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

pulse corticosteroid therapy can be used.64 Various studies have suggested a very rapid recovery if the treatment is augmented by intravitreal steroids.65,66 The corticosteroids are usually very effective in controlling the acute inflammation. However, the main hindrance lies in its prolonged use which is usually associated with unacceptable side effects including hypertension, diabetes mellitus, osteoporosis, adrenal insufficiency, and gastric ulceration. Topical and local peribulbar corticosteroid use is associated with the development of cataract and glaucoma.

Other treatment modalities include Cyclosporine and cytotoxic immunosuppressive drugs.67-71 They are usually used in corticosteroid resistant cases or as a steroid sparing modality in patients requiring prolonged therapy or in patients with serious ocular or systemic corticosteroid related side effects. Cyclosporine may be more useful as the predominant cells

involved in the disease process are T lymphocytes. Nussenblatt et al68 have reported successful use of cyclosporine A in conjunction with prednisone in patients with sympathetic ophthalmia with favourable outcome (20/40 or better vision) in 16 of the 32 treated patients. Immunosuppressive drugs successfully used as monotherapy or as a drug-combination include cyclophosphamide, azathioprine and chlorambucil with or without corticosteroids.69-71 Hakin et al71 reported 6/9 or better vision in 10 of the 18 patients treated with azathioprine, cyclosporine or both in addition to corticosteroids.

Surgical intervention is usually reserved for ocular complications such as complicated cataract or glaucoma. However, the surgery should be performed only under adequate immunosuppressive therapy when the eye has been quiet for at least three months.

PROGNOSIS

A poor visual outcome is usually associated with glaucoma, macular scarring or persistent inflammation while good visual outcome has been reported after early aggressive immunotherapy.72,73 Relapses are very common and may be delayed for several years. Long term follow-up is necessary in all patients even when the disease has been quiet for years. Gupta et al51 observed recurrences in 30% eyes over a course of five years and these recurrences predominantly involved the anterior segment. They also reported a final visual acuity of 20/40 or better in nearly 80% eyes.

SUMMARY

Sympathetic Ophthalmia is a bilateral inflammatory disease that usually follows a penetrating injury or an intraocular surgery. The pathogenesis most probably involves an aberrant immune response to certain specific ocular self-antigens in predisposed (HLA-DR4 or HLA-A11 positive) individuals. It presents as granulomatous panuveitis, which spares the choriocapillaris histologically. The prognosis is favourable with timely diagnosis and early initiation of immunosuppressive or immunomodulatory therapy.

KEY POINTS

1.Sympathetic ophthalmia is a bilateral, diffuse granulomatous panuveitis that occurs after trauma or surgery in one or both of the eyes.

2.Gass6 reported a prevalence of 0.06% and 0.01% following penetrating eye injury and pars plana vitrectomy respectively.

3.It has also been reported after other surgical and laser procedures like glaucoma filtration surgery, peripheral iridectomy, scleral buckling, cataract surgery, evisceration, cyclocryotherapy, Nd-YAG laser cyclotherapy and following helium ion or proton beam irradiation for choroidal melanoma.

4.Aetiopathogenesis involves an aberrant immune response to certain specific ocular self-antigens which interact with HLA-DR4 in a particular manner in these predisposed individuals, triggering the bilateral inflammatory response.

5.Histopathological findings are diffuse non-necrotizing granulomatous inflammation throughout the uveal tissue, except for the choriocapillaris.

6.Clinically presents as granulomatous panuveitis with mutton fat KP’s, vitritis, papillitis, mid-equatorial yellowish-white choroidal lesions and exudative RD.

7.Complications include secondary glaucoma, cataract, chronic maculopathy, choroidal neovascularization, optic atrophy and phthisis bulbi.

8.FFA and ICG are useful in assessing the disease activity and the total extend of involvement.

9.Current treatment includes long term corticosteroids, cyclosporine and immunosuppressive agents although the role of enucleation is still controversial.

10.Visual prognosis is good in a majority of the cases (80%) while poor visual outcome is usually associated with glaucoma, macular scarring or persistent inflammation.

REFERENCES

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26.Romaine H. Malignant melanoma of the choroid with sympathetic ophthalmia. Arch Ophthalmol 1949;42:102-3.

27.Margo CE, Pautler SE. Granulomatous uveitis after treatment of a choroidal melanoma with proton-beam irradiation. Retina 1990;10:140-3.

28.Fries PD, Char DH, Crawford JB, Waterhouse W. Sympathetic ophthalmia complicating helium ion irradiation of a choroidal melanoma. Arch Ophthalmol 1987;105:1561-4.

29.Elschnig A. Studies in sympathetic ophthalmia. II. The antigenic effect of eye pigments. Albrecht von Graefes Arch Ophthalmol 1910;76:509-46.

30.Woods AC. Immune reactions following injuries to the uveal tract. JAMA 1921;77:1317-22.

31.Chan CC, Palestine AG, Nussenblatt RB, et al. Anti-retinal auto-antibodies in Vogt-Koyanagi-Harada syndrome, Behçet’s disease, and sympathetic ophthalmia. Ophthalmology 1985;92:1025-8.

32.de Smet MD, Yamamoto JH, Mochizuki M, et al. cellular immune responses of patients with uveitis to retinal antigens and their fragments. Am J Ophthalmol 1990;110: 135-42.

33.Hammer H. Lymphocyte transformation test in sympathetic ophthalmitis and the Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 1971;55:850-2.

34.Wong VG, Anderson R, O’Brien PJ. Sympathetic ophthalmia and lymphocyte transformation. Am J Ophthalmol 1971;72:960-6.

35.Marak GE Jr, Font RL, Johnson MC, Alepa FP. Lymphocyte stimulating activity of ocular tissues in sympathetic ophthalmia. Invest Ophthalmol 1971;10:770-4.

36.Azen SP, Marak GE, Minckler DS, et al. Histocompatibility antigens in sympathetic ophthalmia. Am J Ophthalmol 1984;98:117-9.

37.Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican DC, Palestine AG, et al. HLA associations and ancestry in Vogt-

Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology 1990;97:1137-42.

38.Joy HH. Sympathetic ophthalmia. Am J Ophthalmol 1953; 36:1100-20.

39.Boyd SR, Young S, Lightman S. Immunopathology of the noninfectious posterior and intermediate uveitides. Surv Ophthalmol 2001;46:209-33.

40.Rao NA, Robin J, Hartmann D, et al. The role of the penetrating wound in the development of sympathetic ophthalmia experimental observations. Arch Ophthalmol 1983;101:102-4.

41.Lubin JR, Albert DM, Weinstein M. Sixty-five years of sympathetic ophthalmia. A clinicopathologic review of 105 cases (1913–1978). Ophthalmology 1980;87:109-21.

42.Croxatto JO, Rao NA, McLean IW, Marak GE. Atypical histopathologic features in sympathetic ophthalmia. A study of a hundred cases. Int Ophthalmol 1982;4:129-35.

43.Wu GS, Swiderek KM, Rao NA. A novel retinal pigment epithelial protein suppresses neutrophil superoxide generation: II. Purification and microsequencing analysis. Exp Eye Res 1996;63:727-37.

44.Chan CC, Benezra D, Rodrigues MM, Palestine AG, Hsu SM, Murphree AL, et al. Immunohistochemistry and electron microscopy of choroidal infiltrates and DalenFuchs nodules in sympathetic ophthalmia. Ophthalmology 1985;92:580-90.

45.Chan CC, Nussenblatt RB, Fujikawa LS, Palestine AG, Stevens G Jr, Parver LM, et al. Sympathetic ophthalmia. Immunopathological findings. Ophthalmology 1986;93: 690-5.

46.Jakobiec FA, Marboe CC, Knowles DM 2nd, Iwamoto T, Harrison W, Chang S, et al. Human sympathetic ophthalmia. An analysis of the inflammatory infiltrate by hybridoma-monoclonal antibodies immunochemistry, and correlative electron microscopy. Ophthalmology 1983; 90:76-95.

47.Muller-Hermelink HK, Kraus-Mackiw E, Daus W. Early stage of human sympathetic ophthalmia. Histologic and immunopathologic findings. Arch Ophthalmol 1984;102: 1353-7.

48.Bib Marak GE. Recent advances in sympathetic ophthalmia. Surv Ophthalmol 1979;24:141-56.

49.Zaharia MA, Lamarche J, Laurin M. Sympathetic uveitis 66 years after injury. Can J Ophthalmol 1984;19:240-3.

50.Goto H, Rao NA. Sympathetic ophthalmia and Vogt- Koyanagi-Harada syndrome. Int Ophthalmol Clin 1990; 30:279-85.

51.Gupta V, Gupta A, Dogra MR. Posterior sympathetic ophthalmia: a single centre long-term study of 40 patients from North India. Eye 2007; doi:10.1038/sj.eye.6702927.

52.Comer M, Taylor C, Chen S, Martin K, Jordan K, Meyer P. Sympathetic ophthalmia associated with high frequent deafness. Br J Ophthalmol 2001;85:496.

53.Rao NA, Marak GE. Sympathetic ophthalmia simulating Vogt-Koyanagi-Harada’s disease: a clinico-pathologic study of four cases. Jpn J Ophthalmol 1983;27:506-11.

54.Power WJ, Foster CS. Update on sympathetic ophthalmia. Int Ophthalmol Clin 1995;35:127-37.

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angiographic correlation. Arch Ophthalmol 1984;102:232- 5.

56.Bernasconi O, Auer C, Zografos L, Herbort CP. Indocyanine green angiographic findings in sympathetic ophthalmia. Graefes Arch Clin Exp Ophthalmol 1998;236:635-8.

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60.Reynard M, Riffenburgh RS, Maes EF. Effect of corticosteroid treatment and enucleation on the visual prognosis of sympathetic ophthalmia. Am J Ophthalmol 1983; 96:290-4.

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62.Woods AC. Clinical and experimental observations on the use of ACTH and cortisone in ocular inflammatory disease. Am J Ophthalmol 1950;33:1325-49.

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64.Hebestreit H, Huppertz HI, Sold JE, Dammrich J. Steroidpulse therapy may suppress inflammation in severe sympathetic ophthalmia. J Pediatr Ophthalmol Strabismus 1997;34:124-6.

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Carl P Herbort

INTRODUCTION—HISTORY

Birdshot chorioretinopathy (BC) is a bilateral intraocular inflammatory condition of the posterior segment, first reported as such in 1980 by Ryan and Maumenee.1 A year later Gass published a series of 11 patients and called it vitiliginous chorioretinitis.2 In 1982 the strong association, now known to be close to 100%, of birdshot chorioretinopathy with the major histopathology complex (MHC) type 1 antigen HLAA29 was reported3 and in 1992 it was established that the association occurred exclusively with the subtype antigen HLA-A29.2.4 The pecularity of BC is that it is one of the most strongly associated diseases with an MHC type 1 locus and nevertheless the disease seems to be limited to the eye, as no systemic association has been documented so far.

Clinically, the particularity of BC is that both the choroid and the retina are independent primary targets and sites of an inflammatory reaction in opposition to

most uveitides where inflammation originates in one structure and causes secondary inflammation in the surrounding structures.5,6 The retinal involvement is characterised by a vasculitis involving both small capillaries and large retinal vessels. The choroidal involvement typically is a primary stromal choroiditis, characterised by the typical oval cream coloured depigmented areas in the posterior pole and midperiphery (Figure 1A). A recent histopathological report has shown that in the choroid it is the choroidal stroma that is the primary target of BC while the choriocapillaris and the pigment epithelium are intact.7 Birdshot chorioretinopathy has been erroneously amalgamated with primary inflammatory choriocapillaropathies (PICCPs) such as multiple evanescent white dot syndrome (MEWDS), acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and multifocal choroiditis (MFC) within the purely descriptive pot-pourri term of “white dot syndromes”.

Figures 1A and B: Birdshot chorioretinopathy fundus appearance: Typical oval shaped depigmented fundus lesions distributed in the midperiphery in a patient with a disease evolving since more than 7 years

Histological evidence has now confirmed that it is a stromal choroiditis as the choroidal inflammatory reaction occurs within the stroma.8 Moreover, it is a primary stromal choroiditis because in contrast to a disease like sarcoidosis that affects the choroid at random as an innocent bystander of the granulomatous reaction, the choroidal stroma is the obligatory primary site of inflammation in birdshot chorioretinopathy.8

In contrast to Vogt-Koyanagi-Harada disease, another primary stromal choroiditis, where the target of the immune reaction, a stromal choroidal melanine associated protein, has been identified, the target of the suspected autoimmune reaction in BC is not known.9

However, the functional deleterious impact in BC comes from the retinal inflammatory involvement due to massive leakage from capillaries and larger vessels.10

EPIDEMIOLOGICAL ASPECTS

Birdshot chorioretinopathy is a rare disease affecting principally Caucasian patients which is also the ethnic group that has a high prevalence of the HLA-A29.2 subtype antigen.11 The presence of the HLA-A29.2 antigen increases the risk of developing the disease up to 224-fold.12 The proportion of BC patients in European and North American uveitis series is around 1.2% of uveitis cases.13,14 In the Southeast Asian populations it is exclusively the HLA-A29.1 subtype that is present and BC has virtually never been found or described in this area.11 Typically, BC affects age groups from 30 to 70 years with a median age around 50 and there is a strong gender predilection for women with an F/M ratio of 3/2.15

CLINICAL SYMPTOMS AND SIGNS

The presenting complaints of patients usually are floaters, decreased visual acuity and very often patients complain of dimness of vision, loss of brightness and lustre of colours. In the absence of macular oedema, however, central vision remains excellent in most cases and is not a good functional parameter to monitor disease activity, whereas visual field changes more appropriately identify activity of the disease.16,17 Involvement is always bilateral but can be asymmetric and BC occurs predominantly in women in their fourth to sixth decade. Human leucocyte antigen HLA-A29 is present in nearly all cases and its absence should cast serious doubts on the correctness of diagnosis.3 Subtyping showed that it is the HLA-A-29.2 subtype that is found in BC patients.4 Anterior chamber inflammation is usually slight at most with a flare only recordable by laser flare photometry and rare cells. Nevertheless careful examination of the anterior

segment is important. In cases with a longstanding evolution that have not been treated it is not rare to find very few or even a single microgranulomatous keratic precipitate (KP) (Figure 1B). This element does not appear in the literature on birdshot. Some authors have even listed the presence of KPs as an exclusion criterium for birdshot chorioretinopathy. The granulomatous nature of the inflammation in BC has been verified histopathologically in a recent autopsy case of BC.7 Vitreous infiltration is usually present and can be prominent in some cases. At the onset of disease, fundus examination shows papillitis, vasculitis of veins but very few cream coloured lesions so typical for BC (Figures 2A and B). However, subclinical choroidal involvement is clearly shown by ICGA that reveals numerous hypofluorescent dark dots indicating choroidal stromal infiltration (Figures 2C and D). The extent of retinal involvement is shown by FA that, in addition to vasculitis of large vessels, reveals massive capillary exudation to the point that there is not enough fluorescein upon venous return to mark the large veins18 (Figure 2E). In our experience, cystoid macular oedema is less frequent than reported in the past and occurs in up to 40% of cases at any time of the evolution of the disease. Even when there is massive exudation from retinal vessels the macula can remain free of CME (Figure 2F). On the other hand in comparatively equally inflamed eyes one eye can present CME whereas the other eye remains free of CME (Figure 2G). For ongoing disease the fundus examination reveals progressively more cream coloured oval fundus lesions despite corticosteroid/ immunosuppressive therapy which goes in parallel with regresion of the ICGA dark dots under therapy (Figures 2H-J). It is supposed that this corresponds to the resolution of the granuloma without stromal scarring but bearing with it the depletion of melanocytes corresponding to the cream coloured lesions. Therapy usually allows stabilisation of the disease but in some cases the process can evolve towards a pseudo-retinitis pigmentosa when extensive damage is caused to the retina (Figure 3A). The functional corollary is a badly damaged visual field (Figure 3B).

LASER FLARE PHOTOMETRY

Anterior chamber inflammation is minimal in BC, although in some cases one isolated or two mutton fat

keratic precipitates can be seen indicating the granulomatous nature of the inflammation that has now been proven by the only good quality BC histopathology report available to date.7 Cells and flare are minimal and synechiae are classically absent. The mean presenting flare measured by laser flare photometry (LFP) in a group of 10 birdshot patients was 5.8 ± 0.7 ph/ms.19 As demonstrated in the past, posterior inflammatory conditions with a presenting flare of less than 15 ph/ms are not suitable for reliable LFP follow-up.20 However, if individual cases in a given posterior uveitis present initially with an LFP values superior to 15 ph/ms, LFP will be a reliable parameter to be used for follow-up purposes.20

FUNDUS FLUORESCEIN ANGIOGRAPHY

Fundus fluorescein angiography (FFA) accounts for the retinal involvement and optic nerve inflammation in BC.

The FFA findings in the active phase of disease have to be distinguished from FFA findings in quiet or burned out disease. In early active disease, FFA shows sectorial vasculitis of large vessels, mainly retinal veins. The predominant sign, however, is diffuse vasculitis of small vessels (capillaries) that is at the origin of mottled hyperfluorescence all over the fundus (Figure 4A). These widespread mottled areas of hyperfluorescence do not correspond to the dark hypofluorescent dots seen in ICG, clearly indicating that choroidal or retinal inflammations are not the consequence of each other but develop independently. In many cases this massive fluorescein leakage from capillaries or precapillary arterioles is at the origin of diffuse retinal fluorescein impregnation. The leakage is often such that there is not enough fluorescein to mark the large veins18 (Figures 4B and 2E). This was erroneously interpreted by Gass in his article on “vitiliginous chorioretinitis” as an arteriovenous circulatory delay.2 When dual fluorescein and indocyanine green angiography is performed it is, however, shown beyond doubt that there is no arteriovenous perfusion delay as the ICG dye reaches the central vein within 20 seconds after injection into the antecubital vein (Figures 4B and 2E). The failure to see fluorescein in the large veins is explained by the fact that, due to massive retinal exudation, there is never enough fluorescein to sufficiently impregnate the large veins

and make them fluoresce (Figures 4B and 2E). It is comprehensible that retinal function is impaired in cases with such a massive exudation from small retinal vessels. However the occurrence of a highly pathologic FFA is not an absolute indication to begin systemic immunosuppressive therapy, as long as there is no decrease of visual acuity and, more importantly, as long as no other functional impairment such as visual field changes are detected. Disc hyperfluorescence of diverse intensity is usually seen in all cases of early active disease. Cystoid macular oedema is best investigated by FFA at onset and can be followed by FFA and possibly by ocular coherence tomography (OCT). In our series of patients mostly under corticosteroid/Immunosuppressive treatment, the rate of patients presenting a cystoid macular oedema did not exceed 40% (Figure 2G). This is possibly explained by the tight functional follow-up we performed putting emphasis on visual field examination and monitoring rather than visual acuity.

Figure 4B: Pseudo-delay in retinal arteriovenous circulation. Massive retinal exudation causing pseudo-delay of arteriovenous circulation as large veins are still not opacified at 45 seconds

In burned-out or quite long lasting cases, the main FFA findings are mostly window defects of atrophic areas, showing early hypofluorescence and late hyper-

fluorescence. Retinal vessels tend to become slender and in some cases chorioretinal atrophy can evolve towards a pseudoretinitis pigmentosa fundus picture. There are very often chronic oedematous macular changes or macular retinal pigment alterations as a sequela of longstanding retinal fluid impregnation.

INDOCYANINE GREEN (ICG) ANGIOGRAPHY

So far only the retinal involvement was accessible to clinical and angiographic examination and could be analysed in detail. Since indocyanine green angiography (ICGA) has become available, choroidal inflammatory involvement became accessible to analysis and monitoring.21,22 Indocyanine green angiography represents a major improvement in the investigation of BC by showing the importance of choroidal disease.5 The interpretations given to the characteristic ICGA images obtained from birdshot patients were only conjectures that have, however,

now been confirmed by histopathological analysis of an autopsy case of BC.7

As for FFA, angiographic findings have to be distinguished according to the stage and activity of the disease. For diagnostic purposes ICGA is most useful in newly presenting disease as it detects subclinical choroidal stromal disease when no fundus signs can be seen yet. In case of therapeutic intervention ICGA is also very useful and the only means to monitor choroidal inflammatory involvement.

In early and non-treated disease the principal findings are numerous hypofluorescent dark dots, that we now know to correspond to stromal granuloma (Figures 2C and D, 5A-E, 6A and B). They have a regular size and are evenly distributed in the posterior pole and the midperiphery and should be considered as a diagnostic criterion in early disease with compatible clinical findings at a time when the characteristic oval shaped cream coloured fundus lesions are not yet

present (Figures 5A-C). These hypofluorescent dark dots are detected from the post-early angiographic frames but are best seen during the intermediate phase of angiography (Figures 2C and 4A). They either persist up to the late angiographic phase or become isofluorescent in the late phase depending on whether the granulomas occupy the whole thickness of the stroma or are only partial thickness granulomas (Figures 2C and D, 6A and B). Typically the physiopathological process explaining the hypofluorescent

dark dots in BC is the principle proper to ICGA of a “mass effect” where a space occupying inflammatory lesion in the choroidal stroma impairs the normal diffusion of the ICG dye physiologically extruding from the fenestrated choriocapillaris (Figure 7). In addition to visualisation of the granulomas, ICGA also shows vasculitis of the larger choroidal vessels that have a fuzzy appearance in the intermediary phase of angiography and give rise to late diffuse choroidal hyperfluorescence5 (Figures 8A and B). The hypothesis