Pediatric choroidal neovascularization: should we be more afraid of Virginia Woolf or of the big bad wolf?


Eur J Ophthalmol 2016; 26(5): 385 - 387

Article Type: EDITORIAL



Paolo Nucci, Francesco Pichi

Article History


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Conflict of interest: None.

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In this issue, Barth et al present a retrospective case series of 10 pediatric choroidal neovascular membranes (CNV) and advocate their treatment with intravitreal anti-vascular endothelial growth factor (VEGF). Thus, they join those of us pediatric ophthalmologists who are chanting “Who’s afraid of the big bad wolf?” Same as the 3 little pigs, in this era of intravitreal injections, we sometimes arrogantly believe that our houses of straw and twigs (anti-VEGF) will protect our children from the big bad wolf (CNV).

In the pediatric population, CNV are an uncommon but important cause of visual impairment (1). In this age group, CNVs are typically idiopathic or secondary to infection (2), inflammatory causes (2), optic nerve head anomalies (3, 4), retinal dystrophies, or trauma (5). The infrequency of pediatric CNVs, the limited published data on their natural history, as well as delay in their presentation make the diagnosis and management of pediatric CNVs challenging.

To further complicate things, in the CNV associated with age-related macular degeneration, the cellular constituents of the membranes and the signaling pathways leading to their development are being elucidated. It is not known what types of cells and signaling pathways are responsible for membranogenesis in children. On pathologic analysis, pediatric CNV usually contains an admixture of retinal pigment epithelium (RPE), fibrocytes, collagen, vascular endothelium, and lymphocytes, whereas basal laminar deposits commonly seen in adult CNV are absent (6). Although inflammatory cells appear to play an important role in some of the pediatric CNV cases, RPE cells are the most commonly seen cells of these CNV. The RPE is thought to play an important role in CNV formation, first by recruiting macrophages that produce the membrane matrix itself, and subsequently by elaborating tissue inhibitors of metalloproteinases producing the fibrin scaffold on which the CNV grows.

There is no uniform consensus on the management of these cases because of lack of randomized or controlled clinical trials comparing the different management options for pediatric CNVs, including observation, laser photocoagulation, submacular surgery, photodynamic therapy, and more recently intravitreal injections of anti-VEGF agents.

In terms of observation (7), there is some evidence to suggest that vision-threatening CNVs, secondary to a variety of etiologies, may undergo spontaneous involution with a corresponding recovery in some vision. The decision to observe CNVs in children may be reasonable; however, it is difficult to predict which CNVs will regress without treatment and which will progress with permanent vision loss. Outcomes with observation are guarded in children presenting with visual acuity of 20/200 or worse, and an actively leaking CNV with a neurosensory detachment can put the infant at risk for deprivation amblyopia (8).

Macular laser photocoagulation is possible under anesthesia in a child, usually with the indirect ophthalmoscope laser delivery system. However, even in the presence of a significant neurosensory detachment over the CNV, associated RPE alterations and atrophy are inevitable and a central scotoma tends to develop (8, 9).

Photodynamic therapy also seems to be a viable option for managing pediatric CNVs (7); several case reports suggest that pediatric patients require fewer retreatments than adult patients to achieve improvement in visual acuity. However, we do not know whether there is systemic toxicity from verteporfin in young children.

Submacular surgery has been effective in advanced pediatric cases that are chronic, where the starting visual acuity is poor (<20/200), and in cases in which there is significant neurosensory detachment with severe vision loss; Sears and colleagues (7) reported improved vision in 10 of 12 children, and Uemura (8) reported improved vision after surgery in 15 of 17 children.

Recent work has investigated the possible role of VEGF in the pathogenesis of pediatric CNVs, and reports have demonstrated potential efficacy of anti-VEGF therapy. VEGF is a naturally occurring protein that causes increased vascular permeability (important for the initiation of angiogenesis), endothelial cell migration, and proliferation.

Bevacizumab is a humanized monoclonal antibody that competitively inhibits all isoforms of the VEGF-A family in the extracellular space. While bevacizumab is currently approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer, metastatic breast cancer, and non-small-cell lung cancer, recently it was also introduced in the off-label management of pediatric retinal diseases, as in retinopathy of prematurity (ROP) and Coats disease (8-9-10).

Previous case reports and series have demonstrated the efficacy of intravitreal bevacizumab (IVB) and intravitreal ranibizumab in the management of children with CNVs associated with toxoplasmosis (2), noninfectious uveitis, optic nerve coloboma (3, 4), optic nerve head drusen (5), Best disease (11), choroidal rupture, and various other etiologies.

More recently, Kozak and colleagues (11) retrospectively analyzed the results of 45 eyes of 39 children treated with IVB or ranibizumab for CNVs over a mean follow-up period of 12.8 months. A mean of 2.2 injections per eye were required for treatment. An improvement in visual acuity of >3 lines was seen in 22 eyes (49%), and only 1 eye had worsening of vision after treatment. In the current study, 86% of children treated with IVB for CVNM had improvement or stabilization of their vision. In the retrospective study by Henry et al (12), children receiving bevacizumab as part of the management of pediatric retinal and choroidal conditions other than ROP achieved statistically significant visual gains and reductions in central macular thickness through 12 months’ follow-up.

In adult patients with CNVs secondary to age-related macular degeneration, a treatment regimen with a given anti-VEGF agent is possible following the protocol of large randomized controlled trials. In the pediatric population, however, CNVs are rare and secondary to a variety of etiologies, making it difficult to follow a standardized treatment protocol with all patients. Fewer injections of anti-VEGF agents to stabilize CNVs seem to be required in children compared with adults because of the relative good health of the RPE pump in patients in the younger age group compared with the RPE in adults with age-related macular degeneration.

As for the dosage to employ, children have physically smaller eyes than adults, but children with CNVs also present with very high intraocular VEGF levels prior to treatment (2,394.5 pg/mL compared to 66.8 pg/mL in adults with naive neovascular age-related macular degeneration). At this time, the ideal dosing or specific intravitreal anti-VEGF agent are not known in regards to the treatment of children with pediatric retinal and choroidal diseases. Children in some series received a full 1.25 mg/0.05 mL dose of bevacizumab (11). Other series have used lower doses of IVB, either 0.625 mg or 0.3125 mg, with reported efficacy for ROP (8-9-10-11).

Safety is the major concern with the use of anti-VEGF agents in the pediatric population. We know that VEGF plays an important role in normal angiogenesis, regulation of vascular permeability, endothelial differentiation during fetal brain development, signaling between major neural cells, and the maintenance and development of the blood-brain barrier. The short- and long-term consequences of inhibiting these functions with the use of anti-VEGF agents in children need to be further investigated before we can reliably conclude that anti-VEGF agents are safe in children. Several studies, ranging from case reports to case series involving up to 13 pediatric patients (11, 12), have documented the use of intravitreal anti-VEGF agents for refractory ROP, Coats disease, and familial exudative vitreoretinopathy; these studies reported no ocular or systemic adverse events for the duration of follow-up (ranging from 6 to 12 months). All children treated in the literature presented with potentially blinding ocular conditions (13), and families were consented appropriately that the systemic effects of anti-VEGF in children are not well-known. In general, Avastin was well-tolerated with minimal ocular side effects (8, 9). No serious systemic adverse events can be identified either (11-12-13). The wide variability in the ages of children throughout the literature makes comparison of blood pressure measurements difficult. Nevertheless, a potentially concerning finding from one study was that a statistically significant increase in mean diastolic blood pressure was seen at 12 months (12). Further prospective studies are required to elucidate if this is a valid finding. Finally, if we turn to the pediatric oncology literature, the systemic use of much larger doses of anti-VEGF agents for prolonged periods for the management of refractory pediatric solitary tumors is well-tolerated by most children with few side effects. Ideally, much larger studies with longer follow-up periods are required to document the safety of these medications in children.

When it comes to pediatric intraocular VEGF and anti-VEGF intravitreal treatment, we should drop the arrogance of the three little pigs and think of these two as Martha and George in the 1962 play “Who’s afraid of Virginia Woolf?” These two characters resent each other but still need each other at a profound level. All the current studies hereby discussed are retrospective in design and are not sufficiently powered to assess the safety profile of IVB in the pediatric population. Furthermore, it is likely that anti-VEGF agents will remain off-label in the pediatric population, despite their potential effectiveness, because randomized controlled trials are ethically and logistically difficult. Therefore, we should approach the enemy that we are fighting in these children not with arrogance but with respect.


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Conflict of interest: None.
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  •  San Giuseppe Hospital, University Eye Clinic, Milan - Italy
  •  Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio - USA

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