Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis Michael D. Ober, MD,1 K. Bailey Freund, MD,2 Manthan Shah, MD,3 Shareef Ahmed, MD,3 Tamer H. Mahmoud, MD, PhD,4 Thomas M. Aaberg, Jr., MD,5 David N. Zacks, MD,6 Hua Gao, MD,3 Krishna Mukkamala, MD,2 Uday Desai, MD,3 Kirk H. Packo, MD,7 Lawrence A. Yannuzzi, MD2 Purpose: To describe a new classification of stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR). Design: Retrospective case series and literature review. Participants: A total of 17 patients from 5 institutions. Methods: Detailed case history, multimodal imaging, and genetic testing were reviewed for patients with macular schisis without a known predisposing condition. Patients with a stellate appearance centered on the fovea with correlating confirmed expansion of the outer plexiform layer (OPL) by optical coherence tomography (OCT) were included. Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or advanced glaucomatous optic nerve changes. Main Outcome Measures: Clinical features, anatomic characteristics, and visual acuity. Results: A total of 22 eyes from 16 female patients and 1 male patient with foveomacular schisis were reviewed from 5 institutions. Initial visual acuity was 20/50 in all eyes (mean, 20/27), but visual acuity in a single eye decreased from 20/20 to 20/200 after the development of subfoveal fluid. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to >5 years. Conclusions: In this largest known series of patients with SNIFR, all patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (20/40) except in a single patient in whom subretinal fluid developed under the fovea. Ophthalmology 2014;-:1e8 ª 2014 by the American Academy of Ophthalmology. Supplemental material is available at www.aaojournal.org.
Stellate foveal retinoschisis is most commonly associated with congenital juvenile X-linked retinoschisis (CXLR) due to a defect in the RS1 gene. Foveal retinoschisis is found in nearly all cases of CXLR, with a variable number also developing peripheral retinoschisis. This disorder accounts for nearly all cases of congenital foveal retinoschisis. Given its inheritance pattern, the entity is almost exclusively found bilaterally in men.1 There are many other reported causes of macular retinoschisis aside from defects in the RS1 gene, including myopic degeneration,2e5 optic pit maculopathy,6e10 degenerative retinoschisis,11 glaucoma,12e14 myotonic dystrophy,15 enhanced S-cone syndrome,16e18 autosomal dominant retinoschisis,19 and vitreomacular traction,20 among others. Although the pathogenesis in each of these is multivariate, an underlying defect in retinal structural integrity is a commonality. We report 22 eyes from 16 female patients and 1 male patient with foveal retinoschisis without a known hereditary or acquired predisposition (Figs 1e6). The majority of these cases are unilateral, none have pertinent family history, and all those tested had negative results for known defects in the RS1 gene. For these reasons, we believe these cases represent a new category, which we have titled “stellate nonhereditary idiopathic foveomacular retinoschisis” (SNIFR). 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
Methods This is a review of the clinical histories and multimodal imaging for a series of patients found to have macular schisis without a known predisposing condition. This project was approved by the institutional review board at Henry Ford Health Systems. Inclusion criteria were the stellate appearance of the retina centered on the fovea noted on clinical examination with expansion of the outer plexiform layer (OPL) confirmed by optical coherence tomography (OCT). Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or glaucomatous optic nerve changes. All patients had undergone complete ocular examinations, including slit-lamp biomicroscopy, indirect ophthalmoscopy, and best-corrected Snellen visual acuity, refractive error, and intraocular pressure. Color photography, fluorescein angiography (FA), and OCT were reviewed for all patients. Genetic analyses for known mutations to the RS1 gene were performed in 8 of 16 patients available who consented to testing. Snellen visual acuities were converted to logarithm of the minimum angle of resolution visual acuities to calculate means.
Results The records of 22 eyes from 17 patients with foveomacular schisis were reviewed from 5 institutions. Fundus photography, OCT, and ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2014.02.002
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Figure 1. Images from the right eye of patient 1, a 36-year-old asymptomatic woman who has remained stable for >5 years: the proband for the series. A, Color fundus photograph demonstrating radial spoking around the fovea. B, Late fluorescein angiography (FA) image showing no leakage. C, Vertical optical coherence tomography (OCT) through the fovea.
FA were performed in all patients. Clinical findings are summarized in Table 1 (available at www.aaojournal.org). Twelve patients presented with monocular findings, and 5 patients had bilateral findings. Initial visual acuity was 20/50 or better in all eyes, but visual acuity in a single eye of 1 patient decreased from 20/20 to 20/200 after the development of subfoveal fluid. Mean visual acuity on presentation was 20/27 and decreased to 20/30 when the decreased vision in patient 5 was included. Twenty eyes were phakic, and 2 eyes were pseudophakic. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. No eyes demonstrated features of vitreoretinal interface disorders or myopic traction maculopathy, such as epiretinal membrane, vitreomacular traction, staphyloma, chorioretinal thinning, or macular retinal pigment epithelium (RPE) atrophy. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to more than 5 years without significant change in examination findings. Genetic testing for the RS1 gene was performed on 8 patients (comprising 11 eyes) and revealed no known disease-causing mutations in any. None of the patients had a family history of CXLR or other hereditary maculopathy.
Discussion We present the largest known case series of eyes with SNIFR, the majority of which were asymptomatic or minimally symptomatic on presentation. Stellate foveomacular
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retinoschisis is classically associated with CXLR. This disorder has been mapped to Xp22.1-3 and codes for the retinoschisin,21 a complex, octamerizing protein implicated in cellecell interactions and adhesions. All affected individuals manifest foveal schisis with approximately half also developing peripheral schisis. Given the inheritance pattern, the phenotypic manifestations of this genetic disorder are almost exclusively found in male patients; however, affected female patients rarely have been reported. Women with homozygous mutations,22,23 XO (Turner syndrome),24 and carrier states25,26 have all been described. None of the patients in our series tested positive for a known mutation or had a positive family history for CXLR. Enhanced S-cone syndrome is an autosomal recessive disorder with foveomacular retinoschisis; however, it also characteristically demonstrates severe night blindness from childhood, complicated cataracts with an optically empty vitreous, and RPE pigmentary alterations. In general, the pattern of the macular and peripheral retinoschisis is more extensive than in our patients, and the severe visual disturbance also easily distinguishes this disorder from those we are describing.16e18 Optic disc pits can lead to macular schisis with fluid extending into a variety of inner and outer retinal layers.8e10
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Figure 2. Images from patient 8. A, Color fundus photograph of the right eye showing radial spoking around the fovea. B, Corresponding late fluorescein angiography (FA) image demonstrating no leakage. C, Horizontal optical coherence tomography (OCT) through the macula.
Spaide et al27 described a case similar to optic disc pit maculopathy with unilateral macular schisis and outer layer detachment in a male patient, but no optic disc or scleral pit. He postulated that vitreous fluid could be pumped into the schisis cavity via a valve-like fenestrated membrane, which opens and closes with the heart beateinduced physiologic pulsatile anatomic displacement of the disc. Glaucomatous optic nerve damage has been implicated in the pathogenesis of some cases of macular schisis. The thinning of the nerve fiber layer and optic disc cupping may lead to microholes and structural defects in the inner retinal layers around the optic disc, creating a pathway for fluid to enter a potential schisis cavity.12e14,28 Two eyes of 1 patient in our series showed schisis fluid extending into the optic nerve (Fig 3), suggesting the possibility that fluid emanated from the disc; however, no optic or scleral pits were found, and there was no history of glaucoma or glaucomatous optic nerve damage. The previously described fenestrated membrane27,29 noted in cases of optic disc pit maculopathy (with or without a pit) was not visible in either of the 2 eyes in our series, suggesting it likely represents a distinct disorder. Pathologic myopia also is well known to generate foveomacular retinoschisis secondary to anterior-posterior forces leading to myopic traction maculopathy.2e4,30,31 VanderBeek and Johnson31 described multiple causative
mechanisms, including vitreomacular traction after partial posterior vitreous detachment, remaining cortical vitreous after posterior vitreous detachment (vitreoschisis), epiretinal membrane, retinal arteriolar stiffness, and relatively poor internal limiting membrane compliance failing to configure to the staphyloma surface. These mechanisms yield obvious visible signs on spectral-domain OCT31e33 except for stiff internal limiting membrane; however, myopic traction maculopathy occurs in the setting of a myopic staphyloma that is discernible on examination or OCT. Improvement and resolution of myopic foveomacular retinoschisis after surgical reduction or elimination of traction forces lend further evidence to the underlying mechanisms.4,34e36 Our series does include myopic patients, but we carefully excluded eyes with evidence of myopic traction maculopathy. Niacin and taxane-derived medications cause cystoid spaces in the OPL and inner nuclear layer that do not leak during FA and closely resemble those from our patients.37e39 This is generally reversible with discontinuation of the medication. The mechanism is unclear; however, it indicates that factors other than traction alone can play a role in foveomacula schisis-like maculopathy in the absence of a known RS1 mutation. Several small case series and reports of foveomacular retinoschisis in female patients have been reported with various modes of inheritance. Shimazaki and Matsuhashi40
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Figure 3. Images from patient 6. A, Fundus autofluorescence photograph of the right eye showing slight radial hypofluorescence around the fovea corresponding to cortical spoking. B, Late fluorescein angiography (FA) image showing no leakage or staining. C, Horizontal optical coherence tomography (OCT) showing retinoschisis extending into the optic nerve.
reported a mother and daughter, each with bilateral findings of foveal schisis resembling CXLR. Both patients were myopic (spherical equivalent 6.25 and 3.75 in each eye of the daughter and mother, respectively) with peripheral abnormalities in each, including retinoschisis with confluent inner layer holes in the daughter and retinal tears with retinal detachment in the mother. Lewis et al41 described 3 sisters with bilateral foveal retinoschisis from nonconsanguineous, unaffected parents. All were mildly hyperopic (þ1.00) with visual acuity ranging from 20/30 to 20/50. One patient developed symptomatic metamorphopsia associated with a decrease in visual acuity from 20/25 to 20/50. Fluorescein angiography showed no leakage, but the symptomatic patient showed “the faintest hyperfluorescence,” suggesting an RPE abnormality. All patients were unable to perceive certain entopic phenomena that the authors suggest may imply a deficiency of macular xanthophyll or reduced sensitivity of foveal blue cones. There is striking similarity between the patients in these 2 case series and our patients. None of our patients had known relatives with foveomacular retinoschisis; however, examinations were not performed in the majority of family members. Given that the clinical findings on fundus examination were subtle in the
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majority of our series and most of the patients were asymptomatic or had minimal visual symptoms, affected relatives would not necessarily pursue ophthalmologic visits. It is possible a hereditary component was missed in our series. Three eyes of 2 patients in our series manifested bullous peripheral retinoschisis in addition to the typical foveomacular retinoschisis (Fig 4). Han et al11 described a 56-year-old woman with bilateral findings nearly identical to these, including symmetric inner retinal plication within 300 mm of the fovea and bullous peripheral retinoschisis. Fluorescein angiography showed faint transmission defects in the macula, but no leakage. One of their patient’s 4 daughters also demonstrated peripheral retinoschisis, but none had macular findings. Three additional eyes in our series showed subtle shallow peripheral schisis visible only with scleral depression. Dr Edward Cherney described a 60year-old woman in Gass’ Atlas of Macular Diseases with bilateral noneX-linked macular schisis, including OCT findings showing the findings were limited to the OPL.42 This case also would fit well into the case series we are presenting. Within the macula, all of the patients in our series showed splitting within the OPL with lesser involvement of
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Figure 4. Images from patient 10. Red-free images of the right (A) and left (B) eyes, showing radial spoking around the fovea. Horizontal optical coherence tomography (OCT) images through the fovea of the right (C) and left (D) eyes demonstrating schisis predominantly in the outer plexiform layer (OPL). E, Montage OCT of the left eye showing increasing retinoschisis with multilayered involvement toward the periphery. N ¼ nasal; T ¼ temporal.
the outer nuclear layer. All peripheral areas where OCT imaging was possible (3 eyes of 2 patients) showed variable involvement of the inner plexiform layer (Fig 4). Histopathologic studies of eyes with CXLR suggested the retina split in superficial layers, including the nerve fiber layer and ganglion cell layer43,44; however, time-domain OCT revealed confluent schisis in the OPL with less involvement of the inner nuclear layer45 within the macula. Spectral-domain OCT revealed that the macular component most commonly involves the inner nuclear layer, with less common involvement of the outer plexiform, outer nuclear layers, and rarely the nerve fiber layer/ganglion cell layer.46 The OCT findings in enhanced S-cone syndrome show severe degeneration with a splitting just above the photoreceptor layer.17 Optic disc pit and
glaucoma-induced macular schisis showed fluid accumulation in a multitude of inner and outer retinal layers, including the nerve fiber layer, inner plexiform layer, and OPL.9,10,12e14,28,29,47 Niacin and taxane maculopathy also showed OPL and inner nuclear layer fluid accumulation. These findings suggest that the distinction between disorders is not possible on the basis of currently available OCT technology alone. One eye of 1 patient developed the accumulation of subfoveal fluid isolated to the macula associated with a significant decrease in visual acuity (Fig 5). This phenomenon is known to occur with other causes of macular retinoschisis, including myopic degeneration and CXLR.30,48 The cause of the strong female predominance in this series is unknown. Gender differences have been reported in
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Figure 5. Images from patient 5. Color fundus photograph of the right (A) and left (B) eyes. C, optical coherence tomography (OCT) through the right eye demonstrating extensive retinoschisis. D, OCT through the left eye showing retinoschisis with subretinal fluid in the fovea.
retinal thickness,49 which may play a role in structural susceptibility to SNIFR. An X-linked dominant genetic inheritance pattern cannot be ruled out; however, given its rarity and the lack of heritance in any of our subjects, it should be considered unlikely.
In conclusion, we present the largest known series of SNIFR. All patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (20/40) except in a single patient in whom subretinal fluid developed under the fovea.
Figure 6. A, B, Images from patient 4. Color fundus (A) and infrared photographs (B) of the right eye showing radial spoking around the fovea. Optical coherence tomography (OCT) montage image of the right eye demonstrating retinoschisis extending from the central macula out temporally.
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References 1. Sieving PA, MacDonald IM, Meltzer MR, Smaoui N. X-linked juvenile retinoschisis. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviews [database online]. Seattle, WA; University of Washington, Seattle; updated May 12, 2009. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20301401. Accessed January 5, 2014. 2. Gaucher D, Haouchine B, Tadayoni R, et al. Long-term follow-up of high myopic foveoschisis: natural course and surgical outcome. Am J Ophthalmol 2007;143:455–62. 3. Panozzo G, Mercanti A. Optical coherence tomography findings in myopic traction maculopathy. Arch Ophthalmol 2004;122:1455–60. 4. Johnson MW. Myopic traction maculopathy: pathogenic mechanisms and surgical treatment. Retina 2012;32(Suppl): S205–10. 5. Smiddy WE, Kim SS, Lujan BJ, Gregori G. Myopic traction maculopathy: spectral domain optical coherence tomographic imaging and a hypothesized mechanism. Ophthalmic Surg Lasers Imaging 2009;40:169–73. 6. Imamura Y, Zweifel SA, Fujiwara T, et al. High-resolution optical coherence tomography findings in optic pit maculopathy. Retina 2010;30:1104–12. 7. Lalwani GA, Punjabi OS, Flynn HW Jr, et al. Documentation of optic nerve pit with macular schisis-like cavity by spectral domain OCT. Ophthalmic Surg Lasers Imaging 2007;38: 262–4. 8. Lincoff H, Lopez R, Kreissig I, et al. Retinoschisis associated with optic nerve pits. Arch Ophthalmol 1988;106:61–7. 9. Lincoff H, Schiff W, Krivoy D, Ritch R. Optic coherence tomography of optic disk pit maculopathy. Am J Ophthalmol 1996;122:264–6. 10. Spaide RF, Fisher Y, Ober M, Stoller G. Surgical hypothesis: inner retinal fenestration as a treatment for optic disc pit maculopathy. Retina 2006;26:89–91. 11. Han DP, Sieving PA, Johnson MW, Martonyi CL. Foveal retinoschisis associated with senile retinoschisis in a woman. Am J Ophthalmol 1988;106:107–9. 12. Hollander DA, Barricks ME, Duncan JL, Irvine AR. Macular schisis detachment associated with angle-closure glaucoma. Arch Ophthalmol 2005;123:270–2. 13. Farjad H, Besada E, Frauens BJ. Peripapillary schisis with serous detachment in advanced glaucoma [report online]. Optom Vis Sci 2010;87:e205–17. 14. Zhao M, Li X. Macular retinoschisis associated with normal tension glaucoma. Graefes Arch Clin Exp Ophthalmol 2011;249:1255–8. 15. Krishnan R, Lochhead J. Spontaneous bilateral lamellar macular holes and foveal schisis associated with myotonic dystrophy type 1. Clin Experiment Ophthalmol 2010;38:82–4. 16. Khairallah M, Ladjimi A, Ben Yahia S, et al. Elevated macular retinoschisis associated with Goldmann-Favre syndrome successfully treated with grid laser photocoagulation. Retina 2002;22:234–7. 17. Theodossiadis PG, Koutsandrea C, Kollia AC, Theodossiadis GP. Optical coherence tomography in the study of the Goldmann-Favre syndrome. Am J Ophthalmol 2000;129: 542–4. 18. Fishman GA, Jampol LM, Goldberg MF. Diagnostic features of the Favre-Goldmann syndrome. Br J Ophthalmol 1976;60: 345–53. 19. Yassur Y, Nissenkorn I, Ben-Sira I, et al. Autosomal dominant inheritance of retinoschisis. Am J Ophthalmol 1982;94:338–43.
20. Hotta K, Hotta J. Retinoschisis with macular retinal detachment associated with vitreomacular traction syndrome. Retina 2004;24:307–9. 21. Grayson C, Reid SN, Ellis JA, et al. Retinoschisin, the Xlinked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells. Hum Mol Genet 2000;9:1873–9. 22. Rodriguez FJ, Rodriguez A, Mendoza-Londono R, Tamayo ML. X-linked retinoschisis in three females from the same family: a phenotype-genotype correlation. Retina 2005;25:69–74. 23. Ali A, Feroze AH, Rizvi ZH, Rehman TU. Consanguineous marriage resulting in homozygous occurrence of X-linked retinoschisis in girls. Am J Ophthalmol 2003;136:767–9. 24. Hommura S, Nakano H, Hamaguchi H. A family of foveal retinoschisis including a female with Turner syndrome [in Japanese]. Rinsho Ganka 1982;36:291–6. 25. Mendoza-Londono R, Hiriyanna KT, Bingham EL, et al. A Colombian family with X-linked juvenile retinoschisis with three affected females finding of a frameshift mutation. Ophthalmic Genet 1999;20:37–43. 26. Wu G, Cotlier E, Brodie S. A carrier state of X-linked juvenile retinoschisis. Ophthalmic Paediatr Genet 1985;5:13–7. 27. Spaide RF, Costa DL, Huang SJ. Macular schisis in a patient without an optic disk pit optical coherence tomographic findings. Retina 2003;23:238–40. 28. Zumbro DS, Jampol LM, Folk JC, et al. Macular schisis and detachment associated with presumed acquired enlarged optic nerve head cups. Am J Ophthalmol 2007;144:70–4. 29. Bonnet M. Serous macular detachment associated with optic nerve pits. Graefes Arch Clin Exp Ophthalmol 1991;229:526–32. 30. Ripandelli G, Rossi T, Scarinci F, et al. Macular vitreoretinal interface abnormalities in highly myopic eyes with posterior staphyloma: 5-year follow-up. Retina 2012;32:1531–8. 31. VanderBeek BL, Johnson MW. The diversity of traction mechanisms in myopic traction maculopathy. Am J Ophthalmol 2012;153:93–102. 32. Sayanagi K, Morimoto Y, Ikuno Y, Tano Y. Spectral-domain optical coherence tomographic findings in myopic foveoschisis. Retina 2010;30:623–8. 33. Benhamou N, Massin P, Haouchine B, et al. Macular retinoschisis in highly myopic eyes. Am J Ophthalmol 2002;133: 794–800. 34. Ikuno Y, Sayanagi K, Ohji M, et al. Vitrectomy and internal limiting membrane peeling for myopic foveoschisis. Am J Ophthalmol 2004;137:719–24. 35. Panozzo G, Mercanti A. Vitrectomy for myopic traction maculopathy. Arch Ophthalmol 2007;125:767–72. 36. Wu TY, Yang CH, Yang CM. Gas tamponade for myopic foveoschisis with foveal detachment. Graefes Arch Clin Exp Ophthalmol 2013;251:1319–24. 37. Joshi MM, Garretson BR. Paclitaxel maculopathy. Arch Ophthalmol 2007;125:709–10. 38. Spirn MJ, Warren FA, Guyer DR, et al. Optical coherence tomography findings in nicotinic acid maculopathy. Am J Ophthalmol 2003;135:913–4. 39. Teitelbaum BA, Tresley DJ. Cystic maculopathy with normal capillary permeability secondary to docetaxel. Optom Vis Sci 2003;80:277–9. 40. Shimazaki J, Matsuhashi M. Familial retinoschisis in female patients. Doc Ophthalmol 1987;65:393–400. 41. Lewis RA, Lee GB, Martonyi CL, et al. Familial foveal retinoschisis. Arch Ophthalmol 1977;95:1190–6. 42. Agarwal A. Heredodystrophic disorders affecting the pigment epithelium and retina. In: Agarwal A, ed. Gass’ Atlas of
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43. 44. 45. 46.
Macular Diseases. Vol. 1. 15th ed. Edinburgh, Scotland: Elsevier Saunders; 2012:374–6. Manschot WA. Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol 1972;88:131–8. Yanoff M, Kertesz Rahn E, Zimmerman LE. Histopathology of juvenile retinoschisis. Arch Ophthalmol 1968;79: 49–53. Brucker AJ, Spaide RF, Gross N, et al. Optical coherence tomography of X-linked retinoschisis. Retina 2004;24:151–2. Yu J, Ni Y, Keane PA, et al. Foveomacular schisis in juvenile X-linked retinoschisis: an optical coherence tomography study. Am J Ophthalmol 2010;149:973–8.
47. Kahook MY, Noecker RJ, Ishikawa H, et al. Peripapillary schisis in glaucoma patients with narrow angles and increased intraocular pressure. Am J Ophthalmol 2007;143:697–9. 48. Garg SJ, Lee HC, Grand MG. Bilateral macular detachments in X-linked retinoschisis. Arch Ophthalmol 2006;124:1053–5. 49. Wexler A, Sand T, Elsas TB. Macular thickness measurements in healthy Norwegian volunteers: an optical coherence tomography study. BMC Ophthalmol [serial online] 2010;10:13. Available at: http://www.biomedcentral.com/1471-2415/ 10/13. Accessed January 5, 2014.
Footnotes and Financial Disclosures Originally received: July 31, 2013. Final revision: February 1, 2014. Accepted: February 4, 2014. Available online: ---.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2013-1259.
1
Retina Consultants of Michigan, Southfield, Michigan.
2
Vitreous-Retina-Macula Consultants of New York, New York.
3
Department of Ophthalmology, Henry Ford Health Systems, Detroit, Michigan.
4
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
5
Retinal Specialists of Michigan, Grand Rapids, Michigan.
6
Kellogg Eye Institute, University of Michigan, Ann Arbor, Michigan.
7
Rush University, Chicago, Illinois.
8
Supported in part by The Macula Foundation, Inc, and The CONNECT Network, Inc. Abbreviations and Acronyms: CXLR ¼ congenital juvenile X-linked retinoschisis; FA ¼ fluorescein angiography; OCT ¼ optical coherence tomography; OPL ¼ outer plexiform layer; RPE ¼ retinal pigment epithelium; SNIFR ¼ stellate nonhereditary idiopathic foveomacular retinoschisis. Correspondence: Michael D. Ober, MD, 29201 Telegraph Road, Southfield, MI 48034. E-mail: [email protected].
Stellate foveal retinoschisis is most commonly associated with congenital juvenile X-linked retinoschisis (CXLR) due to a defect in the RS1 gene. Foveal retinoschisis is found in nearly all cases of CXLR, with a variable number also developing peripheral retinoschisis. This disorder accounts for nearly all cases of congenital foveal retinoschisis. Given its inheritance pattern, the entity is almost exclusively found bilaterally in men.1 There are many other reported causes of macular retinoschisis aside from defects in the RS1 gene, including myopic degeneration,2e5 optic pit maculopathy,6e10 degenerative retinoschisis,11 glaucoma,12e14 myotonic dystrophy,15 enhanced S-cone syndrome,16e18 autosomal dominant retinoschisis,19 and vitreomacular traction,20 among others. Although the pathogenesis in each of these is multivariate, an underlying defect in retinal structural integrity is a commonality. We report 22 eyes from 16 female patients and 1 male patient with foveal retinoschisis without a known hereditary or acquired predisposition (Figs 1e6). The majority of these cases are unilateral, none have pertinent family history, and all those tested had negative results for known defects in the RS1 gene. For these reasons, we believe these cases represent a new category, which we have titled “stellate nonhereditary idiopathic foveomacular retinoschisis” (SNIFR). 2014 by the American Academy of Ophthalmology Published by Elsevier Inc.
Methods This is a review of the clinical histories and multimodal imaging for a series of patients found to have macular schisis without a known predisposing condition. This project was approved by the institutional review board at Henry Ford Health Systems. Inclusion criteria were the stellate appearance of the retina centered on the fovea noted on clinical examination with expansion of the outer plexiform layer (OPL) confirmed by optical coherence tomography (OCT). Exclusion criteria included a family history of macular retinoschisis, a known genetic abnormality associated with retinoschisis, myopic traction maculopathy, epiretinal membrane, vitreoretinal traction, optic or scleral pit, or glaucomatous optic nerve changes. All patients had undergone complete ocular examinations, including slit-lamp biomicroscopy, indirect ophthalmoscopy, and best-corrected Snellen visual acuity, refractive error, and intraocular pressure. Color photography, fluorescein angiography (FA), and OCT were reviewed for all patients. Genetic analyses for known mutations to the RS1 gene were performed in 8 of 16 patients available who consented to testing. Snellen visual acuities were converted to logarithm of the minimum angle of resolution visual acuities to calculate means.
Results The records of 22 eyes from 17 patients with foveomacular schisis were reviewed from 5 institutions. Fundus photography, OCT, and ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2014.02.002
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Figure 1. Images from the right eye of patient 1, a 36-year-old asymptomatic woman who has remained stable for >5 years: the proband for the series. A, Color fundus photograph demonstrating radial spoking around the fovea. B, Late fluorescein angiography (FA) image showing no leakage. C, Vertical optical coherence tomography (OCT) through the fovea.
FA were performed in all patients. Clinical findings are summarized in Table 1 (available at www.aaojournal.org). Twelve patients presented with monocular findings, and 5 patients had bilateral findings. Initial visual acuity was 20/50 or better in all eyes, but visual acuity in a single eye of 1 patient decreased from 20/20 to 20/200 after the development of subfoveal fluid. Mean visual acuity on presentation was 20/27 and decreased to 20/30 when the decreased vision in patient 5 was included. Twenty eyes were phakic, and 2 eyes were pseudophakic. The refractive status was myopic in 16 eyes, plano in 3 eyes, and hyperopic in 2 eyes. No eyes demonstrated features of vitreoretinal interface disorders or myopic traction maculopathy, such as epiretinal membrane, vitreomacular traction, staphyloma, chorioretinal thinning, or macular retinal pigment epithelium (RPE) atrophy. Three eyes had a preexisting vitreous separation, and 19 eyes had an attached posterior hyaloid. Follow-up ranged from 6 months to more than 5 years without significant change in examination findings. Genetic testing for the RS1 gene was performed on 8 patients (comprising 11 eyes) and revealed no known disease-causing mutations in any. None of the patients had a family history of CXLR or other hereditary maculopathy.
Discussion We present the largest known case series of eyes with SNIFR, the majority of which were asymptomatic or minimally symptomatic on presentation. Stellate foveomacular
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retinoschisis is classically associated with CXLR. This disorder has been mapped to Xp22.1-3 and codes for the retinoschisin,21 a complex, octamerizing protein implicated in cellecell interactions and adhesions. All affected individuals manifest foveal schisis with approximately half also developing peripheral schisis. Given the inheritance pattern, the phenotypic manifestations of this genetic disorder are almost exclusively found in male patients; however, affected female patients rarely have been reported. Women with homozygous mutations,22,23 XO (Turner syndrome),24 and carrier states25,26 have all been described. None of the patients in our series tested positive for a known mutation or had a positive family history for CXLR. Enhanced S-cone syndrome is an autosomal recessive disorder with foveomacular retinoschisis; however, it also characteristically demonstrates severe night blindness from childhood, complicated cataracts with an optically empty vitreous, and RPE pigmentary alterations. In general, the pattern of the macular and peripheral retinoschisis is more extensive than in our patients, and the severe visual disturbance also easily distinguishes this disorder from those we are describing.16e18 Optic disc pits can lead to macular schisis with fluid extending into a variety of inner and outer retinal layers.8e10
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Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis
Figure 2. Images from patient 8. A, Color fundus photograph of the right eye showing radial spoking around the fovea. B, Corresponding late fluorescein angiography (FA) image demonstrating no leakage. C, Horizontal optical coherence tomography (OCT) through the macula.
Spaide et al27 described a case similar to optic disc pit maculopathy with unilateral macular schisis and outer layer detachment in a male patient, but no optic disc or scleral pit. He postulated that vitreous fluid could be pumped into the schisis cavity via a valve-like fenestrated membrane, which opens and closes with the heart beateinduced physiologic pulsatile anatomic displacement of the disc. Glaucomatous optic nerve damage has been implicated in the pathogenesis of some cases of macular schisis. The thinning of the nerve fiber layer and optic disc cupping may lead to microholes and structural defects in the inner retinal layers around the optic disc, creating a pathway for fluid to enter a potential schisis cavity.12e14,28 Two eyes of 1 patient in our series showed schisis fluid extending into the optic nerve (Fig 3), suggesting the possibility that fluid emanated from the disc; however, no optic or scleral pits were found, and there was no history of glaucoma or glaucomatous optic nerve damage. The previously described fenestrated membrane27,29 noted in cases of optic disc pit maculopathy (with or without a pit) was not visible in either of the 2 eyes in our series, suggesting it likely represents a distinct disorder. Pathologic myopia also is well known to generate foveomacular retinoschisis secondary to anterior-posterior forces leading to myopic traction maculopathy.2e4,30,31 VanderBeek and Johnson31 described multiple causative
mechanisms, including vitreomacular traction after partial posterior vitreous detachment, remaining cortical vitreous after posterior vitreous detachment (vitreoschisis), epiretinal membrane, retinal arteriolar stiffness, and relatively poor internal limiting membrane compliance failing to configure to the staphyloma surface. These mechanisms yield obvious visible signs on spectral-domain OCT31e33 except for stiff internal limiting membrane; however, myopic traction maculopathy occurs in the setting of a myopic staphyloma that is discernible on examination or OCT. Improvement and resolution of myopic foveomacular retinoschisis after surgical reduction or elimination of traction forces lend further evidence to the underlying mechanisms.4,34e36 Our series does include myopic patients, but we carefully excluded eyes with evidence of myopic traction maculopathy. Niacin and taxane-derived medications cause cystoid spaces in the OPL and inner nuclear layer that do not leak during FA and closely resemble those from our patients.37e39 This is generally reversible with discontinuation of the medication. The mechanism is unclear; however, it indicates that factors other than traction alone can play a role in foveomacula schisis-like maculopathy in the absence of a known RS1 mutation. Several small case series and reports of foveomacular retinoschisis in female patients have been reported with various modes of inheritance. Shimazaki and Matsuhashi40
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Figure 3. Images from patient 6. A, Fundus autofluorescence photograph of the right eye showing slight radial hypofluorescence around the fovea corresponding to cortical spoking. B, Late fluorescein angiography (FA) image showing no leakage or staining. C, Horizontal optical coherence tomography (OCT) showing retinoschisis extending into the optic nerve.
reported a mother and daughter, each with bilateral findings of foveal schisis resembling CXLR. Both patients were myopic (spherical equivalent 6.25 and 3.75 in each eye of the daughter and mother, respectively) with peripheral abnormalities in each, including retinoschisis with confluent inner layer holes in the daughter and retinal tears with retinal detachment in the mother. Lewis et al41 described 3 sisters with bilateral foveal retinoschisis from nonconsanguineous, unaffected parents. All were mildly hyperopic (þ1.00) with visual acuity ranging from 20/30 to 20/50. One patient developed symptomatic metamorphopsia associated with a decrease in visual acuity from 20/25 to 20/50. Fluorescein angiography showed no leakage, but the symptomatic patient showed “the faintest hyperfluorescence,” suggesting an RPE abnormality. All patients were unable to perceive certain entopic phenomena that the authors suggest may imply a deficiency of macular xanthophyll or reduced sensitivity of foveal blue cones. There is striking similarity between the patients in these 2 case series and our patients. None of our patients had known relatives with foveomacular retinoschisis; however, examinations were not performed in the majority of family members. Given that the clinical findings on fundus examination were subtle in the
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majority of our series and most of the patients were asymptomatic or had minimal visual symptoms, affected relatives would not necessarily pursue ophthalmologic visits. It is possible a hereditary component was missed in our series. Three eyes of 2 patients in our series manifested bullous peripheral retinoschisis in addition to the typical foveomacular retinoschisis (Fig 4). Han et al11 described a 56-year-old woman with bilateral findings nearly identical to these, including symmetric inner retinal plication within 300 mm of the fovea and bullous peripheral retinoschisis. Fluorescein angiography showed faint transmission defects in the macula, but no leakage. One of their patient’s 4 daughters also demonstrated peripheral retinoschisis, but none had macular findings. Three additional eyes in our series showed subtle shallow peripheral schisis visible only with scleral depression. Dr Edward Cherney described a 60year-old woman in Gass’ Atlas of Macular Diseases with bilateral noneX-linked macular schisis, including OCT findings showing the findings were limited to the OPL.42 This case also would fit well into the case series we are presenting. Within the macula, all of the patients in our series showed splitting within the OPL with lesser involvement of
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Stellate Nonhereditary Idiopathic Foveomacular Retinoschisis
Figure 4. Images from patient 10. Red-free images of the right (A) and left (B) eyes, showing radial spoking around the fovea. Horizontal optical coherence tomography (OCT) images through the fovea of the right (C) and left (D) eyes demonstrating schisis predominantly in the outer plexiform layer (OPL). E, Montage OCT of the left eye showing increasing retinoschisis with multilayered involvement toward the periphery. N ¼ nasal; T ¼ temporal.
the outer nuclear layer. All peripheral areas where OCT imaging was possible (3 eyes of 2 patients) showed variable involvement of the inner plexiform layer (Fig 4). Histopathologic studies of eyes with CXLR suggested the retina split in superficial layers, including the nerve fiber layer and ganglion cell layer43,44; however, time-domain OCT revealed confluent schisis in the OPL with less involvement of the inner nuclear layer45 within the macula. Spectral-domain OCT revealed that the macular component most commonly involves the inner nuclear layer, with less common involvement of the outer plexiform, outer nuclear layers, and rarely the nerve fiber layer/ganglion cell layer.46 The OCT findings in enhanced S-cone syndrome show severe degeneration with a splitting just above the photoreceptor layer.17 Optic disc pit and
glaucoma-induced macular schisis showed fluid accumulation in a multitude of inner and outer retinal layers, including the nerve fiber layer, inner plexiform layer, and OPL.9,10,12e14,28,29,47 Niacin and taxane maculopathy also showed OPL and inner nuclear layer fluid accumulation. These findings suggest that the distinction between disorders is not possible on the basis of currently available OCT technology alone. One eye of 1 patient developed the accumulation of subfoveal fluid isolated to the macula associated with a significant decrease in visual acuity (Fig 5). This phenomenon is known to occur with other causes of macular retinoschisis, including myopic degeneration and CXLR.30,48 The cause of the strong female predominance in this series is unknown. Gender differences have been reported in
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Figure 5. Images from patient 5. Color fundus photograph of the right (A) and left (B) eyes. C, optical coherence tomography (OCT) through the right eye demonstrating extensive retinoschisis. D, OCT through the left eye showing retinoschisis with subretinal fluid in the fovea.
retinal thickness,49 which may play a role in structural susceptibility to SNIFR. An X-linked dominant genetic inheritance pattern cannot be ruled out; however, given its rarity and the lack of heritance in any of our subjects, it should be considered unlikely.
In conclusion, we present the largest known series of SNIFR. All patients demonstrated splitting of the OPL in the macula with relatively preserved visual acuity (20/40) except in a single patient in whom subretinal fluid developed under the fovea.
Figure 6. A, B, Images from patient 4. Color fundus (A) and infrared photographs (B) of the right eye showing radial spoking around the fovea. Optical coherence tomography (OCT) montage image of the right eye demonstrating retinoschisis extending from the central macula out temporally.
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47. Kahook MY, Noecker RJ, Ishikawa H, et al. Peripapillary schisis in glaucoma patients with narrow angles and increased intraocular pressure. Am J Ophthalmol 2007;143:697–9. 48. Garg SJ, Lee HC, Grand MG. Bilateral macular detachments in X-linked retinoschisis. Arch Ophthalmol 2006;124:1053–5. 49. Wexler A, Sand T, Elsas TB. Macular thickness measurements in healthy Norwegian volunteers: an optical coherence tomography study. BMC Ophthalmol [serial online] 2010;10:13. Available at: http://www.biomedcentral.com/1471-2415/ 10/13. Accessed January 5, 2014.
Footnotes and Financial Disclosures Originally received: July 31, 2013. Final revision: February 1, 2014. Accepted: February 4, 2014. Available online: ---.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2013-1259.
1
Retina Consultants of Michigan, Southfield, Michigan.
2
Vitreous-Retina-Macula Consultants of New York, New York.
3
Department of Ophthalmology, Henry Ford Health Systems, Detroit, Michigan.
4
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina.
5
Retinal Specialists of Michigan, Grand Rapids, Michigan.
6
Kellogg Eye Institute, University of Michigan, Ann Arbor, Michigan.
7
Rush University, Chicago, Illinois.
8
Supported in part by The Macula Foundation, Inc, and The CONNECT Network, Inc. Abbreviations and Acronyms: CXLR ¼ congenital juvenile X-linked retinoschisis; FA ¼ fluorescein angiography; OCT ¼ optical coherence tomography; OPL ¼ outer plexiform layer; RPE ¼ retinal pigment epithelium; SNIFR ¼ stellate nonhereditary idiopathic foveomacular retinoschisis. Correspondence: Michael D. Ober, MD, 29201 Telegraph Road, Southfield, MI 48034. E-mail: [email protected].
