Predictors of Vitrectomy Outcomes in Myopic Foveoschisis

• Detailed Study Summary

  • Study title:** *Structural and functional determinants of surgical outcomes in vitrectomy for myopic foveoschisis*

  • Protocol number:** R2028/71/2023 (SHF-SNEC 0923-2)

  • Version/date:** Version 1.0, 20 September 2023

  • Study site:** Singapore National Eye Centre (SNEC)

  • Principal investigator:** Tsai Shih Hsiang Andrew

  • Funding:** SHF SNEC grant

    • Background and rationale

Myopic foveoschisis (MFS) is a potentially sight-threatening macular complication in highly myopic eyes, particularly those with posterior staphyloma. It is characterised by splitting of retinal layers at the macula and may progress to foveal detachment, full-thickness macular hole, macular-hole retinal detachment, macular atrophy, and substantial visual impairment. MFS has been reported in approximately 8-34% of patients with posterior staphyloma. Optical coherence tomography (OCT) has become central to diagnosis and monitoring because it allows detailed assessment of the degree of macular schisis and identifies complications that may require surgery.

The accepted surgical treatment for MFS requiring intervention is pars plana vitrectomy, with techniques directed at relieving anteroposterior and tangential vitreomacular traction. These techniques may include internal limiting membrane (ILM) peeling or fovea-sparing ILM flap procedures, sometimes with gas tamponade. The intended result is restoration of retinal anatomy and improvement or preservation of visual function.

Current indications for surgery generally include progressive deterioration in best-corrected visual acuity that corresponds with structural worsening on OCT, and the presence of foveal detachment. Additional proposed criteria include symptomatic visual decline or metamorphopsia, visual acuity of 20/40 or worse, and absence of major macular atrophy. These criteria aim to identify patients likely to benefit while avoiding surgery in eyes where advanced atrophy makes meaningful visual recovery unlikely.

However, clinical decision-making remains difficult. Waiting for clear anatomical or functional progression can allow irreversible visual loss or macular atrophy to develop, even if surgery later resolves the schisis. Conversely, operating earlier in patients with relatively good pre-operative visual acuity remains controversial because these patients have less potential for measurable visual gain and may be exposed to surgical complications, including permanent loss of vision. Prior studies suggest that better pre-operative visual acuity may predict greater likelihood of post-operative visual improvement, but the full set of structural and functional factors that determine surgical outcomes remains unclear.

This study therefore seeks to improve understanding of which pre-operative features are associated with successful vitrectomy outcomes in MFS. It evaluates both conventional anatomical imaging parameters and a broader set of functional assessments, including visual acuity, metamorphopsia, retinal sensitivity, and contrast sensitivity.

### Hypothesis and objectives

The study hypothesises that both functional and anatomical improvement can occur after vitrectomy across a wide range of MFS severity. It further hypothesises that structural OCT features and functional baseline measures-best-corrected visual acuity (BCVA), M-chart performance, microperimetry, and contrast sensitivity-can predict surgical success at 12 months after surgery.

The primary aims are:

• To assess structural and functional changes after vitrectomy for MFS.
• To identify novel prognostic factors associated with outcomes after MFS surgery.
• To explore whether pre-operative OCT and functional testing can help predict patients' likelihood of achieving successful post-operative visual and anatomical outcomes.

Functional success is defined as stability or improvement in BCVA. Anatomical success is defined as improvement in retinoschisis and resolution of foveal detachment when detachment was present before surgery.

### Study design

This is a prospective pilot study of 30 highly myopic patients with OCT-confirmed MFS who require vitrectomy surgery. The study will be conducted at SNEC and will follow participants for 12 months after surgery. (parallel studies will be conducted with overseas collaborators)

The study is primarily observational in its outcome assessment. Participants will receive clinically indicated standard-of-care surgery; the research component consists of collecting demographic, clinical, structural imaging, and visual-function data before and after surgery. No formal sample-size calculation is planned because the study is intended as a pilot investigation.

Potential participants will be identified and recruited from SNEC surgical retina clinics. The recruiting doctor will confirm that a patient meets all eligibility criteria, provide counselling, and obtain informed consent before enrolment. Participants may withdraw from the research study voluntarily at any time. If withdrawal occurs, they may be asked to continue scheduled evaluations or complete an end-of-study assessment, and they will continue to receive appropriate medical care and monitoring of adverse events as clinically necessary.

### Study population

The target population is 30 adults with high myopia and MFS requiring vitrectomy.

Eligible participants must:

- Be 40-90 years old.

• Have high myopia, defined as refractive error worse than -6 dioptres and axial length longer than 26 mm.
• Be mentally competent to provide informed consent.
• Have MFS that meets clinical criteria for surgical intervention, specifically:
• progressively worsening vision that correlates with structural OCT deterioration over six months; and/or
• foveal detachment.

The study excludes patients with ocular disorders, prior treatments, or other conditions that could affect structural imaging or functional measurements. Exclusions include corneal opacity, uveitis, dense cataract, vitreous haemorrhage, central serous chorioretinopathy, prior retinal laser photocoagulation or photodynamic therapy, previous or concurrent retinal detachment, retinal dystrophies, macular scarring, retinal vascular occlusion, ocular ischaemic syndrome, and ungradable OCT/OCTA imaging.

Patients who are cognitively impaired or prisoners are excluded. Patients considered poor highly myopic surgical candidates are also excluded, including those with myopic choroidal neovascularisation, macular scar, or complete macular atrophy according to the ATN classification. Participants may also be discontinued from study assessments if OCT imaging is unsatisfactory or ungradable, or if they are unable to complete functional tests such as microperimetry, contrast sensitivity testing, or M-chart assessment.

### Surgical intervention

All patients will undergo pars plana vitrectomy as clinically indicated for MFS. Surgery may be performed using 23- or 25-gauge instrumentation. The procedure may include:

• Vitrectomy with fovea-sparing ILM peeling or ILM flap technique.
• Gas tamponade where appropriate.
• Concurrent cataract surgery, particularly in patients with significant cataract or those older than 50 years, where clinically appropriate.
• Use of intraoperative adjuncts such as triamcinolone acetonide and/or membrane blue dual dye.

Post-operative face-down positioning may be advised when clinically required, particularly where gas tamponade is used. The protocol regards the surgical procedure as standard clinical care and does not introduce additional surgical treatment beyond what is considered appropriate for each participant.

### Study procedures and outcome assessments

Participants will undergo assessment at baseline and after surgery, with follow-up visits scheduled at approximately postoperative months 1, 3, 6, and 12. A ±14-day visit window is permitted.

The protocol includes the following assessments:

**Best-corrected visual acuity and refracted logMAR visual acuity** BCVA will be recorded at baseline, month 1, and month 12. Refracted logMAR visual acuity will be assessed at baseline and selected follow-up visits. Visual acuity is a key functional endpoint because stable or improved BCVA defines functional success.

**M-chart testing** M-chart testing evaluates metamorphopsia, or perceived distortion of straight lines, which is a relevant symptom in patients with MFS. This assessment is intended to capture functional visual disturbance that may not be fully reflected by conventional visual acuity measurements.

**Microperimetry** Microperimetry evaluates retinal sensitivity at specific macular locations. It may provide a more detailed assessment of central retinal function than visual acuity alone and could identify functional changes associated with structural recovery or persistent retinal damage.

**Contrast sensitivity testing** Contrast sensitivity will be measured with the AST Manifold Contrast Vision Meter (MCVM), which uses an active machine-learning quantitative contrast sensitivity function algorithm. The device measures contrast sensitivity across multiple spatial frequencies while aiming to reduce testing time without substantially compromising precision. It is FDA-listed and has been used as an investigational device in clinical trial settings. Contrast sensitivity may detect functional deficits in patients who retain relatively good conventional visual acuity.

**Swept-source OCT**

Swept-source OCT will be used to monitor MFS anatomy throughout the study. Baseline OCT is performed as part of standard clinical care, with serial scans at follow-up visits. Specific structural features assessed include:

• Presence of epiretinal membrane.
• Central retinal thickness.
• Presence or resolution of foveal detachment.
• Inner macular schisis.
• Outer macular schisis.
• Inner lamellar hole.
• Outer lamellar hole.

These OCT characteristics will be evaluated as possible predictors of post-operative visual and anatomical outcomes.

**Clinical and demographic data** Case records will include age, sex, ocular and systemic co-morbidities, and lens status. These factors may be incorporated into analyses of surgical prognosis.

### Follow-up schedule

At the baseline visit, participants will undergo visual acuity assessment, refraction, microperimetry, M-chart testing, MCVM contrast sensitivity testing, and swept-source OCT. They will then be assessed at postoperative month 1, month 3, month 6, and month 12. OCT will be obtained at all major follow-up visits, while the functional tests are concentrated at baseline, month 1, and month 12, with refraction performed at baseline and later follow-up as specified in the protocol.

The 12-month period is intended to capture both early anatomical changes after surgery and longer-term functional recovery. This is important because retinal anatomy may improve before visual function fully recovers, and some patients may have persistent functional deficits despite anatomical resolution.

### Data management and quality assurance

Clinical data will be recorded in case report forms. Physical research documents will be stored securely in the SERI clinical research office with controlled lock-and-key access. Electronic research data will be stored in secure, password-protected shared folders. If data are removed from the cluster premises, they will be held on encrypted, secure portable media in accordance with SingHealth information-technology policy.

Access to participant information will be restricted to the principal investigator, co-principal investigator, and authorised study team members. The protocol also refers to encrypted thumb-drive storage for certain study data. Research records and regulatory documentation will be retained securely for 15 years after study completion and will be available for authorised monitoring, audit, institutional review board review, and regulatory inspection.

Data quality will be supported by trained personnel and review by qualified ophthalmologists to ensure integrity and accuracy. The principal investigator will assess protocol adherence and data quality every three months.

### Statistical analysis

Because this is a pilot study, the protocol does not specify a formal sample-size calculation. Analyses will first use descriptive statistics to summarise participant demographics, clinical features, baseline visual function, and OCT findings.

Univariate analyses using appropriate statistical tests will compare:

• Participants with relatively good pre-operative visual acuity, approximately 6/12 to 6/15, with those whose pre-operative visual acuity is worse than 6/15.
• Participants with good post-operative visual recovery with those who have poorer post-operative recovery.

Multivariable logistic regression will then be used to identify prognostic factors for surgical success. Candidate covariates will include the collected demographic, clinical, structural OCT, and functional testing measures. The analysis is intended to determine whether baseline features can predict which patients are most likely to experience stable or improved vision and favourable anatomical recovery after surgery.

### Risks and benefits

The principal potential clinical risks are those associated with vitrectomy surgery, estimated in the protocol as less than 3% for surgical complications. These are considered usual risks of the standard surgical procedure rather than additional risks created by research participation. There is also a risk of loss of confidentiality, which will be mitigated through restricted access, secure storage, password protection, and encryption.

The additional research tests-microperimetry, M-chart assessment, contrast sensitivity testing, and swept-source OCT-are non-invasive and are expected to pose minimal or no physical health risk. The study will monitor and record adverse events as appropriate.

Potential benefits to participants include the expected clinical benefit of surgically indicated treatment, such as visual improvement or structural stabilisation. The broader benefit is improved understanding of MFS and the possible role of novel functional tests in evaluating disease severity and predicting surgical outcomes.

### Safety monitoring and adverse-event reporting

The protocol defines a serious adverse event as an untoward medical occurrence related to human biomedical research that results in or contributes to death, is life-threatening, requires or prolongs hospitalisation, causes persistent or significant disability or incapacity, results in congenital anomaly or birth defect, or meets other prescribed criteria.

Adverse events that are not serious include unfavourable or unintended signs, symptoms, diseases, or abnormal findings that may be associated with research participation. Because the research tests are non-invasive and surgery is standard clinical care, the protocol considers overall research-related risk to be minimal beyond routine surgical care.

Related serious adverse events-those definitely, probably, or possibly related to study participation-will be reported to the Centralised Institutional Review Board (CIRB) according to applicable requirements at the time of the event. Follow-up information will be actively collected and submitted as it becomes available. Related non-serious adverse events will be recorded at the study site but will not necessarily be reported to CIRB. Complaints will be managed by the principal investigator and SNEC quality systems.

The protocol also addresses reportable adverse events involving medical devices. Events associated with a device that result in serious public-health threat, death, serious deterioration in health, or a recurrence risk that could cause death or serious injury will be reported to the Health Sciences Authority according to the applicable requirements.

### Ethical considerations

The study will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice principles, and relevant regulatory requirements. Final approval from CIRB, including approval of the participant information and consent form, is required before recruitment begins.

Patients will provide informed consent in English where possible. Where required, a translator will be used to ensure that participants understand the study and consent process. The principal investigator is responsible for notifying CIRB of protocol amendments and other study-related changes in accordance with local requirements.

Participant confidentiality will be protected through restricted study-team access, secure physical and electronic data storage, password protection, and encryption. The protocol specifies long-term retention of study documentation for 15 years following study completion.

### Overall significance

This study addresses an important clinical gap in the management of myopic foveoschisis: identifying when surgery is likely to provide benefit and which patients are most likely to achieve meaningful functional recovery. By combining detailed swept-source OCT assessment with BCVA, metamorphopsia measurement, microperimetry, and contrast sensitivity testing, the study aims to move beyond conventional visual-acuity-based decision-making.

The findings may help clarify whether patients with good pre-operative acuity can still benefit from earlier intervention, identify structural signs associated with poor or favourable prognosis, and determine whether newer functional measures detect clinically important deficits not captured by visual acuity alone. Although limited by its small pilot sample, the study may provide data to support larger future studies and more individualised surgical counselling for patients with MFS.