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

Figures 7A-C: Hypofluorescent dark dots: (A) Line diagram explaining the “mass-effect” of a granuloma occupying the choroidal stroma partially (B) Recent histopathology seems to confirm this hypothesis, clearly showing partial thickness choroidal infiltrate (Courtesy Drs Gaudio, Brooks-Crafword and Rao). Exudation from inflamed large choroidal vessels explains both the late diffuse hyperfluorescence and the fact the partial thickness lesions are “erased” in the late angiographic phase

(C)

Figures 8A and B: Fuzziness of large choroidal vessels:

(A) Line diagram explaining the pathological choroidal hyperfluorescence, in addition to the physiological background fluorescence from the choriocapillaris, coming from nonfenestrated large vessels. Inflamed vessels appear fuzzy in area with numerous hypofluorescent dark dots, (B, left) rapidly responding to corticosteroid therapy with their pattern more sharply visible again (B, right)

of a vasculitic process at the origin of the fuzzy appearance seen on ICGA also been confirmed by histopathology since the first ICGA reports.5,7 This abnormal leakage from large choroidal vessels contributes also to “erase” the partial thickness stromal inflammatory lesions (Figure 9). It has to be stressed that these findings are not pathognomonic to BC but the signs can be found in other diseases such as Vogt- Koyanagi-Harada disease where the same physiopathological process is occurring.

The ICGA findings in treated or quiet disease are less pronounced and reflect the good response of choroidal lesions to corticosteroid/immunosuppressive therapy. Hypofluorescent dark dots tend to resolve and the larger choroidal vessels regain a

Figure 9: Differential inflammatory involvement (and evolution) of retina and choroid in birdshot chorioretinopathy measured by FA and ICGA: At presentation the inflammation is mainly present in the choroid and moderate in the retina. After inflammation suppressive therapy, retinal inflammation (yellow line) is barely under control, whereas ICGA (green line) shows that HDDs rapidly disappear, leaving depigmented areas that progressively appear over time (pink line)

normal aspect with progressive resolution of their fuzzy aspect. The remaining hypofluorescent dark dots have a less regular shape and correspond to chorioretinal atrophy.

VISUAL FIELD TESTING

We have recently shown that apart from central visual impairment due to macular oedema, visual field changes are more frequently found than acknowledged in BC and have probably more deleterious effects on visual function than recognised so far.16,17 These visual field changes probably are a consequence of retinal dysfunction rather than from choroidal or optic nerve disease and are seen in parallel to massive fluorescein exudation9 (Figures 6C and D). In our hands, since our first results on the importance of visual field testing, computerised visual field testing is a routine follow-up examination and the occurrence or progression of visual field changes are considered an indication to introduce therapy, despite full visual acuity.16 This attitude may be an explanation why the rate of cystoid macular oedema is relatively low in our centre.4 The importance of visual field testing is only now being recognised at large and begins to be investigated.23

ELECTRORETINOGRAPHY AND PATHOPHYSIOLOGICAL IMPLICATIONS

Full-field electroretinogram (ERG) becomes abnormal as disease progresses indicating relentless retinal

deterioration. The ERG can show decrease of the rod a and b wave amplitudes with an increase of their implicit times,24 but the most sensitive and prevalent abnormality is a delay of the cone-system derived 30 Hz flicker ERG.25 Priem and colleagues showed that in BC the neural layers of the retina were more diffusely and severely involved than the receptorretinal pigment epithelium-choroid complex with the observation of an electronegative ERG,26 and that has been confirmed by recent reports.24,26,27 Moreover, in the first years of evolution, there is little evidence indicating outer retinal dysfunction resulting from choroidal inflammation.27,28

These reports and findings are in contrast to ERG findings reported in PICCPs where outer retinal dysfunction is found and therefore, distinguishes BC from PICCPs also electrophysiologically.

EVOLUTION, PROGNOSIS AND TREATMENT

In our series of fifteen birdshot patients seen at the Centre for Ophthalmic Specialised Care, Lausanne, Switzerland, the disease evolution was studied by comparing funduscopy, FFA and ICGA in early intermediate and late disease6 (Figure 9). In the “early disease group” dual FFA / ICGA showed more severe choroidal than retinal involvement with respective scores of 2 ± 1.17 and 3 ± 0.79 while there were very few depigmented fundus lesions to be seen (score 1 ± 0.27). The choroidal involvement responded well to systemic corticosteroids ± immunosuppressive therapy (scores in groups 2 and 3 decreasing to 1.2 and 0.75), while retinal disease was stabilised at best (scores in groups 2 and 3 = 2.2 and 2.4) and depigmented fundus lesions increased (scores in groups 2 and 3 = 2.8 and 3). The evolution and response to therapy of retinal and choroidal disease in BC have a different course with choroidal disease responding well to therapy while retinal disease being more resistant, possibly explaining the slow deterioration of functional parameters despite therapy. The increase of “creamcoloured” fundus lesions despite good choroidal response to therapy could be explained by depigmentation left behind after resolution of choroidal stromal granulomas, a hypothesis recently confirmed by the first autopsy case of birdshot chorioretinopathy.

Management of BC is empirical as is the case for many of the rare diseases where controlled studies

cannot be performed. Birdshot chorioretinopathy should be observed only as long as no functional impairment is detected. Three of our 15 patients (20%) have been followed without treatment because of stable functional parameters despite prominent fundus, FFA and ICGA findings. In the absence of cystoid macular oedema, the first functional parameter to deteriorate is the visual field. If this deterioration is progressing, action should be taken and therapy can be started using subTenon’s corticosteroid injections. The use of periocular steroids allows usually to delay the use of systemic therapy. In case of sufficient functional impairment to justify treatment but asymmetrical involvement, our patients were treated with up to 3 posterior subTenon’s triamcinolone acetate injections (40 mg) in a period of 3 months. Systemic therapy had to be initiated in 3/4 patients at a time interval of 14.5±4.1 months and 1 patient avoided systemic treatment free and is controlled with occasional sub-Tenon’s injections. Posterior subTenon’s steroid injections were effective on all functional and inflammatory parameters and allowed to avoid systemic therapy in 1 patient and permitted to delay it for more than one year in the 3 patients that had to go on to systemic therapy.

Recently, it has been shown that the objective data provided by ERG can play a major role in the management of BC, in terms of objectively characterising the severity of disease and determining the efficacy of treatment25-28 and even in the initiation of treatment.25 It is assumed that restoration of normal function to an abnormally functioning retina is of benefit to the longterm health of that retina.

In case of progressive functional loss, systemic therapy has to be tried beginning with corticosteroids and subsequent association of immunosuppressants. We have good experience by using azathioprine (2.5-3 mg/day) as the first choice immunosuppressant, adding or substituting it with cyclosporine if necessary. Immunoglobulins have shown some effect but are expensive and difficult to administer.29 The use of anti-TNF-alpha drugs is presently under investigation.30 The ICGA dark dots respond well to therapy and resolve leaving behind depigmented areas that appear as oval cream coloured fundus lesions. However, the impact of therapy on retinal involvement is less satisfactory explaining the progression of

functional loss despite therapy in some cases with a deleterious course.10

In recent years additional knowledge has been gained and significant progress has been made in the understanding and management of birdshot chorioretinitis. Despite these new elements, as it is a rare disease, misconceptions are perpetuated and erroneous concepts are still published.31 The clinical signs such as microgranulomatous KPs, although rare and not well known beyond centres seeing greater series of BC patients, clearly indicate that BC is a granulomatous disease and have now been confirmed by histopathological analysis of the choroid. The importance of ICGA to make the diagnosis in early disease when there are no fundus lesions present yet and its use to follow choroidal involvement has been clearly demonstrated and the presence of ICGA lesions should be part of the diagnostic criteria of the disease. Finally, the importance of visual field testing in the therapeutic decision process and for the follow-up of the disease has only recently been recognised at large and should be the principal functional parameter to follow.

KEY POINTS

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

•Retinal involvement includes vasculitis of large and small vessels, cystoid macular oedema (in about half of cases) and there is an associated papillitis.

•Choroidal involvement is a primary stromal choroiditis consisting of small, even granulomas regularly distributed in the midperiphery.

•Fundus findings : Retinal vasculitis; oval yellow choroidal lesions faint and scarce at onset (granulomas), numerous and well visible in chronic treated disease (choroidal depigmentation); at end stage retinitis pigmentosa like atrophy.

•FFA findings : (1) generalised vasculitis of large and small vessel with profuse intraretinal leakage → pseudo arteriovenous delay, (2) disc hyperfluorescence,

(3) cystoid macular oedema when present.

•ICGA: At onset: numerous, even, regularly distributed oval shaped hypofluorescent dark dots present in the intermediate phase mostly becoming isofluorescent in the late phase (partial thickness granulomas) Chronic, treated stage : resolution of ICG hypofluorescent dark dots : resolution of granulomas without scarring leaving depigmented areas. Hypofluorescent areas corresponding to chorioretinal scars.

•Visual field is most important follow-up parameter. ERG shows inner retinal involvement and later inner and outer retinal dysfunction.

•Evolution: Choroidal disease responds to therapy, retinal involvement slowly progressive despite treatment.

•Treatment (empirical): Combination of corticosteroids, immunosuppressants and biological agents.

•Severity of the disease is diverse with about one-fifth of patients having a benign course managed by observation only and one-fifth having a deleterious evolution despite maximal therapy.

REFERENCES

1.Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy. Am J Ophthalmol 1980;89:31-45.

2.Gass JDM. Vitiliginous chorioretinitis. Arch Ophthalmol 1981;99:1778-87.

3.Nussenblatt RB, Mittal KK, Ryan S, et al. Birdshot retinochoroidopathy associated with HLA-A29 antigen and immune responsiveness to retinal S-antigen. Am J Ophthalmol 1982;94:147-58.

4.LeHoang P, Ozdemir N, Benhamou A, et al. HLA-A29.2 subtype associated with birdshot retinochoroidopathy. Am J Ophthalmol 1992;113:33-5.

5.Fardeau C, Herbort CP, Kullman N, Quentel GG,LeHoang P. Indocyanine green angiography in birdshot chorioretinopathy. Ophthalmology 1999;106:1928-34.

6.Herbort CP, Probst K, Cimino L, Tran VT. Differential inflammatory involvement in retina and choroïd in birdshot chorioretinopathy. Klin Monatsbl Augenheilkd 2004;221:351-6.

7.Gaudio PA, Kaye DB, Brooks Crawford J. Histopathology of birdshot retinochoroidopathy. Br J Ophthalmol 2002; 86:1439-41.

8.Bouchenaki N, Herbort CP. Stromal choroiditis. In: Pleyer U, Mondino B (Eds). Essentials in Ophthalmology: Uveitis and Immunological Disorders, Berlin, Heidelberg, New York: Springer; 2004;234-53.

9.Kobayashi H, Kokubo T, Takahashi, et al. Tyrosinase epitope recognized by an HLA-DR restricted T cell line from a Vogt-Koyanagi-Harada disease patient. Immunogenetics 1988;47:398-403.

10.Oh KT, Christmas NJ, Folk JC. Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease. Am J Ophthalmol 2002;133:622-9.

11.de Waal LP, Laerdy NM, van der horst AR, et al. HLAA29 subtypes and birdshot chorioretinopathy. Immunogenetics 1992;35:51-3.

12.Baarsma, GS, Priem HA, Kijlstra A. Association of birdshot retinochoroidopathy and HLA-A29 antigen. Curr Eye Res 1990;9:63-8.

13.Henderli DE, Genstler AJ, Smith RE, et al. Changing patterns of uveitis. Am J Ophthalmol 1987;103:131-6.

14.Herbort CP, Tran VT, Auer C, Spertini F. Uveitis: epidemiology in western Switzerland and multidisciplinary approach. Med Hyg 2003;61:1371-80.

15.Gasch AT, Smith JA, Whitcup SM. Birdshot retinochoroidopathy. Br J Ophthalmol 1999;83:241-9.

16.De Courten C, Herbort CP. The potential role of computerized field testing for the appraisal and follow-up of birdshot chorioretinopathy. Arch Ophthalmol 1998; 116:1389-91.

17.Cimino L, Tran VT, Herbort CP. Importance of visual field testing in the functional evaluation and follow-up of birdshot chorioretinopathy. Ophthalmic Res 2002;34 (S1):141

18.Guex-Crosier Y, Herbort CP. Prolonged retinal arteriovenous circulation time by fluorescein but not indocyanine green angiography in birdshot chorioretinopathy. Ocul Immunol Inflamm 1997;5:203-6.

19.Guex-Crosier Y, Pittet N, Herbort CP. Sensitivity of laser flare photometry to monitor inflammation in uveitis of the posterior segment. Ophthalmology 1995;102:613-21.

20.Herbort CP, De Ancos E, Guex-Crosier Y, Pittet N. Use of laser flare photometry to assess and monitor inflammation in uveitis. Ophthalmology 1997;104:64-71.

21.Herbort CP. Posterior uveitis: new insights provided by indocyanine green angiography. Eye 1998;12:757-9.

22.Herbort CP, Bodaghi B, LeHoang P. Angiographie au vert d’indocyanine au cours des maladies oculaires inflammatoires: principles, interprétation schématique, sémiologie et intérêt clinique. J Fr Ophtalmol 2001;24:423-47.

23.Gordon LK, Goldhardt R, Holland GN, Levinson RD. Standardized visual field assessement for patients with birdshot chorioretinopathy. Ocul Immunol Inflamm 2006; 14:325-32.

24.Fuerst DJ, Tesler HH, Fishman A, Yokoyama MM, Wyhinny GJ, Vygantas CM. Birdshot retinochoroidopathy. Arch Ophthalmol 1984;102:214-16.

25.Holder GE, Robson AG, Pavesio CP, Graham EM. Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy. Br J Ophthalmol 2005;89:709-18.

26.Priem H, De Rouck A, De Laey JJ, Bird AC. Electrophysiologic studies in birdshot chorioretinopathy. Am J Ophthalmol 1988;106:430-36.

27.Oh KT, Christmas NJ, Folk, JC. Birdshot retinochoroiditis: long term follow-up of a chronically progressive disease. Am J Ophthalmol 2002;133:622-9.

28.Zacks DN, Samson CM, Loewenstein J, Foster CS. Electroretinograms as an indicator of disease activity in birdshot retinochoroidopathy. Graefe’s Arch Clin Exp Ophthalmol 2002;240:601-7.

29.LeHoang P, Cassoux N, George F, Kullmann, Kazatchkine. Intravenous immunoglobulin (IVIg) for the treatment of birdshot retinochoroidopathy. Ocular Immunol Inflamm 2000;8:49-57.

30.RESCU

31.Levinson RD, Brezin A, Rothova A, Accorinti M, Holland GN. Research criteria for the diagnosis of birdshot chorioretinopathy: results of an international concensus conference. Am J Ophthalmol 2006;141:185-7

Tuberculosis (TB) is one of the leading infectious causes of death, next to Malaria and human immunodeficiency virus (HIV). Although the primary focus of infection is usually the lung, it can involve various organs, including the eye. The eye is involved secondary to haematogenous spread from the primary complex or the secondary lesions where the organisms may remain latent for a long time.1 Years later the organisms may get reactivated in the eye. By the time the ocular TB manifests, the patients may not show evidence of concurrent active systemic disease; however, uncommonly it may occur simultaneously with active pulmonary or extra pulmonary TB.

EPIDEMIOLOGY

According to the World Health Organisation (WHO) estimates,2 about one-third of the world’s population is infected with Mycobacterium tuberculosis. The infection remains latent in the immunocompetent individuals who run a 10% life time risk of systemic reactivation which is alarmingly increased to 10% annual risk in the HIV infected people. Approximately, 8-10 million people get TB every year (95% in the developing countries), and about 3 million deaths are reported from TB every year.3-5 Its prevalence is largely governed by poor socio-economic conditions, as

evidenced by its predominance in countries of Asia, Africa and Latin America.

In the absence of any definitive diagnostic guidelines or criteria, there is no reliable data to indicate the true prevalence of tuberculosis as a cause of uveitis (0.5% in USA,6 6.31% in Italy,7 6.9% in Japan8 and 10.5% in Saudi Arabia9). The prevalence rates are highly variable from 0.39 to 9.86% in the south and north Indian uveitis clinic population respectively.10,11 A recent report based on Medline search of presumed tubercular uveitis (between January 1995 and May 2005) highlighted the predominance of India as the country with largest number of cases reported in the world.12

PATHOGENESIS13

Tuberculosis is a classic aerosol infection, acquired through the lungs via the inhaled droplets carrying the tubercular bacilli. In a resistant host, the inhaled bacilli are usually destroyed by the activated alveolar macrophages in the lungs. However, in a susceptible host, the alveolar macrophages are overwhelmed and destroyed by the multiplying tubercular bacilli with the release of various cytokines and chemokines to attract circulating monocytes which although phago-

cytose the bacilli are incapable of destroying them. A delayed type of hypersensitivity (DTH) response destroys the bacteria-laden macrophages with attendant tissue destruction and formation of an epitheloid cell granuloma with central area of necrosis containing the acid-fast bacilli (AFB) surrounded by activated and nonactivated macrophages, giant cells and T lymphocytes. The activated macrophages representing the cell mediated immunity (CMI) serve to contain the infection. However, inactivated macrophages containing bacilli may escape via the lymphatic channels and circulation and reach the extrapulmonary organ(s) where these may remain dormant. Later, it is the reactivation of these dormant lesions at some stage of life that may cause active TB infection.14,15 Recently, it has been shown that tubercular bacilli may be ingested by the retinal pigment epithelium cells where these may remain dormant.16

CLINICAL SPECTRUM

Tubercular intraocular inflammation presents with wide spectrum of clinical manifestations including chronic, recurrent anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, or rarely endophthalmitis, panophthalmitis or neuroretinitis.

ANTERIOR UVEITIS

Besides the cellular reaction and flare, tubercular anterior uveitis is characterised by the presence of mutton-fat keratic precipitates (KPs) and broad based posterior synechiae (though not pathognomonic) (Figure 1).17-19 The keratic precipitates may be few or diffuse, occupying inferior half of the corneal endothelium (Figure 2A). Koeppe nodules may be seen on the pupillary border (Figure 2) or Bussaca nodules on the surface of the iris (Figure 1). Uncommonly, there may be formation of granulomas in the angle of the anterior chamber or hypopyon. Chronic recurrent inflammation is complicated by the formation of cataract. Posterior synechiae formation is inevitable (Figure 3), sometimes leading to pupillary block and secondary glaucoma. If treated early and appropriately with antitubercular therapy and corticosteroids the inflammation resolves with minimum residua (Figures 4 and 5). Inadequate treatment may be complicated by band shaped keratopathy and iris neovascularisation (Figures 6 and 7).

INTERMEDIATE UVEITIS

Commonly, there is spillover of inflammatory cells into the anterior vitreous from the anterior uveitis. Inflammation of the ciliary body (Figures 8-10), beginning in

the region of pars plana, simulating pars planitis is seen as moderate to severe vitritis with or without snowballs and pars plana exudates (snow bank).20 Peripheral vascular sheathing and cystoid macular oedema are usually present. Tuberculomas may form in the ciliary body21 that may be detectable only on ultrasound biomicroscopic (UBM) examination (Figure 8 B).

POSTERIOR UVEITIS

Posterior segment involvement is the most common form of tubercular uveitis and choroidal tubercle is the most characteristic clinical presentation. Choroidal tubercles are granulomas located deep in the choroid. These are few in number (usually less than 5), most commonly situated in the posterior pole, grayish-white to yellowish in colour, discrete with indistinct borders, and typically elevated in the centre. These may or may not be associated with subretinal fluid (Figure 11). Nearly 30% of the patients suffering from disseminated tuberculosis or tubercular meningitis may show tubercular granulomas.22-24 On fundus fluorescein angiography, they exhibit early hypofluorescence and late hyperfluorescence.Very often, retino-choroidal anastomotic vessels are apparent in the centre of the granuloma. They heal with pale, atrophic, sharply demarcated borders with variable pigmentation (Figures 12-14). Histologically, they are similar to tubercular granulomas elsewhere in the body, containing epitheloid cells and giant cells, granuloma with caseation necrosis that may contain AFB.

SUBRETINAL ABSCESS

Very large granulomas are usually solitary and may appear like a subretinal abscess and are invariably

accompanied by extensive exudative retinal detachment.25 The subretinal abscess is seen as a yellowish, solitary, elevated subretinal mass-like lesion (Figure 12). It develops as a result of progressive, liquefied caseation necrosis with rapid multiplication of bacilli and tissue destruction. Very often these patients would have evidence of systemic disseminated tuberculosis.26

SERPIGINOUSLIKE CHOROIDITIS

We (AG, VG) have earlier described the clinical presentations of serpiginouslike choroiditis and retinal vasculitis of tubercular aetiology.27 This has been reported so far in people of Asian-Indian origin. Serpiginouslike choroiditis may have different morphological patterns: (1) Multifocal discrete lesions may be the initial presentation which show a wave-like progression and then become confluent. These lesions begin as yellowish-white, well-defined round lesions, ¼ to 1 disc diameter in size with raised edges. On fundus fluorescein angiography, they show initial hypo fluorescence, followed by hyperfluorescence in the late stages (Figures 15 and 16). (2) It may manifest as diffuse, larger, yellowish-white, plaque-like lesion. The edges are elevated, and the centre is less elevated and shows pigmentary changes, indicating the process of healing. The fundus fluorescein angiography shows mixed fluorescence; the advancing edge initial hypofluorescence and late hyperfluorescence. (3) The third pattern could be a mixed pattern, with discrete lesions in one eye and diffuse, plaque-like lesion in the opposite eye.

(4) A less common type is seen as a reactivation at the edge of an old scar of serpiginouslike choroiditis. Unlike the autoimmune serpiginous choroiditis, tubercular serpiginouslike choroiditis is seen at a younger age,