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Alterations of the Lamina Cribrosa Are Associated with Peripapillary Retinoschisis in Glaucoma and Pachychoroid Spectrum Disease
Alterations of the Lamina Cribrosa Are Associated with Peripapillary Retinoschisis in Glaucoma and Pachychoroid Spectrum Disease Jae Hyung Lee, MD, PhD,* Hae-Young Lopilly Park, MD, PhD,* Jiwon Baek, MD, Won Ki Lee, MD, PhD Purpose: To describe the findings of enhanced depth imaging (EDI) optical coherence tomography (OCT) of the lamina cribrosa (LC) in glaucoma and pachychoroid spectrum diseases associated with peripapillary retinoschisis. Design: Retrospective, observational case series. Participants: A total of 16 patients from 1 institution. Methods: Detailed medical case histories, optic disc and retinal imaging with EDI using the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), and clinical course were reviewed for patients with peripapillary retinoschisis without a known predisposing condition. Main Outcome Measures: Clinical features and findings of the EDI OCT. Results: Among the 16 eyes with peripapillary retinoschisis that had abnormal findings on EDI of the LC, 8 had glaucoma and 8 had pachychoroid spectrum diseases, including chronic central serous chorioretinopathy (CSC) (6 eyes), small pigment epithelium detachment (1 eye), and polypoidal choroidal vasculopathy (PCV) (1 eye). The abnormal LC findings were central or peripheral focal LC defects in eyes with glaucoma and LC disinsertions or peripheral focal LC defects in eyes with pachychoroid spectrum diseases. Central LC defects were related to inner layer retinoschisis, whereas LC disinsertions and peripheral LC defects were related to outer layer retinoschisis. The peripapillary retinoschisis did not show a topographic association with the underlying chronic CSC- or PCV-associated lesions. In 6 treated eyes with pachychoroid, peripapillary retinoschisis resolved along with subretinal fluid after antievascular endothelial growth factor injection in 4 eyes, whereas retinoschisis persisted after the resolution of subretinal fluid in 2 eyes. Conclusions: Enhanced depth imaging OCT of the LC demonstrated alterations associated with peripapillary retinoschisis, pachychoroid spectrum diseases, and glaucoma. Ophthalmology 2016;-:1e11 ª 2016 by the American Academy of Ophthalmology.
Retinoschisis is a splitting of the neurosensory retina and has been described in various ocular conditions, including X-linked retinoschisis, congenital optic disc abnormalities such as optic disc pit and optic disc coloboma, and myopia.1,2 Recently, retinoschisis has been found in eyes with glaucoma. Glaucomatous eyes often have focal structural abnormalities of the optic nerve head (ONH), referred to as “acquired pits of the optic nerve” (APONs).3 Previous case reports have suggested that APONs are correlated with the presence of macular retinoschisis or macular detachment.4,5 With the advent of spectral-domain (SD) optical coherence tomography (OCT) with enhanced depth imaging (EDI), evaluation of the detailed and deep architecture of the ONH has been accessible, and approximately 77% of the APONs in glaucoma showed alterations in the lamina cribrosa (LC).6 Choi et al6 reported that, among glaucomatous eyes with APON, only eyes with associated LC alterations had episodes of retinoschisis (incidence of 13%) compared with eyes without LC alterations 2016 by the American Academy of Ophthalmology Published by Elsevier Inc.
(incidence of 0%). That study suggested that the LC defect in the peripheral region of the ONH may serve as an entrance of fluid from the subarachnoid space and contribute to retinoschisis. A study by Yoshitake et al7 observed the presence of late fluorescein staining at the optic disc corresponding to the location of focal LC alterations in glaucomatous eyes with macular retinoschisis, also suggesting that changes in the LC may provide a conduit that allows fluid into the intraretinal space.7 Although the exact pathogenic mechanism and the source of intraretinal fluid of retinoschisis require further evaluation, we can assume from these studies that the LC alterations may play a role in the development of retinoschisis. We present 16 cases with peripapillary retinoschisis to add important evidence demonstrating that LC alteration may contribute to retinoschisis. These patients had abnormal LC findings as revealed by EDI of the ONH. We separated these patients into 2 categories by the underlying causative http://dx.doi.org/10.1016/j.ophtha.2016.06.033 ISSN 0161-6420/16
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Ophthalmology Volume -, Number -, Month 2016 disease. The first group of patients had chorioretinal disease associated with choroidal thickening secondary to choroidal hyperpermeability, which has not been reported as a possible cause of peripapillary retinoschisis. Diseases that are associated with thickened choroid, including central serous chorioretinopathy (CSC) and polypoidal choroidal vasculopathy (PCV), recently have been suggested as a spectrum of diseases that share a common pathophysiology and named as “pachychoroid spectrum diseases.”8,9 The second group included patients with glaucoma, in whom peripapillary retinoschisis was associated with the location of the glaucomatous optic disc and retinal nerve fiber layer (RNFL) damage.
Methods This is a retrospective review of the clinical and imaging features for a series of patients found to have peripapillary retinoschisis and abnormal LC findings on EDI OCT of the optic disc. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, Seoul, South Korea, and followed the tenets of the Declaration of Helsinki. Consecutive patients who visited the ophthalmology department of Seoul St. Mary’s Hospital, The Catholic University of Korea, between November 2014 and October 2015 and who demonstrated peripapillary retinoschisis on macular or RNFL OCT were evaluated for the presence of LC abnormalities. Patients with disorders that are generally considered as the causes of retinoschisis were excluded, including juvenile retinoschisis, myopic foveoschisis, vitreomacular traction syndrome, and congenital optic pit. Eyes with peripapillary retinoschisis that showed interconnections with area of retinal pigment epithelial (RPE) atrophy also were excluded in patients with pachychoroid spectrum diseases. All patients had undergone complete ophthalmologic examinations, including best-corrected visual acuity, refraction, slit-lamp biomicroscopy, fundoscopy with dilated pupils, fundus and disc photography (Kowa VX-20 fundus camera; Kowa Co, Inc. Tokyo, Japan), and fluorescein angiography (FA) (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). Macular and optic disc cube scan using SD OCT (Spectralis; Heidelberg Engineering) was used to evaluate the LC and chorioretinal features. Enhanced depth imaging of the retina and ONH was performed using the same machine. According to the findings of baseline examinations, further detailed examinations were performed depending on the suspected diagnosis. Indocyanine green angiography (ICGA) (Heidelberg Retina Angiograph; Heidelberg Engineering) was performed in patients with a thickened choroid.
Enhanced Depth Imaging Optical Coherence Tomography Serial horizontal and vertical cross-sectional scans covering the ONH, approximately 30 mm apart, were obtained using the EDI technique of the Spectralis OCT (Heidelberg Engineering, GmbH, Dossenheim, Germany) for LC analyses, as previously described.10e12 Each section incorporated an average of at least 35 OCT frames. Images with a quality score >15 were obtained (w65e70 sections per eye). The volume scan with 25 sections of Spectralis OCT was performed on each eye, covering 9.06.0 mm in the macular area centered on the fovea. The subfoveal choroidal thickness was measured with the digital calipers that were included in the review software. The EDI OCT images of the ONH were reviewed by an experienced glaucoma specialist (H.-Y.L.P.) The examination
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focused on the presence of any alteration in the smooth curvilinear U- or W-shaped cross-sectional contour of the LC with an upward slope at the far periphery of the LC toward its insertion.13e16 Alterations of the LC were defined using the guidelines that were specified by Kiumehr et al16 and classified as focal LC defects or LC disinsertions for this study. A focal LC defect was defined as a hole-like defect with a discontinuous anterior laminar surface, which appeared to be a full-thickness defect. An LC disinsertion was defined as a posteriorly displaced laminar insertion with downward sloping at the far periphery of the LC toward the neural canal wall. Focal LC defects were classified into 2 typesdperipheral or centraldaccording to their location from the neural canal wall.6 A peripheral LC defect was defined as a defect located near the LC insertion but maintaining the contour of the U- or Wshaped LC, with the anterior LC visible on only the central side of the defect. A central LC defect referred to an LC defect with the LC visible on either side of the defect. These LC findings had to be present in 2 neighboring B-scans to avoid false-positives in both the horizontal and vertical scans; therefore, the LC defect was expected in 4 scans to be defined.
Results During the 1-year study period, a total of 23 patients with peripapillary retinoschisis (8 patients from the glaucoma clinic and 15 patients from the retina clinic) received ONH scanning with EDI-OCT. In the glaucoma clinic, 8 eyes of 8 patients (normaltension glaucoma in 6 eyes and primary open-angle glaucoma in 2 eyes) demonstrated LC alterations on EDI of the ONH. In the retina clinic, 8 eyes of 7 patients did not show discernable LC abnormalities: chronic CSC in 6 eyes (5 patients), choroidal hemangioma in 1 eye, and unknown cause in 1 eye. The diagnosis of the 8 included eyes (8 patients) was chronic CSC in 6 eyes, small pigment epithelium detachment in 1 eye, and PCV in 1 eye. The characteristics of imaging examinations and clinical features in these patients are summarized in Tables 1 and 2.
Lamina Cribrosa Alterations The abnormal LC findings were focal LC defects or LC disinsertions, which varied according to the underlying diseases. Among 8 eyes with chorioretinal diseases with pachychoroid, 6 had LC disinsertions and 2 had peripheral focal LC defects near the LC insertions. Among 8 eyes with glaucoma, 2 had central focal LC defects, 5 had peripheral focal LC defects, and 1 had both features. The clock-hour location of LC deformity was mainly at the 7 o’clock position in eyes with glaucoma in right eye format, which was more variable in eyes with pachychoroid spectrum diseases (Fig 1).
Association between Peripapillary Retinoschisis and Lamina Cribrosa Alterations In all eyes, the clock-hour location of the LC abnormalities correlated well with the location of the retinoschisis. The involved retinal layers ranged from the RNFL to the outer nuclear layer (ONL), which varied according to the pattern and location of LC abnormalities. When LC disinsertions were present or focal LC defects were located in the peripheral region near the LC insertion, retinoschisis involved the inner nuclear layer (INL) to the ONL. In 8 pachychoroid cases with LC disinsertions or peripheral focal defects, 6 involved both the INL and the ONL, and 2 involved the ONL. Among 5 glaucoma cases with peripheral LC defects, 1 involved both the INL and the ONL, and 4 had ONL retinoschisis. In contrast, in 2 glaucoma cases with central focal LC defects, only
Table 1. Summary of Patients’ Characteristics with Peripapillary Retinoschisis in Eyes with Pachychoroid-Related Retinal Diseases
58 51 77 48 76 69 66 67
M M M F M M M M
OD OD OS OD OD OD OS OD
Chronic Chronic Chronic Chronic Chronic PED PCV Chronic
Subfoveal Choroidal Thickness (mm)
CSC CSC CSC CSC CSC
Pachychoroid neovasculopathy Atypical CSC with ERD Chronic CSC d d PCV d CSC Chronic CSC
Contralateral Eye
Involved Retinal Layer
Extent of Involvement
Features of the LC
506 472 623 465 482 506 402 413
644 513 537 511 NA 389 417 401
ONL INL, ONL ONL INL, ONL INL, ONL INL, ONL INL, ONL INL, ONL
Around the ONH Around the ONH ONH to near macula ONH to fovea ONH to fovea ONH to near macular ONH to near macular ONH to near macular
Disinsertion Disinsertion Focal peripheral defect Disinsertion Disinsertion Focal peripheral defect Disinsertion Disinsertion
Treatment Numbers of Each Drug
Response/Recurrence of Retinoschisis after Treatment
NA 1 NA 4 (1/3)
NA No change/NA NA Complete regression/þ
2 (1/1)
Complete regression/þ
3 6 2 (1/1)
Partial regression/þ increase/þ Complete regression/
Topographic Association with Underlying Retinal Lesion
Hyperpermeability Next to ONH on ICGA
Late Disc Stain on FA
Initial BCVA
Final BCVA
Follow-up (mos)
1 2 3 4
þ
þ þ þ
0.8 1.0 0.16 0.63
1.0 1.0 0.16 1.0
12 24 15 12
Patient 5
þ
þ
0.5
0.4
40
Patient 6 Patient 7 Patient 8
þ
þ
0.8 0.63 0.1
0.8 0.63 0.16
18 12 20
Patient Patient Patient Patient
Features of the Retinoschisis
Involved Eye
Treatment Observation Laser at leaking point Observation Anti-VEGF (bevacizumab/ aflibercept) Anti-VEGF (bevacizumab/ aflibercept) Anti-VEGF (ranibizumab) Anti-VEGF (aflibercept) Anti-VEGF (bevacizumab/ aflibercept)
BCVA ¼ best-corrected visual acuity; CSC ¼ central serous chorioretinopathy; ERD ¼ exudative retinal detachment; FA ¼ fluorescein angiography; ICGA ¼ indocyanine green angiography; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; NA ¼ not available; OD ¼ right eye; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; OS ¼ left eye; PCV ¼ polypoidal choroidal vasculopathy; PED ¼ pigment epithelial detachment; VEGF ¼ vascular endothelial growth factor.
LC alteration and Peripapillary Retinoschisis
1 2 3 4 5 6 7 8
Diagnosis of the Contralateral Eye
Patient Patient Patient Patient Patient Patient Patient Patient
Diagnosis
Lee et al
Age, yrs Gender Laterality
3
4
BCVA ¼ best-corrected visual acuity; GCL ¼ ganglion cell layer; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; MD ¼ mean deviation; NFL ¼ nerve fiber layer; NTG ¼ normal-tension glaucoma; OCT ¼ optical coherence tomography; OD ¼ right eye; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; OS ¼ left eye; POAG ¼ primary open-angle glaucoma; VF ¼ visual field.
Location
Peripheral Central Peripheral Peripheral Peripheral Central Peripheral Central and peripheral
Type
Focal defect Focal defect Focal defect Focal defect Focal defect Focal defect Focal defect 2 focal defects
Extent of Involvement
1.28 2.67 2.42 16.40 4.50 12.50 16.15 2.13
ONH to near macula Around the ONH ONH to the fovea ONH to near macula ONH to near macula Around the ONH ONH to near macular ONH to the fovea ONL NFL ONL INL, ONL ONL NFL, GCL ONL NFL, INL, ONL
VF MD Baseline
13 18 16 16 18 15 22 19 High myopia Myopia Emmetropia Myopia Hyperopia Emmetropia High myopia Myopia 0.8 1.0 0.8 0.8 1.0 1.0 0.32 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.32 1.0
Refraction Diagnosis
NTG NTG NTG POAG NTG NTG POAG NTG OD OS OS OD OS OS OD OS
Laterality Gender
F M F M F F M M 60 42 67 73 62 61 48 39 Patient Patient Patient Patient Patient Patient Patient Patient
9 10 11 12 13 14 15 16
Age, yrs
10 16 15 9 11 11 15 15
Involved Retinal Layer
Features of the Retinoschisis IOP
At OCT Scan Last BCVA Initial BCVA
Table 2. Summary of Patients’ Characteristics with Peripapillary Retinoschisis in Glaucoma
Features of the LC
Ophthalmology Volume -, Number -, Month 2016 the RNFL or ganglion cell layer was involved. The other glaucoma case that had both central and peripheral LC defects involved the nerve fiber layer, INL, and ONL. The extent of retinoschisis was restricted around the ONH in 4 (25.0%), extended near the macula in 8 (50.0%), and involved the fovea in 4 (25.0%) of 16 eyes, which was closely related to the location of LC deformity (central or peripheral). In eyes with central focal LC defects, the extent was limited around the ONH. In contrast, retinoschisis involved the macula or the foveal region in eyes with peripheral LC defects or LC disinsertions.
Other Features on Imaging Examinations and Clinical Course The subfoveal choroidal thickness of the 8 cases with chorioretinal diseases accompanying pachychoroid ranged from 402 to 623 mm. In 6 eyes, the peripapillary retinoschisis did not show a topographic association with the underlying chronic CSC- or PCV-associated lesions, including pigment epithelial detachment (PED), subretinal fluid, and polypoidal lesions. In the other 2 cases, retinoschisis was noted adjacent to subretinal fluid. All eyes showed choroidal hyperpermeability within major vascular arcades on ICGA, especially in the papillomacular area in 4 cases. Two cases showed late fluorescein staining of the temporal ONH border. The clinical course of these 16 cases varied. All but 1 (case 16) of the eyes with retinoschisis combined with glaucoma were asymptomatic, and the retinoschisis resolved spontaneously. Patient 16 had persisting retinoschisis throughout the 5 months of follow-up. Among 8 cases with retinoschisis combined with pachychoroid, 6 received treatment for the underlying chronic CSC- or PCV-related lesions and 2 were observed because there was no subretinal fluid or PED involving the fovea. In these 2 eyes, peripapillary retinoschisis persisted until 12 and 15 months, respectively, although the lesions showed a fluctuating pattern (patients 1 and 3). Among the 6 treated eyes, peripapillary retinoschisis resolved completely in 3 eyes (patients 4, 5, and 8) and partially in 1 eye (patient 6) after antievascular endothelial growth factor injections. Complete resolution of peripapillary retinoschisis was achieved in these 3 cases after switching from bevacizumab (Avastin; Genentech, Inc., San Francisco, CA) to aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY). One case with partial resolution of peripapillary retinoschisis received ranibizumab (Lucentis; Genentech Inc.) injections. However, the lesions recurred 2 to 6 months after the last injection in all 4 eyes. In the other 2 eyes (patients 2 and 7), peripapillary retinoschisis did not resolve after focal photocoagulation and antievascular endothelial growth factor injections, although subretinal fluid decreased after the treatment.
Representative Cases Eyes with peripapillary retinoschisis related to pachychoroid spectrum diseases had LC findings of a peripheral focal LC defect (Fig 2) or an LC disinsertion (Figs 3 and 4). These cases showed thickened choroid with dilated choroidal vessels on macular OCT (Figs 2 and 3). A hyporeflective tract connecting the LC disinsertion and the retinoschisis cavity was observed (Fig 3), suggesting an association between the LC disinsertion and the peripapillary retinoschisis. Late fluorescein staining at the temporal ONH border was observed (Fig 4F) where the LC disinsertion site may be located, suggesting the LC disinsertion as a conduit of the leakage. Eyes with peripapillary retinoschisis related to glaucoma had central (Fig 5) or peripheral focal LC defects (Figs 6 and 7). A hyporeflective tract connecting the LC defect and the retinoschisis cavity also was observed in several cases (Figs 6 and 7). In some cases, a retinoschisis-like change
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LC alteration and Peripapillary Retinoschisis
Figure 1. Frequency distribution of the presence of lamina cribrosa (LC) abnormalities in eyes with peripapillary retinoschisis according to clock-hour location at the disc in right eye format. The inner white region indicates the central region of the LC at cup base, and the gray region indicates the rim. The numbers in the circles indicate the patient’s numbers. Gray circles are eyes with peripapillary retinoschisis involving the nerve fiber layer (NFL) and ganglion cell layer (GCL), and white circles are eyes with peripapillary retinoschisis involving the deeper retinal layers. INL ¼ inner nuclear layer; ONL ¼ outer nuclear layer.
of optic disc was observed at the prelaminar region, which appeared to be associated with the peripapillary retinoschisis (Figs 4E and 5A).
Discussion Peripapillary retinoschisis is reported to be more frequently present in glaucomatous eyes compared with normal control eyes.17e23 The pathogenic mechanism of retinoschisis in these eyes was supposed to be associated with LC damage, which frequently manifests as an optic disc pit. Recent study data on ONH changes using the EDI technique of SD OCT support this hypothesis.7,21 In the current study, we made new observations in patients with glaucoma, which might provide evidence for the contribution of LC defects to the development of peripapillary retinoschisis. The location of the LC abnormalities (central vs. peripheral) appeared to be associated with the involved retinal layers. Inner layer retinoschisis developed in eyes with central focal LC defects. Retinoschisis ranging from the INL to the ONL developed in eyes with peripheral focal LC defects. In addition, similar involvements were noted in eyes having pachychoroid spectrum diseases with LC disinsertions or peripheral focal LC defects. Retinoschisis in these eyes tended to be involved near the macula or fovea. We observed small retinoschisis cavities or a hyporeflective tract between the LC alteration and the cavity of the retinoschisis in some eyes. The pattern and location of LC abnormalities in these eyes were somewhat different compared with those of the eyes with glaucoma. The most
frequent abnormality was LC disinsertion, which develops at the far peripheral region of the ONH, and no eye showed a central focal defect. The clock-hour location in each patient tended to disperse around the temporal side (7e10 clock-hour position in the right eye format). In our cases with glaucoma, the abnormality was a focal defect, either central or peripheral, which was concentrated in the inferotemporal area (7 o’clock-hour position). Lamina cribrosa abnormalities in glaucoma are located in the superotemporal or inferotemporal region where the LC has fewer supporting connective tissues; this may in part reflect a different pathogenic mechanism involved in the development of LC deformity. We speculate that a thickened choroid due to hyperpermeable choroidal vessels is directly involved in the development of LC changes. Choroidal hyperpermeability was noted on ICGA in all 8 cases. In CSC, increased extravasated fluid from the hyperpermeable choroidal vessels exerts mechanical stress on the RPE layer, which frequently elevates the RPE (serous PED) and finally leads to the focal disruption of the RPE manifested as a focal leak on FA.24,25 The area of leakage from the RPE on FA, choroidal vascular hyperpermeability on ICGA, and increased choroidal thickness on OCT are commonly co-localized.26,27 The increased extravasated fluids and thickened choroid may impose stress not only vertically on RPE but also laterally on ONH. As observed in our images of the ONH, the anterior scleral canal wall is prominent and elongated, perhaps as a result of choroid thickening. This change may displace the LC posteriorly and medially, leading to a break at the weakest point, which is the LC flange where the LC is attached to the sclera and anterior
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Figure 2. Images from the right eye of patient 6, a 69-year-old man with a diagnosis of pigment epithelial detachment (PED). A, Fluorescein angiography shows a focal hyperfluorescent spot at the fovea that corresponds to a small PED on optical coherence tomography (OCT), with no definite leakage. B, On indocyanine green angiography (ICGA), choroidal hyperfluorescence was noted at the papillomacular area. C, On macular OCT, peripapillary retinoschisis (yellow arrowheads) was not topographically associated with the subfoveal PED. Macular OCT also showed choroidal thickening and dilated choroidal vessels (green asterisk); however, subretinal fluid was not noted. D, After a single ranibizumab injection, the height of retinoschisis lesion reduced but the lesion persisted. E, Enhanced depth imaging of the optic nerve head of this patient shows a focal laminar defect (red arrow).
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Figure 3. Images from the right eye of patient 4, a 48-year-old woman with a diagnosis of chronic central serous chorioretinopathy (CSC). A, Fluorescein angiography showed faint leakage nasal to the fovea, and (B) choroidal hyperfluorescence was noted at the papillomacular area on indocyanine green angiography. C, Macular optical coherence tomography shows choroidal thickening and dilated choroidal vessels with large lumens (green asterisk) and peripapillary retinoschisis involving the macular region (yellow arrowheads). The retinoschisis lesion involves the inner nuclear layer and outer nuclear layer. D and E, The enhanced depth imaging of the optic nerve head of this patient shows laminar disinsertion at the temporal side of the disc (red arrow) and retinoschisis cavity connected to this laminar disinsertion (white arrowheads). The peripapillary sclera is displaced posteriorly (orange glyphs) because of the thickened choroid.
Figure 4. Images that represent different clinical courses of peripapillary retinoschisis. Top row: Images from the right eye of patient 2, a 51-year-old man with a diagnosis of chronic chorioretinopathy (CSC). A, The enhanced depth imaging (EDI) of the optic nerve head (ONH) of this patient shows a laminar disinsertion (red arrow). B, The midphase of fluorescein angiography (FA) showed a widespread area of irregular hyperfluorescence with a suspicious leaking point (red arrow). C, Macular optical coherence tomography (OCT) showed diffuse, irregular retinal pigment epithelial (RPE) elevation with subretinal fluid nasal to the fovea and peripapillary retinoschisis involving the inner nuclear layer (INL) and outer nuclear layer (ONL). D, Focal photocoagulation targeted the RPE at the suspicious leaking point. Complete resolution of subretinal fluid was noted at 1 month; however, the retinoschisis lesion remained stable, persisting during the 22-month follow-up period. Middle row: Images from the right eye of patient 5, a 76-year-old man with a diagnosis of chronic CSC. E, The EDI of the ONH of this patient shows a laminar disinsertion (red arrow). A schisis-like change also was noted in the prelaminar lesion of the ONH (green asterisk). F, On FA, late fluorescein staining of the optic disc was observed in the region of the laminar disinsertion. G, Macular OCT showed subfoveal fluid and a small pigment epithelial detachment (PED) temporal to the fovea. Peripapillary retinoschisis lesion involved the INL and ONL. H, After a single aflibercept injection, both subfoveal fluid and peripapillary retinoschisis showed complete resolution. The subfoveal choroidal thickness decreased from 456 to 430 mm. Bottom row: Images from the right eye of patient 7, a 66-year-old man with a diagnosis of polypoidal choroidal vasculopathy (PCV). I, The EDI of the ONH of this patient shows laminar disinsertion (red arrow) from the peripapillary sclera (orange glyphs). J, Indocyanine green angiography revealed multiple polyps with branching vascular network and choroidal hyperpermeability at the macula. K, Macular OCT showed subfoveal fluid that extended temporal to the fovea. Peripapillary retinoschisis involving the INL and ONL were detected apart from the subfoveal PCV lesion. L, After 3 loading injections of intravitreal aflibercept, subretinal fluid decreased and subfoveal choroidal thickness decreased from 394 to 338 mm; however, the peripapillary retinoschisis increased vertically and extended laterally.
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Figure 5. A, Images from the left eye of patient 10, a 42-year-old man with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) is involving the nerve fiber layer around the inferotemporal area where a localized retinal nerve fiber layer (white arrowheads) is present. The enhanced depth imaging (EDI) of this patient shows a focal laminar defect (red arrow) in the paracentral region of the optic nerve head (ONH). A schisislike change is noted in the prelaminar lesion of the ONH (green asterisk), which appears to be connected with the peripapillary retinoschisis. B, Images from the left eye of patient 14, a 61-year-old woman with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) involves the nerve fiber layer and ganglion cell layer around the ONH. The EDI of this patient shows a focal laminar defect (red arrow) in the paracentral region of the ONH.
scleral canal wall. The possibility of the increased susceptibility of the LC insertion site to deformation by compressive or tensile force has been suggested by others, supporting our hypothesis.28,29
Although we observed LC change in our patients, the exact pathogenic mechanism underlying the development of peripapillary retinoschisis is still a matter of speculation. Previous studies have demonstrated that the ONH lacks the
Figure 6. A, Images from the right eye of patient 9, a 60-year-old woman with a diagnosis of normal-tension glaucoma with high myopia. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers and is connected to the laminar defect in the peripheral region of the optic nerve head (ONH) (red arrow). The area with peripapillary retinoschisis is in the region where localized retinal nerve fiber layer (white arrowheads) is located. B, Images from the left eye of patient 11, a 67-year-old woman with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers and the fovea. The enhanced depth imaging of this patient shows a focal laminar defect (red arrow) in the peripheral region of the ONH like a disconnection from the sclera. A hyporeflective tract connecting the peripapillary schisis cavity and the laminar region is observed (white arrowheads).
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Figure 7. Images from the left eye of patient 15, a 48-year-old man with a diagnosis of primary open-angle glaucoma with high myopia. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers. The enhanced depth imaging of this patient shows a focal laminar defect (red arrow) in the peripheral region of the optic nerve head. A hyporeflective tract (white arrowheads) connecting the peripapillary schisis cavity and the focal laminar defect to the near subarachnoid space (green asterisk) region is observed.
classic bloodebrain barrier properties.30e33 Normally, a small amount of fluid from the choriocapillaris appears to freely diffuse into the ONH, including the prelaminar and LC regions. Tso et al31 suggested that the glial barrier of Kuhnt between the ONH and the retina prevented proteins and fluid from entering the subretinal space, and this barrier might be absent in a congenital optic pit with serous detachment.31 In our cases, increased leakage from the hyperpermeable choroidal vessels may lead to greater inflow of fluid to the ONH in eyes with pachychoroid. It is possible that fluid reached the ONH from the subarachnoid space through peripheral LC defects/LC disinsertion or from the vitreous region through central LC defects. This may explain the retinoschisis-like changes of the optic disc at the prelaminar region in our series (Figs 4E and 5A). However, a disruption of the glial barrier, which permits inflow of protein-containing fluid into the interlamellar spaces of the retina, seems to be a prerequisite for the development of retinoschisis, as in a congenital optic pit with serous detachment. Subsequently, additional fluid from any source nearby may move into the retinal tissue to balance the osmotic gradient. In pachychoroid eyes, increased fluid inflow and thickened choroid at the border of ONH may stress the border tissue of Kuhnt. In glaucoma, the bloodebrain barrier in the ONH may even be weaker.34 More severe loss of LC and atrophic changes of inner neural tissue would be apt to cause a disruption of the glial barrier and greater intraretinal penetration of serous fluid. This may be another explanation for the involvement of the RNFL and the ganglion cell layer only in the glaucomatous eyes, and not in the eyes with pachychoroid. Study Limitations First, only patients from a single ethnic group were included. Thus, these results may not be generalizable to all patients worldwide. The clinical characteristics of glaucoma and pachychoroid spectrum diseases are thought to have distinct
racial differences. Second, issues of poor visualization of the LC under the optic disc rim and vessels exist. It is possible that some LC alterations in areas with poor OCT penetration may have been missed. The classification of peripheral and central LC defects was based on the visible portions of the LC. Some central LC defects could have been considered as peripheral LC defects because the peripheral portion of the LC was not captured. To reduce the false-positive detection of focal LC defects, we defined an LC defect as having a diameter of 100 mm and a depth of >30 mm. The LC defect also had to be present in 2 neighboring B-scans. The definition of LC defects was based on previous studies and may not be ideal. However, previous studies have mentioned that the definition we used may exclude normal anatomic variations and artifacts. Third, it is possible that the peripapillary retinoschisis that was noted in pachychoroid eyes might be intraretinal edema associated with chronic CSC or PCV. However, most of the peripapillary retinoschisis did not show a topographic relationship with the underlying chronic CSC or PCV lesion, and 1 case demonstrated small PED without any intraretinal or subretinal fluid. Although intraretinal cystoid cavities can be observed in chronic CSC, they tend to occur over areas of RPE atrophy, which were excluded in our cases. The discrepancy of the clinical course of peripapillary retinoschisis and subretinal fluid noted in some cases also suggests that peripapillary retinoschisis is indeed independent of underlying choroidal disease. Finally, we observed CSC cases associated with pachychoroid and peripapillary retinoschisis, but without LC alterations, which were excluded from this study. Pautler and Browning35 reported a similar case with thickened choroid and hypothesized that a temporal peripapillary crescent may be the site of entry of fluid from the choroid. Because the photoreceptors and RPE are attenuated at that area, serous exudation may extend from the choroid into the extracellular space in the outer neurosensory retina. It is possible that other mechanisms besides alterations of the LC and the ONH bloodebrain barrier are involved in the development of peripapillary retinoschisis in pachychoroid eyes.
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Ophthalmology Volume -, Number -, Month 2016 In conclusion, our results indicate that the LC alteration is associated with peripapillary retinoschisis in glaucoma and pachychoroid spectrum diseases. The mechanism that contributes to the formation of LC abnormalities may be different between the 2 disease categories; however, we suspect that the LC alteration and the disruption of the normal barrier in the ONH seem to have a role in the development of peripapillary retinoschisis. Further studies with larger patient cohorts are required to elucidate the exact pathophysiology.
References 1. Shah SD, Yee KK, Fortun JA, Albini T. Optic disc pit maculopathy: a review and update on imaging and treatment. Int Ophthalmol Clin 2014;54:61–78. 2. Jain N, Johnson MW. Pathogenesis and treatment of maculopathy associated with cavitary optic disc anomalies. Am J Ophthalmol 2014;158:423–35. 3. Radius RL, Maumenee AE, Green WR. Pit-like changes of the optic nerve head in open-angle glaucoma. Br J Ophthalmol 1978;62:389–93. 4. Rath EZ, Rumelt S. Acute visual loss due to serous retinal detachment from acquired optic pit may be a rare presentation of primary open-angle glaucoma. Can J Ophthalmol 2007;42: 339–40. 5. Song IS, Shin JW, Shin YW, Uhm KB. Optic disc pit with peripapillary retinoschisis presenting as a localized retinal nerve fiber layer defect. Korean J Ophthalmol 2011;25:455–8. 6. Choi YJ, Lee EJ, Kim BH, Kim TW. Microstructure of the optic disc pit in open-angle glaucoma. Ophthalmology 2014;121:2098–106. 7. Yoshitake T, Nakanishi H, Setoguchi Y, et al. Bilateral papillomacular retinoschisis and macular detachment accompanied by focal lamina cribrosa defect in glaucomatous eyes. Jpn J Ophthalmol 2014;58:435–42. 8. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina 2013;33:1659–72. 9. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina 2015;35:1–9. 10. Park HY, Jeon SH, Park CK. Enhanced depth imaging detects lamina cribrosa thickness differences in normal tension glaucoma and primary open-angle glaucoma. Ophthalmology 2012;119:10–20. 11. Park HY, Park CK. Diagnostic capability of lamina cribrosa thickness by enhanced depth imaging and factors affecting thickness in patients with glaucoma. Ophthalmology 2013;120:745–52. 12. Park HY, Shin HY, Jung KI, Park CK. Changes in the lamina and prelamina after intraocular pressure reduction in patients with primary open-angle glaucoma and acute primary angleclosure. Invest Ophthalmol Vis Sci 2014;55:233–9. 13. Lee EJ, Kim TW, Kim M, et al. Recent structural alteration of the peripheral lamina cribrosa near the location of disc hemorrhage in glaucoma. Invest Ophthalmol Vis Sci 2014;55: 2805–15. 14. Park SC, Hsu AT, Su D, et al. Factors associated with focal lamina cribrosa defects in glaucoma. Invest Ophthalmol Vis Sci 2013;54:8401–7. 15. Tatham AJ, Miki A, Weinreb RN, et al. Defects of the lamina cribrosa in eyes with localized retinal nerve fiber layer loss. Ophthalmology 2014;121:110–8.
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16. Kiumehr S, Park SC, Syril D, et al. In vivo evaluation of focal lamina cribrosa defects in glaucoma. Arch Ophthalmol 2012;130:552–9. 17. Prinzi RA, Desai A, Gao H. Laser treatment of macular retinoschisis due to acquired optic nerve pit from glaucoma. BMJ Case Rep 2015;2015. 18. Inoue M, Itoh Y, Rii T, et al. Spontaneous resolution of peripapillary retinoschisis associated with glaucomatous optic neuropathy. Acta Ophthalmol 2015;93:317–8. 19. Farjad H, Besada E, Frauens BJ. Peripapillary schisis with serous detachment in advanced glaucoma. Optom Vis Sci 2010;87:205–17. 20. Orazbekov L, Yasukawa T, Hirano Y, et al. Vitrectomy without gas tamponade for macular retinoschisis associated with normal-tension glaucoma. Ophthalmic Surg Lasers Imaging Retina 2015;46:107–10. 21. Lee EJ, Kim TW, Kim M, Choi YJ. Peripapillary retinoschisis in glaucomatous eyes. PLoS One 2014;9:e90129. 22. Ornek N, Buyuktortop N, Ornek K. Peripapillary and macular retinoschisis in a patient with pseudoexfoliation glaucoma. BMJ Case Rep 2013;2013. 23. Kahook MY, Noecker RJ, Ishikawa H, et al. Peripapillary schisis in glaucoma patients with narrow angles and increased intraocular pressure. Am J Ophthalmol 2007;143:697–9. 24. Gass JDM. Pathogenesis of disciform detachment of the neuroepithelium, II: idiopathic central serous chorioretinopathy. Am J Ophthalmol 1967;63:587–615. 25. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–62. 26. Razavi S, Souied EH, Cavallero E, et al. Assessment of choroidal topographic changes by swept source optical coherence tomography after photodynamic therapy for central serous chorioretinopathy. Am J Ophthalmol 2014;157: 852–60. 27. Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. Ophthalmology 2012;119:1666–78. 28. Burgoyne CF, Downs JC, Bellezza AJ, et al. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res 2005;24:39–73. 29. Sigal IA, Flanagan JG, Tertinegg I, Ethier CR. Predicted extension, compression and shearing of optic nerve head tissues. Exp Eye Res 2007;85:312–22. 30. Cohen AI. Is there a potential defect in the blood-retinal barrier at the choroidal level of the optic nerve canal? Invest Ophthalmol 1973;12:513–9. 31. Tso MO, Shih CY, McLean IW. Is there a blood-brain barrier at the optic nerve head? Arch Ophthalmol 1975;93:815–25. 32. Grayson MC, Laties AM. Ocular localization of sodium fluorescein. Effects of administration in rabbit and monkey. Arch Ophthalmol 1971;85:600–3. 33. Flage T. The distribution of intravenously administered peroxidase in the optic nerve head of rabbit and monkey. Acta Ophthalmol 1975;53:801–8. 34. Grieshaber MC, Flammer J. Does the blood-brain barrier play a role in glaucoma? Surv Ophthalmol 2007;52(Suppl 2): S115–21. 35. Pautler SE, Browning DJ. Isolated posterior uveal effusion: expanding the spectrum of the uveal effusion syndrome. Clin Ophthalmol 2014;9:43–9.
Lee et al
LC alteration and Peripapillary Retinoschisis
Footnotes and Financial Disclosures Originally received: February 10, 2016. Final revision: May 21, 2016. Accepted: June 10, 2016. Available online: ---.
Overall responsibility: JH Lee, Park, Baek, WK Lee
Manuscript no. 2016-278.
Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. *J.H.L. and H.-Y.L.P. contributed equally to this work. Financial Disclosure(s): The author(s) have made the following disclosure(s): W.K.L: Advisory boards for and received consultant fees e Novartis, Bayer, Allergan, Alcon, and Santen; Payments for lectures e Novartis, Bayer, Allergan, and Alcon. Author Contributions: Conception and design: JH Lee, Park, WK Lee Data collection: JH Lee, Park, Baek, WK Lee Analysis and interpretation JH Lee, Park, Baek, WK Lee
Abbreviations and Acronyms: APON ¼ acquired pits of the optic nerve; CSC ¼ central serous chorioretinopathy; EDI ¼ enhanced depth imaging; FA ¼ fluorescein angiography; GCL ¼ ganglion cell layer; ICGA ¼ indocyanine green angiography; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; OCT ¼ optical coherence tomography; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; PCV ¼ polypoidal choroidal vasculopathy; PED ¼ pigment epithelial detachment; RNFL ¼ retinal nerve fiber layer; RPE ¼ retinal pigment epithelium; SD ¼ spectral-domain; VEGF ¼ vascular endothelial growth factor. Correspondence: Won Ki Lee, MD, PhD, Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea. E-mail: [email protected].
Obtained funding: Not applicable
11
Retinoschisis is a splitting of the neurosensory retina and has been described in various ocular conditions, including X-linked retinoschisis, congenital optic disc abnormalities such as optic disc pit and optic disc coloboma, and myopia.1,2 Recently, retinoschisis has been found in eyes with glaucoma. Glaucomatous eyes often have focal structural abnormalities of the optic nerve head (ONH), referred to as “acquired pits of the optic nerve” (APONs).3 Previous case reports have suggested that APONs are correlated with the presence of macular retinoschisis or macular detachment.4,5 With the advent of spectral-domain (SD) optical coherence tomography (OCT) with enhanced depth imaging (EDI), evaluation of the detailed and deep architecture of the ONH has been accessible, and approximately 77% of the APONs in glaucoma showed alterations in the lamina cribrosa (LC).6 Choi et al6 reported that, among glaucomatous eyes with APON, only eyes with associated LC alterations had episodes of retinoschisis (incidence of 13%) compared with eyes without LC alterations 2016 by the American Academy of Ophthalmology Published by Elsevier Inc.
(incidence of 0%). That study suggested that the LC defect in the peripheral region of the ONH may serve as an entrance of fluid from the subarachnoid space and contribute to retinoschisis. A study by Yoshitake et al7 observed the presence of late fluorescein staining at the optic disc corresponding to the location of focal LC alterations in glaucomatous eyes with macular retinoschisis, also suggesting that changes in the LC may provide a conduit that allows fluid into the intraretinal space.7 Although the exact pathogenic mechanism and the source of intraretinal fluid of retinoschisis require further evaluation, we can assume from these studies that the LC alterations may play a role in the development of retinoschisis. We present 16 cases with peripapillary retinoschisis to add important evidence demonstrating that LC alteration may contribute to retinoschisis. These patients had abnormal LC findings as revealed by EDI of the ONH. We separated these patients into 2 categories by the underlying causative http://dx.doi.org/10.1016/j.ophtha.2016.06.033 ISSN 0161-6420/16
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Ophthalmology Volume -, Number -, Month 2016 disease. The first group of patients had chorioretinal disease associated with choroidal thickening secondary to choroidal hyperpermeability, which has not been reported as a possible cause of peripapillary retinoschisis. Diseases that are associated with thickened choroid, including central serous chorioretinopathy (CSC) and polypoidal choroidal vasculopathy (PCV), recently have been suggested as a spectrum of diseases that share a common pathophysiology and named as “pachychoroid spectrum diseases.”8,9 The second group included patients with glaucoma, in whom peripapillary retinoschisis was associated with the location of the glaucomatous optic disc and retinal nerve fiber layer (RNFL) damage.
Methods This is a retrospective review of the clinical and imaging features for a series of patients found to have peripapillary retinoschisis and abnormal LC findings on EDI OCT of the optic disc. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital, Seoul, South Korea, and followed the tenets of the Declaration of Helsinki. Consecutive patients who visited the ophthalmology department of Seoul St. Mary’s Hospital, The Catholic University of Korea, between November 2014 and October 2015 and who demonstrated peripapillary retinoschisis on macular or RNFL OCT were evaluated for the presence of LC abnormalities. Patients with disorders that are generally considered as the causes of retinoschisis were excluded, including juvenile retinoschisis, myopic foveoschisis, vitreomacular traction syndrome, and congenital optic pit. Eyes with peripapillary retinoschisis that showed interconnections with area of retinal pigment epithelial (RPE) atrophy also were excluded in patients with pachychoroid spectrum diseases. All patients had undergone complete ophthalmologic examinations, including best-corrected visual acuity, refraction, slit-lamp biomicroscopy, fundoscopy with dilated pupils, fundus and disc photography (Kowa VX-20 fundus camera; Kowa Co, Inc. Tokyo, Japan), and fluorescein angiography (FA) (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). Macular and optic disc cube scan using SD OCT (Spectralis; Heidelberg Engineering) was used to evaluate the LC and chorioretinal features. Enhanced depth imaging of the retina and ONH was performed using the same machine. According to the findings of baseline examinations, further detailed examinations were performed depending on the suspected diagnosis. Indocyanine green angiography (ICGA) (Heidelberg Retina Angiograph; Heidelberg Engineering) was performed in patients with a thickened choroid.
Enhanced Depth Imaging Optical Coherence Tomography Serial horizontal and vertical cross-sectional scans covering the ONH, approximately 30 mm apart, were obtained using the EDI technique of the Spectralis OCT (Heidelberg Engineering, GmbH, Dossenheim, Germany) for LC analyses, as previously described.10e12 Each section incorporated an average of at least 35 OCT frames. Images with a quality score >15 were obtained (w65e70 sections per eye). The volume scan with 25 sections of Spectralis OCT was performed on each eye, covering 9.06.0 mm in the macular area centered on the fovea. The subfoveal choroidal thickness was measured with the digital calipers that were included in the review software. The EDI OCT images of the ONH were reviewed by an experienced glaucoma specialist (H.-Y.L.P.) The examination
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focused on the presence of any alteration in the smooth curvilinear U- or W-shaped cross-sectional contour of the LC with an upward slope at the far periphery of the LC toward its insertion.13e16 Alterations of the LC were defined using the guidelines that were specified by Kiumehr et al16 and classified as focal LC defects or LC disinsertions for this study. A focal LC defect was defined as a hole-like defect with a discontinuous anterior laminar surface, which appeared to be a full-thickness defect. An LC disinsertion was defined as a posteriorly displaced laminar insertion with downward sloping at the far periphery of the LC toward the neural canal wall. Focal LC defects were classified into 2 typesdperipheral or centraldaccording to their location from the neural canal wall.6 A peripheral LC defect was defined as a defect located near the LC insertion but maintaining the contour of the U- or Wshaped LC, with the anterior LC visible on only the central side of the defect. A central LC defect referred to an LC defect with the LC visible on either side of the defect. These LC findings had to be present in 2 neighboring B-scans to avoid false-positives in both the horizontal and vertical scans; therefore, the LC defect was expected in 4 scans to be defined.
Results During the 1-year study period, a total of 23 patients with peripapillary retinoschisis (8 patients from the glaucoma clinic and 15 patients from the retina clinic) received ONH scanning with EDI-OCT. In the glaucoma clinic, 8 eyes of 8 patients (normaltension glaucoma in 6 eyes and primary open-angle glaucoma in 2 eyes) demonstrated LC alterations on EDI of the ONH. In the retina clinic, 8 eyes of 7 patients did not show discernable LC abnormalities: chronic CSC in 6 eyes (5 patients), choroidal hemangioma in 1 eye, and unknown cause in 1 eye. The diagnosis of the 8 included eyes (8 patients) was chronic CSC in 6 eyes, small pigment epithelium detachment in 1 eye, and PCV in 1 eye. The characteristics of imaging examinations and clinical features in these patients are summarized in Tables 1 and 2.
Lamina Cribrosa Alterations The abnormal LC findings were focal LC defects or LC disinsertions, which varied according to the underlying diseases. Among 8 eyes with chorioretinal diseases with pachychoroid, 6 had LC disinsertions and 2 had peripheral focal LC defects near the LC insertions. Among 8 eyes with glaucoma, 2 had central focal LC defects, 5 had peripheral focal LC defects, and 1 had both features. The clock-hour location of LC deformity was mainly at the 7 o’clock position in eyes with glaucoma in right eye format, which was more variable in eyes with pachychoroid spectrum diseases (Fig 1).
Association between Peripapillary Retinoschisis and Lamina Cribrosa Alterations In all eyes, the clock-hour location of the LC abnormalities correlated well with the location of the retinoschisis. The involved retinal layers ranged from the RNFL to the outer nuclear layer (ONL), which varied according to the pattern and location of LC abnormalities. When LC disinsertions were present or focal LC defects were located in the peripheral region near the LC insertion, retinoschisis involved the inner nuclear layer (INL) to the ONL. In 8 pachychoroid cases with LC disinsertions or peripheral focal defects, 6 involved both the INL and the ONL, and 2 involved the ONL. Among 5 glaucoma cases with peripheral LC defects, 1 involved both the INL and the ONL, and 4 had ONL retinoschisis. In contrast, in 2 glaucoma cases with central focal LC defects, only
Table 1. Summary of Patients’ Characteristics with Peripapillary Retinoschisis in Eyes with Pachychoroid-Related Retinal Diseases
58 51 77 48 76 69 66 67
M M M F M M M M
OD OD OS OD OD OD OS OD
Chronic Chronic Chronic Chronic Chronic PED PCV Chronic
Subfoveal Choroidal Thickness (mm)
CSC CSC CSC CSC CSC
Pachychoroid neovasculopathy Atypical CSC with ERD Chronic CSC d d PCV d CSC Chronic CSC
Contralateral Eye
Involved Retinal Layer
Extent of Involvement
Features of the LC
506 472 623 465 482 506 402 413
644 513 537 511 NA 389 417 401
ONL INL, ONL ONL INL, ONL INL, ONL INL, ONL INL, ONL INL, ONL
Around the ONH Around the ONH ONH to near macula ONH to fovea ONH to fovea ONH to near macular ONH to near macular ONH to near macular
Disinsertion Disinsertion Focal peripheral defect Disinsertion Disinsertion Focal peripheral defect Disinsertion Disinsertion
Treatment Numbers of Each Drug
Response/Recurrence of Retinoschisis after Treatment
NA 1 NA 4 (1/3)
NA No change/NA NA Complete regression/þ
2 (1/1)
Complete regression/þ
3 6 2 (1/1)
Partial regression/þ increase/þ Complete regression/
Topographic Association with Underlying Retinal Lesion
Hyperpermeability Next to ONH on ICGA
Late Disc Stain on FA
Initial BCVA
Final BCVA
Follow-up (mos)
1 2 3 4
þ
þ þ þ
0.8 1.0 0.16 0.63
1.0 1.0 0.16 1.0
12 24 15 12
Patient 5
þ
þ
0.5
0.4
40
Patient 6 Patient 7 Patient 8
þ
þ
0.8 0.63 0.1
0.8 0.63 0.16
18 12 20
Patient Patient Patient Patient
Features of the Retinoschisis
Involved Eye
Treatment Observation Laser at leaking point Observation Anti-VEGF (bevacizumab/ aflibercept) Anti-VEGF (bevacizumab/ aflibercept) Anti-VEGF (ranibizumab) Anti-VEGF (aflibercept) Anti-VEGF (bevacizumab/ aflibercept)
BCVA ¼ best-corrected visual acuity; CSC ¼ central serous chorioretinopathy; ERD ¼ exudative retinal detachment; FA ¼ fluorescein angiography; ICGA ¼ indocyanine green angiography; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; NA ¼ not available; OD ¼ right eye; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; OS ¼ left eye; PCV ¼ polypoidal choroidal vasculopathy; PED ¼ pigment epithelial detachment; VEGF ¼ vascular endothelial growth factor.
LC alteration and Peripapillary Retinoschisis
1 2 3 4 5 6 7 8
Diagnosis of the Contralateral Eye
Patient Patient Patient Patient Patient Patient Patient Patient
Diagnosis
Lee et al
Age, yrs Gender Laterality
3
4
BCVA ¼ best-corrected visual acuity; GCL ¼ ganglion cell layer; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; MD ¼ mean deviation; NFL ¼ nerve fiber layer; NTG ¼ normal-tension glaucoma; OCT ¼ optical coherence tomography; OD ¼ right eye; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; OS ¼ left eye; POAG ¼ primary open-angle glaucoma; VF ¼ visual field.
Location
Peripheral Central Peripheral Peripheral Peripheral Central Peripheral Central and peripheral
Type
Focal defect Focal defect Focal defect Focal defect Focal defect Focal defect Focal defect 2 focal defects
Extent of Involvement
1.28 2.67 2.42 16.40 4.50 12.50 16.15 2.13
ONH to near macula Around the ONH ONH to the fovea ONH to near macula ONH to near macula Around the ONH ONH to near macular ONH to the fovea ONL NFL ONL INL, ONL ONL NFL, GCL ONL NFL, INL, ONL
VF MD Baseline
13 18 16 16 18 15 22 19 High myopia Myopia Emmetropia Myopia Hyperopia Emmetropia High myopia Myopia 0.8 1.0 0.8 0.8 1.0 1.0 0.32 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.32 1.0
Refraction Diagnosis
NTG NTG NTG POAG NTG NTG POAG NTG OD OS OS OD OS OS OD OS
Laterality Gender
F M F M F F M M 60 42 67 73 62 61 48 39 Patient Patient Patient Patient Patient Patient Patient Patient
9 10 11 12 13 14 15 16
Age, yrs
10 16 15 9 11 11 15 15
Involved Retinal Layer
Features of the Retinoschisis IOP
At OCT Scan Last BCVA Initial BCVA
Table 2. Summary of Patients’ Characteristics with Peripapillary Retinoschisis in Glaucoma
Features of the LC
Ophthalmology Volume -, Number -, Month 2016 the RNFL or ganglion cell layer was involved. The other glaucoma case that had both central and peripheral LC defects involved the nerve fiber layer, INL, and ONL. The extent of retinoschisis was restricted around the ONH in 4 (25.0%), extended near the macula in 8 (50.0%), and involved the fovea in 4 (25.0%) of 16 eyes, which was closely related to the location of LC deformity (central or peripheral). In eyes with central focal LC defects, the extent was limited around the ONH. In contrast, retinoschisis involved the macula or the foveal region in eyes with peripheral LC defects or LC disinsertions.
Other Features on Imaging Examinations and Clinical Course The subfoveal choroidal thickness of the 8 cases with chorioretinal diseases accompanying pachychoroid ranged from 402 to 623 mm. In 6 eyes, the peripapillary retinoschisis did not show a topographic association with the underlying chronic CSC- or PCV-associated lesions, including pigment epithelial detachment (PED), subretinal fluid, and polypoidal lesions. In the other 2 cases, retinoschisis was noted adjacent to subretinal fluid. All eyes showed choroidal hyperpermeability within major vascular arcades on ICGA, especially in the papillomacular area in 4 cases. Two cases showed late fluorescein staining of the temporal ONH border. The clinical course of these 16 cases varied. All but 1 (case 16) of the eyes with retinoschisis combined with glaucoma were asymptomatic, and the retinoschisis resolved spontaneously. Patient 16 had persisting retinoschisis throughout the 5 months of follow-up. Among 8 cases with retinoschisis combined with pachychoroid, 6 received treatment for the underlying chronic CSC- or PCV-related lesions and 2 were observed because there was no subretinal fluid or PED involving the fovea. In these 2 eyes, peripapillary retinoschisis persisted until 12 and 15 months, respectively, although the lesions showed a fluctuating pattern (patients 1 and 3). Among the 6 treated eyes, peripapillary retinoschisis resolved completely in 3 eyes (patients 4, 5, and 8) and partially in 1 eye (patient 6) after antievascular endothelial growth factor injections. Complete resolution of peripapillary retinoschisis was achieved in these 3 cases after switching from bevacizumab (Avastin; Genentech, Inc., San Francisco, CA) to aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY). One case with partial resolution of peripapillary retinoschisis received ranibizumab (Lucentis; Genentech Inc.) injections. However, the lesions recurred 2 to 6 months after the last injection in all 4 eyes. In the other 2 eyes (patients 2 and 7), peripapillary retinoschisis did not resolve after focal photocoagulation and antievascular endothelial growth factor injections, although subretinal fluid decreased after the treatment.
Representative Cases Eyes with peripapillary retinoschisis related to pachychoroid spectrum diseases had LC findings of a peripheral focal LC defect (Fig 2) or an LC disinsertion (Figs 3 and 4). These cases showed thickened choroid with dilated choroidal vessels on macular OCT (Figs 2 and 3). A hyporeflective tract connecting the LC disinsertion and the retinoschisis cavity was observed (Fig 3), suggesting an association between the LC disinsertion and the peripapillary retinoschisis. Late fluorescein staining at the temporal ONH border was observed (Fig 4F) where the LC disinsertion site may be located, suggesting the LC disinsertion as a conduit of the leakage. Eyes with peripapillary retinoschisis related to glaucoma had central (Fig 5) or peripheral focal LC defects (Figs 6 and 7). A hyporeflective tract connecting the LC defect and the retinoschisis cavity also was observed in several cases (Figs 6 and 7). In some cases, a retinoschisis-like change
Lee et al
LC alteration and Peripapillary Retinoschisis
Figure 1. Frequency distribution of the presence of lamina cribrosa (LC) abnormalities in eyes with peripapillary retinoschisis according to clock-hour location at the disc in right eye format. The inner white region indicates the central region of the LC at cup base, and the gray region indicates the rim. The numbers in the circles indicate the patient’s numbers. Gray circles are eyes with peripapillary retinoschisis involving the nerve fiber layer (NFL) and ganglion cell layer (GCL), and white circles are eyes with peripapillary retinoschisis involving the deeper retinal layers. INL ¼ inner nuclear layer; ONL ¼ outer nuclear layer.
of optic disc was observed at the prelaminar region, which appeared to be associated with the peripapillary retinoschisis (Figs 4E and 5A).
Discussion Peripapillary retinoschisis is reported to be more frequently present in glaucomatous eyes compared with normal control eyes.17e23 The pathogenic mechanism of retinoschisis in these eyes was supposed to be associated with LC damage, which frequently manifests as an optic disc pit. Recent study data on ONH changes using the EDI technique of SD OCT support this hypothesis.7,21 In the current study, we made new observations in patients with glaucoma, which might provide evidence for the contribution of LC defects to the development of peripapillary retinoschisis. The location of the LC abnormalities (central vs. peripheral) appeared to be associated with the involved retinal layers. Inner layer retinoschisis developed in eyes with central focal LC defects. Retinoschisis ranging from the INL to the ONL developed in eyes with peripheral focal LC defects. In addition, similar involvements were noted in eyes having pachychoroid spectrum diseases with LC disinsertions or peripheral focal LC defects. Retinoschisis in these eyes tended to be involved near the macula or fovea. We observed small retinoschisis cavities or a hyporeflective tract between the LC alteration and the cavity of the retinoschisis in some eyes. The pattern and location of LC abnormalities in these eyes were somewhat different compared with those of the eyes with glaucoma. The most
frequent abnormality was LC disinsertion, which develops at the far peripheral region of the ONH, and no eye showed a central focal defect. The clock-hour location in each patient tended to disperse around the temporal side (7e10 clock-hour position in the right eye format). In our cases with glaucoma, the abnormality was a focal defect, either central or peripheral, which was concentrated in the inferotemporal area (7 o’clock-hour position). Lamina cribrosa abnormalities in glaucoma are located in the superotemporal or inferotemporal region where the LC has fewer supporting connective tissues; this may in part reflect a different pathogenic mechanism involved in the development of LC deformity. We speculate that a thickened choroid due to hyperpermeable choroidal vessels is directly involved in the development of LC changes. Choroidal hyperpermeability was noted on ICGA in all 8 cases. In CSC, increased extravasated fluid from the hyperpermeable choroidal vessels exerts mechanical stress on the RPE layer, which frequently elevates the RPE (serous PED) and finally leads to the focal disruption of the RPE manifested as a focal leak on FA.24,25 The area of leakage from the RPE on FA, choroidal vascular hyperpermeability on ICGA, and increased choroidal thickness on OCT are commonly co-localized.26,27 The increased extravasated fluids and thickened choroid may impose stress not only vertically on RPE but also laterally on ONH. As observed in our images of the ONH, the anterior scleral canal wall is prominent and elongated, perhaps as a result of choroid thickening. This change may displace the LC posteriorly and medially, leading to a break at the weakest point, which is the LC flange where the LC is attached to the sclera and anterior
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Figure 2. Images from the right eye of patient 6, a 69-year-old man with a diagnosis of pigment epithelial detachment (PED). A, Fluorescein angiography shows a focal hyperfluorescent spot at the fovea that corresponds to a small PED on optical coherence tomography (OCT), with no definite leakage. B, On indocyanine green angiography (ICGA), choroidal hyperfluorescence was noted at the papillomacular area. C, On macular OCT, peripapillary retinoschisis (yellow arrowheads) was not topographically associated with the subfoveal PED. Macular OCT also showed choroidal thickening and dilated choroidal vessels (green asterisk); however, subretinal fluid was not noted. D, After a single ranibizumab injection, the height of retinoschisis lesion reduced but the lesion persisted. E, Enhanced depth imaging of the optic nerve head of this patient shows a focal laminar defect (red arrow).
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Figure 3. Images from the right eye of patient 4, a 48-year-old woman with a diagnosis of chronic central serous chorioretinopathy (CSC). A, Fluorescein angiography showed faint leakage nasal to the fovea, and (B) choroidal hyperfluorescence was noted at the papillomacular area on indocyanine green angiography. C, Macular optical coherence tomography shows choroidal thickening and dilated choroidal vessels with large lumens (green asterisk) and peripapillary retinoschisis involving the macular region (yellow arrowheads). The retinoschisis lesion involves the inner nuclear layer and outer nuclear layer. D and E, The enhanced depth imaging of the optic nerve head of this patient shows laminar disinsertion at the temporal side of the disc (red arrow) and retinoschisis cavity connected to this laminar disinsertion (white arrowheads). The peripapillary sclera is displaced posteriorly (orange glyphs) because of the thickened choroid.
Figure 4. Images that represent different clinical courses of peripapillary retinoschisis. Top row: Images from the right eye of patient 2, a 51-year-old man with a diagnosis of chronic chorioretinopathy (CSC). A, The enhanced depth imaging (EDI) of the optic nerve head (ONH) of this patient shows a laminar disinsertion (red arrow). B, The midphase of fluorescein angiography (FA) showed a widespread area of irregular hyperfluorescence with a suspicious leaking point (red arrow). C, Macular optical coherence tomography (OCT) showed diffuse, irregular retinal pigment epithelial (RPE) elevation with subretinal fluid nasal to the fovea and peripapillary retinoschisis involving the inner nuclear layer (INL) and outer nuclear layer (ONL). D, Focal photocoagulation targeted the RPE at the suspicious leaking point. Complete resolution of subretinal fluid was noted at 1 month; however, the retinoschisis lesion remained stable, persisting during the 22-month follow-up period. Middle row: Images from the right eye of patient 5, a 76-year-old man with a diagnosis of chronic CSC. E, The EDI of the ONH of this patient shows a laminar disinsertion (red arrow). A schisis-like change also was noted in the prelaminar lesion of the ONH (green asterisk). F, On FA, late fluorescein staining of the optic disc was observed in the region of the laminar disinsertion. G, Macular OCT showed subfoveal fluid and a small pigment epithelial detachment (PED) temporal to the fovea. Peripapillary retinoschisis lesion involved the INL and ONL. H, After a single aflibercept injection, both subfoveal fluid and peripapillary retinoschisis showed complete resolution. The subfoveal choroidal thickness decreased from 456 to 430 mm. Bottom row: Images from the right eye of patient 7, a 66-year-old man with a diagnosis of polypoidal choroidal vasculopathy (PCV). I, The EDI of the ONH of this patient shows laminar disinsertion (red arrow) from the peripapillary sclera (orange glyphs). J, Indocyanine green angiography revealed multiple polyps with branching vascular network and choroidal hyperpermeability at the macula. K, Macular OCT showed subfoveal fluid that extended temporal to the fovea. Peripapillary retinoschisis involving the INL and ONL were detected apart from the subfoveal PCV lesion. L, After 3 loading injections of intravitreal aflibercept, subretinal fluid decreased and subfoveal choroidal thickness decreased from 394 to 338 mm; however, the peripapillary retinoschisis increased vertically and extended laterally.
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Figure 5. A, Images from the left eye of patient 10, a 42-year-old man with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) is involving the nerve fiber layer around the inferotemporal area where a localized retinal nerve fiber layer (white arrowheads) is present. The enhanced depth imaging (EDI) of this patient shows a focal laminar defect (red arrow) in the paracentral region of the optic nerve head (ONH). A schisislike change is noted in the prelaminar lesion of the ONH (green asterisk), which appears to be connected with the peripapillary retinoschisis. B, Images from the left eye of patient 14, a 61-year-old woman with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) involves the nerve fiber layer and ganglion cell layer around the ONH. The EDI of this patient shows a focal laminar defect (red arrow) in the paracentral region of the ONH.
scleral canal wall. The possibility of the increased susceptibility of the LC insertion site to deformation by compressive or tensile force has been suggested by others, supporting our hypothesis.28,29
Although we observed LC change in our patients, the exact pathogenic mechanism underlying the development of peripapillary retinoschisis is still a matter of speculation. Previous studies have demonstrated that the ONH lacks the
Figure 6. A, Images from the right eye of patient 9, a 60-year-old woman with a diagnosis of normal-tension glaucoma with high myopia. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers and is connected to the laminar defect in the peripheral region of the optic nerve head (ONH) (red arrow). The area with peripapillary retinoschisis is in the region where localized retinal nerve fiber layer (white arrowheads) is located. B, Images from the left eye of patient 11, a 67-year-old woman with a diagnosis of normal-tension glaucoma. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers and the fovea. The enhanced depth imaging of this patient shows a focal laminar defect (red arrow) in the peripheral region of the ONH like a disconnection from the sclera. A hyporeflective tract connecting the peripapillary schisis cavity and the laminar region is observed (white arrowheads).
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Figure 7. Images from the left eye of patient 15, a 48-year-old man with a diagnosis of primary open-angle glaucoma with high myopia. Peripapillary retinoschisis (yellow arrowheads) involves the outer retinal layers. The enhanced depth imaging of this patient shows a focal laminar defect (red arrow) in the peripheral region of the optic nerve head. A hyporeflective tract (white arrowheads) connecting the peripapillary schisis cavity and the focal laminar defect to the near subarachnoid space (green asterisk) region is observed.
classic bloodebrain barrier properties.30e33 Normally, a small amount of fluid from the choriocapillaris appears to freely diffuse into the ONH, including the prelaminar and LC regions. Tso et al31 suggested that the glial barrier of Kuhnt between the ONH and the retina prevented proteins and fluid from entering the subretinal space, and this barrier might be absent in a congenital optic pit with serous detachment.31 In our cases, increased leakage from the hyperpermeable choroidal vessels may lead to greater inflow of fluid to the ONH in eyes with pachychoroid. It is possible that fluid reached the ONH from the subarachnoid space through peripheral LC defects/LC disinsertion or from the vitreous region through central LC defects. This may explain the retinoschisis-like changes of the optic disc at the prelaminar region in our series (Figs 4E and 5A). However, a disruption of the glial barrier, which permits inflow of protein-containing fluid into the interlamellar spaces of the retina, seems to be a prerequisite for the development of retinoschisis, as in a congenital optic pit with serous detachment. Subsequently, additional fluid from any source nearby may move into the retinal tissue to balance the osmotic gradient. In pachychoroid eyes, increased fluid inflow and thickened choroid at the border of ONH may stress the border tissue of Kuhnt. In glaucoma, the bloodebrain barrier in the ONH may even be weaker.34 More severe loss of LC and atrophic changes of inner neural tissue would be apt to cause a disruption of the glial barrier and greater intraretinal penetration of serous fluid. This may be another explanation for the involvement of the RNFL and the ganglion cell layer only in the glaucomatous eyes, and not in the eyes with pachychoroid. Study Limitations First, only patients from a single ethnic group were included. Thus, these results may not be generalizable to all patients worldwide. The clinical characteristics of glaucoma and pachychoroid spectrum diseases are thought to have distinct
racial differences. Second, issues of poor visualization of the LC under the optic disc rim and vessels exist. It is possible that some LC alterations in areas with poor OCT penetration may have been missed. The classification of peripheral and central LC defects was based on the visible portions of the LC. Some central LC defects could have been considered as peripheral LC defects because the peripheral portion of the LC was not captured. To reduce the false-positive detection of focal LC defects, we defined an LC defect as having a diameter of 100 mm and a depth of >30 mm. The LC defect also had to be present in 2 neighboring B-scans. The definition of LC defects was based on previous studies and may not be ideal. However, previous studies have mentioned that the definition we used may exclude normal anatomic variations and artifacts. Third, it is possible that the peripapillary retinoschisis that was noted in pachychoroid eyes might be intraretinal edema associated with chronic CSC or PCV. However, most of the peripapillary retinoschisis did not show a topographic relationship with the underlying chronic CSC or PCV lesion, and 1 case demonstrated small PED without any intraretinal or subretinal fluid. Although intraretinal cystoid cavities can be observed in chronic CSC, they tend to occur over areas of RPE atrophy, which were excluded in our cases. The discrepancy of the clinical course of peripapillary retinoschisis and subretinal fluid noted in some cases also suggests that peripapillary retinoschisis is indeed independent of underlying choroidal disease. Finally, we observed CSC cases associated with pachychoroid and peripapillary retinoschisis, but without LC alterations, which were excluded from this study. Pautler and Browning35 reported a similar case with thickened choroid and hypothesized that a temporal peripapillary crescent may be the site of entry of fluid from the choroid. Because the photoreceptors and RPE are attenuated at that area, serous exudation may extend from the choroid into the extracellular space in the outer neurosensory retina. It is possible that other mechanisms besides alterations of the LC and the ONH bloodebrain barrier are involved in the development of peripapillary retinoschisis in pachychoroid eyes.
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Ophthalmology Volume -, Number -, Month 2016 In conclusion, our results indicate that the LC alteration is associated with peripapillary retinoschisis in glaucoma and pachychoroid spectrum diseases. The mechanism that contributes to the formation of LC abnormalities may be different between the 2 disease categories; however, we suspect that the LC alteration and the disruption of the normal barrier in the ONH seem to have a role in the development of peripapillary retinoschisis. Further studies with larger patient cohorts are required to elucidate the exact pathophysiology.
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16. Kiumehr S, Park SC, Syril D, et al. In vivo evaluation of focal lamina cribrosa defects in glaucoma. Arch Ophthalmol 2012;130:552–9. 17. Prinzi RA, Desai A, Gao H. Laser treatment of macular retinoschisis due to acquired optic nerve pit from glaucoma. BMJ Case Rep 2015;2015. 18. Inoue M, Itoh Y, Rii T, et al. Spontaneous resolution of peripapillary retinoschisis associated with glaucomatous optic neuropathy. Acta Ophthalmol 2015;93:317–8. 19. Farjad H, Besada E, Frauens BJ. Peripapillary schisis with serous detachment in advanced glaucoma. Optom Vis Sci 2010;87:205–17. 20. Orazbekov L, Yasukawa T, Hirano Y, et al. Vitrectomy without gas tamponade for macular retinoschisis associated with normal-tension glaucoma. Ophthalmic Surg Lasers Imaging Retina 2015;46:107–10. 21. Lee EJ, Kim TW, Kim M, Choi YJ. Peripapillary retinoschisis in glaucomatous eyes. PLoS One 2014;9:e90129. 22. Ornek N, Buyuktortop N, Ornek K. Peripapillary and macular retinoschisis in a patient with pseudoexfoliation glaucoma. BMJ Case Rep 2013;2013. 23. Kahook MY, Noecker RJ, Ishikawa H, et al. Peripapillary schisis in glaucoma patients with narrow angles and increased intraocular pressure. Am J Ophthalmol 2007;143:697–9. 24. Gass JDM. Pathogenesis of disciform detachment of the neuroepithelium, II: idiopathic central serous chorioretinopathy. Am J Ophthalmol 1967;63:587–615. 25. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol 1994;112:1057–62. 26. Razavi S, Souied EH, Cavallero E, et al. Assessment of choroidal topographic changes by swept source optical coherence tomography after photodynamic therapy for central serous chorioretinopathy. Am J Ophthalmol 2014;157: 852–60. 27. Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of macular choroidal thickness by optical coherence tomography and angiographic changes in central serous chorioretinopathy. Ophthalmology 2012;119:1666–78. 28. Burgoyne CF, Downs JC, Bellezza AJ, et al. The optic nerve head as a biomechanical structure: a new paradigm for understanding the role of IOP-related stress and strain in the pathophysiology of glaucomatous optic nerve head damage. Prog Retin Eye Res 2005;24:39–73. 29. Sigal IA, Flanagan JG, Tertinegg I, Ethier CR. Predicted extension, compression and shearing of optic nerve head tissues. Exp Eye Res 2007;85:312–22. 30. Cohen AI. Is there a potential defect in the blood-retinal barrier at the choroidal level of the optic nerve canal? Invest Ophthalmol 1973;12:513–9. 31. Tso MO, Shih CY, McLean IW. Is there a blood-brain barrier at the optic nerve head? Arch Ophthalmol 1975;93:815–25. 32. Grayson MC, Laties AM. Ocular localization of sodium fluorescein. Effects of administration in rabbit and monkey. Arch Ophthalmol 1971;85:600–3. 33. Flage T. The distribution of intravenously administered peroxidase in the optic nerve head of rabbit and monkey. Acta Ophthalmol 1975;53:801–8. 34. Grieshaber MC, Flammer J. Does the blood-brain barrier play a role in glaucoma? Surv Ophthalmol 2007;52(Suppl 2): S115–21. 35. Pautler SE, Browning DJ. Isolated posterior uveal effusion: expanding the spectrum of the uveal effusion syndrome. Clin Ophthalmol 2014;9:43–9.
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Footnotes and Financial Disclosures Originally received: February 10, 2016. Final revision: May 21, 2016. Accepted: June 10, 2016. Available online: ---.
Overall responsibility: JH Lee, Park, Baek, WK Lee
Manuscript no. 2016-278.
Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. *J.H.L. and H.-Y.L.P. contributed equally to this work. Financial Disclosure(s): The author(s) have made the following disclosure(s): W.K.L: Advisory boards for and received consultant fees e Novartis, Bayer, Allergan, Alcon, and Santen; Payments for lectures e Novartis, Bayer, Allergan, and Alcon. Author Contributions: Conception and design: JH Lee, Park, WK Lee Data collection: JH Lee, Park, Baek, WK Lee Analysis and interpretation JH Lee, Park, Baek, WK Lee
Abbreviations and Acronyms: APON ¼ acquired pits of the optic nerve; CSC ¼ central serous chorioretinopathy; EDI ¼ enhanced depth imaging; FA ¼ fluorescein angiography; GCL ¼ ganglion cell layer; ICGA ¼ indocyanine green angiography; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; OCT ¼ optical coherence tomography; ONH ¼ optic nerve head; ONL ¼ outer nuclear layer; PCV ¼ polypoidal choroidal vasculopathy; PED ¼ pigment epithelial detachment; RNFL ¼ retinal nerve fiber layer; RPE ¼ retinal pigment epithelium; SD ¼ spectral-domain; VEGF ¼ vascular endothelial growth factor. Correspondence: Won Ki Lee, MD, PhD, Department of Ophthalmology and Visual Science, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea. E-mail: [email protected].
Obtained funding: Not applicable
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