Clinical and immunological features of retinal vasculitis in systemic diseases

Background/Aim. Vasculitis is a clinical, pathologic process characterized by inflammation and necrosis of blood vessel occuring anywhere in the body. The aim of the study was to present some clinical and immunologic features of retinal vasculitis in systemic diseases: systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Behcet’s diseases, and others. Methods. A total of 1 254 peatients with uveitis were included in the study. The immunochemical diagnostic methods were used to determine the pathogenesis of ocular manifestations. Ocular manifestations were examined using biomicroscope, direct or indirect ophtalmoscopy. Results. Primary retinal vasculitis was diagnosed in 85/1254 (6.8%) of total uveitis. In more than half of the cases of vasculitis (58.8%), both arteries and veins were involved in inflammatory process. Periphlebitis was diagnosed far more commonly (36.5%) than periarteritis (4.7%). Retinal vasculitis associated with systemic lupus erythematosus was characterized by microinfarctions and the consequent foci of inflammatory cells or diseases of large arteries manifesting in vasospasm and occlusions. Cotton wool spots occured in 38.3% and retinal hemorrhages in 34% of the cases. In this study periphlebitis of the retina was one of the less frequent ocular manifestations of multiple sclerosis. Comparing with the other changes of the retinal blood vessels, venous sheating occured in 25.1% and occlusion and vein trombosis in 43.75% of the cases. Retinal vasculitis associated with chronic sarcoidosis occured in 37.5% of patients with sarcoidosis. The most frequent manifestation of ocular sarcoidosis was intermediary uveitis (43.75%). Anterior granulomatous uveitis occured in 37.5% of patients with sarcoidoses. Immune complexes occured in 13/20 (65%) of the patients. Antiretinal anti-S antibody in the serum occured in 73% of the patients with retinal detachment as a complication of primary disease and in 25% those with vasculitis. Conclusion. Systemic diseases such as Behcet's syndrome, collagen vascular diseases, systemic granulomatous diseases (sarcoidosis and tuberculosis) were the main causes of retinal vasculitis. Knowledge of the symptomatology and pathogenesis of retinal vasculitis is of the major significance for the diagnosis and therapy of the disease.


Introduction
Vasculitis is a clinical, pathologic process characterized by inflammation and necrosis of blood vessels.It can occur as a primary manifestation of the disease or as a secondary phenomenon.Inflammation may affect vessels of different sizes, in all parts of the body.
Inflammatory changes on the blood vessels were first reported by John Hunten in 1784.Retinal vasculitis was described a hundred years later by Henry Eales in 1880 1 .
Association of retinal vasculitis and uveitis with systemic diseases was widely recognized.To classify vasculitis as caused by retinal autoantigens, vasculitis in the course of systemic diseases, vasculitis caused by infectious agents and, finally, vasculitis induced by degenerative diseases and neoplasms, etiopathogenetic criteria are used 2,3 .
According to the type of the affected vessel vasculitis can be divided into arteritis and periarteritis, phlebitis and periphlebitis and capillaritis, i.e. capillaropathies.According to the size of the vessel affected by inflammation vasculitis can be classified as affecting major, medium blood vessels, arterioles and venules and capillaries.
Localization of inflammation related to the type and size of the affected vessel determines a characteristic clinical finding and symptoms of the disease.
The aim of the study was to present some clinical and immunologic features of retinal vasculitis in systemic diseases.

Methods
A total of 1 254 peatients with uveitis were included in the study.The immunochemical diagnostic methods were used to determine the pathogenesis of ocular manifestations.Ocular manifestations were examined using biomicroscope, direct or indirect ophtalmoscopy.

Results
Retinal vasculitis was examined in 1 254 patients with the uveoretinal inflammation.
Primary evolutive retinal vasculitis was diagnosed in 85 patients (6.8% of the total uveitis) and was the important cause of uveitis complications, namely: cystoid macular edema as the most common, but also partial hemophthalmos, proliferative vitreoretinopathy (PVR) and retinal detachment as the least common but the most serious and potentially devastating to the eye.In more than a half of the cases of vasculitis (58.8%) both arteries and veins were involved in the inflammatory process (Table 1).Periphlebitis was diagnosed far more commonly (36.5%) than periarteritis (4.7%).
Systemic diseases such as Behcet's syndrome, collagen vascular diseases, systemic granulomatous diseases (sarcoidosis and tuberculosis) and others were the main causes of retinal vasculitis.
Retinal vasculitis associated with periarteritis nodes manifested by changes on tiny arteries.The disease was localized in arteries in several organs and systems.The basis of the disease was fibrinoid necrosis of the blood vessel wall.Changes in the eye fundus were localized only in the tiny retinal arteries and choriocapillaries and may lead to segmental occlusion of the choriocapillaries.
Immune complexes occured in 65%, rheumatoid factor (RF) in 40%, C-reactive protein (CRP) in 30%, and antinuclear antibodies in 15% of the patients (Table 2), but complement activity was normal in the serum of patients.The results of the antiretinal anti-S antigen antibody analyzing in the serum of 105 patients are shown in Table 3. Antiretinal anti-S antibody in the serum occured in 73% of the patients with retinal detachment, in 60% of the patients with neurouveitis, in 56% of the patients with choriocapillaritis and in 25% of the patients with vasculitis.Retinal vasculitis associated with SLE was characterized by micro infarctions and the consequent foci of inflammatory cells or diseases of large arteries manifesting in vasospasm and occlusions.
Narrowing of the arterioles leads to hypoxia of the retinal tissue and lesions of the endothelial cells of both capillaries and veins.Absence of perfusion or peripheral vessels lesions may result in neovascularisation either of the disc or the retinal periphery.The most frequent manifestations in SLE were cotton wool spots in 38.3%, retinal hemorrhages in 34% and retinal microaneurismus in 29.9% of the cases.
Findings in the retina of seventy-one patients with systemic lupus erythematosus are presented in Table 4.
Ophtalmocopic finding of retinal vascluitis in the SLE is shows in Figure 1.
Retinal vasculitis was examined in 42 patients with multiple sclerosis.5).
Periphlebitis of the retina in multiple sclerosis is presented in Figure 2.
Ocular manifestations in chronic sarcoidosis were examined in 16 of the patients (Table 6).The major change in sarcoidosis was the occurrence of non-caseating granulomas in hilar glands.
Retinal vasculitis occured in 37.5% of the patients with sarcoidosis.

Fig. 2 -Periphlebitis of the retina in multiple sclerosis
Vasculitis in sarcoidosis was multifocal periphlebitis.It was usually associated with snow-balls on the hyaloid membrane and basal exudates.Intermediary uveitis was the most frequent clinical form of uveitis associated with sarcoidosis (43.75).In addition, inflammation of the conjunctiva, iris, ciliary body and orbital tissues may occur.Anterior granulomatous uveitis occured in 37.5% of the cases.
Figure 3 shows a case of an anterior granulomatous uveitis.

Fig. 3 -Anterior granulomatous uveitis
Retinal vasculitis associated with Behcet's disease was localized on the retinal arteries and veins.The veins were more commonly affected.As a consequence of phlebitis on the retinal periphery, cystoid macular edema developed, while atrophy of the disc may occur due to inflammation and occlusion of the retinal arteries.Cystic macular edema and the disc atrophy were the most common causes of vision impairment in these patients (Figure 4).

Fig. 4 -Cystic macular edema in the Behcet syndrome Discussion
In this study the clinical and immunological characteristics of retinal vasculitis in the course of systemic diseases were presented.
Vasculitis includes a wide range of heterogeneous disorders in which specific vessels in the body are the target of an abnormal immune response causing pathological changes.Necrosis of the vascular endothelium layers leads to destruction and occlusion of vessels with subsequent poor perfusion and ischemia of the end organ.Due to that, clinical features of vasculitis vary immensely depending on the site, type, size and distribution of the vessels involved by the inflammatory response 1,2 .In most cases vasculitis is caused by inflammatory reaction mediated by immune responses directed against antigens present in the vessel structures.Immunopathology of vasculitis can be explained by immune responses (types I-III).
Eye examination is important for the diagnosis and treatment of systemic vasculitis [3][4][5] .Systemic vasculitis is manifested by diseases of retinal blood vessels accompanied either by inflammation of retinal arteries or veins in the course of Behcet's syndrome, SLE, periarteritis nodosa and other [6][7][8] .
The diseases of the connective tissue such as collagenosis are more frequent systemic diseases manifesting by changes in the eyes.Approximatley 30% of SLE patients demonstrate ocular manifestations.Keratoconjunctivitis sicca is the most common ophthalmic manifestation occurring in approximately 25% of SLE patients.Retinal vasculitis is observed in approximately 5% of SLE patients 9 .In this study, findings of 71 patients retina in the patients with SLE showed retinal hemorrhages (34%), cotton wool spots (38.3%) and retinal microaneurismus (29.9%).
There is a well-established association of acute optic neuritis with demyelinating disease.Acute optic neuritis usually presents with the patient experiencing monocular loss of central vision, commonly associated with pain in, around, or behind the eye.
The majority of patients who develop multiple sclerosis after an attack of optic neuritis do so within 7 years of the onset of visual symptoms 10 .
Visual impairment eventually occurs in at least 80% of patients with multiple sclerosis and may be the presenting symptom in up to 50% of patients with multiple sclerosis 10 .
Sheathing of retinal veins (periphlebitis) is often seen in multiple sclerosis patients.The sheathing may present as focal, hazy gray patches that obscure the blood column in the vein.In other patients, sheathing may appear as fine, white, linear streaks that parallel the blood column 6 .In this study periphlebitis of the retina is one of the less frequent ocular manifestations of multiple sclerosis.Comparing with other changes of the retinal blood vessels, venous sheating occurs in 25.1% and occlusion and vein thrombosis in 43.75% of the patients.
Systemic granulomatouses such as sarcoidosis are manifested by changes in the eyes in the form of granuloma associated with inflammations of all parts of the eye 5  though a frequency of 20 to 25% is most often cited.The reported frequency of specific types of ocular manifestations are quite variable; however, the most common finding is anterior granulomatous uveitis, occurring in 50 to 85% of patients with ocular involvement.Posterior segment lesions of the choroid and retina may occur in 25%, and optic nerve involvement in as few as 5% of the patients.Sarcoidosis of the skin of the eyelid has been variably reported as occurring in 12 to 27%, and conjunctival granulomas in 44 to 56% of the patients.Keratoconjunctivitis sicca, secondary to lacrimal gland involvement, has been reported in as few as 4% and as many as 66% of the patients 4 .
In this study vasculitis in sarcoidosis was multifocal periphlebitis (37.5%).It was usually associated with snowballs on the hyaloids membrane and basal exudates.Intermediary uveitis was the most frequent clinical form of uveitis associated with sarcoidosis (43.75%).In addition, inflammation of the conjunctiva, iris, ciliary body and orbital tissues may occur.Anterior granulomatous uveitis occured in 37.5% of our patients with sarcoidosis.
Immunological investigations were performed in 20 patients with systemic vasculitis.Immune complexes occured in 65% of these patients.

Conclusion
Systemic diseases such as Behcet's syndrome, collagen vascular diseases, systemic granulomatous diseases (sarcoidosis and tuberculosis) were the main cuses of retinal vasculitis.Knowledge of the symptomatology and pathogenesis of retinal vaculitis is of the major singificance for the diagnosis and therapy of the disease.

Fig. 1 -
Fig. 1 -Retinal vasculitis in the systemic lupus erythematousPeriphlebitis of the retina was one of the less frequent ocular manifestations of multiple sclerosis.The retinal vasculitis consists of peripheral venous sheathing, vitritis and macular edema.The different changes of the retinal blood vessels in forty-two patients with multiple slerosis were proved (Table5).Periphlebitis of the retina in multiple sclerosis is presented in Figure2.Ocular manifestations in chronic sarcoidosis were examined in 16 of the patients (Table6).The major change in sarcoidosis was the occurrence of non-caseating granulomas in hilar glands.Retinal vasculitis occured in 37.5% of the patients with sarcoidosis.