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

Figure 6: Scars from Dalen-Fuchs nodules. Patient originally from Lebanon with chronically evoluting VKH disease

Indocyanine Green Angiography (ICGA)21-23

There are 4 main characteristic features seen on ICG angiography in the acute phase of the disease.

One of the constant signs present in close to 100% of cases is early hyperfluorescent medium sized choroidal stromal vessels (Figure 7). The second sign very useful for disease monitoring also present in all cases is represented by disseminated, even, regularly distributed hypofluorescent dark dots (HDD) in the intermediate phase (Figure 8). For the most part these HDDs remain hypofluorescent in the late angiographic phase but some become isofluorescent indicating partial thickness choroidal infiltration. In association HDD are always surrounded by fuzzy choroidal leaking vessels indicating choroidal vasculitis that can be very severe in some cases (Figure 9). The corollary

Figure 7: Early patchy hyperfluorescence of medium sized stromal vessels, seen in the area below the fovea

Figure 9: Fuzzy leaking stromal vessels making impossible to recognise the normal pattern of choroidal vessel arrangement

Figure 8: Hypofluorescent dark dots indicating the presence of choroidal granulomas. The normal pattern of the choroidal cannot be distinguished any more

of fuzzy vessels in the intermediate phase is late phase diffuse choroidal hyperfluorescence. In very acute disease the disc that is usually hypofluorescent can become hyperfluorescent, indicating severe papillitis (Figure 3). In case of exudative detachments, ICGA shows the same hyperfluorescent pinpoints seen on fluorescein angiography (Figure 4C). These signs all

regress with treatment. ICGA was found to be essential not only for the diagnosis in the atypical cases but also for the follow-up where it can detect subclinical recurrences. It also contributes to reduce the number of apparently unilateral cases by showing fellow eye subclinical involvement. As discussed under therapy precise follow-up of subclinical choroidal disease is only possible using ICGA.

Fluorescein Angiography

Fluorescein angiography (FA), in the acute stage of the disease or during recurrences, serous exudative detachements appear as multifocal hyperfluorescent pinpoints showing the leaking points at the level of retinal pigment epithelium (RPE) also seen on ICGA. FA also shows late pooling of the dye in the subretinal space (Figure 4B). Optic disc staining and leakage also appears in the acute stage. In the chronic stage FA clearly shows the diffuse RPE alterations classically appearing as a mixture of window and masking effects a consequence of the exudative retinal detachment(s) the limits of which are well shown on FA and called high water marks. In the chronic phase a hyperfluorescent ”hot” disc may be the only fluorescein angiographic sign indicating inflammatory activity, whereas ICGA often shows subclinical choroidal granuloma (Figure 10).

Figure 10: Fluorescein angiographic frames of post-acute stage of VKH. Retinal pigment epithelium mottling with pigment clumps. The limits of the reabsorbed exudative retinal detachment are very well determined. Note also the hyperfluorescence of the disc

Additional Diagnostic Imaging

Additional diagnostic modalities include echography (ultrasonography) that may be of interest in the workup of VKH when the media are opacified or pupillary dilatation is difficult. It can show thickening of the choroid and serous retinal detachments. Echography is however not sufficient to detect subtle intrachoroidal inflammatory lesions. Optical coherence tomography (OCT), nicely shows the subretinal fluid already evidenced by fundoscopy or fluorescein angiography but has a higher sensitivity to show shallow accumulation of subretinal fluid. OCT is only as good as what it can show, namely structures above the RPE. However subretinal fluid seen by OCT can be used to monitor response to therapy but is no different than clinical observation or FA as it does not account directly for choroidal activity that can only be shown by ICGA.

Therapy

Systemic high-dose corticosteroids is the mainstay of VKH treatment.24,25 The introduction of therapy should be prompt and aggressive to shorten the duration of the disease and possibly avoid the

progression into a chronic stage.20 Intravenous pulse methylprednisolone infusions should be given for 3 days in acute initial or recurrent disease to be followed by high-dose (1.5-2 mg/kg) oral prednisone therapy. Slow tapering over 9-12 months is necessary. Additional immunosuppressants can be discussed if clinical or ICGA recurrence predicts a high response threshold to corticosteroid therapy. In chronically evolving disease, it was shown that despite apparent clinical control the disease was slowly progressing towards sunset glow fundus.26 This is due to the most often inappropriate smoldering sub-clinical disease that is best avoided by performing ICGA follow-up, the only means to monitor sub-clinical evolution.23 Therefore ICGA-guided adjustment of therapy in case of subclinical reappearance of HDD has to be highly recommended to put the disease in remission and avoid sunset glow fundus.23 The sensitivity to monitor subclinical disease is shown in the example presented here under.

OTHER PRIMARY STROMAL CHOROIDITIS

Sympathetic ophthalmia (SO) and birdshot chorioretinopathy (BC) are the two other entities classified in the group of primary stromal choroiditis and will be developed in the next chapters.

STROMAL CHOROIDITIS AS A RANDOM INVOLVEMENT OF A SYSTEMIC DISEASE (SECONDARY STROMAL CHOROIDITIS)

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

SARCOIDOSIS

Sarcoidosis is good example of a secondary stromal choroiditis. It is a multisystemic granulomatous disease of unknown aetiology. Lung involvement occurs most frequently and skin and eye lesions are next in frequency. Distribution is worldwide and prevalence of the disease differs according to racial groups, being 10 to 20 times more frequent among blacks than whites. Sarcoidosis is characterised by the presence of noncaseating granuloma in involved organs. Sarcoidosis may affect any ocular tissue.

Figure 11A: Numerous HDDs and fuzzy stromal vessels the pattern of which cannot be recognised

Figure 11C: After 6 months of prednisone therapy, during tapering of treatment reappearance of HDDs without any signs of clinical recurrence

Figure 11B: Most HDDs have disappeared after 1 month of high dose intravenous and oral corticosteroid therapy. Note that choroidal vessels can again be individualised and the pattern of choroidal circulation can be recognised

Figure 11D: After increase of the dosage of corticosteroids and adjunction of mycophenolate mofetyl immunosuppression again vanishing of dark dots and normal structure of choroidal vessels

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.27 No specific test is available for sarcoidosis diagnosis, except typical histology on biopsy. Nonspecific tests can help to orient the diagnosis. Chest X-ray may show hilar or mediastinal lymphadenopathy or interstitial fibrosis and may also help to exclude tuberculosis. Serum angiotensin-converting enzyme (ACE) is usually elevated in active sarcoidosis as is serum lysozyme. Tuberculin test anergy is present in 50% of cases. A frequent but often ignored feature is polyclonal immunoglobulin activation that can mislead when high titres to infectious agents are found but can also be used as a diagnostic indication.28 Gallium scintigraphy shows increased uptake in salivary or lacrymal glands and in the mediastinum and liver. Bronchoalveolar lavage typically shows a lymphocytosis with an elevated CD4/CD8 ratio. Diagnostic criteria for ocular sarcoidosis have been established recently by an international workshop on ocular sarcoidosis (IWOS) (in press).

Symptoms and Signs

Symptoms are diverse and depend on the type of involvement. Patients can complain of blurred vision if cystoid macular oedema or vitritis is prominent or if significant anterior uveitis is present.

Anterior uveitis is often seen in association of choroiditis and retinitis. It is a granulomatous uveitis usually with large mutton-fat KPs, synechiae and iris nodules and infiltration.

Choroiditis and retinal inflammation can occur independently both being possible random sites of involvement or retinal involvement can be the consequence of underlying foci of choroiditis.29 Retinal periphlebitis is the most common feature of posterior segment sarcoidosis, vascular sheathing may persist to the characteristic “candle-wax” appearance. Multifocal choroiditis appears as multiple, pale-yellow, elevated lesions resembling those seen in birdshot chorioretinochoroidopathy however distribution is more at random and this is especially evident on ICGA. 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.

Indocyanine Green Angiography is the Method of Choice to Assess Sarcoidosis Choroiditis

The signs seen on ICGA are not specific for sarcoidosis but can also be seen in other granulomatous involvements such as tuberculosis. Four principal features have been identified. The first and most common feature is the presence of hypofluorescent dark dots (HDDs) in the early and intermediate phases of the angiogram that are randomly distributed over the fundus (Figures 12A and B). These HDDs either become isofluorescent or remain hypofluorescent in the late phase depending on their size within the choroidal stroma. As in most stromal choroiditis the accompanying feature to HDDs is fuzzyness of choroidal vessels due to perivascular choroidal leakage in the intermediate phase. Thirdly a diffuse zonal hyperfluorescence representing choroidal staining in the late phase is seen in acute choroiditis and is consecutive to the fuzzy leaking stromal vessels. Often focal hyperfluorescent pinpoints are seen in the intermediate and late phases in the areas of HDDs and this probably represents fixation of ICG in areas with granulomas. All features can resolve after systemic corticosteroid or other inflammation suppressive treatments.30

Fluorescein Angiography

Fluorescein angiography is used to analyse the effects of inflammation at the level of the retina and retinal pigment epithelium. Depending on the type of involvement it can show disc hyperfluorescence, cystoid macular oedema or retinal vasculitis as well as the combination of window effect and masking effect of chorioretinal atrophy of healed areas of granulomatous inflammation.

Therapy

Indication for therapy depends on severity of the lesions. Sarcoidosis, including posterior involvement, is usually well responsive to corticosteroids that can be given by periocular sub-Tenon’s injections. If necessary, systemic steroids are usually efficient to control the disease and can be tapered over a period of 4-6 months.

In severe forms of disease or in case of corticosteroid intolerance an immunosuppressive agent such

Figure 12B: Fluorescein angiogram that shows no signs of the underlying choroidal granulomas (Photographs courtesy Dr. A. Mantovani, Como, Italy)

Figure 13A: Intermediate phase ICG frames of choroiditis due to sarcoidosis seen at presentation showing loss of definition of stromal vessels patterns and numerous hypofluorescent dark dots (HDD)

as azathioprine or mycophenolate mofetil can be added. Anti-TNF-alpha therapy is presently being evaluated but will have to be reserved for severe cases. Assessment and monitoring of sarcoidosis choroiditis can only be performed using ICGA (Figures 14A and B).

TUBERCULOUS CHOROIDITIS

Tuberculosis is a good example of secondary infectious stromal choroiditis.Ocular involvement of tuberculosis can occur without evidence of involvement of other organs.31

Figure 13B: Late phase ICGA frame of same patient showing persistence of HDDs, lack of definition of stromal vessels and diffuse choroidal hyperfluorescence

Tuberculous uveitis has to be suspected when a granulomatous anterior uveitis or panuveitis or a chorioretinitis is associated with a hyperreactive delayed type hypersensitivity skin tuberculine test.32,33 Tuberculous choroiditis is a chance localisation of an 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.34-36

For infectious choroiditis such as tuberculosis choroidal lesions could precisely be determined only thanks to indocyanine green angiography.

Angiographic Characteristics

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

Figure 14A: Same case of choroiditis caused by sarcoidosis as in Figure 13 before treatment. ICGA in intermediate phase shows HDDs and fuzzy vessels

Figure 14B: Resolution of most HDDs and recovery of normal recognizable pattern for stromal choroidal vessels after treatment

angiographic phase representing full thickness or partial thickness lesions; they are of variable sizes and are randomly distributed (Figures 15A and B); (2) choroidal fuzzy vessels that loose their sharp pattern indicating vasculitis of larger choroidal vessels not normally leaking (Figures 15A and B); (3) Diffuse choroidal hyperfluorescence coming from leaking large choroidal vessels that adds to the physiologic background fluorescence coming from the choriocapillaris (4). Hyperfluorescent pinpoints seen in the late angiographic phase. All lesions respond to specific

anti-tuberculous therapy combined with low doses of systemic corticosteroids for those patient that have no prediagnostic corticosteroids and/or immunosuppressants.37

OTHER INFECTIOUS CHOROIDITIDES

Syphilis is another current cause of secondary stromal choroiditis and will be dealt in Table 1. Multiple other infectious agents can cause secondary stromal choroiditis. Although immune mechanisms, possibly secondary to an infectious trigger, are suspected in a large proportion of choroiditis cases, such direct infectious causes should always be kept in mind as a possibility as more and more emerging infectious

agents are identified thanks to newly availabe technologies such as the polymerase chain reaction techniques.The infectious agents that can cause choroiditis are numerous. A non-exhaustive list of infectious choroiditis is given in Table 1.

CONCLUSION

The precision with which choroidal inflammatory involvement can now be detected and followed thanks to ICGA opened this space to better understanding and henceforth more adequate classification of choroiditis. Moreover it added to our performance in managing these pathologies, allowing a more global and comprehensive approach to intraocular inflammation.47,48

KEY POINTS

•Choroidal inflammation may involve either the choriocapillaris or the choroidal stroma, two disease mechanisms that should be distinguished.

•Stromal choroiditis includes Vogt-Koyanagi-Harada (VKH) disease, Sympathetic Ophthalmia (SO) and birdshot chorioretinopathy (BC), where the inflammatory target is situated within the choroidal stroma and inflammatory foci develop selectively in the choroidal stroma, associated with inflammation of larger stromal vessels.

•Stromal choroiditis should further be subdivided into 2 groups. In the first group including diseases such as VKH, SO and BC, the choroidal stroma is the primary target of the inflammatory process whereas in most other diseases, such as sarcoidosis and tuberculous choroiditis, the choroid is only one of the sites of a multisystem disease.

•Histopathology has shown that stromal choroiditis is characterised by inflammatory, mostly granulomatous, foci of different sizes.

•These foci appear as hypofluorescent areas (HDDs) on indocyanine green angiography (ICGA).

•ICGA has also shown in addition to the hypofluorescent dark areas, hyperfluorescent large choroidal vessels and late diffuse hyperluorescence indicating choroidal vasculitis.

•Vogt-Koyanagi-Harada disease is a good example of primary stromal choroiditis as the immune mediated process is specifically targeting the stromal melanocytes.

•Indocyanine green angiography (ICGA) can detect the early inflammatory events when disease is still subclinical and has not yet caused secondary inflammation to neighbouring structures such as the retina (exudative retinal detachment).

•ICGA is essential in optimal follow-up of VKH.

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