Prospective Evaluation of Patients With X-Linked Retinoschisis During 18 Months

Mark E Pennesi, David G Birch, K Thiran Jayasundera, Maria Parker, Ou Tan, Rabia Gurses-Ozden, Carrie Reichley, Kathleen N Beasley, Paul Yang, Richard G Weleber, Lea D Bennett, John R Heckenlively, Kalyani Kothapalli, Jeffrey D Chulay, For The Xlrs-Study Group, Mark E Pennesi, David G Birch, K Thiran Jayasundera, Maria Parker, Ou Tan, Rabia Gurses-Ozden, Carrie Reichley, Kathleen N Beasley, Paul Yang, Richard G Weleber, Lea D Bennett, John R Heckenlively, Kalyani Kothapalli, Jeffrey D Chulay, For The Xlrs-Study Group

Abstract

Purpose: Prospective evaluation of patients with X-linked retinoschisis (XLRS).

Methods: Fifty-six males XLRS patients, age ≥7 years, had retinal structure and function tests performed every 6 months during an 18-month period.

Results: Best corrected visual acuity (BCVA) was abnormal (mean ± SD logMAR 0.57 ± 0.32 OD and 0.50 ± 0.27 OS), with weak correlation between visual acuity and age (R = -0.24, P = 0.0095). Mean cyst cavity volume (CCV) determined on optical coherence tomography showed weak correlation with age (R = -0.33, P = 0.0009) and no correlation with visual acuity. Subjects had modest reduction in mean kinetic and static perimetry results, reduced b-wave amplitude on electroretinography, abnormal reading speed results, and decreased visual function quality of life scores. Contrast sensitivity results were normal in 85 of 99 eyes tested. Most subjects had no meaningful change in BCVA during follow-up. Subjects who started carbonic anhydrase inhibitor (CAI) treatment at enrollment had improved BCVA (mean ± SD change 3.15 ± 7.8 ETDRS letters, with increase of ≥15 ETDRS letters at 8 of 110 visits [in 3 subjects]). There were no significant changes in other parameters tested.

Conclusions: Structural and functional results were stable during the 18-month follow-up period. Some patients starting CAI treatment at the baseline visit showed improvement in BCVA that was not correlated with changes in CCV. Natural history data such as these will be important for comparisons to the changes in measures of retinal structure and function following gene replacement therapy in patients with XLRS.

Trial registration: ClinicalTrials.gov NCT02331173.

Figures

Figure 1
Figure 1
Calculation of total cyst cavity volume (CCV) by ocular coherence tomography. For each of 97 sequential b-scans across the 20-degree OCT volume scan, a custom software program identified and outlined each schisis cavity. An experienced reader manually corrected each scan to eliminate artifacts, and the total cyst cavity area for each scan was summed across all 97 scans to calculate the total CCV.
Figure 2
Figure 2
Correlation of visual acuity with age at baseline. There was a weak correlation between visual acuity and age that was statistically significant for the left eye (OS) but not the right eye (OD).
Figure 3
Figure 3
Changes from baseline best corrected visual acuity (ETDRS letter score) at study month 1, 3, 6, 12, or 18. Subjects are arranged from left to right within each group, with the value for right eye plotted first and the value for left eye plotted second. Subjects who did not have a study visit at a given time point are indicated by an X.
Figure 4
Figure 4
Correlation of retinal cyst cavity volume (CCV) with age and visual acuity at baseline. There was a significant correlation between CCV and age but no significant correlation between CCV and visual acuity.
Figure 5
Figure 5
Changes from baseline cyst cavity volume (mm3) at study month 1, 3, 6, 12, or 18. Subjects are arranged from left to right within each group, with the value for right eye plotted first and the value for left eye plotted second. Subjects who did not have a study visit at a given time point are indicated by an X. * = Eyes with no baseline value. ‡ = Time points when OCT images were not of sufficient quality to allow CCV to be calculated. Values for one subject with CCV decreases of more than 4 mm3 are listed.
Figure 6
Figure 6
Correlation of changes in visual acuity and cyst cavity volume at study months 6, 12, and 18.
Figure 7
Figure 7
ERG parameters vs. age for different types of RS1 variants. Dark-adapted 3.0 a-wave, b-wave and b/a ratio data for 78 subjects with missense variants (circles) and 22 subjects with other variants (nonsense, splice site or exon deletion; diamonds). Summary statistics are provided in the table below the figure.
Figure 8
Figure 8
Comparison of MNREAD results in XLRS subjects with published results for normal subjects. The solid line represents mean values and the dashed line represents the 95% confidence interval estimated by bi- or trilinear regression modeling as described by Calebrèse et al. Open circles are results in XLRS subjects.

References

    1. Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res. 2012;31:195–212.
    1. Rudanko SL, Flage T, Hansen E, Rosenberg T, Viggosson G, Riise R. Visual impairment in Nordic children. V. X-linked juvenile retinoschisis. Acta Ophthalmol (Copenh) 1993;71:586–589.
    1. Apushkin MA, Fishman GA, Rajagopalan AS. Fundus findings and longitudinal study of visual acuity loss in patients with X-linked retinoschisis. Retina. 2005;25:612–618.
    1. Forsius H, Krause U, Helve J, et al. Visual acuity in 183 cases of X-chromosomal retinoschisis. Can J Ophthalmol. 1973;8:385–393.
    1. George ND, Yates JR, Moore AT. Clinical features in affected males with X-linked retinoschisis. Arch Ophthalmol. 1996;114:274–280.
    1. Pimenides D, George ND, Yates JR, et al. X-linked retinoschisis: clinical phenotype and RS1 genotype in 86 UK patients. J Med Genet. 2005;42:e35.
    1. Sieving PA, MacDonald IM, Chan S. X-linked juvenile retinoschisis. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. Gene Reviews [Internet] Seattle: University of Washington; 2004. Available at: .
    1. Tantri A, Vrabec TR, Cu-Unjieng A, Frost A, Annesley WH, Jr,, Donoso LA. X-linked retinoschisis: a clinical and molecular genetic review. Surv Ophthalmol. 2004;49:214–230.
    1. Kim LS, Seiple W, Fishman GA, Szlyk JP. Multifocal ERG findings in carriers of X-linked retinoschisis. Doc Ophthalmol. 2007;114:21–26.
    1. Zeng Y, Takada Y, Kjellstrom S, et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci. 2004;45:3279–3285.
    1. Min SH, Molday LL, Seeliger MW, et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Mol Ther. 2005;12:644–651.
    1. Kjellstrom S, Bush RA, Zeng Y, Takada Y, Sieving PA. Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration. Invest Ophthalmol Vis Sci. 2007;48:3837–3845.
    1. Janssen A, Min SH, Molday LL, et al. Effect of late-stage therapy on disease progression in AAV-mediated rescue of photoreceptor cells in the retinoschisin-deficient mouse. Mol Ther. 2008;16:1010–1017.
    1. Takada Y, Vijayasarathy C, Zeng Y, Kjellstrom S, Bush RA, Sieving PA. Synaptic pathology in retinoschisis knockout (Rs1-/y) mouse retina and modification by rAAV-Rs1 gene delivery. Invest Ophthalmol Vis Sci. 2008;49:3677–3686.
    1. Park TK, Wu Z, Kjellstrom S, et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther. 2009;16:916–926.
    1. Byrne LC, Ozturk BE, Lee T, et al. Retinoschisin gene therapy in photoreceptors, Muller glia or all retinal cells in the Rs1h-/- mouse. Gene Ther. 2014;21:585–592.
    1. Apushkin MA, Fishman GA. Use of dorzolamide for patients with X-linked retinoschisis. Retina. 2006;26:741–745.
    1. Ghajarnia M, Gorin MB. Acetazolamide in the treatment of X-linked retinoschisis maculopathy. Arch Ophthalmol. 2007;125:571–573.
    1. Bastos AL, Freitas Bde P, Villas Boas O, Ramiro AC. Use of topical dorzolamide for patients with X-linked juvenile retinoschisis: case report. Arq Bras Oftalmol. 2008;71:286–290.
    1. Walia S, Fishman GA, Molday RS, et al. Relation of response to treatment with dorzolamide in X-linked retinoschisis to the mechanism of functional loss in retinoschisin. Am J Ophthalmol. 2009;147:111–115.
    1. Genead MA, Fishman GA, Walia S. Efficacy of sustained topical dorzolamide therapy for cystic macular lesions in patients with X-linked retinoschisis. Arch Ophthalmol. 2010;128:190–197.
    1. Khandhadia S, Trump D, Menon G, Lotery AJ. X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype. Eye (Lond) 2011;25:922–928.
    1. Thobani A, Fishman GA. The use of carbonic anhydrase inhibitors in the retreatment of cystic macular lesions in retinitis pigmentosa and X-linked retinoschisis. Retina. 2011;31:312–315.
    1. Ali S, Seth R. X-linked juvenile retinoschisis in females and response to carbonic anhydrase inhibitors: case report and review of the literature. Semin Ophthalmol. 2013;28:50–54.
    1. Gurbaxani A, Wei M, Succar T, McCluskey PJ, Jamieson RV, Grigg JR. Acetazolamide in retinoschisis: a prospective study. Ophthalmology. 2014;121:802–803.e3.
    1. Collison FT, Genead MA, Fishman GA, Stone EM. Resolution of mid-peripheral schisis in X-linked retinoschisis with the use of dorzolamide. Ophthalmic Genet. 2014;35:125–127.
    1. Rocha Cabrera P, Pareja Rios AC, Cordoves Dorta L, Mantolan Sarmiento C, Serrano Garcia MA. A combination of topical and systemic carbonic anhydrase in the treatment of chromosome X-linked retinoschisis. Arch Soc Esp Oftalmol. 2014;89:320–323.
    1. Zhang L, Reyes R, Lee W, et al. Rapid resolution of retinoschisis with acetazolamide. Doc Ophthalmol. 2015;131:63–70.
    1. Verbakel SK, van de Ven JP, Le Blanc LM, et al. Carbonic anhydrase inhibitors for the treatment of cystic macular lesions in children with X-linked juvenile retinoschisis. Invest Ophthalmol Vis Sci. 2016;57:5143–5147.
    1. Sadaka A, Sisk RA. Dramatic regression of macular and peripheral retinoschisis with dorzolamide 2% in X-linked retinoschisis: a case report. J Med Case Rep. 2016;10:142.
    1. Collison FT, Fishman GA. Structural and functional monitoring of extramacular cystoid spaces in a case of X-linked retinoschisis treated with acetazolamide. Retin Cases Brief Rep. 2018;12:318–321.
    1. Andreuzzi P, Fishman GA, Anderson RJ. Use of a carbonic anhydrase inhibitor in X-linked retinoschisis: effect on cystic-appearing macular lesions and visual acuity. Retina. 2017;37:1555–1561.
    1. Coussa RG, Kapusta MA. Treatment of cystic cavities in X-linked juvenile retinoschisis: the first sequential cross-over treatment regimen with dorzolamide. Am J Ophthalmol Case Rep. 2017;8:1–3.
    1. Menke B, Walters A, Payne JF. Paradoxical anatomic response to topical carbonic anhydrase inhibitor in X-linked retinoschisis. Ophthalmic Surg Lasers Imaging Retina. 2018;49:142–144.
    1. Beck RW, Moke PS, Turpin AH, et al. A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol. Am J Ophthalmol. 2003;135:194–205.
    1. Bressler NM, Bressler SB, Hawkins BS, Marsh MJ, Sternberg P, Jr,, Thomas MA. Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1. Am J Ophthalmol. 2000;130:387–407.
    1. Ferris FL, III,, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol. 1982;94:91–96.
    1. Grobbel J, Dietzsch J, Johnson CA, et al. Normal values for the full visual field, corrected for age- and reaction time, using semiautomated kinetic testing on the Octopus 900 perimeter. Trans Vis Sci Tech. 2016;5(2):5.
    1. Schiefer U, Pascual JP, Edmunds B, et al. Comparison of the new perimetric GATE strategy with conventional full-threshold and SITA standard strategies. Invest Ophthalmol Vis Sci. 2009;50:488–494.
    1. Marmor MF, Fulton AB, Holder GE, Miyake Y, Brigell M, Bach M. ISCEV. Standard for full-field clinical electroretinography (2008 update) Doc Ophthalmol. 2009;118:69–77.
    1. Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD. Development of the 25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001;119:1050–1058.
    1. Chan TF, Vese LA. Active contours without edges. IEEE Trans Image Process. 2001;10:266–277.
    1. Chiu SJ, Li XT, Nicholas P, Toth CA, Izatt JA, Farsiu S. Automatic segmentation of seven retinal layers in SDOCT images congruent with expert manual segmentation. Opt Express. 2010;18:19413–19428.
    1. Schiefer U, Patzold J, Dannheim F. Conventional perimetry I: introduction – basics [in German] Ophthalmologe. 2005;102:627–644. quiz, 645–626.
    1. Weleber RG, Smith TB, Peters D, et al. VFMA: topographic analysis of sensitivity data from full-field static perimetry. Trans Vis Sci Tech. 2015;4(2):14.
    1. Patel PJ, Chen FK, Da Cruz L, Rubin GS, Tufail A. Test-retest variability of reading performance metrics using MNREAD in patients with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52:3854–3859.
    1. Calabrese A, Owsley C, McGwin G, Legge GE. Development of a Reading Accessibility Index using the MNREAD Acuity Chart. JAMA Ophthalmol. 2016;134:398–405.
    1. Mangione CM. NEI VFQ-25 scoring algorithm. 2000 Available at: . Accessed November 19, 2018.
    1. Calebrèse A, Cheong AM, Cheung SH, et al. Baseline MNREAD measures for normally sighted subjects from childhood to old age. Invest Ophthalmol Vis Sci. 2016;57:3836–3843.
    1. Apushkin MA, Fishman GA, Janowicz MJ. Correlation of optical coherence tomography findings with visual acuity and macular lesions in patients with X-linked retinoschisis. Ophthalmology. 2005;112:495–501.
    1. Jeffrey BG, Cukras CA, Vitale S, Turriff A, Bowles K, Sieving PA. Test-retest intervisit variability of functional and structural parameters in X-linked retinoschisis. Trans Vis Sci Tech. 2014;3(5):5.
    1. Bennett LD, Wang YZ, Klein M, Pennesi ME, Jayasundera T, Birch DG. Structure/psychophysical relationships in X-linked retinoschisis. Invest Ophthalmol Vis Sci. 2016;57:332–337.
    1. Huang Q, Chen R, Lin X, Xiang Z. Efficacy of carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa: a meta-analysis. PLoS One. 2017;12:e0186180.
    1. Bakthavatchalam M, Lai FHP, Rong SS, Ng DS, Brelen ME. Treatment of cystoid macular edema secondary to retinitis pigmentosa: a systematic review. Surv Ophthalmol. 2018;63:329–339.
    1. Kjellström S, Vijayasarathy C, Ponjavic V, Sieving PA, Andreasson S. Long-term 12 year follow-up of X-linked congenital retinoschisis. Ophthalmic Genet. 2010;31:114–125.
    1. Duncan JL, Ratnam K, Birch DG, et al. Abnormal cone structure in foveal schisis cavities in X-linked retinoschisis from mutations in exon 6 of the RS1 gene. Invest Ophthalmol Vis Sci. 2011;52:9614–9623.
    1. Bowles K, Cukras C, Turriff A, et al. X-linked retinoschisis: RS1 mutation severity and age affect the ERG phenotype in a cohort of 68 affected male subjects. Invest Ophthalmol Vis Sci. 2011;52:9250–9256.
    1. Eksandh LC, Ponjavic V, Ayyagari R, et al. Phenotypic expression of juvenile X-linked retinoschisis in Swedish families with different mutations in the XLRS1 gene. Arch Ophthalmol. 2000;118:1098–1104.
    1. Renner AB, Kellner U, Fiebig B, Cropp E, Foerster MH, Weber BH. ERG variability in X-linked congenital retinoschisis patients with mutations in the RS1 gene and the diagnostic importance of fundus autofluorescence and OCT. Doc Ophthalmol. 2008;116:97–109.
    1. Alexander KR, Rajagopalan AS, Seiple W, Zemon VM, Fishman GA. Contrast response properties of magnocellular and parvocellular pathways in retinitis pigmentosa assessed by the visual evoked potential. Invest Ophthalmol Vis Sci. 2005;46:2967–2973.
    1. Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthalmology. 2016;123:1606–1620.
    1. Parvaresh MM, Ghiasian L, Ghasemi Falavarjani K, Soltan Sanjari M, Sadighi N. Normal values of standard full field electroretinography in an Iranian population. J Ophthalmic Vis Res. 2009;4:97–101.
    1. Ponjavic V, Andreasson S, Ehinger B. Full-field electroretinograms in patients with central areolar choroidal dystrophy. Acta Ophthalmol (Copenh) 1994;72:537–544.
    1. Heckenlively JR, Arden GB. Principles and Practice of Clinical Electrophysiology of Vision 2nd ed. Cambridge, MA: MIT Press;; 2006.

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