Abstract
Introduction
Macular telangiectasia (MacTel) is a rare retinal condition that can cause vision loss, and anti-vascular endothelial growth factor (anti-VEGF) agents have emerged as a potential treatment. This study aimed to evaluate the clinical outcomes of anti-VEGF therapy in patients with MacTel.
Methods
A systematic literature search on Ovid MEDLINE, Embase, and Cochrane Library was performed from inception to June 2024 for comparative studies on anti-VEGF agents in MacTel. The primary outcome was the change in best-corrected visual acuity (BCVA). Secondary outcomes were central macular thickness (CMT), central choroidal thickness (CCT), and fluorescein angiography (FA) leakage.
Results
Ten studies on 377 eyes of 239 patients followed up over 23.4 ± 8.3 months were included. Mean (SD) BCVA changed from 0.42 (0.39) to 0.35 (0.18) over 23.4 (8.3) months of follow-up in non-proliferative MacTel. Mean BCVA changed from 0.66 (0.43) to 0.52 (0.34) at final follow-up in eyes with choroidal neovascularization (CNV). Five studies reported improved visual acuity, one showed improved FA leakage without visual acuity benefit, and four found no functional benefit. In non-proliferative MacTel, four studies showed no functional improvement, two reported significant functional and morphological improvements, and one suggested potential benefits in improving BCVA. In proliferative MacTel, two studies demonstrated improvement in both anatomical and functional outcomes, while one indicated that anti-VEGF treatment might produce improved results. In non-proliferative MacTel, mean CMT changed from 201 (32) µm to 199 (29) µm. CMT in patients with CNV decreased from an initial value of 328.23 (161.16) µm to 267.44 (118.56) µm at the final follow-up. CCT in proliferative MacTel eyes decreased from 272.37 (52.65) µm and 247.40 (48.80) µm on anti-VEGF therapy. Overall, FA leakage outcomes were improved on ranibizumab therapy. No study documented any significant adverse effects with treatment.
Conclusion
Anti-VEGF agents may be associated with favorable anatomical and functional outcomes, particularly in proliferative MacTel; however, future large-scale clinical trials are warranted.
Keywords: Anti-vascular endothelial growth factor, Macular telangiectasia type 2, Macular telangiectasia
Introduction
Macular telangiectasia type 2 (MacTel) is a bilateral, asymmetric, progressive disease with an estimated 0.1% prevalence. Eyes affected by MacTel tend to have intraretinal hyporeflective regions that may not be associated with fluorescein leakage or increased macular thickness on optical coherence tomography (OCT) [1]. The internal limiting membrane (ILM) drape sign, presenting as a thin membrane overhanging a central cystoid lesion at the foveal base of normal contour and thickness, is also a characteristic sign of MacTel [2]. Additionally, MacTel is associated with deep intraretinal leakage in the temporal parafoveal region on fluorescein angiography (FA) [1]. Ancillary imaging modalities such as OCT and OCT angiography have proven instrumental in localizing and delineating pathology, offering insight into microvascular abnormalities and structural changes to aid clinicians and retina specialists in diagnosing conditions such as MacTel [3, 4].
Hence, early studies of patients with temporal parafoveal telangiectasis attempted argon laser photocoagulation in regions with fluorescein leakage, reporting improvements in visual acuity [5–7]. However, the efficacy of laser photocoagulation in the setting of MacTel was challenged by later studies, which demonstrated that the treatment modality was associated with either no visual improvement or further deterioration of visual acuity [8]. Furthermore, laser photocoagulation increases the risk of choroidal neovascularization (CNV) in MacTel [7].
MacTel patients can be further classified as either non-proliferative, where telangiectasia and foveal atrophy are present, or proliferative, where CNV is also observed [7]. Current treatment options for MacTel tend to be largely ineffective in managing the non-proliferative stage, whereas anti-vascular endothelial growth factor (VEGF) therapies have been demonstrated to be efficacious in treating CNV secondary to proliferative MacTel [7]. Although anti-VEGF agents may lead to pruning of abnormal vessels in eyes with MacTel, treatment responses may differ considerably across diverse patient populations [9]. Overall, there is a paucity of data on the comparative safety and efficacy of different anti-VEGF therapies in the setting of MacTel. Some studies have noted improved functional and structural outcomes following anti-VEGF therapy; however, other clinical trials have revealed no significant improvement in visual acuity in MacTel [10–13]. Hence, our investigation aims to provide a comprehensive analysis of the safety and efficacy of the anti-VEGF agents bevacizumab and ranibizumab in patients with proliferative and non-proliferative MacTel.
Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement [14]. This project represented a sub-study of a project registered in PROSPERO (registration number: CRD42023393712). Ethical approval from our Institutional Review Board was not required given the study design. This study adhered to the tenets of the Declaration of Helsinki.
Search Methods for Identifying Studies
The search strategy was developed in collaboration with an experienced librarian. A comprehensive literature search was conducted on Ovid MEDLINE, Ovid Embase, and Cochrane CENTRAL from inception to June 11, 2024. To ensure search sensitivity, a formal search involving variations of similar terms and synonymous free-text words to capture all articles pertaining to MacTel was developed. The full search strategy for all databases can be found in online supplementary Table S1 (for all online suppl. material, see https://doi.org/10.1159/000543771). Only English language studies were considered.
Study Selection
Three independent reviewers (A.S., A.M., and J.G.) screened study titles and abstracts and examined full-text articles using Covidence (www.covidence.org). Data collection was independently completed using standardized data collection forms by two reviewers (A.S. and J.G.). Disagreements during the selection and extraction process were resolved through consensus or discussion with a third reviewer (A.M.). Assessors were not masked to study details due to resource limitations.
Eligibility Criteria for considering Studies for This Review
Studies were included if they met the following criteria: (1) examined patients with MacTel and outcomes of anti-VEGF treatment; (2) compared anti-VEGF treatment group outcomes to another comparison group, whether it be observational or another treatment modality; and (3) had a minimum follow-up of 6 months. Studies were excluded if they reported on animal research, were reviews, did not include MacTel patients undertaking anti-VEGF treatments, or did not include a comparison group.
Data Collection, Risk of Bias, and Certainty of Evidence
The following data were extracted from all included studies: study characteristics, baseline characteristics of participants and treated eyes, best-corrected visual acuity (BCVA), retinal thickness, central macular thickness (CMT), central choroidal thickness (CCT), FA leakage, anti-VEGF agent treatment, dosage, number of injections, and follow-up periods.
To ensure consistency, the interclass correlation coefficient (ICC) was calculated between reviewers for key outcomes, yielding an ICC of 0.89, indicating excellent agreement. Data collection forms were piloted to reduce variability. Randomization of included studies was not applicable as this was a systematic review; however, extracted data were digitized and systematically organized to minimize errors.
Risk of Bias and Certainty of Evidence Assessment
Risk of bias assessments for all included studies were conducted using the ROBINS-I tool [15]. The following parameters were assessed for non-randomized, observational studies: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of reported results.
Certainty of evidence and strength of recommendations of each included study were assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria [16]. The process adhered to Cochrane guidelines, which utilize subjective metric grading to assess studies based on factors such as risk of bias, inconsistency, indirectness, and publication bias [17]. Each outcome was assigned a quality rating of high, moderate, low, or very low.
Data Synthesis
A descriptive synthesis of evidence was undertaken for all included studies. Meta-analytic methods were not employed given the heterogeneity of study designs, control treatments, and anti-VEGF therapeutic regimens. For each study, the study type, country of publication, type of anti-VEGF agents used (bevacizumab [Avastin, Genentech/Roche, South San Francisco, CA, USA]; ranibizumab [Lucentis, Genentech/Roche, South San Francisco, CA, USA]), the outcome measures assessed, and the effect of injections on different visual, macular, and foveal parameters were recorded. Data extracted by both investigators were compared, and a consensus was reached when any discrepancies were noted.
Results
Overall, 1,107 studies underwent title and abstract screening, of which 1,082 studies underwent title and abstract screening, 205 studies underwent full-text screening, and 10 studies reporting on 377 eyes of 239 patients at baseline were included (shown in Fig. 1) [11–13, 18–24]. Reasons for exclusion included incorrect intervention (43%), incorrect study design (27%), only abstract (7%), ongoing study (5%), non-English (5%), incorrect patient population (5%), incorrect study design (5%), incorrect outcomes (3%), and incorrect intervention (1%).
Fig. 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flow diagram of study selection process.
Included studies were conducted in Turkey (n = 2), USA (n = 2), India (n = 2), Germany (n = 2), and Austria (n = 1). Six of the studies were retrospective by design, while four were prospective. One study was a follow-up assessment of visual outcomes from a clinical trial [12, 24]. Participants among all ten studies were aged between 52.2 and 65.3 years and were followed up over a mean of 23.4 ± 8.3 months. Thirty-seven percent of participants were male, and 63% were female. Seventy-four participants across two studies had comorbidities, including diabetes mellitus (n = 39), hypertension (n = 28), and hyperlipidemia (n = 7) [21, 22]. Seven studies (70%) reported anti-VEGF outcomes in non-proliferative MacTel [11–13, 20, 21, 23, 24], and three studies (30%) studied proliferative MacTel [18, 19, 22]. Proliferative MacTel assessed 109 eyes of 92 patients with CNV [18, 19, 22]. The anti-VEGF agents included in the analysis dataset were intravitreal ranibizumab (IVR, n = 6) [1–13, 19, 22, 24], bevacizumab (IVB, n = 5) [19–23], and aflibercept (IVA, n = 1) [19]. One study did not specify the anti-VEGF agent [18]. A summary of baseline demographic and patient characteristics is included in Table 1, study outcomes are summarized in Table 2, and outcomes of anti-VEGF treatment are detailed in Table 3.
Table 1.
Baseline characteristics of included studies
| Study | Study type | Study type | Study period | Country | Anti-VEGF agent | Comparator | Eyes affected, n | Age, years, mean (SD) | Males, n |
|---|---|---|---|---|---|---|---|---|---|
| Charbel Issa et al. [12] (2011) | Prospective | Non-randomized clinical trial | 2007–2008 | Germany | RAN | Treated eye | 10 | 62.9 | 3/10 |
| Untreated fellow eye | 10 | 62.9 | 3/10 | ||||||
| Coban Karatas et al. [18] (2022) | Retrospective | Chart review | 2012–2019 | Turkey | NR | MacTel 2 | 49 | 65.4 | 3/26 |
| Control group | 60 | 61.86 | 0/30 | ||||||
| Subgroup with macular neovascularization | 8 | NR | NR | ||||||
| Do et al. [11] (2014) | Prospective | Randomized trial | 2006–2007 | USA | RAN | RAN higher dose | 5 | 53.5 | 7/10 |
| RAN lower dose | 5 | 53.5 | |||||||
| All RAN | 10 | 53.5 | 7/10 | ||||||
| All fellow eyes | 10 | 53.5 | 7/10 | ||||||
| Karasu et al. [19] (2020) | Retrospective | Retrospective chart review | 2016–2018 | Turkey | AFL, RAN, BEV | AFL | 10 | 64.4 (9.62) | 6/8 |
| RAN | 14 | 59.71 (4.49) | 6/13 | ||||||
| BEV | 14 | 54 (18.31) | 8/13 | ||||||
| Kupitz et al. [24] (2015) | Prospective | Follow-up of a nonrandomized clinical trial | 2007–2013 | Germany | RAN | Treated eye | 9 | 62.6 | 2/9 |
| Untreated fellow eye | 9 | 62.6 | 2/9 | ||||||
| Matt et al. [20] (2020) | Retrospective | Case series | N/A | Austria | BEV | BEV | 7 | 58.6 (6.8) | 3/7 |
| Control (eyes with silent MacTel 2) | 16 | 59.8 (10.4) | 8/16 | ||||||
| Manayath et al. [21] (2020) | Retrospective | Case series | 2016–2018 | India | BEV, RAN | BEV or RAN | 8 | 52.2 (6.1) | 0/13 |
| Observation | 8 | 52.2 (6.1) | |||||||
| Sen et al. [22] (2021) | Retrospective | Chart review | 2015–2019 | India | BEV, RAN | BEV | 56 | 57.3 (9.9) | 23/64 |
| RAN | 8 | NR | |||||||
| Sigler et al. [23] (2013) | Retrospective | Case series | 2007–2012 | USA | BEV, PPV | BEV | 15 | 65 (9.2) | 13/28 |
| Observation | 33 | 65 (9.2) | |||||||
| PPV with ILM peel | 8 | 65 (9.2) | |||||||
| Toy et al. [13] (2012) | Prospective | Nonrandomized trial | 2009–2010 | USA | RAN | RAN | 5 | 65.3 (3.3) | 3/5 |
| Control (fellow eyes) | 5 | 65.3 (3.3) |
AFL, aflibercept; BEV, bevacizumab; NR, not reported; RAN, ranibizumab.
Table 2.
Baseline characteristics of study patients and Anti-VEGF treatment regimens
| Study | Anti-VEGF agent | Comparator | Eyes affected, n | Initial BCVA, mean (SD) | Initial choroidal thickness, μm, mean (SD) | Initial macular thickness, μm, mean (SD) | Initial retinal thickness, μm, mean (SD) | Fluorescein leakage MPS DA (SD) | Injections, n | Time to last follow-up, months, mean (SD) |
|---|---|---|---|---|---|---|---|---|---|---|
| Charbel Issa et al. [12] (2011) | RAN | Treated eye | 10 | 20/50 | NR | NR | 333 (39.2) | NR | 12 injections monthly | 13 |
| Untreated fellow eye | 10 | 20/40 | NR | NR | NR | NR | NR | 13 | ||
| Coban Karatas [18] (2022) | NR | MacTel 2 | 49 | NR | 168.0 | NR | NR | 2.35 | 5 (1.4) | 33.6 |
| Control group | 60 | NR | 231.0 | NR | NR | 1.36 | 5.4 (0.89) | 33.6 | ||
| Subgroup with macular neovascularization | 8 | NR | NR | NR | N/A | 1.39 | NR | 33.6 | ||
| Do et al. [11] (2014) | RAN | 0.3 mg RAN | 5 | 54 (42–84); 20/80 (20/160–20/20) | 182.0 (133–233) | NR | 168.0 | 2.35 | 6.0 | 6 |
| 0.5 mg RAN | 5 | 61 (58–87); 20/64 (20/64–20/20) | 246.80 (64.10) | NR | 231.0 | 1.36 | 2.2 (1.54) | 6 | ||
| All RAN | 10 | NR | 274 (51.77) | NR | NR | 1.39 | 5.14 (1.40) | 6 | ||
| All fellow eyes | 10 | 79 (57–82); 20/25 (20/80–20/25) | 289.57 (42.07) | NR | 182.0 (133–233) | 1.28 | 2.64 (1.82) | 6 | ||
| Karasu and Gunay [19] (2020) | AFL, RAN, BEV | AFL | 10 | 0.90 (0.42) | NR | 326.40 (168.03) | 246.80 (64.10) | NR | 2.3 (1.3) | 14.6 (7.70) |
| RAN | 14 | 0.72 (0.53) | NR | 374.57 (124.28) | 274 (51.77) | NR | NR | 18.5 (2.68) | ||
| BEV | 14 | 0.84 (0.46) | NR | 383 (156.40) | 289.57 (42.07) | NR | 2 (1.07) | 14.42 (8.49) | ||
| Kupitz et al. [24] (2015) | RAN | RAN | 9 | 65.1 (10.9) | NR | NR | NR | NR | NR | 72 (4.8) |
| Untreated fellow eyes | 9 | 69.7 (9.1) | NR | NR | NR | NR | NR | 72 (4.8) | ||
| Matt et al. [20] (2020) | BEV | BEV | 7 | 0.47 (0.32) | NR | 260 (83) | NR | Early = 1.80 (1.35), Late = 2.99 (1.31) | NR | 32 (5.7) |
| Control (eyes with silent IMT2) | 16 | 0.30 (0.40) | NR | 201 (32) | NR | Early = 1.03 (1.24), Late = 1.60 (1.56) | 2.11 (1.15) | 29 (8.8) | ||
| Mayanath et al. [21] (2020) | BEV, RAN | BEV or RAN | 8 | NR | NR | NR | NR | NR | 2.37 (1.60) | 9.38 (5.5) |
| Observation | 8 | NR | NR | NR | NR | NR | 5 (1.4) | 7.3 (2.2) | ||
| Sen et al. [22] (2021) | BEV, RAN | BEV | 56 | 0.58 (0.39) | NR | 314.12 (160.21) | NR | NR | 5.4 (0.89) | 15.75 (11.15) |
| RAN | 8 | 0.56 (0.46) | NR | 328.25 (232.04) | NR | NR | NR | 17.87 (23.05) | ||
| Sigler et al. [23] (2013) | BEV, PPV | BEV | 15 | 0.34 (0.49) | NR | NR | NR | NR | 2.5 (3.5) | 18 (6) |
| Observation | 33 | 0.19 (0.18) | NR | NR | NR | NR | NR | 25 (7) | ||
| PPV with ILM peel | 8 | 0.63 (0.63) | NR | NR | NR | NR | NR | 29 (9) | ||
| Toy et al. [13] (2012) | RAN | RAN | 5 | 62.8 (13.3); 20/63 | NR | NR | 204 (38) | NR | Late = 2.5 (1.9) | 14 |
| Control (fellow eyes) | 5 | 61.4 (10); 20/63 | NR | NR | 219 (44) | NR | Late = 2.3 (2.3) | 14 |
AFL, aflibercept; BEV, bevacizumab; MPS DA, macular photocoagulation study disc area; NR, not reported; RAN, ranibizumab.
Table 3.
Outcomes of anti-VEGF-treated MacTel patients and control groups
| Study | Anti-VEGF agent | Comparator (clean up) | Eyes affected, n | Final BCVA, mean (SD) (separate into final and change columns) | Final choroidal thickness, mean (SD) | Final macular thickness, μm, mean (SD) | Final retinal thickness, μm, mean (SD) | Final Fluorescein leakage MPS DA (unit) | Injections, n | Time to last follow-up, months |
|---|---|---|---|---|---|---|---|---|---|---|
| Charbel Issa et al. [12] (2011) | RAN | Treated eye | 10 | Change: + 3.5 (5.4) letters | NR | NR | Decrease 16%; −53 (26.8) | NR | 12 injections monthly | 13 |
| Untreated fellow eye | 10 | Change: + 3.7 (5.9) letters | NR | NR | NR | NR | NR | 13 | ||
| Coban Karatas et al. [18] (2022) | NR | MacTel 2 | 49 | NR | NR | NR | NR | NR | 5 (1.4) | 33.6 |
| Control group | 60 | NR | NR | NR | NR | NR | 5.4 (0.89) | 33.6 | ||
| Subgroup with macular neovascularization | 8 | N/A | 262 | 237.33 | NR | NR | NR | 33.6 | ||
| Do et al. [11] (2014) | RAN | 0.3 mg RAN | 5 | Change: + 4.0 (−5 to +10) | NR | NR | NR | Change: −0.68 (−0.68 to −0.43) | 6.0 | 6 |
| 0.5 mg RAN | 5 | Change: + 8.0 (2 to +16) | NR | NR | NR | Change: −0.82 (−0.88 to −0.36) | 2.2 (1.54) | 6 | ||
| All RAN | 10 | Change: + 6.0 (−5 to +16) | NR | NR | NR | Change: −0.72 (−0.88 to −0.36) | 5.14 (1.40) | 6 | ||
| All fellow eyes | 10 | Change: + 5.0 (−7 to +7) | NR | NR | NR | Change: −0.12 (−0.79 to +0.13) | 2.64 (1.82) | 6 | ||
| Karasu and Gunay [19] (2020) | AFL, RAN, BEV | AFL | 10 | 0.52 (0.41) | NR | 236.00 (58.33) | 219.60 (64.91) | NR | 2.3 (1.3) | 14.6 (7.70) |
| RAN | 14 | 0.50 (0.45) | NR | 339.71 (126.10) | 242.14 (35.25) | NR | NR | 18.5 (2.68) | ||
| BEV | 14 | 0.55 (0.21) | NR | 343.85 (146.25) | 265.85 (46.24) | NR | 2 (1.07) | 14.42 (8.49) | ||
| Kupitz et al. [24] (2015) | RAN | RAN | 9 | 57.0 [20/80+] (change: −8.9) | NR | NR | NR | NR | NR | NR |
| Untreated fellow eyes | 9 | 69.1 [20/50+] (change: −1.5) | NR | NR | NR | NR | NR | NR | ||
| Matt [20] (2020) | BEV | BEV | 7 | logMAR, 0.33 (0.31) | NR | 202 (37) | NR | Early = 1.61 (1.5) mm2; late = 2.52 (1.35) mm | NR | 32 (5.7) |
| Control (eyes with silent MacTel 2) | 16 | logMAR 0.30 (0.40) | NR | 199 (29) | NR | Early = 1.13 (1.05) mm2; late = 1.60 (1.56) mm | 2.11 (1.15) | 29 (8.8) | ||
| Manayath et al. [21] (2020) | BEV, RAN | BEV or RAN | 8 | 20/80 (2); 20/30 (4); 20/20 (2) | NR | NR | NR | NR | 2.37 (1.60) | 9.38 (5.5) |
| Observation | 8 | 20/40 (2); 20/30 (2); 20/80 (1); 20/120 (1); 20/60 (2) | NR | NR | NR | NR | 5 (1.4) | 7.3 (2.2) | ||
| Sen et al. [22] (2021) | BEV, RAN | BEV | 56 | 0.53 (0.33) | NR | 246.75 (119.30) | NR | NR | 5.4 (0.89) | 15.75 (11.15) |
| RAN | 8 | 0.45 (0.31) | NR | 221.50 (127.09) | NR | NR | NR | 17.87 (23.05) | ||
| Sigler et al. [23] (2013) | BEV, PPV | BEV | 15 | 0.25 (0.08); change: 0.02 (0.10) | NR | NR | NR | NR | 2.5 (3.5) | 18 (6) |
| Observation | 33 | 0.18 (0.05); change: 0.09 (0.29) | NR | NR | NR | NR | NR | 25 (7) | ||
| PPV with ILM peel | 8 | 0.57 (0.12); change: −0.06 (0.32) | NR | NR | NR | NR | NR | 29 (9) | ||
| Toy et al. [13] (2012) | RAN | RAN | 5 | Change: 0.0 (7.5) letters | NR | NR | Change: −11.7 (7.0)% | Late = −33 (20)% | NR | 14 |
| Late = +1 (8)% | ||||||||||
| Control (fellow eyes) | 5 | Change: +2.2 (1.9) | NR | NR | Change: −2.9 (3.5)% | NR | NR | 14 |
AFL, aflibercept; BCVA, best-corrected visual acuity; BEV, bevacizumab; ILM, internal limiting membrane; MPS DA, macular photocoagulation study disc area; PPV, pars plana vitrectomy; RAN, ranibizumab.
Risk of Bias and Certainty of Evidence Assessment
The risk of bias evaluation is included in online supplementary Table S2. We evaluated one RCT using the Risk of Bias 2 tool, with 3 domains (42.9%) having a low risk of bias and 4 domains (57.1%) being associated with some concerns. We evaluated 9 observational studies using the ROBINS-I tool, with 44 domains (69.8%) having a moderate risk of bias, 17 domains (27.0%) having a low risk of bias, and 2 domains (3.2%) being associated with a high risk of bias. The proportion of observational studies with a low risk of bias across domains of the ROBINS-I tool was as follows: measurement of outcomes (66.7%), deviations from intended interventions (66.7%), missing data (55.6%), classification of interventions (33.3%), selection of participants into study (33.3%), selection of the reported results (0%), and confounding (0%).
GRADE evaluations of the certainty of evidence found three moderate and two low ratings (online supplementary Table S3). Studies were downgraded for risk of bias (100%), publication bias (100%), and inconsistency (70%). No study had serious inconsistencies, and none were upgraded based on study characteristics and outcomes.
Treatment
Sixty-eight eyes received IVR, 94 eyes received IVB, and 12 eyes received IVA. Patients received an average of 4.65 ± 1.46 injections over a mean of 23.35 ± 6.59 months. While most studies compared anti-VEGF treatment outcomes in MacTel eyes to fellow eyes or healthy controls, the study by Sigler et al. [23] was the only one to compare IVB outcomes to pars plana vitrectomy (PPV) with ILM peeling in MacTel with a lamellar macular hole configuration, epimacular membrane, or vitreo-foveal traction.
Best-Corrected Visual Acuity in Non-Proliferative MacTel
Mean initial logMAR best-corrected visual acuity (BCVA) was found to be 0.42 ± 0.39, or 20/52 across 7 studies of non-proliferative MacTel (n = 119) [11–13, 20, 23, 24]. At final follow-up, BCVA was noted to have a mean of 0.35 ± 0.18, or 20/45 (n = 87) [20, 23, 24]. BCVA of eyes treated with IVR and untreated fellow eyes were improved by 3.5 ± 5.4 and 3.7 ± 5.9 letters, respectively, in one study, whereas a BCVA change from baseline by 0.0 ± 7.5 letters and +2.2 ± 1.9 letters was seen in IVR-treated eyes and untreated fellow eyes in another study, respectively [12, 13]. A comparison of IVR doses in the study by Do et al. [11] found a median change of 4.0 (−5 to +10) and 8.0 (2–16+) ETDRS letters at the 6-month follow-up in the IVR 0.3 mg and IVR 0.5 mg study arms, respectively. The study by Matt et al. [20] noted improvement in 4 eyes (57.1%) by one or more lines and 3 eyes remaining stable (42.9%) in the study arm of MacTel patients receiving IVB (n = 7), while 2 eyes (12.5%) saw improvement by one or more lines, 4 eyes (25%) remained stable, and worsening occured in 10 eyes (62.5%) by one or more lines in the study arm of untreated patients (n = 16). In the study by Manayath et al. [21], the treatment arm of patients receiving IVR or IVB (n = 8) saw BCVA improvement by two or more lines in 3 eyes (37.5%), one line improvement in 4 eyes (50.0%), and no improvement in 1 eye (12.5%), whereas the untreated fellow eye study arm (n = 8) saw no change in 3 eyes (37.5%), worsening by one line in 2 eyes (25%), and worsening by two lines in 3 eyes (37.5%).
BCVA in Proliferative MacTel
Mean initial logMAR BCVA was found to be 0.66 ± 0.43, or 20/92, across two studies of MacTel with CNV (n = 102) [19, 22]. Final BCVA was 0.52 ± 0.34, or 20/66. While Coban Karatas et al. [18] did not report initial or final BCVA values, in the subgroup of participants with CNV (n = 8), 5 experienced VA improvement, 2 experienced worsening of vision, and 1 participant experienced no change. In another study of eyes with CNV (n = 38), the BCVA changed from 0.82 ± 0.47 to 0.52 ± 0.36 at 15.8 ± 6.3 months of follow-up [19]. In one study involving 8 eyes with CNV, 5 eyes (62.5%) showed improvement in BCVA, 1 eye (12.5%) maintained the same vision, and 2 eyes (25%) experienced a decline in vision [18].
Central Macular Thickness and Central Choroidal Thickness in Non-Proliferative MacTel
CMT outcomes were reported in four out of the 10 studies [18–20, 22], three of which reported on proliferative MacTel [18, 19, 22]. Initial CMT in silent MacTel eyes (n = 16) was reported in one study with 201 ± 32 µm and a final 199 ± 29 µm [20]. CCT outcomes were not reported in non-proliferative MacTel study arms.
CMT and CCT in Proliferative MacTel
CMT for patients with CNV across three studies was 328.23 ± 161.16 µm at initial evaluation and 267.44 ± 118.56 µm at final evaluation (n = 110) over a mean follow-up of 17.3 ± 10.2 months [18, 19, 22]. CMT for healthy control eyes was noted in one study, with an initial mean CMT of 263.58 µm (range 225–297, median 263) (n = 30) [18]. Average CMT in participants with CNV changed from 341.75 µm to 294.34 µm from initial to final evaluation [18, 19]. CCT outcomes were reported in 46 eyes with CNV across two studies [18, 19]. Initial and final CCT was 273.72 ± 51.44 µm and 244.94 ± 47.10 µm, respectively (n = 46) [18, 19].
FA Leakage
Three studies reported FA leakage outcomes from anti-VEGF treatment [11, 13, 20], none of which reported on proliferative MacTel. Do et al. [11] noted an initial leakage of 1.39 mm2 (range: 0.96–2.75) among eyes receiving IVR and 1.28 mm2 (range: 0.92–2.88) among untreated fellow eyes. At 6 months of treatment, a change of −0.72 mm2 (−0.88 to −0.36) and −0.12 mm2 (range: −0.79 to +0.13) was seen in IVR-treated and untreated fellow eyes, respectively. In the study by Matt et al. [20], initial early and late leakage in IVB-treated eyes was 1.80 ± 1.35 mm2 and 2.99 ± 1.31 mm2, respectively, and final early and late leakage was 1.61 ± 1.5 mm2 and 2.52 ± 1.35 mm2 after 32 ± 5.7 months of follow-up, respectively. In untreated silent MacTel eyes, initial early and late leakage was 1.03 ± 1.24 mm2 and 1.60 ± 1.56 mm2, respectively, and final early and late leakage was 1.13 ± 1.05 mm2 and 1.60 ± 1.56 mm2 after 29 ± 8.8 months of follow-up, respectively. Toy et al. [13] reported a late leakage of 2.5 ± 1.9 mm2 and 2.3 ± 2.3 mm2 in treatment and observation study arms before treatment initiation. A change of −33 ± 20% and +1 ± 8% in late leakage among IVR-treated and untreated fellow eyes at final follow-up, respectively [13].
Adverse Events
Out of the 10 included studies, 4 reported no adverse events [11, 13, 20, 22], in which 1 reported on proliferative MacTel [22]. Charbel Issa et al. [12] reported no serious adverse events aside from 1 patient with known diabetic peripheral neuropathy with a history of an increased frequency of falls, who experienced a transient ischemic attack 4 weeks after the 11th treatment of IVR. The last scheduled treatment was omitted as a consequence. Manayath et al. [21] reported recurrence of subfoveal detachment (SFD) in 5 out of 8 treated eyes between 3 and 6 months after initial resolution. IVB (n = 4) and IVR (n = 1) were administered as re-treatment. The remaining studies did not report on the incidence of adverse events [18, 19, 23, 24]. No study reported on significant adverse effects from treatment.
Summary
Overall, 5 studies (50%) suggested that anti-VEGF agents may improve visual acuity and provide favorable functional and anatomical outcomes for MacTel [18–22]. One study (10%) suggested that IVR improved retinal vascular leakage on FA but failed to provide visual acuity benefits [11]. Finally, 4 studies (40%) reported no functional benefit from anti-VEGF therapy in MacTel [12, 13, 23, 24]. When comparing outcomes of proliferative versus non-proliferative MacTel, 4 studies (40%) reporting on non-proliferative MacTel reported no functional improvement or benefit of anti-VEGF therapy [12, 13, 23, 24], 2 studies (20%) reporting on non-proliferative MacTel reported marked functional and morphological outcomes [20, 21], and 1 study (10%) on non-proliferative MacTel suggested that anti-VEGF therapy may be beneficial in improving BCVA [11]. Two studies (20%) reporting on proliferative MacTel reported improvement of anatomical and functional outcomes [19, 22], and 1 study (10%) on proliferative MacTel [18] suggested that anti-VEGF may potentially produce improved outcomes. Overall, it appears that anti-VEGF produces modest results when compared to baseline, with increased potential of improving functional and anatomical outcomes in proliferative MacTel. However, further large-scale studies are warranted to corroborate these findings.
Discussion
This systematic review investigated the comparative efficacy and outcomes of different intravitreal anti-VEGF therapies in eyes with MacTel. Overall, the studies in our review reported favorable anatomical and functional outcomes in MacTel patients receiving anti-VEGF injections compared to observation groups. Based on our findings, there appears to be a pronounced functional benefit of anti-VEGF agents for proliferative MacTel but uncertain benefit in non-proliferative MacTel. The studies also generally reported similarly positive outcomes with minimal adverse events, irrespective of the agent. However, there was a paucity of literature in this area, and our systematic review only included 10 studies that collectively reported on 377 eyes.
MacTel participants with CNV demonstrated more significant improvements of BCVA compared to non-proliferative MacTel. Proliferative MacTel also demonstrated noticeable improvements in proliferative MacTel compared to non-proliferative MacTel. This is in line with evidence of improved BCVA and CMT outcomes with anti-VEGF therapy in the literature [25].
Anti-VEGF agents are increasingly becoming the preferred treatment option for MacTel. By blocking the activation of VEGF and the downstream pathway, anti-VEGF agents reduce vascular permeability, inhibit the growth of CNV, and alleviate macular edema to improve visual acuity [26]. However, the role of VEGF in patients who develop macular neovascularization remains controversial. One hypothesis suggested that endothelial cell degeneration may trigger a vasogenic mechanism without ischemia and inflammation [27], whereas another hypothesis suggested that endothelial cell degeneration may be initiated by Müller cell dysfunction [28, 29].
Most studies reported slightly favorable outcomes with regard to visual acuity. Four out of the five included clinical trials (including the follow-up study by Kupitz et al. [24]) found that visual acuity improvements remained similar in affected and fellow eyes, despite showing evidence of decreased retinal vascular leakage secondary to MacTel [11–13]. On the other hand, the other clinical study reported improved BCVA outcomes, recommending the use of anti-VEGF agents as treatment [20].
Anatomic improvements were sustained only with treatment continuation. Paracentral scotomas and subretinal vascular proliferation were more frequently reported in treated eyes in the years after the study period than in untreated fellow eyes [10, 12, 24]. Across study arms using different treatment regimens of anti-VEGF monotherapy, our systematic review found outcomes to be similar following AFL, BEV, and RAN [19]. Evidence shows that anti-VEGF agents lead to improvements in FA retinal vascular leakage, suggesting an effect on vessel stability and permeability despite an insignificant change in visual acuity [12, 13, 24]. It has been suggested that the discrepancy between anatomical improvement and functional stability could be attributed to the primary microstructural changes in the neuronal retina or due to chronic leakage into the neurosensory retina [7, 12, 30]. Anti-VEGF agents may also cause photoreceptor degeneration through retinal pigment epithelial cell dysfunction [31].
Sigler et al. [23] was the only study to compare anti-VEGF treatment outcomes to PPV surgery. Patients with poor vision and no neovascular process underwent PPV with ILM peeling for a lamellar macular hole configuration, epimacular membrane, or vitreo-foveal traction evident on spectral-domain OCT (SD-OCT). The study noted a recurrence of FA leakage after cessation of anti-VEGF treatment, despite promising results observed during the treatment study period. These patients demonstrated a minimal mean change of 0.09 ± 0.29 EDTRS letters during the follow-up period of a mean of 29 ± 9 months, compared to −0.06 ± 0.32 EDTRS letters with PPV [23].
Several previous reports of MacTel outcomes after IVB reported mixed and inconsistent visual outcomes. Some noted decreased transient angiographic leakage and no definite visual benefit [32–38]. This inconsistency highlights the complexity of disease and the limited efficacy of anti-VEGF therapies in non-neovascular cases. A systematic review by Khodabande et al. [10] highlighted the importance of distinguishing intraretinal fluid typically responsive to anti-VEGF therapy. The review also emphasized the potential neuroprotective role of VEGF in the retina, which may be compromised by anti-VEGF treatment. Evidence supporting this includes the identification of VEGF-A receptors in normal retinal neuronal cells, suggesting a possible functional role for VEGF-A in the neural retina [39–42].
OCT devices, including SD-OCT, swept-source OCT, and enhanced depth imaging OCT, are vital for high-resolution visualization for various retinal conditions, such as MacTel. While SD-OCT offers excellent resolution for detecting subtle structural changes, swept-source OCT can provide added structural visualization, and enhanced depth imaging OCT enhances choroidal imaging, which can help evaluate associated neovascular complications [43, 44].
Advanced imaging, standardized imaging protocols, automated quantification tools, and AI-driven analysis could improve detection of intraretinal changes in both proliferative and non-proliferative MacTel. These imaging techniques have been applied to other settings, requiring the interpretation of subtle imaging findings, such as optic disc maculopathy [45] and management of submacular hemorrhage [46]. These advancements have the potential to help reduce diagnostic variability and refine the monitoring of treatment responses, particularly for anti-VEGF therapies, by providing accurate and reproducible retinal analytics tailored to the unique features of MacTel [47, 48].
This study provides critical insights into the efficacy of anti-VEGF therapies, particularly those with proliferative disease, a condition with limited effective treatment options. It highlights the potential for improved visual and anatomical outcomes in this rare disease population which is otherwise difficult to study. By providing a comprehensive analysis of treatment outcomes, this study serves as a valuable resource for retina specialists, enabling them to make evidence-based decisions tailored to patient needs.
Additionally, the findings emphasize the importance of anti-VEGF therapies in improving both anatomical and functional outcomes in proliferative MacTel, providing evidence that may support practice. Given the lack of large-scale studies in this area, our results call for future research and clinical trials for MacTel.
Limitations of this study should be considered. There were limited studies meeting inclusion criteria, few participants studied, a short duration of treatment, and few randomized controlled trials. The limited number of studies in our review precluded a meta-analysis and any synthesis of evidence for the impact of injection frequency, anti-VEGF agent, anti-VEGF dosage, or treatment regimen on clinical outcomes. Most included studies reported on ranibizumab or bevacizumab (n = 7, n = 5, respectively), and only two studies reported on aflibercept. Adverse events were rarely and inconsistently reported. Our analysis may be impacted by the short follow-up period and limited number of studied eyes.
Conclusion
Our systematic review of 377 eyes of 239 patients found that, in general, there is a lack of literature on visual acuity outcomes in the setting of MacTel. Patients with proliferative MacTel experienced marked functional and anatomical benefits compared to patients with non-proliferative MacTel. Our study suggests that current treatment regimens may be somewhat beneficial and efficacious; however, the limited evidence suggests that further trials are needed, which may also allow for evidence-based guidelines for management of the disease. As a result, this paper calls for further investigation into the long-term impact of anti-VEGF treatment in eyes with MacTel through well-designed randomized controlled trials.
Acknowledgments
Dr. Radha Kohly was not available to confirm co-authorship, but the corresponding author, Mr. Aswen Sriranganathan, affirms that Dr. Radha Kohly contributed to the paper, had the opportunity to review the final version to be published, and guarantees Dr. Radha Kohly co-authorship status and the accuracy of the author contribution and conflict of interest statements.
Statement of Ethics
An ethics statement is not applicable as this study is based exclusively on published literature. This study was conducted ethically and in accordance with the World Medical Association Declaration of Helsinki.
Conflict of Interest Statement
M.M.P.: Financial support (to institution) – PSI Foundation, Fighting. Blindness Canada. P.J.K.: Advisory board – Novartis, Bayer, Roche, Apellis, Novelty Nobility, Viatris, Biogen; Financial support (to institution) – Bayer, Roche, Novartis, RegenxBio, Janssen, Neuracle Genetics; Ora Gene; Financial support – Novartis, Bayer, Roche, Boehringer Ingelheim, RegenxBio. R.H.M.: Consultant - Alcon, Apellis, AbbVie, Bayer, Bausch Health, Roche; Financial Support (to institution) - Alcon, AbbVie, Bayer, Novartis, Roche. R.P.K.: Financial disclosures – Bayer, Novartis.
Funding Sources
Drs. Kohly and Muni acknowledge financial support for this project by the Silber TARGET Fund.
Author Contributions
Aswen Sriranganathan, Justin Grad, Andrew Mihalache, Marko M. Popovic, Peter J. Kertes, Radha P. Kohly, and Rajeev H. Muni: conception and design, acquisition of data, analysis and interpretation of data, preparation of the manuscript, and final approval of the completed manuscript.
Funding Statement
Drs. Kohly and Muni acknowledge financial support for this project by the Silber TARGET Fund.
Data Availability Statement
All available data are available in this article and online as supplementary information. Further inquiries may be directed to the corresponding author.
Supplementary Material.
Supplementary Material.
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Data Availability Statement
All available data are available in this article and online as supplementary information. Further inquiries may be directed to the corresponding author.
