Diabetic retinopathy (DR) has long been known to be the leading cause of vision loss in the working-age adult population.¹ Over time, it has been estimated that up to 60% of individuals with diabetes will develop proliferative diabetic retinopathy (PDR), the more advanced form of this condition that is associated with an increased risk for significant vision loss due to complications such as vitreous hemorrhage (VH) and tractional retinal detachment (TRD).² Although these complications are manageable with surgery, many times there is residual visual impairment due to ischemic and inflammatory damage to the retina. There are also significant secondary costs to patients, health care systems, and society, due to travel, reoperations, additional interventions that are sometimes needed, and lost work days.³

Efforts to prevent these severe complications of PDR have been undertaken for decades, starting with the Diabetic Retinopathy Study, which defined high-risk PDR and demonstrated that panretinal photocoagulation (PRP) reduced the risk for severe vision loss by 50% in these patients.^4,5 Laser PRP has since been the mainstay of preventing TRD and VH in patients with PDR.⁶ However, since anti-vascular endothelial growth factor (anti-VEGF) therapy became part of the treatment paradigm for diabetic macular edema (DME), it has been noted that it is also capable of regressing the severity of diabetic retinopathy of treated patients. This was first noted with ranibizumab treatment in the RISE and RIDE studies,⁷ and it was later directly investigated in the DRCRnet Protocol S study, which compared ranibizumab and PRP in patients with PDR. The results showed that the 2 treatments were equivalent in terms of visual acuity and regression of retinal neovascularization, but there was a significantly lower rate of DME and need for pars plana vitrectomy (PPV) in eyes treated with ranibizumab.⁸ Noninferiority in comparison to PRP in PDR patients was later also shown in large studies with aflibercept⁹ and bevacizumab,¹⁰ and at the present anti-VEGF therapy is considered an alternative modality for the treatment of PDR.

Although any treatment for PDR is primarily preventive, some concern exists that anti-VEGF therapy may induce tractional retinal detachment. This potential complication has been dubbed “crunch” phenomenon, effect, or syndrome, and it has been described in cases of retinopathy of prematurity, PDR, and other conditions, such as Coats disease, Eales disease, and familial exudative vitreoretinopathy.¹¹ Tractional retinal detachment is a potential complication of these retinal diseases, and to be considered a complication of anti-VEGF therapy, it should have a sudden onset, up to 6 weeks from an intravitreal injection of an anti-VEGF agent.

A review of “crunch” cases in patients with PDR revealed that the majority of cases reported in the literature were in eyes treated with bevacizumab, with incidence varying from 1.5% to 18.4%, although it should be noted these series were not large, and they included patients with varying severity of PDR and length of follow-up, explaining this wide range.¹¹ These rates are higher than those reported in large-scale clinical trials, in which TRD has seldom been reported as a complication of anti-VEGF therapy. The real-world incidence of this complication in difficult to estimate, but it is likely relatively low.

It is important to remember that TRD is an inherent part of the natural history of PDR itself, and it has also been reported following PRP treatment.¹² It is worthy to note that in the above-mentioned comparative 5-year study, the rate of TRD occurrence was lower in the group of PDR patients treated with ranibizumab than in those treated with PRP.¹² This leads to the clinical question: which is greater, the risk of anti-VEGF-induced TRD or this therapy’s ability to prevent it?

In an attempt to answer this question, a pooled analysis of 5 DRCR Retina Network studies — Protocols I, J, N, S, and T — was performed. In these studies, patients with pre-existing TRD involving or threatening the macula were not included, nor were patients with extramacular TRD who were expected to require surgical intervention. At 1 year, the cumulative probability of TRD development was lower in eyes treated with anti-VEGF injections than in controls (4.8% vs 6.8%), as was the cumulative probability of undergoing PPV (2.2% vs 4.4%). It should be noted that due to the overall low rate of TRD, these differences did not achieve statistical significance.¹³ The results of this analysis indicate that anti-VEGF therapy in PDR does not increase the risk for TRD or surgical intervention and likely has a good efficacy and safety profile for its prevention.

Moreover, preoperative anti-VEGF injections, administered prior to planned PPV in diabetic patients, is considered a useful adjunct that aids in reducing intraoperative bleeding, surgical visualization, surgery time, and intraoperative and postoperative complications; also, it has been advocated in cases with TRD.¹⁴ Because most cases of crunch following anti-VEGF injection occur up to 4 weeks from the injection, with a mean of 13 days,¹¹ it is recommended to perform preoperative injections no longer than 7 days to 10 days prior to surgery.

Anti-VEGF-induced TRD is a relatively rare complication of therapy, whose benefit greatly overweighs this risk. Review of the available literature identified a few risk factors, including pre-existing extensive areas of angiogenesis and fibrous proliferation (especially a ring-shaped fibrovascular membrane surrounding the macula), absence of PRP, long duration of diabetes (more than 15 years), and a delay of more than 2 weeks between anti-VEGF injection and planned PPV.¹¹ Additionally, one study reported higher rates of this complication using an increased dose of bevacizumab (2.5 mg), which is seldom used in clinical practice.¹⁵

The mechanism of this complication is not fully elucidated, but the leading theory refers to an “angiofibrotic switch.” It has been shown that anti-VEGF therapy reduces levels of VEGF in the vitreous, but not those of connective tissue growth factor (CTGF).¹⁶ Anti-VEGF therapy increases the CTGF/VEGF ratio and promotes fibrosis, which may lead to rapid traction and TRD in PDR. In a study of PDR patients who underwent surgery for TRD, it was shown that in eyes treated with bevacizumab prior to surgery, vitreous levels of VEGF were lower than in eyes that were not injected prior to surgery, with similar levels of CTGF. Membranes obtained from eyes treated with bevacizumab prior to surgery demonstrated higher rates of apoptosis.¹⁷ It has also been suggested that VEGF-inhibition upregulates the expression of transforming growth factor-β and contracts retinal blood vessels, thus affecting the vascular microenvironment and promoting fibrosis.¹⁸

CONCLUSION

Although not frequently encountered, anti-VEGF-induced TRD is a possible complication. Patients with DR — and especially PDR — are numerous, expected to increase in the future, and require long-term follow up and management. As more of these patients are treated with anti-VEGF injections, induced TRD may complicate treatment in some of them. Available literature suggests that the benefits of anti-VEGF therapy for PDR are much greater than its risks, specifically when comparing TRD prevention and induction, and it may also facilitate surgery in eyes with TRD. Clinicians following and treating such patients should be aware of this potential complication following intravitreal injections, especially in patients with pre-existing TRDs and considerable retinal fibrosis. It is possible that risk of this phenomenon is higher with bevacizumab than with other anti-VEGF agents, but this has not been substantiated. Additionally, in TRD cases scheduled for PPV, if a preoperative anti-VEGF injection is performed, surgery must not be delayed. RP

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