Testing an established medicine in XLRS

X-linked retinoschisis (XLRS) is an inherited retinal condition in which the layers of the retina can separate, or “split.” Many people with XLRS develop cystoid fluid collections (CFCs): small fluid-filled spaces within the central retina, including the fovea, which is responsible for detailed central vision. These changes can contribute to reduced vision and may be monitored using optical coherence tomography (OCT), an imaging test that measures retinal structure.

Because there are currently limited treatment options for the retinal changes associated with XLRS, researchers continue to investigate whether existing medicines can help. The 2026 AXIS trial tested oral acetazolamide, a medication that has been considered for reducing retinal fluid in several eye conditions. Its central question was straightforward: can acetazolamide reduce cystoid fluid collections and improve vision-related outcomes for people with XLRS?

How the AXIS trial was designed

AXIS was an investigator-initiated, single-centre, open-label randomised controlled trial. Nineteen people aged 12 years or older with XLRS and fovea-involving cystoid fluid collections took part.

Participants were randomly assigned to one of two groups:

  • Acetazolamide group: 10 participants, representing 17 eyes, received oral acetazolamide at 500 mg per day for 16 weeks. After that point, the medicine was tapered or stopped depending on the individual’s response.
  • Control group: Nine participants, representing 16 eyes, received no treatment and were monitored over the same period.

The trial lasted 32 weeks and included seven study visits. Researchers examined both retinal structure and visual function. The main measurement was central subfield thickness (CST), an OCT-based measure of thickness in the central part of the retina. They also assessed cystoid fluid volume, best-corrected visual acuity, low-luminance visual acuity, retinal sensitivity using microperimetry, and patient-reported visual disability.

The main finding: no overall reduction in retinal fluid

The study did not find a clinically meaningful overall benefit of acetazolamide for reducing central retinal thickness. Across the 32-week follow-up period, the average difference in CST change between the acetazolamide and control groups was +2.7 micrometres. This difference was not statistically significant (p = 0.9), meaning the observed result was consistent with no meaningful treatment effect.

Importantly, acetazolamide also did not significantly improve the volume of cystoid fluid collections compared with observation alone. For patients and families, this result suggests that oral acetazolamide should not be expected to reliably reduce the foveal cyst-like spaces seen in XLRS across the broader patient population.

Vision outcomes were largely unchanged

Reducing fluid on a retinal scan is only one possible goal. A treatment must also be evaluated by whether it helps people see better or function more easily in daily life.

In AXIS, acetazolamide did not produce significant improvements in:

  • Best-corrected visual acuity, the familiar letter-chart measurement of vision
  • Low-luminance visual acuity, which evaluates vision under dimmer conditions
  • Patient-reported visual disability

One result did favour treatment: retinal sensitivity measured by microperimetry showed a modest, statistically significant improvement with acetazolamide. Microperimetry tests how well a person detects small lights at specific locations in the retina. However, this measured improvement was not accompanied by significant gains in visual acuity, low-light vision, or reported visual disability. Taken together, the findings do not demonstrate a broad functional benefit for the treatment group.

Why individual responses still matter

Although the average trial result was negative, the researchers noted that a small subset of participants may have experienced benefit. This is an important observation in XLRS, where retinal structure, visual function, and progression can vary substantially among individuals.

The AXIS trial therefore supports a more personalised way of thinking about treatment. Rather than assuming that acetazolamide will help all people with cystoid fluid collections, clinicians and researchers may need to identify characteristics that distinguish possible responders from non-responders. Future studies could explore whether factors such as baseline retinal appearance, the amount or pattern of fluid, or other clinical measures are associated with an individual response.

What AXIS means for treatment research

This trial provides valuable evidence because it tested acetazolamide against a randomly assigned untreated control group and measured outcomes over 32 weeks. In rare inherited retinal diseases, well-designed controlled trials are especially important: retinal fluid can change over time, and an apparent improvement in an individual patient may not necessarily be caused by treatment.

The findings indicate that oral acetazolamide did not offer a meaningful overall advantage for cystoid fluid reduction or most vision-related outcomes in this XLRS population. At the same time, the microperimetry finding and the possibility of benefit in a small subset point to unanswered questions about which outcomes are most sensitive to change and which patients, if any, may be more likely to respond.

Looking ahead

The AXIS trial adds a rigorous piece of evidence to the XLRS research landscape. Its results help clarify the limits of a repurposed oral medicine while reinforcing the need for treatments that address the underlying biology of the disease and produce meaningful improvements in vision and daily life.

Future XLRS research can build on this work by studying larger groups, identifying potential response patterns, and continuing to develop therapies designed for inherited retinal disease. Even when a trial does not show a broad treatment benefit, it advances the field by giving patients, families, clinicians, and researchers clearer evidence on which to base the next steps.