Topical brinzolamide for foveal schisis in juvenileretinoschisisFrancine P. Yang, MBBS,a Katharina Willyasti, MD,b and Seo Wei Leo, MBBS, FRCSEda,c

We describe a case series of 4 consecutive patients diagnosed withX-linked retinoschisis seen at a pediatric ophthalmology clinic dur-ing a 3-year period. All patients were treated with topical brinzola-mide; 3 patients experienced significantly decreased severity ofmacular cysts on OCT in at least one eye.

The medical records of 4 consecutive patients (allmales) seen at Tan Tock Seng Hospital between2008 and 2011 with a clinical diagnosis of

X-linked retinoschisis (XLRS) were reviewed. The diagno-sis was based on a combination of family history, decreasedvisual acuity, characteristic macula and peripheral fundusfindings, and an electronegative/borderline electronegativeelectroretinogram. Genetic testing was not performed.Bilateral cystic maculopathy was confirmed in all 4 patientsby optical coherence tomography (OCT: Stratus OCT 3;Carl-Zeiss Meditec, Dublin, CA). Central foveal thicknesswas computed as the mean thickness at the point of inter-section of 6 radial scans. Patients were prescribed topicalbrinzolamide 1% 3 times daily to each eye. Visual acuityand OCT measurements before and after treatment werecompared. On the basis of published data on the intervisitvariability in foveal thickness of untreated patients withXLRS, a change of.19.6% from pretreatment was consid-ered significant.1

Cases 1 and 2

Two brothers presented for evaluation of poor visual ac-uity. Family history was remarkable for a maternal unclewith poor vision who was later determined to have bilateralretinoschisis. Patient 1 was a 4-year-old boy with best-corrected visual acuity of 20/400 in the right eye and20/100 in the left eye; patient 2, a 7-year-old boy withbest-corrected visual acuity of 20/50 in each eye. Anteriorsegment examination of patient 1 revealed a normal left eyebut a posterior subcapsular cataract in the right eye.Dilated fundus examination showed bilateral inferior reti-noschisis (Figure 1A and B), with no retinal detachment.

Author affiliations: aDepartment of Ophthalmology, Tan Tock Seng Hospital, Singapore;bNetra Eye Clinic, Bandung, Indonesia; cDr Leo Adult & Paediatric Eye Specialist Pte Ltd,SingaporeSubmitted July 13, 2012.Revision accepted November 30, 2012.Published online April 1, 2013.Correspondence: Francine Peilin Yang,MBBS, Department of Ophthalmology, Tan Tock

Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433 Singapore (email:Francine_Yang@ttsh.com.sg).J AAPOS 2013;17:225-227.Copyright � 2013 by the American Association for Pediatric Ophthalmology and

Strabismus.1091-8531/$36.00http://dx.doi.org/10.1016/j.jaapos.2012.11.016

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Retinal pigment epithelial mottling and cystic changeswere noted over both maculae. OCT confirmed the pres-ence of bilateral foveal schisis (Figure 1C). The anteriorsegment examination of patient 2 was unremarkable, andthe findings of a dilated fundus examination revealeda spoke-wheel pattern of folds radiating from the foveabilaterally, with no peripheral retinoschisis. OCT showedbilateral foveal schisis, and the electroretinogram wasborderline electronegative.

The right cataract of patient 1 was deemed visuallysignificant, and cataract extraction with intraocular lensimplantation was performed. Amblyopia therapy followed,but visual acuity remained unchanged after treatment.

Cases 3 and 4

Two brothers presented for evaluation of poor visual acuityat 7 and 10 years of age. In patient 3, best-corrected visualacuity was 20/40 in each eye; in patient 4, 20/60 in eacheye. There was no family history of retinal diseases or visualimpairment. Dilated fundus examination of both childrenshowed a spoke-wheel appearanceof themaculae bilaterally,with the absence of peripheral retinoschisis. OCT showedbilateral foveal schisis and electroretinography demon-strated a characteristic electronegative electroretinogram.

Results

Patients 1 and2were followedup for 24months and theother2 patients for 6 months (Figure 2). After treatment with top-ical brinzolamide, patients 1, 2, and4 showed a significant de-crease in the severityofmacularcystsonOCT(Figure1CandD) in at least one eye. Reduction in foveal thickness rangedfrom 72 to 209 mm (21%-33%) (Table 1). Patient 4 showedbilateral improvement, patients 1 and 2 experienced unilat-eral improvement, with no response in the fellow eye. Patient3 showed no response bilaterally. Eyes with no responseshowed change in foveal thickness after treatment rangingfrom a reduction of 11% to an increase of 19% that werewithin the defined limits of intervisit variability. There wasno difference in visual acuity before and after treatment,and no adverse drug effects were reported.

Discussion

XLRS is one of the most common causes of juvenile macu-lar degeneration in males. Foveal schisis is a characteristicfeature, present in 98% to 100% of cases; approximatelyhalf have peripheral retinoschisis.2 As the diseaseprogresses, coalescence of the macular cysts occurs,with flattening of the foveal schisis cavity and atrophic

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FIG 1. Fundus photographs and OCT of patient 1. A, Fundus photograph of the right eye showing inferior retinoschisis. B, Fundus photograph of theleft eye showing inferior and infero-temporal retinoschisis. C, OCT of the right eye showing foveal schisis. D, OCT of the right eye after treatment,which shows a reduction in foveal cysts.

FIG 2. Change in central foveal thickness on follow-up. A, Patients 1and 2 at 24 months’ follow-up. B, Patients 3 and 4 at 6 months’follow-up. OD, right eye; OS, left eye.

226 Yang, Willyasti, and Leo Volume 17 Number 2 / April 2013

maculopathy.3,4 Best-corrected visual acuity in childrenwith XLRS ranges from 20/20 to 20/600.3 In the absenceof complications, visual acuity is often stable until thefourth and fifth decades of life, when deterioration occursdue to macular atrophy.3 Although there are no establishedtherapeutic interventions known to halt disease progres-sion, it has been postulated that reduction of foveal cystsand preservation of the retinal architecture from an earlystage might prevent or reduce the rate of visual decline.1,5

XLRS is caused by a mutation of the RS1 gene that codesfor retinoschisin. Retinoschisin promotes cell adhesion anddysfunction leads to the formation of cystic cavities in theinner nuclear and outer plexiform layers of the retina.5

The clinical effects of carbonic anhydrase inhibitors arepresumed to be attributed to their ability to facilitate fluidtransport across the retinal pigment epithelium, decreasingthe volume of the subretinal space and increasing retinaladhesiveness.6

Apushkin and Fishman1 demonstrated a reduction infoveal thickness in 7 of 8 patients treated with 2% topicaldorzolamide in adults with XLRS, with 5 patients showingan improvement in visual acuity. Response to dorzolamidewas independent of the mutation responsible for retino-schisin protein dysfunction.5 Studies involving the pediat-ric population are limited. A single case report on the useof oral acetazolamide in an 8-year-old boy with XLRSdemonstrated a near-complete resolution of macularedema, with an improvement in visual acuity, but edemarecurred on cessation of treatment.7 Given the potential re-quirement for long-term treatment, the utility of

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Table 1. Comparison of central foveal thickness and visual acuity before and after treatment with topical brinzolamide

Patient Treatment duration, months

Central foveal thickness Best-corrected visual acuity

Before treatment, mm After treatment, mm Differencea Before treatment After treatment

OD OS OD OS OD OS OD OS OD OS

1 24 639 432 430 515 �33% 119% 20/400 20/100 20/400 20/1002 24 340 348 304 276 �11% �21% 20/50 20/50 20/50 20/603 6 293 287 340 304 116% 16% 20/40 20/40 20/50 20/304 6 560 408 425 313 �24% �23% 20/60 20/60 20/70 20/70

OD, right eye; OS, left eye.aPositive percentage difference represents an increase in central foveal thickness after treatment; negative, a decrease.

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acetazolamide may be limited by potential systemic side ef-fects, and a topical medication would be preferable. In ourcase series, topical brinzolamide achieved a favorable out-come in the reduction of macular cysts, with no reportedadverse drug effects. Although this result seems encourag-ing, longer follow-up is still required to determine whetherthis will indeed translate into the desired effect of slowingvisual decline in these patients.

References

1. Apushkin MA, Fishman GA. Use of dorzolamide for patients withX-linked retinoschisis. Retina 2006;26:741-5.

2. Sikkink SK, Biswas S, Parry NRA, Stanga PE, Trump D. X-linkedretinoschisis: An update. J Med Genet 2007;44:225-32.

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3. George ND, Yates JR, Moore AT. Clinical features in affectedmales with X-linked retinoschisis. Arch Ophthalmol 1996;114:274-80.

4. Roesch MT, Ewing CC, Gibson AE, Weber BH. The naturalhistory of X-linked retinoschisis. Can J Ophthalmol 1998;33:149-58.

5. Walia S, Fishman GA, Molday RS. Relation of response to treat-ment with dorzolamide in X-linked retinoschisis to the mechanismof functional loss in retinoschisin. Am J Ophthalmol 2009;147:111-15.

6. Wolfensberger TJ. The role of carbonic anhydrase inhibitors inthe management of macular edema. Doc Ophthalmol 1999;97:236-38.

7. Ghajarnia M, Gorin MB. Acetazolamide in the treatment ofX-linked retinoschisis maculopathy. Arch Ophthalmol 2007;125:571-3.