Background/aims To investigate the effect of peripapillary retinoschisis on the peripapillary retinal nerve fibre layer (RNFL) thickness measurement by using optical coherence tomography (OCT) in glaucomatous eyes.
Methods We included 19 glaucomatous eyes of 19 subjects with peripapillary retinoschisis defined as the splitting of the peripapillary RNFL with schisis cavities (retinoschisis group) and 38 age-matched, refractive error-matched and visual field mean deviation-matched glaucomatous eyes from 38 subjects without peripapillary retinoschisis (control group) that had undergone RNFL thickness measurements by using OCT. RNFL thickness was compared between the two groups. For the retinoschisis group, the RNFL thicknesses prior to peripapillary retinoschisis formation, at the time of peripapillary retinoschisis, and after peripapillary retinoschisis resolution were compared.
Results The average RNFL was greater in the eyes in the retinoschisis group (median, 81.6 µm) than in those in the control group (median, 69.7 µm, p=0.009). In the retinoschisis group, the average RNFL thickness at the time of peripapillary retinoschisis was greater than that prior to peripapillary retinoschisis formation (p=0.013) or after peripapillary retinoschisis resolution (p=0.001). The RNFL thickness was not different prior to peripapillary retinoschisis formation and after peripapillary retinoschisis resolution (p>0.05).
Conclusions Transient increase in RNFL thickness as determined by OCT was observed in glaucomatous eyes with peripapillary retinoschisis. Caution is warranted when interpreting the RNFL thickness measurement in eyes with peripapillary retinoschisis.
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Because glaucoma is characterised by progressive thinning of the peripapillary retinal nerve fibre layer (RNFL), detection of a thinned RNFL or a progressive decrease in RNFL thickness is important for diagnosing or detecting the progression of glaucoma. Optical coherence tomography (OCT) is a widely used imaging device that can measure RNFL thickness with high resolution and excellent reproducibility.1–3 When the longitudinal RNFL thickness change is assessed by using OCT, various factors can lead to increase or decrease in RNFL thickness, including true glaucoma progression,4 OCT measurement variability,2 changes in the OCT signal strength,5 optic nerve head (ONH) swelling,6 vitreous opacity around the ONH7 or vitreopapillary traction.8 ,9
Previously, a few case reports demonstrated the presence of peripapillary retinoschisis, which is characterised by the splitting of the peripapillary RNFL with schisis cavities, within the RNFL in glaucomatous eyes.10–12 Our clinical observations demonstrated that peripapillary retinoschisis in glaucomatous eyes was associated with transient increase in RNFL thickness as determined by OCT (figure 1), indicating that this condition can affect RNFL thickness assessment by OCT. Thus, this study was performed to investigate the effect of peripapillary retinoschisis on RNFL thickness measurement by using OCT in glaucomatous eyes.
This study was performed following the approval of the Institutional Review Board of Kim's Eye Hospital, Seoul, Korea. All procedures conformed to the Declaration of Helsinki. Participants seen by a glaucoma specialist (YHH) were recruited consecutively between May 2012 and May 2013 at the glaucoma clinic of Kim's Eye Hospital. Each subject underwent a full ophthalmic examination, including assessment of visual acuity, refractive error with a model TX-20P auto refracto-keratometer (Canon, Tokyo, Japan) and intraocular pressure (IOP) with a Goldmann applanation tonometer, ONH evaluation and fundus examination with a 90-dioptre lens, red-free fundus photography by using a Kowa Nonmyd7 fundus camera (Kowa, Tokyo, Japan), the 24-2 Swedish Interactive Threshold Algorithm standard automated visual field (VF) test (Humphrey VF Analyzer; Carl Zeiss Meditec, Dublin, California, USA), and peripapillary RNFL thickness measurements by using Cirrus high-definition OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA). A 200×200 cube Optic Disc Scan of Cirrus HD-OCT was used for the RNFL measurements. The Cirrus HD-OCT algorithm automatically identifies the centre of the ONH, determines the vitreoretinal surface and posterior borders of the RNFL, and calculates circumpapillary RNFL thickness on a 3.46-mm circle consisting of 256 A-scans. The RNFL thicknesses in the global area and the superior, nasal, inferior and temporal quadrants were calculated automatically. A macular cube scan of Cirrus HD-OCT was also obtained to identify abnormalities in the macular area.
Inclusion criteria were ONH with glaucomatous changes (ie, increased cup-disc ratio and neuroretinal rim narrowing); RNFL defect on red-free fundus photography (ie, a dark wedge-shaped area with its apex touching the optic disc border in the brightly striated pattern of the surrounding RNFL13 or generalised loss of RNFL visibility in the upper or lower retina14); and glaucomatous VF defects (ie, a cluster of three points with probabilities of <5% on the pattern deviation map in at least one hemifield, including at least one point with a probability of <1% or a cluster of two points with a probability of <1%, glaucomatous hemifield test results outside of normal limits, or a pattern SD beyond 95% of normal limits15) as confirmed by at least two reliable examinations; in our clinical practice, most patients showed reliable indices <15%; therefore, we used false positives/negatives with a value <15% and fixation losses <15% as cut-off values to ensure reliability during examinations.
In the present study, peripapillary retinoschisis was defined as the splitting of the peripapillary RNFL with the presence of schisis cavities within the RNFL in the cross-sectional circumpapillary RNFL image of Cirrus HD-OCT (figure 1). Among the eyes with glaucoma, those with peripapillary retinoschisis that was newly found during the study period or those with a history of peripapillary retinoschisis were assigned to the retinoschisis group and age-matched, refractive error-matched and VF mean deviation-matched glaucomatous eyes without peripapillary retinoschisis to the control group. When peripapillary retinoschisis was observed in both eyes, one eye was randomly selected for the analysis. Exclusion criteria were the presence of concurrent retinal disease (ie, vascular disorder or macular degeneration), optic nerve disease other than glaucoma or a brain disorder that could influence VF results.
The Mann–Whitney U test was used to compare clinical characteristics, including age, refractive error, IOP, IOP fluctuation defined as a SD of multiple IOP measurements, VF indices and RNFL thickness, between the control and retinoschisis groups. In cases with multiple measurements, the mean value of the multiple measurements was used for the comparison. Variables, including IOP, IOP fluctuation, VF indices, RNFL thickness and time intervals between measurements were obtained throughout the follow-up period. For the eyes in the retinoschisis group, IOP, VF indices and RNFL thickness prior to peripapillary retinoschisis formation, at the time of peripapillary retinoschisis and after peripapillary retinoschisis resolution within the same eye were compared by using the Wilcoxon signed rank test. Bonferroni adjustments were made based on the number of comparisons for the multiple comparisons. For the other analyses, p<0.05 was considered statistically significant. Statistical analyses were performed by using SPSS V.12.0 (SPSS, Chicago, Illinois, USA).
During the study period, we found 21 glaucomatous eyes with peripapillary retinoschisis in 19 subjects, 2 of whom had bilateral peripapillary retinoschisis. This study included 19 glaucomatous eyes with peripapillary retinoschisis in 19 subjects (retinoschisis group) and 38 glaucomatous eyes without peripapillary retinoschisis in 38 subjects (control group). All of the eyes were phakic and had primary open-angle glaucoma; the eyes had a normal anterior segment without history of inflammation or trauma.
The clinical characteristics of the two groups are listed in table 1. Age, refractive error, IOP, IOP fluctuation and VF indices were not significantly different between the two groups (p>0.05). For the eyes in the retinoschisis group, the peripapillary retinoschisis was located in the superior quadrant in 12 eyes (63.2%), the inferior quadrant in 3 eyes (15.8%), the nasal quadrant in 2 eyes (10.5%) and the superior-nasal area in 1 eye (5.3%); 1 eye (5.3%) showed alternating peripapillary retinoschisis in the superior and inferior quadrants. In all cases, retinoschisis was detected throughout the inner retinal layers, including the nerve fibre layer, ganglion cell layer and inner plexiform layer. No eye in the retinoschisis group showed retinoschisis in the OCT scan of the macular area and no eye showed an optic disc pit in the fundus examination. The median (range) number of RNFL measurements was 3.0 (2–4) and the interval between measurements was 10.5 (2–14) months during the entire follow-up period. The peripapillary retinoschisis resolved without additional treatment in all cases and the median (range) interval between the presence of peripapillary retinoschisis and the resolution of peripapillary retinoschisis was 9.0 (4–14) months during the entire follow-up period. No recurrence was found within the same area after the resolution during the observation period.
The eyes in the retinoschisis group had a greater OCT RNFL thickness measurement in the global area and superior quadrant than those in the control group (p<0.01, table 2). For the eyes with peripapillary retinoschisis, RNFL thickness at the time of peripapillary retinoschisis was greater than the RNFL thickness prior to peripapillary retinoschisis formation or after peripapillary retinoschisis resolution within the same eye in the global area and superior quadrant (p≤0.013, table 3). No significant differences were found between the IOP and VF indices at the time of peripapillary retinoschisis and prior to peripapillary retinoschisis formation or after peripapillary retinoschisis resolution within the same eye (p>0.05, table 3). Further, no significant differences were found when the IOP, VF indices and RNFL thickness prior to peripapillary retinoschisis formation were compared with those after the resolution of peripapillary retinoschisis (p>0.05, table 3). The intervals (median (first and third quartiles)) between before development of peripapillary retinoschisis and with peripapillary retinoschisis, and before development of peripapillary retinoschisis and after resolution of peripapillary retinoschisis was 13.0 (6.0, 14.0) months and 26.0 (7.5, 30.5) months, respectively.
In the present study, peripapillary retinoschisis was found in glaucomatous eyes and it was associated with transient increase in RNFL thickness as determined by OCT. The presence of peripapillary retinoschisis was not associated with changes in IOP or VF. To the best of our knowledge, this is the first study investigating the effect of peripapillary retinoschisis on RNFL thickness and VF in glaucomatous eyes by using statistical analyses.
During the study period, we found peripapillary retinoschisis in 21 glaucomatous eyes in 19 subjects and in 3 healthy eyes in 2 subjects. Thus far, little is known about the prevalence and the factors associated with peripapillary retinoschisis. Because a cross-sectional OCT image is needed in order to confirm peripapillary retinoschisis, we only investigated subjects for whom OCT measurements had been taken. This selection bias may make it difficult to estimate the prevalence of peripapillary retinoschisis and whether this condition is found more frequently in glaucomatous eyes than in healthy eyes based on the results of this study.
In the present study population, peripapillary retinoschisis was most commonly found in the superior quadrant, followed by the inferior quadrant and the nasal quadrant. All cases of peripapillary retinoschisis were transient and were resolved without additional management within a median period of 9 months, and no eye showed recurrent peripapillary retinoschisis within the same area during the study period. Previous studies also reported spontaneous resolution of peripapillary retinoschisis.10 ,11
Regarding the pathogenesis of peripapillary retinoschisis in glaucoma, Kahook et al10 suggested that in an eye with high IOP and narrow angle, the small changes in axial length that accompany fluctuations in IOP play a role in peripapillary retinoschisis formation. However, in our cases, all of the eyes had open angle, stable IOP with medical treatment, and eyes with peripapillary retinoschisis did not have a greater IOP fluctuation than eyes without peripapillary retinoschisis. Another possible pathogenic mechanism of peripapillary retinoschisis is vitreopapillary traction. In a previous study, Batta et al8 reported that the RNFL thickness measured by OCT was greater at the point of vitreous attachment, presumably because of the traction exerted by the vitreous. Hwang and Kim also reported that vitreopapillary traction was associated with increase in RNFL thickness as determined by OCT.9 However, vitreopapillary traction was not found in the cross-sectional OCT images of the RNFL in the present cases. Peripapillary retinoschisis may be found in combination with optic pit16 or foveal retinoschisis.17–20 Song et al16 reported a case with optic disc pit with peripapillary retinoschisis presenting as a localised RNFL defect. Further, Meirelles et al17 reported a case with deep colobomatous excavation of the optic disc and secondary retinoschisis extending from the temporal side of the optic disc, and they speculated that the connection between the optic disc pit and the RNFL is a cause of retinoschisis. However, optic disc pits were not found in the current study population. In addition, no eye showed retinoschisis in the macular area.
Several investigators have suggested that another possible mechanism of peripapillary retinoschisis may be glaucoma-related development of micro holes within the thinned tissue of the ONH or RNFL.18–20 These authors speculated that micro holes develop in the thinned area of the ONH or RNFL, and that these micro holes may allow liquid vitreous to enter the retina, resulting in a schisis cavity within the RNFL. Xin et al21 also demonstrated the presence of hypodense regions (holes) within the areas of glaucomatous RNFL defects, which were not found in healthy eyes. However, according to our clinical observation, peripapillary retinoschisis was also found in healthy eyes without glaucomatous changes. Therefore, it should be noted that peripapillary retinoschisis is not a specific sign of glaucoma.
It remains unclear whether peripapillary retinoschisis is associated with the progression of glaucoma. In glaucomatous eyes with peripapillary retinoschisis, the RNFL thickness and VF indices did not change after the resolution of peripapillary retinoschisis compared with those prior to peripapillary retinoschisis formation. In addition, no significant difference was found when the VF indices at the time of peripapillary retinoschisis and prior to peripapillary retinoschisis formation or after peripapillary retinoschisis resolution were compared, suggesting that peripapillary retinoschisis is not associated with functional deterioration. Further studies with a longer observation period may be needed to clarify the association between peripapillary retinoschisis and glaucoma progression.
Peripapillary retinoschisis was associated with transient increase in RNFL thickness as measured by OCT. Given that the RNFL margins automatically identified by the OCT algorithm included schisis cavities, this finding may represent a measurement artefact rather than true RNFL thickening (figure 1). Transient increase in RNFL thickness in eyes with peripapillary retinoschisis may cause misidentification of RNFL defect and confusion in detecting RNFL abnormality progression by using OCT. For example, in the case presented in figure 1, the RNFL thickness change could be considered progressive thinning when the inferior RNFL thickness at the fourth visit was compared with the RNFL thickness of the second visit, whereas no profound change was found when it was compared with the RNFL thickness of the first visit. Therefore, caution is warranted when interpreting RNFL thickness in eyes with peripapillary retinoschisis. We propose that the presence of peripapillary retinoschisis should be considered if transient increase in RNFL thickness or rapid decrease in RNFL thickness is observed by OCT measurement.
While the presence of peripapillary retinoschisis was identified by using cross-sectional OCT images in the current study, OCT is not available in all of the cases in a clinical setting. A characteristic finding of peripapillary retinoschisis in fundus photography is the visibility of a prominent RNFL with thick striae (figure 2). The possibility of peripapillary retinoschisis should be considered when these characteristics are revealed in fundus examination.
In the present study, retinoschisis was identified by using a 3.46 mm-diameter scan circle centred to the ONH. Therefore, any changes within or outside the scan circle may have been overlooked. Ideally, in order to evaluate the effect of peripapillary retinoschisis on OCT RNFL thickness measurement, the RNFL thickness measured using automated segmentation algorithm of the Cirrus HD-OCT and the RNFL thickness obtained after manual correction of the segmentation should be compared. However, in the present study, correction of segmentation error was not performed. We think that the segmentation error of Cirrus HD-OCT for the RNFL margin detection may have partly contributed to the results of the present study.
In conclusion, peripapillary retinoschisis was found in glaucomatous eyes and it affected the RNFL thickness measurement by OCT. Further studies are needed to identify the mechanism of peripapillary retinoschisis and its correlation with glaucoma progression.
Contributors YHH, YYK, HKK and YHS: study design, acquisition of data, and analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be published.
Competing interests None.
Ethics approval This study was performed after approval of the Institutional Review Board of the Kim's Eye Hospital, Seoul, Korea. All procedures conformed to the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.