908
Journal of the Royal Society of Medicine Volume 72 December 1979
Retinal vasculitis: a review' M D Sanders FRCP FRCS The National Hospitals for Nervous Diseases Queen Square, London WCIN 3BG
Retinal vasculitis is in no sense a disease entity but a nonspecific clinical manifestation of many infective and perhaps toxic states (Duke-Elder & Dobree 1967). In view of the controversy and disparity of views on the terminology of vasculitis, it is perhaps worth considering first some historical factors that have contributed to our present terminology. In the year 1880 the Birmingham ophthalmologist Henry Eales published a paper 'Retinal Haemorrhage associated with Epistaxis and Constipation'. The typical features were shown in four patients who were young men, all of whom had constipation and all of whom had symptoms of what Eales described as high arterial tension, which included a slow pulse rate and accentuation of the sounds of the heart. In a personally written postscript to his paper sent with compliments to one of his colleagues in London he indicated that the existence of high arterial tension was not confirmed in any patient by sphygmomanometry. Though it is difficult retrospectively to come to any convincing diagnosis about these patients, the fact that the retinal veins were dilated in all the patients, with no mention of neovascularization, suggests this may be part of a venous occlusive process. Since Eales' description there have been many reports suggesting an inflammatory aetiology, either tuberculous (Gilbert 1935) or due to sarcoidosis (Ashton 1962, Sanders 1978). In 1961 Lyle & Wybar described a series of cases which they considered demonstrated a central form of retinal vasculitis. They described 6 cases with unilateral involvement and a clinical picture consisting of haemorrhages, disc swelling, macular oedema and marked dilatation of the retinal veins. Most of the patients were fit, healthy adults though one patient had active pulmonary tuberculosis. They considered this was a form of retinal vasculitis because one patient had peripheral vessel changes which seemed consistent with the disease described by Eales. A further paper in 1966 by Lonn & Hoyt suggested that papillophlebitis seemed a preferable term, and Hart et al. (1971) suggested that this was primarily a haematological or rheological disorder. The subject of retinal and papillary vasculitis was reviewed by Cogan (1969) in the William McKenzie lecture and he described 12 cases of vasculitis in whom a number had vasculitis secondary to inflammatory disease and this included herpes simplex, herpes zoster, mycotic infection, toxacara, syphilis and meningitis. In all these cases there was other systemic evidence of disease. He also described 4 cases in which the predominant involvement was within the eye. One patient was thought to have a demyelinating condition, another a granulomatous angiitis, and the remaining two showed no specific cause but the visual loss came on after a sore throat in one patient, and following an ill-defined febrile episode in a second. This brief historical review indicates some of the problems in accurate terminology because, of the clinical cases described, few have included any pathological information and similarly those with pathological examination have not been adequately clinically documented. There is a major need, therefore, for a precise and close clinicopathological correlation of future patients with well-defined vasculitis. The difficulty of obtaining retinal vessels for microscopic study may be overcome on occasion by the necessity for either a renal or cutaneous biopsy. The need therefore arises to define the ophthalmological entity, to investigate fully the 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 28 March 1978. Accepted 9 June 1978, updated 24 August 1979
0141-0768/79/120908-08/$01.00/0
,'-.
1979 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 72 December 1979
909
immunological and haematological status of the patient and, if possible, to obtain thorough clinicopathological correlation. Definition of retinal vasculitis Evidence for inflammatory ocular disease: Biomicroscopy of the media of the eye and examination of the retinal vessels by direct/indirect ophthalmoloscopy and fluorescein angiography enables one to differentiate with some degree of accuracy the retinal conditions which are inflammatory in nature and those which are due to a vascular cause. Inflammatory conditions usually produce cells in the anterior chamber, vitreous or pars plana and there is leakage of dye in relation to arteries, veins and capillaries on fluorescein angiography. There is an area, however, in which precise differentiation can be difficult. Signs ofa systemic disease: The systemic process may be primarily inflammatory, necessitating active exclusion of bacterial, viral and other infective agents. Modem diagnostic techniques have also defined the immu'nological basis of many previously recognized disorders, and the demonstration of immunological changes in other tissues of the body strongly suggests that the ocular changes are due to similar mechanisms. A further potential basis for the classification of retinal vasculitis is to categorize involvement of the arteries, capillaries or veins. In this paper I would like to try and demonstrate that both these classifications may be used together and I would like to indicate some of the major forms of arterial, venous and capillary disease which are associated with a well-defined systemic entity. It is also important for ophthalmologists to realize that the recent improvement of the understanding of rheological and immunological disorders may necessitate a radical change in our preconceived ideas of the morphological appearances of retinal vasculitis. Retinal arteritis The development of haemoptysis, anaemia and proteinuria in a patient with pathological examination led Goodpasture (1919) to describe the first patient of a syndrome that bears his name. The main feature of Goodpasture's syndrome is deposition of the immunoglobulin IgG in a linear pattern on the basement membrane of the kidney, lung and other vessels. Ocular changes were described in this disease by Jampol et al. (1975) and they showed linear IgG deposition in Bruch's membrane and the basement membranes of the choroidal vessels. A patient with Goodpasture's syndrome was admitted to St Thomas' Hospital under the care of Dr Brian Creamer with multiple retinal micro-infarcts in both eyes (Figure 1). Examination of the renal glomerulus showed linear deposition of IgG, and in the absence of any rheological cause for the micro-infarction it is likely this is also due to linear deposition of
Figure 1. Goodpasture's syndrome. Right fundus showing retinal micro-infarcts and superficial haemorrhages
910
Journal of the Royal Society of Medicine Volume 72 December 1979
IgG within the retinal precapillary arterioles. This patient demonstrates the correlation between renal disease and retinal disease, but also emphasizes the importance of searching for an immunological basis for retinal ischaemic disease.
Systemic lupus erythematosus Recent advances in the understanding of lupus erythematosus are derived from immunological studies which show that the SLE cell is an IgG antibody to native DNA tissue. These antibodies are often found and marker bodies such as the antibody to SM antigen has been reported. Retinal changes have been described in about 25% of cases of SLE (Balantyne & Michaelson 1970). The retinal vascular changes may, as in many of the immunological conditions that affect the microcirculation, be produced by different mechanisms. These include: (1) associated hypertension; (2) embolization from Libman-Sacks endocarditis; (3) retinal vasculitis. Examples of the changes seen with fluorescein angiography in a normotensive patient with haematologically confirmed SLE with cutaneous and joint manifestations but without any cardiac lesions are demonstrated (Figure 2). There is attenuation of the retinal arteriole in an area of reduced perfusion and leakage of dye in the late pictures from the arterioles, veins and capillaries. It is possible to speculate that the primary event lay in the arteriole with secondary hypoxic damage to endothelial cells in the capillaries and veins. The arteriolar disease may become so severe in some cases that there is nonperfusion of large segments of retina and this may induce the development of new vessels either at the disc or in the periphery. These vessels have a propensity to bleed and produce either retinal or vitreous haemorrhages.
Figure 2. Systemic lupus erythematosus. Fluorescein angiograms of upper temporal quadrant to show arterial occlusions with reduced retinal perfusion in 1975 (LEFT) and the same region in 1976 (RIGHT) when compensatory changes have occurred
Venous disease Behget's disease consists of a triad of relapsing iritis, oral ulceration and genital ulceration. It was first described in 1908 by Bluthe and ocular signs are common (Chajek & Fainaru 1975). Beh9et's disease produces interesting ocular features which include the rapid onset of a pan uveitis and it is one of the few conditions that produces hypopyon formation. Involvement of both the anterior and posterior segment occurs and in untreated cases blindness ensues due to inflammation of the macula, the retinal and choroidal vessels. These changes are due to vasculitis accompanied by fibrinoid necrosis, exudation and cellular inifitration (Shikano 1966). The immunological basis of Behget's disease has received major study over the past few years and there is increasing evidence for an immunological disorder associated with
Journal of the Royal Society of Medicine Volume 72 December 1979
911
circulating immune complexes (Williams & Lehner 1977). Visual loss occurs in up to threequarters of patients and in the early stages visual acuity is critically dose dependent. Fluorescein angiographic studies in Beh9et's disease show that the major retinal changes occur on the venous side with leakage from both small and large veins. Leakage is initially in the peripheral vessels but also involves the central vessels to produce macular oedema. Characteristic changes are seen in a patient with a 4-year history of Beh9et's disease whose condition has been well controlled with careful manipulation of steroids, azathioprine and levamisole (Figure 3).
Figure 3. Behqet's disease. Fluorescein angiograms of temporal periphery of right eye with leakage from capillaries, venules and veins (LEFT), and resolution after 3 months with treatment consisting of steroids, azathioprine and levamisole (RIGHT)
A severe example is shown in the only remaining eye of a 33-year-old man with a 5-year history of undiagnosed Behget's disease (Figure 4). The right eye had no perception of light due to thrombotic glaucoma secondary to Beh9et's disease and his remaining left eye demonstrated vision of 6/36. There is diffuse leakage from the retinal vessels, all of which are dilated, and above the macular there is an area of retinal infiltration and inflammation.
Figure 4. Behqet's disease - response to treatment. Fluorescein angiograms of left eye (vision 6/36), with extensive infiltration, nonperfusion and dilatation of retinal vessels (LEFr). One month later (RIGHT) vision is 6/12 and marked resolution of retinal inflammatory lesion and vascular changes area of retinal
912
Journal of the Royal Society of Medicine Volume 72 December 1979
Within one month, with the use of high dose steroids and azathioprine, his vision had improved to 6/12 and the retinal vascular changes had remarkably diminished. In a recent review of 15 patients with ocular Behcet's disease it has been evident that there has been a high incidence of HLA B5 in the patients with ocular involvement (Sanders 1979). These figures correspond with reports on HLA typing in ethnic groups from other parts of the world. Sarcoidosis Sarcoidosis is thought to produce mainly an anterior uveitis though the ocular signs are diffuse and involve the conjunctiva, the lacrimal gland and the orbit. Recently emphasis has been placed on the degree of involvement of the posterior fundus and Sanders & Shilling (1976) classified posterior pole sarcoid into four groups: (1) focal retinal periphiebitis; (2) venous occlusive disorder; (3) acute retinopathy; (4) late-stage neovascularization with vitreous haemorrhage. The frequency of venous involvement in sarcoidosis is important because this condition in other parts of the body tends to involve the lymphoreticular system and particularly the lymph glands. The absence of lymphoid tissue within the eye probably results in the formation of sarcoid granuloma in relation to the veins, and this has been confirmed histologically. Sarcoidosis appears to be one of the few conditions that produces a focal periphlebitis and therefore recognition of this is an important diagnostic finding. Attempts have been made to differentiate granulomatous angiitis which affects arteries and veins usually in the CNS with vascular necrosis and giant cell granulomas, from sarcoidosis in which the lesions are mainly extravascular, multisystem and free from necrosis (Kolodny et al. 1968). Several cases with sarcoidosis, however, have been shown to produce vascular damage, so it is probable that the two groups cannot be satisfactorily separated. It is interesting that in some patients with sarcoidosis, focal arterial occlusion as evidenced by cotton wool spots is seen in the retina and this suggests that occasionally the granulomatous response may be periarteriolar. Multiple areas of focal periphlebitis are demonstrated in a patient with other neurological signs of sarcoidosis, a positive Kveim test and hilar lymph adenopathy (Figure 5). The response to steroids was dramatic and confirms the rapid resolution of granulomatous lesions to steroid therapy. Experimental evidence has also been produced to demonstrate improvement in the endothelial cell function after steroid administration (Kitchens 1977). The immunological studies performed on patients with sarcoidosis suggest a relative deficiency of cell-mediated immunity with a general hyperreactivity of humoral immunity.
Figure 5. Sarcoidosis. Focal periphlebitis shown by fluorescein angiography in right eye (LEFT) with marked resolution after high dose steroid therapy (RIGHT)
Journal of the Royal Society of Medicine Volume 72 December 1979
913
Diffuse capillary involvement There are some conditions in which the retinal changes are seen as diffuse capillary involvement, which is represented on fluorescein angiography as dilation of the capillaries over the whole posterior pole, with diffuse leakage of dye from all the vessels. Experimental work has shown abnormalities in certain lymphocytes which may damage endothelial cell function and some mechanism of this nature may be postulated in these conditions. This diffuse capillary deficiency may be seen in either specific (ankylosing spondylitis) or nonspecific forms of uveitis and it may also be seen in certain immunological disorders where interaction between the endothelial cells and the leukocytes is presumably abnormal (e.g. Whipple's disease, Figure 6).
,i,~~~~':.
_
Figure 6. Whipple's disease. Diffuse capillary leakage from retinal capillaries over the whole posterior pole in a patient with histologically proven Whipple's disease
Retinal vasculitis of unknown aetiology The central retinal vasculitis described by Lyle & Wybar (1961), which occurs in healthy young adults usually with unilateral involvement, continues to defy accurate aetiological definition. One recent 18-year-old girl, with unilateral central vasculitis and visual deterioration, was found to have abnormalities of the fibrinolytic system and appeared to be responsive to fibrinolytic therapy. Further investigations on these patients with the sophisticated haematological and rheological tests now available should provide further understanding and possible therapy. Similarly, there are young patients with retinal arteritis which may produce severe bilateral visual loss and elude diagnosis despite intensive investigation. An 18-year-old boy presented with bilateral visual loss and was referred to Mr Geoffrey Davies at King's College Hospital. The main involvement was in the retinal arteries and the fluorescein angiograms showed bilateral local retinal arterial lesions (Figure 7).. Despite intensive treatment with steroids, the deterioration of vision could not be alleviated. Retinal vasculitis occurring in other parts of the body is susceptible to biopsy and immunofluorescent study of the vessel walls. Renal involvement is usually arterial, either of the major renal artery or interlobular arterioles. In the skin, however, when cutaneous vasculitis is associated with immune complexes, the predominant involvement appears to be on the venous side rather than on the arterial. It may therefore be unique that in the eye we are able to localize retinal inflammatory disease to the arteries, the veins or the capillaries and this may be of value diagnostically.
914
Journal of the Royal Society of Medicine Volume 72 December 1979
Figure 7. Idiopathic retinal arteritis. Irregular and tortuous retinal arterioles, with associated macular lesions in both eyes of an 18-year-old boy with progressive visual loss; right eye (LEFr), left eye (RIGHT)
The present paper illustrates patterns of involvement of the arteries in lupus erythematosus, of the veins in Behget's disease and sarcoidosis, and capillary involvement in certain other conditions. Thus in all cases of vasculitis, precise criteria are needed for the ophthalmic diagnosis, and ocular inflammatory disease and systemic vascular diseases have to be excluded. Occurrence of systemic vasculitis following viral infections has been well described (e.g. hepatitis B, Sergent et al. 1976), so that the separation of primary inflammatory disease from a primary immunological disease may be difficult. It may also be important in the presence of unexplained retinal vascular disease to investigate patients immunologically. The retinal morphological appearances of immune complex diseases have not yet been fully documented and interesting speculation arises about the size and characteristics of circulating immune complexes. Immune complexes have been found in retinal vasculitis by Andrews et al. (1977) and they examined 17 patients with retinal vasculitis, 11 with the peripheral type of disease and 6 with central involvement. A systemic disease process was identified in 6 patients. They performed a series of tests searching for immune complexes and these were suggested by the presence of complement activation rheumatoid factor, CLQ or monoclonal rheumatoid factor precipitins, anticomplementary activity, elevated cryoglobulins and inhibition of erythrocyte antibody rosette formation. They also assessed increased numbers of peripheral blood lymphocytes bearing IgG and spontaneous neutrophil chemotactic activity in plasma. In 13 of the 17 cases, two or more parameters were elevated and they found that chemotactic activity and inhibition of EA rosette formation were the most frequent positive tests. Rheological studies with particular emphasis on fibrinolytic activity and platelet aggregation may also be indicated in the group to evaluate flow factors which contribute to retinal vascular changes. There is therefore a need for a major study of this type to place retinal vasculitis on a secure base with recognizable morphological characters which may provide diagnostic, therapeutic and prognostic information.
References Andrews B S, McIntosh J, Pett V & Penny R (1977) Clinical and Experimental Immunology 29, 23-29 Ashton N (1962) XIX Concilium Ophthalmologicum 11, 828 Balantyne A J & Michaelson I C (1970) Textbook of the Fundus of the Eye. E & S Livingstone, Edinburgh Bluthe L (1908) Inaugural Thesis, Heidelberg University Chajek T & Fainaru M (1975) Medicine 54, 179 Cogan D G (1969) William McKenzie Centenary Symposium on the Ocular Circulation in Health and Disease. Ed. J S Cant. Kimpton, London; pp 249-270
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Duke-Elder S & Dobree J H (1967) System of Ophthalmology, vol X: Diseases of the Retina. Kimpton, London Eales H (1880) Birmingham Medical Review 9, 262 Gilbert W (1935) Klinische Monatsblatter fur Augenheilkunde 94, 335 Goodpasture E W (1919) American Journal of the Medical Sciences 158, 863 Hart C D, Sanders M D & Miller S J H (1971) British Journal of Ophthalmology 55, 721 Jampol L M, Lahar M, Albert D M & Graft J (1975) American Journal of Ophthalmology 79, 452 Kitchens C S (1977) Journal of Clinical Investigation 60, 1129 Kolodny E H, Rebeiz J J, Caviness V S & Richardson E P (1968) Archives of Neurology (Chicago) 19, 510-524 Lonn L & Hoyt W F (1966) ENT monthly 45, 62 Lyle T K & Wybar K (1961) British Journal of Ophthalmology 45, 778 Sanders M D (1978) 5th Congress of the European Society of Ophthalmology. Ed. J Franqois. Ferdinande Enke Verlag, Stuttgart; pp 239-246 Sanders M D (1979) In: Behqet's Disease. Ed. T Lehner and C E Barnes. Academic Press, London (in press) Sanders M D & Shilling J S (1976) Transactions of the Ophthalmological Societies of the United Kingdom 96, 140 Sergent J S, Lockshin M I) Christian C L & Gocke D J (1976) Medicine 55, 1-18 Shikano S (1966) International Symposium on Behqet's Disease, Rome 1965. Karger, Basel & New York; p 111 Williams B D & Lehner T (1977) British Medical Journal i, 1387
Journal of the Royal Society of Medicine Volume 72 December 1979
Retinal vasculitis: a review' M D Sanders FRCP FRCS The National Hospitals for Nervous Diseases Queen Square, London WCIN 3BG
Retinal vasculitis is in no sense a disease entity but a nonspecific clinical manifestation of many infective and perhaps toxic states (Duke-Elder & Dobree 1967). In view of the controversy and disparity of views on the terminology of vasculitis, it is perhaps worth considering first some historical factors that have contributed to our present terminology. In the year 1880 the Birmingham ophthalmologist Henry Eales published a paper 'Retinal Haemorrhage associated with Epistaxis and Constipation'. The typical features were shown in four patients who were young men, all of whom had constipation and all of whom had symptoms of what Eales described as high arterial tension, which included a slow pulse rate and accentuation of the sounds of the heart. In a personally written postscript to his paper sent with compliments to one of his colleagues in London he indicated that the existence of high arterial tension was not confirmed in any patient by sphygmomanometry. Though it is difficult retrospectively to come to any convincing diagnosis about these patients, the fact that the retinal veins were dilated in all the patients, with no mention of neovascularization, suggests this may be part of a venous occlusive process. Since Eales' description there have been many reports suggesting an inflammatory aetiology, either tuberculous (Gilbert 1935) or due to sarcoidosis (Ashton 1962, Sanders 1978). In 1961 Lyle & Wybar described a series of cases which they considered demonstrated a central form of retinal vasculitis. They described 6 cases with unilateral involvement and a clinical picture consisting of haemorrhages, disc swelling, macular oedema and marked dilatation of the retinal veins. Most of the patients were fit, healthy adults though one patient had active pulmonary tuberculosis. They considered this was a form of retinal vasculitis because one patient had peripheral vessel changes which seemed consistent with the disease described by Eales. A further paper in 1966 by Lonn & Hoyt suggested that papillophlebitis seemed a preferable term, and Hart et al. (1971) suggested that this was primarily a haematological or rheological disorder. The subject of retinal and papillary vasculitis was reviewed by Cogan (1969) in the William McKenzie lecture and he described 12 cases of vasculitis in whom a number had vasculitis secondary to inflammatory disease and this included herpes simplex, herpes zoster, mycotic infection, toxacara, syphilis and meningitis. In all these cases there was other systemic evidence of disease. He also described 4 cases in which the predominant involvement was within the eye. One patient was thought to have a demyelinating condition, another a granulomatous angiitis, and the remaining two showed no specific cause but the visual loss came on after a sore throat in one patient, and following an ill-defined febrile episode in a second. This brief historical review indicates some of the problems in accurate terminology because, of the clinical cases described, few have included any pathological information and similarly those with pathological examination have not been adequately clinically documented. There is a major need, therefore, for a precise and close clinicopathological correlation of future patients with well-defined vasculitis. The difficulty of obtaining retinal vessels for microscopic study may be overcome on occasion by the necessity for either a renal or cutaneous biopsy. The need therefore arises to define the ophthalmological entity, to investigate fully the 1 Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 28 March 1978. Accepted 9 June 1978, updated 24 August 1979
0141-0768/79/120908-08/$01.00/0
,'-.
1979 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 72 December 1979
909
immunological and haematological status of the patient and, if possible, to obtain thorough clinicopathological correlation. Definition of retinal vasculitis Evidence for inflammatory ocular disease: Biomicroscopy of the media of the eye and examination of the retinal vessels by direct/indirect ophthalmoloscopy and fluorescein angiography enables one to differentiate with some degree of accuracy the retinal conditions which are inflammatory in nature and those which are due to a vascular cause. Inflammatory conditions usually produce cells in the anterior chamber, vitreous or pars plana and there is leakage of dye in relation to arteries, veins and capillaries on fluorescein angiography. There is an area, however, in which precise differentiation can be difficult. Signs ofa systemic disease: The systemic process may be primarily inflammatory, necessitating active exclusion of bacterial, viral and other infective agents. Modem diagnostic techniques have also defined the immu'nological basis of many previously recognized disorders, and the demonstration of immunological changes in other tissues of the body strongly suggests that the ocular changes are due to similar mechanisms. A further potential basis for the classification of retinal vasculitis is to categorize involvement of the arteries, capillaries or veins. In this paper I would like to try and demonstrate that both these classifications may be used together and I would like to indicate some of the major forms of arterial, venous and capillary disease which are associated with a well-defined systemic entity. It is also important for ophthalmologists to realize that the recent improvement of the understanding of rheological and immunological disorders may necessitate a radical change in our preconceived ideas of the morphological appearances of retinal vasculitis. Retinal arteritis The development of haemoptysis, anaemia and proteinuria in a patient with pathological examination led Goodpasture (1919) to describe the first patient of a syndrome that bears his name. The main feature of Goodpasture's syndrome is deposition of the immunoglobulin IgG in a linear pattern on the basement membrane of the kidney, lung and other vessels. Ocular changes were described in this disease by Jampol et al. (1975) and they showed linear IgG deposition in Bruch's membrane and the basement membranes of the choroidal vessels. A patient with Goodpasture's syndrome was admitted to St Thomas' Hospital under the care of Dr Brian Creamer with multiple retinal micro-infarcts in both eyes (Figure 1). Examination of the renal glomerulus showed linear deposition of IgG, and in the absence of any rheological cause for the micro-infarction it is likely this is also due to linear deposition of
Figure 1. Goodpasture's syndrome. Right fundus showing retinal micro-infarcts and superficial haemorrhages
910
Journal of the Royal Society of Medicine Volume 72 December 1979
IgG within the retinal precapillary arterioles. This patient demonstrates the correlation between renal disease and retinal disease, but also emphasizes the importance of searching for an immunological basis for retinal ischaemic disease.
Systemic lupus erythematosus Recent advances in the understanding of lupus erythematosus are derived from immunological studies which show that the SLE cell is an IgG antibody to native DNA tissue. These antibodies are often found and marker bodies such as the antibody to SM antigen has been reported. Retinal changes have been described in about 25% of cases of SLE (Balantyne & Michaelson 1970). The retinal vascular changes may, as in many of the immunological conditions that affect the microcirculation, be produced by different mechanisms. These include: (1) associated hypertension; (2) embolization from Libman-Sacks endocarditis; (3) retinal vasculitis. Examples of the changes seen with fluorescein angiography in a normotensive patient with haematologically confirmed SLE with cutaneous and joint manifestations but without any cardiac lesions are demonstrated (Figure 2). There is attenuation of the retinal arteriole in an area of reduced perfusion and leakage of dye in the late pictures from the arterioles, veins and capillaries. It is possible to speculate that the primary event lay in the arteriole with secondary hypoxic damage to endothelial cells in the capillaries and veins. The arteriolar disease may become so severe in some cases that there is nonperfusion of large segments of retina and this may induce the development of new vessels either at the disc or in the periphery. These vessels have a propensity to bleed and produce either retinal or vitreous haemorrhages.
Figure 2. Systemic lupus erythematosus. Fluorescein angiograms of upper temporal quadrant to show arterial occlusions with reduced retinal perfusion in 1975 (LEFT) and the same region in 1976 (RIGHT) when compensatory changes have occurred
Venous disease Behget's disease consists of a triad of relapsing iritis, oral ulceration and genital ulceration. It was first described in 1908 by Bluthe and ocular signs are common (Chajek & Fainaru 1975). Beh9et's disease produces interesting ocular features which include the rapid onset of a pan uveitis and it is one of the few conditions that produces hypopyon formation. Involvement of both the anterior and posterior segment occurs and in untreated cases blindness ensues due to inflammation of the macula, the retinal and choroidal vessels. These changes are due to vasculitis accompanied by fibrinoid necrosis, exudation and cellular inifitration (Shikano 1966). The immunological basis of Behget's disease has received major study over the past few years and there is increasing evidence for an immunological disorder associated with
Journal of the Royal Society of Medicine Volume 72 December 1979
911
circulating immune complexes (Williams & Lehner 1977). Visual loss occurs in up to threequarters of patients and in the early stages visual acuity is critically dose dependent. Fluorescein angiographic studies in Beh9et's disease show that the major retinal changes occur on the venous side with leakage from both small and large veins. Leakage is initially in the peripheral vessels but also involves the central vessels to produce macular oedema. Characteristic changes are seen in a patient with a 4-year history of Beh9et's disease whose condition has been well controlled with careful manipulation of steroids, azathioprine and levamisole (Figure 3).
Figure 3. Behqet's disease. Fluorescein angiograms of temporal periphery of right eye with leakage from capillaries, venules and veins (LEFT), and resolution after 3 months with treatment consisting of steroids, azathioprine and levamisole (RIGHT)
A severe example is shown in the only remaining eye of a 33-year-old man with a 5-year history of undiagnosed Behget's disease (Figure 4). The right eye had no perception of light due to thrombotic glaucoma secondary to Beh9et's disease and his remaining left eye demonstrated vision of 6/36. There is diffuse leakage from the retinal vessels, all of which are dilated, and above the macular there is an area of retinal infiltration and inflammation.
Figure 4. Behqet's disease - response to treatment. Fluorescein angiograms of left eye (vision 6/36), with extensive infiltration, nonperfusion and dilatation of retinal vessels (LEFr). One month later (RIGHT) vision is 6/12 and marked resolution of retinal inflammatory lesion and vascular changes area of retinal
912
Journal of the Royal Society of Medicine Volume 72 December 1979
Within one month, with the use of high dose steroids and azathioprine, his vision had improved to 6/12 and the retinal vascular changes had remarkably diminished. In a recent review of 15 patients with ocular Behcet's disease it has been evident that there has been a high incidence of HLA B5 in the patients with ocular involvement (Sanders 1979). These figures correspond with reports on HLA typing in ethnic groups from other parts of the world. Sarcoidosis Sarcoidosis is thought to produce mainly an anterior uveitis though the ocular signs are diffuse and involve the conjunctiva, the lacrimal gland and the orbit. Recently emphasis has been placed on the degree of involvement of the posterior fundus and Sanders & Shilling (1976) classified posterior pole sarcoid into four groups: (1) focal retinal periphiebitis; (2) venous occlusive disorder; (3) acute retinopathy; (4) late-stage neovascularization with vitreous haemorrhage. The frequency of venous involvement in sarcoidosis is important because this condition in other parts of the body tends to involve the lymphoreticular system and particularly the lymph glands. The absence of lymphoid tissue within the eye probably results in the formation of sarcoid granuloma in relation to the veins, and this has been confirmed histologically. Sarcoidosis appears to be one of the few conditions that produces a focal periphlebitis and therefore recognition of this is an important diagnostic finding. Attempts have been made to differentiate granulomatous angiitis which affects arteries and veins usually in the CNS with vascular necrosis and giant cell granulomas, from sarcoidosis in which the lesions are mainly extravascular, multisystem and free from necrosis (Kolodny et al. 1968). Several cases with sarcoidosis, however, have been shown to produce vascular damage, so it is probable that the two groups cannot be satisfactorily separated. It is interesting that in some patients with sarcoidosis, focal arterial occlusion as evidenced by cotton wool spots is seen in the retina and this suggests that occasionally the granulomatous response may be periarteriolar. Multiple areas of focal periphlebitis are demonstrated in a patient with other neurological signs of sarcoidosis, a positive Kveim test and hilar lymph adenopathy (Figure 5). The response to steroids was dramatic and confirms the rapid resolution of granulomatous lesions to steroid therapy. Experimental evidence has also been produced to demonstrate improvement in the endothelial cell function after steroid administration (Kitchens 1977). The immunological studies performed on patients with sarcoidosis suggest a relative deficiency of cell-mediated immunity with a general hyperreactivity of humoral immunity.
Figure 5. Sarcoidosis. Focal periphlebitis shown by fluorescein angiography in right eye (LEFT) with marked resolution after high dose steroid therapy (RIGHT)
Journal of the Royal Society of Medicine Volume 72 December 1979
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Diffuse capillary involvement There are some conditions in which the retinal changes are seen as diffuse capillary involvement, which is represented on fluorescein angiography as dilation of the capillaries over the whole posterior pole, with diffuse leakage of dye from all the vessels. Experimental work has shown abnormalities in certain lymphocytes which may damage endothelial cell function and some mechanism of this nature may be postulated in these conditions. This diffuse capillary deficiency may be seen in either specific (ankylosing spondylitis) or nonspecific forms of uveitis and it may also be seen in certain immunological disorders where interaction between the endothelial cells and the leukocytes is presumably abnormal (e.g. Whipple's disease, Figure 6).
,i,~~~~':.
_
Figure 6. Whipple's disease. Diffuse capillary leakage from retinal capillaries over the whole posterior pole in a patient with histologically proven Whipple's disease
Retinal vasculitis of unknown aetiology The central retinal vasculitis described by Lyle & Wybar (1961), which occurs in healthy young adults usually with unilateral involvement, continues to defy accurate aetiological definition. One recent 18-year-old girl, with unilateral central vasculitis and visual deterioration, was found to have abnormalities of the fibrinolytic system and appeared to be responsive to fibrinolytic therapy. Further investigations on these patients with the sophisticated haematological and rheological tests now available should provide further understanding and possible therapy. Similarly, there are young patients with retinal arteritis which may produce severe bilateral visual loss and elude diagnosis despite intensive investigation. An 18-year-old boy presented with bilateral visual loss and was referred to Mr Geoffrey Davies at King's College Hospital. The main involvement was in the retinal arteries and the fluorescein angiograms showed bilateral local retinal arterial lesions (Figure 7).. Despite intensive treatment with steroids, the deterioration of vision could not be alleviated. Retinal vasculitis occurring in other parts of the body is susceptible to biopsy and immunofluorescent study of the vessel walls. Renal involvement is usually arterial, either of the major renal artery or interlobular arterioles. In the skin, however, when cutaneous vasculitis is associated with immune complexes, the predominant involvement appears to be on the venous side rather than on the arterial. It may therefore be unique that in the eye we are able to localize retinal inflammatory disease to the arteries, the veins or the capillaries and this may be of value diagnostically.
914
Journal of the Royal Society of Medicine Volume 72 December 1979
Figure 7. Idiopathic retinal arteritis. Irregular and tortuous retinal arterioles, with associated macular lesions in both eyes of an 18-year-old boy with progressive visual loss; right eye (LEFr), left eye (RIGHT)
The present paper illustrates patterns of involvement of the arteries in lupus erythematosus, of the veins in Behget's disease and sarcoidosis, and capillary involvement in certain other conditions. Thus in all cases of vasculitis, precise criteria are needed for the ophthalmic diagnosis, and ocular inflammatory disease and systemic vascular diseases have to be excluded. Occurrence of systemic vasculitis following viral infections has been well described (e.g. hepatitis B, Sergent et al. 1976), so that the separation of primary inflammatory disease from a primary immunological disease may be difficult. It may also be important in the presence of unexplained retinal vascular disease to investigate patients immunologically. The retinal morphological appearances of immune complex diseases have not yet been fully documented and interesting speculation arises about the size and characteristics of circulating immune complexes. Immune complexes have been found in retinal vasculitis by Andrews et al. (1977) and they examined 17 patients with retinal vasculitis, 11 with the peripheral type of disease and 6 with central involvement. A systemic disease process was identified in 6 patients. They performed a series of tests searching for immune complexes and these were suggested by the presence of complement activation rheumatoid factor, CLQ or monoclonal rheumatoid factor precipitins, anticomplementary activity, elevated cryoglobulins and inhibition of erythrocyte antibody rosette formation. They also assessed increased numbers of peripheral blood lymphocytes bearing IgG and spontaneous neutrophil chemotactic activity in plasma. In 13 of the 17 cases, two or more parameters were elevated and they found that chemotactic activity and inhibition of EA rosette formation were the most frequent positive tests. Rheological studies with particular emphasis on fibrinolytic activity and platelet aggregation may also be indicated in the group to evaluate flow factors which contribute to retinal vascular changes. There is therefore a need for a major study of this type to place retinal vasculitis on a secure base with recognizable morphological characters which may provide diagnostic, therapeutic and prognostic information.
References Andrews B S, McIntosh J, Pett V & Penny R (1977) Clinical and Experimental Immunology 29, 23-29 Ashton N (1962) XIX Concilium Ophthalmologicum 11, 828 Balantyne A J & Michaelson I C (1970) Textbook of the Fundus of the Eye. E & S Livingstone, Edinburgh Bluthe L (1908) Inaugural Thesis, Heidelberg University Chajek T & Fainaru M (1975) Medicine 54, 179 Cogan D G (1969) William McKenzie Centenary Symposium on the Ocular Circulation in Health and Disease. Ed. J S Cant. Kimpton, London; pp 249-270
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