Highlights
- Cystoid macular edema (CME) occurs in about one-quarter of eyes following cultured human corneal endothelial cell (cHCEC) injection therapy.
- Preoperative use of prostaglandin analogs significantly increases the risk of postoperative CME development.
- Despite CME occurrence, six-month visual outcomes remain comparable between affected and unaffected eyes after appropriate anti-inflammatory treatment.
- Routine postoperative optical coherence tomography (OCT) and careful perioperative management of prostaglandin analogs facilitate early CME detection and treatment.
Background
Corneal endothelial dysfunction is a leading cause of visual impairment worldwide, with therapeutic advancements shifting towards cell-based regenerative approaches. Cultured human corneal endothelial cell (cHCEC) injection therapy has emerged as a promising minimally invasive treatment alternative to conventional corneal transplantation for endothelial failure. Although cHCEC injection demonstrates favorable anatomical and functional restoration, postoperative complications remain incompletely characterized.
Cystoid macular edema (CME), characterized by intraretinal cystic spaces predominantly in the macula leading to visual impairment, is a recognized complication after various intraocular surgeries, including cataract extraction and glaucoma procedures. Its occurrence following cHCEC injection has been recently reported but lacks comprehensive epidemiological and clinical outcome data. Understanding CME’s incidence, associated risk factors, and visual impact is critical for optimizing patient management and prognostication.
Key Content
Incidence and Temporal Profile of CME Post cHCEC Injection
A multicenter retrospective cohort analysis involving 57 eyes from Japanese tertiary ophthalmic centers found that CME occurred in 26.3% of cases following cHCEC injection therapy (Ogino et al., 2026). Spectral-domain optical coherence tomography (SD-OCT) facilitated sensitive detection of intraretinal cystoid changes. Kaplan-Meier analysis demonstrated that CME predominantly manifests within the early postoperative period, underscoring the need for vigilant monitoring during this timeframe.
Associated Clinical and Medication Factors
Univariate analyses identified preoperative prostaglandin analog use as a significant risk factor (60.0% in CME eyes vs 14.3% in non-CME, P=0.001). This association aligns with known prostaglandin-induced alterations in retinal vascular permeability and inflammatory pathways that may predispose to CME formation. Additionally, underlying glaucoma diagnosis and use of topical glaucoma medications correlated with increased CME risk, potentially reflecting the interplay of elevated intraocular pressure dynamics and ocular surface inflammation. Worse baseline best-corrected visual acuity (BCVA) was also linked with CME development, indicating that poorer preoperative ocular status may predispose to macular complications.
Interestingly, lens status (phakic vs pseudophakic) did not demonstrate a significant relationship with CME incidence, contrasting with some reports in cataract surgery literature that emphasize lens removal as a CME risk factor. Limitations in preoperative macular status assessment—undetermined in the majority of eyes—suggest that some CME cases might represent persistence or worsening of pre-existing lesions rather than genuinely new onset.
Visual Outcomes and Resolution of CME
Despite CME’s frequency, no significant difference in six-month postoperative BCVA was detected between CME and non-CME groups (logMAR 0.44 vs 0.60, P=0.52), indicating that CME associated with cHCEC injection may not adversely affect medium-term visual acuity if appropriately managed. Treatment protocols employed topical nonsteroidal anti-inflammatory drugs (NSAIDs) and sub-Tenon triamcinolone acetonide injections, resulting in CME resolution in all affected cases.
Mechanistic Insights and Translational Implications
The endothelial cell injection procedure introduces biological and mechanical perturbations potentially contributing to intraocular inflammation and disruption of the blood-retinal barrier—key pathophysiological mechanisms underpinning CME. Prostaglandin analogs may exacerbate these effects by promoting vascular permeability and inflammatory mediator release. These mechanistic insights advocate for perioperative cessation or cautious use of prostaglandin analogs in susceptible patients undergoing cHCEC therapy.
Routine postoperative SD-OCT is essential for earlier CME identification, especially since clinical symptoms might be subtle or masked by other visual recovery phenomena. Early anti-inflammatory intervention can prevent chronic CME and preserve visual function.
Expert Commentary
This study by Ogino et al. represents a critical advancement in understanding complications following the novel therapeutic modality of cHCEC injection. Identifying prostaglandin analog use as a modifiable risk factor invites adjustments in preoperative medication regimens to mitigate CME risk. The resolution of CME without long-term visual detriment is reassuring, though longer-term follow-up is warranted to ensure sustained outcomes.
Comparatively, CME rates following traditional corneal surgeries vary widely, suggesting that cHCEC injection has a distinct risk profile. The lack of association with lens status may reflect differences in intraocular tissue manipulation compared to phacoemulsification surgeries. However, the retrospective design and limited baseline macular assessment are notable limitations, underscoring the need for prospective studies with comprehensive multimodal imaging before and after cHCEC therapy.
From a translational standpoint, these findings emphasize the importance of integrating ocular pharmacotherapy management, advanced imaging modalities, and tailored anti-inflammatory strategies to optimize patient outcomes in regenerative ophthalmology. The study also highlights potential avenues for biomarker discovery and risk stratification based on inflammatory and vascular parameters.
Conclusion
Cystoid macular edema occurs in approximately 25% of eyes post cultured human corneal endothelial cell injection, with preoperative prostaglandin analog use and glaucoma-related factors significantly increasing the risk. Importantly, CME predominantly emerges in the early postoperative phase and resolves with standard anti-inflammatory treatments without compromising six-month visual acuity. Careful perioperative management of prostaglandin analogs, routine OCT surveillance, and prompt intervention constitute best practice for CME management in this emerging therapeutic context. Future prospective studies are required to confirm these findings, evaluate long-term visual function, and refine preventive strategies for CME following cHCEC therapy.
References
- Ogino R, Shirane M, Yagi-Yaguchi Y, Akasaki Y, Sugita S, Mori N, Yamaguchi T, Kobayashi A, Higashide T, Negishi K. Cystoid Macular Edema After Cultured Human Corneal Endothelial Cell Injection: Frequency, Associated Factors, and Visual Outcomes. Am J Ophthalmol. 2026 Sep 10;177:95-104. doi:10.1016/j.ajo.2026.07.002. PMID: 42722115.
- Yoshida N, et al. Cystoid Macular Edema and Its Management in Glaucoma Patients Using Prostaglandin Analog Eye Drops. J Glaucoma. 2024;33(7):498-503. doi:10.1097/IJG.0000000000002219.
- Nguyen QD, et al. Pathophysiology and treatment of postoperative cystoid macular edema: current concepts. Prog Retin Eye Res. 2022;87:100976. doi:10.1016/j.preteyeres.2022.100976.
- Chang SH, Sun JK. Inflammation and Prostaglandin-Induced Vascular Permeability Leading to Macular Edema. Retina. 2023;43(2):269-279. doi:10.1097/IAE.0000000000003347.
