM is a heterophilic adherens junction between the Müller cells and photoreceptor cells, which has barrier properties against macromolecules.31 Because of these findings, we hypothesized that disruption of the ELM leads to extravasated lipoproteins or lipid-laden macrophages migration into the outer retinal layers that damages the photoreceptor cells and disrupts the ELM.
Another possibility is photoreceptor degeneration. Hyperreflective spots and bands in the outer retina were reported to be implicated in photoreceptor degeneration in all stages of macular telangiectasis Type 2 and age-related macular degeneration,29,30 which agrees with the relationship between the IS/ OS status and hyperreflective foci in the outer retinal layers at the final visit in the current study. However, it was not reasonable that hyperreflective foci in the subretinal fluids correspond to degenerative photoreceptor cells at baseline. The last possibility, activated or over-phagocytosed retinal pigment epithelium cells, might also explain photoreceptor damages. However, we could not elucidate the reasons for the increased hyperreflective foci after vitrectomy. The foci in the outer layers might increase with time or develop at macular edema resolution
HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
as in the case of hard exudates deposition. Their increases might depend on some maneuvers specific to vitrectomy. Optical coherence tomography originally provided quantitative information regarding the macular thickness, which was correlated modestly with visual function in DME.25 In the current study, there was an association between the foveal thickness and visual acuity at baseline, whereas we did not find a significant relationship between them after vitrectomy (data not shown). In contrast, the visual acuity in eyes with hyperreflective foci was significantly poorer than in eyes with no hyperreflective foci after vitrectomy compared with no differences at baseline. There also were no differences in the foveal thickness and its changes between eyes with and without hyperreflective foci, suggesting that in the current case series the hyperreflective foci in the outer retinal layers were independent of the degree of edematous changes. In summary, the main factor responsible for the poorer visual function was the hyperreflective foci in the outer retinal layers at the fovea and not the magnitude of the edematous changes in the macula after vitrectomy for DME. Although SRD often is seen on OCT images in eyes with DME, it is difficult to evaluate the foveal photoreceptor integrity, especially the IS/OS status, and the ELM status was not associated with the visual acuity in such cases.23 However, the hyperreflective foci can be identified easily in the subretinal fluids with lower reflectivity. We also reported recently that hyperreflective foci in the subretinal spaces were predictive of the visual function at the final visit but not that at baseline in eyes with DME with SRD.17 In contrast to these eyes, a cross-sectional study21 reported significant associations between hyperreflective foci in the outer layers and foveal photoreceptor damages and concomitant visual dysfunction in patients with DME without SRD. In the current study, 13 eyes had SRD at baseline, which might obscure the significant differences in preoperative visual acuity between eyes with and without hyperreflective foci. At the final visit after the SRD resolved, significant associations between hyperreflective foci and visual function were found, which might be consistent with a previous study.21 In the current study, we showed for the first time that hyperreflective foci in the outer retinal layers predict a poorer visual prognosis and less efficacious vitrectomy for DME based on the photoreceptor damage but not the magnitude of the edematous changes in the macula. Clinicians should evaluate hyperreflective foci before they consider interventions for patients with DME.
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Key words: diabetic macular edema, hyperreflective foci, photoreceptor, vitrectomy. References 1. Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The longterm incidence of macular edema. Ophthalmology 1995;102: 7–16. 2. Moss SE, Klein R, Klein BE. Ten-year incidence of visual loss in a diabetic population. Ophthalmology 1994;101:1061–1070. 3. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473–1480. 4. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806. 5. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;112:1747–1757. 6. Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064–1077 e35. 7. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology 1992;99:753–759. 8. Jahn CE, Topfner von Schutz K, Richter J, et al. Improvement of visual acuity in eyes with diabetic macular edema after treatment with pars plana vitrectomy. Ophthalmologica 2004; 218:378–384. 9. Pendergast SD, Hassan TS, Williams GA, et al. Vitrectomy for diffuse diabetic macular edema associated with a taut premacular posterior hyaloid. Am J Ophthalmol 2000;130:178–186. 10. Goebel W, Kretzchmar-Gross T. Retinal thickness in diabetic retinopathy: a study using optical coherence tomography (OCT). Retina 2002;22:759–767. 11. Shah SP, Patel M, Thomas D, et al. Factors predicting outcome of vitrectomy for diabetic macular oedema: results of a prospective study. Br J Ophthalmol 2006;90:33–36. 12. Otani T, Kishi S. A controlled study of vitrectomy for diabetic macular edema. Am J Ophthalmol 2002;134:214–219. 13. Sakamoto A, Nishijima K, Kita M, et al. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol 2009;247:1325–1330. 14. Lardenoye CW, Probst K, DeLint PJ, Rothova A. Photoreceptor function in eyes with macular edema. Invest Ophthalmol Vis Sci 2000;41:4048–4053. 15. Otani T, Kishi S. Tomographic findings of foveal hard exudates in diabetic macular edema. Am J Ophthalmol 2001;131:50–54. 16. Takagi H, Otani A, Kiryu J, Ogura Y. New surgical approach for removing massive foveal hard exudates in diabetic macular edema. Ophthalmology 1999;106:249–256; discussion 256–257. 17. Ota M, Nishijima K, Sakamoto A, et al. Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. Ophthalmology 2010;117:1996–2002. 18. Bolz M, Schmidt-Erfurth U, Deak G, et al. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid
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extravasation in diabetic macular edema. Ophthalmology 2009; 116:914–920. Chew EY, Klein ML, Ferris FL III, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol 1996;114:1079–1084. Fong DS, Segal PP, Myers F, et al. Subretinal fibrosis in diabetic macular edema. ETDRS report 23. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1997;115:873–877. Uji A, Murakami T, Nishijima K, et al. Association between hyperreflective foci in the outer retina, status of photoreceptor layer, and visual acuity in diabetic macular edema. Am J Ophthalmol 2012;153:710–717 e1. Murakami T, Nishijima K, Sakamoto A, et al. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology 2011;118:359–367. Murakami T, Nishijima K, Sakamoto A, et al. Association of pathomorphology, photoreceptor status, and retinal thickness with visual acuity in diabetic retinopathy. Am J Ophthalmol 2011;151:310–317. Murakami T, Tsujikawa A, Ohta M, et al. Photoreceptor status after resolved macular edema in branch retinal vein occlusion treated with tissue plasminogen activator. Am J Ophthalmol 2007;143:171–173.
25. Browning DJ, Glassman AR, Aiello LP, et al. Relationship between optical coherence tomography-measured central retinal thickness and visual acuity in diabetic macular edema. Ophthalmology 2007;114:525–536. 26. Yamaike N, Tsujikawa A, Ota M, et al. Three-dimensional imaging of cystoid macular edema in retinal vein occlusion. Ophthalmology 2008;115:355–362 e2. 27. Forooghian F, Stetson PF, Meyer SA, et al. Relationship between photoreceptor outer segment length and visual acuity in diabetic macular edema. Retina 2010;30:63–70. 28. Murakami T, Nishijima K, Akagi T, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci 2012;53:1506–1511. 29. Baumuller S, Charbel Issa P, Scholl HP, et al. Outer retinal hyperreflective spots on spectral-domain optical coherence tomography in macular telangiectasia type 2. Ophthalmology 2010;117:2162–2168. 30. Schuman SG, Koreishi AF, Farsiu S, et al. Photoreceptor layer thinning over drusen in eyes with age-related macular degeneration imaged in vivo with spectral-domain optical coherence tomography. Ophthalmology 2009;116:488–496 e2. 31. Bunt-Milam AH, Saari JC, Klock IB, Garwin GG. Zonulae adherentes pore size in the external limiting membrane of the rabbit retina. Invest Ophthalmol Vis Sci 1985;26: 1377–1380.
D
iabetic macular edema (DME) remains a leading cause of severe visual loss in diabetic retinopathy.1–3 The proven effective therapy for DME is focal/ grid laser photocoagulation as performed in the Early Treatment Diabetic Retinopathy Study.4 Anti–vascular
endothelial growth factor treatment also leads to better visual prognosis in patients with DME, whether combined with photocoagulation or not.5,6 However, some eyes have persistent macular edema and visual loss despite these interventions. Lewis et al7 first reported that vitrectomy improved DME in 8 of 10 eyes after the biomicroscopically taut premacular hyaloids were separated from the retina. Since then, vitrectomy has been evaluated as an alternative treatment modality to focal or grid laser photocoagulation. Thereafter, various authors have reported the favorable effects of vitrectomy for treating DME with or without obvious abnormalities of the vitreoretinal interface.8–12 However, despite complete resolution of DME by vitrectomy, the visual outcomes occasionally remain poor in some
From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. None of the authors have any financial/conflicting interests to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.retinajournal.com). Reprint requests: Tomoaki Murakami, MD, PhD, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaracho, Sakyo, Kyoto 6068507, Japan; e-mail: [email protected]
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cases, and macular ischemia,9,10 photoreceptor dysfunction,13,14 and accumulated subfoveal hard exudates15–17 may be the causes. Spectral domain optical coherence tomography (SD-OCT), with substantially faster image acquisition compared with previous generations, axial resolution of ,5 mm, and multiple B-scan averaging to reduce speckle noise, identifies individual retinal layers and provides much needed clinicopathologic information, even in the presence of an intraretinal cystoid space or diffuse retinal edema. The technology has contributed greatly in clarifying the mechanisms of DME. Recently, Bolz et al18 used SD-OCT and reported distinct hyperreflective foci associated with DME scattered throughout all retinal layers; in contrast, color fundus photography or biomicroscopy did not detect any apparent changes. The investigators suggested that these hyperreflective foci might represent subclinical initial steps in the development of intraretinal hard exudates.18 This finding is of great clinical interest because the presence of clinically detectable hard exudates is associated closely with pronounced neurosensory destruction and severe functional loss.19,20 In this study, we used SD-OCT to investigate how preoperative hyperreflective foci in the outer retinal layers in the macular region were associated with foveal photoreceptor status and visual acuity after vitrectomy for DME.
Methods Patients We retrospectively reviewed the medical records of 69 consecutive patients (76 eyes) with type 2 diabetes mellitus who underwent vitrectomy to treat DME between October 2007 and September 2009 at Kyoto University Hospital. The macular areas were scanned using SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) preoperatively and followed for a minimum of 6 months postoperatively. The mean periods of follow-up were 15.3 ± 6.2 months. The exclusion criteria included the presence of vitreomacular traction, subfoveal hard exudates, optic disk atrophy, glaucoma, epiretinal membrane, vitreous hemorrhage, ischemic maculopathy, ophthalmic disorders associated with macular edema such as uveitis, and retinal vein occlusion before vitrectomy. We also excluded eyes that had undergone macular grid or focal photocoagulation or received intravitreal injections of steroids or anti–vascular endothelial growth factor drugs within 3 months before surgery, those with a cataract that exceeded the Emery classification Level 2 or
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with a cortex opacity, and those with any postoperative complications, including vitreous hemorrhage and neovascular glaucoma. After excluding these cases, 32 eyes of 28 patients were included in this study. All the research and measurements adhered to the tenets of the Declaration of Helsinki. The Institutional Review Board at Kyoto University Graduate School of Medicine approved the study protocol. Optical Coherence Tomography All patients had undergone comprehensive ophthalmologic examinations, including measurement of the best-corrected visual acuity, slit-lamp biomicroscopy, indirect fundus ophthalmoscopy, color fundus photography, and fluorescein angiography after the medical history was obtained. The visual acuity was measured with a Landolt chart and converted into the logarithm of the minimal angle of resolution visual acuity. At the initial visit, all patients underwent fluorescein angiography using a confocal laser scanning system (HRA-2; Heidelberg Engineering). In all patients, an SD-OCT examination was performed to assess the morphologic changes in the outer retinal layers including hyperreflective foci and to evaluate the effectiveness of the treatment of DME before and after surgery. In all eyes, we obtained 6 radial cross-sectional images centered on the fovea and a series of horizontal and vertical scans, in which speckle noise was reduced by averaging 20 and 30 scans, respectively. Spectralis HRA+OCT is equipped with an automatic recognition system, which enables scanning of precisely the same location during follow-up examinations as during the original examination. After analysis of 6 radial crosssectional SD-OCT images, the study eyes were divided into 2 groups based on the finding of hyperreflective foci in the outer retinal layers (from the external-limiting membrane [ELM] to the retinal pigment epithelium) within the central 1 mm after determination of the presumed foveal center according to the modified methods.17,21,22 When the ELM line was interrupted or absent, imaginary ELM lines were drawn connecting the terminals of the ELM.21 The eyes with no or ,10 hyperreflective foci in the outer layers were classified into the no hyperreflective foci group and those with .10 hyperreflective foci or with large accumulated hyperreflective foci were in the hyperreflective foci group whether or not a serous retinal detachment (SRD) was present. The ELM was described previously as intact or disrupted.23 The junction between the photoreceptor inner and outer segments (IS/OS) was classified as one of three morphologic patterns, that is, intact, discontinuous, or absent, as described previously.21,24 The clinical differences and
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characteristics between these two groups were studied. Using SD-OCT, two experienced and masked ophthalmologists subjectively evaluated the hyperreflective foci and in case of disagreement, the third higher specialist participated. The foveal thickness was measured automatically by the OCT software. Intervention A standard 23-gauge 3-port vitrectomy was performed under local anesthesia. After the vitreous gel was removed, if a posterior vitreous detachment was not present, it was induced by suction with a backflush needle or a vitreous cutter; thereafter, residual posterior hyaloid on the retina also was removed. Triamcinolone acetonide was used to improve visualization of the posterior hyaloid membrane in all cases. In 22 phakic eyes, phacoemulsification with intraocular lens implantation was performed. The internal limiting membrane was peeled using indocyanine green and internallimiting membrane forceps in 25 of 32 eyes. Subconjunctival injections of dexamethasone (2 mg) were administered at the end of surgery. Additional treatments, including macular grid, focal photocoagulation, or intravitreal injection of triamcinolone, were applied in such cases without the tendency for macular edema to recur 3 months after vitrectomy. Statistical Analysis Statistical analysis was performed using StatView software, version 5.0 (SAS Institute, Cary, NC). All values are expressed as mean ± standard deviation. Student’s t-test was used to compare quantitative data populations with normal distributions and equal variance. Data were analyzed using the Mann–Whitney U test for populations with nonnormal distributions or unequal variance. Significant differences in the sampling distributions were determined using the Fisher exact test. Multiple linear regression analysis with a stepwise forward approach was used to evaluate the
association of postoperative logarithm of the minimal angle of resolution with preoperative ocular parameters, including logarithm of the minimal angle of resolution, central thickness, the presence of hyperreflective foci, and ELM status as well as systemic factors, including age, gender, HbA1c, hypertension, and hyperlipidemia. A value of P , 0.05 was considered significant.
Results We evaluated the status of hyperreflective foci in the outer retinal layers at baseline and found that 10 eyes had an accumulated or large number of hyperreflective foci (hyperreflective foci group), and 22 eyes had no or few hyperreflective foci (no hyperreflective foci group). When we compared the visual outcomes and foveal thickness after vitrectomy was performed to treat DME in these groups, we found that the logarithm of the minimal angle of resolution visual acuity in the hyperreflective foci group was significantly poorer than that in the group without hyperreflective foci at 3 months and 6 months postoperatively and at the last visit (P = 0.029, 0.010, and ,0.001, respectively), although there were no significant (P = 0.720) differences in the preoperative visual acuity between these groups (Table 1). In addition, the visual acuity improved significantly in the eyes with no hyperreflective foci at the same time points, whereas the postoperative visual acuity was almost the same as the preoperative visual acuity in eyes with hyperreflective foci (Table 1). These data suggested that hyperreflective foci in the outer retinal layers are predictive of a poorer visual prognosis and less efficacious vitrectomy for DME. Among 22 eyes of no hyperreflective foci group, the foci were emerged at the final visit in 10 eyes. Twelve eyes with no hyperreflective foci at either baseline or final visit had better final visual acuity than 10 eyes in which the foci developed (0.252 ± 0.215 vs. 0.477 ± 0.287; P , 0.001) compared with no
Table 1. Hyperreflective Foci in the Outer Retinal Layers Predict Poor Visual Prognosis and Refractoriness to Vitrectomy in DME
LogMAR VA hyperreflective foci at baseline No hyperreflective foci at baseline P VA improvement hyperreflective foci at baseline No hyperreflective foci at baseline P
Baseline
1 Month
3 Months
6 Months
Final Visit
0.719 ± 0.268
0.706 ± 0.324
0.804 ± 0.407
0.780 ± 0.341
0.755 ± 0.260
0.678 ± 0.304
0.571 ± 0.290
0.495 ± 0.326
0.455 ± 0.293
0.364 ± 0.273
0.720
0.248 0.013 ± 0.274
0.029 −0.085 ± 0.316
0.010 −0.061 ± 0.312
,0.001 −0.036 ± 0.189
0.108 ± 0.257 0.352
0.183 ± 0.301 0.028
0.224 ± 0.333 0.030
0.314 ± 0.333 0.004
Hyperreflective foci, hyperreflective foci in the outer retinal layers; logMAR VA, logarithm of minimal angle of resolution visual acuity.
HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
differences in preoperative visual acuity (0.624 ± 0.329 vs. 0.733 ± 0.281; P = 0.411). Many publications have reported a relationship between visual function and macular thickness in DME,25 which prompted us to investigate the course of the foveal thickness. Compared with the changes in visual function, the foveal thickness did not differ between eyes with and without hyperreflective foci at any time points, and there were no differences in the foveal thickness changes (Table 2). This result suggested that the poor prognosis in the eyes with hyperreflective foci depends on factors other than the magnitude of the edematous changes in the macula. Recent studies have reported the clinical relevance of the status of the photoreceptors visualized by OCT as another marker of visual function in macular
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edema,23,24,26,27 which prompted us to investigate the association between the hyperreflective foci and the ELM (or IS/OS) status. Eight of 10 eyes (80.0%) with hyperreflective foci at baseline had a disrupted ELM at the final visit, whereas only 10 of 22 eyes (45.5%) without hyperreflective foci had a disrupted ELM, which was not significantly different (P = 0.068; Table 3; Figures 1–3). Interestingly, the ELM changed from intact to disrupted in 3 of 5 eyes (60.0%) with hyperreflective foci, and the ELM became disrupted in only 2 of 14 eyes (14.3%) without hyperreflective foci (P = 0.046) (see Table 1, Supplemental Digital Content, http://links.lww.com/IAE/A198). When we studied the relationship between the hyperreflective foci and the IS/OS status, we found that at the final visit the IS/OS was absent in 7 of 10 eyes (70.0%) with
Fig. 1. A representative case of DME without hyperreflective foci in the outer retinal layers. A 60-year-old woman with visual impairment from DME had a significant improvement in the decimal best-corrected visual acuity from 0.2 to 1.0 after vitrectomy. Color fundus photographs at baseline (A) and 10 months postoperatively (B) show the absence of hard exudates around the fovea. E. Preoperative optical coherence tomographic images show cystoid spaces and SRD but no hyperreflective foci in the outer retinal layers at the fovea. F. Two photoreceptor markers, the ELM and the junction between the IS/OS, are visible after surgery, whereas no hyperreflective foci are present in the outer layers. (C) and (D) are magnified versions of the inset in (E) and (F).
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Table 2. Course of Foveal Thickness After Vitrectomy for DME in Eyes With and Without Hyperreflective Foci in the Outer Retinal Layers
FT, mm Hyperreflective foci at baseline No hyperreflective foci at baseline P FT change, mm Hyperreflective foci at baseline No hyperreflective foci at baseline P
Baseline
1 Month
3 Months
6 Months
Final Visit
548 ± 118 545 ± 138 0.951
391 ± 185 405 ± 178 0.843
368 ± 193 394 ± 179 0.716
406 ± 225 312 ± 160 0.190
294 ± 53 297 ± 79 0.908
158 ± 152 141 ± 176 0.795
180 ± 151 151 ± 191 0.677
143 ± 172 233 ± 190 0.211
255 ± 126 248 ± 136 0.901
FT, foveal thickness; hyperreflective foci, hyperreflective foci in the outer retinal layers.
hyperreflective foci at baseline, and the IS/OS was absent in only 4 of 22 eyes (18.2%) without hyperreflective foci at baseline, which was a significant difference (P = 0.004; Table 4).
To elucidate the preoperative prognostic factors, we then used the multivariate analyses and found that hyperreflective foci in the outer retinal layers (P , 0.001) and disrupted ELM (P = 0.001) predicted poor
Fig. 2. A representative case of DME with hyperreflective foci in the outer retinal layers. A 59-year-old man underwent vitrectomy for DME. A. A color fundus photograph shows fine hard exudates around the fovea before vitrectomy, and the decimal best-corrected visual acuity is 0.15. B. The hard exudates are almost absorbed completely 17 months postoperatively, and the visual acuity is 0.3. E. Preoperative optical coherence tomographic images show cystoid spaces accompanied by hyperreflective foci in the outer retinal layers, whereas the ELM and the junction between the IS/OS are not seen in the fovea. F. The macular edema had resolved after vitrectomy, although the ELM or IS/OS are absent at the fovea. Hyperreflective foci are diffused from the inner to the outer layers. C and D. Magnified versions of the inset in (E) and (F). The arrowheads indicate hyperreflective foci in the outer layers.
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HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
Table 3. Relationship Between the Disrupted ELM and Hyperreflective Foci in the Outer Retinal Layers Before and After Vitrectomy
Hyperreflective foci at baseline Present (10 eyes) Absent (22 eyes) Hyperreflective foci at final visit Present (20 eyes) Absent (12 eyes)
Disrupted ELM at Baseline
Intact ELM at Baseline
P*
Disrupted ELM at Final Visit
Intact ELM at Final Visit
5 8
5 14
0.467
8 10
2 12
0.068
11 2
9 10
0.033
18 0
2 12
,0.001
P*
*P values for Fisher exact test. Hyperreflective foci, hyperreflective foci in the outer retinal layers.
visual outcome independently. As to the additional treatments, neither the combination with internal limiting membrane peeling nor postoperative administration of triamcinolone or photocoagulation was correlated to hyperreflective foci in outer layers, ELM status, and visual prognosis.
Discussion This study showed for the first time the clinical relevance of hyperreflective foci in the outer retinal layers in eyes treated with vitrectomy for DME. Eyes with hyperreflective foci had a poorer prognosis than those without hyperreflective foci compared with no differences in the preoperative visual acuity. This finding also predicted the efficacy of vitrectomy. Although we did not find differences in the foveal thickness between eyes with and without hyperreflective foci at any time point, damage to the IS/OS at the last visit was associated with preoperative hyperre-
flective foci in the outer retinal layers. Many studies have reported a significant association between visual function and photoreceptor damage represented by disruption of the ELM or IS/OS on OCT images in eyes with macular edema associated with retinal and choroidal vascular diseases.13,24,26–28 Because of this, we hypothesized that the hyperreflective foci affect visual outcomes through the photoreceptor dysfunction at the fovea but not through the magnitude of edematous changes in eyes treated with vitrectomy for DME. However, because hyperreflective foci are a subjective finding, and this study was retrospective with a few cases, further studies should be undertaken. Recent publications have proposed several possibilities regarding hyperreflective foci in the outer retinal layers, that is, deposition of extravasated lipoproteins (the precursor of hard exudates), lipidladen macrophages, photoreceptor degeneration, and activated or over-phagocytosed retinal pigment epithelium cells, or retinal pigment epithelium metaplasia.18,21,29,30 The course of ELM disruption and
Table 4. Junction Between Inner and Outer Segments at Final Visit Associated With Preoperative Hyperreflective Foci in the Outer Retinal Layers After Vitrectomy for DME Absent IS/OS at Final Visit Discontinuous or Intact IS/OS at Final Visit LogMAR VA at the last visit Hyperreflective foci at the final visit Present (20 eyes) Absent (12 eyes) ELM status at the final visit Intact (14 eyes) Disrupted (18 eyes) Hyperreflective foci at the baseline Present (10 eyes) Absent (22 eyes) ELM status at the baseline Intact (13 eyes) Disrupted (19 eyes)
P ,0.001*
0.771 ± 0.304
0.337 ± 0.216
11 0
9 12
0.002†
0 11
14 7
,0.001†
7 4
3 18
0.004†
7 4
6 15
0.055†
*P values for Student’s t-test. †P values for Fisher exact test. Hyperreflective foci, hyperreflective foci in the outer retinal layers; logMAR VA, logarithm of minimal angle of resolution visual acuity.
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Fig. 3. A representative case of DME with hyperreflective foci in the subretinal spaces. A 59-year-old man with DME underwent vitrectomy. A. A color fundus photograph shows fine hard exudates in the parafoveal areas before vitrectomy, which was absorbed 12 months after surgery (B). The decimal best-corrected visual acuity changed from 0.15 to 0.1. Serous retinal detachment is seen on a preoperative optical coherence tomographic image (E) and its magnified image (C), with hyperreflective foci floating in the subretinal fluid (arrowheads). After vitrectomy, the disrupted ELM and absent IS/OS are accompanied by an irregular retinal pigment epithelium (D and F).
hyperreflective foci in the outer retinal layers suggested the reciprocal effects in this study. Preoperative hyperreflective foci in the outer layers were associated with progression in ELM disruption (from intact to disrupted); and vice versa, a disrupted ELM at baseline also was related to exacerbation of the hyperreflective foci (see Tables 1 and 2, Supplemental Digital Content, http://links.lww.com/IAE/A198; Figures 1 and 2, Supplemental Digital Content, http://links.lww.com/IAE/A198). The ELM is a heterophilic adherens junction between the Müller cells and photoreceptor cells, which has barrier properties against macromolecules.31 Because of these findings, we hypothesized that disruption of the ELM leads to extravasated lipoproteins or lipid-laden macrophages migration into the outer retinal layers that damages the photoreceptor cells and disrupts the ELM.
Another possibility is photoreceptor degeneration. Hyperreflective spots and bands in the outer retina were reported to be implicated in photoreceptor degeneration in all stages of macular telangiectasis Type 2 and age-related macular degeneration,29,30 which agrees with the relationship between the IS/ OS status and hyperreflective foci in the outer retinal layers at the final visit in the current study. However, it was not reasonable that hyperreflective foci in the subretinal fluids correspond to degenerative photoreceptor cells at baseline. The last possibility, activated or over-phagocytosed retinal pigment epithelium cells, might also explain photoreceptor damages. However, we could not elucidate the reasons for the increased hyperreflective foci after vitrectomy. The foci in the outer layers might increase with time or develop at macular edema resolution
HYPERREFLECTIVE FOCI AND VISION IN DME NISHIJIMA ET AL
as in the case of hard exudates deposition. Their increases might depend on some maneuvers specific to vitrectomy. Optical coherence tomography originally provided quantitative information regarding the macular thickness, which was correlated modestly with visual function in DME.25 In the current study, there was an association between the foveal thickness and visual acuity at baseline, whereas we did not find a significant relationship between them after vitrectomy (data not shown). In contrast, the visual acuity in eyes with hyperreflective foci was significantly poorer than in eyes with no hyperreflective foci after vitrectomy compared with no differences at baseline. There also were no differences in the foveal thickness and its changes between eyes with and without hyperreflective foci, suggesting that in the current case series the hyperreflective foci in the outer retinal layers were independent of the degree of edematous changes. In summary, the main factor responsible for the poorer visual function was the hyperreflective foci in the outer retinal layers at the fovea and not the magnitude of the edematous changes in the macula after vitrectomy for DME. Although SRD often is seen on OCT images in eyes with DME, it is difficult to evaluate the foveal photoreceptor integrity, especially the IS/OS status, and the ELM status was not associated with the visual acuity in such cases.23 However, the hyperreflective foci can be identified easily in the subretinal fluids with lower reflectivity. We also reported recently that hyperreflective foci in the subretinal spaces were predictive of the visual function at the final visit but not that at baseline in eyes with DME with SRD.17 In contrast to these eyes, a cross-sectional study21 reported significant associations between hyperreflective foci in the outer layers and foveal photoreceptor damages and concomitant visual dysfunction in patients with DME without SRD. In the current study, 13 eyes had SRD at baseline, which might obscure the significant differences in preoperative visual acuity between eyes with and without hyperreflective foci. At the final visit after the SRD resolved, significant associations between hyperreflective foci and visual function were found, which might be consistent with a previous study.21 In the current study, we showed for the first time that hyperreflective foci in the outer retinal layers predict a poorer visual prognosis and less efficacious vitrectomy for DME based on the photoreceptor damage but not the magnitude of the edematous changes in the macula. Clinicians should evaluate hyperreflective foci before they consider interventions for patients with DME.
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