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

to 1 gm of corticosteroid) followed by oral prednisone at levels of about 1 mg/kg/day. Sasamoto and colleagues27 evaluated the final visual acuity of patients receiving pulsed corticosteroid therapy, highdose systemic corticosteroid therapy (200 mg of prednisone), and conventional prednisone therapy. The final visual acuities of those patients receiving pulsed or high oral dose therapy appeared to be better than those receiving conventional therapy.

The duration of treatment and how slow or fast the drug is tapered must be individualised to each case. In the severe ocular cases, steroid therapy may continue for at least a year with a slow, gradual taper over this time. Since recurrences are possible, patients need to be monitored.

KEY POINTS

•Multisystem autoimmune disorder aimed at the melanocytes, and selectively affects tissues containing melanocytes, such as the skin, uvea, inner ear, and meninges.

•A few days before the onset of ocular symptoms, patients complain precursory symptoms like headache, dysacousia, or tinnitus.

•Ocular involvement shows non-traumatic bilateral uveitis.

•Fundus findings: at the acute stage: bilateral and multifocal serous retinal detachment, swelling of the optic disc; at the convalescent stage: sunset-glow fundus, irregular and linear pigmentation might be seen long after the onset.

•FA finding: at the acute stage: (1) numerous punctuate hyperfluorescent dots at the level of the retinal pigment epithelium, (2) multiple areas of dye pooling into the subretinal space, (3) dye leakage from the optic disc; at the convalescent stage: granular hyperfluorescence due to window defect caused by the damage to retinal pigment epithelium may be seen.

•ICGA findings: at the acute stage: (1) filling delay of large choroidal artery, (2) fewer choroidal vessels in the posterior as well as peripheral fundus, (3) patchy filling delay of choriocapillaris, (4) ICG dye leakage, (5) multiple hypofluorescent spots; at the convalescent stage: dramatic improvement of filling delay of large choroidal artery, an increase of visible choroidal vessels, multiple hypofluorescent spots sometimes remain even after a large dose of corticosteroid treatment.

•Four consistent ICGA signs for evaluation of inflammation and follow-up: (1) hypofluorescent dark dots (choroidal granuloma), (2) early hyperfluorescent choroidal vessels (wall inflammation), (3) fuzzy indistinct choroidal stromal vessels (vasculitis) and (4) ICGA disc hyperfluorescence.

•Evolution: Ocular inflammation responds to corticosteroid therapy, however, depigmentation of the fundus progresses despite treatment. Damage to melanocytes also progresses in other pigmented tissue, and causes vitiligo, poliosis, and alopecia.

•Treatment: large dose of systemic corticosteroid and topical steroid.

REFERENCES

1.Pattison EM. Uveo-meningoencephalitic syndrome (Vogt- Koyanagi-Harada). Arch Neurol 1965;12:197-205.

2.Vogt A. Fruhzeitigers Ergrauen der Zilien und Bemerkungen uber den sogenannten plotlzichen Eintritt dieser Veranderung. Klin Monatsbl Augenheilkd 1906;4:228-42.

3.Harada E. Beitrag zur klinischen Kenntnis von Michteitriger Choroiditis (choroiditis diffusa acta). Acta Soc Ophthalmol Jpn 1926;30:356-78.

4.Koyanagi Y. Dysakusis, alopecia und poliosis bei schwerer uveitis nicht traumatischen ursprungs. Klin Monatsbl Augenheilkd 1929;82:194-211.

5.Schenkl A. Ein Fall vov plotzlich aufgetretener Poliosis circumscripta der Wimpern. Arch Dermatol Syph 1873;5:137-9.

6.Babel J. Syndrome de Vogt-Koyanagi (Uveite bilaterale, poliosis, alopecie, vitiligo et dysacousie). Schweiz Med Wochenschr Nr 1932;44:1136-40.

7.Bruno MG, McPherson SD Jr. Harada’s disease. Am J Ophthalmol 1949;32:513-22.

8.Sugiura S. Vogt-Koyanagi-Harada disease. Jpn J Ophthalmol 1978;22:9-35.

9.Mimura Y. Vogt-Koyanagi-Harada disease, in Uyama M (Ed): Ganka Mook Vol. 12. Tokyo, Kanehara, 1980;11644.

10.Shimizu K. Harada’s, Behcet’s, Vogt-Koyanagi synd- romes–are they clinical entities? Trans Am Acad Ophthalmol Otolaryngol 1973;77:OP281-OP290.

11.Ohno S, Char DH, Kimura SJ, O’Connor GR. Vogt- Koyanagi-Harada syndrome. Am J Ophthalmol 1977;83: 735-40.

12.Snyder DA, Tessler HA. Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1980;90:69-75.

13.Murakami S, Inaba Y, Mochizuki M, Nakajima A, Urayama A. A nationwide survey on the occurrence of Vogt-Koyanagi-Harada disease in Japan. Jpn J Ophthalmol 1994;38:208-13.

14.Wakabayashi T, Morimura Y, Miyamoto Y, Okada AA. Changing patterns of intraocular inflammatory disease in Japan. Ocul Immunol Inflam 2003;11:277-86.

15.Davis JL, Mittal KK, Freidlin V, Mellow SR, Optican DC, Palestine AG, Nussenblatt RB. HLA associations and ancestry in Vogt-Koyanagi-Harada disease and sympathetic ophthalmia. Ophthalmology 1990;97:1137-42.

16.Shindo Y, Inoko H, Yamamoto T, Ohno S. HLA-DRB1 typing of Vogt-Koyanagi-Harada’s disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410. Br J Ophthalmol 1994;78:223-6.

17.Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease. Report of an international committee on nomenclature. Am J Ophthalmol 2001;131:647-52.

18.Bouchenaki N, Herbort CP. The contribution of indocyanine green angiography to the appraisal and management of Vogt-Koyanagi-Harada disease. Ophthalmology 2001;108:54-64.

19.Okada AA, Mizusawa T, Sakai J, Usui M. Videofunduscopy and videoangiography using the scanning laser ophthalmoscope in Vogt-Koyanagi-Harada syndrome. Br J Ophthalmol 1998;82:1175-81.

20.Yuzawa M, Kawamura A, Matsui M. Indocyanine green video-angiographic findings in Harada’s disease. Jpn J Ophthalmol 1993;37:456-66.

21.Herbort CP, Mantovani A, Bouchenaki N. Indocyanine green angiography in Vogt-Koyanagi-Harada disease : angiographic signs and utility in patient follow-up. Int. Ophthalmol : in press

22.Massin P, Vicaut E, Haouchine B, et al. Reproducibility of retinal mapping using optical coherence tomography. Arch Ophthalmol 2001;119:1135-42.

23.Maruyama Y, Kishi S. Tomographic features of serous retinal detachment in Vogt-Koyanagi-Harada syndrome. Ophthalmic Surg Lasers Imaging 2004;35:239-42.

24.Parc C, Guenoun JM, Dhote R, Brezin A. Optical coherence tomography in the acute and chronic phases of Vogt- Koyanagi-Harada disease. Ocul Immunol Inflamm 2005;13:225-7.

25.Yamanaka E, Ohguro N, Yamamoto S, et al. Evaluation of pulse corticosteroid therapy for Vogt-Koyanagi-Harada disease assessed by optical coherence tomography. Am J Ophthalmol 2002;134:454-6.

26.Hayasaka S, Okabe H, Takahashi J. Systemic corticosteroid treatment in Vogt-Koyanagi-Harada disease. Graefes Arch Clin Exp Ophthalmol 1982;218:9-13.

27.Sasamoto Y, Ohno S, Matsuda H. Studies on corticosteroid therapy in Vogt-Koyanagi-Harada disease. Ophthalmologica 1990;201:162-7.

Nishant Sachdev, Vishali Gupta, Amod Gupta

INTRODUCTION

Sympathetic ophthalmia is a bilateral, diffuse granulomatous panuveitis that occurs after trauma or surgery in one or both of the eyes. The eye which is responsible for initiation of the inflammation is known as the exciting eye while the fellow eye is known as the sympathizing eye. Penetrating or surgical injury to the exciting eye leads to an inflammatory response in both the exciting and the sympathizing eyes.1

The disease ‘sympathetic ophthalmitis’, although known since ancient times; was first coined and characterised in 1865 when Mackenzie reported six patients who had developed this bilateral diasese following penetrating eye injury in one eye.2 However, Fuchs provided the histological description of sympathetic ophthalmia in 1905 and hence, established this disease as a distinctive clinical entity.3

EPIDEMIOLOGY

Being a relatively rare disease, the true incidence of sympathetic ophthalmia is difficult to ascertain. Studies in the early part of twentieth century suggested that the average incidence of sympathetic ophthalmia was approximately 2% or even higher.4,5 However in

the last few decades there has been a dramatic decrease in the incidence of sympathetic ophthalmia mostly attributed to significant improvement in the management of ocular trauma and the availability of a better and more effective immunomodulatory therapy. Gass reported a prevalence of 0.06% and 0.01% following penetrating eye injury and pars plana vitrectomy respectively.6 Other studies too, conducted in the more recent past, have shown the incidence to be 0.2% to 0.5% after penetrating ocular injuries and 0.01% after intraocular surgery.7,8 In a recent prospective study in the United Kingdom and Ireland, 17 patients with newly diagnosed sympathetic ophthalmia were reported in a 12-month period drawn from a surveillance of 59 million citizens, and hence a minimum estimated incidence of 0.03 in 100,000 was calculated.9 Sympathetic ophthalmia has been reported to account for nearly 0.3 to 1.4% of all the patients seen in various uveitis clinics.10,11

Sympathetic ophthalmia subsequent to penetrating eye injury is more commonly reported in males than females, most probably due to the higher frequency of ocular injury among males. However, there is no gender difference in the incidence of sympathetic ophthalmia subsequent to ocular surgery. There is no

racial predisposition and the disease has been reported to occur in all age groups although the frequency of occurrence is higher in children less than 10 years because of the higher frequency of injuries in this age group; and it also increases in those over 60 years because of an increase in eye surgery in this age group.

AETIOLOGY

In the past, trauma was the most common precipitating event; however, ocular surgery is now considered the major risk factor, particularly vitreoretinal surgery. Better access to eye care following accidental trauma, combined with advances in microsurgical techniques resulting in an increase in the number of ocular surgeries, may be responsible for this change in the aetiologic profile from penetrating injury to surgical trauma. It has also been reported after other surgical and laser procedures like glaucoma filtration surgery, peripheral iridectomy, scleral buckling, cataract surgery, evisceration, cyclocryotherapy and Nd-YAG laser cyclotherapy. It has even been reported after laser therapy for retinal tear.11 Similarly, sympathetic ophthalmia has also been reported after helium ion or proton beam irradiation for choroidal melanoma.26-28

PATHOGENESIS

The pathogenesis of sympathetic ophthalmia is still incompletely understood. Initially, MacKenzie postulated that the inflammatory process spreads from one eye to another via the optic nerve and the optic chiasma.2 However the more widely accepted belief is that bilateral diffuse inflammation occurs secondarily to a variety of inciting events like ocular trauma or surgery which lead to exposure of certain ‘immuneprivileged’ ocular antigens in the exciting eye to the host immune system leading to its activation against these self antigens in both the eyes. The self antigens may include choroidal melanocytes, melanin pigment or uveo-retinal extracts including retinal S-antigen and interphotoreceptor retinoid binding protein.29-32 There is evidence suggesting that choroidal melanocytes may be an inciting target in developing sympathetic ophthalmia. Studies have suggested that in patients with sympathetic ophthalmia there is T cell proliferative responses on exposure to uveal and uveoretinal

extracts. In addition, selective loss of choroidal melanocytes as observed on histopathology further supports the role of these melanocytes as a possible trigger agent for the inflammatory response.

The fact that sympathetic ophthalmia occurs infrequently following ocular trauma or surgery suggests that genetic predisposition is also essential in development of this disease in certain predisposed individuals. The association of this disease with a particular major histocompatibility antigen (MHC) haplotypes (HLA-DR4 and HLA-A11) further suggests a role for immune deregulation in its pathogenesis. Hence the current concept is that in patients with sympathetic ophthalmia, there is an aberrant immune response to certain specific ocular self-antigens. These antigens may interact with HLA-DR4 in a particular manner in these predisposed individuals, triggering an inflammatory response directed primarily at the choroid and ultimately affecting both the eyes.36,37

The role of an infectious agent in the development of sympathetic ophthalmia has long been speculated. However, no organism has ever been consistently isolated from eyes with sympathetic ophthalmia, and it has still not been possible to incite the disease in animal models following injection of an infective agent. Nonetheless, through molecular mimicry of an endogenous ocular antigen, a bacterial antigen may be the inciting agent in the immune response.38,39

Rao et al studied the relationship between penetrating ocular wound and development of sympathetic ophthalmia by inducing bilateral sympathetic uveitis in rabbits after subconjunctival injection of bovine retinal S antigens. They also observed that when the retinal S antigen was directly injected into the globe it did not have the same effect. These findings made them postulate that when uveoretinal antigen is presented to the lymphatic system via the conjunctiva, the immune system responds by developing a disease similar to sympathetic ophthalmia in rabbits.40

PATHOLOGY

Sympathetic ophthalmia is characterised by a diffuse non-necrotizing granulomatous inflammation throughout the uveal tissue, except for the choriocapillaris.3 The histological features are similar in both the exciting and the sympathizing eye. The inflammatory cells involved are primarily lymphocytes,

epithelioid cells, and multinucleated giant cells. The classic non-necrotizing granuloma formation with mononuclear and epithelioid cell infiltration are seen in the choroid. The infiltrates in the choroid can also consist of a large number of eosinophils and plasma cells as observed by Lubin et al.41 Retinal changes are also seen not so infrequently as mild retinal infiltrates (18% cases), retinal vasculitis and retinal detachment (50% cases) as described by Croxatto et al.42 The sparing of choriocapillaris is one of the classic findings in sympathetic ophthalmia. This is probably due to the protective effect of RPE cells which release certain antiinflammatory mediators like retinal pigment epithelial protective protein, which is believed to suppress neutrophil superoxide generation.43

On histopathologic inspection, the yellowish-white choroidal lesions seen clinically correspond to collections of lymphocytes, histiocytes, and depigmented retinal pigment epithelial cells lying beneath Bruch’s membrane. The lesions are known as ‘Dalen-Fuchs’ nodules and are seen in approximately one-third of the patients with sympathetic ophthalmia.40 These ‘DalenFuchs nodules’ are typical but not pathognomic of sympathetic ophthalmia. These nodules are postulated to be an extension of the choroidal inflammatory process towards the retina and retinal pigment epithelium. The retinal pigment epithelium (RPE) generally remains normal-appearing, but it may or may not be intact anterior to these nodules.44-46

Immunopathologic studies suggest an early infiltration of CD4+ helper/inducer T cells followed by an infiltration of CD8+ suppressor/ cytotoxic T cells. These findings indicate that during the inflammatory process of sympathetic ophthalmia, there is a continuous dynamic cellular immune response, mediated predominantly by T lymphocytes. So as the disease progresses, the body tries to down-regulate the immune system and majority of the T helper cells are replaced by T suppressor cells.44,47

CLINICAL FEATURES

The disease can begin as early as a week to as late as a couple of decades following ocular trauma or surgery.48,49 However, majority of cases present between two weeks to six months of the precipitating insult with nearly 80% cases presenting within the first three

months and 90% cases by one year of the penetrating insult.41,50

Patients may present with symptoms ranging from mild visual disturbance to significant visual loss with associated pain, watering, and photophobia in the sympathizing eye. This is accompanied by conjunctival injection and a granulomatous anterior chamber reaction with mutton fat keratic precipitates on the corneal endothelium. However in early case, the inflammation may be non-granulomatous and mild in the anterior chamber with inflammatory cells seen in the retrolental space. The iris may become oedematous with severe inflammation and can lead to formation of posterior or peripheral anterior synechiae. Intraocular pressure may be elevated probably secondary to inflammatory cell blockage of the trabecular meshwork, or it may be low as a result of ciliary body shutdown. The posterior segment examination typically reveals a moderate to severe vitritis with papillitis and mid-equatorial yellowish-white choroidal lesions, which may later become confluent. The presence of papillitis is useful as it can be used to follow the progress of the disease. In severe cases exudative retinal detachment may also occur in the posterior pole or inferiorly (Figures 1 and 2). Chorioretinal scarring is frequently observed as the inflammation subsides (Figures 3 and 4).

Gupta et al51 described ‘posterior sympathetic ophthalmia’ where the only presenting sign in a majority of the sympathising eyes, was the presence of fundus lesions with no or minimal associated anterior segment inflammation. In their series, only 10% of eyes at presentation, showed granulomatous anterior uveitis. The fundus lesions (Figures 5 and 6) predominately included exudative retinal detachment (72.5% eyes), yellowish-white mid-peripheral subretinal lesions (25% eyes), optic disc oedema (37.5% eyes) and vasculitis (7.5% eyes).

COMPLICATIONS

Chronic inflammation in sympathetic ophthalmia frequently results in various ocular complications that may limit visual recovery. These include secondary glaucoma, cataract, and chronic maculopathy. Delay in diagnosis and inappropriate treatment may at times result in Choroidal neovascularization, optic atrophy, and even phthisis bulbi.51 Sympathetic ophthalmia may present with extraocular manifestations similar

to those observed with Vogt-Koyanagi-Harada disease (VKH), including cerebrospinal fluid pleocytosis, auditory and integumentary disturbances although these findings are relatively rare compared to the VKH disease.52,53

INVESTIGATIONS

Fundus Fluorescein angiography (FFA) and indocyanine green angiography (ICG) are useful adjuncts in establishing the diagnosis of sympathetic ophthalmia. In the acute phase, FFA (Figures 7 and 8) shows multiple hyperfluorescent areas in the dye transit with late leakage. Late staining of the optic nerve head is sometimes observed, even in the absence of clinical papillitis or optic nerve head swelling. Depending on the state of the overlying retinal

pigment epithelium, the Dalen-Fuchs nodules may appear either hyperor hypofluorescent lesions.54,55

Indocyanine green angiography (Figures 9 and 10) shows areas of hypofluorescence during the intermediate phase.56 Two patterns are seen in the late phase; the hypofluorescent lesions may persist as hypofluorescent or fade to isofluorescence. These ICG characteristics are thought to be reflective of active stromal choroidal lesions (granulomas), the lesions which persist as hypofluorescent representing full thickness stromal granulomas while the fading lesions probably represent partial thickness stromal granulomas. These lesions resolve after long-term corticosteroid therapy. The atrophic or cicatricial lesions in sympathetic ophthalmia also appear as persistent hypofluorescent lesions but they differ from the

Figure 3: Residual extensive chorioretinal scarring in a patient with previous episode of sympathetic ophthalmia

hypofluorescent active lesions as they do not respond even to prolonged corticosteroid therapy.

Optical coherence tomography (OCT) is useful in these patients to detect associated cystoid macular oedema and monitor the resolution of exudative retinal detachment in serial follow up examinations at which point systemic corticosteroid tapering can be initiated. B-scan ultrasonography can also be useful to demonstrate the amount of choroidal thickening prior to treatment.57

DIFFERENTIAL DIAGNOSIS

The clinical presentation of sympathetic ophthalmia can be strikingly similar to VKH disease, often making the distinction between the two diagnoses difficult.50

However, a few points are helpful in distinguishing the two entities. First and foremost is that the patients with VKH do not report a prior history of ocular injury or ocular surgery. Secondly, VKH patients usually present with systemic signs and symptoms, such as auditory dysfunction, integumentary changes and meningeal signs, which are very rarely reported with sympathetic ophthalmia. But the question remains whether these two entities can be distinguished histopathologically as the two have same immunogenetic pathogenesis. It is commonly believed that sympathetic ophthalmia classically does not involve the choriocapillaris nor has chorioretinal scarring both of which are common in VKH disease. However, it must be remembered that most of the eyes with sympathetic ophthalmia are removed early in the course of the disease compared to

the VKH disease where eyes are removed late in the course of the disease. In fact, Rao et al have suggested that the only reliable feature that could differentiate sympathetic ophthalmia from VHK disease was the history of a penetrating wound in the former and the absence of such trauma in the latter. 53

Other important differentials which also present as granulomatous panuveitis include sarcoidosis, tuberculosis, infective endophthalmitis and lens induced uveitis. However, most of these entities can be diagnosed based on relevant investigations. Another differential diagnosis that requires consideration is intraocular lymphoma, which can present with vitreal cells and choroidal abnormality. If necessary, a vitreous sample must be obtained for diagnostic purpose.57,58

MANAGEMENT

Enucleation of the injured eye if performed before the onset of sympathetic ophthalmia is known to prevent the onset of the disease. This strategy is believed to be completely effective if performed within two weeks from the penetrating injury.59 However, with the widespread availability of current advanced surgical techniques, this approach is no longer favourable with most surgeons as many eyes previously considered as nonviable may now have a fair prognosis. Moreover, with the decreasing incidence of sympathetic ophthalmia, prophylactic enucleation is no longer advised. The benefit of enucleation of the inciting eye, once the disease process is apparent in the sympathizing eye,

is even more controversial. The reported results range from complete control of inflammation to total absence of benefit.60,61 If it is to be performed, it should be carried out within two weeks of the onset of inflammation. The decision to enucleate a traumatised or an inciting eye should be made very cautiously as the inciting eye may ultimately be the eye with the better vision.

The mainstay of therapy for sympathetic ophthalmia is corticosteroids, which are used as intravenous, oral, topical, and in the form of regional injections.62-66 Oral prednisone is most frequently employed in the treatment of sympathetic ophthalmia and is usually given in the dose of 1 to 2 mg/kg/day. However in case of a very severe inflammatory disease, intravenous