A retrospective review of infants with APROP was performed, and the infants who demonstrated capillary-free zones in vascularized retina were included in this study. The infants' demographics, including gestational period, gender, and birth weight were investigated, along with systemic diseases and the performance of oxygen therapy. The institutional review board of Seoul National University Hospital approved this study.

All infants underwent initial ROP screening and follow-up examinations guided by previously reported recommendations [10]. After APROP was noted on funduscopic examination, fundus photographs were obtained serially using a RetCam (Massie Research Laboratories Inc., Pleasanton, CA, USA) at the initial and follow-up examinations.

Laser treatment was performed in a near confluent pattern, and the timing of the treatment was within 24 hours after APROP was noted, even though threshold disease was not recognized. In addition to avascular retina, capillary-free zones were treated with laser photocoagulation, except for the posterior pole. In infants with an avascular area uncovered with confluent laser burns by the first laser treatment, additional laser treatments were performed. The post-conceptual age at the time of first and second laser treatments was also reviewed. After the treatment, follow-up examinations were performed weekly until the infant was discharged from the neonatal intensive care unit. The capillary-free zones in vascularized retina were meticulously inspected for any changes on follow-up examinations.

At the final visit, fundus photographs were obtained, and complete ophthalmic examinations were performed to evaluate anatomic and visual outcomes with complications. Anatomically-favorable outcomes were defined as the normal formation of a posterior pole without retinal distortion, whereas an unfavorable outcome included retinal detachment or a retinal fold-distorting posterior pole. The visual outcome was measured by the best-corrected visual acuity (BCVA) in patients who could read a visual acuity chart or by the presence of fix-and-follow behavior in patients who could not read the chart due to young age or mental retardation.

Among the 25 infants with APROP who were examined and diagnosed between July 2000 and May 2010 at Seoul National University Children's Hospital, 6 infants (24%) had capillary-free zones in vascularized retina. Among the six infants, Table 1 demonstrated the funduscopic findings and incidence. Other funduscopic findings included retinal vessels limited to zone I (100%), prominent plus sign (100%), retinal or pre-retinal hemorrhage (50%), and focal ridge or extra-retinal fibrovascular proliferation (33%).

For the six infants with APROP who demonstrated capillary-free zones in vascularized retina, the demographic characteristics including age, gender, gestational age, birth weight, and any systemic diseases are summarized in Table 2. The mean gestational age at birth was 30.5 weeks with a range of 27.5 to 35.4 weeks, and the mean birth weight was 1,432 g (range, 1,120 to 1,960 g). All of the infants in this study were >27 weeks of gestation, and their birth weights were >1,000 g. Except for 1 infant, all others in this study received oxygen therapy, mostly for respiratory distress syndrome (67%); no other co-existing systemic diseases were present.

The capillary-free zones in vascularized retina are shown in Fig. 1. The capillary-free zones are multiple, conspicuous, isolated lesions surrounded by retinal vasculature or retina with capillary formation. In this study, the capillary-free zones could be discriminated in fundus photographs obtained by a RetCam.

All infants underwent laser treatment within 24 hours after the diagnosis of APROP. The mean post-conceptual age at the time of the first laser treatment was 35.2 weeks (range, 33 to 39.2 weeks), and second laser treatments were performed in two cases at 37.2 and 38.4 weeks post-conceptual age. After laser treatment, follow-up examinations were performed at an average of 25.2 months to evaluate anatomic and visual outcomes with complications, as summarized in Table 3. Among the 12 eyes, normal formation of the posterior pole was noted in 7 (58.3%) eyes, which were classified as anatomically-favorable outcomes. However, in the anatomically-unfavorable group, 4 eyes (33.3%) eventually progressed to tractional retinal detachment, and 1 eye (8.3%) developed retinal fold-dragging macula.

In infants with anatomically-favorable outcomes, the short- and long-term clinical courses are demonstrated in Figs. 2 and 3, respectively. During the short-term course, the areas of capillary-free zones in vascularized retina revealed late capillary filling. In Fig. 2A, 10 days after laser treatment, a broad capillary-free zone was noted in the vascularized retina. At 2 weeks after treatment, the area was slightly decreased (Fig. 2B). The gradual shrinkage of the capillary-free zones was demonstrated concurrently with capillary filling. Finally, 5 weeks after treatment, the capillary-free zones in vascularized retina resolved. The long-term follow-up examination of another patient 15 months after laser treatment revealed normal formation of the posterior pole with insignificant fibrous membrane, including previous capillary-free zones, as demonstrated in Fig. 3.

Fix-and-follow behavior was present in both eyes and BCVA was 20 / 30 in both eyes among 2 infants with favorable outcomes, in whom the behavior or visual acuity could be examined. However, fix-and-follow behavior was absent in 3 eyes, and eccentric fix was present in 1 eye, which indicated that visual outcome was associated with anatomic outcome. Complications noted in this study included glaucoma in 2 eyes (16.7%), strabismus in 1 patient (16.7%), and fine nystagmus in 1 eye (8.3%).

While APROP has been reported to occur in the smallest, most premature infants [5-7,11,12], this study demonstrated that APROP, especially with capillary-free zones in vascularized retina, can occur in infants at more advanced gestational ages and with greater birth weights compared to previously reported APROP cases. The associated factors with APROP in our study were respiratory distress syndrome (66.7%) and oxygen therapy, previously recognized risk factors for ROP [13,14]. In addition, this report demonstrated late capillary formation in capillary-free zones in vascularized retina by serial photographic documentation. These features of APROP were first revealed in this study.

Most cases of APROP occurred in ultra-premature infants with a gestational age <26 weeks and birth weights <750 g [5-7,15]. However, all of the infants in this study had gestational ages >27 weeks and birth weights >1,000 g. Therefore, these findings suggest that APROP can occur in the absence of APROP risk factors, such as extremely low gestational age and very low birth weight [5-7]. Thus, the possibility of APROP should be considered in cases of posterior ROP, regardless of gestational age and birth weight. Accordingly, frequent follow-up examinations should be performed to identify the progression of the ROP. For the other possible explanations of the atypical clinical features, the difference in the level of care in neonatal intensive care units and ethnic differences of APROP are suggested.

Complications of APROP included glaucoma, strabismus, and nystagmus. All of the cases with glaucoma occurred in patients with retinal detachment, which was consistent with the previous result, which indicated that glaucoma can develop after laser treatment for severe ROP [16]. Other complications were not remarkable compared to previous reports [5].

Regarding the pathogenesis of APROP, previous studies have discussed the relationship between ROP and its risk factors. Vascular endothelial growth factor (VEGF) is known to be essential in the normal development of retinal vasculature [17,18]. In premature babies, insulin-like growth factor-1 (IGF-1), which exerts a permissive role in VEGF-mediated new vessel growth, is at very low levels due to insufficient production by the premature liver [17,18]. Additionally, long-term hyperoxia inhibits VEGF [19-23] and more immature retinal vessels are known to be more vulnerable to oxygen toxicity [24,25]. Therefore, prematurity and hyperoxia disturb the normal development of retinal vasculature. However, for our cases in which APROP occurred in the absence of commonly associated risk factors of APROP, such as low gestational age and low birth weight, a different mechanism could be involved in the pathogenesis. Further investigation into the mechanism of APROP and into what interrupts the formation of retinal vasculature in APROP cases with relatively long gestational periods needs to be performed.

Interestingly, all of the infants with a favorable outcome of APROP revealed normal capillary formation in vascularized retina as capillary-free zones decreased gradually after laser treatment (Fig. 2). The capillary filling was done for a short period of time, at most 5 weeks after laser treatment in this study. To understand the mechanism underlying capillary filling, the normal vascular development of the retina and factors involved in the process should be considered.

Two distinct processes have been suggested for vascularization of the retina. Vasculogenesis occurs in an early phase and is responsible for the formation of major arcades. Vasculogenesis is known to be completed by 21 weeks gestation [26], and angiogenesis subsequently proceeds and forms the remaining retinal vessels, including capillaries [12]. Angiogenesis is known to be associated with VEGF, whereas vasculogenesis is insensitive to VEGF modulation. Considering the gestational period in our cases (significantly >21 weeks), and the process mediating capillary formation, we believe that angiogenesis executed the late capillary filling identified in this study.

More specifically, as infants grow, the retina matures and the serum concentration of IGF-1 rises as production in the liver increases [17]. The developing retina with a large avascular area and multiple capillary-free zones in APROP becomes hypoxic, and thus increases the expression of VEGF [17,18]. However, because of the permissive role of IGF-1 on VEGF, excessive VEGF with an increased amount of IGF-1 can result in neovascular proliferation, rather than normal vascular formation [17,18]. However, after laser treatment, the level of VEGF decreases significantly, which prevents neovascularization [17]. In addition, the retina without capillary formation within the posterior pole might produce a suitable amount of VEGF that leads to normal capillary formation on the area by the process of angiogenesis.

Previous reports have advocated that capillary-free zones in vascularized retina should be treated with laser photocoagulation [7,9]. Accordingly, the avascular retina and capillary-free zones were treated with laser photocoagulation, except for the posterior pole in our study, which has never been studied for its efficacy. Although further investigation with a larger number of infants is required, the anatomic success (58.3% in this study after laser treatment) was comparable to that previously reported for laser-treated cases of zone I ROP (54.4%) [15]. However, the rate in another study was 81.8% [5], but an anatomically-unfavorable outcome was only defined as retinal detachment. If our outcomes were similarly defined, then the anatomical success of the current study was 66.7%, which is not significantly different from the previous rate by chi-square test.

After treatment, follow-up examinations should be performed frequently to identify normal capillary formation in capillary-free vascularized retina within the posterior pole, in addition to regression signs of ROP. However, laser treatment in avascular retina alone is potentially unsafe in APROP cases because considerable production of VEGF on wide areas without capillary formation in vascularized retina might lead to neovascularization and subsequent retinal detachment.

In conclusion, this study demonstrated the late capillary filling on capillary-free zones of vascularized retina after laser treatment. For these patients, the interaction of IGF-1 and VEGF on angiogenesis and its modification after laser treatment are considered to play a role in the underlying mechanism. To validate our findings, further studies are warranted and better understandings of the pathogenesis might lead to more appropriate treatment options and more favorable outcomes in patients with APROP.