A Systematic Analysis of the Off-Label Use of Bevacizumab for Severe Retinopathy of Prematurity

Micieli, Jonathan A; Surkont, Michael; Smith, Andrew F.

doi:10.1016/j.ajo.2009.05.031

Cited by 111 publications

(72 citation statements)

References 42 publications

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“…To date, 9 reports (including 6 case reports, 2 retrospective studies, and 1 prospective study) document results of therapy with a VEGF-specific neutralizing antibody (bevacizumab) in ROP, and these have been reviewed in ref. 149. Timing (stage/zone of ROP), dose (0.4-12.5 mg intravitreal), and frequency of administration of bevacizumab, as well as cotreatment with photocoagulation, varied tremendously among reports.…”

Section: Figurementioning

confidence: 99%

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Sapieha¹,

Joyal²,

Rivera³

et al. 2010

J. Clin. Invest.

217

226

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Retinopathy of prematurity (ROP) is a major complication of preterm birth. It encompasses a spectrum of pathologies that affect vision, from mild disease that resolves spontaneously to severe disease that causes retinal detachment and subsequent blindness. The pathologies are characterized by an arrest in normal retinal vascular development associated with microvascular degeneration. The resulting ischemia and retinal hypoxia lead to excessive abnormal compensatory blood vessel growth. However, this neovascularization can lead to fibrous scar formation and culminate in retinal detachment. Present therapeutic modalities to limit the adverse consequences of aberrant neovascularization are invasive and/or tissue-destructive. In this Review, we discuss current concepts on retinal microvascular degeneration, neovascularization, and available treatments, as well as present future perspectives toward more profound elucidation of the pathogenesis of ROP.Retinopathy of prematurity (ROP) is the major ocular disorder of the neonate (1, 2) and the dominant cause of severe visual impairment in childhood in North America and Europe. ROP is associated with significant sequelae, the most serious being retinal detachment, which results in blindness. However, even milder forms of ROP increase the incidence of pathologies that negatively impact visual acuity, for example, ametropias, refractive errors that reduce visual acuity; strabismus, a condition in which the eyes are not properly aligned, preventing proper binocular vision and adversely affecting depth perception; and disorders of color discrimination (3-6). ROP proceeds following an initial phase of degeneration of the retinal microvasculature (vasoobliteration) (7,8) (Figure 1) that is associated with cessation of progression of vascular growth toward the retinal periphery. In the subsequent phase of the disease, the ensuing retinal ischemia predisposes to abnormal compensatory neovascularization (9, 10). Of the various factors that have been associated with the development of ROP, low birth weight, low gestational age, supplemental oxygen therapy, and its associated relative hyperoxia dominate.The development of the human retinal vasculature commences at approximately the 16th week of gestation and concludes at term (i.e., the 40th week of gestation) (11). Hence, when an infant is born prematurely, its retinal blood supply is incomplete and highly vulnerable to decay. This immaturity in vascular development predisposes the retina to complications. Major advances have been made over the past 30 years in identifying mechanisms implicated in the genesis of ROP. Comprehension of mechanisms underlying this disorder has, in turn, enhanced understanding of the pathogenesis of ischemic retinal vasculopathies in the adult, for example, diabetic retinopathy (a complication of diabetes mellitus) and neovascular forms of age-related macular degeneration (the major cause of visual impairment in adults over 50 years of age).The oxygen-induced retinopathy (OIR) model of ischemic retinop...

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Section: Figurementioning

confidence: 99%

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Sapieha¹,

Joyal²,

Rivera³

et al. 2010

J. Clin. Invest.

217

226

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“…Therefore, it has been widely assumed that blood vessel formation per se should be prevented to treat these common blinding diseases (4). A series of anti-VEGF drugs are now being clinically evaluated for their antiangiogenic potency in treating PDR and ROP (5,6). However, to fundamentally resolve disease pathogenesis, the promotion of properly guided angiogenesis to reoxygenize the ischemic retina would be of far greater benefit.…”

Section: Introductionmentioning

confidence: 99%

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

Fukushima¹,

Okada²,

Kataoka³

et al. 2011

J. Clin. Invest.

189

272

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During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuronderived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGFinduced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.

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“…It should be noted that the standard treatment for ROP in the threshold stage is LPC; however, the use of VEGF inhibitors, like bevacizumab, has shown promising results in selected cases. 9 From a pathophysiological standpoint, retinopathy of prematurity is characterized by vascular proliferation promoted by high levels of VEGF; therefore, w h e n using an inhibitor of this molecule, the aim is to conduct a treatment directed against the mechanism of disease production. 10 The intravitreal injection of bevacizumab is a less aggressive procedure on the retina since it prevents peripheral retinal destruction as the one that occurs with the use of laser.…”

Section: Discussionmentioning

confidence: 99%

Intravitreal bevacizumab as single drug therapy for retinopathy of prematurity in 12 patients

2014

Arch Argent Pediat

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Ophthalmological outcomes in a series of children with retinopathy of prematurity (ROP) in the threshold stage treated with intravitreal bevacizumab are reported. Twelve very low birth weight (VLBW) preterm infants who were administered intravitreal bevacizumab as monotherapy for retinopathy of prematurity in the threshold stage and in whom standard laser photocoagulation therapy was contraindicated were evaluated. Ophthalmological examinations were carried out and response to treatment, second interventions, and complications were evaluated. The gestational age of these patients was 26.3 ± 1.8 weeks and their birth weight was 845 ± 153 g. A good response was observed in eight cases, while four patients required to be reintervened with laser photocoagulation. No immediate complications were detected and there were no deaths.

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A Systematic Analysis of the Off-Label Use of Bevacizumab for Severe Retinopathy of Prematurity

Cited by 111 publications

References 42 publications

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice

Intravitreal bevacizumab as single drug therapy for retinopathy of prematurity in 12 patients

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