February 2014
Volume 55, Issue 2
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Clinical and Epidemiologic Research  |   February 2014
The Clinical Spectrum of Microcystic Macular Edema
Author Affiliations & Notes
  • Marloes C. Burggraaff
    Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands
  • Jennifer Trieu
    Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands
  • Willemien A. E. J. de Vries-Knoppert
    Department of Ophthalmology, VU University Medical Center, Amsterdam, The Netherlands
  • Lisanne Balk
    Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
  • Axel Petzold
    Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
  • Correspondence: Marloes C. Burggraaff, Department of Ophthalmology, VU University Medical Center Amsterdam, De Boelelaan 1117, PO Box 7057, 1007 MB Amsterdam, The Netherlands; m.burggraaff@vumc.nl
Investigative Ophthalmology & Visual Science February 2014, Vol.55, 952-961. doi:10.1167/iovs.13-12912
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      Marloes C. Burggraaff, Jennifer Trieu, Willemien A. E. J. de Vries-Knoppert, Lisanne Balk, Axel Petzold; The Clinical Spectrum of Microcystic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2014;55(2):952-961. doi: 10.1167/iovs.13-12912.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: Microcystic macular edema (MME), originally described in British literature as microcystic macular oedema (MMO), defines microcysts in the inner nuclear layer (INL) of the retina. Microcystic macular edema was described in multiple sclerosis (MS), but can be found in numerous disorders. The presence of MME has important prognostic and therapeutic implications; however, the differential diagnosis is unknown. This study aimed to describe the clinical spectrum of MME.

Methods.: A single-center, retrospective cohort study. A bootstrap analysis was performed to reduce the 5865 patients (22,376 scans), who had undergone OCT imaging between January 2010 and February 2013, to a representative dataset. The presence of MME was rated by independent observers.

Results.: The dataset consisted of 1368 patients (mean age 62, range, 4–101 years), 2589 eyes and 6449 scans. Microcystic macular edema was present in 133/1303 (10%) of patients and 0/65 (0%) of healthy controls. The interrater agreement for detecting MME was substantial (kappa 0.6) and could be further improved after refining the criteria (kappa 0.8). The clinical spectrum included age-related macular degeneration, epiretinal membranes, postoperative lesions, diabetic retinopathy, vascular occlusion, MS (with/without optic neuritis), optic neuropathy, central serous chorioretinopathy, medication, and miscellaneous causes. The longitudinal pattern of MME was transient (84%) or static. Microcystic macular edema could be associated with an increase or decrease in INL thickness and was predominantly located nasally (48%) and/or temporally (50%).

Conclusions.: This study substantially widened the clinical spectrum of MME. Diagnostic criteria were refined and validated. The associated phenotype may imply Müller cell dysfunction within the watershed zone. The longitudinal data and evidence from previous studies suggest follow-up of these patients and their visual function.

Introduction
Microcystic macular edema (MME) consists of retinal microcysts which are predominantly located in the inner nuclear layer (INL). 1,2 The optically empty spaces are more or less square-shaped with at least one of the borders appearing concave or straight. They have no obvious wall; therefore, the term “pseudocysts” is preferred by some authors. 3  
Recent studies predominantly have focused on MME in multiple sclerosis 1,4,5 and neuromyelitis optica (NMO). 6,7 It was suggested that MME originated from breakdown of the blood-retinal barrier or focal inflammation. 1 However, microcystic changes in the INL were also described in compressive optic neuropathy (due to glioma), 8 Leber's hereditary optic neuropathy, dominant optic atrophy, 9 and endemic optic neuropathy, 10 suggesting retrograde trans-synaptic degeneration from optic neuropathy as a causative factor for degeneration of the INL with formation of cystic spaces. 8 Microcystic macular edema is not restricted to neurologic etiologies and has been described in ARMD, group 2A idiopathic juxtafoveolar retinal telangiectasis, and tamoxifen retinopathy. 3,1114  
Following the original description of MME, 1 it might be suggested that because of the almost exclusive localization of MME within the poorly vascularized perimacular rim, a relationship may exist with Müller cell function. Anatomically, Müller cells transverse through the entire retina from the inner limiting membrane down to the basal membrane, with the bulk of their cell bodies residing in the INL. The function of Müller cells are to maintain the neurochemical and water homeostasis of the retina, to support neuronal activity, and to regulate the integrity of the blood-retina barrier. It has been known that edema formation is related to pathologies affecting Müller cell function. In animal models of various retinopathies (retinal ischemia, ocular inflammation, retinal detachment, and diabetes), Müller cells decreased the expression of their major potassium channel Kir4.1, which impaired the rapid water transport across Müller cell membranes and resulted in cellular swelling. 15 Interestingly, Kir4.1 is also the dominant potassium channel of the human brain and spinal cord, against which recently autoantibodies were detected, suggesting an acquired channelopathy might be related to the development of MME in MS. 2,16,17  
Since the clinical spectrum of MME is not yet known, it remains difficult to formulate focused and testable hypotheses on the underlying pathophysiology. Furthermore, the presence of microcysts was associated with a poor long-term functional outcome both in patients with ARMD and patients with MS, compared with these patients without MME. 1,3,4 Therefore, detection of MME might have important prognostic and therapeutic implications. The present study aimed to carefully describe the extent, location, sequential pattern, and clinical spectrum of MME as observed in a mixed neurological and ophthalmological patient population. 
Methods
Study Design and Patients
This study complied with the tenets of the Declaration of Helsinki and was in accordance with the Dutch guidelines for good clinical practice. The patient flow of this retrospective cohort study is summarized in Figure 1. Optical coherence tomography (OCT) scans in this study were derived from patients who underwent spectral-domain OCT (SD-OCT) imaging at the VU University Medical Center in Amsterdam, The Netherlands, between January 1, 2010, and February 15, 2013. During this period, 22,376 macular volume scans were derived from 5865 patients. To reduce the large number of scans and patients to a manageable sample size, bootstrap was used. In total, 6548 macular scans from 1370 patients (2593 eyes, Fig. 1) were randomly selected. Sequential OCT scans were available in 100 patients. These were included to determine if MME was a transient phenomenon or remained static over time. 1,4 Because poor quality scans can give rise to artefacts resembling MME, such scans were excluded. Control subjects were included if they had macular volume scans of sufficient quality, 18 and no ophthalmologic or neurologic abnormalities. 
Figure 1
 
Study design and patient flow.
Figure 1
 
Study design and patient flow.
The SD-OCT images were screened by one of the authors (JT) for the presence of MME. As a sensitivity analysis, 3520 (54%) scans were rated by an independent second observer (MCB). The interrater agreement was determined. The reasons for disagreement between the two raters were discussed in a consensus revision of all relevant scans (JT, MCB, WAEJdV, AP). This led to refinement of the diagnostic criteria for MME. These criteria were then reapplied to the dataset. All four authors individually rated the presence of MME in a substantial part of the original data. If at least three raters agreed on the presence of MME, the patient was included in the MME group. Clinical details of these patients were retrieved by a retrospective case note analysis. Because of the retrospective nature of the study, visual acuity (VA) was not measured systematically and the decimal notation was used in this paper. 
Optical Coherence Tomography
Retinal OCT images were obtained with SD-OCT (Spectralis software version 1.1.6.3.; Heidelberg Engineering, Inc., Heidelberg, Germany). 
Microcystic Macular Edema
Based on previous publications, MME was defined as cystic, lacunar areas of hyporeflectivity with clear boundaries in the INL. 1,19 Gelfand et al. 1 also suggested to only include those cases where MME was seen on at least two adjacent scans. Because of the retrospective nature of the present study, the distance between two sections (or B-scans) was not standardized, and the number of sections ranged from 10 to 193 (median 25). Therefore, patients presenting with MME in only one section/B-scan were included as well. The macular volume scans evaluated in this study represent scans from a routine clinical setting. 
Inner Nuclear Layer Segmentation
Image post-processing was performed using three different algorithms incorporated in automated segmentation software: first, a purpose build algorithm from Heidelberg Engineering, Inc. (beta software, version 5.9.0.3) 20 ; second, the OCT segmentation and evaluation graphical user interface (OCTSEG) algorithm that allows us to suppress retinal blood vessels and void signal artefacts 21 ; and third, a graph-based multisurface segmentation combining aspects of the two other algorithms with machine learning. 22 Of the three algorithms, only the Heidelberg beta software permitted isolated segmentation of the INL. The two other algorithms provided data on a combined INL and outer plexiform layer (OPL) segmentation. 
For every layer, the OCT software generated a thickness map on a 1-, 3-, and 6-mm grid. After the automated segmentation process, all scans and all layers were carefully revised for algorithm failures (LB, AP). Manual correction was performed using the Heidelberg software. 
All three automated retinal layer segmentation algorithms used in this study were previously shown to be reliable in analyzing the retinas of healthy control subjects 20 and patients with drusen. 22  
Statistical Analysis
Statistical analyses were performed using statistical software (SPSS version 17.0; SPSS, Inc., Chicago, IL); programming language (R; R Development Core Team, University of Auckland, Auckland, New Zealand); and analytical software (SAS version 9.3; SAS Institute, Cary, NC). Bootstrap analyses were performed with analytical software (SAS Institute). Kappa statistics were calculated to assess the interrater agreement, Cohen's kappa for data rated by two raters, and Fleiss' multirater kappa for data from more than two raters. The level of agreement was rated as slight (0–0.2), fair (0.2–0.4), moderate (0.4–0.6), substantial (0.6–0.8), or almost perfect (0.8–1). 23 The overall prevalence of MME was estimated by dividing the number of eyes with MME in the INL, by the total number of eyes scanned. 3 Proportions were presented as total number (%). Parametric tests (t-tests) were used for Gaussian data. Categorical data was analyzed using the χ2 test. Statistical significance was accepted for two-sided testing with P < 0.05. 
Results
Patients
A total of 22,376 macular volume scans were obtained from 5865 patients between January 1, 2010, and February 15, 2013. After bootstrap, a representative dataset of 6548 macular scans from 1370 patients (2593 eyes) was subject to in-depth analyses; 99 scans of 13 patients failed quality control criteria. Two patients were excluded from further analyses because all their scans were of poor quality. Therefore, the final dataset consisted of 6449 scans from 1368 patients (2589 eyes; see Fig. 1). 
Validation of Diagnostic Criteria for MME
The screening set was split into two parts. In the first part, the observed percentage of agreement between the two raters was 92%. The interrater agreement for identifying MME was substantial (kappa 0.6). The consensus revision of the scans revealed that interrater disagreement was due to: (1) size/configuration—could the cysts be identified as MME/pseudocysts or did they have cell walls and could be classified as cystic macular edema? (2) location: presence of cysts within or just outside the INL; (3) confluence of cysts with cyst in other retinal layers; (4) coexisting lesions in other layers; and (5) the longitudinal pattern of presumed MME (i.e., the presence of cysts could be transient or static if macular volume scans of different dates were available). Representative examples of OCT scans which caused interrater disagreement are illustrated in Figure 2. Taking the reasons for disagreement into account, we refined the diagnostic criteria for MME as summarized in Table 1
Figure 2
 
Two examples of OCT macular volume scans with interrater disagreement on presence of MME. (A) In this patient, there was doubt if the hyporeflective lesion was a cyst or an artefact, and if the lesion was not to close to the foveola, which does not have an INL. (B) The cyst might be in the INL or in the adjacent layer. There might be confluence of the cyst in both layers.
Figure 2
 
Two examples of OCT macular volume scans with interrater disagreement on presence of MME. (A) In this patient, there was doubt if the hyporeflective lesion was a cyst or an artefact, and if the lesion was not to close to the foveola, which does not have an INL. (B) The cyst might be in the INL or in the adjacent layer. There might be confluence of the cyst in both layers.
Table 1
 
Refined and Validated Diagnostic Criteria for MME
Table 1
 
Refined and Validated Diagnostic Criteria for MME
Inclusion Criteria Exclusion Criteria
Configuration Small hyporeflective lesions in the INL Cysts with a clearly visible cell wall
Location Within or outside the perimacular rim Small cysts directly adjacent to or within the foveola, where there is no INL
Confluence Permitted within the INL Confluence with cysts in adjacent retinal layers
Coexisting lesions Small cysts in other retinal layers or subretinal fluid is permitted but should be documented as such MME needs to be distinguished from blood vessel artefacts which can give the impression of hyporeflectivity
Longitudinal pattern MME fulfilling all of the above criteria needs to be seen on two macular volume scans taken at separate time points, at least 1 week apart
Transient/dynamic pattern Transient/dynamic: MME fulfilling all of the above criteria needs to be seen on at least one macular volume scan, whereas MME is not present in a previous or follow-up volume scan
Static pattern MME fulfilling all of the above criteria needs to be seen on all macular volume scans of one patient, taken at separate time points, at least 1 week apart
Based on the refined diagnostic criteria for MME, the overall interrater agreement improved to kappa 0.8. Of note, two patients who were thought to have MME during the first rating were unanimously excluded using our refined diagnostic criteria. 
Clinical Spectrum of MME
In 133/1303 (10.2%) of patients from our cohort, MME was present according to the refined diagnostic criteria (Table 1). There was a slight female predominance (57.1%) in the MME group. Patients with MME were significantly older (72.8 years, SD 13.8, range, 23–95 years) compared with patients without MME (63.2 years, SD 17.8, range, 4–101 years; P = 0.002), and healthy control subjects (50.5 years, SD 7.2, range, 28–63 years; P < 0.001). The clinical spectrum and demographic data of patients with MME is summarized in Table 2. Most frequently, MME was observed in patients with ARMD (27.1%) followed by patients with preceding ophthalmic surgery (20.3%) or presence of an epiretinal membrane (18.8%). Furthermore, MME was identified following a retinal vascular occlusion (6.8%), uveitis (6.8%), diabetic retinopathy (6.8%), MS (3.0%), posterior ischemic optic neuropathy (0.8%), and miscellaneous/other retinal conditions (5.3%). Three of the four patients with MS had a history of optic neuritis in the affected eye. Importantly, the patient who never suffered from optic neuritis had a long disease duration (14 years), was severely disabled (EDSS 6.0), showed severe white and gray matter atrophy involving the optic pathways on magnetic resonance imaging (MRI), and had bilaterally delayed visual evoked potentials (this patient never received fingolimod). Figure 3 shows an example of a normal retina of a healthy control subject compared with the retina of a patient with MME based on ARMD. Other examples of OCT images of patients found in the different disease categories are presented in Figure 4. Figure 5 shows an example of a patient presenting both with an optic neuritis and a branch retinal vein occlusion at the same time (MME was seen 11 years after onset). 
Figure 3
 
An example of a normal retina compared with the retina of a patient with MME. (A) A normal retina from a healthy control subject. The pseudocolored surface image is the infrared surface photo; the vertical stacked gray image an OCT B-scan. (B) Optical coherence tomography image taken from a 76-year-old woman with a 3-year history of ARMD, for which she received regular injections with ranibizumab and bevacizumab. At time of imaging, her best corrected VA OS was 0.7. (C) Illustrates layer segmentation for the OCT B-scan shown in (A). The INL is bordered by the blue and orange lines. (D) The same for the patient with ARMD. Clearly, there is focal thickening of the INL were MME is observed. (E) Pan-retinal thickness map from the healthy control subject and the corresponding INL thickness map (F). (G) In the patient with ARMD, there is overall thinning of the retina. (H) There is marked heterogeneity of the INL thickness map in the ARMD patient compared with the healthy control subject.
Figure 3
 
An example of a normal retina compared with the retina of a patient with MME. (A) A normal retina from a healthy control subject. The pseudocolored surface image is the infrared surface photo; the vertical stacked gray image an OCT B-scan. (B) Optical coherence tomography image taken from a 76-year-old woman with a 3-year history of ARMD, for which she received regular injections with ranibizumab and bevacizumab. At time of imaging, her best corrected VA OS was 0.7. (C) Illustrates layer segmentation for the OCT B-scan shown in (A). The INL is bordered by the blue and orange lines. (D) The same for the patient with ARMD. Clearly, there is focal thickening of the INL were MME is observed. (E) Pan-retinal thickness map from the healthy control subject and the corresponding INL thickness map (F). (G) In the patient with ARMD, there is overall thinning of the retina. (H) There is marked heterogeneity of the INL thickness map in the ARMD patient compared with the healthy control subject.
Figure 4
 
Representative OCT images of patients with MME from the clinical spectrum are shown. The infrared surface photo and OCT image are presented to the left and the manually segmented INL to the right. (A) Microcystic macular edema in the right eye of a 70-year-old male patient with a history of proliferative diabetic retinopathy treated with panretinal photocoagulation (VA OD 0.3). (B) Optical coherence tomography image showing MME 8 months after occlusion of the vena temporalis superior OD in a 66-year-old female patient (VA OD 0.7). Microcystic macular edema was located in the temporal superior quadrant of the inner 3-mm EDTRS grid. However, INL thickening extended to the periphery. In addition, hyperreflective spots were observed in all inner retinal layers. (C) Microcystic macular edema in a 66-year-old female patient with sarcoidosis and posterior uveitis in the right eye. Fluorescein angiography showed an ischemic maculopathy (VA OD 1.0). Serum ACE was 29, CT-thorax showed mediastinal and hilar lymphadenopathy. In this case, hyperreflective spots were restricted to the retinal nerve fiber layer, ganglion cell layer, and INL. (D) Microcystic macular edema in a 58-year-old female patient with a newly diagnosed pucker in the right eye (VA OD 0.2). Again, there were multiple hyperreflective spots in the inner retinal layers. (E) Microcystic macular edema 3 months after vitrectomy, in a 71-year-old female patient with a retinal detachment in the left eye (VA OS 0.05).
Figure 4
 
Representative OCT images of patients with MME from the clinical spectrum are shown. The infrared surface photo and OCT image are presented to the left and the manually segmented INL to the right. (A) Microcystic macular edema in the right eye of a 70-year-old male patient with a history of proliferative diabetic retinopathy treated with panretinal photocoagulation (VA OD 0.3). (B) Optical coherence tomography image showing MME 8 months after occlusion of the vena temporalis superior OD in a 66-year-old female patient (VA OD 0.7). Microcystic macular edema was located in the temporal superior quadrant of the inner 3-mm EDTRS grid. However, INL thickening extended to the periphery. In addition, hyperreflective spots were observed in all inner retinal layers. (C) Microcystic macular edema in a 66-year-old female patient with sarcoidosis and posterior uveitis in the right eye. Fluorescein angiography showed an ischemic maculopathy (VA OD 1.0). Serum ACE was 29, CT-thorax showed mediastinal and hilar lymphadenopathy. In this case, hyperreflective spots were restricted to the retinal nerve fiber layer, ganglion cell layer, and INL. (D) Microcystic macular edema in a 58-year-old female patient with a newly diagnosed pucker in the right eye (VA OD 0.2). Again, there were multiple hyperreflective spots in the inner retinal layers. (E) Microcystic macular edema 3 months after vitrectomy, in a 71-year-old female patient with a retinal detachment in the left eye (VA OS 0.05).
Figure 5
 
Microcystic macular edema in a patient with multiple sclerosis and a history of optic neuritis and branch retinal vein occlusion in the right eye. This 55-year-old female patient was diagnosed with clinical definite MS in 1992. Magnetic resonance imaging showed multiple periventricular brain lesions, and spinal T2 hyperintense lesions. In 2001, she experienced one episode of optic neuritis OD; coincidentally, an occlusion of the vena temporalis superior was found (VA 0.4). This case illustrates coexistence of MME with both a thinned (green box) and thickened (blue box) aspect of the INL. (A) The OCT B-scan clearly shows MME in the INL, which is thickened in the center and thinned near the peripheral parts of the image. The OCT image was taken 11 years after conduction of the fundus photograph in 2001, which showed superficial intraretinal hemorrhages inline with occlusion of the vena temporalis superior (B). There was thinning of the nerve fiber layer of the right optic disc, with normal appearance on the left (not shown). (C) The corresponding fluorescein angiography does not reveal leakage. Furthermore, there seemed to be a preocclusion of the vena temporalis inferior. (D) The thickness map of the INL showed more prominent thickening along the course of the inferior temporal vein, with relative thinning along the course of the superior temporal vein. (E) The destruction of the INL related to the thickness difference can be best appreciated by comparing the temporal part of the inferior retina (blue box) with the corresponding area shown on top of the image (green box). Interestingly, hyperreflective spots of the inner retinal layers were found, which were also seen in other entities of the clinical spectrum of MME.
Figure 5
 
Microcystic macular edema in a patient with multiple sclerosis and a history of optic neuritis and branch retinal vein occlusion in the right eye. This 55-year-old female patient was diagnosed with clinical definite MS in 1992. Magnetic resonance imaging showed multiple periventricular brain lesions, and spinal T2 hyperintense lesions. In 2001, she experienced one episode of optic neuritis OD; coincidentally, an occlusion of the vena temporalis superior was found (VA 0.4). This case illustrates coexistence of MME with both a thinned (green box) and thickened (blue box) aspect of the INL. (A) The OCT B-scan clearly shows MME in the INL, which is thickened in the center and thinned near the peripheral parts of the image. The OCT image was taken 11 years after conduction of the fundus photograph in 2001, which showed superficial intraretinal hemorrhages inline with occlusion of the vena temporalis superior (B). There was thinning of the nerve fiber layer of the right optic disc, with normal appearance on the left (not shown). (C) The corresponding fluorescein angiography does not reveal leakage. Furthermore, there seemed to be a preocclusion of the vena temporalis inferior. (D) The thickness map of the INL showed more prominent thickening along the course of the inferior temporal vein, with relative thinning along the course of the superior temporal vein. (E) The destruction of the INL related to the thickness difference can be best appreciated by comparing the temporal part of the inferior retina (blue box) with the corresponding area shown on top of the image (green box). Interestingly, hyperreflective spots of the inner retinal layers were found, which were also seen in other entities of the clinical spectrum of MME.
Table 2
 
The Clinical Spectrum of MME
Table 2
 
The Clinical Spectrum of MME
Disease* n (%) Age (y) Sex, % F
Age-related macular degeneration 36 (27.1) 84.1 ± 7.0 (61–95) 69.4
Epiretinal membrane/vitreomacular traction 25 (18.8) 72.7 ± 9.0 (52–93) 48.0
Iatrogen† 27 (20.3) 72.7 ± 10.6 (50–88) 55.6
Diabetic retinopathy 9 (6.8) 64.6 ± 10.0 (44–80) 33.3
Vascular occlusion 9 (6.8) 75.2 ± 9.0 (64–91) 55.6
Uveitis 9 (6.8) 57.8 ± 18.8 (23–85) 77.8
Multiple sclerosis‡ 4 (3.0) 57.8 ± 7.8 (51–69) 50.0
Optic neuropathy§ 1 (0.8) 78.0 0.0 (1 male)
Central serous chorioretinopathy 3 (2.3) 51.0 ± 17.0 (34–68) 0.0 (3 male)
Retinitis pigmentosa 1 (0.8) 30.0 0.0 (1 male)
Medication‖ 2 (1.5) 53.5 ± 6.4 (49–58) 100.0
Other/unknown 7 (5.3) 72.6 ± 13.8 (52–85) 71.4
Healthy subjects 65 50.5 ± 7 (28–63) 65.1
Bilateral MME
Bilateral MME was present in 9/133 (6.8%) of patients. The diagnosis was ARMD in four, an epiretinal membrane in three, iatrogenic (postoperative) in one, and central serous chorioretinopathy in one. 
Longitudinal Pattern of MME
Longitudinal data was available from 100 out of 133 patients with MME (75.2%). Microcystic macular edema was transient in 84% of patients. It remained static for the available observation period (mean 233 days, SD 157 days; range, 46–494 days) in the remaining 16% of patients. Of note, 42% of patients with a transient pattern of MME developed cystic macular edema (n = 35). 
Localization of MME
The perimacular rim was affected in all cases with MME, but the localization could be within any quadrant or combination of quadrants of the superimposed Early Treatment Diabetic Retinopathy Study (EDTRS) grid (Table 3). Most frequently a single quadrant was affected (67.7%). Two quadrants were affected in 15.0% of patients, three quadrants in 9.0%, and all four quadrants in 8.3% (Fig. 6). The nasal (48.1%) and temporal (49.6%) quadrants were more frequently involved compared with the superior (29.3%) and inferior (30.1%) quadrants. 
Figure 6
 
Sectoral localization and perimacular rim extension of MME. One quadrant was affected in the vast majority of cases (67.7%). Within this group, MME was most often found in the temporal and nasal quadrants. In a small proportion of patients, MME was extensive and lesions were found in two (15.0%), three (9.0%), or four quadrants (8.3%).
Figure 6
 
Sectoral localization and perimacular rim extension of MME. One quadrant was affected in the vast majority of cases (67.7%). Within this group, MME was most often found in the temporal and nasal quadrants. In a small proportion of patients, MME was extensive and lesions were found in two (15.0%), three (9.0%), or four quadrants (8.3%).
Table 3
 
Location of MME With Respect to the EDTRS Grid
Table 3
 
Location of MME With Respect to the EDTRS Grid
Disease Superior, n (%) Inferior, n (%) Nasal, n (%) Temporal, n (%)
Age-related macular degeneration 6 (16.7) 12 (33.3) 19 (52.8) 14 (38.9)
Epiretinal membrane/vitreomacular traction 12 (18.0) 11 (44.0) 12 (48.0) 15 (60.0)
Iatrogenic 7 (25.9) 6 (22.2) 15 (55.6) 14 (51.9)
Diabetic retinopathy 3 (50.0) 1 (20.0) 4 (44.4) 2 (40.0)
Vascular occlusion 2 (22.0) 0 (0.0) 2 (22.2) 5 (56.0)
Uveitis 5 (55.6) 4 (44.4) 4 (44.4) 7 (77.8)
Multiple sclerosis 2 (50.0) 2 (50.0) 2 (50.0) 2 (50.0)
Optic neuropathy 1 (100) 0 (0.0) 0 (0.0) 0 (0.0)
Central serous chorioretinopathy 1 (25.0) 0 (0.0) 3 (75.0) 0 (0.0)
Retinitis pigmentosa 0 (0.0) 0 (0.0) 0 (0.0) 1 (100)
Medication 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0)
Other/unknown 1 (14.3) 2 (28.6) 2 (28.6) 4 (57.1)
Total 39 (29.3) 40 (30.1) 64 (48.1) 66 (49.6)
MME and INL Thickness
The failure rate of automated segmentation of the INL and other retinal layers was above 90% of scans from patients with MME for all three algorithms used. Therefore, no statistical analyses were performed on this data. Manual segmentation was performed in scans representative for the main disease categories. Noteworthy, the INL thickness was increased in most, but not all areas with MME (Fig. 3). 
Discussion
In this large, retrospective, single-center study, the prevalence of MME was 10.2% (n = 133). To put our data into context, thus far only approximately 127 patients with MME have been reported in literature. The present study more than doubled this number, and substantially widened the clinical spectrum of MME (Table 4). Furthermore, the diagnostic criteria for MME were refined such that a substantial level of agreement (kappa 0.8) could be achieved. 
Table 4
 
Number of Patients (Eyes) With MME Found in Literature
Table 4
 
Number of Patients (Eyes) With MME Found in Literature
Disease MME Cases Reference(s)
ARMD 22 eyes of 22 patients Querques3
24 eyes Cohen11
Retinal telangiectasis 20 eyes (of 10 patients) Gaudric12
Tamoxifen 1 eye of 1 patient Park33
MS 20 eyes of 15 patients Gelfand1
12 eyes of 10 patients Saidha4
1 eye of 1 patient Balk5
Relapsing isolated optic neuropathy 1 eye of 1 patient Balk5
Chronic relapsing inflammatory optic neuropathy 1 patient Petzold and Plant34
NMO 10 patients Sotirchos7
7 eyes of 5 patients Gelfand1
Leber's hereditary optic neuropathy/dominant optic atrophy 10 patients Barboni9
Endemic optic neuropathy 25 eyes of 16 patients Shalchi10
Optic nerve glioma 2 eyes of 1 patient Abegg8
Retrograde optic neuropathy (compressive, n = 9 eyes; vascular, n = 3; hereditary, n = 2; not clear, n = 2) 16 eyes of 9 patients Abegg30
Autosomal dominant optic atrophy 4 eyes of 2 patients Gocho31
Autosomal dominant optic atrophy 2 eyes of 1 patient Lujan32
Total cases of MME* Approximately 178 eyes of 127 patients
This study 142 eyes of 133 patients
Microcystic changes were most frequently observed in ARMD, postoperatively after vitrectomy, cataract extraction, or intraocular lens exchanges, and in epiretinal membranes or vitreomacular traction. The percentage of patients with MME due to MS (optic neuritis) in our study was relatively small, which might be due to our study population (i.e., a random sample of all patients receiving an OCT scan at an ophthalmologic department). In the present study, MME occurred in a large number of underlying disorders, which is in line with the finding of Bringmann et al. 24 that Müller cells become activated upon virtually all pathogenic stimuli. Therefore, our study supports Müller cell dysfunction as part of the pathophysiology of MME. This interpretation is in line with the literature. 5 7  
Interestingly, MME was most often found in the nasal and temporal quadrants of the perimacular rim. It can be hypothesized that the end-arterial nature of the choroidal vasculature and the existence of watershed zones in the choroid may have a role in the location of MME. Watershed zones are borderline areas between the territories of distribution of two end-arteries, and these areas with a relatively poor blood flow are most vulnerable to hypoxia-ischemia. 25,26 The main watershed zone of the choroid is located between the nasal edge of the optic disc and the fovea and represents the area between territories supplied by the temporal and nasal posterior ciliary arteries. 27 Furthermore, hyperreflective lesions were anecdotally observed in some scans of patients presenting with MME. They were distributed throughout all retinal layers. Similar foci were found in patients with diabetic macular edema, which were thought to represent extravasated (lipo)proteins preceding hard exudates or blood-retina barrier breakdown. 28 In patients with ARMD, such lesions were thought to represent activated microglial cells from early biological inflammatory reactions (resolution was associated with a better visual outcome). 29  
A particularly salient limitation of the study was that, because the SD-OCT scans were acquired without a systematic protocol, the macular volume scans consisted of different rasters with a median of 25 sections. Consequently, resolution was limited and cases with MME in between the sections may have been missed. 3  
In addition, it proved to be difficult to identify MME. In previous studies, problems with the identification of MME were not reported. To our knowledge, there are only few criteria applying to MME. Microcystic macular edema was defined as lacunar areas of hyporeflectivity with clear boundaries and absence of a clearly visible cell wall, in the INL, present on at least two adjacent scans. 1,3,19 These criteria were used in the first part of the screening-set, by two independent raters. Of note, patients presenting with MME on only one of the sections of the macular volume scan were also included because of the limited number of sections. The interrater agreement was kappa 0.6, which can be considered substantial. 23 However, including almost exclusively patients (and just a few healthy controls) with most OCT scans showing absence of MME (n = 2937) might have caused the interrater agreement to be somewhat smaller than expected (whereas the observer agreement was 0.9). Clearly, when layers become difficult to separate from each other (e.g., due to poor contrast) or presence of (pseudo)cysts in adjacent layers, it can be expected that difficulties arise with localizing MME. Therefore, the present study refined the criteria for MME such that they considered abnormalities found in the INL and adjacent layers; differences in the configuration and location of cysts; confluence of cysts with cysts in other retinal layers; the presence of coexisting lesions; artefacts; and the heterogeneous longitudinal pattern. Despite the good interrater agreement (kappa 0.8), there might be other problems in rating MME that we did not account for. Therefore, we would be keen to learn how these refined criteria perform in other hands. 
Furthermore, we did not consider degenerative pseudocysts located just below the internal limiting membrane (50%), in the outer nuclear layer (36%), or in all retinal layers (27%), as described by Querques et al. 3 for patients with ARMD. 
Finally, it needs to be discussed that current automated retinal layer segmentation was not feasible in patients with MME. Three different algorithms were used, which were reliable analyzing retinas of healthy control subjects and patients with drusen. 2022 The first limitation to mention was the time necessary to segment the retinal layers, which took 2 to 3 weeks for each algorithm. Second, two of the algorithms did not permit a separate segmentation of the INL. 21,22 Third, the algorithm failure rate of accurate layer segmentation in eyes with MME was almost 100%, requiring extremely time-consuming manual corrections. The automated layer segmentation could not be completed for those eyes in which the primary pathology affected the structure of the layers, resulting in a change of contrast of the layers. However, local pathology (such as highly reflective spots and shadow artefacts) also led to difficulty segmenting the layers. Therefore, retinal pathology proved to be a severe limitation to the routine application of currently available retinal layer segmentation software. It has been proposed that machine learning might help to overcome this problem. 22 Acknowledging the failure to provide quantitative data on INL thickness, the qualitative revision of the scans (manually corrected INL thickness maps) presented in this study suggested that it might not be appropriate to pool data from the four sectors composing the perimacular rim. Areas with visible thinning coexisted to areas with visible thickening. A more sophisticated and detailed analysis of the INL thickness may need to be performed in future studies, requiring segmentation software reliable in pathological conditions and statistical models feasible for refined retinal area surface analyses. We would be keen to hear of such efforts and discuss whether the data compiled in this study, an anonymous dataset of MME patients, may contribute to advancing the field. 
Further research is needed to determine the clinical significance of MME. Because MME was not present in healthy controls, further examination is suggested when microcysts are present on OCT images in (new) patients presenting in a (neuro)ophthalmologic service. Especially since imaging of the central nervous system might be needed in some cases (4% of patients with MME in the present study suffered from a neurologic condition). Furthermore, the presence of microcysts may negatively predict long-term functional outcome both in patients with ARMD and patients with MS. 1,3,4 These studies showed that visual acuity decreased when microcysts were present. On the other hand, a relation between the presence of MME, visual acuity and overall disease disability was not found in patients with NMO. However, the sample size of the latter study might have been too small for determining such associations. 6 In the present study, visual function was not systematically investigated. Follow-up of patients with MME in a neuro-ophthalmological service may be advised to better understand the potential prognostic and therapeutical implications of this new clinical sign. 
Acknowledgments
Disclosure: M.C. Burggraaff, None; J. Trieu, None; W.A.E.J. de Vries-Knoppert, None; L. Balk, None; A. Petzold, None 
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Figure 1
 
Study design and patient flow.
Figure 1
 
Study design and patient flow.
Figure 2
 
Two examples of OCT macular volume scans with interrater disagreement on presence of MME. (A) In this patient, there was doubt if the hyporeflective lesion was a cyst or an artefact, and if the lesion was not to close to the foveola, which does not have an INL. (B) The cyst might be in the INL or in the adjacent layer. There might be confluence of the cyst in both layers.
Figure 2
 
Two examples of OCT macular volume scans with interrater disagreement on presence of MME. (A) In this patient, there was doubt if the hyporeflective lesion was a cyst or an artefact, and if the lesion was not to close to the foveola, which does not have an INL. (B) The cyst might be in the INL or in the adjacent layer. There might be confluence of the cyst in both layers.
Figure 3
 
An example of a normal retina compared with the retina of a patient with MME. (A) A normal retina from a healthy control subject. The pseudocolored surface image is the infrared surface photo; the vertical stacked gray image an OCT B-scan. (B) Optical coherence tomography image taken from a 76-year-old woman with a 3-year history of ARMD, for which she received regular injections with ranibizumab and bevacizumab. At time of imaging, her best corrected VA OS was 0.7. (C) Illustrates layer segmentation for the OCT B-scan shown in (A). The INL is bordered by the blue and orange lines. (D) The same for the patient with ARMD. Clearly, there is focal thickening of the INL were MME is observed. (E) Pan-retinal thickness map from the healthy control subject and the corresponding INL thickness map (F). (G) In the patient with ARMD, there is overall thinning of the retina. (H) There is marked heterogeneity of the INL thickness map in the ARMD patient compared with the healthy control subject.
Figure 3
 
An example of a normal retina compared with the retina of a patient with MME. (A) A normal retina from a healthy control subject. The pseudocolored surface image is the infrared surface photo; the vertical stacked gray image an OCT B-scan. (B) Optical coherence tomography image taken from a 76-year-old woman with a 3-year history of ARMD, for which she received regular injections with ranibizumab and bevacizumab. At time of imaging, her best corrected VA OS was 0.7. (C) Illustrates layer segmentation for the OCT B-scan shown in (A). The INL is bordered by the blue and orange lines. (D) The same for the patient with ARMD. Clearly, there is focal thickening of the INL were MME is observed. (E) Pan-retinal thickness map from the healthy control subject and the corresponding INL thickness map (F). (G) In the patient with ARMD, there is overall thinning of the retina. (H) There is marked heterogeneity of the INL thickness map in the ARMD patient compared with the healthy control subject.
Figure 4
 
Representative OCT images of patients with MME from the clinical spectrum are shown. The infrared surface photo and OCT image are presented to the left and the manually segmented INL to the right. (A) Microcystic macular edema in the right eye of a 70-year-old male patient with a history of proliferative diabetic retinopathy treated with panretinal photocoagulation (VA OD 0.3). (B) Optical coherence tomography image showing MME 8 months after occlusion of the vena temporalis superior OD in a 66-year-old female patient (VA OD 0.7). Microcystic macular edema was located in the temporal superior quadrant of the inner 3-mm EDTRS grid. However, INL thickening extended to the periphery. In addition, hyperreflective spots were observed in all inner retinal layers. (C) Microcystic macular edema in a 66-year-old female patient with sarcoidosis and posterior uveitis in the right eye. Fluorescein angiography showed an ischemic maculopathy (VA OD 1.0). Serum ACE was 29, CT-thorax showed mediastinal and hilar lymphadenopathy. In this case, hyperreflective spots were restricted to the retinal nerve fiber layer, ganglion cell layer, and INL. (D) Microcystic macular edema in a 58-year-old female patient with a newly diagnosed pucker in the right eye (VA OD 0.2). Again, there were multiple hyperreflective spots in the inner retinal layers. (E) Microcystic macular edema 3 months after vitrectomy, in a 71-year-old female patient with a retinal detachment in the left eye (VA OS 0.05).
Figure 4
 
Representative OCT images of patients with MME from the clinical spectrum are shown. The infrared surface photo and OCT image are presented to the left and the manually segmented INL to the right. (A) Microcystic macular edema in the right eye of a 70-year-old male patient with a history of proliferative diabetic retinopathy treated with panretinal photocoagulation (VA OD 0.3). (B) Optical coherence tomography image showing MME 8 months after occlusion of the vena temporalis superior OD in a 66-year-old female patient (VA OD 0.7). Microcystic macular edema was located in the temporal superior quadrant of the inner 3-mm EDTRS grid. However, INL thickening extended to the periphery. In addition, hyperreflective spots were observed in all inner retinal layers. (C) Microcystic macular edema in a 66-year-old female patient with sarcoidosis and posterior uveitis in the right eye. Fluorescein angiography showed an ischemic maculopathy (VA OD 1.0). Serum ACE was 29, CT-thorax showed mediastinal and hilar lymphadenopathy. In this case, hyperreflective spots were restricted to the retinal nerve fiber layer, ganglion cell layer, and INL. (D) Microcystic macular edema in a 58-year-old female patient with a newly diagnosed pucker in the right eye (VA OD 0.2). Again, there were multiple hyperreflective spots in the inner retinal layers. (E) Microcystic macular edema 3 months after vitrectomy, in a 71-year-old female patient with a retinal detachment in the left eye (VA OS 0.05).
Figure 5
 
Microcystic macular edema in a patient with multiple sclerosis and a history of optic neuritis and branch retinal vein occlusion in the right eye. This 55-year-old female patient was diagnosed with clinical definite MS in 1992. Magnetic resonance imaging showed multiple periventricular brain lesions, and spinal T2 hyperintense lesions. In 2001, she experienced one episode of optic neuritis OD; coincidentally, an occlusion of the vena temporalis superior was found (VA 0.4). This case illustrates coexistence of MME with both a thinned (green box) and thickened (blue box) aspect of the INL. (A) The OCT B-scan clearly shows MME in the INL, which is thickened in the center and thinned near the peripheral parts of the image. The OCT image was taken 11 years after conduction of the fundus photograph in 2001, which showed superficial intraretinal hemorrhages inline with occlusion of the vena temporalis superior (B). There was thinning of the nerve fiber layer of the right optic disc, with normal appearance on the left (not shown). (C) The corresponding fluorescein angiography does not reveal leakage. Furthermore, there seemed to be a preocclusion of the vena temporalis inferior. (D) The thickness map of the INL showed more prominent thickening along the course of the inferior temporal vein, with relative thinning along the course of the superior temporal vein. (E) The destruction of the INL related to the thickness difference can be best appreciated by comparing the temporal part of the inferior retina (blue box) with the corresponding area shown on top of the image (green box). Interestingly, hyperreflective spots of the inner retinal layers were found, which were also seen in other entities of the clinical spectrum of MME.
Figure 5
 
Microcystic macular edema in a patient with multiple sclerosis and a history of optic neuritis and branch retinal vein occlusion in the right eye. This 55-year-old female patient was diagnosed with clinical definite MS in 1992. Magnetic resonance imaging showed multiple periventricular brain lesions, and spinal T2 hyperintense lesions. In 2001, she experienced one episode of optic neuritis OD; coincidentally, an occlusion of the vena temporalis superior was found (VA 0.4). This case illustrates coexistence of MME with both a thinned (green box) and thickened (blue box) aspect of the INL. (A) The OCT B-scan clearly shows MME in the INL, which is thickened in the center and thinned near the peripheral parts of the image. The OCT image was taken 11 years after conduction of the fundus photograph in 2001, which showed superficial intraretinal hemorrhages inline with occlusion of the vena temporalis superior (B). There was thinning of the nerve fiber layer of the right optic disc, with normal appearance on the left (not shown). (C) The corresponding fluorescein angiography does not reveal leakage. Furthermore, there seemed to be a preocclusion of the vena temporalis inferior. (D) The thickness map of the INL showed more prominent thickening along the course of the inferior temporal vein, with relative thinning along the course of the superior temporal vein. (E) The destruction of the INL related to the thickness difference can be best appreciated by comparing the temporal part of the inferior retina (blue box) with the corresponding area shown on top of the image (green box). Interestingly, hyperreflective spots of the inner retinal layers were found, which were also seen in other entities of the clinical spectrum of MME.
Figure 6
 
Sectoral localization and perimacular rim extension of MME. One quadrant was affected in the vast majority of cases (67.7%). Within this group, MME was most often found in the temporal and nasal quadrants. In a small proportion of patients, MME was extensive and lesions were found in two (15.0%), three (9.0%), or four quadrants (8.3%).
Figure 6
 
Sectoral localization and perimacular rim extension of MME. One quadrant was affected in the vast majority of cases (67.7%). Within this group, MME was most often found in the temporal and nasal quadrants. In a small proportion of patients, MME was extensive and lesions were found in two (15.0%), three (9.0%), or four quadrants (8.3%).
Table 1
 
Refined and Validated Diagnostic Criteria for MME
Table 1
 
Refined and Validated Diagnostic Criteria for MME
Inclusion Criteria Exclusion Criteria
Configuration Small hyporeflective lesions in the INL Cysts with a clearly visible cell wall
Location Within or outside the perimacular rim Small cysts directly adjacent to or within the foveola, where there is no INL
Confluence Permitted within the INL Confluence with cysts in adjacent retinal layers
Coexisting lesions Small cysts in other retinal layers or subretinal fluid is permitted but should be documented as such MME needs to be distinguished from blood vessel artefacts which can give the impression of hyporeflectivity
Longitudinal pattern MME fulfilling all of the above criteria needs to be seen on two macular volume scans taken at separate time points, at least 1 week apart
Transient/dynamic pattern Transient/dynamic: MME fulfilling all of the above criteria needs to be seen on at least one macular volume scan, whereas MME is not present in a previous or follow-up volume scan
Static pattern MME fulfilling all of the above criteria needs to be seen on all macular volume scans of one patient, taken at separate time points, at least 1 week apart
Table 2
 
The Clinical Spectrum of MME
Table 2
 
The Clinical Spectrum of MME
Disease* n (%) Age (y) Sex, % F
Age-related macular degeneration 36 (27.1) 84.1 ± 7.0 (61–95) 69.4
Epiretinal membrane/vitreomacular traction 25 (18.8) 72.7 ± 9.0 (52–93) 48.0
Iatrogen† 27 (20.3) 72.7 ± 10.6 (50–88) 55.6
Diabetic retinopathy 9 (6.8) 64.6 ± 10.0 (44–80) 33.3
Vascular occlusion 9 (6.8) 75.2 ± 9.0 (64–91) 55.6
Uveitis 9 (6.8) 57.8 ± 18.8 (23–85) 77.8
Multiple sclerosis‡ 4 (3.0) 57.8 ± 7.8 (51–69) 50.0
Optic neuropathy§ 1 (0.8) 78.0 0.0 (1 male)
Central serous chorioretinopathy 3 (2.3) 51.0 ± 17.0 (34–68) 0.0 (3 male)
Retinitis pigmentosa 1 (0.8) 30.0 0.0 (1 male)
Medication‖ 2 (1.5) 53.5 ± 6.4 (49–58) 100.0
Other/unknown 7 (5.3) 72.6 ± 13.8 (52–85) 71.4
Healthy subjects 65 50.5 ± 7 (28–63) 65.1
Table 3
 
Location of MME With Respect to the EDTRS Grid
Table 3
 
Location of MME With Respect to the EDTRS Grid
Disease Superior, n (%) Inferior, n (%) Nasal, n (%) Temporal, n (%)
Age-related macular degeneration 6 (16.7) 12 (33.3) 19 (52.8) 14 (38.9)
Epiretinal membrane/vitreomacular traction 12 (18.0) 11 (44.0) 12 (48.0) 15 (60.0)
Iatrogenic 7 (25.9) 6 (22.2) 15 (55.6) 14 (51.9)
Diabetic retinopathy 3 (50.0) 1 (20.0) 4 (44.4) 2 (40.0)
Vascular occlusion 2 (22.0) 0 (0.0) 2 (22.2) 5 (56.0)
Uveitis 5 (55.6) 4 (44.4) 4 (44.4) 7 (77.8)
Multiple sclerosis 2 (50.0) 2 (50.0) 2 (50.0) 2 (50.0)
Optic neuropathy 1 (100) 0 (0.0) 0 (0.0) 0 (0.0)
Central serous chorioretinopathy 1 (25.0) 0 (0.0) 3 (75.0) 0 (0.0)
Retinitis pigmentosa 0 (0.0) 0 (0.0) 0 (0.0) 1 (100)
Medication 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0)
Other/unknown 1 (14.3) 2 (28.6) 2 (28.6) 4 (57.1)
Total 39 (29.3) 40 (30.1) 64 (48.1) 66 (49.6)
Table 4
 
Number of Patients (Eyes) With MME Found in Literature
Table 4
 
Number of Patients (Eyes) With MME Found in Literature
Disease MME Cases Reference(s)
ARMD 22 eyes of 22 patients Querques3
24 eyes Cohen11
Retinal telangiectasis 20 eyes (of 10 patients) Gaudric12
Tamoxifen 1 eye of 1 patient Park33
MS 20 eyes of 15 patients Gelfand1
12 eyes of 10 patients Saidha4
1 eye of 1 patient Balk5
Relapsing isolated optic neuropathy 1 eye of 1 patient Balk5
Chronic relapsing inflammatory optic neuropathy 1 patient Petzold and Plant34
NMO 10 patients Sotirchos7
7 eyes of 5 patients Gelfand1
Leber's hereditary optic neuropathy/dominant optic atrophy 10 patients Barboni9
Endemic optic neuropathy 25 eyes of 16 patients Shalchi10
Optic nerve glioma 2 eyes of 1 patient Abegg8
Retrograde optic neuropathy (compressive, n = 9 eyes; vascular, n = 3; hereditary, n = 2; not clear, n = 2) 16 eyes of 9 patients Abegg30
Autosomal dominant optic atrophy 4 eyes of 2 patients Gocho31
Autosomal dominant optic atrophy 2 eyes of 1 patient Lujan32
Total cases of MME* Approximately 178 eyes of 127 patients
This study 142 eyes of 133 patients
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