Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

Figure 15B: Late diffuse choroidal hyperfluorescence in the same case as 15A

choroidal vessels (Figure 16A) and no more hyperfluorescence (Figure 16B) in the same areas.

2.In ICG angiography the disc usually remains hypofluorescent throughout the angiographic sequences. In case of severe inflammation disc capillaries can become permeable to large particles such as the protein-bound ICG, causing disc hyperfluorescence which is always indicating severe inflammation (Figures 17A and B).

3.In case of granulomatous inflammation such as sarcoidosis, tuberculosis or syphilis the late phase frames can show focal fluorescence or hyperfluorescent pinpoints. It is thought that granulomatous lesions progressively fix the ICG molecules (Figure 18).

4.ICG angiography is useful to demonstrate inflammatory neovessels and often allows to make the difference between an inflammatory lesion and inflammatory neovascular membranes that appear hyperfluorescent since early frames and throughout the angiographic sequence (Figure 19).

The purpose here is not to report all other rare

situations outside the four categories of hyperfluorescence mentioned where hyperfluorescence can occur such as inflammatory macroaneurysms that can be seen

Figure 16B: Same case as 16A after treatment showing normal background fluorescence in the late angiographic phase

Figure 17A: Fundus photography of acute VKH.

Posterior pole serous retinal detachments

in sarcoid uveitis (Figure 20) or hyperfluorescent pinpoints in exudative serous retinal detachment (Figure 21).

DIFFERENCES BETWEEN FLUORESCEIN AND INDOCYANINE GREEN ANGIOGRAPHY

In most cases, unlike in FA where most pathologies produce hyperfluorescence, the lesions in ICGA are mostly seen in a negative dark pattern due to impaired physiological choroïdal fluorescence.

Figure 17B: Disc hyperfluorescence in acute VKH disease.

The top frames both show hyperfluorescent choroidal vessels (vasculitis) and hypofluorescent diffuse areas (choriocapillaris non perfusion. The disc is already hyperfluorescent in the intermediate phase (bottom left) and even more so in the late phase (bottom right)

Figure 17C: Disc hyperfluorescence has resolves after introduction of inflammation suppressive therapy

When analysing ICGA it is of utmost importance to make abstraction in most inflammatory situations of two factors that are important in the interpretation of fluorescein angiograms, namely blockage and window defect. Because infrared fluorescence can be seen through structures that are a screen for visible light, blockage has to be considered only if the interfering structures in front of the choroid are sufficiently thick and/or heavily pigmented. Similarly the notion of window defect does not usually apply for ICGA as the retinal pigment epithelium does mostly not act as a screen as for FA. Because of these reasons ICGA is useless in the analysis of pigment epithelium changes

Figure 18: Focal granulomatous late hyperfluorescence in a case of intraocular sarcoidosis. Most prominent in the bottom right frame

Figure 19: Inflammatory choroidal neovascular membrane (NVM). Fluorescein angiography (left frame) shows one central hyperfluorescent zone corresponding to the NVM and 4 satellite hyperfluorescent lesions. ICGA allows to clearly differentiate between NVM, hyperfluorescent and perilesional inflammatory foci that are hypofluorescent

that are, however, very precisely shown by FA (Figure 22).

ICGA (right frame) does not give any information on the pigment epithelium but shows remaining inflammatory foci (HDDs) in the choroidal stroma indicating remaining activity of the disease.

CLINICO-PATHOLOGIC-ANGIOGRAPHIC CORRELATIONS

The pathologic processi at the origin of the ICGA images we see have been verified histopathologically for some of the diseases such as the primary stromal choroiditides including Vogt-Koyanagi-Harada disease, sympathetic ophthalmia and birdshot chorioretinopathy, as well as the choroidal lesions due to sarcoidosis and tuber-

Figures 20A and B: Rare hyperfluorescent situations: macroaneurism in sarcoidosis. Brightly hyperfluorescent dot showing accumulation of dye within the macroaneurism on the superior temporal arcade. Note HDD in the intermediate phase

(A) mostly erased in the late phase (B)

culosis. When looking at histology sections of the choroid coming from pathology specimen of VKH disease it is easily understandable that full thickness

Figure 21: Hyperfluorescent pinpoints in exudative retinal detachment (ERD) in a VKH patient. The leaking points are equally well shown on FA and ICGA

Figure 22: Pigment epithelium anomalies are very clearly put in evidence by FA (left frame) showing a salt and paper aspect of alternating blockage and window defects caused by the resolved serous detachment in a case of VKH disease

Figure 23: Histological section of choroid in sympathetic ophthalmia showing inflammatory focus in the choroidal stroma

granuloma produce round evenly sized hypofluorescent dark dots (HDDs) remainig hypofluorescent during all angiographic sequences (Figure 12C). The same type of histopathological lesions cause evenly sized hypofluorescent dark dots on ICG angiography in sympathetic ophthalmia (Figure 23). Two recent papers have published histopathological findings in a

case of birdshot chorioretinopathy showing the presence of choroidal granulomatous foci very well explaining the hypofluorescent dark dots typically seen on ICG angiography in birdshot chorioretinopathy20,21 (Figure 13C). In other diseases such as the group of inflammatory choriocapillaropathies (see below) including multiple evanescent white dots syndrome (MEWDS) and others, the ICGA signs can only be hypothesized so far, still needing confirmation by histopathological sections.

RELEVANCE OF ICG ANGIOGRAPHY IN OCULAR INFLAMMATORY DISEASES

Indocyanine green angiography showed occult choroidal lesions not shown by fundoscopy and/or FA in 100% of patients with a well-established diagnosis known to involve the choroid and these findings had an essential impact either on diagnosis or management in 12.3% of these cases, stressing the importance of ICGA for the proper management of most inflammatory processi of the back of the eye.22

KEY POINTS: ICGA PRINCIPLES

•ICGA is indicated and the examination of choice for the proper investigation of choroidal inflammatory involvement

•ICGA hypofluorescence results from at least 2 mechanisms:

1.Choriocapillaris non-perfusion (patchy/geographic disposition; persistent or even increased hypofluorescence on late frames),

2.Stromal inflammatory infiltration (more regular dots and more even distribution)

-hypofluorescence up to late frames (full-thickness lesion)

-isofluorescence on late frames (partial-thickness lesions)

-usually surrounded by leakage of large choroidal vessels (fuzzy aspect in intermediate phase followed by diffuse choroidal fluorescence in late phase)

•ICGA hyperfluorescence:

1.In its diffuse form results from increased leakage from larger inflamed stromal choroidal vessels.

2.When present at the level of disc indicates severe inflammation.

3.When present in the form of numerous late hyperfluorescent pinpoints indicates granulomatous disease.

•FA principle of window effect (window defect) not applicable to ICGA as infrared fluorescence is perceived through the RPE that is not a screen in ICGA.

•FA principle of blockage only rarely plays a role in ICGA (unless thick or strongly pigmented screen) in which hypofluorescence is mostly caused by choriocapillaris non perfusion or choroidal stromal infiltration (mass effect)

Figure 24: Cartoon showing the different layers of the choroid from sclera to retina

THE CONCEPTS OF INFLAMMATORY

CHORIOCAPILLAROPATHY AND

STROMAL CHOROIDITIS23

Indocyanine green angiography has allowed to reclassify choroidal inflammation according to the structure that is preponderantly or initially involved. At the present stage of our knowledge there seem to be at least two main mechanisms of inflammation touching the choroid, inflammation of the choriocapillaris or choriocapillaritis and inflammation of the choroidal stroma or stromal choroiditis (Figure 24).

CHORIOCAPILLARIS CHOROIDITIS (CHORIOCAPILLARITIS OR INFLAMMATORY CHORIOCAPILLAROPATHY)

In this first group of choroidal inflammatory diseases, inflammation can involve primarily and electively the choriocapillaris causing closure of the choriocapillaris net in which case this group of diseases is called pimary inflammatory choriocapillaropathies. On the other hand, the choriocapillaris can be involved by vicinity, by an inflammatory process in neighbouring structures and it is then called secondary inflammatory choriocapillaropathy.

Primary Inflammatory Choriocapillaropathies (PICCP)16,18

This group of diseases, formerly mostly included in the inadequate terminology of “white dot syndromes”,

results from inflammation at the level of the choriocapillaris causing areas of choriocapillaris non perfusion or hypoperfusion. The ischaemic consequences produce lesions both at the level of the choroidretinal interface in particular on the RPE but also at the level of the outer retina that depends on the choriocapillaris for oxygen and nutrients. ICG angiography shows usually irregularly shaped hypofluorescent dark areas of small to large size, geographically confluent, that are hypofluorescent throughout the angiogram remaining hypofluorescent in the later phases of the angiography. They are the result of diminished or absent physiological exudation of the ICG molecule from the choriocapillaris (Figure 25A). FA shows early hypofluorescence in the same areas where ICGA hyperfluorescence is located. In the late FA angiographic phase the same areas show profuse hyperfluorescence due to leakage and pooling that can only come from inner retinal vessels in reaction to outer retina hypoxemia (Figure 25B). This edematous retina is at the origin of the yellowish plaques typically seen in this group of diseases and acute posterior multifocal placoid pigmentary epitheliopathy (APMPPE) is typically illustrating this type of choriocapillaris inflammation (Figure 25C). The spectrum of choriocapillaritides goes from benign disease such as multiple evanescent white dot syndrome (MEWDS) on one end of the spectrum towards APMPPE, usually still favourable in outcome, and multifocal choroiditis, a disease having more severe consequences needing corticosteroid and/or immmunosuppressive therapy, and finally, at the other end of the spectrum, serpiginous choroiditis, a disease which often has a deleterious outcome.

Secondary Inflammatory Choriocapillaropathy

As usual in inflammatory disorders, the inflammation is not strictly limited to the primary site of involvement but can also touch adjacent structures. For example, severe retinitis caused by Toxoplasma gondii usually extends to the choriocapillaris causing secondary inflammatory choriocapillaropathy24 (Figures 25D125D3). Likewise severe stromal disease can cause inflammation at the level of the choriocapillaris and beyond involving the retinal pigment epithelium and the retina as in Vogt-Koyanagi-Harada disease when

Figure 25B: Fluorescein angiography in a case of choriocapillaritis (APMPPE). The early FA frames (two top frames) show choriocapillaris hypofluorescence. FA does not allow to say whether it is due to total non perfusion that can only be shown by ICGA. In the late FA phases profuse hyperfluorescence is seen due to exudation from inner retinal vessels in response to outer retinal ischaemia produced by choriocapillaris non perfusion as shown on Figure 25A coming from the same case

Figure 25C: Fundus aspect of APMPPE showing pronounced retinal oedema. The yellow discoloured foci are explained by the retinal edema seen on FA in response to outer retinal ischaemia due to choriocapillaris non perfusion seen on ICGA

Figure 25D1: Subclinical reactivation of toxoplasmic retinochoroiditis. Fundus view

Figure 25D2: Secondary inflammatory choriocapillaropathy around a focus of toxoplasmic retinochoroiditis. Hypofluorescent areas (secondary choriocapillaritis) in ICGA are far more widespread than what FA pictures or fundus pictures show

Figure 25D3: Focus of toxoplasmic retinochoroiditis seen by FA. It does not show the choriocapillaritis very well identified by ICGA as shown on Figure 25D2

serous retinal detachments occur followed by RPE changes.

In other words, any severe inflammation in the vicinity of the choriocapillaris either in the retina or in the underlying stroma can produce secondary inflammation at the level of the choriocapillaris and cause closure of the choriocapillaris net, producing hypofluorescence due to secondary inflammatory choriocapillaropathy.

STROMAL CHOROIDITIS25

In the second group of diseases, the primary mechanism is the development of inflammatory foci, mostly granulomatous at the level of the stroma appearing hypofluorescent on ICG angiography, usually associated with inflammation of larger non-fenestrated stromal vessels appearing as fuzzy vessels in the intermediate angiographic phase followed by diffuse late choroidal hyperfluorescence. Stromal involvement can occur as a primary inflammation where the target is specifically situated at the level of the choroidal stroma. Vogt-Koyanagi-Harada disease, sympathetic ophthalmia or birdshot chorioretinopathy are typical

illustrations of this type of primary stromal choroidal inflammation. In this situation neighbouring structures can be involved secondarily as a consequence of a splillover of the choroidal inflammation. In case of birdshot chorioretinopathy, unlike for VKH or sympathetic ophthalmia where choroidal inflammation produces secondary retinal changes, the retina is a second primary target beside the choroidal stroma with both structures having independent progression of inflammation. On the other hand, the choroidal stroma can be the innocent host or by-stander of a systemic type of inflammation that occurs by chance in the choroid as one of the possible localisations. Sarcoid choroiditis or tuberculous choroiditis are typical illustrations of these secondary types of stromal choroiditis. When such a systemic inflammation also involves the retina we speak of chorioretinitis.

Although the mechanism is completely different from the primary inflammatory choriocapillaropathies, these conditions have also been included mistakenly by some authors in the potpourri group of “white dot syndromes”, uniquely based on similar fundus aspects.1

KEY POINTS: CLASSIFICATION OF CHOROIDITIS

Two main lesional mechanisms determine the classification of choroiditis:

1.Choriocapillaris inflammation (primary inflammatory choriocapillaropathies)

-MEWDS / AIBSE

-APMPPE

-Multifocal choroiditis / PIC

-Serpiginous choroiditis

-Rare entities : AMN, AZOOR

2.Stromal inflammation (stromal choroiditis) further subdivided into two categories

• Primary obligatory stromal choroiditis

-Vogt-Koyanagi-Harada disease

-Sympathetic Ophthalm

-Birdshot chorioretinopathy

•Stromal choroiditis as a random location of a systemic disease

-Sarcoidosis

-Tuberculosis

-Syphilis

-Other infectious choroiditides

ICGA SIGNS IN INFLAMMATORY

CHORIOCAPILLAROPATHIES

INTRODUCTION

Primary inflammation at the level of the choriocapillaris leading to hypoperfusion or non perfusion

is a common denominator for several diseases of the fundus that have formerly been assembled under the purely descriptive pot pourri term of “white dot syndromes”. Knowledge about these entities has been increasing particularly since indocyanine green angiography (ICGA) has become available.26,27 The ICGA pattern correlated with functional (visual field testing) and electrophysiologic parameters strongly points towards choriocapillaropathy and consequent ischaemic dysfunction of the outer retina in this group of diseases.28,29 Included in this group are multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy or more accurately named after Deutman acute multifocal ischaemic choroiditis (APMPPE/AMIC),28,30 multifocal choroiditis including punctate inner choroidopathy (MFC/PIC) and pseudo-histoplasmosis, serpiginous choroiditis, and possibly also rare entities such as acute macular neuroretinopathy (AMN) and acute zonal occult outer retinopathy (AZOOR). Between these rather well determined clinical entities, intermediary forms occur that can hardly be made to fit into these well determined diseases. Thus, intermediary forms of disease between APMPPE and serpiginous choroiditis has been reported to which the names of AMPPiginous choroiditis or relentless placoid chorioretinitis were given.31,32

ANGIOGRAPHIC SIGNS IN

PRIMARY INFLAMMATORY CHORIOCAPILLAROPATHIES (PICCP)

Indocyanine green angiographic signs in inflammatory choriocapillaropathies are well determined and have contributed to the recognition of the common mechanism involved and to regroup these entities formerly classified under the inadequate term of “white dot syndromes”.16,18,33

The following ICGA signs have to be looked for:

1.The hallmark sign of inflammatory choriocapillaropathy is patchy or geographic ICGA hypofluorescent areas of variable sizes present in the early, intermediate and late angiographic phases but usually more clearly visible on the late frames, indicating choriocapillaris non-perfusion or hypoperfusion (Figure 25A).

2.Complete or partial regression of the ICGA hypofluorescence for some entities or absence of

regression in other diseases in the convalescent phase. The areas remaining hypofluorescent in the convalescent phase represent chorioretinal atrophy and on fluorescein angiography they correspond to areas of window effect where RPE is removed and masking effect where pigment from damaged RPE accumulates.

3.In diseases with a progressing course such as serpiginous choroiditis, ICGA can show diffuse choroidal hyperfluorescence at the edges of the progressing lesions in areas having no translation on fundoscopy or fluorescein angiography (Figures 26A to C).

Whereas the ICGA signs are quite uniform, the FA angiographic signs depend on the severity and extension of the choriocapillaris non perfusion and on the outer retinal ischaemic damage.

1.On FA there is likewise early hypofluorescence showing the choriocapillaris non perfusion identified on ICGA (Figure 25B).

2.Depending on the severity of the choriocapillaris non perfusion seen on ICGA, late FA frames either show no hyperfluorescence (for instance in mild MEWDS), discrete patchy late hyperfluorescence seen in some MEWDS cases or extensive late hyperfluorescence seen in APMPPE (Figures 25B and C).

To understand the genesis of the FA signs it is important to be aware that late FA fluorescence is coming from retinal vessels of the internal retina overlying areas of ischaemic outer retina. These internal retina capillaris present increased permeability in response to the ischaemia of the outer retina due to choriocapillaris non perfusion.

3.In the convalescent phase there is a delayed regression of FA signs (hyperfluorescence due to staining and pooling) as compared to the regression of ICGA signs. In case of chorioretinal atrophy window effect and masking effect due to

chorioretinal/RPE scarring are seen.

Any severe inflammation in an adjacent structure to the choriocapillaris (retina or choroidal stroma) can cause inflammation at the level of the choriocapillaris and produce similar angiographic signs. In that situation we speak of secondary inflammatory choriocapillaropathy (Figure 25D).

Figure 26A: Serpiginous choroiditis—ICGA. Hypofluorescent areas show choriocapillaris non perfusion / atrophy. Active choroiditis is seen at the margin of lesions marked by choroidal hyperfluorescence. FA of the same area (Figure 26B) does not allow to determine whether there is activity

Figure 26B: Serpiginous choroiditis—FA. Alternation of hyperfluorescent (window-effect) and hypofluorescent (blocking effect) show the atrophy caused by scars. No clear information on activity of disease is available from FA

Figure 26C: Serpiginous choroiditis. Fundus photography of the same case shown on Figures 26A and B

KEY POINTS: ANGIOGRAPHIC SIGNS IN INFLAMMATORY CHORIOCAPILLAROPATHIES

•ICGA 1: in acute phase of disease, patchy or geographic ICGA hypofluorescent areas of variable sizes present in the early, intermediate and late angiographic frames but usually more clearly visible on the late frames after partial wash-out of ICG from choroid.

•ICGA 2: in post-acute phase, ICGA hypofluorescent areas representing choroidal atrophy and scarring.

•ICGA 3: hyperfluorescent ICGA rims around progressing (serpiginous) lesions.

•FA 1: in acute phase of disease, early FA hypofluorescent areas indicating choriocapillaris non perfusion.

•FA 2: in acute phase of disease, late FA hyperfluorescent areas going from faint to profuse depending on the severity of ischaemic process at the level of the outer retina.

•FA 3: in post-acute phase, zones of alternating areas of window-effects and masking effects indicating chorioretinal atrophy and scars.

•In convalescent phase of disease, regression of FA signs lags behind normalisation of ICGA signs.

INFLAMMATORY CHORIOCAPILLAROPATHIES: SPECIFIC ENTITIES

Multiple Evanescent White

Dot Syndrome (MEWDS)

Multiple evanescent white dot syndrome (MEWDS), first described by Jampol et al. in 198434 affects young patients, predominantly women, tends to be unilateral and is frequently preceded by a flue-like syndrome.35

The symptomatology of photopsias and scotoma, the clinical findings of visual field loss and decrease of visual acuity as well as electrophysiologic findings all point towards external retinal dysfunction. Indocyanine green angiography gives us the morphological element explaining the clinical presentation of MEWDS. It shows numerous hypofluorescent small (one third disc diameter) to medium sized (one disc diameter) usually confluent dark areas predominant in the mid-periphery, present in the intermediate phase and even more clearly visible in the late phase36,37 (Figure 27A).

Around the optic disc hypofluorecence is confluent usually surrounding the disc on 360° (Figure 27A). In a variant form of the disease called acute idiopathic blind spot enlargement (AIBSE) the circumpapillary confluent hypofluorescence extends further away from the disc.38 Interestingly these dark dots are much more clearly delineated in the late phase and less so in the

Figure 27A: ICGA in MEWDS. Discrete peripapillary hypofluorescence and widespread patchy confluent hypofluorescent areas not suspected by FA (Figure 27B)

Figure 27B: Fluorescein angiography in MEWDS. The intensity of FA signs depend on the severity of choriocapillaris non-perfusion. Signs can be quasi absent or very minimal as in this case showing very faint patchy areas of late hyperfluorescence. Note the presence of disc hyperfluorescence

early angiographic times, speaking more for choriocapillaris hypoperfusion rather than strict nonperfusion, which possibly could also explain the usual favourable outcome of MEWDS. The disposition of the lesions is widespread up to the mid-periphery and more of the patchy type except around the optic disc where the lesions have a more geographic confluent form. FA signs are usually very faint and usually comprise a hyperfluorescent disc on late frames and patchy late hyperfluorescence in the areas corresponding to ICGA hypofluorescence (Figure 27B). They can also be very pronounced in some cases. The widespread although mostly faint involvement explains the constant and significant visual field anomalies and electrophysiologic changes. Taken together, ICGA signs clearly indicate choriocapillaris hypoor non perfusion that induce outer retinal ischaemia and dysfunction that accounts for the symptomatology of photopsias, the visual field changes and the electrophysiologic findings.

In clinical practice ICGA is especially precious in reaching a diagnosis in the situation when the patient is seen in the post-acute phase and ICGA is the only positive finding. ICGA lesions almost integrally resolve without treatment in the convalescent phase of disease after 6-10 weeks of evolution. The discrepancy between the very prominent ICGA signs compared to the very discrete FA signs in many cases is a particularity of MEWDS. To monitor disease evolution, ICGA is the most precise parameter to follow. Because of the discrete and sometimes absent FA signs, fluorescein angiography is of limited use in MEWDS.

Acute Idiopathic Blind Spot Enlargement (AIBSE)

Acute idiopathic blind spot enlargement (AIBSE) first described in 1988 presents a peripapillary scotoma producing symptomatic enlargement of the blind spot objectively identified by visual field testing. Most probably AIBSE and MEWDS are the same disease with the fundus findings being absent in AIBSE probably because the retinal lesions may already have subsided at the time of examination or were subclinical.39,40 ICGA is presently the method of choice for making the diagnosis of atypical MEWDS in patients consulting at a later stage of the disease or