Contralateral effect of systemic absorption of low dose bevacizumab (Avastin) after unilateral intravitreal injection in severe retinopathy of prematurity (ROP)

Abstract

An extremely premature baby boy born at 23 weeks’ gestational age was treated with unilateral low dose of 0.16 mg/0.025 mL intravitreal bevacizumab in the left eye for aggressive retinopathy of prematurity (ROP). He developed photographically documented changes in his contralateral right eye on imaging 5 days later. Second eye treatment was at 12 days. He has development assessment and ophthalmic review beyond age 2, which is normal. Systemic absorption of the drug caused an end organ effect to slow down and reverse ROP in his untreated right eye. Both eyes vascularised fully. His normal Bayley III developmental score at age 2 is uncommon for a 23-week gestation baby. Even at a low dose, bevacizumab has the potential for end organ effect on the second eye, and therefore other organs. In this case, there are no medium-term measurable neurodevelopmental side-effects. We suggest longer term follow-up is required before excluding unwanted side-effects.

Background

Systemic absorption of bevacizumab (Avastin) is known to occur in retinopathy of prematurity (ROP) following intravitreal injection.^1–3 Reports have been published of second eye reversal of vascular changes associated with a partial treatment effect after contralateral injection of vascular endothelial growth factor (anti-VEGF) drugs.⁴

This is the first report of a contralateral effect of a micro-dose of bevacizumab (Avastin) occurring following a systemic absorption effect.

Case presentation

Baby ‘A’ was born in 2016, at 23 weeks plus 2 days, weighing 600 g. At 10 weeks of age, his left eye was at threshold for treatment with the appearance of posterior aggressive retinopathy of prematurity (ROP), with peripheral flat vascular loops in posterior zone 2 and dilated posterior pole vessels, fulfilling the definition of PLUS disease. The right eye posterior vessels were mildly dilated at a pre-plus stage, with stage 1 ROP at the posterior margin of zone 2. It is the policy within our department to offer laser or bevacizumab (Avastin) for posterior ROP, explaining the known risks and benefits of either, as well as the unknown potential side-effects of systemic VEGF suppression. The parents gave consent for bevacizumab (Avastin) low dose injection, for left eye with right to be injected at the time it had reached threshold for treatment. Intravitreal injection of a pharmacy pre-prepared bevacizumab (Avastin) 0.16 mg/0.025 mL was performed at the cot side. The technique is a standard technique for intravitreal injections, using a lid speculum after instillation of topical anaesthetic, and betadine 5% drops to sterilise the eye. An injection was given at 1.5 mm from the limbus in the infratemporal quadrant, using a 30 gauge, 12 mm long needle inserted several millimetres into the vitreous cavity, with a drop of chloramphenicol post injection. Retinal images were taken prior injection at D=0, then at D=5, then at D=12 and at D=26 post injection (figures 1 and 2). At 12 days, the right eye was injected, due to stasis of vascular development in posterior zone 2, and widening of the ridge (figure 2). Screening was performed according to standard follow-up protocol with two weekly examinations until vascularisation into zone 3 was complete. The sequence is shown in table 1.

Figure 1.

Left eye RetCam images from treatment (Rx) of posterior aggressive retinopathy of prematurity at D=0, to 5 days later D=5, at D=12 then D=26 showing resolution of the abnormal dilated vessels and gradual retinal vascularisation over time.

Figure 2.

Right eye. Sequence of RetCam images showing vessels prior left eye treatment on D=0, after 5 days D=5, D=12 when the right eye was injected (Rx), and D=26 as the fundal vasculature extends into zone 2 with no retinopathy of prematurity.

Table 1.

Gestational age Birth GA 23+2 days	ROP status right eye	ROP status left eye	Action right	Action left
GA 33 plus 5 days (D=0)	Posterior Z2, stage 1, pre-plus	APROP with PLUS, posterior Z2 stage 1	Observe	Treat 0.16 mg Avastin
GA 34 plus 3 (D=5)	Posterior Z2, stage 1, less tortuous, pre-plus	Posterior Z2, stage1, no plus	Observe	Observe
GA 35 plus 3 (D=12)	Posterior Z2, pre-plus, wider stage 1	Z2, no ROP, no plus	Treat 0.16 mg Avastin	Observe
GA 37 plus 3 (D=26)	Z2, no ROP	Z2, no ROP	Observe	Observe

ROP, retinopathy of prematurity.

At D=5, a significant reduction in both tortuosity and dilatation was noted in the left, injected eye. The right eye was also noted to have less tortuosity than previously seen without progression of ROP at the peripheral border. This change was confirmed by direct comparison of photographic images. Right eye treatment was therefore postponed (figure 3).

Figure 3.

Right eye at D=0, and D=5. The magnified macular images show the reduced tortuosity of macular vessels. Note the curves are ‘straighter’ on the right image with less vessel ‘kinks’. This demonstrates the effect of the bevacizumab, via systemic absorption from contralateral left eye injection at D=0.

Outcome and follow-up

The 2-year follow-up of visual acuity and refraction was normal with orthophoria, Cardiff cards 0.2 in either eye and minimal refractive error. Neurodevelopmental assessment at age 2, as part of a Bayley III score was well within the normal range for 2 years old as shown in table 2.

Table 2.

Bayley development assessment age 2 years corrected age

	Total raw score	Percentile rank	Development age in months
Cognitive	63	50th	24
Receptive communication	26		23
Expressive communication	26		21
Sum of communication scores		34th
Fine motor	42		28
Gross motor	52		18
Sum of motor scores		50th

A score in any category greater than 16 is considered normal. These scores are suggestive of a child developing well despite extreme prematurity.

Discussion

This case report demonstrates that injections of a low dose of bevacizumab (Avastin) to each eye, separated by 12 days, are effective in preventing ROP progression and allowing full retinal vascularisation in both eyes. It also demonstrates that even a low dose of bevacizumab (Avastin) can be seen to have an end organ effect via systemic absorption in the blood stream affecting retinal vessels and therefore binding VEGF in the contralateral eye. It is the first case report demonstrating the effect of even a low dose of bevacizumab (Avastin) on the untreated contralateral eye. One case report exists documenting photographic evidence of decreased dilatation of posterior pole and peripheral retinal shunt vessels in the contralateral eye of a baby treated for type 1 ROP with a 0.625 mg dose of bevacizumab (Avastin) injected intravitreally. The images do not show a reduction in tortuosity of these vessels, but do show a comparative reduction in vessel dilatation and engorgement.⁴Ours is the first case report that documents decreased tortuosity in the contralateral eye of a baby treated with a low dose of bevacizumab (Avastin) by intravitreal injection. The dose is 25% of that previously described causing contralateral reduction in vascular dilatation.

This dose has been effective in treating ROP and reported in several case series for ROP treatment.^5–7 This systemic absorption is at the heart of developmental concerns because of VEGF suppression.¹ Our initial concern was that the time gap between doses for the second eye might prolong the exposure of circulating VEGF in the blood stream to the drug and therefore have a potential for affecting development, more so than a simultaneous bilateral injection? At the age of 2, vision is good in both eyes, without strabismus or significant refractive error. Neurodevelopment is well in the normal range according to the internationally accepted Bayley III scale, although higher neurological functions will be assessed as the child approaches school age. Therefore, the effect that suppression of VEGF on the developing fetus is clearly not easily elucidated, particularly considering the normal development demonstrable in other case reports and case series.

Since its use for ROP began, concerns have existed that anti-VEGF drugs, namely ranizumab (Lucentis) and bevacizumab (Avastin) might cause unwanted systemic side effects by reducing circulating VEGF in the developing baby.⁸ The literature is growing demonstrating that both

drugs are absorbed, but that bevacizumab’s (Avastin) suppressive effect on serum VEGF is probably of the order of several weeks in the systemic circulation.¹

This is comparable to ranizumab (Lucentis) which possibly has a very short effect on systemic circulating VEGF of the order of days.⁸Evidence also exists that ranizumab (Lucentis) may have a shorter effect on VEGF in the eye, requiring possible more retreatments or a greater incidence of laser pan retinal photocoagulation for reactivation off sight threatening ROP, compared with bevacizumab (Avastin) which has a longer effect.⁹

Dose finding studies also suggest that lower doses of bevacizumab (Avastin) may have a reduced suppressive effect on circulating VEGF compared with higher doses and may lead to better peripheral retinal vascularisation.^{6 7 10}Neurodevelopment is a concern for this modern treatment. While one paper can be found that showed the treatment group had lower developmental score,¹¹ there are several others that show little or no difference between babies treated with bevacizumab (Avastin).^12–15No long-term studies exist and there are no large prospective trials exist assessing longer term safety. Bevacizumab (Avastin) is a widely used drug in treatment of type 1 ROP, particularly zone 1 or posterior zone 2 APROP, where a large ischaemic retina exists at presentation, and laser treatment is less effective at preventing retinal detachment than anti-VEGF treatment.¹⁶ Bevacizumab (Avastin) has become the drug of choice worldwide. Ranizumab (Lucentis) is becoming more prominent following an increasing number of articles and trials demonstrating treatment success, with evidence of shorter duration of systemic VEGF suppression. Question marks remain for both drugs regarding optimal dosing and follow-up because of relatively high retreatment rates with laser or re injection, particularly for ranizumab (Lucentis).^{9 17 18} These drugs are extremely effective in treating the most aggressive and posterior forms of ROP. There has so far been no significant evidence of side effects that compromise their use, but optimal dosing, and long-term follow-up of treated cases remain significant questions requiring further research.

Learning points.

• Bevacizumab (Avastin), even in low doses is absorbed into the systemic circulation and has a demonstrable effect on retinopathy of prematurity and blood vessels in the contralateral eye.

• End organ effects of anti-vascular endothelial growth factor drugs are demonstrable in the untreated eye, and therefore may haven effect on other organ and brain development.

• Neurological development appears to be normal in the short and medium term but longer term possible side-effects cannot be excluded.