Grading fluorescein angiograms in malarial retinopathy

Abstract

Background: Malarial retinopathy is an important finding in Plasmodium falciparum cerebral malaria, since it strengthens diagnostic accuracy, predicts clinical outcome and appears to parallel cerebral disease processes. Several angiographic features of malarial retinopathy have been described, but observations in different populations can only be reliably compared if consistent methodology is used to capture and grade retinal images. Currently no grading scheme exists for fluorescein angiographic features of malarial retinopathy.

Methods: A grading scheme for fluorescein angiographic images was devised based on consensus opinion of clinicians and researchers experienced in malarial retinopathy in children and adults. Dual grading were performed with adjudication of admission fluorescein images from a large cohort of children with cerebral malaria.

Results: A grading scheme is described and standard images are provided to facilitate future grading studies. Inter-grader agreement was >70 % for most variables. Intravascular filling defects are difficult to grade and tended to have lower inter-grader agreement (>57 %) compared to other features.

Conclusions: This grading scheme provides a consistent way to describe retinal vascular damage in paediatric cerebral malaria, and can facilitate comparisons of angiographic features of malarial retinopathy between different patient groups, and analysis against clinical outcomes. Inter-grader agreement is reasonable for the majority of angiographic signs. Dual grading with expert adjudication should be used to maximize accuracy.

Fig. 1

FA montage and grading overlay. a A montage composed of several FA images from similar time points can provide a useful summary of FA features. b Addition of a grading overlay assists identification of retinal areas. Detail of retinal areas are in Table 1 and Fig. 2

Fig. 2

Definitions of retinal areas. Schematic retina from [8] adapted to show three different extents of peripheral retina for the right eye (Table 1). The disc and vessels are shown for reference. Note that the disc is always on the nasal edge of the macula. The distance from the outer edge of the disc to the centre of the fovea is referred to as one disc-fovea distance, and is equivalent to ~2.5 ETDRS disc diameters. Working from the centre of the image outwards, the fovea and macula are shown as circles (broken lines). The red circle indicates the limit of zone 1, which extends one disc-fovea distance beyond the macula. The blue circle indicates the limit of zone 2, which extends a further disc-fovea distance from zone 1. Zone 3 includes all retina outwith the blue circle. The outer black circle nominally represents the ora serrata, but note the actual distance between the zone 2/3 boundary and the ora is much greater than suggested by this diagram. Superior, temporal, inferior, and nasal quadrants are shown by broken lines extending from the edge of the macula

Fig. 3

The post-capillary venule complex, small venules, large venules. Left eye point A represents the beginning of a ‘small venule’ segment, which ends at point B when two small venules converge. Point B is also the beginning of a large venule, which ends at the optic disc. The scale bar shows 1/3 disc diameter (~500 μm) from the convergence of capillaries on to the post-capillary venule, and approximates the length of the post-capillary venule complex. The post-capillary venule complex begins at the junction of two capillaries and extends a distance of 1/3 disc diameter downstream towards the small venules. Other visible features in this figure include disc leak, and intravascular filling defects (e.g. small venule at point A)

Fig. 4

Segments of the venous network (small and large venules). Montage of FA images (left eye). Large vessel segments are marked in red, and small vessel segments in yellow. A break in a line indicates the junction between two vessel segments. New vessel segments begin where a vessel meets another vessel of similar or larger calibre. Small vessels extend from the downstream limit of the post-capillary venule complex (~500 μm from capillary bed) to the point where the small vessel joins another vessel of similar or larger calibre. Large vessels extend from this point to the disc. Sections of large vessels begin and end at junctions between one large vessel and another large vessel of similar or greater calibre. Other visible features in this figure include disc leak, and one site of large focal leak (inferior to the disc)

Fig. 5

Grade 1 macular capillary non-perfusion (CNP). Right eye a few small areas of CNP are seen at the macula (arrow), which is outlined by a white circle

Fig. 6

Grade 1 macular capillary non-perfusion (CNP). Right eye a few small areas of CNP are seen at the macula (arrow), which is outlined by a white circle

Fig. 7

Grade 2 macular capillary non-perfusion (CNP). Right eye the upper limit of grade 2 macular CNP. Combined area of macular CNP is <1/3 disc area, after mentally subtracting a notional area for the normal foveal avascular zone. Macula, disc, and 1/3 disc area are shown as white circles. A single site of punctate focal leak is also visible in the macula (arrow)

Fig. 8

Grade 2 macular capillary non-perfusion (CNP). Right eye the upper limit of grade 2 macular CNP. Combined area of macular CNP is <1/3 disc area. CNP is clearly seen around the foveal avascular zone, and less obviously in the temporal macula (arrow). Macula and 1/3 disc area are shown as white circles. Masking of fluorescein from haemorrhage is also visible (double arrow). CNP has geographic boundaries (e.g. the abnormally irregular edge of the foveal avascular zone in this image), while haemorrhages tend to have rounded edges

Fig. 9

Grade 3 macular capillary non-perfusion (CNP). Right eye the upper limit of grade 3 macular CNP. Combined area of macular CNP is 1/3–1 disc area. Macula and one disc area are shown as white circles

Fig. 10

Grade 3 macular capillary non-perfusion (CNP). Right eye the upper limit of grade 3 macular CNP. Combined area of macular CNP is 1/3–1 disc area. Macula and one disc area are shown as white circles

Fig. 11

Grade 4 macular capillary non-perfusion (CNP). Left eye combined areas of macular CNP are >1 disc area. Macula and disc area are shown as white circles. Disc leak and punctate focal leak are also visible

Fig. 12

Grade 4 macular capillary non-perfusion (CNP). Right eye combined areas of macular CNP are >1 disc area. Macula and disc area are shown as white circles. Intravascular filling defects are visible in small and large venules

Fig. 13

Grade 1 peripheral capillary non-perfusion (CNP). Superior retina (right eye). Individual areas of CNP are <1/3 disc area. 1/3 disc area is shown as a white circle. Note that the dark lesion (arrow) is a haemorrhage, and not CNP. Haemorrhage masks background fluorescence and has rounded edges, while CNP has a geographic boundary. Punctate focal leak is visible at the macula

Fig. 14

Grade 1 peripheral capillary non-perfusion (CNP). Inferior retina (right eye). Individual areas of CNP are <1/3 disc area, which is shown by a white circle. Intravascular filling defects are visible in small venules (arrow), and adjacent large venules

Fig. 15

Grade 2 peripheral capillary non-perfusion (CNP). Inferior retina (right eye). Individual areas of CNP are between 1/3 and 1 disc area. 1 disc area is shown as a white circle at the bottom of the image. An enlarged foveal avascular zone is seen at the top of the image

Fig. 16

Grade 2 peripheral capillary non-perfusion (CNP). Infero-nasal retina (right eye). Individual areas of CNP are between 1/3 and 1 disc area. Other visible features include disc leak, punctate focal leak, and intravascular filling defects in small and large venules (arrows)

Fig. 17

Grade 3 peripheral capillary non-perfusion (CNP). Montage of FA images (left eye). Individual areas of CNP are >1 disc area (superior and temporal quadrants), but do not extend into zone 2 nasally or zone 1 in other quadrants. Bays of CNP cut across large vessels and ghost vessels may be visible (e.g. temporal quadrant)

Fig. 18

Grade 4 peripheral capillary non-perfusion (CNP). Montage of FA images (right eye). One or more large bays of CNP encroach on zone 1 (inferior quadrant). Bays of CNP cut across large venules and arterioles, which may appear as ghost vessels in the affected area

Fig. 19

Large focal leak. Right eye one site of large focal leak is visible in the temporal macula (white arrow). Large focal leak appears to represent the evolution of retinal haemorrhage

Fig. 20

Large focal leak. Montage of FA images, left eye. Many sites of large focal leak are visible in the context of severe retinal haemorrhage, which causes masking of background fluorescein and the appearance of multiple dark blots that obscure the vasculature. Disc leak is also visible. Distinguishing sites of large focal leak can be difficult in severe cases

Fig. 21

Punctate focal leak. Left eye multiple sites of punctate focal leak are visible

Fig. 22

Post-capillary venule leak. Left eye post-capillary venule leak affecting many vessel segments. Subtle leak from venules can be detected by comparing venules (e.g. double arrow) with corresponding arterioles (single arrow). The alternating pattern of arterioles and venules makes this sign particularly clear in well focussed images of the fovea (centre of image). Disc leak is also visible

Fig. 23

Post-capillary venule leak. Left eye post-capillary venule leak around the fovea. Disc leak and large/small venule leak are also visible

Fig. 24

Grade 1 large/small venule leak. Left eye <1/3 of all large/small venule segments are leaking (superior quadrant). Disc leak is visible

Fig. 25

Grade 2 large/small venule leak. Montage of FA images, left eye. Between 1/3 and 2/3 of all large/small venule segments are leaking. Very severe macular and peripheral CNP are also visible, with ghost vessels in areas of CNP in the temporal quadrant

Fig. 26

Grade 3 large/small venule leak. Montage of FA images (right eye). >2/3 of all large/small venule segments are leaking. Image quality is affected by extensive leakage of fluorescein. Other visible features include very severe peripheral CNP (large bays enter zone 1 in temporal and inferior quadrants. Note ghost vessel in temporal quadrant—white arrow), grade 4 post-capillary venule leak, and disc leak

Fig. 27

Disc leak. a Normal disc with no leak (7 min after injection of fluorescein). b Disc leak is visible as increasing brightness over time and blurring of the disc margin (2 min after injection). Peripapillary haemorrhages are seen as black flame-shaped lesions, due to masking of background fluorescence

Fig. 28

Intravascular filling defects (IVFD). 20° image (right eye). In this image IVFD are prominent in vessels at the disc (white arrow). The venules appear to be affected much more severely than corresponding arterioles

Fig. 29

Intravascular filling defects (IVFD). a Left eye 50º image of the macula and temporal periphery. IVFD are prominent in venules and arterioles. b Full size image of the vessel junction marked in a (white arrow), illustrates mottling of the blood column