Short Reports Resolution of foveal schisis in X-linked retinoschisis in the setting of retinal detachment Mrinali Patel Gupta, MD,a George Parlitsis, MD,a Stephen Tsang, MD, PhD,b and R. V. Paul Chan, MDa Patients who have undergone vitrectomy for complications of X-linkedretinoschisis (XLRS) have demonstrated an improvement in foveal schisis after pars plana vitrectomy. We report the case of a 10-year-old boy with XLRS and bilateral foveal schisis in whom macula-involving retinal detachment in one eye was associated with a resolution of foveal schisis in that eye. This case provides additional support for a role of vitreoretinal traction in the pathogenesis of foveal schisis in XLRS.
T
he pathogenesis of foveal schisis in X-linked retinoschisis (XLRS; OMIM 312700) has yet to be fully elucidated. We present a case of a patient with bilateral foveal schisis in whom development of a macula-involving retinal detachment was associated with resolution of foveal schisis. This case suggests that changes in the vitreoretinal interface in the setting of retinal detachment may prompt resolution of cystic changes, thereby implicating a potential role for vitreoretinal traction in foveal schisis in XLRS.
Case Report A 10-year-old boy presented at Weill Cornell Medical College with decreased vision of the right eye. He had been diagnosed with XLRS 1.5 years prior to presentation and possessed a mutation (A211X) in the RS1 gene, which results in a truncated retinoschisin protein. His uncorrected visual acuity at XLRS diagnosis was 20/50 in the right eye and 20/50 in the left eye. He was taking oral acetazolamide for treatment of bilateral foveal schisis. Family history was significant for a maternal grandfather who had been diagnosed with “retinitis pigmentosa” and had a history of retinal detachment in one eye. Fundus photographs (Figure 1A) and optical coherence tomography (OCT) (Figure 1B) acquired prior to presentation showed attached retina with foveal schisis in the Author affiliations: aDepartment of Ophthalmology, Weill Cornell Medical College, New York, New York; bDepartment of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, New York Submitted April 18, 2014. Revision accepted September 30, 2015. Correspondence: R.V. Paul Chan, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Ave, 11th Floor, New York, NY 10021 (email: roc9013@med. cornell.edu). J AAPOS 2015;19:172-174. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.09.015
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FIG 1. Findings prior to of retinal detachment. Fundus photograph (A) and OCT (B) demonstrating attached retina with foveal schisis in the right eye.
right eye. At presentation the patient’s uncorrected visual acuity was 20/150 (pinhole no improvement) in the right eye and 20/50 (pinhole no improvement) in the left eye. Fundus examination revealed an inferior, maculainvolving retinal detachment with multiple inner retinal holes and one full-thickness hole in the right eye (Figure 2A) and foveal schisis and inferior peripheral retinoschisis with a large inner retinal hole in the left eye (Figure 2B). OCT demonstrated subretinal fluid consistent with a macula-involving retinal detachment but no schisis cavities in the right eye (Figure 2C). There was foveal schisis in the left eye (Figure 2D). The patient was scheduled for surgical repair of the retinal detachment in the right eye. After extensive discussion with the parents of the risks and benefits of and alternatives to surgery, scleral buckle surgery was performed. There was initially gradual resolution of subretinal fluid such that the macula was attached by 6 weeks (Figure 3A-B), at which time uncorrected visual acuity was 20/600 (pinhole 20/150) in the right eye. No foveal schisis nor intraretinal cystic changes were noted (Figure 3B). Over the next 10 weeks, increasing subretinal fluid was noted inferiorly and ultimately involved much of the inferior macula, while sparing the fovea (Figure 3C-D). A few very small cystic changes developed in the superior macula (Figure 3E) in the area of attached retina, sparing the fovea itself (Figure 3D). Uncorrected visual acuity was 20/250 (pinhole 20/100). At all time points, examination in the left eye remained stable, with
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Volume 19 Number 2 / April 2015
FIG 2. Preoperative findings after development of retinal detachment. A, Large inferior, macula-involving retinal detachment with inner retinal holes and a full thickness hole in the right eye. B, Inferior retinoschisis with a large inner retinal hole in the left eye. C, OCT showing subretinal fluid but no foveal schisis in the right eye. D, OCT showing foveal schisis in the left eye.
foveal schisis, inferior peripheral schisis, and no retinal detachment.
Discussion XLRS is a generalized retinal degeneration that manifests clinically with variable loss of vision, foveal schisis producing clinically visible radial streaks, an electronegative electroretinogram (ie, a waveform with a b-wave smaller than the awave), and, in 50% of cases, peripheral schisis.1,2 The pathophysiologic basis of foveal schisis in XLRS is poorly understood, although it is known to be due to a mutation in the RS1 gene, which encodes retinoschisin, a protein expressed in and secreted from photoreceptors and bipolar cells. Retinoschisin is thought to be involved in cell-to-cell adhesion, Muller cell function, and possibly regulation of intracellular and extracellular fluid in the retina.2 Prior studies of XLRS patients after vitrectomy suggest a role for vitreoretinal interface in foveal schisis. In our patient the foveal schisis resolved in the setting of a macula-involving retinal detachment. After repair of the
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retinal detachment, there was gradual development of only a few small superior cystic changes, but no schisis changes in the fovea itself, suggesting that changes at the vitreoretinal interface alone may not account for foveal schisis. Other factors, such as posterior tractional forces from the retinal pigment epithelium (RPE)/choroid may also play a role. The contralateral eye had notable foveal schisis at all visits. Systemic carbonic anhydrase treatment was unlikely to have contributed significantly to schisis resolution, given persistent foveal schisis in the contralateral eye. As this is a single report of a single case, it is also possible that the resolution of schisis in the right eye was simply a manifestation of asymmetric fluctuations in foveal schisis, which can be seen in XLRS but were not previously noted in this patient and that the concurrence of foveal schisis resolution with the retinal detachment in the right eye was coincidental. In the setting of deficient cell-to-cell adhesion due to the mutation in retinoschisin (RS1), the tensile strength of the retina may be reduced sufficiently that it is unable to withstand the normal anteroposterior traction at the vitreoretinal interface and posteriorly from the RPE/choroid. This mismatch between the tensile strength on the retina versus the tensile strength of the retina may in turn lead to schisis cavities. This hypothesis is supported by the decreased prevalence of foveal schisis in XLRS with age,3,4 given that older patients are more likely to have posterior vitreous detachments (PVD) and thus less foveal vitreoretinal traction. A role of the vitreoretinal interface in foveal schisis in XLRS is further supported by findings in post-vitrectomy XLRS patients. Several publications report improvement of or resolution of foveal schisis in patients who have undergone vitrectomy with or without internal limiting membrane peel.5-7 Ikeda and colleagues5 reported failure of initial vitrectomy to achieve a complete PVD and persistent schisis; a second surgery with completion of the PVD resulted in resolution of foveal schisis and restoration of the normal foveal depression. These reports suggest that tractional forces from the vitreoretinal interface may contribute to foveal schisis in XLRS. This case and prior reports of schisis resolution in postvitrectomy XLRS eyes suggest that interventions that alter the vitreoretinal interface, such as vitreoretinal surgery or pharmacologic vitreolysis, may have a role in the management of foveal schisis. Of note, Yu and colleagues6 reported that, at an average follow-up of 34.7 months, final visual acuities and retinal attachment rates were better in patients treated with vitrectomy than in those without surgical intervention. The benefit of internal limiting membrane peeling is unclear, given that a minority of patients without peeling achieved favorable outcomes with vitrectomy alone.5-7 In our case, the eventual development of small superior macular cystic changes after retinal reattachment suggests that other factors, possibly posterior tractional forces, may also contribute to foveal schisis and thereby limit the success of vitreoretinal
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FIG 3. Postoperative findings. Fundoscopy (A) and OCT (B) 6 weeks after scleral buckle surgery revealed resorption of subretinal fluid (A) and no foveal schisis (B). Ten weeks postoperatively, subretinal fluid increased inferiorly (C-D), although foveal schisis continued to be absent (D). Subtle cystic schisis changes were noted in the superior macula (E).
interface–based interventions. Moreover, it is possible that surgical manipulations at the vitreoretinal interface in these eyes with a thinned and tented foveal surface due to schisis may predispose to macular hole. Further studies are necessary to understand the mechanisms driving foveal schisis development in XLRS and to determine whether interventions that modify the vitreoretinal interface may promote resolution of schisis. It should be noted that retinoschisin is present in the photoreceptor-bipolar synapse, and in XLRS patients mutated retinoschisin may induce a functional deficit that produces the reduced b-wave ERG amplitude seen in XLRS. Even if surgical manipulation can improve the structural changes in XLRS, it is unknown whether this structural improvement will be accompanied by an improvement in the synaptic pathology at the photoreceptor-bipolar cell junction.
References 1. George ND, Yates JR, Moore AT. X-linked retinoschisis. Br J Ophthalmol 1995;79:697-702. 2. Molday S, Kellner U, Weber BHF. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res 2012;31:195-212. 3. Menke MN, Feke GT, Hirose T. Effect of aging on macular features of x-linked retinoschisis assessed with optical coherence tomography. Retina 2011;31:1186-92. 4. Apushkin MA, Fishman GA, Rajagopalan AS. Fundus findings and longitudinal study of visual acuity loss in patients with x-linked retinoschisis. Retina 2005;25:612-18. 5. Ikeda F, Iida T, Kishi S. Resolution of retinoschisis after vitreous surgery in X-linked retinoschisis. Ophthalmology 2008;115: 718-22. 6. Yu H, Li T, Luo Y, et al. Long-term outcomes for vitrectomy for progressive X-linked retinoschisis. Am J Ophthalmol 2013;154: 394-402. 7. Iordanous Y, Sheidow TG. Vitrectomy for x-linked retinoschisis: a case report and literature review. Can J Ophthalmol 2013;48:e71-4.
Journal of AAPOS
T
he pathogenesis of foveal schisis in X-linked retinoschisis (XLRS; OMIM 312700) has yet to be fully elucidated. We present a case of a patient with bilateral foveal schisis in whom development of a macula-involving retinal detachment was associated with resolution of foveal schisis. This case suggests that changes in the vitreoretinal interface in the setting of retinal detachment may prompt resolution of cystic changes, thereby implicating a potential role for vitreoretinal traction in foveal schisis in XLRS.
Case Report A 10-year-old boy presented at Weill Cornell Medical College with decreased vision of the right eye. He had been diagnosed with XLRS 1.5 years prior to presentation and possessed a mutation (A211X) in the RS1 gene, which results in a truncated retinoschisin protein. His uncorrected visual acuity at XLRS diagnosis was 20/50 in the right eye and 20/50 in the left eye. He was taking oral acetazolamide for treatment of bilateral foveal schisis. Family history was significant for a maternal grandfather who had been diagnosed with “retinitis pigmentosa” and had a history of retinal detachment in one eye. Fundus photographs (Figure 1A) and optical coherence tomography (OCT) (Figure 1B) acquired prior to presentation showed attached retina with foveal schisis in the Author affiliations: aDepartment of Ophthalmology, Weill Cornell Medical College, New York, New York; bDepartment of Ophthalmology, Columbia University College of Physicians and Surgeons, New York, New York Submitted April 18, 2014. Revision accepted September 30, 2015. Correspondence: R.V. Paul Chan, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Ave, 11th Floor, New York, NY 10021 (email: roc9013@med. cornell.edu). J AAPOS 2015;19:172-174. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.09.015
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FIG 1. Findings prior to of retinal detachment. Fundus photograph (A) and OCT (B) demonstrating attached retina with foveal schisis in the right eye.
right eye. At presentation the patient’s uncorrected visual acuity was 20/150 (pinhole no improvement) in the right eye and 20/50 (pinhole no improvement) in the left eye. Fundus examination revealed an inferior, maculainvolving retinal detachment with multiple inner retinal holes and one full-thickness hole in the right eye (Figure 2A) and foveal schisis and inferior peripheral retinoschisis with a large inner retinal hole in the left eye (Figure 2B). OCT demonstrated subretinal fluid consistent with a macula-involving retinal detachment but no schisis cavities in the right eye (Figure 2C). There was foveal schisis in the left eye (Figure 2D). The patient was scheduled for surgical repair of the retinal detachment in the right eye. After extensive discussion with the parents of the risks and benefits of and alternatives to surgery, scleral buckle surgery was performed. There was initially gradual resolution of subretinal fluid such that the macula was attached by 6 weeks (Figure 3A-B), at which time uncorrected visual acuity was 20/600 (pinhole 20/150) in the right eye. No foveal schisis nor intraretinal cystic changes were noted (Figure 3B). Over the next 10 weeks, increasing subretinal fluid was noted inferiorly and ultimately involved much of the inferior macula, while sparing the fovea (Figure 3C-D). A few very small cystic changes developed in the superior macula (Figure 3E) in the area of attached retina, sparing the fovea itself (Figure 3D). Uncorrected visual acuity was 20/250 (pinhole 20/100). At all time points, examination in the left eye remained stable, with
Journal of AAPOS
Volume 19 Number 2 / April 2015
FIG 2. Preoperative findings after development of retinal detachment. A, Large inferior, macula-involving retinal detachment with inner retinal holes and a full thickness hole in the right eye. B, Inferior retinoschisis with a large inner retinal hole in the left eye. C, OCT showing subretinal fluid but no foveal schisis in the right eye. D, OCT showing foveal schisis in the left eye.
foveal schisis, inferior peripheral schisis, and no retinal detachment.
Discussion XLRS is a generalized retinal degeneration that manifests clinically with variable loss of vision, foveal schisis producing clinically visible radial streaks, an electronegative electroretinogram (ie, a waveform with a b-wave smaller than the awave), and, in 50% of cases, peripheral schisis.1,2 The pathophysiologic basis of foveal schisis in XLRS is poorly understood, although it is known to be due to a mutation in the RS1 gene, which encodes retinoschisin, a protein expressed in and secreted from photoreceptors and bipolar cells. Retinoschisin is thought to be involved in cell-to-cell adhesion, Muller cell function, and possibly regulation of intracellular and extracellular fluid in the retina.2 Prior studies of XLRS patients after vitrectomy suggest a role for vitreoretinal interface in foveal schisis. In our patient the foveal schisis resolved in the setting of a macula-involving retinal detachment. After repair of the
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retinal detachment, there was gradual development of only a few small superior cystic changes, but no schisis changes in the fovea itself, suggesting that changes at the vitreoretinal interface alone may not account for foveal schisis. Other factors, such as posterior tractional forces from the retinal pigment epithelium (RPE)/choroid may also play a role. The contralateral eye had notable foveal schisis at all visits. Systemic carbonic anhydrase treatment was unlikely to have contributed significantly to schisis resolution, given persistent foveal schisis in the contralateral eye. As this is a single report of a single case, it is also possible that the resolution of schisis in the right eye was simply a manifestation of asymmetric fluctuations in foveal schisis, which can be seen in XLRS but were not previously noted in this patient and that the concurrence of foveal schisis resolution with the retinal detachment in the right eye was coincidental. In the setting of deficient cell-to-cell adhesion due to the mutation in retinoschisin (RS1), the tensile strength of the retina may be reduced sufficiently that it is unable to withstand the normal anteroposterior traction at the vitreoretinal interface and posteriorly from the RPE/choroid. This mismatch between the tensile strength on the retina versus the tensile strength of the retina may in turn lead to schisis cavities. This hypothesis is supported by the decreased prevalence of foveal schisis in XLRS with age,3,4 given that older patients are more likely to have posterior vitreous detachments (PVD) and thus less foveal vitreoretinal traction. A role of the vitreoretinal interface in foveal schisis in XLRS is further supported by findings in post-vitrectomy XLRS patients. Several publications report improvement of or resolution of foveal schisis in patients who have undergone vitrectomy with or without internal limiting membrane peel.5-7 Ikeda and colleagues5 reported failure of initial vitrectomy to achieve a complete PVD and persistent schisis; a second surgery with completion of the PVD resulted in resolution of foveal schisis and restoration of the normal foveal depression. These reports suggest that tractional forces from the vitreoretinal interface may contribute to foveal schisis in XLRS. This case and prior reports of schisis resolution in postvitrectomy XLRS eyes suggest that interventions that alter the vitreoretinal interface, such as vitreoretinal surgery or pharmacologic vitreolysis, may have a role in the management of foveal schisis. Of note, Yu and colleagues6 reported that, at an average follow-up of 34.7 months, final visual acuities and retinal attachment rates were better in patients treated with vitrectomy than in those without surgical intervention. The benefit of internal limiting membrane peeling is unclear, given that a minority of patients without peeling achieved favorable outcomes with vitrectomy alone.5-7 In our case, the eventual development of small superior macular cystic changes after retinal reattachment suggests that other factors, possibly posterior tractional forces, may also contribute to foveal schisis and thereby limit the success of vitreoretinal
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FIG 3. Postoperative findings. Fundoscopy (A) and OCT (B) 6 weeks after scleral buckle surgery revealed resorption of subretinal fluid (A) and no foveal schisis (B). Ten weeks postoperatively, subretinal fluid increased inferiorly (C-D), although foveal schisis continued to be absent (D). Subtle cystic schisis changes were noted in the superior macula (E).
interface–based interventions. Moreover, it is possible that surgical manipulations at the vitreoretinal interface in these eyes with a thinned and tented foveal surface due to schisis may predispose to macular hole. Further studies are necessary to understand the mechanisms driving foveal schisis development in XLRS and to determine whether interventions that modify the vitreoretinal interface may promote resolution of schisis. It should be noted that retinoschisin is present in the photoreceptor-bipolar synapse, and in XLRS patients mutated retinoschisin may induce a functional deficit that produces the reduced b-wave ERG amplitude seen in XLRS. Even if surgical manipulation can improve the structural changes in XLRS, it is unknown whether this structural improvement will be accompanied by an improvement in the synaptic pathology at the photoreceptor-bipolar cell junction.
References 1. George ND, Yates JR, Moore AT. X-linked retinoschisis. Br J Ophthalmol 1995;79:697-702. 2. Molday S, Kellner U, Weber BHF. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res 2012;31:195-212. 3. Menke MN, Feke GT, Hirose T. Effect of aging on macular features of x-linked retinoschisis assessed with optical coherence tomography. Retina 2011;31:1186-92. 4. Apushkin MA, Fishman GA, Rajagopalan AS. Fundus findings and longitudinal study of visual acuity loss in patients with x-linked retinoschisis. Retina 2005;25:612-18. 5. Ikeda F, Iida T, Kishi S. Resolution of retinoschisis after vitreous surgery in X-linked retinoschisis. Ophthalmology 2008;115: 718-22. 6. Yu H, Li T, Luo Y, et al. Long-term outcomes for vitrectomy for progressive X-linked retinoschisis. Am J Ophthalmol 2013;154: 394-402. 7. Iordanous Y, Sheidow TG. Vitrectomy for x-linked retinoschisis: a case report and literature review. Can J Ophthalmol 2013;48:e71-4.
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