Treatment of retinopathy of prematurity with vascular endothelial growth factor inhibitors
Section snippets
Three epidemics of ROP
There have been three epidemics of ROP [1]. ROP first occurred for about a decade from 1943 to 1953 when it became possible to deliver concentrated oxygen to an infant in a closed incubator. In industrialized countries, many infants developed ROP before it was recognized that oxygen was the primary factor causing the disease (first epidemic). In this epidemic, infants were relatively large (> 1000 g””) since medical practice had not advanced sufficiently to save very small preterm infants.
Current classification, screening and treatment of ROP
Clinically, knowledge of the most recent classification of ROP [2], [3], the rules guiding screening for the development of treatment warranted ROP [4], [5], and the recommendations for treatment of ROP [6] are essential for obtaining optimal visual outcomes.
Classification now places plus disease as the most important observation to be made. Many systems are being developed to provide computer assisted analysis of plus disease. However, none of these systems has been adopted as a standard of
Normal intra-uterine inner retinal vascular development
Differentiation of the cellular components of the retina occurs from the optic disc toward the ora serrata and from the vitreal surface toward the sclera surface of the eye. There are two processes that underlie the development of normal inner retinal vascularization. The first process is vasculogenesis which occurs from approximately 12 to 21 weeks gestational age from the optic nerve to the ora serrata and involves vascular precursor cells. These cells do not migrate into the future fovea.
Pathogenesis of ROP—abnormal extra-uterine inner retinal vascular development with neovascularization
ROP is a neovascularization of the inner retinal vessels that progresses in a small percentage of high risk infants in a predetermined timeline that has some variability, but is rather predictable. ROP occurs in two phases: a vaso-obliterative phase and a vaso-proliferative phase [8].
Current treatments
Near confluent laser therapy is the current standard of care and ideally can be performed in Phase II (Type 1—ETROP). Unfortunately, the therapy is destructive and the retinal vessels never advance beyond the original point of treatment (see Fig. 1).
Anti-VEGF therapy is a controversial treatment which also ideally can be employed in Phase II (Type 1—ETROP). Although VEGF is not the only driving force in the pathogenesis of ROP, it is a very significant factor. The therapy is not destructive and
Recurrence of ROP following ROP treatment
If near confluent laser therapy begins as early as 31 weeks, ROP can persist (resistant to ablative therapy) or it can regress and then recur as early as one week following therapy until at least 55 weeks post menstrual age (rarely). Recurrence is observed overlying the treated areas with the return of plus disease and the eventual formation of tractional membranes. Traditionally, recurrence is treated by laser therapy ± vitrectomy as necessary. Anti-VEGF therapy may be used also, recognizing that
Ocular benefits of anti-VEGF therapy
Anti-VEGF therapy may not only stop the advance of severe ROP, but have the added benefit of allowing the vasculature to develop anteriorly as far as the precursors had migrated prior to preterm birth. Normally, the peripheral retina in very small infants never reaches the ora serrata, that is, an anterior avascular zone of the retina is a permanent marker of a former preterm infant [9].
Additionally, anti-VEGF therapy may allow the vasculature of the posterior retina to develop more normally by
Evidence of local safety of anti-VEGF therapy
One immuno-histopathologic case report of both eyes of an infant who received two doses of anti-VEGF therapy (bevacizumab) prior to death has been published. This report makes several important points. Bevacizumab is not toxic to the very immature retina since all layers of the retina and the inner retinal and choroidal vessels developed normally after two, small, sequential doses of bevacizumab (0.050 mg in 0.02 mL). Anti-VEGF therapy is very successful even in treating APROP in the very
Potential complications of local anti-VEGF therapy
Although infection is rare with intravitreal injections, extreme measures must be used to maintain sterility when administering anti-VEGF therapy for ROP to prevent endophthalmitis.
The lens is larger in the premature infant relative to the overall ocular volume and the lens/ocular volume ratio decreases with age. However, this knowledge emphasizes the need to avoid the lens by injecting about 2 mm posterior to the limbus and aiming posteriorly while injecting to avoid the formation of cataract
Specific method of treatment to decrease complications of local anti-VEGF therapy
The specific method for administering anti-VEGF therapy for ROP is very important since their eyes are smaller and the lens is larger than that of the adult eye. In the smallest infants, the lens may occupy at least one third of the anterior-posterior length of the eye. The most important objective is to avoid complications. Sterility will avoid endophthalmitis. Avoiding the lens and its zonules will avoid cataract and lens dislocation. The following protocol has been followed for intravitreal
Evidence of systemic safety of anti-VEGF Therapy
Many surveys have been done to identify cases of systemic toxicity of anti-VEGF drugs administered into the vitreous. To date these surveys have not uncovered any consistent systemic toxicity in the adult when the drug is given intravitreally. In considering use of anti-VEGF drugs for ROP, it is urgent that we consider any damage that may occur from the small amount of drug that may get into the general circulation to the developing organs of the infant. There are some organs that are
Multiple case series of anti-VEGF therapy for ROP with and without supplemental laser and/or vitrectomy
The literature provides many case reports using intravitreal injection of anti-VEGF therapy (primarily bevacizumab, but also pegaptanib, ranibizumab, and aflibercept) in combination with laser (with or without vitrectomy). Further, the literature provides multiple case series, and randomized clinical trials [13], [14], [15] suggesting that intravitreal injection of anti-VEGF as monotherapy offers better efficacy, and fewer local side effects and complications. However, the use of intravitreal
Conflict of interest statement
The author has no conflicts of interest to declare.
Acknowledgements
The author wishes to thank all of the participants in the BEAT-ROP Clinical Trial, Members of the University of Texas Health Science Center (CPHS, CCTS, CRU, and other faculty), Pediatrix, Inc., and Clarity Medical Instruments, Inc., who have provided patients, technical assistance, oversight, and encouragement in the studies concerning the use of anti-VEGF therapy for retinopathy of prematurity.
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2023, International Journal of OphthalmologyAppropriate dose of intravitreal ranibizumab for ROP: a retrospective study
2022, BMC OphthalmologyComparison of bevacizumab, ranibizumab and aflibercept in retinopathy of prematurity treatment
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