(Avastin, Genentech) has been used for the treatment of ROP. The first cases were treated by our group in September 2005,23,24 and included patients in whom neither cryotherapy nor laser could be applied because of poor pupil dilation or vitreous hemorrhage, with very good results, which led to a larger series.25

Injection Technique

Treatment can be administered under sedation or general anesthesia. Intravitreal bevacizumab injection is performed as follows. The patient must be prepped with sterile povidone-iodine solution around the eye to be injected. A lid speculum is used to retract the lids, and 2–3 drops of 5% povidone-iodine are placed on the eye to be injected. Using a caliper, 2 mm are measured posterior to the limbus in the inferotemporal quadrant, and 0.05 ml (1.25 mg) of bevacizumab are then injected at this location with a 27 or 30-gauge needle. Anterior-chamber paracentesis must be performed in order to achieve appropriate intraocular pressure.

Patients

Patients to be treated with intravitreal bevacizumab for ROP were divided into three groups. Group I (n = 4 eyes) consisted of ROP stage 4A or 4B that did not respond to conventional treatment. Group II (n = 5 eyes) consisted of threshold disease which was difficult to treat because of vitreous hemorrhage or poor pupil dilation. Group III consisted of high-risk prethreshold or threshold disease (n = 9 eyes). In addition to complete ophthalmologic evaluation, patients underwent complete pediatric evaluation at baseline, 1 day after injection, and in weeks 1, 2, 4, 12, 24, and 38.

risk of touching the lens; and (2) if the patient has retrolental tissue, it can be damaged with the needle, and a vitreous hemorrhage or rhegmatogenous retinal detachment may be induced. Special care must be taken to place the injection site in a meridian where there is no evidence of retrolental tissue or peripheral traction.

Another theoretic ocular complication of intravitreal bevacizumab in patients with ROP is failure of normal peripheral retinal vascularization to complete properly, since VEGF is required for this process. On one hand, this complication has not been described in any of the series or case reports published so far. On the other hand, it has been described as the most common vascular sequela in patients with regressed ROP, even without treatment.28 However, more experience is needed with this treatment to evaluate possible ocular complications.

Systemic Complications

Great attention has been paid to the possible systemic absorption and consequent side-effects of intravitreal bevacizumab in newborns with ROP. Systemic side-effects described in adult patients who have received intravitreal injections of bevacizumab include acute elevation of systemic blood pressure (0.59%), cerebrovascular accidents (0.5%), myocardial infarctions (0.4%), or even death (0.4%).24 Additional questions have been raised in the case of premature infants, because in animal models, VEGF is crucial for normal organ development.29

Evaluating systemic side-effects in preterm newborns becomes very difficult because prematurity itself may be the cause of multiple-organ dysfunction, neurodevelopmental, behavioural, or other sequelae.30 To date, no systemic complication has been reported in published series or case reports. However, there is a need for more solid evidence regarding this treatment, to assess possible systemic side-effects.

Results

Of the four eyes in group I, two of them required vitrectomy, and remained with the retina attached at 38 weeks follow-up. The other two eyes (both of the same patient) had complete regression of neovascularization with spontaneous reattachment of the retina (Figure 25.2).

Of the five eyes in group II, all of them presented regression of neovascularization in the retina and/or the tunica vasculosa lentis at 38-week follow-up, without the need for further treatment (Figure 25.3).

Of the nine eyes in group III, all of them presented complete regression of neovascularization at 38-week follow-up, without the need for further treatment.

There were no adverse ocular or systemic side-effects after intra­ vitreal bevacizumab injection.

Other Reported Results

Travassos et al.26 reported treatment with 0.75 mg intravitreal bevacizumab in three eyes of three patients with AP ROP. Two of the eyes received bevacizumab as the sole treatment for ROP, while one eye also received laser treatment. In the three eyes, complete regression of anteriorand posterior-segment neovascularization was seen, without any ocular or systemic side-effects.

Chung et al.27 reported a case of bilateral aggressive zone I ROP treated with indirect laser and intravitreal bevacizumab as an adjuvant. After 3 months, treatment resulted in ROP regression, prompt resolution of plus signs, and neovascular proliferation in both eyes, without apparent systemic or ocular adverse events.

Concerns with Intravitreal Anti-VEGF Therapy for ROP

Ocular complications

Intravitreal injection of any substance carries the risk for ocular complications, which are more thoroughly discussed in Section 4 of this book. Patients with ROP have ocular pathology that may increase the risk of complications: (1) the injection must be via pars plicata, with increased

Vitrectomy

The technique, outcome, and prognosis of surgical treatment for ROP are beyond the scope of this chapter and may be reviewed elsewhere.31

SUMMARY

ROP is one of the most important causes of preventable blindness among children. Treatment with cryotherapy or laser therapy dramatically modifies the natural history of the disease, but results are far from optimal. Since VEGF plays a prominent role in the pathogenesis of ROP, intravitreal injection of bevacizumab is a promising alternative for the treatment of patients with this disease. Studies so far have yielded encouraging results with very few short-term complications. However, further studies need to be performed to determine the timing, safety, and long-term efficacy and safety of intravitreal bevacizumab for the treatment of ROP, either as first-line therapy with or without laser or after failure of conventional therapy.

Key points

•  ROP is among the leading causes of blindness in children. •  Main risk factors for ROP are birth weight less than 1500 g,

gestational age at birth of 32 weeks or less, and prolonged exposure to high concentrations of oxygen after birth.

•  VEGF plays a key role in the development of the normal retinal vasculature, but in excess may lead to ROP.

•  Conventional treatment for prethreshold and threshold ROP includes laser therapy and cryotherapy.

•  Intravitreal antiangiogenic drugs have proven to be beneficial for the treatment of ROP, alone or in conjunction with conventional treatment.

•  As our understanding of the pathophysiology of ROP becomes clearer, better treatments can be designed to avoid the disastrous consequences in the eyes afflicted with this disease.