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 reti- noschisis. 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 per- sisted 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;123:2066-2076 ª 2016 by the American Academy of Ophthalmology.

Retinoschisis is a splitting of the neurosensory retina and (incidence of 0%). That study suggested that the LC has been described in various ocular conditions, including defect in the peripheral region of the ONH may serve as X-linked retinoschisis, congenital optic disc abnormalities an entrance of fluid from the subarachnoid space and such as optic disc pit and optic disc coloboma, and contribute to retinoschisis. A study by Yoshitake et al7 myopia.1,2 Recently, retinoschisis has been found in eyes observed the presence of late fluorescein staining at the with glaucoma. Glaucomatous eyes often have focal struc- optic disc corresponding to the location of focal LC tural abnormalities of the optic nerve head (ONH), referred alterations in glaucomatous eyes with macular to as “acquired pits of the optic nerve” (APONs).3 Previous retinoschisis, also suggesting that changes in the LC may case reports have suggested that APONs are correlated with provide a conduit that allows fluid into the intraretinal the presence of macular retinoschisis or macular space.7 Although the exact pathogenic mechanism and the detachment.4,5 With the advent of spectral-domain (SD) source of intraretinal fluid of retinoschisis require further optical coherence tomography (OCT) with enhanced depth evaluation, we can assume from these studies that the LC imaging (EDI), evaluation of the detailed and deep archi- alterations may play a role in the development of tecture of the ONH has been accessible, and approximately retinoschisis. 77% of the APONs in glaucoma showed alterations in the We present 16 cases with peripapillary retinoschisis to lamina cribrosa (LC).6 Choi et al6 reported that, among add important evidence demonstrating that LC alteration glaucomatous eyes with APON, only eyes with associated may contribute to retinoschisis. These patients had abnormal LC alterations had episodes of retinoschisis (incidence of LC findings as revealed by EDI of the ONH. We separated 13%) compared with eyes without LC alterations these patients into 2 categories by the underlying causative

2066 2016 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.ophtha.2016.06.033 Published by Elsevier Inc. ISSN 0161-6420/16 Lee et al LC alteration and Peripapillary Retinoschisis disease. The first group of patients had chorioretinal disease focused on the presence of any alteration in the smooth curvilinear associated with choroidal thickening secondary to choroidal U- or W-shaped cross-sectional contour of the LC with an upward 13e16 hyperpermeability, which has not been reported as a slope at the far periphery of the LC toward its insertion. Al- terations of the LC were defined using the guidelines that were possible cause of peripapillary retinoschisis. Diseases that fi 16 fi are associated with thickened choroid, including central speci ed by Kiumehr et al and classi ed as focal LC defects or LC disinsertions for this study. A focal LC defect was defined as serous chorioretinopathy (CSC) and polypoidal choroidal a hole-like defect with a discontinuous anterior laminar surface, vasculopathy (PCV), recently have been suggested as a which appeared to be a full-thickness defect. An LC disinsertion spectrum of diseases that share a common pathophysiology was defined as a posteriorly displaced laminar insertion with 8,9 and named as “pachychoroid spectrum diseases.” The downward sloping at the far periphery of the LC toward the neural second group included patients with glaucoma, in whom canal wall. Focal LC defects were classified into 2 typesdpe- peripapillary retinoschisis was associated with the location ripheral or centraldaccording to their location from the neural of the glaucomatous optic disc and retinal nerve fiber layer canal wall.6 A peripheral LC defect was defined as a defect located (RNFL) damage. near the LC insertion but maintaining the contour of the U- or W- shaped 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 Methods 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 This is a retrospective review of the clinical and imaging features the horizontal and vertical scans; therefore, the LC defect was for a series of patients found to have peripapillary retinoschisis and expected in 4 scans to be defined. 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 Results the Declaration of Helsinki. Consecutive patients who visited the ophthalmology department of Seoul St. Mary’s Hospital, The During the 1-year study period, a total of 23 patients with peri- Catholic University of Korea, between November 2014 and papillary retinoschisis (8 patients from the glaucoma clinic and October 2015 and who demonstrated peripapillary retinoschisis on 15 patients from the retina clinic) received ONH scanning with macular or RNFL OCT were evaluated for the presence of LC EDI OCT. In the glaucoma clinic, 8 eyes of 8 patients (normal- abnormalities. Patients with disorders that are generally considered tension glaucoma in 6 eyes and primary open-angle glaucoma in 2 as the causes of retinoschisis were excluded, including juvenile eyes) demonstrated LC alterations on EDI of the ONH. In the retinoschisis, myopic foveoschisis, vitreomacular traction syn- retina clinic, 8 eyes of 7 patients did not show discernable LC drome, and congenital optic pit. Eyes with peripapillary reti- abnormalities: chronic CSC in 6 eyes (5 patients), choroidal noschisis that showed interconnections with area of retinal pigment hemangioma in 1 eye, and unknown cause in 1 eye. The diagnosis epithelial (RPE) atrophy also were excluded in patients with of the 8 included eyes (8 patients) was chronic CSC in 6 eyes, pachychoroid spectrum diseases. small pigment epithelium detachment in 1 eye, and PCV in 1 eye. All patients had undergone complete ophthalmologic exami- The characteristics of imaging examinations and clinical features in nations, including best-corrected visual acuity, refraction, slit-lamp these patients are summarized in Tables 1 and 2. biomicroscopy, fundoscopy with dilated pupils, fundus and disc photography (Kowa VX-20 fundus camera; Kowa Co, Inc. Tokyo, Lamina Cribrosa Alterations Japan), and fluorescein angiography (FA) (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). The abnormal LC findings were focal LC defects or LC dis- Macular and optic disc cube scan using SD OCT (Spectralis; insertions, which varied according to the underlying diseases. Heidelberg Engineering) was used to evaluate the LC and cho- Among 8 eyes with chorioretinal diseases with pachychoroid, 6 rioretinal features. Enhanced depth imaging of the retina and ONH had LC disinsertions and 2 had peripheral focal LC defects near the was performed using the same machine. According to the findings LC insertions. Among 8 eyes with glaucoma, 2 had central focal of baseline examinations, further detailed examinations were per- LC defects, 5 had peripheral focal LC defects, and 1 had both formed depending on the suspected diagnosis. Indocyanine green features. The clock-hour location of LC deformity was mainly at angiography (ICGA) (Heidelberg Retina Angiograph; Heidelberg the 7 o’clock position in eyes with glaucoma in right eye format, Engineering) was performed in patients with a thickened choroid. which was more variable in eyes with pachychoroid spectrum diseases (Fig 1). Enhanced Depth Imaging Optical Coherence Tomography Association between Peripapillary Retinoschisis and Lamina Cribrosa Alterations Serial horizontal and vertical cross-sectional scans covering the ONH, approximately 30 mm apart, were obtained using the EDI In all eyes, the clock-hour location of the LC abnormalities technique of the Spectralis OCT (Heidelberg Engineering, GmbH, correlated well with the location of the retinoschisis. The involved Dossenheim, Germany) for LC analyses, as previously retinal layers ranged from the RNFL to the outer nuclear layer e described.10 12 Each section incorporated an average of at least 35 (ONL), which varied according to the pattern and location of LC OCT frames. Images with a quality score >15 were obtained abnormalities. When LC disinsertions were present or focal LC (w65e70 sections per eye). The volume scan with 25 sections of defects were located in the peripheral region near the LC insertion, Spectralis OCT was performed on each eye, covering 9.06.0 mm retinoschisis involved the inner nuclear layer (INL) to the ONL. In in the macular area centered on the fovea. The subfoveal choroidal 8 pachychoroid cases with LC disinsertions or peripheral focal thickness was measured with the digital calipers that were included defects, 6 involved both the INL and the ONL, and 2 involved the in the review software. ONL. Among 5 glaucoma cases with peripheral LC defects, 1 The EDI OCT images of the ONH were reviewed by an involved both the INL and the ONL, and 4 had ONL retinoschisis. experienced glaucoma specialist (H.-Y.L.P.) The examination In contrast, in 2 glaucoma cases with central focal LC defects, only

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Table 1. Summary of Patients’ Characteristics with Peripapillary Retinoschisis in Eyes with Pachychoroid-Related Retinal Diseases

Subfoveal Choroidal Thickness (mm) Features of the Retinoschisis Diagnosis of the Contralateral Age, yrs Gender Laterality Diagnosis Eye Involved Eye Contralateral Eye Involved Retinal Layer Extent of Involvement Features of the LC Ophthalmology Patient 1 58 M OD Chronic CSC Pachychoroid neovasculopathy 506 644 ONL Around the ONH Disinsertion Patient 2 51 M OD Chronic CSC Atypical CSC with ERD 472 513 INL, ONL Around the ONH Disinsertion Patient 3 77 M OS Chronic CSC Chronic CSC 623 537 ONL ONH to near macula Focal peripheral defect Patient 4 48 F OD Chronic CSC d 465 511 INL, ONL ONH to fovea Disinsertion Patient 5 76 M OD Chronic CSC d 482 NA INL, ONL ONH to fovea Disinsertion Patient 6 69 M OD PED PCV 506 389 INL, ONL ONH to near macular Focal peripheral defect Patient 7 66 M OS PCV d 402 417 INL, ONL ONH to near macular Disinsertion Patient 8 67 M OD Chronic CSC Chronic CSC 413 401 INL, ONL ONH to near macular Disinsertion 2016 October 10, Number 123, Volume

Topographic Association with Hyperpermeability Response/Recurrence Underlying Retinal Next to ONH on Late Disc Stain Follow-up Treatment Numbers of Retinoschisis after Lesion ICGA on FA Initial BCVA Final BCVA (mos) Treatment of Each Drug Treatment Patient 1 þ0.8 1.0 12 Observation NA NA Patient 2 þ1.0 1.0 24 Laser at leaking point 1 No change/NA Patient 3 þ0.16 0.16 15 Observation NA NA Patient 4 þ0.63 1.0 12 Anti-VEGF (bevacizumab/ 4 (1/3) Complete regression/þ aflibercept) Patient 5 þþ0.5 0.4 40 Anti-VEGF (bevacizumab/ 2 (1/1) Complete regression/þ aflibercept) Patient 6 þ0.8 0.8 18 Anti-VEGF (ranibizumab) 3 Partial regression/þ Patient 7 þ0.63 0.63 12 Anti-VEGF (aflibercept) 6 increase/þ Patient 8 0.1 0.16 20 Anti-VEGF (bevacizumab/ 2 (1/1) Complete regression/ 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. Lee et al LC alteration and Peripapillary Retinoschisis

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 peripheral 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,

eld. which was closely related to the location of LC deformity (central fi or peripheral). In eyes with central focal LC defects, the extent was limited around the ONH. In contrast, retinoschisis involved the visual normal-tension glaucoma; macula or the foveal region in eyes with peripheral LC defects or ¼ ¼ LC disinsertions.

Other Features on Imaging Examinations and Clinical Course

ber layer; NTG The subfoveal choroidal thickness of the 8 cases with chorioretinal fi diseases accompanying pachychoroid ranged from 402 to 623 mm. In 6 eyes, the peripapillary retinoschisis did not show a topographic nerve ONH to near maculaAround the ONHONH Focal to defect the fovea FocalONH Peripheral defect to near macula Focal defect Central ONH Focal to defect near macular Peripheral Focal Peripheral defect Peripheral

¼ association with the underlying chronic CSC- or PCV-associated lesions, including pigment epithelial detachment (PED), sub- retinal fluid, and polypoidal lesions. In the other 2 cases, reti- primary open-angle glaucoma; VF noschisis was noted adjacent to subretinal fluid. All eyes showed ¼ choroidal hyperpermeability within major vascular arcades on Features of the Retinoschisis Features of the LC Layer Extent of Involvement Type Location ICGA, especially in the papillomacular area in 4 cases. Two cases fl Involved Retinal showed late uorescein staining of the temporal ONH border. The clinical course of these 16 cases varied. All but 1 (case 16) mean deviation; NFL

¼ of the eyes with retinoschisis combined with glaucoma were left eye; POAG 2.672.42 NFL ONL 4.50 ONL 2.13 NFL, INL, ONL ONH to the fovea 2 focal defects Central and 1.28 ONL

16.40 INL, ONL12.5016.15 NFL, GCL ONL ONH to near macula Around Focal the defect ONH Peripheral Focal defect Central asymptomatic, and the retinoschisis resolved spontaneously. Pa- ¼ VF MD tient 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

Scan CSC- or PCV-related lesions and 2 were observed because there At OCT was no subretinal fluid or PED involving the fovea. In these 2 eyes, IOP

lamina cribrosa; MD peripapillary retinoschisis persisted until 12 and 15 months,

¼ respectively, although the lesions showed a fluctuating pattern

Baseline (patients 1 and 3). Among the 6 treated eyes, peripapillary reti- outer nuclear layer; OS noschisis resolved completely in 3 eyes (patients 4, 5, and 8) and ¼ partially in 1 eye (patient 6) after antievascular endothelial growth factor injections. Complete resolution of peripapillary retinoschisis Characteristics with Peripapillary Retinoschisis in Glaucoma

’ 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

inner nuclear layer; LC with partial resolution of peripapillary retinoschisis received rani- ¼ Last

BCVA Refraction bizumab (Lucentis; Genentech Inc.) injections. However, the le-

optic nerve head; ONL sions recurred 2 to 6 months after the last injection in all 4 eyes. In

¼ the other 2 eyes (patients 2 and 7), peripapillary retinoschisis did not resolve after focal photocoagulation and antievascular endo- Initial BCVA thelial growth factor injections, although subretinal fluid decreased after the treatment.

Table 2. Summary of Patients Representative Cases right eye; ONH ganglion cell layer; INL ¼ ¼ 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

Age, yrs Gender Laterality Diagnosis as a conduit of the leakage. Eyes with peripapillary retinoschisis best-corrected visual acuity; GCL

optical coherence tomography; OD related to glaucoma had central (Fig 5) or peripheral focal LC ¼ fl ¼ defects (Figs 6 and 7). A hypore ective tract connecting the LC defect and the retinoschisis cavity also was observed in several BCVA Patient 10Patient 11Patient 42 12Patient 67 13Patient M 73 14Patient F 62 15Patient M 61 16 OS F 48 F 39 OS OD M NTG M OS OS NTG OD POAG OS 1.0 NTG 1.0 1.0 NTG POAG 1.0 NTG 1.0 0.8 0.8 Myopia 0.32 1.0 Myopia Emmetropia 1.0 1.0 0.32 1.0 Hyperopia 16 High 18 myopia 1.0 Emmetropia 16 22 Myopia 18 15 15 16 9 15 11 11 19 15 Patient 9 60 F OD NTG 1.0 0.8 High myopia 13 10 OCT cases (Figs 6 and 7). In some cases, a retinoschisis-like change

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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 frequent abnormality was LC disinsertion, which develops appeared to be associated with the peripapillary retinoschisis (Figs at the far peripheral region of the ONH, and no eye showed 4E and 5A). a central focal defect. The clock-hour location in each pa- tient tended to disperse around the temporal side (7e10 clock-hour position in the right eye format). In our cases Discussion with glaucoma, the abnormality was a focal defect, either central or peripheral, which was concentrated in the infe- Peripapillary retinoschisis is reported to be more frequently rotemporal area (7 o’clock-hour position). Lamina cribrosa present in glaucomatous eyes compared with normal con- abnormalities in glaucoma are located in the superotemporal trol eyes.17e23 The pathogenic mechanism of retinoschisis or inferotemporal region where the LC has fewer supporting in these eyes was supposed to be associated with LC connective tissues; this may in part reflect a different path- damage, which frequently manifests as an optic disc pit. ogenic mechanism involved in the development of LC Recent study data on ONH changes using the EDI tech- deformity. nique of SD OCT support this hypothesis.7,21 In the current We speculate that a thickened choroid due to hyper- study, we made new observations in patients with glau- permeable choroidal vessels is directly involved in the coma, which might provide evidence for the contribution of development of LC changes. Choroidal hyperpermeability LC defects to the development of peripapillary reti- was noted on ICGA in all 8 cases. In CSC, increased noschisis. The location of the LC abnormalities (central vs. extravasated fluid from the hyperpermeable choroidal ves- peripheral) appeared to be associated with the involved sels exerts mechanical stress on the RPE layer, which retinal layers. Inner layer retinoschisis developed in eyes frequently elevates the RPE (serous PED) and finally with central focal LC defects. Retinoschisis ranging from leads to the focal disruption of the RPE manifested as a focal the INL to the ONL developed in eyes with peripheral leak on FA.24,25 The area of leakage from the RPE on focal LC defects. FA, choroidal vascular hyperpermeability on ICGA, and In addition, similar involvements were noted in eyes increased choroidal thickness on OCT are commonly having pachychoroid spectrum diseases with LC dis- co-localized.26,27 The increased extravasated fluids and insertions or peripheral focal LC defects. Retinoschisis in thickened choroid may impose stress not only vertically on these eyes tended to be involved near the macula or fovea. RPE but also laterally on ONH. As observed in our images We observed small retinoschisis cavities or a hyporeflective of the ONH, the anterior scleral canal wall is prominent and tract between the LC alteration and the cavity of the reti- elongated, perhaps as a result of choroid thickening. This noschisis in some eyes. The pattern and location of LC change may displace the LC posteriorly and medially, abnormalities in these eyes were somewhat different leading to a break at the weakest point, which is the LC compared with those of the eyes with glaucoma. The most flange where the LC is attached to the sclera and anterior

2070 Lee et al LC alteration and Peripapillary Retinoschisis

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.

2072 Lee et al LC alteration and Peripapillary Retinoschisis

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 schisis- like 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 suscep- Although we observed LC change in our patients, the tibility of the LC insertion site to deformation by exact pathogenic mechanism underlying the development compressive or tensile force has been suggested by others, of peripapillary retinoschisis is still a matter of speculation. supporting our hypothesis.28,29 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 racial differences. Second, issues of poor visualization of the small amount of fluid from the choriocapillaris appears to LC under the optic disc rim and vessels exist. It is possible freely diffuse into the ONH, including the prelaminar and that some LC alterations in areas with poor OCT penetration LC regions. Tso et al31 suggested that the glial barrier of may have been missed. The classification of peripheral and Kuhnt between the ONH and the retina prevented central LC defects was based on the visible portions of the proteins and fluid from entering the subretinal space, and LC. Some central LC defects could have been considered as this barrier might be absent in a congenital optic pit with peripheral LC defects because the peripheral portion of the serous detachment.31 In our cases, increased leakage from LC was not captured. To reduce the false-positive detection the hyperpermeable choroidal vessels may lead to greater of focal LC defects, we defined an LC defect as having a inflow of fluid to the ONH in eyes with pachychoroid. It diameter of 100 mm and a depth of >30 mm. The LC defect is possible that fluid reached the ONH from the also had to be present in 2 neighboring B-scans. The defi- subarachnoid space through peripheral LC defects/LC nition of LC defects was based on previous studies and may disinsertion or from the vitreous region through central not be ideal. However, previous studies have mentioned that LC defects. This may explain the retinoschisis-like the definition we used may exclude normal anatomic varia- changes of the optic disc at the prelaminar region in our tions and artifacts. Third, it is possible that the peripapillary series (Figs 4E and 5A). However, a disruption of the glial retinoschisis that was noted in pachychoroid eyes might be barrier, which permits inflow of protein-containing fluid intraretinal edema associated with chronic CSC or PCV. into the interlamellar spaces of the retina, seems to be a However, most of the peripapillary retinoschisis did not show prerequisite for the development of retinoschisis, as in a a topographic relationship with the underlying chronic CSC congenital optic pit with serous detachment. Subsequently, or PCV lesion, and 1 case demonstrated small PED without additional fluid from any source nearby may move into the any intraretinal or subretinal fluid. Although intraretinal retinal tissue to balance the osmotic gradient. In pachych- cystoid cavities can be observed in chronic CSC, they tend to oroid eyes, increased fluid inflow and thickened choroid at occur over areas of RPE atrophy, which were excluded in our the border of ONH may stress the border tissue of Kuhnt. cases. The discrepancy of the clinical course of peripapillary In glaucoma, the bloodebrain barrier in the ONH may retinoschisis and subretinal fluid noted in some cases also even be weaker.34 More severe loss of LC and atrophic suggests that peripapillary retinoschisis is indeed indepen- changes of inner neural tissue would be apt to cause a dent of underlying choroidal disease. Finally, we observed disruption of the glial barrier and greater intraretinal CSC cases associated with pachychoroid and peripapillary penetration of serous fluid. This may be another retinoschisis, but without LC alterations, which were explanation for the involvement of the RNFL and the excluded from this study. Pautler and Browning35 reported a ganglion cell layer only in the glaucomatous eyes, and similar case with thickened choroid and hypothesized that a not in the eyes with pachychoroid. temporal peripapillary crescent may be the site of entry of fluid from the choroid. Because the photoreceptors and Study Limitations RPE are attenuated at that area, serous exudation may extend from the choroid into the extracellular space in the First, only patients from a single ethnic group were included. outer neurosensory retina. It is possible that other Thus, these results may not be generalizable to all patients mechanisms besides alterations of the LC and the ONH worldwide. The clinical characteristics of glaucoma and bloodebrain barrier are involved in the development of pachychoroid spectrum diseases are thought to have distinct peripapillary retinoschisis in pachychoroid eyes.

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In conclusion, our results indicate that the LC alteration 16. Kiumehr S, Park SC, Syril D, et al. In vivo evaluation of focal is associated with peripapillary retinoschisis in glaucoma lamina cribrosa defects in glaucoma. Arch Ophthalmol and pachychoroid spectrum diseases. The mechanism that 2012;130:552–9. contributes to the formation of LC abnormalities may be 17. Prinzi RA, Desai A, Gao H. Laser treatment of macular reti- different between the 2 disease categories; however, we noschisis due to acquired optic nerve pit from glaucoma. BMJ Case Rep 2015;2015. suspect that the LC alteration and the disruption of the 18. Inoue M, Itoh Y, Rii T, et al. Spontaneous resolution of per- normal barrier in the ONH seem to have a role in the ipapillary retinoschisis associated with glaucomatous optic development of peripapillary retinoschisis. Further studies neuropathy. Acta Ophthalmol 2015;93:317–8. with larger patient cohorts are required to elucidate the exact 19. Farjad H, Besada E, Frauens BJ. Peripapillary schisis with pathophysiology. serous detachment in advanced glaucoma. Optom Vis Sci 2010;87:205–17. References 20. Orazbekov L, Yasukawa T, Hirano Y, et al. Vitrectomy without gas tamponade for macular retinoschisis associated with normal-tension glaucoma. Ophthalmic Surg Lasers Im- 1. Shah SD, Yee KK, Fortun JA, Albini T. Optic disc pit mac- aging Retina 2015;46:107–10. ulopathy: a review and update on imaging and treatment. Int 21. Lee EJ, Kim TW, Kim M, Choi YJ. Peripapillary retinoschisis Ophthalmol Clin 2014;54:61–78. in glaucomatous eyes. PLoS One 2014;9:e90129. 2. Jain N, Johnson MW. Pathogenesis and treatment of macul- 22. Ornek N, Buyuktortop N, Ornek K. Peripapillary and macular opathy associated with cavitary optic disc anomalies. Am J retinoschisis in a patient with pseudoexfoliation glaucoma. Ophthalmol 2014;158:423–35. BMJ Case Rep 2013;2013. 3. Radius RL, Maumenee AE, Green WR. Pit-like changes of the 23. Kahook MY, Noecker RJ, Ishikawa H, et al. Peripapillary optic nerve head in open-angle glaucoma. Br J Ophthalmol schisis in glaucoma patients with narrow angles and increased 1978;62:389–93. intraocular pressure. Am J Ophthalmol 2007;143:697–9. 4. Rath EZ, Rumelt S. Acute visual loss due to serous retinal 24. Gass JDM. Pathogenesis of disciform detachment of the neu- detachment from acquired optic pit may be a rare presentation roepithelium, II: idiopathic central serous chorioretinopathy. of primary open-angle glaucoma. Can J Ophthalmol 2007;42: Am J Ophthalmol 1967;63:587–615. 339–40. 25. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine 5. Song IS, Shin JW, Shin YW, Uhm KB. Optic disc pit with green videoangiography of central serous chorioretinopathy. peripapillary retinoschisis presenting as a localized retinal Arch Ophthalmol 1994;112:1057–62. nerve fiber layer defect. Korean J Ophthalmol 2011;25:455–8. 26. Razavi S, Souied EH, Cavallero E, et al. Assessment of 6. Choi YJ, Lee EJ, Kim BH, Kim TW. Microstructure of the choroidal topographic changes by swept source optical optic disc pit in open-angle glaucoma. Ophthalmology coherence tomography after photodynamic therapy for central 2014;121:2098–106. serous chorioretinopathy. Am J Ophthalmol 2014;157: 7. Yoshitake T, Nakanishi H, Setoguchi Y, et al. Bilateral pap- 852–60. illomacular retinoschisis and macular detachment accompa- 27. Jirarattanasopa P, Ooto S, Tsujikawa A, et al. Assessment of nied by focal lamina cribrosa defect in glaucomatous eyes. Jpn macular choroidal thickness by optical coherence tomography J Ophthalmol 2014;58:435–42. and angiographic changes in central serous chorioretinopathy. 8. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment Ophthalmology 2012;119:1666–78. epitheliopathy. Retina 2013;33:1659–72. 28. Burgoyne CF, Downs JC, Bellezza AJ, et al. The optic nerve 9. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina head as a biomechanical structure: a new paradigm for un- 2015;35:1–9. derstanding the role of IOP-related stress and strain in the 10. Park HY, Jeon SH, Park CK. Enhanced depth imaging detects pathophysiology of glaucomatous optic nerve head damage. lamina cribrosa thickness differences in normal tension glau- Prog Retin Eye Res 2005;24:39–73. coma and primary open-angle glaucoma. Ophthalmology 29. Sigal IA, Flanagan JG, Tertinegg I, Ethier CR. Predicted 2012;119:10–20. extension, compression and shearing of optic nerve head tis- 11. Park HY, Park CK. Diagnostic capability of lamina cribrosa sues. Exp Eye Res 2007;85:312–22. thickness by enhanced depth imaging and factors affecting 30. Cohen AI. Is there a potential defect in the blood-retinal barrier thickness in patients with glaucoma. Ophthalmology at the choroidal level of the optic nerve canal? Invest Oph- 2013;120:745–52. thalmol 1973;12:513–9. 12. Park HY, Shin HY, Jung KI, Park CK. Changes in the lamina 31. Tso MO, Shih CY, McLean IW. Is there a blood-brain barrier and prelamina after intraocular pressure reduction in patients at the optic nerve head? Arch Ophthalmol 1975;93:815–25. with primary open-angle glaucoma and acute primary angle- 32. Grayson MC, Laties AM. Ocular localization of sodium closure. Invest Ophthalmol Vis Sci 2014;55:233–9. fluorescein. Effects of administration in rabbit and monkey. 13. Lee EJ, Kim TW, Kim M, et al. Recent structural alteration of Arch Ophthalmol 1971;85:600–3. the peripheral lamina cribrosa near the location of disc hem- 33. Flage T. The distribution of intravenously administered orrhage in glaucoma. Invest Ophthalmol Vis Sci 2014;55: peroxidase in the optic nerve head of rabbit and monkey. Acta 2805–15. Ophthalmol 1975;53:801–8. 14. Park SC, Hsu AT, Su D, et al. Factors associated with focal 34. Grieshaber MC, Flammer J. Does the blood-brain barrier play lamina cribrosa defects in glaucoma. Invest Ophthalmol Vis a role in glaucoma? Surv Ophthalmol 2007;52(Suppl 2): Sci 2013;54:8401–7. S115–21. 15. Tatham AJ, Miki A, Weinreb RN, et al. Defects of the lamina 35. Pautler SE, Browning DJ. Isolated posterior uveal effusion: cribrosa in eyes with localized retinal nerve fiber layer loss. expanding the spectrum of the uveal effusion syndrome. Clin Ophthalmology 2014;121:110–8. Ophthalmol 2014;9:43–9.

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Footnotes and Financial Disclosures

Originally received: February 10, 2016. Obtained funding: Not applicable Final revision: May 21, 2016. Overall responsibility: JH Lee, Park, Baek, WK Lee Accepted: June 10, 2016. Abbreviations and Acronyms: Available online: August 6, 2016. Manuscript no. 2016-278. APON ¼ acquired pits of the optic nerve; CSC ¼ central serous chorior- Department of Ophthalmology and Visual Science, Seoul St. Mary’s etinopathy; EDI ¼ enhanced depth imaging; FA ¼ fluorescein angiog- Hospital, College of Medicine, The Catholic University of Korea, Seoul, raphy; GCL ¼ ganglion cell layer; ICGA ¼ indocyanine green Korea. angiography; INL ¼ inner nuclear layer; LC ¼ lamina cribrosa; *J.H.L. and H.-Y.L.P. contributed equally to this work. OCT ¼ optical coherence tomography; ONH ¼ optic nerve head; ONL ¼ PCV ¼ Financial Disclosure(s): outer nuclear layer; polypoidal choroidal vasculopathy; PED ¼ pigment epithelial detachment; RNFL ¼ retinal nerve fiber layer; The author(s) have made the following disclosure(s): W.K.L: Advisory RPE ¼ SD ¼ boards for and received consultant fees e Novartis, Bayer, Allergan, Alcon, retinal pigment epithelium; spectral-domain; VEGF ¼ and Santen; Payments for lectures e Novartis, Bayer, Allergan, and Alcon. vascular endothelial growth factor. Author Contributions: Correspondence: Won Ki Lee, MD, PhD, Department of Ophthalmology and Visual Science, Conception and design: JH Lee, Park, WK Lee Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Data collection: JH Lee, Park, Baek, WK Lee Korea, 505 Banpo-dong, Seocho-ku, Seoul 137-701, Korea. E-mail: Analysis and interpretation JH Lee, Park, Baek, WK Lee [email protected].

Pictures & Perspectives

Epicapsular Stars A 27-year-old woman was admitted to our hospital for keratoconjunctivitis of her right eye. She had no symptoms in her left eye. Slit lamp microscopic photography of the left eye showed epicapsular stars appearing as several tiny, stellate, brown-pigmented, embroidery- like opacities in the central anterior lens capsule (Fig 1). The epicapsular stars are remnants of the tunica vasculosalentis, a vascular network that surrounds the lens during embryogenesis. As the opacities were not dense, they had no effect on the visual function of the left eye. Accordingly, surgical removal of the deposits was not required, but regular follow-up exams were recommended.

RENPAN ZENG, MD, PHD XIAOQIONG LIANG,MD GUOPING WANG,MD Department of Ophthalmology, Sichuan Provincial Corps Hospital, Chinese People’s Armed Police Forces, Leshan, China

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