Fig. 6.1
(Right eye) Example of prominent plus disease with tortuosity of arteries in four quadrants and venous dilation in four quadrants and venous tortuosity in the nasal quadrant. The nasal quadrants showed more vascular activity with dilation and tortuosity of second- and third-order arterioles and venules than the temporal quadrants. There is no agreed-upon standard for the term prominent plus disease (RETCAM 80 degree lens)
We found two substantive limitations in the R-ICROP description of APROP: First, R-ICROP presents APROP with very heavy emphasis on the severe case, with “prominence of plus disease”, which requires immediate treatment. In particular, the statement “can be diagnosed on a single visit and it does not require evaluation over time” essentially applies to the moderately severe and severe disease. In fact, ROP that is destined to become APROP does not arise from CROP. ROP that is destined to reach APROP may often be identified before development of prominent plus disease. The pre-APROP (or early APROP) eye has predictable features that often present with pre-plus and show minimal changes at the vascular–avascular junction or a thin demarcation vessel without distinct neovascularization (Fig. 6.2). Pre-APROP may also present with minimum plus (less than prominent plus) disease and thick demarcation vessels or fine vessel neovascularization (Fig. 6.3). The lack of recognition in R–ICROP of milder APROP leads to unhelpful delay while waiting for prominent plus disease [15].
Fig. 6.2
Superior view of right eye of the patient seen in Figs. 6.8 and 6.9. A demarcation vessel is seen at arrows. Hemorrhages associated with neovascularization are within circles. Neovascularization appears indistinct as a pink sheet above retinal vessels and obscures details. In this eye, the NV appears slightly posterior to the circumferential vessel
Fig. 6.3
(courtesy of H. Hayashi) Japanese type 2 ROP notes the clear demarcation vessel indicated by a set of long arrows. This is definite APROP despite the absence of posterior plus disease. Evaluated alone, the posterior frame does not show pre-plus
Clinically there is a surprising consequence to this definition. Since the R-ICROP description of APROP required prominent plus disease (Fig. 6.1.), it excluded an APROP equivalent to early treatment of ROP (ETROP) [16] type 1 ROP. For example, there is no equivalent of stage 3 zone I without plus in this definition of APROP. In fact, there is also no true equivalent ETROP type 1 ROP category for APROP stage 2 or 3 with minimum plus, since prominent plus is more than minimal plus and occurs later. Therefore, the ETROP moment for indicated treatment (type 1 or high-risk prethreshold) has no technical APROP equivalent. This diminishes the key contribution of ETROP: that treatment at type 1 ROP had a better response to treatment than the CRYO-ROP threshold ROP. The R-ICROP definition of APROP may result in its being treated later in the disease process closer to CRYO-ROP [17] threshold ROP while CROP is treated at ETROP type 1 ROP. This may contribute to more unfavorable outcomes in eyes with APROP.
Second, R–ICROP did not provide a distinct category with specific diagnostic criteria of APROP. ICROP described the characteristic features for APROP as “posterior location, prominence of plus disease, and the ill-defined nature of the retinopathy.” However, since posterior location is also seen in zone I CROP and prominence of plus disease can be seen in severe CROP these features do not distinguish APROP from CROP. Moreover, using the description “ill-defined” also did not help identify any specific findings that distinguish the diagnosis of APROP from CROP. Although some examples were provided in the figures, there was no specific criterion to identify retinopathy that meets the description of “ill-defined.” This lack has resulted in an APROP literature that is very hard to interpret. It is especially difficult to interpret articles that lack photographic documentation [18, 19].
Part 2: Practical Diagnosis and Management of APROP
The diagnosis of APROP becomes more helpful when it allows earlier identification and earlier treatment because the response to early treatment improves outcomes as seen in the ETROP study (15). Therefore, the practical objective is to diagnose eyes destined to reach APROP, for example, when plus disease is mild, minimal, or only pre-plus disease is present. For this diagnosis two elements are needed: (1) a reliable positive finding of APROP, when prominent plus disease may not be present; (2) a basis to suspect APROP may be developing.
In our opinion, the most specific positive finding of APROP is neovascularization composed of fine vessels [20] at the border zone between vascular and avascular retina (Figs. 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.10, 6.11 and 6.12). Neovascularization is the purely vascular form of fibrovascular proliferation (stage 3). Because of the lack of opaque fibrous elements, the neovascularization may be very low contrast and blend into the background. In the R-ICROP this low contrast neovascularization was referred to as “ill-defined” “deceptive” “featureless” and “modest”. This particular language implied that this feature might be easily missed by routine exam. Often, the fine vessels of APROP are not in perfect focus and/or not adequately magnified, therefore, the neovascularization functions as a partially transparent pink overlay that subtly distorts or colors the details of the retina. The transition in color and details may be the key observation. In distinction from the subtlety of APROP, most ROP eyes show high-contrast CROP and the presence of stage 1, 2, or 3 is readily seen with a brief exam. The routine screening exam reflects this reality. Unfortunately, this exam routine cannot detect fine vessel neovascularization. In order to detect pre-APROP as a type 1 ROP equivalent, the clinician must take the extra time required to make critical observations. Taking extra time on every exam is burdensome; therefore, identification of APROP suspects is helpful.
Fig. 6.4
Temporal view of same eye as Fig. 6.1. There is a mild lobular configuration. There is a demarcation vessel (long arrows). The fine vessels are not clearly seen temporally but are suspected as the explanation for the increased loss of clear view of blood vessels as one follows the vessels to the periphery indicated by short arrows. Higher magnification and improved focus may be achieved with indirect ophthalmoscope
Fig. 6.5
Nasal view of same eye as Fig. 6.1. Prominent plus disease is present. Nasal vessels terminate with a vascular blush that reflects the extensive band of fine neovascularization. Arrows denote the posterior border of the neovascular band. Posterior Termination is zone 1. CROP is absent. No foveal reflex is present. A light halo is seen at the posterior edge of avascular retina (Mach Band) without a “definite structure” and is not stage 1 ROP
Fig. 6.6
This shows recurrent APROP 11 weeks after injection of bevacizumab. The original diagnosis was APROP and the recurrent neovascularization shows flat brush boarder fronds extending anterior from arteriovenous anastamosis (arrows and NV) without the opaque elements seen in classic stage 1, 2, or 3. (RETCAM 80 degree). The arteriole is marked with a and venule with v. They anastamose behind the fronds
Fig. 6.7
RETCAM 130 image shows a left eye with prominent plus disease with arterial and venous tortuosity. Superiorly, an extensive band of neovascular proliferation is seen as a vascular thickening or sheet above the retina that obscures the retinal vessels as they approach the junction of vascular and avascular retina. Again a slight halo, but no definite structure is seen at the edge of the avascular retina (a Mach band). Note dark artifact from small pupil at the lower right part of the frame
Fig. 6.8
Retcam 130 of left eye shows prominent plus disease with tortuosity of arteries and veins. Subtle vascular proliferation is present posterior to the junction. An annular hemorrhage is present. A modest light halo at junction is seen again. Note dark artifact moved to superior temporal area
Fig. 6.9
RETCAM 80 degree photograph of the same eye as Fig. 6.8 shows loss of retinal vessel detail approaching the junction since they are obscured by overlying fine vessel neovascularization (especially at arrows). Hemorrhage surrounding an area of new vessels (arrowhead) is demonstrated. The halo seen in the previous photograph is not a definite retinal structure and may represent a Mach band or a change in the choroid. Note the dark artifact seen in Fig. 6.8 of this same eye is reduced in the 80 degree lens view
Fig. 6.10
Left eye shows a pink blush of vascular proliferation posterior at the junction. The vessels posteriorly show pre-plus disease and they remain dilated as they extend to the junction. Following the artery (a) and vein (v) an arterior-venous anastamoses is seen. A frond of vessels grows from anastamosis (arrow)
Fig. 6.11
This 80 degree RETCAM image shows prominent plus disease with fine neovascular fronds at the vascular–avascular junction with areas of retina and vitreous hemorrhage. The fronds are elevated into the vitreous (arrows). Vitreous hemorrhage contributes to degraded view. Limited depth of field reflect focus above the retina plane
Fig. 6.12
This RETCAM 130 image shows prominent plus disease. The fovea is not vascularized and the vascular retina has a lobular pattern. The flat neovascularization is present and best documented superior temporal but is present around most of the circumference. Inferior temporal there is a white line (arrows). This is not CROP stage 1, which is a distinct line in flat retina, but rather fibrous proliferation in an area of vascular contracture causing local retina elevation
We define APROP suspects, as eyes with a mismatch between the clinical picture and the visible ROP stage or with particular red flags described below. Normally young eyes in zone I show attenuated vessels and an involuting hyloidal artery remnant may be detectable. Over time, the vessels dilate to a normal appearance and at that time normal retinal vessel development anteriorly is expected. Eyes with normal caliber and immature vessels in and near zone I must be examined as suspicious, and that suspicion increases if the vessels do not grow anteriorly from week to week. The suspicion is heightened by anterior vascular dilation without CROP stage 1 or stage 2 (Figs. 6.3, 6.4, 6.6, 6.12, 6.13 and 6.14a). Additional, red flags include: (1) annular, c-shaped or arc-shaped hemorrhages that often arise adjacent to neovascularization (Figs. 6.8, 6.9, 6.10, 6.11 and 6.16), (2) retina vessels that lose detail or disappear as they approach the avascular retina (Figs. 6.2, 6.4, 6.5, 6.7, 6.8, 6.9, 6.11 and 6.12), and (3), persistent dilated tunica vasculosa lentis (papillary membrane) (Fig. 6.17).
Fig. 6.13
Vascular loops with capillary dropout are a common finding in OIROP found in large babies with uncontrolled oxygen supplementation. This is especially suspicious beyond posterior zone 2. This photo was from a smaller baby but we also suspect an oxygen-induced component when we see this pattern. Liberal oxygen use may occur in infants with concurrent illnesses. CDO labels large areas of capillary dropout surrounded by vascular loops. Prominent dark artifact from small pupil is present using RECAM 130 lens
Fig. 6.14
Foveal Vascularization: a APROP prior to bevacizumab injection. Note that temporal macula is avascular and foveal vasculature is incomplete. Also note dilated AV shunt superior to fovea. b Three weeks and 3 days after bevacizumab injection. Perifoveal vascular ring is nearly complete. c Two month and one half months after bevacizumab. Temporal macula is largely vascularized. d Fluorescein angiogram shows foveal avascular zone with few microaneurysms. Laser ablation of persistent avascular retina was performed at this visit. e Four months after bevacizumab and two months after laser. Foveal depression is seen in center. f Fluorescein angiogram shows the perifoveal vascular ring is irregular but clearly present
Fig. 6.15
This is cicatricial phase APROP of a flat neovascular network after bevacizumab and subsequent anterior growth of vessels. Untreated APROP will in time gain opaque fibrous elements. This is not CROP stage 2 or three, but rather represents a maturation, opacification, and contraction of the neovascular interstitial tissue and progression toward retinal detachment
Fig. 6.16
Three months after bevacizumab injection posterior recurrence is seen. a Shows the color photograph with an anterior ridge areas of round annular and arc-shaped hemorrhages and no plus disease. b The angiogram shows the hemorrhages that surround fine vessel neovascularization posterior to a irregularly perfused capillary bed and anterior ridge
Fig. 6.17
Iris and pupillary membrane vessel engorgement is always accompanied by severe plus disease as defined by the dilation and tortuosity of the retinal vessels. Plus disease with CROP stage 2 or 3 or APROP are indications for treatment. However, this situation reduces the ability to dilate the pupil and to see the details of the retinal pathology. The presence of APROP must be considered regardless of the barriers to examination. Photograph was taken with RETCAM external lens and handheld slit-lamp for illumination
In most cases, the view of the retina provided by indirect ophthalmoscopy is not ideal for the visualization of fine vessel neovascularization. Detection of similar fine neovascularization in proliferative diabetic retinopathy usually uses higher magnification optical systems than provided with standard indirect ophthalmoscopy. Therefore, in order to see these fine vessels with an indirect ophthalmoscope, one must employ strategies to improve resolution. They include adequate pupil dilation, clear media, magnification, improved focus, glare reduction, and control of movement. Dilation may require stronger pharmacologic agents. Magnification will require a 20-diopter lens. Glare reduction may require turning off the nursery’s overhead lights or sidelights. Focus may require optimization of the working distance and angles of the condensing lens. The infant may need to be moved out of the bassinette onto a flat surface in order to allow proper working distance. Movement blur may require an assistant to hold the baby’s head. Taken together these steps require that the clinician slow down in order to include or exclude the fine neovascularization of APROP. Excluding fine vessel neovascularization of APROP requires an excellent quality of exam and pattern recognition that comes with experience.
APROP proliferation has a range of appearances and configurations and their recognition can be improved by studying photographs. Many photographs were included with this chapter and more are available at our blog (URL: http://aprophelp.blogspot.com). Studying these photographs may also enhance the examiners pattern recognition of neovascularization and suspicious findings associated with APROP. Review of the text and photos in R-ICROP is also recommended; however, we consider two of the photos in R-ICROP at a later stage of APROP than ideal for a good structural outcome.
Since in APROP, CROP stage 1 and stage 2 are not displayed, APROP may appear to transform from immature to full active APROP. However, APROP is not a transformation but rather a rapid development. The evolution from immature to full form in some cases takes only 2 weeks, which is much faster than CROP. During this developmental interval, examination of posterior vessels will usually show pre-plus disease (Figs. 6.3 and 6.10 and 6.14a). Instead of a line or ridge, the early findings are: (1) vascular dilation posterior to the junction (Figs. 6.10 and 6.14) (this feature may be seen posterior to stage 1 in CROP), (2) posterior intraretinal shunt vessels (Fig. 6.18), (3) limited arteriovenous anastamoses (Figs. 6.6, 6.10 and 6.16) (4) extensive circumferential anastamoses (Figs. 6.4, 6.5 and 6.18), and (5) peripheral shunt vessels (Fig. 6.2 and 6.3). These have also been called demarcation vessels [3]. The retinal vessels may also show general dilation rather than just dilated tips. The circumferential demarcation vessel [21] is a stage 2 equivalent in APROP [8].
Fig. 6.18
A higher magnification and deeper focus (RETCAM 80) of Fig. 6.5 shows extensive intraretinal shunting posterior to the neovascular band. The arrow indicates one example
In APROP, proliferation starts as a fine frond or network of vessels growing from an anastamosis in the border zone (Figs. 6.3, 6.6, 6.9, 6.10 and 6.11). This neovascularization has been called “flat neovascularization”, because it appears flat compared to CROP stage 3. Opaque CROP stage 3 can also give a heightened elevated appearance related to its high contrast. Frequently, APROP proliferation starts as growth along a thin plane above the retina. It also appears especially flat when using the 130-degree RETCAM images. OCT shows it above the retina. In many cases, it will progress by growing anteriorly along the retina and then thicken to become more brush like (Fig. 6.6, 6.10, and also clasic example in blog ). The flat pattern is one of the several neovascular configurations. In other eyes the neovascularization grows as a tangle of blood vessels (Fig. 6.2, 6.3, and 6.7). Some photographs show this broad flat growth while others show thickening and extension into vitreous (Figs. 6.7 and 6.11). The fine vessel neovascularization is not required to be flat in order to progress as APROP. As a rule APROP, neovascularization is composed of fine blood vessels and CROP has opaque fibrovascular tissue that ranges from red to light pink. Ultimately both will involute into white fibrous tissue (Figs. 6.12 and 6.15). APROP eyes will progress to involution with a low-contrast, difficult-to-detect neovascular proliferation and detach more quickly. There is a range of neovascularization, and in the R-ICROP description any form of vascular proliferation other than CROP stage 3 (or stage 2 popcorn) is definitive for APROP. However, where R-ICROP requires prominent plus disease, we suggest that feature should not be a prerequisite for all forms of APROP.
Fig. 6.19
This is a recurrence after injection of bevacizumab. The neovascular proliferation lacks the fibrous elements and there were no signs of CROP stage 1 or 2 at the anterior avascular junction. In this case, the neovascularization is composed of fine vessels that are low contrast and is seen at the original junction. The arteriovenous anastomosis is marked with an x and this is the base of the recurrent neovascularization
After the retina vessels gain moderate plus disease, especially if this is a rapid increase in plus activity, the iris and pupillary vessels may increase in prominence and become reperfused. The hyaloidal arteries may also re-perfuse. Since these vessels may obscure the view of the fundus, the best time to treat is when minimal plus disease appears.
Using the RETCAM retinal camera, the 130-degree lens will often not allow high resolution and there is often a prominent central dark artifact (Figs. 6.8, 6.12, and 6.20). The 130-degree lens best images eyes with blonde fundus pigmentation. Many of the dramatic RETCAM advertisements feature blonde fundi. The 80-degree lens although relatively bulky, is very helpful in this situation, both for the resolution and for reduction of the central dark artifact. In non-blonde eyes it is essential. The RETCAM also has little depth of field and the fine vessels require some fine-tuning in order to focus the image (Figs. 6.8 and 6.9). The central dark artifact is plainly present in many figures included in papers on APROP [13, 17, 22].
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