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

Figure 63: Tuberculous chorioretinitis – ICGA signs.

Hyperfluorescent pinpoints in the fundus periphery (left frame) disappearing after therapy (right frame)

Figure 64A: Syphilitic chorioretinitis. Fundus picture in a case of syphilitic chorioretinitis at presentation (left frame), after 2 weeks of specific treatment (middle frame) and 1 month after start of treatment (right frame)

Figure 64C: FA in syphilitic chorioretinitis. Late hyperfluorescence of area of chorioretinal involvement and hyperfluorescent disc

Figure 64B: ICGA in active syphilitic chorioretinitis. Large zone of hypofluorescence going beyond the area seen on fundus photography and area delineated by fluorescein angiography

Syphilitic Posterior Uveitis

Ocular involvement can occur at any stage of syphilis and is estimated to be the cause of 1% of uveitides and optic neuritis.96,97 It can mimic many different ocular disorders and can present as a posterior uveitis occurring during secondary syphilis taking the form

of a multifocal or unifocal choroiditis, most often affecting the posterior pole and juxtapapillary area.96 Healed lesions appear as areas of chorioretinal atrophy associated with hyperpigmentation (Figure 64A).

Indocyanine green angiographic signs are described on the basis of individual cases. The affected areas are of random size and distribution and usually appear as hypofluorescent in the early and intermediate phases and remain so in the late phase indicating choriocapillaris non perfusion (Figure 64B). The areas involved seen on ICGA are more widespread than what can be seen on fundus examination and fluorescein angiography (Figure 64C). Depending on which structure is involved ICGA findings can take different patterns. Baglivo and colleagues described a case with similar findings showing early ICGA hypofluorescence remaining until late with central increase of fluorescence speaking for central stromal inlvolvement associated with surrounding choriocapillaris hypoperfusion.98 An angiographic sign to look for when syphilitic choroiditis is suspected probably more in the subacute stages of the disease, is the occurrence of patchy or pinpoint size areas of late hyperfluorescence in the affected areas that may have no expression on fluorescein angiography. Any granulomatous choroiditis can show late hyperfluorescent pinpoints and this is also the case of syphilitc chorioretinitis (Figure 65).

Figure 65A: Ocular syphilis. Hyperfluorescent patchy areas seen on ICGA not apparent on fluorescein angiography

Figure 65B: Ocular syphilis. Fluorescein angiography does not show choroidal involvement shown on Figure 65A

Fluorescein angiography in the acute stage can show retinitis with early hypofluorescence and late hyperfluorescence of the inflammatory foci. The areas of retinitis can correspond to underlying areas of hypofluorescence on ICGA which could represent choriocapillaris non perfusion (secondary choriocapillaritis). Old lesions typically show early diffuse or leopard-spot hypofluorescence of the involved area with late staining of atrophic areas and remaining hypofluorescence in areas of pigment accumulation characterisitc of scarring of the retinal pigment epithelium. These old scarred lesions appear hypofluorescent on ICGA.

Other Infectious Choroiditides and Rare Entities

Although immune mechanisms, possibly secondary to an infectious trigger, are suspected in a large proportion of choroiditis cases, 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. Many of these have never been examined with indocyanine green angiography or information is limited to case reports. We will describe ICGA findings for two entities for which more systematic studies are available, ocular histoplasmosis and West Nile virus choroiditis.

Ocular histoplasmosis syndrome

Ocuar hitoplasmosis is a disease endemic in midwestern USA, Central America, Asia, Italy, Turkey, Israel and Australia. It is caused by the fungus Histoplasma capsulatum and systemic disease is usually sublclinical or presents as a mild flue-like episode. Ocular involvement is characterized by subretinal infiltrates with distinct borders, optic neuritis, uveitis and in rare cases endophthalmitis. The diagnosis can be secured by performing a histoplasmin skin test that may, however, possibly reactivate ocular lesions. Analysing the fundus lesions and angiographic signs of many cases, we believe that the cases described as presumed ocular histoplasmosis syndrome (POHS) or pseudoocular histoplasmosis syndrome in patients with a negative hypersensibility skin test to Histoplasma capsulatum and coming from non endemic areas for histoplasmosis should probably be assimilated to the heterogeneous group of multifocal choroiditis and do not justify a seperate disease category related to ocular histoplasmosis. True histoplasmosis cases were found to have focal hyperfluorescent spots on ICGA in the posterior pole at a rate of 55% of the analyzed patients.99 This ICG angiographic sign distinguishes these histoplasmosis positive cases from what is known as POHS. Of all cases that were presented to me with the diagnosis of POHS for ICGA interpretation, none presented these hyperfluorescent spots but ICGA signs compatible with multifocal choroiditis. At this stage the reality of an entity called POHS should be put in doubt and these cases should be classified in the group of multifocal choroiditis.

West Nile virus choroiditis

The West Nile virus (WNV) is one of emerging infectious agents at the origin of choroiditis and a good example of a pathology that may have been included in the “auto-immune” or “idiopathic” choroiditides or in the multifocal choroiditis group because the infectious agent was not searched for. WNV is a singlestranded RNA flavivirus belonging to the Japanese encephalitis virus serocomplex that was first isolated in 1937 in the West Nile district of Uganda. It is transmitted by a mosquito vector with wild birds serving as its reservoir and is distributed extensively throughout Africa, Asia, the Middle East, Europe, and North America. About 20% of infected persons become symptomatic and present a flue-like illness developing into meningitis or encephalitis in 1% of cases.

Posterior lesions, present in 80% of ophthalmic cases, consist of a typical multifocal bilateral choroiditis associated in all cases with a mild vitreous inflammatory reaction. The lesions, circular in shape, vary in number from less than 20 to more than 50 per eye. Chorioretinal lesions involve the midzone and/or pheriphery, more prominently in the temporal and the superonasal quadrants as well as the posterior pole. Lesion size ranges in a mean from 200 μm to 500 μm. Linear clustering of chorioretinal lesions gives the typical pearls on a string aspect of this choroiditis. Active chorioretinal lesions appear as deep, creamy lesions on ophthalmoscopy, with early hypofluorescence and late staining on fluorescein angiography. Resolved chorioretinal lesions appear as scars with central hypofluorescence and peripheral hyperfluorescence.

Associated retinal vascular changes include intraretinal haemorrhages, white-centered haemorrhages, focal vascular sheathing, and retinal vascular leakage. The multifocal chorioretinitis usually has a self-limited favourable course without treatment and vision is conserved.100 ICG angiograph shows bilateral well-delineated hypofluorescent choroidal lesions more numerous than those seen by fundus examination or fluorescein angiography indicating that there can be pure choroiditis.101

ICGA SIGNS IN OTHER POSTERIOR INFLAMMATORY DISEASES OUTSIDE CHOROIDITIS

TOXOPLASMIC RETINOCHOROIDITIS

Classically toxoplasmic retinochoroiditis is considered as an inflammation initiating from the retina. This has been verified in experimental animal studies that localised the infectious agent at the level of the retina.102 Despite the fact that the retina is the primary structure involved, ICGA showed interesting features in toxoplasmic retinochoroiditis. Of the 28 patients with toxoplasmic choroiditis analysed, the main focus was hypofluorescent at all ICG angiographic times in 89% of cases103 (Figure 66A). The hypofluorescent zone extended far beyond the clinically visible and the FA delineated area (Figure 66B). The explanation of the hypofluorescence is most probably a masking effect (of the thick retinal focus) on one hand and choriocapillaris

Figure 66A. Toxoplasmic retinochoroiditis. ICGA shows much more extensive involvement (characterised by choriocapillaris non-perfusion) than suspected by FA (66B); note also the numerous satellite HDDs

Figure 66B: Toxoplasmic retinochoroiditis. The extension of the lesion seems much less widespread compared to the lesion shown on ICGA

Figure 66C: Toxoplasmic retinochoroiditis. Post-treatment ICGA hypofluorescence including choroidal scars silent on FA as well as the focus appearing on fundus view and FA. Resolved hypofluorescence probably corresponds to resolution of choriocapillaris non perfusion

Figure 66D: Toxoplasmic retinochoroiditis. FA of healed focus is less widespread than on ICGA and does not account for purely choroidal scarred areas only seen on ICGA (hypofluorescent areas in excess of surface seen on FA, 66C)

non perfusion (secondary inflammatory choriocapillaropathy), on the other hand, as a large part of the hypofluorescent area recovers after therapy. In 75% of cases, ICGA identified numerous satellite dark dots outside the main focus present all along the angiographic sequences and not seen on fundoscopy or fluorescein angiography (Figure 66A). It was thought that these satellite dark dots were small subclinical foci of infection as they regressed after antibiotic treatment not associated with corticosteroid therapy.104 The more probable explanation is, however, inflammatory choriocapillaris non perfusion (secondary inflammatory choriocapillaropathy) as these satellite dark dots also progressively disappear without treatment in parallel with the decrease of severity of inflammation at the level of the main focus.105 ICGA was more precise than fluorescein angiography or fundus photography to delineate the extent of scarred chorioretina at the end of the inflammatory episode (Figures 66C and D). The functional evolution (visual field) was shown to be well correlated with the regression of the perilesional ICGA hypofluorescence that often preceded the resolution of fluorescein angiographic signs or signs seen on fundus examination. Another situation where ICGA was found to be particularly useful was when suspicion of an inflammatory neovascular membrane arising next to a toxoplasmic retinochoroidal scar was suspected. In that situation ICGA shows early and increasing hyperfluorescence instead of the early and remaining hypofluorescence that would have been produced by a new inflammatory focus. A more rare finding is segmental ICG hyperfluorescence of an inflamed

Figure 67A: Toxoplasmic retinochoroiditis – contribution of ICGA. Clear recurrence can be seen on fundus examination (crimson arrow) with a slightly different aspect at the bottom of the white-yellow zone (black arrow)

Figure 67B: Toxoplasmic retinochoroiditis – contribution of ICGA. FA shows 2 areas of hyperfluorescence (left frame) that become confluent in the very late phase (right frame)

Figure 67C:. Toxoplasmic retinochoroiditis – contribution of ICGA. ICGA clearly makes the difference between the upper and lower zones that look alike on FA. On ICGA the lower area appears hyperfluorescent since the early phase with fluorescence increasing over time, typical for an inflammatory neovascular membrane. On the other hand, the superior part of the lesion, likewise hyperfluorescent in late FA frames, remains hypofluorescent on ICGA indicating the presence of a new inflammatory focus (originally published and reproduced from Ophthalmology 1998;105:432-40)

KEY POINTS: ICGA SIGNS IN TOXOPLASMIC

RETINOCHOROIDITIS

•Hypofluorescence of the main focus up to the late angiographic phase due to the masking effect of the thick focus and most probably choriocapillaris non perfusion due to the severe adjacent retinal inflammation.

•Hypofluorescence up to the late angiographic phase extended beyond the main focus (secondary inflammatory choriocapillaropathy caused by the severe adjacent retinal inflammation).

•Hypofluorescent satellite dark dots present up to the late angiographic phase (secondary inflammatory choriocapillaropathy).

•Hyperfluorescence increasing along the angiographic sequence next to a toxoplasmic scar in case of the presence of a neovascular membrane corresponding to early and progressively increasing hyperfluorescence seen on fluoresceine angiography.

•Fluorescein angiography of the main focus shows early hypofluorescence followed by progressive staining of the active lesion.

•Beside active lesions, there can be scars with the usual FA signs (late hyperfluorescence) and ICGA signs (late hypofluorescence) of chorioretinal scars.

Figure 69: ICGA in posterior scleritis. Hyperfluorescent and dilated choriodal vessels and zone of difuse hyperfluorescence (bottom right)

Figure 68: Toxoplasmic retinochoroiditis. ICGA hyperfluorescent retinal vessels in toxoplasmic retinochoroiditis with severe inflammation. A similar image can be seen in Behçet’s uveitis

POSTERIOR SCLERITIS

Posterior scleritis usually produces secondary inflammatory effects on the adjacent choroid.106 Examinig the choroid through ICGA may, therefore, be useful when investigating a posterior scleritis. We have studied ICGA signs in a series of 7 patients with posterior scleritis.106 Patients were included when 3 of the 4 following clinical elements were present: (1) Posterior inflammatory signs, (2) Nocturnal pain waking the patient up in the morning, (3) Anterior scleritis ±

anterior non granulomatous uveitis, and (4) Scleral thickening by B echography or magnetic resonance.

The main ICGA sign was a diffuse late stromal hypefluorescence with variable extension from case to case, appearing in the intermediate and increasing in the late angiographic phases (Figure 69). This hyperfluorescence regressed quickly after the introduction of systemic corticosteroid and/or immunosuppressive therapy. In 4 of the 7 patients there were diffuse hypofluorescent spots, faintly visible, giving a mottled appearance possibly indicating choroidal perfusion problems. Finally in all patients the vorticose veins were enlarged a sign regressing also readily after the introduction of corticosteroid therapy (Figure 70).

All ICGA signs responded well to the treatment. Localising the zones of diffuse hyperfluorescence allowed to localise the areas of maximal scleral inflammation.

KEY POINTS: ICG ANGIOGRAPHIC SIGNS

IN POSTERIOR SCLERITIS

•Sectorial diffuse intermediate and late choroidal hyperfluorescence

•Choriocapillaris filling delay

•Faint hypofluorescent spots up to the intermediate angiographic phase followed by isofluorescence.

•Enlarged draining choroidal veins (vorticose veins)

Figure 70: ICGA in posterior scleritis. Dilated vorticose veins, a feature that responds to treatment (right frame). Arrow shows a hypofluorescent area that has the same size on both frames (originally published and reproduced from Am J Ophthalmol 1998;126:471-8)

BEHÇET’S UVEITIS

Inflammatory lesions of the posterior ocular segment in Behçet’s disease principally involve the retina and are characterised by a vasculitis involving both veins and arteries in various proportions from case to case as well as by superficial retinal foci. Examination of the choroid by indocyanine green angiography, however, clearly showed that there is also inflammation at the level of the choroidal vessels, showing fuzziness of large choroidal vessels (Figure 71). These ICGA signs were recorded in newly diagnosed patients with Behçet’s uveitis but not seen any more later in disease possibly because of ongoing therapy. In order not to describe secondary non specific ICGA findings we studied a series of 5 newly diagnosed Behçet’s uveitis cases by indocyanine green angiography.107

The consistent ICGA sign was the blurred appearance of choroidal vessels in the intermediate angiographic phase followed by diffuse choroidal late hyperfluorescence indicating inflammatory vasculopathy of choroidal vessels, a sign present in all five cases.

In all five cases late disc ICG hyperfluorescence was noted indicating severe inflammation. Disc ICG hyperfluorescence was already present in the intermediate phase in those cases with very severe inflammation. Most cases presented also a delay in choriocapillaris perfusion.

Other ICGA signs that can be seen is retinal ICG hyperfluorescence in case of retinal neovessels or severe retinal vasculitis and segmetal bright hyperfluorescent impregnation of retinal vessels (Figure 67).

All these signs responded to therapy indicating that choroidal involvement is well accessible and responds more easily to therapy than retinal disease107 (Figure 71). Similar findings were reported in a turkish

Figure 71: Behçet’s uveitis. FA shows extensive retinal involvement in this newly diagnosed case (top frames). ICGA shows completely blurry vessels and disc hyperfluorescence at presentation (middle frames) that completely resolved after inflammation suppressive therapy (bottom frames)

study.108 In this study were, however, included patients at different stages of disease and some of the signs might be secondary and unspecific due to chronic evolution of the disease. Although choroidal involvement is a fact in Behçet’s disease, the practical relevance of ICGA for disease monitoring is limited in contrast to FA that is the method of choice to monitor efficacy of therapy and evolution of disease.

KEY POINTS: ICG ANGIOGRAPHIC SIGNS IN NEWLY

DIAGNOSED BEHÇET’S UVEITIS

•Blurred appearance and/or hyperfluorescence of choroidal vessels followed by late diffuse choroidal hyperfluorescence

•Disc hyperfluorescence in the late angiographic phase

•Choriocapillaris perfusion delay

NECROTIZING HERPETIC RETINOPATHIES (NHRS)

The umbrella term of necrotizing herpetic retinopathies (NHRs) groups several clinical forms of necrotizing retinitis caused by viruses of the herpes family including herpes simplex virus, varicella-zoster virus and more rarely cytomegalovirus. This term includes acute retinal necrosis (ARN) at one end of the spectrum and the deleterious entity of progressive outer retinal necrosis (PORN) later also called only progressive retinal

necrosis (PRN) at the other end of the spectrum as well as all conditions that are in between these well characterised extreme forms.109,110 The clinical form of NHR that results from a retinal herpes virus infection in susceptible persons depends on the state of the immune system.111 The primary target of the inflammation in NHRs is the retina. Fluorescein angiography of small foci shows hypofluorescence in the early phase followed by progressive appearance of

fluorescence and hyperfluorescence in the late phase. The sequence is identical in the confluent peripheral areas. On indocyanine green angiography, although the primary lesion is at the level of the retina, involved areas appear hypofluorescent through all angiographic phases indicating most probably choriocapillaris non perfusion produced by the severe inflammation at the level of the outer retina (secondary inflammatory choriocapillaropathy) (Figure 72).

THE CLINICAL USE OF ICGA

The clinical utility of indocyanine green angiography in everyday uveitis practice is at least threefold: (1) It allows to evaluate precisely the exent and severity of choroidal inflammatory involvement in posterior uveitis. (2) It is an investigational modality that can contribute to establish the diagnosis by showing lesions not accessible to other techniques and giving essential information contributing to reach a diagnosis. Additionally essential ICGA information can also contribute to modify therapeutic intervention. (3) Finally ICGA is a precious follow-up parameter to monitor disease evolution and verify response to therapy in posterior uveitis with choroidal involvement. In a fair proportion of cases ICGA was the only means to detect posterior involvement that would otherwise have been missed (Figure 73). In other cases ICGA allowed to assess bilaterality in cases where only one eye seemed to be clinically involved. By showing that the other eye had subclinical involvement only detected by ICGA it contributed to the diagnosis of those diseases characterised by bilaterality such as Vogt-Koyanagi- Harada disease.

To establish the utility of indocyanine green angiography, we studied a prospective series of patients to determine the proportion of additional information obtained by ICGA22 and the proportion of cases where this information was essential to reach a diagnosis or to influence therapeutic intervention. In a total of 162 patients with a well determined diagnosis, information gained by ICGA was essential in reaching a diagnosis in 16/162 patients (9.8%) and it was essential to modify therapeutic decisions in 4 patients (2.5%) which gave us a yield of essential information in 12.3% of patients.

Figure 73: Precise assessment of choroidal involvement by ICGA. Presumed intraocular tuberculosis. Patient presented as an anterior uveits with a quasi negative fluorescein angiogram (left frame) Numerous choroidal stromal lesions visible on ICGA demonstrate the presence of a choroiditis presumed to be tuberculous because of a hyperpositive PPD skin test (originally published and reproduced from Am J Ophthalmol 1999;127:350- 3)

PRECISE ASSESSMENT OF CHOROIDAL INVOLVEMENT BY ICGA

For all the described inflammatory entities in this article, indocyanine green angiography showed choroidal lesions not detected by other means including fundoscopy or FA. We did not describe entities where ICGA had been performed and did not contribute to the assessment of posterior inflammatory involvement. One such entity is intermediate uveitis of the pars planitis type where ICGA did not contribute additional information to the traditional investigational work-up. In the prospective study where only well determined entities with suspected choroidal involvement were included, the yield of addtional information not detected by other means was 75% of cases in toxoplasmic retinochoroiditis (N=46) and ICGA was contributive in all other entities (100%), including MEWDS (N=6), APMPPE (N=4), active serpiginous choroiditis (N=3), active multifocal choroiditis (N=5), Vogt-Koyanagi-Harada disease and sympathetic ophthalmia (N=14), birdshot chorioretinopathy (N=13), sarcoidosis (N=25), presumed tuberculous chorioretinitis (N=12), newly diagnosed Behçet’s disease (N=7) and posterior scleritis (N=11). For the entities studied, the probability to detect occult lesions by ICGA is considerable because they all present classically either primary or secondary choroidal inflammatory involvement. In order to investigate and follow these cases adequately a dual FA/ICG angiography has to be

Figure 74A: Precise assessement of choroidal involvement.

Fundus picture OD and OS showing dense choroidal infiltration OS and a normal aspect OD

Figure 74B: Precise assessment of choroidal involvement.

ICGA clearly shows HDDs indicating stromal inflammatory foci suggesting the diagnosis of VKH later confirmed by pleiocytosis in the cerebrospinal fluid

performed. As ICGA shows lesions not identified by any other means, therapeutic intervention may be influenced by this test. This is also true for the subsequent follow-up of such cases. In a case of posterior sarcoidosis, dual FA/ICGA angiographic follow-up allowed to differentiate the inflammatory process in two macular recurrences with the same funduscopic aspect; during the first recurrence the lesion was situated at the level of the retina, whereas it was situated at the level of the choroid in the subsequent recurrence90 (Figures 60A and B). Especially for the entities where inflammation is resulting from primary choroidal stromal disease such as VKH and birdshot chorioretinopathy it is inconsequent not to resort to the method most appropriate to explore these structures. This is well illustrated by birdshot chorioretinopathy for which diagnosis in early disease, when depigmented area are still absent, can only be ascertained by ICGA. In many situations with seemingly unilateral disease, including birdshot and VKH, very often bilaterality of the disease

can only be established by ICGA (Figure 74). The patient shown in figure 74 presented with choroidal infiltration in her left eye and no clinical disease in the right eye (Figure 74A). ICGA was the sole investigation clearly showing choroidal involvement in the asymptomatic right eye which lead to CSF that confirmed the diagnosis of VKH (Figure 74B).

DIAGNOSTIC CONTRIBUTION OF ICGA

Indocyanine green angiography like fluorescein angiography does in itself rarely contribute specific pathognomic diagnostic elements. The proportion of cases in which ICGA gave, however, essential additional information to reach a diagnosis was as high as 9.8% in our hands.22 In presence of a given clinical picture, ICGA was shown furthermore to hasten the diagnosis, which in some cases, where rapid treatment is especially important such as Vogt-Koyanagi-Harada disease was particularly helpful. The entities beside VKH where ICGA was especially useful to reduce the diagnostic delay were MEWDS, multifocal choroiditis and birdshot chorioretinopathy. In APMPPE, early disease can resemble VKH and the diagnosis makes no doubt when the typical choriocapillaris lesions showing non perfusion are seen on the ICGA. Similarly in MEWDS the functional impairment can be severe and the typical ICGA signs confirm the diagnosis and allow to tranquilise patients that are usually anxious and have seen more than one eye doctor before. MEWDS is probably the entity where ICGA is most useful for the diagnosis as clinical and FA signs can be very faint, whereas ICGA is very demonstrative. This is well illustrated in a patient presenting with a severe unilateral visual field loss, almost no fundus findings and very discrete papillitis, that was diagnosed as an optic neuritis. (Figures 75A and B) ICGA clearly showed patchy confluent areas of hypofluorescence typical for MEWDS. (Figure 75C) As far as birdshot chorioretinopathy is concerned we have seen several cases with a bilateral vitritis and retinal vasculitis, for whom ICGA showed the numerous rice shaped hypofluorescent dots typical for birdshot, in the absence of depigmented fundus lesions allowing early diagnosis. HLA-A29 antigen was invariably positif in all these cases. In contradiction to which has been published, the search for the HLA-A29 is an essential element to ascertain the diagnosis.