Blepharoptosis After Repeated Intravitreal Anti-VEGF Injections: A Prospective Study

Prospective Evaluation of Blepharoptosis Development in Patients Undergoing Repeated Intravitreal Anti-VEGF Injections

Intravitreal anti-VEGF injections are a mainstay of treatment for retinal diseases such as neovascular age-related macular degeneration, diabetic macular edema and retinal vein occlusion, and usually require repeated administration over years. During each injection an eyelid speculum holds the lids open and the upper eyelid is exposed to repeated mechanical stretch. Aponeurotic ptosis after intraocular surgery is well described, but evidence on blepharoptosis after repeated intravitreal injections is limited and conflicting.

This single-center prospective observational study enrolls 60 patients who are starting intravitreal anti-VEGF therapy in one eye only; the untreated fellow eye of each patient serves as an internal control. Upper eyelid position and function are assessed with margin reflex distance-1 (MRD-1), margin reflex distance-2 (MRD-2) and levator function at baseline and at months 1, 3, 6 and 12. The primary endpoint is the difference between the injected eye and the fellow eye in the change in MRD-1 from baseline to month 12.

Study Overview

• Status: Not yet recruiting
• Conditions: Age-Related Macular Degeneration; Diabetic Macular Edema; Blepharoptosis
• Intervention / Treatment: Other: Repeated intravitreal anti-VEGF injection with eyelid speculum

Detailed Description

Design: prospective, single-center, longitudinal, non-interventional observational study conducted in the Department of Ophthalmology, University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey.

No study-driven intervention is performed. The decision to treat, the anti-VEGF agent (ranibizumab, aflibercept or bevacizumab), the injection interval and the total number of injections are determined solely by the treating retina specialist on clinical grounds. Injections are given under routine sterile conditions, topical anesthesia and with an eyelid speculum, as in standard practice; the study therefore evaluates the combined exposure of injection plus speculum use and cannot isolate the speculum-specific mechanical effect.

The injected eye is the study eye and the non-injected fellow eye is the control eye; each participant serves as their own control. All participants are assessed at baseline and at months 1, 3, 6 and 12. At every visit, for both eyes, MRD-1, MRD-2 and levator function are measured by the same examiner where possible using a standard technique. MRD-1 is the distance in millimetres between the corneal light reflex and the upper eyelid margin in primary gaze; MRD-2 is the distance between the corneal light reflex and the lower eyelid margin; levator function is the upper eyelid excursion from downgaze to upgaze with frontalis action neutralised. The cumulative number of intravitreal injections, the agent used and the number of eyelid speculum uses are recorded at each visit. Clinically significant blepharoptosis is defined as an MRD-1 of 2 mm or less and/or a decrease of 2 mm or more from baseline, evaluated separately for each eye at every visit.

Sample size: based on a paired comparison of the change in MRD-1. Using the 0.60 mm (SD 0.61) MRD-1 reduction at 12 months reported by Bermudez-Castellanos et al., and assuming a conservatively clinically meaningful difference of 0.50 mm with a standard deviation of paired differences of 1.00 mm (dz = 0.50), a two-sided alpha of 0.05 and 90% power require a minimum of 44 evaluable participants; allowing for approximately 25% attrition over 12 months, the target enrollment is 60.

Statistical analysis: normality by the Shapiro-Wilk test; between-eye change compared by paired t-test or Wilcoxon signed-rank test; repeated measures across the five timepoints by repeated-measures ANOVA or the Friedman test; frequency of clinically significant blepharoptosis compared between eyes by the McNemar test; associations between the number of injections or speculum uses and the change in eyelid measurements by Pearson or Spearman correlation; a sensitivity analysis compares eyelid measurement change among anti-VEGF agents. Two-sided p < 0.05 is considered significant. Analyses are performed in SPSS.

• Study Type: Observational
• Enrollment (Estimated): 60

Contacts and Locations

• Study Contact: Name: Abdulkadir Küçük, MD; Phone Number: +90 538 572 5722; Email: akkucuk42@gmail.com
• Study Contact Backup: Name: Fatih Çoban, MD; Phone Number: +90 5392346206

Study Locations

• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye)
    • University of Health Sciences, Fatih Sultan Mehmet Training and Research Hospital
    • Contact: Abdulkadir Küçük, Md; Phone Number: +905385725722; Email: akkucuk42@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults aged 18 years or older with a retinal disease (neovascular age-related macular degeneration, diabetic macular edema or retinal vein occlusion) scheduled to begin intravitreal anti-VEGF therapy in one eye only, with no history of intravitreal injection in either eye, recruited consecutively at a single tertiary ophthalmology clinic in Istanbul, Turkey.

Description

Inclusion Criteria:

• Age 18 years or older
• Planned initiation of intravitreal anti-VEGF injection in one eye only for a retinal disease
• No prior intravitreal injection in either eye
• Able to attend the scheduled follow-up visits and to cooperate for the duration of the study
• Reliable MRD-1, MRD-2 and levator function measurement possible in both eyes (clear corneal light reflex, clearly visible eyelid margin, able to maintain primary gaze)
• Signed informed consent

Exclusion Criteria:

• Pre-existing blepharoptosis or significant eyelid malposition at the baseline examination
• Previous ptosis surgery, blepharoplasty or other eyelid surgery that may affect upper eyelid anatomy
• History of myasthenia gravis, oculomotor nerve palsy, Horner syndrome, facial nerve palsy or a similar neurologic or neuromuscular disorder
• History of orbital trauma, orbital surgery or orbital disease
• Advanced dermatochalasis, eyelid retraction, entropion, ectropion or marked facial asymmetry precluding reliable eyelid measurement
• Need for intravitreal injection in both eyes during the study period
• Ocular or periocular surgery during follow-up that may affect upper eyelid position
• Inability to comply with follow-up visits or incomplete measurements
• Withdrawal of consent
• Inability to obtain reliable eyelid measurements due to severe blepharospasm, advanced corneal opacity, marked eyelid edema, or inability to maintain head or neck position or to cooperate

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients starting unilateral intravitreal anti-VEGF therapy; Adults with a retinal disease starting intravitreal anti-VEGF injections in one eye only. In each participant the injected eye is the study eye and the non-injected fellow eye is the internal control. Both eyes are assessed for MRD-1, MRD-2 and levator function at baseline and at months 1, 3, 6 and 12.	Other: Repeated intravitreal anti-VEGF injection with eyelid speculum; Intravitreal anti-VEGF injection (ranibizumab, aflibercept or bevacizumab) given in the study eye on clinical indication under sterile conditions, topical anesthesia and with an eyelid speculum. Agent, interval and number of injections are determined by the treating retina specialist, not by the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-eye difference in the change in margin reflex distance-1 (MRD-1) from baseline to month 12	MRD-1 (mm) is the distance between the corneal light reflex and the upper eyelid margin in primary gaze. For each patient the change from baseline to month 12 in the injected (study) eye is compared with the corresponding change in the non-injected fellow (control) eye.	Baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-eye difference in the change in margin reflex distance-2 (MRD-2) from baseline to month 12	MRD-2 (mm) is the distance between the corneal light reflex and the lower eyelid margin. The change in the study eye is compared with the change in the fellow eye.	Baseline and 12 months
Between-eye difference in the change in levator function from baseline to month 12	Levator function (mm) is the upper eyelid excursion from downgaze to upgaze with frontalis action neutralised. The change in the study eye is compared with the change in the fellow eye.	Baseline and 12 months
Longitudinal change in MRD-1, MRD-2 and levator function across visits	Change over time in the three eyelid measurements in the study and control eyes across the five study visits.	Baseline, 1, 3, 6 and 12 months
Incidence of clinically significant blepharoptosis	Proportion of eyes with an MRD-1 of 2 mm or less and/or a decrease of 2 mm or more from baseline, compared between the study eye and the control eye.	12 months
Association between cumulative intravitreal injection number and change in eyelid measurements	Correlation between the total number of intravitreal anti-VEGF injections (and the number of eyelid speculum uses) and the change in MRD-1, MRD-2 and levator function in the study eye.	12 months
Change in eyelid measurements by anti-VEGF agent	Sensitivity analysis comparing the change in eyelid measurements among eyes treated with ranibizumab, aflibercept or bevacizumab.	12 months

Collaborators and Investigators

• Sponsor: Abdulkadir Küçük

Publications and helpful links

General Publications

• Bermudez-Castellanos I, Cruz Velasco A, Garcia DM, de la Hoz Montanana MR, Bengoa Gonzalez A, Sanchez Tocino H, Castro-Portillo E, Galindo-Ferreiro A. Blepharoptosis After Intravitreal Anti-VEGF Injections: A Prospective Study. Ophthalmic Plast Reconstr Surg. 2026 May-Jun 01;42(3):305-309. doi: 10.1097/IOP.0000000000003085. Epub 2025 Sep 29.
• Berco E, Ostrovsky M, Esomchukwu O, Zaks O, Schlesinger M, Molina EJC, Ben-Zaken SG, Shoham-Hazon N. Risk of ptosis following eyelid speculum assisted intravitreal anti-VEGF injections. Graefes Arch Clin Exp Ophthalmol. 2025 Jun;263(6):1711-1717. doi: 10.1007/s00417-025-06763-3. Epub 2025 Feb 13.

Study record dates

Study Major Dates

• Study Start (Estimated): September 25, 2026
• Primary Completion (Estimated): December 25, 2027
• Study Completion (Estimated): January 5, 2028

Study Registration Dates

• First Submitted: September 10, 2026
• First Submitted That Met QC Criteria: September 10, 2026
• First Posted (Actual): September 15, 2026

Study Record Updates

• Last Update Posted (Actual): September 15, 2026
• Last Update Submitted That Met QC Criteria: September 10, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: intravitreal injection; anti-VEGF; eyelid speculum; blepharostat; margin reflex distance; aponeurotic ptosis
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Degeneration; Eyelid Diseases; Macular Degeneration; Blepharoptosis
• Other Study ID Numbers: BLFRPTS-2026-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared publicly. De-identified data may be made available from the principal investigator on reasonable request, subject to institutional and ethics committee approval.