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cotton wool spots, up to the level of moderate NPDR. No IRMA or |
systemic factors, and patient's personal circumstances |
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significant beading |
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Moderate |
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• Severe retinal haemorrhages (more than ETDRS standard |
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photograph 2A: about 20 medium-large per quadrant) in 1–3 |
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quadrants or mild intraretinal microvascular abnormalities |
Review in approximately 6 months |
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(IRMA) |
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PDR in up to 26%, high-risk PDR in up to 8% within a year |
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• Significant venous beading can be present in no more than 1 |
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quadrant |
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• Cotton wool spots commonly present |
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Severe |
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The 4-2-1 rule; one or more of: |
Review in 4 months |
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• |
Severe haemorrhages in all 4 quadrants |
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PDR in up to 50%, high-risk PDR in up to 15% within a year |
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• Significant venous beading in 2 or more quadrants |
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• Moderate IRMA in 1 or more quadrants |
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Very severe |
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Review in 2–3 months |
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Two or more of the criteria for severe |
High-risk PDR in up to 45% within a year |
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Proliferative diabetic retinopathy (PDR) |
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Mild-moderate |
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Treatment considered according to severity of signs, stability, systemic |
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New vessels on the disc (NVD) or new vessels elsewhere (NVE), |
factors, and patient's personal circumstances such as reliability of |
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but extent insufficient to meet the high-risk criteria |
attendance for review. If not treated, review in up to 2 months |
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High-risk |
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• New vessels on the disc (NVD) greater than ETDRS standard |
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photograph 10A (about |
disc area) |
Treatment advised – see text |
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• |
Any NVD with vitreous or preretinal haemorrhage |
Should be performed immediately when possible, and certainly same |
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• |
NVE greater than |
disc area with vitreous or preretinal |
day if symptomatic presentation with good retinal view |
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haemorrhage (or haemorrhage with presumed obscured |
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NVD/E) |
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Advanced diabetic eye disease |
See text |
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See text for description |
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Signs
Figure 13.3 shows the location of lesions in background diabetic retinopathy.
Fig. 13.3 Location of lesions in background diabetic retinopathy
Microaneurysms
Microaneurysms are localized out-pouchings, mainly saccular, of the capillary wall that may form either by focal dilatation of the capillary wall where pericytes are absent, or by fusion of two arms of a capillary loop (Fig. 13.4A). Most develop in the inner capillary plexus (inner nuclear layer) frequently in relation to areas of capillary non-perfusion (Fig. 13.4B). Loss of pericytes may also lead to endothelial cell proliferation with the formation of ‘cellular’ microaneurysms (Fig. 13.4C). Microaneurysms may leak plasma constituents into the retina as a result of breakdown in the blood–retinal barrier, or become thrombosed (Fig. 13.4D).
1Signs. Tiny red dots, often initially temporal to the fovea; tend to be the earliest signs of DR (Fig. 13.4E). They may be indistinguishable from dot haemorrhages.
2Fluorescein angiography (FA). Early frames show tiny hyperfluorescent dots (Fig. 13.4F), representing non-thrombosed microaneurysms, typically more numerous than visible clinically. Late frames show diffuse hyperfluorescence due to leakage.
Fig. 13.4 Retinal microaneurysm. (A) Two arms of a capillary loop are not yet fused to become a microaneurysm– flat preparation of Indian ink-injected retina; (B) an area of capillary non-perfusion and adjacent microaneurysms – flat preparation of Indian ink-injected retina; (C) microaneurysmwith endothelial cell proliferation (cellular microaneurysm) – trypsin digest preparation; (D) thrombosed microaneurysm– PAS and haematoxylin stain; (E) microaneurysms at the posterior pole; (F) FA shows scattered hyperfluorescent spots in the posterior fundus
(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; J Harry – figs B–D)
Retinal haemorrhages
Figure 13.5A is a histological section showing the location of blood.
1Retinal nerve fibre layer haemorrhages arise from the larger superficial pre-capillary arterioles and because of the architecture of the retinal nerve fibres are flame-shaped (Fig. 13.5B).
2Intraretinal haemorrhages arise from the venous end of capillaries and are located in the compact middle layers of the retina with a resultant red ‘dot/blot’ configuration (Fig. 13.5C).
3Deeper dark round haemorrhages represent haemorrhagic retinal infarcts and are located within the middle retinal layers (Fig. 13.5D). The extent of involvement is a significant marker of the likelihood of progression to retinal neovascularization.
Fig. 13.5 Retinal haemorrhages. (A) Histology shows blood lying diffusely in the retinal nerve fibre and ganglion cell layers and as globules in the outer layers; (B) retinal nerve fibre layer haemorrhages; (C) deep dot and blot haemorrhages; (D) deep dark haemorrhages
(Courtesy of J Harry and G Misson, from Clinical Ophthalmic Pathology, Butterworth-Heinemann 2001 – fig. A; Moorfields Eye Hospital – fig. C)
Exudates
Exudates, sometimes termed ‘hard’ exudates to distinguish from the older term of ‘soft’ exudates for cotton wool spots, are caused by chronic localized retinal oedema and develop at the junction of normal and oedematous retina. They are composed of lipoprotein and lipidfilled macrophages located mainly within the outer plexiform layer (Fig. 13.6A). Hyperlipidaemia may increase the likelihood of exudate formation.
1Signs
•Waxy yellow lesions with relatively distinct margins, often arranged in clumps and/or rings at the posterior pole, typically surrounding leaking microaneurysms (Fig. 13.6B).
•With time number and size tend to increase (Fig. 13.6C), and the fovea may be threatened or involved (Fig. 13.6D).
•When leakage ceases, exudates absorb spontaneously over a period of months or years, either into the healthy surrounding capillaries or by phagocytosis of their lipid content.
•Chronic leakage leads to enlargement of the exudates and the deposition of cholesterol (Fig. 13.6E).
2 FA shows hypofluorescence due to blockage of background choroidal and retinal capillary fluorescence.
Fig. 13.6 Exudates. (A) Histology shows irregular eosinophilic deposits mainly in the outer plexiformlayer; (B) small exudates and microaneurysms; (C) incomplete ring of exudates and a few small haemorrhages; (D) exudates involving the fovea; (E) plaque of exudates at the macula associated with cholesterol deposition
(Courtesy of J Harry – fig. A)
Diabetic macular oedema
Diabetic maculopathy (foveal oedema, exudates or ischaemia) is the most common cause of visual impairment in diabetic patients, particularly type 2. Diffuse retinal oedema is caused by extensive capillary leakage, and localized oedema by focal leakage from microaneurysms and dilated capillary segments. The fluid is initially located between the outer plexiform and inner nuclear layers; later it may also involve the inner plexiform and nerve fibre layers, until eventually the entire thickness of the retina becomes oedematous. With further accumulation of fluid the fovea assumes a cystoid appearance (cystoid macular oedema – CMO).
1Signs. Retinal thickening is best detected by slit-lamp biomicroscopy with a contact lens, though high-resolution non-contact lenses are also effective.
2FA shows diffuse late hyperfluorescence due to retinal capillary leakage, and may have a flower-petal pattern if CMO is present (Fig. 13.7A).
3OCT shows retinal thickening and, if present, cystoid spaces (Fig. 13.7B). OCT is also useful in assessing response to treatment.
Fig. 13.7 Macular oedema. (A) FA shows diffuse hyperfluorescence with a central flower-petal configuration due to CMO; (B) OCTshows retinal thickening and cystoid spaces
(Courtesy of Moorfields Eye Hospital – fig. A; Oxford Eye Hospital – fig. B)
Focal maculopathy
1 Signs. Well-circumscribed retinal thickening associated with complete or incomplete rings of exudates (Fig. 13.8A). 2 FA shows late, focal hyperfluorescence due to leakage, and good macular perfusion (Fig. 13.8B).
Fig. 13.8 Focal diabetic maculopathy. (A) A ring of hard exudates temporal to the macula; (B) FA late phase shows focal area of hyperfluorescence due to leakage corresponding to the centre of the exudate ring
Diffuse maculopathy
1Signs. Diffuse retinal thickening, which may be associated with cystoid changes. Landmarks are obliterated by severe oedema which may render localization of the fovea impossible (Fig. 13.9A).
2FA shows late diffuse hyperfluorescence (Fig. 13.9B) which may assume a central flower-petal pattern if CMO is present.
Fig. 13.9 Diffuse diabetic maculopathy. (A) Dot and blot haemorrhages; (B) FA late phase shows extensive hyperfluorescence at the posterior pole due to leakage
Ischaemic maculopathy
1Signs are variable and the macula may look relatively normal despite reduced visual acuity. In other cases PPDR may be present (Fig. 13.10A).
2FA shows capillary non-perfusion at the fovea (an enlarged FAZ) and frequently other areas of capillary non-perfusion at the posterior pole and periphery (Fig. 13.10B).
Fig. 13.10 Ischaemic diabetic maculopathy. (A) Dot and blot haemorrhages and cotton wool spots; (B) FA venous phase shows hypofluorescence due to capillary non-perfusion at the macula and elsewhere
(Courtesy of Moorfields Eye Hospital)
Clinically significant macular oedema
Clinically significant macular oedema (CSMO) was defined in the ETDRS (Fig. 13.11):
•Retinal thickening within 500 µm of the centre of the macula (Fig. 13.11, upper left).
•Exudates within 500 µm of the centre of the macula, if associated with retinal thickening (which may be outside the 500 µm – Fig. 13.11, upper right).
•Retinal thickening one disc area (1500 µm) or larger, any part of which is within one disc diameter of the centre of the macula (Fig. 13.11, lower centre).
Fig. 13.11 Clinically significant macular oedema
Cotton wool spots
Cotton wool spots are composed of accumulations of neuronal debris within the nerve fibre layer. They result from disruption of nerve axons, the swollen ends of which are known as cytoid bodies, seen on light microscopy as globular structures in the nerve fibre layer (Fig. 13.12A). As cotton wool spots heal, debris is removed by autolysis and phagocytosis.
1Signs. Small, whitish, fluffy superficial lesions which obscure underlying blood vessels and are clinically evident only in the postequatorial retina, where the nerve fibre layer is of sufficient thickness to render them visible (Fig. 13.12B).
2FA shows focal hypofluorescence due to blockage of background choroidal fluorescence, frequently associated with adjacent capillary non-perfusion.
Fig. 13.12 Cotton wool spots. (A) Histology shows cytoid bodies in the nerve fibre layer; (B) clinical appearance
(Courtesy of J Harry – fig. A; K Slowinski – fig. B)
Venous changes
Venous anomalies seen in ischaemia consist of generalized dilatation and tortuosity, ‘looping’ (Fig. 13.13A), ‘beading’ (focal narrowing and dilatation – Fig. 13.13B) and ‘sausage-like’ segmentation (Fig. 13.13C). The extent of the retinal area exhibiting venous changes correlates well with the likelihood of developing proliferative disease.
Fig. 13.13 Venous changes. (A) Looping; (B) beading; (C) severe segmentation
Intraretinal microvascular abnormalities
Intraretinal microvascular abnormalities (IRMA) are arteriolar-venular shunts that run from retinal arterioles to venules, thus bypassing the capillary bed and are therefore often seen adjacent to areas of marked capillary hypoperfusion (Fig. 13.14A).
1 Signs. Fine, irregular, red intraretinal lines that run from arterioles to venules (Fig. 13.14B), without crossing major blood vessels. 2 FA shows focal hyperfluorescence associated with adjacent areas of capillary closure ('dropout’) but without leakage.
