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

Figure 44A: HDDs already visible in the post-early phase of angiography

Figure 44B: HDDs well visible in the intermediate phase of angiography

Figure 47: ICGA of exudative retinal detachment. Hyperfluorescent pinpoints shown by FA are also seen on ICGA as well as pooling of subretinal fluid

severe papillitis (Figure 46). In case of exudative detachments, ICGA shows the same hyperfluorescent pinpoints seen on fluorescein angiography (Figure 47).

In summary at least seven ICG angiographic signs can be identified in VKH disease:

1.Inhomogeneity of choriocapillaris perfusion with sectorial perfusion delay in the very early phase of angiography (Figure 42).

2.Early hyperfluorescent stromal choroidal vessels indicating inflammatory vasculopathy of the choroid (Figure 43).

3.Hypofluorescent dark dots (HDD) well identified in the intermediate phase mostly remaining in the late phase indicating full thickness inflammatory infiltration (granuloma). Some of these HDD are

erased in the late phase indicating partiel thickness granulomas (Figures 44A to D).

4.Loss of vascular pattern of choroidal vessels appearing fuzzy and indistinct in the intermediate phase followed in the late phase this is followed by diffuse hyperfluorescence (Figure 45).

5.Diffuse late choroidal hyperfluorescence, explained by the fact that abnormal ICG fluorescence coming from leaking stromal vessels adds to the physiologic ICG fluorescence coming from choriocapillaris exudation (Figure 46).

6.Disc hyperfluorescent indicating severe inflammation (Figure 46).

7.Hyperfluorescent pinpoints and diffuse subretinal pooling in severe disease indicating leakage points

and accumulation of subretinal fluid similar to fluorescein images (Figure 47).

Out of these ICGA features, 4 signs were identified to be useful and recommended for the evaluation of choroidal disese in acute VKH disease at presentation and to monitor disease evolution because they were of constant occurrence (close to 100% for all signs), easily evaluable and readily recordable.77

1.Early hyperfluorescent and leaking choroidal vessels.

2.Hypofluorescent dark dots (HDD).

3.Loss of normal stromal vascular pattern with indistinct fuzzy stromal vessels.

4.Disc hyperfluorescence.

ICGA was found to be essential not only for the

precise assessment of choroidal involvement and for the follow-up of choroidal lesions to monitor therapy effect but also for the diagnosis of early and atypical cases. It also contributed to reduce the number of apparently unilateral cases by showing fellow eye subclinical involvement.16 In a recent article we showed that these four main signs resolve within 4 months after the initiation of high-dose inflammation suppressive therapy.77

In contrast to ICGA, fluorescein angiography does not show the primary inflammatory process but only its consequences on adjacent structures such as the retina. In the acute stage of the disease or during recurrences, serous exudative detachments appear as multifocal hyperfluorescent pinpoints showing the leaking points at the level of pigment epithelium also seen on ICGA. FA also shows late pooling of the dye in the subretinal space (Figure 40B). Optic disc staining

and leakage also appears in the acute phase. In the chronic stage FA clearly shows the diffuse retinal pigment epithelium alterations not shown by ICGA and classically appearing as a mixture of window and masking effects (Figure 41). This is a consequence of the exudative retinal detachment the limits of which are well shown and called high-water marks (Figure 41). In the chronic phase a hyperfluorescent “hot” disc may be the only fluorescein angiographic sign indicating inflammatory activity, whereas ICGA can show subclinical choroidal granuloma being a more accurate modality to show the activity of the disease.74-77

ICGA signs in subacute and chronic VKH disease (disease follow-up)

The listed ICGA signs deemed useful for disease monitoring all regress if prolonged high dose inflammation suppressive therapy (IST) is given.78 The chronology of response to high dose IST of ICGA signs starts with resolution of hyperfluorescent disc and early hyperfluorescent leaking vessels within the first 5 weeks of therapy, followed by disappearance of early hyperfluorescence of choroidal vessels within 2 months of therapy. The third sign to respond is the resolution of fuzziness of choroidal vessels within 9 weeks of therapy and finally HDDs within 4 months of high dose IST.78 During the tapering of high dose IST, ICGA was shown to be very sensitive to detect choroidal subclinical recurrence by showing reappearance of HDDs when the disease seemed to be clinically controlled.77 This indicates that low-grade subclinical disease is persisting despite apparent clinical control and explains the fact that a very large proportion of cases progress towards sunset glow fundus despite apparent clinical control of the disease.78 Furthermore, in case chronically evolving cases of VKH disease that newly present to a centre, ICGA is very useful to evaluate activity of the disease and essentially contributes to therapeutic decision taking.

KEY POINTS: ANGIOGRAPHIC SIGNS IN VOGT- KOYANAGI-HARADA (VKH) DISEASE AND SYMPATHETIC OPHTHALMIA

•VKH is primary stromal choroiditis with ICGA being the most sensitive imaging modality to detect incipient and/or subclinical disease and/or subclinical choroidal recurrence and to adjust therapy (ICGA assisted therapy)

•ICGA signs at onset:

• early hyperfluorescent / leaking choroidal vessels

•hypofluorescent dark dots regular in size, evenly distributed, usually present up to late phase

•loss of normal stromal vascular pattern with indistinct fuzzy stromal vessels

•disc hyperfluorescence.

•ICGA in recurrent disease shows similar features to acute disease except for the hyperacute signs. Useful for the assessment of disease activity.

Sympathetic Ophthalmia (SO)

Indocyanine green angiography in SO similarly to VKH shows hypofluorescent dark dots seen in the intermediate angiographic phase with the usual two patterns of evolution, some becoming isofluorescent in the late phase of ICGA corresponding to partial thickness inflammatory foci (granulomas) (Figure 23) and some remaining hypofluorescent up the late angiographic phase. (Figure 48). Both types of HDDs resolve after long term corticosteroid therapy and correspond to active choroidal inflammatory foci78 (Figure 49).

In some cases peripapillary hypofluorescence has been seen possibly corresponding to associated choriocapillaris non perfusion (secondary inflammatory choriocapillaropathy). Mostly ICGA signs are similar to VKH disease.

Birdshot Chorioretinopathy

The particularity of birdshot chorioretinopathy (BC) is that both the choroid and the retina are independent primary targets and sites of an inflammatory reaction in contrast to the other stromal choroiditides where inflammation originates in one structure and causes secondary inflammation in the surrounding structures.80,81 A recent autopsy case of birdshot with histopathology of the eye20,21 has contributed significantly to support the explanations of the ICGA signs that had been given in the past.82 This autopsy case has shown that, as for Vogt-Koyanaga-Harada disease and sympathetic ophthalmia, it is the choroidal stroma that is the primary target of the inflammatory attack in BC while the choriocapillaris and the pigment epithelium are intact (Figure 13C). In association with these inflammatory foci appearing as regularly disposed HDDs there is inflammation of the choroidal vessels that is at the origin of the fuzzy indistinct aspect of larger stromal vessels and that was shown by histopathology in a birdshot autopsy case20,21 (Figure 14). This disease that

Figure 48: Sympathetic ophthalmia – FA and ICGA. Disc hyperfluorescence, hyperfluorescent pinpoints and patchy slightly hyperfluorescent areas (top right frame). ICGA shows HDDs in the intermediated and late phases as well as peripapillary hypofluorescence

Figure 49: Sympathetic ophthalmia – after inflammation suppressive therapy. Resolution of most ICGA signs

was previously included in the “pot-pourri” group of “white dot syndromes”, should not be assimilated to the PICCPs as the pathogeny of the disease is totally different.18 The target of the inflammatory reaction seems to be the islets of stromal melanocytes as in Vogt- Koyanagi-Harada disease leaving the oval shaped depigmented areas seen on fundoscopy in late disease (Figure 50). This autopsy case also showed that birdshot is a granulomatous disease which explains the fact that it is not exceptional to find isolated small granulomatous keratic precipitates on the endothelium especially in

Figure 50: Birdshot fundus. Typical rice shaped depigmented fundus lesions characteristic for birdshot chorioretinopathy

Figure 51: Birdshot, a granulomatous disease. On longitudinal follow-up it is not rare to observe isolated small granulomatous KPs in non treated patients. The granulomatous character of the disease has since been demonstrated on an autopsy case of birdshot

non treated birdshot cases (Figure 51). The functional deleterious impact comes, however, from the retinal inflammatory involvement.83

Since indocyanine green angiography is available, choroidal inflammatory involvement has become accessible to analysis and monitoring.82 The most characteristic ICGA findings are the evenly shaped hypofluorescent dark dots regularly disposed in the mid-periphery present in the intermediate phase which we presently know to correspond to choroidal stromal granulomas20,21,82 (Figure 52). A large proportion of these hypofluorescent dots become isofluorescent in the late angiographic phase probably indicating that in contrast to Vogt-Koyanagi-Harada disease, birdshot granulomas are not as dense and as

Figure52:BirdshotchorioretinopathyICGAsigns.Hypofluorescent dark dots (HDDs). Numerous regularly distributed, evenly sized HHDs in the intermediate phase of angiography

thick to avoid all diffusion of the ICG dye (Figure 52). As in most stromal inflammatory diseases large vessels are indistinct and fuzzy in the intermediate phase and produce late diffuse stromal hyperfluorescence. This additional fluorescence coming from inflamed stromal vessels explains how partial thickness granulomas are “erased” and become isofluorescent in the late angiographic phase (Figures 53A and 54A). Choroidal vasculitis shown on ICGA by the blurry appearance of stromal vessels responds readily to systemic inflammation suppressive therapy (Figures 53B and 54B). In contrast to other granulomatous choroitides, late hyperfluorescent ICGA pinpoints are rarely seen in birdshot chorioretinopathy.

Indocyanine green angiography represents a major improvement in the investigation of BC by showing the importance of choroidal disease.82 More importantly, in newly diagnosed disease ICGA is very useful as it detects subclinical choroidal stromal disease allowing to make the diagnosis at a time (early stage of the disease) when the characteristic depigmented areas are not present (Figure 50). In late treated disease these hypofluorescent dark dots disappear in parallel with an increase of oval fundal depigmented areas, probably indicating that active stromal disease has subsided leaving depigmented areas without scars.

Figure 53A: Birdshot chorioretinopathy ICGA signs-fuzzy indistinct choroidal vessels. In association with HDDs large choroidal vessels appear fuzzy with a hardly recognisable pattern

Figure 53B: Birdshot chorioretinopathy ICGA signs response to inflammation suppressive therapy. Reappearance of normal choroidal pattern after combined corticosteroid and immunosuppressive therapy

Figure 54A: Hyperfluorescent areas associated with hypofluorescent dark dots (HDDs) at a later angiographic stage in a case of non treated birdshot chorioretinopathy

Figure 54B: Disappearance of hyperfluorescent areas and of HDDs after introduction of steroid and immunosuppressive therapy

Figure 55: Birdshot chorioretinopathy. Pseudo-delay of arterio-venous circulation on FA. The larger veins are not marked by the fluorescein dye on FA angiography even after 40’’ due to massive egress of fluorescein into the retina (bottom frame). Presence of ICG in the veins after 19’’ shows that arterio-venous transit is normal (upper frame)

A recent study showed that choroidal disease (evolution of ICGA signs is readily responding to corticosteroid ± immunosuppressive therapy, whereas retinal disease is less responsive.84

Fluorescein angiography accounts for the retinal involvement in BC. Vasculitis of large veins (periphlebitis) is a characteristic FA sign but the specific sign to search is diffuse and massive leakage from small retinal vessels. The leakage is often such that there is not enough fluorescein to mark the large veins, which was erroneously interpreted as an arteriovenous circulatory delay81 (Figure 55). ICGA showed that there is no arterio-venous perfusion delay as the ICGprotein macromolecular complex which remains

KEY POINTS: ANGIOGRAPHIC SIGNS IN BIRDSHOT

CHORIORETINOPATHY

•Dual primary independent inflammation of the retina and the choroid. Retinal pigment epithelium remains intact between the two inflamed sectors.

•Clinical choroidal lesions not present or very scarce at onset of disease. Only ICGA can show subclinical choroidal involvement → with compatible clinical features in the absence of hypopigmented fundus lesions, ICGA is diagnostic in early disease.

•ICGA at onset:

•Numerous, even, regularly distributed oval hypofluorescent dark dots present in the intermediate phase mostly becoming isofluorescent in the late phase (partial thickness granulomas)

•Loss of pattern of stromal choroidal vessels appearing fuzzy and indistinct

•Diffuse late choroidal hyperfluorescence.

•ICGA, treated stage: resolution of ICG hypofluorescent dark dots: resolution of granulomas without significant scarring leaving depigmented areas.

•FA

•Generalised vasculitis of large and small vessel with profuse exudation from small retinal vessels, disc hyperfluorescence, cystoid macular oedema when present.

•Pseudo-delay of arteriovenous circulation on FA, due to massive fluorescein exudation and insufficient to mark venous return but with normal arteriovenous circulation time on ICGA

•Retinal lesions do not correspond to choroidal lesions, indicating independent choroidal and retinal inflammatory process.

intravascularly is seen in the central retinal vein within a normal time span. It is comprehensible that retinal function is impaired in cases with such a massive exudation from both small and large retinal vessels producing major visual field impairment.86,87 Additional FA signs include disc hyperfluorescence and cystoid macular oedema present only in about 30 to 40% of cases in our series but that is reported to reach up to 70%. In late disease the fundus aspect can resemble retinitis pigmentosa and the size of retinal vessels can be markedly reduced.

STROMAL CHOROIDITIS AS A RANDOM INVOLVEMENT OF A SYSTEMIC DISEASE

This group of diseases involves the choroid by mere chance as one of the possible sites of inflammation of a multi-system disease, the choroid being the innocent host of an inflammatory or infectious process but not an elective target.

Figure 56: Sarcoid choroiditis–ICGA signs. Cluster of hypofluorescent dark areas at the Intermediate angiographic phase (top frames), becoming isofluorescent in the late phase (bottom frames) with hyperfluorescent pin points. The fact that hypofluorescent areas are erased in the late angiographic phase is explained by the fact that lesions are of partial thickness and also by the fact that granulomatous lesions fix the ICG molecule

Sarcoidosis

Uveitis is the most common and most serious form of ocular involvement in sarcoidosis and posterior segment inflammation occurs in up to one third of patients with ocular sarcoidosis.88

It is a granulomatous uveitis. Choroiditis and/or retinal inflammation can occur independently or concomitantly.90 Retinal periphlebitis is the most common feature of posterior segment sarcoidosis, vascular sheathing is frequent and may take the characteristic “candle-wax” appearance. Multifocal choroiditis appears as multiple, pale-yellow, elevated lesions resembling those seen in birdshot chorioretinopathy, however, distribution is more at random and this is especially evident on ICGA (Figure 56). A solitary choroidal granuloma is a more rare involvement of the choroid. Vitreous involvement is usually present as well as cystoid macular oedema and papillitis. Another possible presentation is intermediate uveitis with snowballs and snowbanks. In the latter case the presence of posterior irido-crystalline snechiae often allows to make the differential diagnosis with intermediate uveitis of the pars planitis type.

The ICGA signs are not specific for sarcoidosis but can also be seen in other granulomatous conditions

Figure 57: Sarcoid choroiditis. Numerous hypofluorescent dark dots still present at the late angiographic phase indicating full thickness lesions

such as tuberculosis. Four principal features have been identified.90 The first and most common feature is hypofluorescent dark areas in the early and intermediate phases of the angiogram. These dots either become isofluorescent when lesions are of partial thickness (Figure 56) or some remain hypofluorescent in the late phase indicating inflammatory foci occupying the full thickness of the choroid (Figure 57). Their distribution is more at random and their size is less regularly shaped than in VKH, sympathetic ophthalmia or birdshot chorioretinopathy. Most of these choroidal lesions shown by ICGA are barely seen by fluorescein angiography showing faint hypofluorescent areas corresponding to the ICGA signs.

The second feature is focal hyperfluorescent pinpoints mostly seen in the late angiographic phase (Figure 56). The third feature is loss of normal vascular choroidal pattern with indistinct fuzzy appearance of choroidal vessels due to perivascular choroidal leakage in the intermediate phase (Figure 58). Finally, the last feature is a diffuse zonal choroidal hyperfluorescence due to choroidal staining from leaky stromal vessels which is seen in the late phase and is more irregularly disposed than in VKH or birdshot chorioretinopathy according to the usually irregular involvement. Most of these features can resolve after systemic corticosteroid treatment.90

Figure 58: ICGA signs in sarcoid choroiditis. Fuzzy blurred and indistinct vessels in the intermediate phase (left frames) resulting in diffuse choroidal hyperfluorescence in the late angiographic phase (right frames)

Fluorescein angiography identifies the effects of inflammation at the level of the retina and retinal pigment epithelium. It is noteworthy to realise how silent fluorescein angiography is regarding the underlying choroidal lesions that are only shown by ICGA (Figure 59). Depending on the type of involvement it can show disc hyperfluorescence, cystoid macular oedema or retinal perivascular leakage as well as the combination of window effect and masking effect of chorioretinal atrophy of healed areas from granulomatous inflammation.

As the eye is involved at random, sarcoidosis can cause inflammation in different structures from one inflammatory episode to another and dual FA and ICGA should be performed each time when recurrence is diagnosed. In one patient inflammation involved the retina in one recurrence and was well documented by FA and during the next inflammatory episode it involved the choroid which was well documented by ICGA89 (Figures 60A and B).

Tuberculous Choroiditis

Ocular involvement in tuberculosis can occur without evidence of involvement of other organs.91 Tuberculous choroiditis and/or retinits is a random

Figure 59. Sarcoid choroiditis. Randomly scattered stromal foci well identified by a panorama ICCGA picture (top frame), barely seen on fluorescein angiography (bottom frame) (courtesy Alessandro Mantovani, Como, Italy)

KEY POINTS: ICGA SIGNS IN SARCOIDOSIS

(NON PATHOGNOMONIC)

•ICGA: hypofluorescent dark dots (HDD) distributed at random and irregularly shaped present in the early and intermediate phases (granulomas), some of them lasting until late angiographic phase. Focal hyperfluorescent pinpoints in the lesional areas in the late phase. Fuzziness of larger choroidal vessels in intermediate phase and diffuse hyperfluorescence due to choroidal staining in the late phase.

•HDD much more uneven in size and much more irregular in distribution.

•FA: may show retinal vasculitis, disc hyperfluorescence, cystoid macular oedema when present.

localisation of an multi-system entity that can affect different organs. It can involve the choroid or the retina or both or retinal inflammation can be secondary to choroidal granulomas.93,94

Figure 60A: Ocular sarcoidosis – independent choroidal or retinal involvement. Inflammatory episode involving principally the choroid with numerous HDDs (top frames) and no pathology on fluorescein angiography (bottom frames)

Figure 60B: Ocular sarcoidois – independent retinal or choroidal involvement. Same patient as Figure 60A, presenting a retinal recurrence with CME, disc hyperfluorescence and retinal vasculitis, whereas choroidal space is free of inflammatory activity during this recurrence

Since the availability of ICGA, choroidal involvement can be analysed precisely.95 Choroiditis can occur alone or in association with retinal disease. So far only retinal involvement or the consequences of choroidal disease on the retina was accessible to imaging. With

ICGA, subclinical choroidal lesions were detected in all patients analysed showing that choroidal involvement is probably predominant.95

Dual fluorescein and ICG angiography should be performed to assess both retinal and choroidal disease. Fluorescein angiography (FA) is useful to detect macular oedema. It shows often disc hyperfluorescence with leakage, retinal vasculitis and choroidal lesions detected by the changes caused to the overlying retina, characterised by early hypofluorescence followed by progressive hyperfluorescence and leakage around the margins. It can also show secondary changes from choroidal involvement.

ICGA showed four main angiographic signs including:

1.Hypofluorescent areas in the early and intermediate phases of angiography that remain hypofluorescent or become isofluorescent in the late angiographic phase representing full thickness or partial thickness lesions; they are of variable sizes and are randomly distributed (Figure 61);

2.Choroidal fuzzy vessels that loose their sharp pattern indicating vasculitis of larger choroidal vessels not normally leaking (Figure 62);

3.Diffuse choroidal hyperfluorescence coming from leaking large choroidal vessels that adds to the physiologic background fluorescence coming from the choriocapillaris (Figure 62);

4.Hyperfluorescent pinpoints seen in the late angiographic phase (Figure 63). All lesions respond to specific anti-tuberculous therapy combined with low doses of systemic corticosteroids for those patients that have no pre-diagnostic corticosteroids and/or immunosuppressants95 (Figure 64).

KEY POINTS: ICGA SIGNS IN TUBERCULOUS CHOROIDITIS (NON PATHOGNOMIC)

•ICGA:

•Hypofluorescent dark dots (HDD) distributed at random and irregularly shaped present in the early and intermediate phases (granulomas), some of them lasting until late angiographic phase.

•Focal hyperfluorescent pinpoints in the lesional areas in the late phase.

•Fuzziness of larger choroidal vessels in intermediate phase and

•Diffuse hyperfluorescence due to choroidal staining in the late phase (irregular pattern).

•HDD much more uneven in size and much more irregular in distribution.

•FA: may show retinal vasculitis, disc hyperfluorescence, cystoid macular oedema when present.