At the Vascular–Avascular Junction
FA features seen at the vascular–avascular junction included leakage at the active site (Feature 1), abnormal vascular branching (Feature 2) at the large arteriolar level (2a), small arteriolar level (2b), or precapillary level (2c), circumferential vessel formation (i.e., “naked” arteriovenous shunts, Feature 3), hyperfluorescent lesions (i.e., cotton wool like structures or vascular tufts) (Feature 4), and capillary malformations such as capillary tufts (commonly referred to as “popcorn”), focal dilations, and rosary bead-like lesions (Feature 5) (see Figure 2, A–G and Table 4). All eyes (100%, n = 20) examined displayed Features 1 and 5 before treatment, and most of them displayed Feature 4 (90%, n = 18). Concerning the different ROP forms, all eyes examined with posterior Zone II disease (100%, n = 4) displayed, in addition to Features 1 and 5, also Features 2b and 4. This was not the case for Zone I disease and APROP, where only 87% (n = 7) displayed Feature 4 and 50% (n = 4) and 62% (n = 5) Feature 2b, respectively.
At the short-term examination, Feature 2a was always present in Zone I disease (100%, n = 10), but absent in posterior Zone II or APROP. In the latter two groups, Feature 2b was present in 86% (n = 6) of posterior Zone II ROP, and in 50% (n = 3) of APROP. The remaining features were present at low frequency.
At the mid-term examination, Feature 2a was again seen in all Zone I disease eyes (100%, n = 10), whereas only 25% (n = 2) of posterior Zone II and none of the APROP eyes were positive. Feature 3 was observed in almost three quarters of eyes (73%, n = 16), without any correlation to the form of ROP (75%, n = 6; 80%, n = 8; and 50%, n = 2, for posterior Zone II; Zone I; and APROP, respectively).
Long-term examinations revealed the presence of Feature 3 in all eyes examined (100%, n = 10). In addition, albeit at low numbers (n = 2), all eyes (100%) with posterior Zone II showed Feature 2b. Feature 2a was seen in two thirds of cases (n = 4) of Zone I disease.
Inside Vascularized Zone
FA features seen inside the vascularized zone included areas of hypofluorescence (Feature 6) and periarteriolar loss of capillary beds (Feature 7) (Figure 2, H and I and Table 4).
Before treatment, Feature 7 was present in 70% (n = 14) of all eyes, and Feature 6 in 25% (n = 5) (Table 5). Feature 6 was present in 50% (n = 4) of Zone I disease eyes, and only sporadically in the other 2 phenotypes. In contrast, the prevalence of Feature 7 increased from posterior Zone II disease (50%, n = 2) through Zone I disease (62%, n = 5) to APROP (87%, n = 7).
From Week 6 posttreatment onwards, Feature 6 was no longer observed, except in 2 eyes (20%) with Zone I disease at the mid-term evaluation. Similarly, Feature 7 was no longer observed in Zone I disease. In contrast, it was observed in 71% (n = 5) of eyes with posterior Zone II disease and 83% (n = 5) with APROP at the short-term evaluation, and in 75% (n = 6) and 50% (n = 2) at the mid-term evaluation, respectively. Feature 7 was not seen at the long-term follow-up.
FA features analyzed in the macula included absence of the foveal avascular zone (Feature 8), hypoperfusion (Feature 9), and hyperfluorescence due to leakage (Feature 10) (Figure 2, J–L and Table 4). The prevalence of these features before treatment was generally limited, with 25% (n = 5), 5% (n = 1), and 30% (n = 6) for Features 8, 9, and 10, respectively. The prevalence of Feature 8 decreased over time, whereas it increased for Feature 9 from the short-term to the mid-term examination. Feature 10 was seen in 61% (n = 14) of all eyes at the short-term examination, equally distributed among the phenotypes, but was only seen in 9% (n = 2) at the mid-term screening, where it was only present in eyes with APROP (50% of those). None of the features was observed at the long-term examination.
Vascular Outgrowth Into Periphery
For 16 eyes that received IVB successfully as monotherapy, vascular outgrowth into the periphery was documented up to 9 weeks at minimum (range 9–187 weeks) (Figure 3). Calculating the ratio between the distances of the centre of the disc to the border of vascularized zone (D→B) and the centre of the disc to the fovea (D→F) in a 30 weeks old term born child without ROP and unrelated to this study (Figure 3, A and B), we show that the ratio is 4 for the nasal and 5 for the temporal retina in case of full retinal vascularization. This is also schematically visualized in Figure 3C. For the 16 eyes analyzed in this substudy, the mean ratio for the temporal vascularized zone was 4.61 ± 0.27 for all but 2 eyes from one patient (Patient 5), and the mean ratio for the nasal zone (without Patient 5) was 3.73 ± 0.2 (Figure 3D). Patient 5 showed an asymmetric vascularization, as in both eyes the temporal part was not completely vascularized, but the nasal part was (Figure 3D, highlighted in gray). The degree of vascularization did not change significantly from 9 weeks to 11 weeks posttreatment (temporal ratio 4.3 ± 0.3, nasal ratio 3.8 ± 0.16) to 20 weeks to 27 weeks posttreatment (temporal ratio 4.6 ± 0.25, nasal ratio 3.6 ± 0.17), and 187 weeks posttreatment (Patient 6, Figure 3D).
In this study, we describe the effect of intravitreal 0.312 mg/0.025 mL bevacizumab monotherapy IVB in 27 eyes with posterior Zone II or Zone I, Stage 3+ ROP, or APROP. We also report on the FA features observed before and after treatment using definitions set in place by Lepore et al,15,16 and categorized by us.
Treatment success rates for posterior Zone II (100%) and Zone I (80%) disease were within the success rates reported in the literature.13,14 However, in most of the previous studies, 0.625 mg per eye were applied, which corresponds to half of the adult dose per eye. Since the anti-VEGF molecules exit the eye and act on other organs, dosage of bevacizumab is particularly important in premature infants who are extremely fragile and display rapid growth of all organs. Surprisingly, only few studies used lower bevacizumab doses to verify efficacy in the treatment of acute ROP. Harder and colleagues reported on the outcome of 29 patients (57 eyes) with Zone I or Zone II plus disease, and showed that all except one eye were successfully treated with 0.375 mg bevacizumab.17 A group from Japan even used only 0.25 mg bevacizumab in 6 eyes with Zone II and 2 eyes with Zone I disease and observed late recurrence only in Zone I disease.18 These data, together with the results from our study suggest that a single dose of 0.312 mg bevacizumab is sufficient to reliably treat active ROP in posterior Zone II plus disease and very likely in Zone I disease, and hence could be considered preferable over 0.625 mg, since the lower the anti-VEGF levels injected the less likely unwarranted systemic side effects should occur. In line with this, large and multicentre studies currently aim at identifying the lowest effective dosage of bevacizumab (NCT02390531) or, alternatively, ranibizumab (NCT02375971, NCT02134457) in ROP.
The diagnosis of APROP is challenging and agreement of its diagnosis is imperfect even among experts.19 Furthermore, outcome rates depend on whether bevacizumab was given as monotherapy or combination therapy with laser or cryotherapy.20–28 In one case of APROP, simultaneous laser treatment combined with high dose of 0.75 mg IVB was effective.20 Another small case series described successful treatment of APROP with administration of high dose 0.75 mg bevacizumab alone (n = 2) or in combination with laser (n = 2).26 In a single-case description, 0.66 mg bevacizumab as first line therapy was initially sufficient to induce regression of neovascularization, but early recurrence occurred at 2 weeks needing laser treatment to completely halt the disease.25 Law et al reported on 12 eyes with APROP treated with high dose 0.75 mg bevacizumab followed by laser or vitrectomy treatment within 72 hours. Still, 3 of the 12 eyes (25%) progressed to tractional retinal detachment.21 In contrast, Dani et al22 reported on 4 patients with APROP receiving either 0.625 mg bevacizumab alone (n = 2) or in combination with laser coagulation (n = 2) and observed a 100% success rate with no recurrences. Likewise, Mintz-Hittner and Kuffel28 reported one case of APROP and successful treatment outcome after a single 0.625 mg bevacizumab injection. In a more recent chart review, 14 eyes with APROP were all successfully treated with 0.625 mg bevacizumab alone.23 A retrospective study in Sweden observed an even better or at least similar outcome of APROP disease in four eyes with a single IVB of 0.4 mg bevacizumab compared with combination therapy of 0.625 mg with laser or cryotherapy.24
A large study from Turkey observed very good outcome rates of 92% after a single IVB of 0.625 mg in 31 eyes diagnosed with APROP, and 1 or 2 repeated injections regressed the disease in all remaining cases.27 This is in contrast to the results presented here, where 75% of APROP cases needed laser photocoagulation for stopping the disease, or even cryotherapy and vitrectomy. Repeated bevacizumab injections for the management of APROP did not appear to be sufficient in our study (Table 1). The reason for the discrepancy of treatment efficacy compared with other studies might be related to differences in BW, GA, and our diagnosis of APROP. With a mean age of 28.2 weeks and BW of 1,005 g, the Turkish infants were about 4 weeks older and 400 g heavier than the patients enrolled in our study. Since age at treatment was similar at about 33 weeks to 35 weeks, the time frame from birth to treatment was about 6 weeks in the Turkish study and 10 weeks in the present study. The phenotype of APROP might be comparable in both cases but the maturation of the vasculature or growth factor concentrations might vary.
Vascular outgrowth into the periphery is an important feature, which can be well documented with FA, and the presence of a peripheral avascular zone of less than 2 disc diameters may be considered normal in healthy infants up to 11 years.29 A study in 20 eyes with ROP treated with IVB as monotherapy showed that in more than 50% of the eyes (n = 11 eyes), peripheral avascular areas of more than 2 disc diameters were present up to 4 years after treatment, even though the outcome of the IVB was considered to be satisfactory.30 Very recently, large peripheral avascular zones were also observed in children with congenital glaucoma or cataract up to 7.5 years of age, indicating that complete vascularization to the ora may not be the rule.31 Since we could not identify the ora serrata on the FA images, we were not able to use this reference point. We therefore developed a method based on the distances of morphological structures (OD, fovea, peripheral border of vascularization). In case of full vascularization, the calculated ratios of 5 for the temporal and 4 for the nasal retina are essentially similar to what has been the basis for the definition of zones in ROP in 1985.6 If we consider all eyes with a vascularized zone of more than the ratio 4 temporally (i.e., temporal arcade or Zone III) and 3 nasally to be fully vascularized, only 12.5% of eyes (n = 2) included in this substudy would be classified as incompletely vascularized by this definition. Vascularization into the periphery after one IVB appears to occur rapidly, since the level of vascularization at 9 weeks to 11 weeks posttreatment did not differ compared with later examination times in our cohort.
In our study, the time of onset of late recurrence was about 11 weeks after the first treatment. In previous reports, varying mean time intervals have been observed, for example 14 weeks and 19 weeks for Zone I and posterior Zone II disease, respectively, in the BEAT-ROP study,14 and 14 weeks in Stage 3+ disease.32 However, the range of onset varied significantly between 4 weeks and 25 weeks, resulting in the fact that even at postmenstrual age beyond 50 weeks, late recurrences were reported.14 The observation that features typical for acute ROP can be reactivated after a prolonged period of time, regardless of the dose of anti-VEGF drug administered, indicates that the underlying mechanisms leading to the onset of an active ROP continue to be active and may only be temporarily blocked. Long-term follow-up therefore appears mandatory.
In our patient cohort, the course of the different FA features throughout the treatment period was not uniform, as some features decreased in frequency after treatment, thus indicating regression of the disease, whereas others increased with time, the consequences of which are currently not well understood.
Not surprisingly, all or almost all eyes examined with FA showed signs of active ROP at the vascular–avascular junction before treatment, such as leakage (Feature 1), hyperfluorescent lesions (Feature 4), and capillary malformations (Feature 5). Especially the occurrence of dye leakage at the junction in all patients, which is the most important sign for severe ROP and need for surgery is in line with the literature,33 as is the presence of Features 4 and 5.15 In all our patients, all three features decreased after treatment, indicating calming of disease activity at the junction followed by a more controlled outgrowth of vessels into the periphery.
Abnormal vascular branching (Feature 2) had different patterns in the 3 forms of ROP treated in our study. In posterior Zone II disease and APROP, the abnormal branching events occurred rather at the small arteriolar level (Feature 2b), whereas this was not the case for Zone I disease, where these branching events occurred almost exclusively at the large arteriolar level (Feature 2a) (Table 5). Interestingly, this was true regardless of whether FA was analyzed before or after treatment. What is even more interesting is the frequency of the appearance: in posterior Zone II disease, Feature 2b was present before treatment, decreased after treatment and reappeared at the long-term examination. In contrast, in Zone I disease, Feature 2a was present at low frequency before treatment, increased to 100% at the short-term and mid-term examination, and again decreased over time. Only in APROP, the frequency decreased after treatment and disappeared completely. Since Lepore et al15 also observed persistence of abnormal branching after IVB treatment, these reactions of the vasculature to anti-VEGF treatment may be physiologic but materialize in different ways, potentially depending on the immaturity of the vessels at the time of treatment. Interestingly, the reaction of the vasculature to laser treatment seems to be different, as abnormal branching events were reduced after treatment.15
Circumferential vessels or so-called “naked” arteriovenous shunts (Feature 3) appeared in 75% of cases at the mid-term examination, and in 100% of cases at the long-term examination, but were present only at low frequency before treatment. Lepore et al15 observed a high frequency of this feature before and after treatment and described it as a long-lasting characteristic of IVB. Since we found these vessels in all groups, including all eyes successfully treated with single IVB injection, they do not seem to be associated with an increased risk for late recurrence, as suggested by others.15,33,34 It is even possible that these shunts are a typical characteristic of continuing retinal vascular development, outgrowth into the periphery, and remodelling.
The highest incidence of capillary bed loss (Feature 7), which is different from areas of hypofluorescence due to retinal or choroidal filling errors (Feature 6), was observed before treatment in eyes with APROP (7 out of 8 eyes, 87%), an observation that is in line with prior studies that identified this feature as characteristic for APROP.35 Interestingly, the prevalence of this feature decreased over time, an observation not in line with data presented by Lepore et al15 for the IVB treated group. In their study, the rate only decreased in the laser treated group. Since we and others showed that oxygen levels have an influence on the size of the periarteriolar capillary free zone in different animal models of ROP, the question of whether this feature may represent a marker for an altered oxygen supply at birth or within the first weeks of life warrants more investigations.36,37
Macular abnormalities, frequently observed before treatment (100%) and after IVB (75%) in the Lepore study were seen less frequently by us in the eyes before treatment and only sporadically after IVB.15 The reasons for these differences remain speculative but would indicate differences in study populations.
A major limitation of our study is the small sample size, which precludes a statistically relevant analysis, specifically in the APROP group, and that IVB monotherapy was not compared with laser monotherapy. Since this was a retrospective study, data analysis is based on routine clinical documentation and the definition of study arms was not possible. In line with this, no control group of imaging data from healthy infants was included. Variability of dosing is always an issue with bevacizumab, which needs to be prepared from a stock solution at the local pharmacy. In addition, we were not able to obtain FA data from every child for all time points pretreatment or posttreatment, which further decreases the number of cases available.
Nonetheless, the total number of 75 FA imaging data sets examined in this study enabled us to reveal interesting new clinical data in a sufficient number of cases. Specifically, we provide longitudinal imaging data even before treatment that help define eyes as either posterior ROP or APROP. However, this classification may still be somewhat arbitrary and not uniformly accepted or applied by others. Classification is nonetheless crucial as our data show the worst prognosis with IVB 0.312 mg in APROP eyes. Hence, our results may not be directly comparable with previous reports. Since in our study, the APROP phenotype, as one may expect, had the highest need for early and late retreatment, uniform classification among investigators is highly desirable, also in view of finding the optimal treatment regimen for APROP. Sufficient sample sizes can only be addressed in large and multicentre studies with ample photodocumentation.
To summarize, we show here that the use of lower doses of bevacizumab, that is, a quarter of the adult dose very likely shows similar results of disease silencing in posterior Zone II and Zone I disease compared with the use of half the adult dose. At times when systemic consequences of anti-VEGF medication for the developing organism of the infants are still unknown, this information is significant for the research community. In contrast, 0.312 mg bevacizumab did not seem to be the treatment of choice for APROP in our hands. Experience with higher dose anti-VEGF reported by others is also not conclusive, partially related to the loose definition of APROP. Fluorescein angiography is helpful in defining the junction of the vascularized zone and the vascular outgrowth, identifying avascular areas within the vascularized zone, the degree of leakage, and further vessel alterations such as shunt formation, the importance of which remains unknown with regard to any possible late sequelae.
Members of the Giessen cooperative ROP study group: Principle Investigator: Prof. Dr. B. Lorenz, Department of Ophthalmology, Justus-Liebig-University Giessen, Germany. Co-Investigators: Dr. M. Andrassi-Darida, Dr. M. Jäger, Dr. Christoph Friedburg, Dr. Ramona Neutzner, Prof. Dr. K. Stieger, Dr. S. Stieger, C. Mais, Department of Ophthalmology, Justus-Liebig-University Giessen, Germany. Participating neonatologists: Prof. Dr. Matthias Heckmann,* PD Dr. Harald Ehrhardt, Dr. Dirk Faas, Department of Neonatology, Justus-Liebig-University Giessen, Germany, *current address: Department of Neonatology and Pediatric Intensive Medicine, University Greifswald, Germany. Dr. Mechthild Hubert, Childrens Hospital Siegen, Germany. Prof. Dr. Reinald Repp, Childrens Hospital Fulda, Germany. Referring local ophthalmologist: Dr. Hans-Jürgen Krannig, Ophthalmological Practice, Hünfeld, Germany.
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