Intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case report

Introduction

The worldwide prevalence of blindness from retinopathy of prematurity is 50,000. ¹ It is a neovascular retinal disorder that causes blindness through aberrant vascularisation, macular dragging and ultimately retinal detachment.

Normal vascularisation of the innermost retina begins at 16 weeks gestation. Arising from the optic nerve, the retinal vasculature grows out to the peripheral retina by 40 weeks gestation.

Three retinal vascular zones have been identified. Zone I is a circular zone centred on the optic nerve and extending outwards to a radius twice the distance of the optic nerve to the fovea. Zone II encircles Zone I and extends to the nasal extreme of the retina. Zone III is a crescent of retina on the temporal extreme of the retina (see Figure 1). Retinopathy of prematurity affecting Zone I is the most difficult to treat.^2–6 OPEN IN VIEWER

Five stages of retinopathy of prematurity have been defined based on vessel appearance at the interface between the vascular and avascular regions. The interface appears as a fine line for stage 1, a ridge for stage 2 and a ridge with neovascularisation projecting into the vitreous for stage 3. Stage 4 is characterised by fibrous bands causing partial retinal detachment and stage 5 describes total retinal detachment. The term ‘plus disease’ intimates that at least two quadrants have tortuous vessels near the disc.

Conventional treatment of retinopathy of prematurity has centred on peripheral laser therapy since the 1990s. Laser therapy destroys peripheral cells that are producing vascular endothelial growth factor (VEGF). Since VEGF is responsible for the growth of the aberrant vessels, the stimulus for their production is removed and retinal detachment is avoided in approximately 50% of cases with Zone I disease. Unfortunately, this treatment modality requires mass destruction of the peripheral retina and consequently the patient is left with grossly constricted visual fields. Additionally, significant myopia can be induced. ³

Anti-VEGF drugs are an increasingly useful treatment modality within ophthalmology despite their origins as anti-cancer therapy. They are used for the treatment of wet age-related macular degeneration, diabetic retinopathies, vascular occlusions and more. A few case series have been reported in the literature of retinopathy of prematurity treated with bevacizumab, both as monotherapy and in combination with laser therapy or vitrectomy. Successes are reported for patients with stage 3+, 4 and 5, and in February 2011, Mintz-Hittner et al. ² published the first prospective, controlled, randomised, stratified, multicentre trial to ascertain the efficacy of intravitreal bevacizumab for stage 3+ retinopathy of maturity that showed significant benefit over laser therapy for Zone I disease. To our knowledge, we describe the first case in Scotland of a patient with retinopathy of prematurity to be treated with intravitreal bevacizumab.

Case report

A baby boy born prematurely at 26⁺³ weeks was referred to ophthalmology by the special care baby unit to identify any retinopathy of prematurity. At the time of referral, his many problems included intrauterine growth retardation, absent end-diastolic flow (identified on maternal Doppler scan), hyperglycaemia, hypotension, respiratory distress syndrome, thrombocytopaenia, recent sepsis, patent ductus arteriosus, food intolerance, a cardiac arrest and necrotising enterocolitis. He had required two procedures to ligate his patent ductus arteriosus and had a chest drain in situ. He had a post-menstrual age of 36 weeks.

Initially, there was no evidence of retinopathy, but after two weeks, examination revealed stage 3+ retinopathy of prematurity located very posteriorly with widespread haemorrhaging. Unfortunately, due to the precarious condition of the patient and difficulty with positioning, fundal photographs could not be obtained and laser treatment would prove extremely difficult. It was decided, with support from senior hospital management, that bevacizumab seemed the best treatment option.

At the bedside, the patient was prepared using topical proxymetacaine eye drops and betadine antiseptic solution. Bevacizumab (0.625 mg) was administered with ease to both eyes by intravitreal injection. Due to the relatively large size of the lens at this post-menstrual age, it is necessary to inject slightly more posterior to the limbus than usual and to aim very posteriorly.

The patient was examined again two days later and although there was still some ‘plus disease’, the stage III ridge had disappeared and very few haemorrhages remained. Over the next few weeks, normal vasculature appeared out to much of the peripheral retina and no macular traction or retinal detachment was noted (see Figure 2). Ultimately, no evidence of retinopathy of prematurity remained, but there was still some peripheral avascular retina. The long-term outcome of the treatment, including visual potential, remains to be evaluated. OPEN IN VIEWER

Discussion

The use of anti-VEGF drugs in the management of retinopathy of prematurity is an emerging treatment modality. In our patient, severe 3+ disease was easily and successfully treated at the bedside with a single injection to each eye and with no apparent discomfort or distress to the patient.

Bevacizumab is a relatively inexpensive drug that is less cumbersome than laser therapy, requires no specifically designated laser room, no expensive equipment and no endotracheal intubation, and whilst having statistically significant better outcomes for Zone I disease, it avoids the peripheral retinal destruction characteristic of laser therapy. Follow up is required for a longer period with bevacizumab than with laser therapy as recurrence can occur up to 16 weeks post-injection as opposed to six weeks with laser therapy. ²

At the time of writing, no long-term large studies exist that examine the morbidity and mortality of patients treated with bevacizumab. As a large-sized molecule, systemic absorption is not thought to be commonplace with bevacizumab, but it is of interest to note that VEGF is implicated in some of the respiratory complications of prematurity and any systemic effects of bevacizumab might also include an improvement of respiratory recovery.