HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS OF X-LINKED RETINOSCHISIS IN EARLY CHILDHOOD

Abstract

Background/Purpose:

Using handheld spectral domain optical coherence tomography (SDOCT) imaging to investigate in vivo microanatomic retinal changes and their progression over time in young children with juvenile X-linked retinoschisis (XLRS).

Methods:

This retrospective analysis was of handheld SD OCT images obtained under a prospective research protocol in children who had established XLRS diagnosis based on genetic testing or clinical history. Three OCT graders performed standardized qualitative and quantitative assessment of retinal volume scans, which were divided into foveal, parafoveal, and extrafoveal regions. Visual acuity data were obtained when possible.

Results:

Spectral domain OCT images were available of both eyes in 8 pediatric patients with ages 7 months to 10 years. The schisis cavities involved inner nuclear layer in over 90% (15/16) of eyes in all 3 regions. Retinal nerve fiber and ganglion cell layer involvement was present only in the extrafoveal region in 63% (10/16) eyes and outer nuclear and plexiform layer in few others. In 7 children followed over 2 months to 15 months, the location of schisis remained consistent. Central foveal thickness decreased from the baseline to final available visit in 4/6 eyes. Ellipsoid zone disruption seemed to accompany lower visual acuity in 1/4 eyes.

Conclusion:

Early in life, the SD OCT findings in XLRS demonstrate differences in schisis location in fovea–parafoveal versus extrafoveal region, possible association between poor visual acuity and degree of ellipsoid zone disruption and decrease in central foveal thickness over time in this group. Furthermore, they illustrates that the pattern of XLRS in adults is already present in very young children, and unlike in older children and adults, those presenting with earlier disease may have a more aggressive course. Further studies in this early age group may provide more insights into treatment and prevention of progressive visual impairment in children with XLRS.

X-linked retinoschisis (XLRS) is an inherited retinal degenerative disease caused by mutations in the retinoschisin 1 (RS1) gene on chromosome Xp22.1. These mutations lead to defects in the protein retinoschisin which normally binds to the surface of photoreceptors and bipolar cells to maintain retinal integrity.^1,2 XLRS is characterized clinically by stellate spoke-like foveal schisis, and peripheral retinoschisis is often noted in the inferotemporal region.^2,3 In advanced stages, complications may include vitreous hemorrhage, retinal detachment, and neovascular glaucoma.

New diagnosis of XLRS is often challenging, with an average delay of 8 years after the onset of symptoms.⁴ A recent addition to the armamentarium of imaging for XLRS is optical coherence tomography (OCT), the diagnostic approach for XLRS in children old enough to cooperate for imaging.^5-11 Today, OCT is an important diagnostic tool during follow-up examinations and has resolved the long-standing histologic debate over which retinal layer(s) typically undergo splitting in XLRS.^12-14 Previous OCT studies of XLRS have demonstrated schisis cavity within the retina, including nerve fiber layer (NFL), ganglion cell layer (GCL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL) depending on the patient’s age.^15-18 Until now, OCT studies have reported findings from older children (5 years and older) and adults. With the advent of handheld OCT, it is now possible to image infants as young as 30 weeks’ postmenstrual age,¹⁹ thus providing us the ability to explore the retinal structure in pediatric patients who cannot be examined using standard tabletop OCT systems. The early morphologic assessment of XLRS will be critical in the understanding of early manifestations and stages of disease. Such information would be important in assessing anatomical changes before and after onset of therapy in future clinical trials. Our study aims to explore in vivo structural features of juvenile XLRS in the early stages of disease using handheld spectral domain OCT (SDOCT).

Methods

This study is a retrospective, longitudinal review of clinical and ocular imaging data collected in children under a larger prospective study approved by the Duke University Health System Institutional Review Board and adhered to the Health Insurance Portability and Accountability Act and all tenets of the Declaration of Helsinki. A parent or legal guardian consented for the child to participate in the research. The research SDOCT imaging was captured using a portable handheld (Envisu, Leica Microsystems Inc., Buffalo Grove, IL) during a clinically indicated eye examination either under anesthesia or in the outpatient clinic.¹⁹ The research database was reviewed to identify children with a diagnosis of XLRS. Clinical data were obtained as part of this protocol through review of medical records for clinical findings, visual acuity, family history, and genetic testing when available.

Image Analysis

The best-quality macular volume scan which included the fovea was selected for each participant. Three trained graders (S. Mangalesh, D. Tran-Viet, and R. Gunther) masked to ocular and systemic health information analyzed the images for qualitative and quantitative OCT variables. When two of the graders disagreed, the third grader provided arbitration. The images were evaluated at three areas of interest: foveal (1 mm diameter of circle), parafoveal (3-mm-diameter circle), and extrafoveal retina (overall macular volume excluding the fovea and parafovea area) for the presence of schisis in the retinal layers, ellipsoid zone (EZ) disruption, associated traction, and retinal detachment. Quantitative measures included central foveal thickness (CFT), measured from inner limiting membrane to inner retinal pigment epithelium; foveal to parafoveal ratio by measuring the parafoveal thickness at 1,000 μm from the fovea and dividing it by CFT; EZ height measured from EZ to inner retinal pigment epithelium at the fovea and subfoveal choroidal thickness. These were assessed on Invivovue 2.4 (Leica Microsystems Inc., Buffalo Grove, IL).²⁰

Results

From 2010 to 2014, eight male patients aged 7 months to 10 years (mean 3.5 years) with bilateral XLRS were identified. Five of eight patients were younger than 5 years (n = 10 eyes), and three patients were between 5 and 10 years of age (n = 6 eyes). We analyzed SDOCT images acquired from both eyes.

Five of the eight children had a confirmed genetic mutation, and three of the eight children had known family history of retinoschisis. On clinical examination, the 7-month-old and 10-month-old patients had retinal detachment involving the fovea in the left eye before their first imaging session, and 10-year-old patient had tractional retinal detachment a with exudative maculopathy in the left eye. All eight patients were on dorzolamide eye drops.

Optical Coherence Tomography Findings

The OCT volumes were of adequate quality to assess retinal layers for the presence or absence of schisis and detachment in either the foveal (1 mm diameter centered on the fovea) and parafoveal region (1- to 3-mm-diameter annulus centered on the fovea) or extrafoveal (beyond the 3-mm-diameter circle centered on the fovea) region in all eight patients (16 eyes) at the first visit. Of the 16 eyes, 13 were of adequate quality to assess schisis at the foveal–parafoveal region. In three eyes, severe deformation of the retina sometimes with vitreous opacity causing shadowing limited the image quality and our ability to determine the location of the fovea. In all three of these eyes, it was likely that the severe schisis that was visible on OCT involved the fovea and parafoveal region.

Foveal–Parafoveal Region

In all 13 eyes, the extent of schisis involvement in the foveal region matched exactly the involvement in the parafoveal region. Thus, these results are reported for the foveal–parafoveal region. In the foveal–parafoveal region, all 13 eyes (100%) had schisis in the INL, and the cystic cavities were largest in this layer. Six eyes demonstrated schisis in the outer retinal layers with cavities present in the OPL in 4/6 eyes (67%) and in the ONL in 2/6 eyes (33%). We observed merged schisis cavities between the INL and ONL at the foveal–parafoveal region in 2/13 eyes. One eye had inner plexiform layer (IPL) schisis. The non-INL layers involved in schisis were not similar in the right eye and the left eye of each patient. Schisis did not involve either the retinal NFL (RNFL) or GCL in the foveal–parafoveal region (Figures 1 and 2).

Fig. 1.

A representative OCT scan of a fovea in a child with XLRS. Foveal (green, 1 mm diameter centered on the fovea) and parafoveal (red, 1- to 3-mm-diameter annulus centered on the fovea) regions are indicated, and extrafoveal region (not labeled) is everything else beyond the 3-mm-diameter circle centered on the fovea. Retinoschisis is demonstrated in the GCL, INL, OPL, and ONL.

Fig. 2.

Location of schisis at baseline in the right (A) and left (B) eyes of 8 patients. Retinoschisis did not involve either the retinal NFL (RNFL) or the GCL or the ONL in all eyes in the foveal and parafoveal region. In addition, retinoschisis was present and involved more than one retinal layer in all eyes in the extrafoveal region. Inner nuclear layer schisis was present in all but one eye in the foveal and parafoveal region. Merged schisis cavities were marked as continues bars between layers.

Extrafoveal Region

Retinoschisis was present and involved more than one retinal layer in all 16 eyes in the extrafoveal region (beyond the 3-mm-diameter circle centered on the fovea). Similar to the foveal–parafoveal region, 15/16 eyes (94%) showed INL schisis with largest cystic cavities, and of these, one eye had IPL schisis as well. Unlike the foveal–parafoveal findings, extrafoveal schisis cavities often involved the GCL (10/16 eyes, 63%) and RNFL in (6/16 eyes, 37.5%, all of which also had the GCL involvement). We found schisis in the outer retinal layers in 11/16 eyes (69%) with OPL schisis in 7/16 eyes (44%), another eye with ONL schisis alone, and in 3 additional eyes, a combination of schisis of the OPL and ONL (Figures 1 and 2).

Associated Pathologies

We analyzed the scans for other associated findings such as disruption of EZ, vitreous attachment, vitreomacular traction, retinal detachment, and presence of retinal holes and retinal atrophy (Figure 3). We found EZ disruption in 12/16 eyes (75%); 10/16 eyes (63%) had vitreous attachment of which 8/10 (80%) caused traction deforming the retinal surface and one of which involved the foveal–parafoveal region. We found retinal detachment in 6/16 (37.5%) eyes, and one eye had a lamellar retinal hole involving only the inner retinal layers. We did not find atrophic changes in the retinal layers in any of the images. When we compared the location of schisis within retinal layers and presence of associated features in children younger than 5 years to those between 5 and 10 years of age, we found no difference in these manifestations of schisis.

Fig. 3.

Associated retinal findings are illustrated and include EZ disruption (asterisk), retinal detachment (RD), and vitreomacular traction (arrows).

Longitudinal Analysis

We followed these patients and had at least one follow-up imaging visit (range 1–6) in seven of eight children. The time interval for follow-up visits with imaging was not consistent (range 2–15 months). We evaluated these scans for both qualitative and quantitative variables as at the baseline visit. We observed that the location of schisis was consistent with the baseline line visit in all seven patients. At the fovea, we noted a change in contour (Figure 4) and extent of schisis by assessing the CFT, at all visits. We were unable to measure the thickness at all time points in all patients because of poor image quality at some visits. Of those measured, we found a decrease in the CFT in four eyes from the baseline to final visit. We mapped the usage of brinzolamide/dorzolamide eye drops with the CFT and found no obvious change in CFT in those eyes (Figure 5).

Fig. 4.

Representative 3-dimensional OCT volumes (top) and B-scans (bottom) of a 7-month-old (at the time of first visit) child with XLRS over time. The volumes (yellow asterisk indicating optic nerve) show a change in foveal contour and decrease in schisis with treatment. Top left and bottom left are the 3D volume and B-scan before treatment; top middle and bottom middle are scans acquired after laser photocoagulation for peripheral neovascularization and ischemia; top right and bottom right represent scans acquired after laser photocoagulation, vitrectomy, endolaser, and fluid–air exchange for retinal detachment repair.

Fig. 5.

At the foveal center, change in contour and extend of schisis was assessed over time by the CFT in all subjects (denoted by the different colors of the line graph) who had good-quality images available in the right eye. We noted that CFT decreased in four eyes from the baseline to final visit. The brown arrow indicates the use of brinzolamide or dorzolamide at or during the time of visit.

Clinical Assessment

We were able to acquire visual acuity data on four patients from their clinical records. The vision was noted to be fix and follow in two patients. We compared the Snellen visual acuity in the other two patients with the presence and degree of disruption of EZ band at the fovea at the available visits in each eye. Lower visual acuity (20/400) was associated with absence or marked disruption of EZ band at the foveal center and higher visual acuities (20/50, 20/80, and 20/160) when present or slightly disrupted (Figure 6) in either eye.

Fig. 6.

Ellipsoid zone disruption (arrows) and absence from the foveal center were associated with vision loss as illustrated in these OCT scans. A. Ellipsoid zone present with mild disruptions in the foveal center and (B) EZ markedly disrupted in the foveal center.

Discussion

Early studies, by Manschot and Yanoff et al, on postmortem adult eyes with juvenile XLRS have demonstrated retinal splitting in the NFL and GCL on light micrographs.^13,14 Ando et al²¹ also observed cystic separation in the OPL in both foveal and peripheral retinal schisis in enucleated adult eyes. However, there are no histopathologic studies of early stages of foveal schisis, particularly in young children with XLRS. The use of handheld OCT has enabled us to study in vivo the retinal microanatomy and has changed the diagnostic approach to XLRS. Our study represents the first report on handheld SDOCT imaging findings of XLRS in children younger than 10 years (PubMed MeSH terms: OCT, XLRS, and children). First, we demonstrate the use of the handheld system in the clinic and in the operating room to examine young children who are routinely difficult to assess with standard tabletop OCT systems and require an examination under anesthesia. Secondly, to the best of our knowledge and from literature search (PubMed MeSH terms: OCT, XLRS, and children), we are the first study to image children as young as 7 months with XLRS diagnosis, suggesting that XLRS indeed manifests soon after birth.^9,22,23 These findings advocated for the use of handheld SDOCT as a critical screening tool in high-risk newborn infants as it aids in early diagnosis or confirmation and early treatment of XLRS.

In our study, we found the presence of extensive retinoschisis and therefore retinal thickening in the foveal, parafoveal, and extrafoveal regions on SDOCT. Previous studies in older populations have also reported foveomacular schisis, with some exceptions where schisis was confined to the fovea only¹⁸ or where no foveal schisis was observed.²⁴ Our findings indicate that the disease onset is at an early age and that findings themselves may represent early stages of the disease. Other studies in an older patient population reported atrophic macular thinning in patients in their fourth decade of life,^25,26 and these atrophic changes were not seen in our early age group. Therefore, we believe that the atrophic macular thinning in older patient population represents late stages of the disease. In addition, other studies have reported clinical descriptions of macular schisis flattening with age without clear mechanism for these changes,^25,26 and similarly, in our study, we have noted decreases over time in CFT in some patients.

Our findings revealed foveal schisis in the inner and outer nuclear and plexiform layers seen as the disruption of the inner retinal layers and thickening of the macula; these inner retinal changes are believed to be associated with vision loss.²⁷ However, recent studies have suggested that visual acuity does not correspond with the size of the cystic area or retinal thickness^5,16,24 but show an association with photoreceptor outer segment length, EZ height, and cone outer segment tips.²⁸ In our study, we show a possible association with the presence or degree of disruption of EZ band at the fovea with visual acuity in two patients. The absence or marked disruption of EZ band was associated with worse visual acuity while the presence or slight disruption of EZ band at the fovea was associated with better visual acuity. A larger sample size may be helpful in validating this finding which could lead to better strategies to preserve or regain lost vision associated with XLRS.

We also demonstrate that foveal schisis occurs mostly in the INL and OPL/ONL consistent with other recent OCT studies^15,17,18,24 that investigated the disease mostly in adults and in children older than 5 years. Based on our findings, we speculate that schisis at the INL occurs in early stages of the disease. Mouse models have displayed morphological and functional retinal phenotypes similar to human XLRS, with focal areas of retinal splitting within the INLs, and structural abnormalities of synapses within the OPLs.^29,30 Takada et al³¹ demonstrated that all retinal neurons express retinoschisin in the mouse retina during development, beginning with the ganglion cells at the first postnatal day and then progressing successively to amacrine, bipolar, and photoreceptor cells. This may support the idea that schisis first occurs in the INL, or that INL is the most susceptible retinal layer to splitting in the early stages of the disease. By contrast, human studies have shown that there is a wide heterogeneity with variable fundus appearance in patients with various mutations, and also within families with the same mutation, and no correlation has been identified between mutation type and disease severity or progression.^32-34 Our study represents the earliest in vivo imaging time point of the disease so far and has shown INL to be the most susceptible layer for schisis to occur.

George et al⁴ in their clinical report suggest that foveal schisis cavities may be very large and bullous and generally regress, leaving lines of pigment at an older age. They also report that breakage may occur within the inner layer and could vary from smaller holes to larger tears.⁴ We have, in our study, observed the presence of merged cysts between the INL and ONL in the fovea of two of our older children. Gass³⁵ suggested that in adulthood, cystic changes tend to disappear and are followed by alternations in the underlying retinal pigment epithelium and finally develop into atrophic regions in the macula. We found a large intraretinal cyst in the fovea showing splitting of the INL and associated with a lamellar hole. This was not associated with vitreous attachment or traction. We speculate that this maybe an early sign of the disease before developing atrophic changes as suggested by Gass. We did not find any outer retinal corrugations, reported by Agarwal and Rao³⁶ in our series of young children.

Our study also showed a difference in the location of schisis between the foveal–parafoveal and the extrafoveal region. We observed that RNFL and GCL schisis were only found in the extrafoveal regions. This finding is consistent with previously published OCT studies where this difference in the location of schisis between the macula and retinal periphery was documented.^11,15,17,18 This can be explained based on the report published by Benhamou et al³⁷ who found similar findings in retinoschisis found in pathological myopia; they suggested that the RNFL and GCL at the fovea are more closely related to the underlying tissue with more adherent vitreous attachment when compared with the periphery and, therefore, would require a stronger force to separate at the fovea.

We report vitreous traction in 80% of the eyes with vitreous attachment mainly in the extrafoveal region. Traction has been considered to play a role in the pathogenesis of XLRS in previous reports.^38,39 These reports demonstrated resolution of retinoschisis after vitrectomy.^38,39 Roughly 20% of all patients with XLRS may progress to retinal detachment in their first decade causing severe vision loss.^2,39 We found retinal detachment in 37.5% of the eyes in our children examined in their first decade of life. Therefore, early diagnosis and monitoring is warranted, to avoid complications and vision loss in young children.

Our study limitations include retrospective approach and limited sample size with variable follow-up rate. The visual acuities were not documented for each subject and/or visit due to young age or examinations under anesthesia. Despite these limitations, the study reports on in vivo retinal microanatomy changes in the youngest patient group imaged with handheld SDOCT to date.

In summary, we have demonstrated the application and the utility of handheld SDOCT as a screening tool for early diagnosis of retinoschisis and, therefore, early treatment in infants and young children. In addition, we described the differences in the schisis location in foveal–parafoveal and extrafoveal retinal regions, illustrated decreases in CFT over time, and demonstrated an association between EZ disruption and poor visual acuity in our young age group. Moreover, we illustrated that the pattern of XLRS in adults is already present in very young children. Further larger and longer-term prospective OCT studies are indicated to evaluate and follow progression of retinal microanatomy in XLRS patients within the first decade of their life. These studies may provide more insight into the disease and may influence the design of treatment modalities and further monitoring in children with XLRS.