X-linked retinoschisis (XLRS), also known as congenital or juvenile XLRS, is an inherited retinal disease found in approximately 1:10,000 males (1) caused by variants in retinochisin (RS1) (2). RS1 plays an important function in retinal bipolar and photoreceptor cell adhesion and signal transduction (3). Macular retinoschisis, observed in 99% of XLRS patients, reduces visual acuity in childhood until cystic cavities collapse and macular atrophy develops at a mean age of 25 years (4). Recent swept-source optical coherence tomography angiography demonstrates pathologic loss of flow in the deep capillary plexus accompany advancing macular schisis and atrophy (5). Peripheral retinoschisis is present in 50% of XLRS patients (5), favors the inferotemporal quadrant, and is associated with rhegmatogenous retinal detachment (RD) in 10–22% of patients (6).

Currently, limited treatment options are available to prevent macular atrophy and RD in XLRS patients. While gene therapy appears promising for other inherited retinal diseases, initial Phase I/II intravitreal gene therapy clinical trials (NCT02416622) failed to reduce retinoschisis or demonstrate improved outcomes compared to the natural history of disease (7). Several other gene-based trials for XLRS are ongoing (NCT05878860, NCT02317887, NCT05814952). In several small case series, both oral acetazolamide and topical dorzolamide have been found to reduce foveal schisis and improve vision (8–21). The purpose of this study is to investigate whether carbonic anhydrase inhibitors (CAIs) reduce the incidence of complications from XLRS, including macular atrophy, retinal tears, and retinal detachment (RD).

Without intervention, vision loss is inevitable in patients with XLRS from macular atrophy or retinal detachment, although the severity and timing of vision loss varies among patients (4). No patient developed these complications while using CAIs, which is notable considering the relatively large cohort size, long follow-up period, and variable patient adherence during the study period. Our series confirmed findings from other studies that CAIs reduce macular schisis (8–21) and possibly peripheral schisis (17). Some case studies report improved VA while on CAIs (9, 11, 12, 18, 21), which suggests reducing macular schisis preserves macular function. No statistical improvement in VA for our population was observed, which may be related to the high rate of reduced compliance, dysfunction from inadequate retinoschisin, incomplete resolution of macular schisis, or continued progression of macular degeneration from XLRS (4). We suspect that consistent, long-term suppression of macular schisis may yield better visual outcomes or delay macular atrophy, although this could not be concluded from our study. However, as there are likely multiple mechanisms underlying retinoschisis, such as loss of structural integrity, pump failure, and traction (24), CAIs only address some of these mechanisms, so complete resolution of retinoschisis may not be possible depending upon the chronicity of disease and the degree of retinal degeneration or tractional components.

Adherence with CAI use can be particularly challenging, as side effects are common whether administered topically or orally. Topical dorzolamide is acidic and causes ocular stinging, loss of medication from reflexive tearing, and keratopathy with chronic application. Our series may underreport the incidence of this side effect by its retrospective nature, and we routinely recommended refrigerating dorzolamide, applying artificial tears, and ice packs prior to application to reduce this complaint. Brinzolamide produces less stinging but is more expensive. Oral acetazolamide can cause a myriad of unpleasant symptoms, including numbness and tingling of extremities, abdominal pain, reduced appetite (which is problematic in pediatric patients), and metallic taste to carbonated beverages. More serious concerns of photosensitivity, bone marrow suppression, metabolic acidosis, and electrolyte imbalance require periodic monitoring. In our experience, topical and oral CAIs performed similarly in reducing CST, but risks of oral CAIs greatly outweigh topical. Anecdotally, combining oral and topical CAIs reduced macular schisis when topical or oral CAIs individually were ineffective for our patients with XLRS or retinitis pigmentosa. Even short-term reductions in adherence limited the effectiveness of CAIs in reducing CST (Figure 1). However, the lack of difference between maximum reduction in CST despite differences in adherence support prior literature demonstrating recovery of CAI effect in schisis reduction when adherence is improved (25). We found that patients who reported instilling topical CAIs with complete adherence twice a day had a therapeutic effect. However, because nonadherence was common and most commonly involved missing doses rather than days, we recommend dosing three times a day. In addition to medication intolerance, children represent a unique population as they often depend on parents to administer medications at home. Older children or teens may not be accurately report administering medications; we recommend parental confirmation of CAI adherence. Although we observed short-term visual improvements in some patients on CAIs, the need for frequent, chronic dosing for physiologic effect makes durable improvements in vision and structure challenging. Longer follow-up will be required to determine whether early intervention and improved adherence with CAIs will result in more favorable anatomic and functional outcomes. An unmet therapeutic need is the development of sustained-release CAIs for XLRS and glaucoma management.

Retinal detachment complicating XLRS is surgically challenging to repair, frequently complicated by proliferative vitreoretinopathy, and has a poor prognosis for visual recovery. Therefore, prevention of RD is an important goal in the care of XLRS patients. Reducing peripheral schisis may reduce RD risk beyond trauma avoidance, as a significant component of retinoschisis is vitreous traction, which relates to risk for retinal tears and rhegmatogenous RD (26). Resolution of peripheral schisis in XLRS may occur with posterior vitreous separation spontaneously or through surgical induction during vitrectomy (24). It is noteworthy and encouraging that two patients had resolution of their peripheral retinoschisis while on CAIs, although a causal relationship cannot be established. Furthermore, no patient on CAIs developed a RD, retinal tear, or macular atrophy. In addition to serial macular OCTs, peripheral OCT technology may be helpful to objectively monitor clinical response to CAIs in XLRS patients. Rather than simply determining the presence or absence of peripheral retinoschisis, serial measurements may provide further insight into the peripheral retina’s response to CAIs and the degree of vitreous separation from the peripheral retina.

As with other retrospective case series involving rare diseases, there are inherent limitations of this study. Our intent-to-treat bias excluded a control group. Sample size and limited follow-up limits our conclusions about the impact of CAIs on foveal schisis, visual acuity, and RD prevention. Peripheral fundus imaging and ultrasonography were not performed routinely at each visit. This study is subject to recall bias and relied exclusively on medical records for data collection.

In summary, our series showed CAIs reduce macular schisis in XLRS eyes without a significant change in visual acuity. No patient developed macular atrophy, retinal tear, or RD while taking CAIs, even with reduced adherence, but sample size and duration of follow-up limit conclusions about a preventative effect. A larger multicenter retrospective trial or a prospective, randomized, controlled trial is warranted to explore the efficacy of CAIs in preventing RDs or macular atrophy, reducing macular schisis, and preserving visual acuity in patients with XLRS. Strategies to improve tolerability and adherence to chronic topical CAI therapy are needed.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Cincinnati Children’s Hospital Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

SW: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing, Visualization. DB: Conceptualization, Data curation, Formal analysis, Investigation, Supervision, Writing – original draft, Writing – review & editing, Project administration. VMU: Data curation, Investigation, Writing – original draft, Writing – review & editing, Visualization. RS: Data curation, Investigation, Writing – original draft, Writing – review & editing, Conceptualization, Formal analysis, Methodology, Supervision, Project administration, Validation.