Juvenile, or X-linked, retinoschisis (XLRS) is a relatively uncommon cause of macular degeneration in young men.1 This condition is caused by mutations in the RS1 gene, which encodes for the protein retinoschisin.1,2 The schisis, or splitting, typically occurs within the inner retinal layers, leading to visual deterioration. There is characteristically a spoke-wheel pattern of folds radiating from the fovea and peripheral bullous retinal elevations, usually in the inferotemporal quadrant.1,2 The clinical presentation of X-linked retinoschisis is greatly variable, even among patients with the same RS1 mutation.2 The mainstay of treatment in patients affected by X-linked retinoschisis is oral or topical carbonic anhydrase inhibitors (CAIs).1,3,4 These medications inhibit carbonic anhydrase in the retinal pigment epithelium, which is thought to lead to increased fluid outflow, subsequently improving retinal function.1 The purpose of this report is to describe a paradoxical anatomic response after initiation of a topical CAI in XLRS.
An 11-year-old male presented with 6 months of gradual progressive vision blurring in both eyes. His medical history was significant for asthma, migraine headaches, and attention-deficit disorder. Corrected visual acuity was 20/80 in each eye. Slit-lamp biomicroscopy revealed radiating inner retinal striae in the macula peripheral elevated diaphanous retina inferiorly with a few inner holes in each eye. Electrophysiologic testing was refused, but the diagnosis of X-linked retinoschisis was made based on classic clinical features. The patient was started on topical dorzolamide (Trusopt; Santen Pharmaceutical, Osaka, Japan) 2% in each eye three times a day, and at follow-up 3 months later, the cystic macular changes had worsened significantly (Figure). It should be noted that the vision remained stable at 20/60 in each eye. Due to the anatomic response, the medication was stopped and 3 months later the anatomy had returned to baseline. The vision remained stable at 20/70 in the right eye and 20/60 in the left eye and the mild macular schisis persisted 1 year after initial presentation.
Spectral-domain optical coherence tomography of the right and left eyes at presentation (A, B), 3 months after starting topical dorzolamide (C, D), and 3 months after medication cessation (E, F).
Juvenile XLRS is a relatively uncommon disease, affecting approximately 5% of all children with inherited retinal dystrophies and has a prevalence of one in 5,000 to one in 20,000.2 It is the most common cause of juvenile-onset macular degeneration among males.1 Young boys often present with bilateral reduced visual acuity, but the disease usually shows only mild progression.2 Spectral-domain optical coherence tomography (SD-OCT) of the macula, which is now the major diagnostic technique for this disease, can reveal schisis of various retinal layers from the nerve fiber layer to the nuclear layer.2
During the past decade, oral and topical CAIs have been shown to decrease the macular cystic changes and improve vision in some patients with XLRS. Two studies found a reduction in the macular cystic changes occurred in 55% to 66% of cases.3,4 Similarly, visual acuity improves in approximately half of eyes started on CAIs, although there appears to be significant heterogeneity in the response to treatment.1,2 A recent retrospective study of 68 eyes with XLRS by Andreuzzi et al. found that only 4% of eyes anatomically worsened after the initiation of treatment with CAIs.3 The worsening of the macular schisis in our patient was significant, although it should be noted that visual acuity was not compromised.
The mechanism of action for CAIs to improve retinal schisis and cystoid macular edema is unclear. Marmor and Maack experimentally showed that intravenous acetazolamide favorably altered the retinal adhesion and subretinal fluid absorption in a rabbit retinal detachment model.5 Others have suggested that CAIs cause localized changes in acid-base balance and the acidification of the subretinal space increases retinal adhesiveness.6 Even though our patient declined genetic testing, we hypothesize that a specific mutation in the RS1 gene may have may have yielded a retinoschisin protein that is more easily denatured in an acidic environment, subsequently leading to decreased structural integrity of the retina. Alternatively, Thobani and Fishman theorized that the increase in retinal pigment epithelial transport induced by the addition of a CAI may cause significant stress and eventual cellular dysfunction.7 The improvement of retinal cysts following cessation of the drug, after allowing for the recovery of RPE, would seem to promote such a hypothesis. Two studies on XLRS have suggested that the response to treatment is independent of the genotype of the disease, but it should be noted that these studies were relatively small.8,9
Carbonic anhydrase inhibitors are the most established and widely therapy for cystoid macular edema in inherited retinal diseases, including XLRS and retinitis pigmentosa.3,4,10 The anatomic worsening in our patient was dramatic, but the macula returned to baseline within 3 months of medication cessation. Fortunately, there did not appear to be any lasting effects on vision function. The paradoxical response after treatment with CAIs in our patient supports continual and judicious follow up with SD-OCT imaging of patients with XLRS, particularly those being treated with CAIs.
- Gurbaxani A, Wei M, Succar T, McCluskey PJ, Jamieson RV, Grigg JR. Acetazolamide in retinoschisis: A prospective study. Ophthalmology. 2014;121802–803.e3. doi:10.1016/j.ophtha.2013.10.025 [CrossRef]
- Molday RS, Kellner U, Weber BHF. X-linked juvenile retinoschisis: clinical diagnosis, genetic analysis, and molecular mechanisms. Prog Retin Eye Res. 2012;31(3):195–212. doi:10.1016/j.preteyeres.2011.12.002 [CrossRef]
- 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(8):1555–1561. doi:10.1097/IAE.0000000000001379 [CrossRef]
- 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 retinoschisis. Invest Ophthalmol Vis Sci. 2016;57(13):5143–5147. doi:10.1167/iovs.16-20078 [CrossRef]
- Marmor MF, Maack T. Enhancement of retinal adhesion and subretinal fluid resorption by acetazolamide. Invest Oph Vis Sci. 1982;23(1):121–124.
- Wolfensberger TJ. The role of carbonic anhydrase inhibitors in the management of macular edema. Doc Ophthalmol. 1999;97(3–4):387–397. doi:10.1023/A:1017297314386 [CrossRef]
- 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(2):312–315. doi:10.1097/IAE.0b013e3181e587f9 [CrossRef]
- 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.e1. doi:10.1016/j.ajo.2008.07.041 [CrossRef]
- Khandhadia S, Trump D, Menon G, Lotery AJ. X-linked retinoschisis maculopathy treated with topical dorzolamide, and relationship to genotype. Eye (Lond). 2011;25(7):922–928. doi:10.1038/eye.2011.91 [CrossRef]
- Huckfeldt RM, Comander J. Management of cystoid macular edema in retinitis pigmentosa. Semin Ophthalmol. 2017;32(1):43–51. doi:10.1080/08820538.2016.1228404 [CrossRef]