Documenta Ophthalmologica 39,1 : 203-210, 1975 THE PROGRESSION OF SICKLE CELL EYE DISEASE IN JAMAICA P.I. CONDON & G.R. "SERJEANT
(Kingston, Jamaica) INTRODUCTION Ocular complications are frequently recognised in the variants of sickle cell disease (Goldberg, 1971; Condon & Serjeant, 1972a, b, c) but little is known about their natural history. This is important partly because factors contributing to the progression or regression of these lesions may increase our understanding of the pathogenesis of ocular complications and partly because a knowledge of the natural history of sickle cell retinopathy is essential for the assessment of therapeutic procedures. For these reasons, we present here observations on 169 patients with variants of sickle cell disease (70 SS, 60 SC, 39 Sflthal)* followed for periods between 2 years and 2 years and 8 months. MATERIALS AND METHODS Three previous studies have described the ocular pathology in 76 patients with SS disease, 70 patients with SC disease, and 50 patients with sickle /3thalassaemia in Jamaica (Condon & Serjeant, 1972a, b, c). These patients were not selected because of ocular complications but represented a random sample from the sickle cell clinic of the University Hospital of the West From the MRC Epidemiology Unit, University of the West Indies, Kingston, Jamaica. Reprint Requests to: Mr. Patrick I. Condon Consultant Ophthalmic Surgeon, South East Area Regional Eye Department, Ardheen Hospital, Waterford, Ireland. * SS = homozygous sickle cell disease SC = sickle cell - haemoglobin C disease Sfl thai = sickle cell - t3 thaiassaemia 203
Indies. Initial assessments were performed in August 1970 (SS disease), November 1970 (SC disease), and May 1971 (S/~thal). Further groups of 12 patients with SS disease were added in November 1970, and of 6 patients with SC disease were observed in May 1971 bringing the totals for the 3 genotypes to 88, 76, and 50 respectively. Follow-up covered the period up to May 1973 and thus represented periods of 2 years 8 months for SS disease, 2 years 5 months for SC disease and 2 years for S ~thal. One hundred and sixty-nine patients were traced after this period representing a retrieval rate of 82.6% (Table I).
Table 1 Original Group Dead SS
Males Females Total SC Males Females Total SThal Males Females Total Grand Total
41 47 88 36 40 76 13 37 50 214
2 1 3 2 1 3 1 2 3 9
Abroad 1 3 4 3 2 5 9
Traced
Not traced
30 40 70 28 32 60 11 28 39 169
8 3 11 3 5 8 1 7 8 27
% of those in Island Traced 78.9 93.0 86.4 90.3 86.5 88.2 91.7 80.0 83.0 86.2
Techniques of ocular examination have been previously described (Condon & Serjeant, 1972a). Fluorescein angiography was performed in all patients with ophthalmoscopic evidence of proliferative retinopathy. RESULTS Two patients (1 SS, 1 SC) out of the 169 had vitreous haemorrhages in one eye when first seen, rendering retinal assessment impossible, but in these two patients no changes were observed over the 2 year period in the other eye. In the remaining 167 patients, peripheral retinal vessel disease and retinopathy progressed in 107 (64.1%), remained unchanged in 55 (33.2%), and regressed in 5 (3.0%). In the individual genotypes, progression occurred in 44/69 (63.8%) patients with SS disease, in 44/59 (74.5%) patients with SC disease, and in 19/39 (38.7%) those with sickle ~thalassaemia. There was no change in 23/69 (33.3%) SS, in 12/59 (20.3%) SC, and in 20/39 (51.3%) S 13thai, and there was evidence of regression in 2/69 (2.9%) SS, and in 3/59 (5.1%) SC. Progression was more common in younger age groups occurring
204
in 81/114 (71.1%) patients under 30 years compared to 26/53 (49.1%)over this age. This age relationship may, in part, reflect the age distribution of patients with SC disease in which progression was most common, there being 62.5% of SC cases below 30 years and 37.5% above this age. No age group appeared particularly prone to the development of new lesions of proliferative retinopathy since these occurred in 20.8%, 23.2%, 33.3%, 23.1%, and 25% of patients in successive decades starting with the 1 0 - 1 9 year age group. Progression was equally common in males (47/69 (68,1%)) and females (60/98 (61,2%)) although proliferative retinopathy developed slightly more commonly in males (21/69 (30,4%)) compared to females (19/98 (19,4%)). The latter difference was not significant. PERIPHERAL RETINAL VESSEL DISEASE AND RETINAL WHITENING Peripheral retinal vessel disease was most marked at the ora serrata and appeared to progress posteriorly and circumferentially, generally affecting the temporal periphery more extensively than the nasal periphery. In 11 patients there was involvement of the total fundal circumference back to the equator, but vessel disease was not observed posterior to the equator. Over the 2 year period, mild vessel changes consisting of peripheral arteriolar narrowing and tortuosity, and abnormal looping of peripheral venules were observed to develop in new areas in 66 patients (95 eyes). Moderate changes including micro-aneurysmal dilatation of the capillary network, loss of the finer vessels, and abnormal branching of the peripheral venules developed from mild changes in 15 patients (23 eyes) and increased in extent in 36 patients (49 eyes). Peripheral retinal arteriolar occlusions (severe changes) developed from moderate changes in 54 patients (79 eyes). Neovascularisation was difficult to distinguish from microaneurysmal dilatation of the capillary network, although it was observed to develop immediately posterior to ischaemic retina in four patients who had sustained arteriolar occlusions. Mild and moderate peripheral vessel changes were usually associated with 'whitening without pressure' in the same areas of the peripheral fundus. Peripheral whitening of the fundus was observed to increase in extent in 50 patients and was associated with the new appearance of mild peripheral vessel disease in 18 patients, with progression from mild to moderate vessel disease in 15 patients, with increased extent of moderate vessel disease in 6 patients, and with progression from mild to severe vessel disease in 8 patients. In only 3 patients, did areas of peripheral whitening develop without visible evidence of a change in peripheral vessel disease. In general, the progression of vessel changes from mild or moderate to
205
severe disease was attended by a reduction in the extent of retinal whitening. In 27 patients (38 eyes) new arteriolar occlusions were associated with a red retina replacing previous retinal whitening. This change in retinal colour may lag behind the progression of occlusive disease as illustrated in 2 patients in which recently occluded retinal arterioles were associated with a sharply demarcated raised zone of whitened retina in the ischaemic area.
Fig. 1. Retinitis proliferans in infero-temporal periphery of left eye in 19 year old male with SS disease. Avascular retina at upper right was dull red but demonstrated peripheral whitening 2 years earlier. The abnormal arterio-venous communications and retinitis proliferans lesion developed during this period. 206
In most patients with long-standing retinitis proliferans, the ischaemic retina was red, but this sign may be obscured in cases where actively proliferating lesions with serous leakage caused a haziness of the peripheral vitreous.
Illustrative case History. Male SS. Age 19. August 1970: Vision 6/6 Right 6/6 Left Microaneurysmal dilatation of the capillary network and gross peripheral retinal whitening was present in both retinal peripheries. An occluded retinal arteriole was present in each temporal periphery. March 1973: Vision 6/6 Right 6/6 Left Occluded retinal arterioles and arteriovenous fistulae had developed to involve 2/3 of the retinal circumference of both eyes affecting predominantly the temporal region. A large sea-fan lesion was present in the left infero-temporal periphery (Fig. 1.). Retinal whitening persisted in areas peripheral to newly occluded arterioles in the nasal periphery, but a reddish retina was associated with areas of A-V fistulae and retinitis proliferans. PROLIFERATIVE RETINOPATHY Arterio-venous fistulae were present in 38 patients (56 eyes) on initial examination, and in 18 of these (29 eyes), there was no increase or decrease in the number of A - V fistulae over the 2 year period. In the remaining 20 patients, new A - V fistulae appeared in a previously affected eye in 14 patients, developed in a previously unaffected eye in 4 patients, and progressed to retinitis proliferans in 2 patients. Sixteen patients (24 eyes) developed A - V fistulae for the first time during this period. Retinitis proliferans was present in 28 patients (45 eyes) on initial examination, and in 12 patients (19 eyes) there was no increase or decrease in the number of R.P. lesions over the 2 year period. In the remaining 16 patients, retinitis proliferans increased in the previously affected eye in 12 patients, involved a previously unaffected eye in 3 patients, and appeared to regress in one patient. Eleven patients (16 eyes) developed R.P. for the first time during this period. A history of, or evidence of previous vitreous haemorrhage was present in 12 patients at the initial examination, 11 of which had R.P. and one had a retinal haemorrhage and A - V fistulae but without R.P. In 2 patients with histories of previous vitreous haemorrhages, the areas of R.P. were fibrosed and no longer permeable to fluorescein. This spontaneous closure of R.P. lesions was not observed to occur during the 2 year study. In 3 patients, vitreous haemorrhages occurred during the 2 year period. Traction retinal detachments were present in one eye of 3 patients at the initial examination and became more extensive in one of these over the 2 year period. A further 2 patients developed detachment during this period. Detachments were associated with evidence of vitreous haemorrhage 207
in 3 patients and with retinal tears and traction from fibrosing retinitis proliferans in 2. The pattern of visual symptoms depended on their underlying cause. Patients with vitreous haemorrhages demonstrated improvement in visual acuity with resolution of the haemorrhages. Visual loss secondary to detachment tended to become worse. The visual defects associated with posterior ciliary artery occlusive disease in 2 patients did not change over the period of observation. RETINAL HAEMORRHAGES, BROWN MOTTLED AREAS, AND BLACK SUNBURST SPOTS Six new small localised pre-retinal haemorrhages occurred in 5 patients. In three patients these were related to the development of mild or moderate peripheral vessel disease, in one to occluded retinal arterioles, and in another to micro-aneurysmal changes in the capillary circulation of the posterior pole. In 2 patients, resolution of haemorrhages left characteristic brown mottled areas, but in others, no lesions remained. All haemorrhages were asymptomatic and did not extend into the vitreous. Brown mottled areas increased in number in 3 patients, being preceded by pre-retinal haemorrhages in two. Black sunburst spots increased in number in 4 patients over the 2 year period. OTHER RETINAL LESIONS Minute red dots resembling micro-aneurysms at the posterior pole were observed in 41 patients at initial examination. During the 2 year period, these lesions disappeared in 6 patients, increased in number in 13 patients, and remained unchanged in 22 patients. Tortuosity of the major retinal arteries or veins and peripheral arterio-venous anomalies remained unchanged in all patients. Angioid streaks remained unchanged in 3 patients but a ring of dark pigmentation on the temporal side of the disc with radial extensions into the surrounding retina suggestive of an early angioid streak developed in one 25 year old patient with SS disease. DISCUSSION The most striking feature of the present study was the progressive nature of avascular damage at the retinal periphery. During the period of observation, 108 arterio-venous fistulae were formed in 51 eyes of 35 (21%) patients, and 70 new areas of retinitis proliferans developed in 41 eyes of 26 (15%) patients. This rate of progression appeared to slow down with increasing 208
severity of retinal involvement, 47% of patients with arterio-venous fistulae, and 43% of patients with retinitis proliferans, at the initial examination, failing to progress during the observation period compared to 33.3% of those with non-proliferative retinal lesions. This variation in rate of progression according to severity of retinal changes may explain an apparent conflict between our observations and those o f G o l d b e r g (1971). The latter author, in reporting some observations on the natural history of severe retinal pathology in a highly selected group of patients with SC disease, reported only slight and insignificant progression in the retinopathy. The rapid progression in the present series may be attributable in large part to the inclusion of patients with milder grades of vessel disease in which the progressive nature was more marked. Progression of the peripheral retinal changes occurred by either an increase in the area of involved periphery or by an increase in the severity of the disease. In a study of proliferative retinopathy in SC disease, Goldberg (1971 ) postulated a sequential development of retinal changes commencing with arteriolar occlusions. In other studies (Condon & Serjeant 1972a, b, c) minor vessel changes believed to precede arteriolar occlusions were described and there is some evidence to support a longitudinal progression through these stages. In the 11 patients with involvement of the complete retinal circumference extending posteriorly to the equator, it was possible to distinguish 3 zones of retinal involvement. Most anterior (and farthest from the source of blood supply) was a zone of complete retinal ischaemia devoid of patent blood vessels and usually dull red in colour. Posterior to this was a zone containing arterio-venous fistulae and areas of neovascularisation, and behind this a zone of vascular changes including peripheral venular tortuosity and abnormal branching with microaneurysmal dilatation of the capillary bed. It was within this latter zone that arteriolar occlusions developed and preretinal haemorrhages appeared confined to these areas. The histology of these early vessel changes had been described by Romayananda et al. (1973). Such observations suggest that these early changes represent a specific and significant form of peripheral retinal vessel disease in sickling conditions. The apparently relentless progression of vessel disease in the SC genotype with arteriolar occlusions, ischaemia of the peripheral retina, and of proliferative retinopathy, is at variance with the infrequency of severe ocular symptoms in SC adults (Condon & Serjeant, 1972b). In the present series only one patient had bilateral blindness, three had unilateral blindness one with a severe field defect in the other eye, and another had a field defect in one eye associated with a choroidal vascular lesion. All these cases had SC disease representing an overall prevalence of blindness or major field defects in 7/152 (4,6%) eyes in patients with this genotype. This apparent conflict 209
between the rate of progression and severity of end result may be reconciled by several explanations. It is possible that the rate of progression may not be sustained, but alternates with periods of quiescence, or even regression of avascular changes. This may result from spontaneous occlusion of areas of retinitis proliferans as illustrated by one 67 year old patient with SC disease in whom the number of R.P. lesions decreased from 4 to 2 and there was increasing fibrosis of the remaining lesions. In two other patients with histories of vitreous haemorrhage, there was extensive fibrosis of the retinitis proliferans which no longer leaked fluoresecin, and which had presumably undergone spontanenous occlusion (Romayananda et al., 1973). Apart from these examples of sclerosing retinitis proliferans there are probably other factors limiting the spread of retinal vessel disease. The more rapid progression noted in younger age groups is compatible with a factor limiting the spread of retinal vessel disease in older patients. Retinal vessel disease appears to be confined to the retina anterior to the equator which suggests that retinal vascularity posterior to the equator may be relatively immune to these vascular lesions either by anastomatic communications or possibly vessel calibre. An alternative explanation would be afforded by a discrepancy between retinal vascular pathology and ocular symptoms. Gross pathology such as ischaemia of the total retina anterior to the equator may produce only an unnoticed constriction of visual field, whereas most ocular symptoms result from episodes such as vitreous haemorrhage or from retinal detachment. Although these complications are related to the severity of vascular disease, their occurrence probably depends on some additional, possibly random, precipitating factor. ACKNOWLEDGEMENTS We wish to thank the South East Metropolitan Regional Hospital Board for study leave facilities (Mr. Condon). This work was supported by a grant from the Wellcome Trust. REFERENCES Condon, P.I. & Serjeant, G.R. The ocular findings in homozygous sickle cell anemia in Jamaica. Amer. J. OphthaL 73:533-543 (1972a). Condon, P.I. & Serjeant, G.R. The ocular findings in hemoglobin SC disease in Jamaica. Amer. J. OphthaL 74:921-931 (1972b). Condon, P.I. & Serjeant, G.R. The ocular findings in sickle cell thalassemia in Jamaica. Amer. J. Ophthal. 74:1105-1109 (1972c). Goldberg, M.F. Natural history of untreated proliferative sickle retinopathy. Arch. Ophthal. 85:428-437 (1971). Romayananda, N., Goldberg, M.F. & Green, W.R. Histopathology of sickle cell retinopathy. Trans. Amer. Acad. OphthaL Otolaryng. 77:652-676 (1973).
210
(Kingston, Jamaica) INTRODUCTION Ocular complications are frequently recognised in the variants of sickle cell disease (Goldberg, 1971; Condon & Serjeant, 1972a, b, c) but little is known about their natural history. This is important partly because factors contributing to the progression or regression of these lesions may increase our understanding of the pathogenesis of ocular complications and partly because a knowledge of the natural history of sickle cell retinopathy is essential for the assessment of therapeutic procedures. For these reasons, we present here observations on 169 patients with variants of sickle cell disease (70 SS, 60 SC, 39 Sflthal)* followed for periods between 2 years and 2 years and 8 months. MATERIALS AND METHODS Three previous studies have described the ocular pathology in 76 patients with SS disease, 70 patients with SC disease, and 50 patients with sickle /3thalassaemia in Jamaica (Condon & Serjeant, 1972a, b, c). These patients were not selected because of ocular complications but represented a random sample from the sickle cell clinic of the University Hospital of the West From the MRC Epidemiology Unit, University of the West Indies, Kingston, Jamaica. Reprint Requests to: Mr. Patrick I. Condon Consultant Ophthalmic Surgeon, South East Area Regional Eye Department, Ardheen Hospital, Waterford, Ireland. * SS = homozygous sickle cell disease SC = sickle cell - haemoglobin C disease Sfl thai = sickle cell - t3 thaiassaemia 203
Indies. Initial assessments were performed in August 1970 (SS disease), November 1970 (SC disease), and May 1971 (S/~thal). Further groups of 12 patients with SS disease were added in November 1970, and of 6 patients with SC disease were observed in May 1971 bringing the totals for the 3 genotypes to 88, 76, and 50 respectively. Follow-up covered the period up to May 1973 and thus represented periods of 2 years 8 months for SS disease, 2 years 5 months for SC disease and 2 years for S ~thal. One hundred and sixty-nine patients were traced after this period representing a retrieval rate of 82.6% (Table I).
Table 1 Original Group Dead SS
Males Females Total SC Males Females Total SThal Males Females Total Grand Total
41 47 88 36 40 76 13 37 50 214
2 1 3 2 1 3 1 2 3 9
Abroad 1 3 4 3 2 5 9
Traced
Not traced
30 40 70 28 32 60 11 28 39 169
8 3 11 3 5 8 1 7 8 27
% of those in Island Traced 78.9 93.0 86.4 90.3 86.5 88.2 91.7 80.0 83.0 86.2
Techniques of ocular examination have been previously described (Condon & Serjeant, 1972a). Fluorescein angiography was performed in all patients with ophthalmoscopic evidence of proliferative retinopathy. RESULTS Two patients (1 SS, 1 SC) out of the 169 had vitreous haemorrhages in one eye when first seen, rendering retinal assessment impossible, but in these two patients no changes were observed over the 2 year period in the other eye. In the remaining 167 patients, peripheral retinal vessel disease and retinopathy progressed in 107 (64.1%), remained unchanged in 55 (33.2%), and regressed in 5 (3.0%). In the individual genotypes, progression occurred in 44/69 (63.8%) patients with SS disease, in 44/59 (74.5%) patients with SC disease, and in 19/39 (38.7%) those with sickle ~thalassaemia. There was no change in 23/69 (33.3%) SS, in 12/59 (20.3%) SC, and in 20/39 (51.3%) S 13thai, and there was evidence of regression in 2/69 (2.9%) SS, and in 3/59 (5.1%) SC. Progression was more common in younger age groups occurring
204
in 81/114 (71.1%) patients under 30 years compared to 26/53 (49.1%)over this age. This age relationship may, in part, reflect the age distribution of patients with SC disease in which progression was most common, there being 62.5% of SC cases below 30 years and 37.5% above this age. No age group appeared particularly prone to the development of new lesions of proliferative retinopathy since these occurred in 20.8%, 23.2%, 33.3%, 23.1%, and 25% of patients in successive decades starting with the 1 0 - 1 9 year age group. Progression was equally common in males (47/69 (68,1%)) and females (60/98 (61,2%)) although proliferative retinopathy developed slightly more commonly in males (21/69 (30,4%)) compared to females (19/98 (19,4%)). The latter difference was not significant. PERIPHERAL RETINAL VESSEL DISEASE AND RETINAL WHITENING Peripheral retinal vessel disease was most marked at the ora serrata and appeared to progress posteriorly and circumferentially, generally affecting the temporal periphery more extensively than the nasal periphery. In 11 patients there was involvement of the total fundal circumference back to the equator, but vessel disease was not observed posterior to the equator. Over the 2 year period, mild vessel changes consisting of peripheral arteriolar narrowing and tortuosity, and abnormal looping of peripheral venules were observed to develop in new areas in 66 patients (95 eyes). Moderate changes including micro-aneurysmal dilatation of the capillary network, loss of the finer vessels, and abnormal branching of the peripheral venules developed from mild changes in 15 patients (23 eyes) and increased in extent in 36 patients (49 eyes). Peripheral retinal arteriolar occlusions (severe changes) developed from moderate changes in 54 patients (79 eyes). Neovascularisation was difficult to distinguish from microaneurysmal dilatation of the capillary network, although it was observed to develop immediately posterior to ischaemic retina in four patients who had sustained arteriolar occlusions. Mild and moderate peripheral vessel changes were usually associated with 'whitening without pressure' in the same areas of the peripheral fundus. Peripheral whitening of the fundus was observed to increase in extent in 50 patients and was associated with the new appearance of mild peripheral vessel disease in 18 patients, with progression from mild to moderate vessel disease in 15 patients, with increased extent of moderate vessel disease in 6 patients, and with progression from mild to severe vessel disease in 8 patients. In only 3 patients, did areas of peripheral whitening develop without visible evidence of a change in peripheral vessel disease. In general, the progression of vessel changes from mild or moderate to
205
severe disease was attended by a reduction in the extent of retinal whitening. In 27 patients (38 eyes) new arteriolar occlusions were associated with a red retina replacing previous retinal whitening. This change in retinal colour may lag behind the progression of occlusive disease as illustrated in 2 patients in which recently occluded retinal arterioles were associated with a sharply demarcated raised zone of whitened retina in the ischaemic area.
Fig. 1. Retinitis proliferans in infero-temporal periphery of left eye in 19 year old male with SS disease. Avascular retina at upper right was dull red but demonstrated peripheral whitening 2 years earlier. The abnormal arterio-venous communications and retinitis proliferans lesion developed during this period. 206
In most patients with long-standing retinitis proliferans, the ischaemic retina was red, but this sign may be obscured in cases where actively proliferating lesions with serous leakage caused a haziness of the peripheral vitreous.
Illustrative case History. Male SS. Age 19. August 1970: Vision 6/6 Right 6/6 Left Microaneurysmal dilatation of the capillary network and gross peripheral retinal whitening was present in both retinal peripheries. An occluded retinal arteriole was present in each temporal periphery. March 1973: Vision 6/6 Right 6/6 Left Occluded retinal arterioles and arteriovenous fistulae had developed to involve 2/3 of the retinal circumference of both eyes affecting predominantly the temporal region. A large sea-fan lesion was present in the left infero-temporal periphery (Fig. 1.). Retinal whitening persisted in areas peripheral to newly occluded arterioles in the nasal periphery, but a reddish retina was associated with areas of A-V fistulae and retinitis proliferans. PROLIFERATIVE RETINOPATHY Arterio-venous fistulae were present in 38 patients (56 eyes) on initial examination, and in 18 of these (29 eyes), there was no increase or decrease in the number of A - V fistulae over the 2 year period. In the remaining 20 patients, new A - V fistulae appeared in a previously affected eye in 14 patients, developed in a previously unaffected eye in 4 patients, and progressed to retinitis proliferans in 2 patients. Sixteen patients (24 eyes) developed A - V fistulae for the first time during this period. Retinitis proliferans was present in 28 patients (45 eyes) on initial examination, and in 12 patients (19 eyes) there was no increase or decrease in the number of R.P. lesions over the 2 year period. In the remaining 16 patients, retinitis proliferans increased in the previously affected eye in 12 patients, involved a previously unaffected eye in 3 patients, and appeared to regress in one patient. Eleven patients (16 eyes) developed R.P. for the first time during this period. A history of, or evidence of previous vitreous haemorrhage was present in 12 patients at the initial examination, 11 of which had R.P. and one had a retinal haemorrhage and A - V fistulae but without R.P. In 2 patients with histories of previous vitreous haemorrhages, the areas of R.P. were fibrosed and no longer permeable to fluorescein. This spontaneous closure of R.P. lesions was not observed to occur during the 2 year study. In 3 patients, vitreous haemorrhages occurred during the 2 year period. Traction retinal detachments were present in one eye of 3 patients at the initial examination and became more extensive in one of these over the 2 year period. A further 2 patients developed detachment during this period. Detachments were associated with evidence of vitreous haemorrhage 207
in 3 patients and with retinal tears and traction from fibrosing retinitis proliferans in 2. The pattern of visual symptoms depended on their underlying cause. Patients with vitreous haemorrhages demonstrated improvement in visual acuity with resolution of the haemorrhages. Visual loss secondary to detachment tended to become worse. The visual defects associated with posterior ciliary artery occlusive disease in 2 patients did not change over the period of observation. RETINAL HAEMORRHAGES, BROWN MOTTLED AREAS, AND BLACK SUNBURST SPOTS Six new small localised pre-retinal haemorrhages occurred in 5 patients. In three patients these were related to the development of mild or moderate peripheral vessel disease, in one to occluded retinal arterioles, and in another to micro-aneurysmal changes in the capillary circulation of the posterior pole. In 2 patients, resolution of haemorrhages left characteristic brown mottled areas, but in others, no lesions remained. All haemorrhages were asymptomatic and did not extend into the vitreous. Brown mottled areas increased in number in 3 patients, being preceded by pre-retinal haemorrhages in two. Black sunburst spots increased in number in 4 patients over the 2 year period. OTHER RETINAL LESIONS Minute red dots resembling micro-aneurysms at the posterior pole were observed in 41 patients at initial examination. During the 2 year period, these lesions disappeared in 6 patients, increased in number in 13 patients, and remained unchanged in 22 patients. Tortuosity of the major retinal arteries or veins and peripheral arterio-venous anomalies remained unchanged in all patients. Angioid streaks remained unchanged in 3 patients but a ring of dark pigmentation on the temporal side of the disc with radial extensions into the surrounding retina suggestive of an early angioid streak developed in one 25 year old patient with SS disease. DISCUSSION The most striking feature of the present study was the progressive nature of avascular damage at the retinal periphery. During the period of observation, 108 arterio-venous fistulae were formed in 51 eyes of 35 (21%) patients, and 70 new areas of retinitis proliferans developed in 41 eyes of 26 (15%) patients. This rate of progression appeared to slow down with increasing 208
severity of retinal involvement, 47% of patients with arterio-venous fistulae, and 43% of patients with retinitis proliferans, at the initial examination, failing to progress during the observation period compared to 33.3% of those with non-proliferative retinal lesions. This variation in rate of progression according to severity of retinal changes may explain an apparent conflict between our observations and those o f G o l d b e r g (1971). The latter author, in reporting some observations on the natural history of severe retinal pathology in a highly selected group of patients with SC disease, reported only slight and insignificant progression in the retinopathy. The rapid progression in the present series may be attributable in large part to the inclusion of patients with milder grades of vessel disease in which the progressive nature was more marked. Progression of the peripheral retinal changes occurred by either an increase in the area of involved periphery or by an increase in the severity of the disease. In a study of proliferative retinopathy in SC disease, Goldberg (1971 ) postulated a sequential development of retinal changes commencing with arteriolar occlusions. In other studies (Condon & Serjeant 1972a, b, c) minor vessel changes believed to precede arteriolar occlusions were described and there is some evidence to support a longitudinal progression through these stages. In the 11 patients with involvement of the complete retinal circumference extending posteriorly to the equator, it was possible to distinguish 3 zones of retinal involvement. Most anterior (and farthest from the source of blood supply) was a zone of complete retinal ischaemia devoid of patent blood vessels and usually dull red in colour. Posterior to this was a zone containing arterio-venous fistulae and areas of neovascularisation, and behind this a zone of vascular changes including peripheral venular tortuosity and abnormal branching with microaneurysmal dilatation of the capillary bed. It was within this latter zone that arteriolar occlusions developed and preretinal haemorrhages appeared confined to these areas. The histology of these early vessel changes had been described by Romayananda et al. (1973). Such observations suggest that these early changes represent a specific and significant form of peripheral retinal vessel disease in sickling conditions. The apparently relentless progression of vessel disease in the SC genotype with arteriolar occlusions, ischaemia of the peripheral retina, and of proliferative retinopathy, is at variance with the infrequency of severe ocular symptoms in SC adults (Condon & Serjeant, 1972b). In the present series only one patient had bilateral blindness, three had unilateral blindness one with a severe field defect in the other eye, and another had a field defect in one eye associated with a choroidal vascular lesion. All these cases had SC disease representing an overall prevalence of blindness or major field defects in 7/152 (4,6%) eyes in patients with this genotype. This apparent conflict 209
between the rate of progression and severity of end result may be reconciled by several explanations. It is possible that the rate of progression may not be sustained, but alternates with periods of quiescence, or even regression of avascular changes. This may result from spontaneous occlusion of areas of retinitis proliferans as illustrated by one 67 year old patient with SC disease in whom the number of R.P. lesions decreased from 4 to 2 and there was increasing fibrosis of the remaining lesions. In two other patients with histories of vitreous haemorrhage, there was extensive fibrosis of the retinitis proliferans which no longer leaked fluoresecin, and which had presumably undergone spontanenous occlusion (Romayananda et al., 1973). Apart from these examples of sclerosing retinitis proliferans there are probably other factors limiting the spread of retinal vessel disease. The more rapid progression noted in younger age groups is compatible with a factor limiting the spread of retinal vessel disease in older patients. Retinal vessel disease appears to be confined to the retina anterior to the equator which suggests that retinal vascularity posterior to the equator may be relatively immune to these vascular lesions either by anastomatic communications or possibly vessel calibre. An alternative explanation would be afforded by a discrepancy between retinal vascular pathology and ocular symptoms. Gross pathology such as ischaemia of the total retina anterior to the equator may produce only an unnoticed constriction of visual field, whereas most ocular symptoms result from episodes such as vitreous haemorrhage or from retinal detachment. Although these complications are related to the severity of vascular disease, their occurrence probably depends on some additional, possibly random, precipitating factor. ACKNOWLEDGEMENTS We wish to thank the South East Metropolitan Regional Hospital Board for study leave facilities (Mr. Condon). This work was supported by a grant from the Wellcome Trust. REFERENCES Condon, P.I. & Serjeant, G.R. The ocular findings in homozygous sickle cell anemia in Jamaica. Amer. J. OphthaL 73:533-543 (1972a). Condon, P.I. & Serjeant, G.R. The ocular findings in hemoglobin SC disease in Jamaica. Amer. J. OphthaL 74:921-931 (1972b). Condon, P.I. & Serjeant, G.R. The ocular findings in sickle cell thalassemia in Jamaica. Amer. J. Ophthal. 74:1105-1109 (1972c). Goldberg, M.F. Natural history of untreated proliferative sickle retinopathy. Arch. Ophthal. 85:428-437 (1971). Romayananda, N., Goldberg, M.F. & Green, W.R. Histopathology of sickle cell retinopathy. Trans. Amer. Acad. OphthaL Otolaryng. 77:652-676 (1973).
210
