Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

Core Messages

Sickle cell disease is a hemoglobinopathy caused by a hereditary mutation of the betachain of hemoglobin. Patients have the abnormal hemoglobin S (HbS), which makes their erythrocytes more rigid and causes sickling on deoxygenation. When patients are homozygous for HbS, we speak of HbSS disease, which carries the most severe prognosis in terms of general health; when double heterozygous for another abnormal hemoglobin (C), it is HbSC; when heterozygous for HbS and normal HbA it is called sickle cell trait (HbAS)

Sickle cell disease can be combined with abnormalities in the synthesis of the alpha chains of hemoglobin, called the thalassemias

The hallmark of sickle cell disease is vasoocclusion, primarily by the abnormal erythrocytes, but also by secondary changes in endothelium and leukocytes

Salmon patch hemorrhages, iridescent deposits and black sunbursts are early and late manifestations respectively of burst-out retinal hemorrhages and do not cause lasting visual complaints

Proliferative sickle retinopathy (PSR) is the major cause of severe prolonged visual loss in sickle cell patients

PSR is much more prevalent in patients with sickling disease of genotypes with a more benign general health course, such as patients with HbSC and HbS-beta-thal. It is not well understood why the peripheral retinal capillaries are particularly targeted in such patients, resulting in more extensive non-perfusion and ischemia

Although feeder vessel treatment is effective in closing even elevated and large sea fans, it

may cause choroidal neovascularization and should only be considered with recurrent vitreous hemorrhages

Extensive midperipheral scatter laser coagulation reduces the incidence of vitreous hemorrhage and may decrease the incidence of longterm visual loss. Evidence for the need for yearly fundus examinations and prophylactic laser coagulation in patients with PSR is not as strong, however, as in proliferative diabetic retinopathy

Vitreoretinal surgery for non-clearing vitreous hemorrhage or retinal detachment in patients with PSR may be associated with perand postoperative severe systemic complications (acute chest syndrome) as well as ocular ones (anterior segment ischemia). Empiric advice includes: local anesthesia instead of general anesthesia, no injury to the recti muscles, no encircling elements, prevention and early treatment of hyphema, and careful control of perand postoperative intraocular pressure

Retinal artery or vein occlusions may occur in patients with any sickling genotype, but remain rare and are approached as in non-sickling patients

Sickle cell trait should not be associated with vaso-occlusive events in the retina; if so, a search for an explanatory co-morbidity should be made

Hyphema, however, may run a severe clinical course even in HbAS carriers. Acetazolamide and mannitol may increase erythrocyte sickling; avoid these medications, but rely on topical medications such as atropine, timolol, apraclonidine, and latanopost and consider early and repeated surgical removal of the intracameral blood

27.2.1 Introduction to Sickle Cell Disease

Sickle cell disease (SCD) is clinically the most important hemoglobinopathy worldwide [97]. It is caused by a single point mutation in the -globin gene that leads to the synthesis of sickle hemoglobin (HbS). This hemoglobin has the property of polymerizing when devoid of oxygen, leading to the formation of a rigid sickle-shaped erythrocyte [10] (Fig. 27.2.1). SCD is a heterogeneous disorder, with clinical manifestations including chronic hemolysis, increased susceptibility to infections and recurrent vaso-occlu- sive events that culminate in ischemic organ damage, a diminished quality of life and early death [93, 98].

Fig. 27.2.1. Blood smear of a 20-year-old HbSS patient showing sickled erythrocytes with the sodium metabisulfite method

27.2.1.1Normal Hemoglobin and Sickle Hemoglobin

The most important protein of the red blood cells (RBCs) is hemoglobin, which consists of four globin chains, each folded around a heme molecule. Hemoglobin delivers oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs. The predominant hemoglobin in adulthood is HbA (±97 %), which consists of two - and two -globin chains (22). Other hemoglobins are HbA2 (2 – 3.5 %; 22) and HbF (< 2 %; 2 2). During intrauterine development, several globin chains are synthesized (, , , , and ), with the predominant hemoglobin type during fetal life being HbF. In the first 12 weeks after birth, the HbF % quickly declines, leaving HbA and HbA2 as the remaining hemoglobins [72]. The -globin gene is found on chromosome 11p15.5. A single point mutation in the 6th codon leads to substitution of glutamic acid for valine, resulting in an abnormal globin: S. This results in the formation of “sickle hemoglobin,” or HbS (2S2). Upon deoxygenation, S forms hydrophobic interactions with adjacent S-globins, ulti-

mately resulting in the polymerization of HbS. This is the molecular hallmark of SCD [10]. As a consequence, the normally pliable RBC assumes a rigid sickled shape, with ensuing erythrocyte membrane damage and hemolysis.

Inheritance of two S genes leads to homozygous SCD, or sickle cell anemia (HbSS). Other genotypes

that give rise to SCD include double heterozygous III 27 states in which the S gene is inherited together with

other abnormal genes, or with mutations that result in decreased synthesis of -globin genes (- thalassemias). In HbC a mutation in the gene results in substitution of glutamic acid by lysine. The HbSC genotype is the most common compound heterozygous state, followed by HbS--thalassemia [67]. People that carry just one S mutation have the sickle cell trait (HbAS), and are generally asymptomatic [97]. Hence, the disease is recessive with respect to clinical manifestations, but the gene is dominant in its expression since sickled cells can always be visualized in deoxygenated blood of individuals with HbAS. Combinations of HbAS with -thalassemias and of HbSS (or other forms of SCD) with -thalas- semias (mutations that result in decreased synthesis of -globin genes) give rise to SCD with varying severity depending on the number and type of gene deletions [67]. The survival advantage of people with sickle cell trait with regard to infections with Plasmodium falciparum may explain the association of malaria distribution and the distribution of the sickle cell gene, as well as the balanced polymorphism of the S gene in the African population [2, 97, 98]. In some parts of Africa, 45 % of the population is heterozygous for the S gene and in the United States and the Caribbean about 8 % of blacks carry one S gene. The S gene also occurs in the Caribbean, the Mediterranean basin, Saudi Arabia and parts of India [113].

27.2.1.2Determinants of HbS Polymerization and Patient Categories

The pathophysiological hallmark of SCD is intracellular polymerization of HbS upon deoxygenation [10]. Decreases in pH (which reduce the affinity of hemoglobin for oxygen) enhance HbS polymerization, as does a rise in temperature [64]. The concentration of HbS in the erythrocytes is also of great importance, with higher concentrations of HbS leading to more rapid polymerization. Another determinant of the tendency for polymerization is the presence of other hemoglobins, with HbF and HbA2 limiting the HbS polymerization to a greater extent than HbC and HbA. HbSS patients have no HbA, an HbS % greater than 85 %, a normal HbA2 % and an elevated HbF %. In people with HbAS the HbS % is

approximately 40 %. In HbSC patients the HbS % is about 10 – 15 % higher and the mean corpuscular hemoglobin concentration (MCHC) is elevated (due to HbC induced erythrocyte potassium and water loss), explaining why people with HbSC can be severely affected (as opposed to the largely asymp-

27 III tomatic people with sickle cell trait) [55].

27.2.1.3 Combinations with Thalassemia

In combinations of HbS and 0-thalassemia (no - globin synthesis from the affected thalassemic allele), there is no normal -globin production and hence no HbA. These patients show a HbS % similar to that of HbSS patients (> 85 %). Inheritance of HbS with +-thalassemia (reduced -globin synthesis from the affected thalassemic allele) leads to a variable HbA % (ranging from 1 % to 25 %), and hence a variable HbS % [67]. Combinations of HbSS with - thalassemia lead to a slight elevation of the HbA2 % with a concomitant reduction of the HbS %. In patients with HbS--thalassemias and HbSS with - thalassemia, the mean corpuscular volume (MCV) and the MCHC are reduced, thereby lowering the HbS polymerization rate as compared to HbSS patients [33, 67].

27.2.1.4Current Concepts in the Pathogenesis of Vaso-occlusion

Vaso-occlusion accounts for a major part of the clinical picture of SCD. Essential to the management of sickle cell patients is the increasing fundamental understanding of this complex process. Upon delivery of oxygen to the tissues, sickle hemoglobin polymerizes, resulting in the formation of a rigid, nondeformable sickle red blood cell (SRBC) that becomes trapped in the microcirculation, resulting in vaso-occlusion and tissue ischemia. Upon reoxygenation, sickled cells “unsickle,” but with each sickling cycle red cells become less pliable, and ultimately irreversibly sickled dehydrated dense SRBCs are formed. Fortunately, the delay time (the time required for polymer formation) is generally longer than the transit time of red cells through the microcirculation and SRBCs do not usually form in the microcirculation. Furthermore, the number of irreversibly sickled cells is only related to the hemolytic component of the disease in most studies [7, 10, 64].

Therefore, it has become evident that other factors greatly influence the vaso-occlusive process. Factors that delay the transit time, such as the adhesion of leukocytes and sickle reticulocytes to cytokine activated vessel wall endothelium, are now recognized of importance in the initiation and propagation of sickle cell vaso-occlusion [10, 65].

Other factors, such as endothelial dysfunction, a hypercoagulable state, and cell dehydration (which shortens the delay time) also contribute [8, 35, 54, 55].

These events result in obstruction of the microcirculation, tissue ischemia and, with prolonged duration, organ damage. The resolution stage remains largely uncharacterized, but it is well established that reperfusion of ischemic areas also contributes to tissue injury [65, 80].

27.2.1.5Pathophysiology of Ocular Vaso-occlusion

In the last decade, sophisticated histological and immunohistological studies in patients’ eyes, as well in transgenic animal models, performed mainly at the Wilmer Eye Institute, have increased our insight into the pathophysiological events in the ocular circulation of sickle cell patients (please refer to Chapter 27.1 by G. Lutty).

27.2.2Retinal Vascular Disease in Sickle Cell Patients

27.2.2.1 Introduction

Except for two occasions, the ocular manifestations of sickle cell disease are caused or initiated by vasoocclusions, and those affecting the choroid and retina are described in this chapter.

The association with angioid streaks is the only manifestation not directly explained by vaso-occlu- sion, but may be a sequela of reperfusion injury after a vaso-occlusive event, with oxidative damage to elastin [1]. The other exception, hyphema, is clinically more important, particularly because it is the only ocular manifestation in which people with HbAS are also at risk.

Within the anterior chamber, erythrocytes sickle and compromise trabecular outflow, leading to a high and prolonged intraocular pressure rise; moreover, bloodflow of the disk and retina may be compromised earlier than in non-sickling persons. Early surgical evacuation of the blood is advised as well as the avoidance of acetazolamide, which may acidify the anterior chamber and encourage further sickling [112].

27.2.2.2 Database

The majority of the clinical reports on sickle cell retinopathy date from the two decades following the first detailed descriptions in 1971 and 1972 from the two major study centers, Chicago (Goldberg, Jampol) and Kingston, Jamaica (Serjeant, Condon, Talbot,

Bird). In the 1990s only three more modest prevalence studies were published (from Curacao, Miami and Togo: van Meurs, Clarcson and Balo, respectively).

The best information, however, is derived from the prospective sickle cell cohort study, initiated in 1973 by Serjeant, based on all sickle cell patients detected among 100,000 consecutive normal deliveries in Kingston, Jamaica. The cohort also included age matched controls. A comprehensive report with follow-up data up to 2000 was published in 2005 [30].

27.2 Retinal Vascular Disease in Sickle Cell Patients 715

III 27

27.2.3 Choroid

Four sickle cell patients (two SC, one SS and one Sthal) with possible ciliary artery occlusions have been reported [25, 28, 29]. Dizon and coworkers were able to observe the course of these lesions: midperipheral wedge-shaped whitish areas deep to the retina in the acute stage were seen, which became mottled areas within weeks. The recurrent triangular lesions in Dizon’s patient showed a striking resemblance to the ones produced by ligation of the lateral or all ciliary arteries in monkeys [53, 54]. Apart from choroidal occlusions, the HbSS patient studied by Dizon and colleagues had retinal arteriolar occlusions and occlusion of one internal carotid artery with amaurosis fugax. In this patient with an exceptional vaso-occlusive tendency, it is likely that emboli of erythrocyte plugs or thrombi from the carotid or ophthalmic artery occluded either a ciliary artery or simultaneously several short posterior ciliary or choroidal arteries.

As a complication of feeder-vessel photocoagulation for elevated sea fans (see Sect. 27.2.9.1 below), similar lesions were noted more frequently in sickle cell patients [43].

However, choroidal infarction remains a rare manifestation in sickle cell disease, probably because the flow rate of the choroid is very high (i.e., the transit time is considerably shorter than the delay time of polymerization; refer to Sect. 27.2.1.4).

27.2.3.1 Choriocapillary

Speculating that the uneven filling of the choriocapillaris in the early arteriovenous phase observed in some sickle cell patients (Fig. 27.2.2) might be related to impaired rheology, van Meurs studied choroidal filling in HbSS and HbSC patients as well as in age and race matched HbAS and HbAA controls [107]. He found no difference in choroidal filling pattern between sickle cell patients and controls; consequently, at least in African Caribbeans, a delayed filling pattern of the choriocapillaris in the early arteriovenous phase only cannot be regarded as pathologic.

Fig. 27.2.2. Late filling in a geographic pattern, merging with the watershed zone, in a 24-year-old HbAS control patient

27.2.4 Retinal Vessel Occlusions

Vessel involvement at the posterior pole in sickle cell disease presents a spectrum ranging from central retinal artery occlusion to perimacular capillary drop-out, with the formation of perifoveal avascular zones. The smaller vessel occlusions are frequently asymptomatic and without reduced visual acuity, whereas arterial occlusions usually present with acute symptoms of visual loss.

Peripheral retinal vessel occlusions with capillary loss in large, often confluent areas extending from the ora serrata posteriorly are mostly described in relation to proliferative retinopathy. In many patients, however, these occlusions do not lead to proliferative changes.

As sequelae to arteriolar occlusion retinal hemorrhages, salmon patches, iridescent spots and black sunbursts are grouped together.

27.2.4.1 Major Retinal Vessel Occlusions

Central retinal artery occlusions have been reported in ten sickle cell patients. Symptomatic branch and macular artery occlusions have been reported in nine sickle cell patients; visual loss in the latter patients was often relatively mild (Table 27.2.1). Although major retinal arterial occlusions cause severe visual symptoms, only one central retinal occlusion (following retrobulbar anesthesia) and two minor branch occlusions were noted over a period of 15 years in approximately 800 HbSS and 300 HbSC patients in Jamaica [18, 19, 26]. Since an association with sickling disorders tends to hasten reporting, there may be underreporting of “idiopathic” young patients with these occlusions [3]. Given the plausibility of a causative relationship, however, we regard retinal arterial occlusion as a relatively rare ocular manifestation of sickle cell disease.

Table 27.2.1. Symptomatic vessel occlusions in sickle cell patients

ca central retinal artery, NLA no light perception, ba branch retinal artery, LE lupus erythematodes, ma macular arteriole, VA visual acuity

As in all arterial occlusions, treatment of the underlying disorder is important to decrease the risk of a recurrent occlusion; in sickle cell disease, unfortunately, few specific and proven measures are available.

27.2.4.2 Retinal Vein Occlusions

Interestingly, there is no mention in the literature of an increased occurrence of central or branch vein occlusion in sickle cell patients. Only Hasan et al. [50] reported one patient with HbSS, who was found to have a protein S deficiency as well. Lieb and coworkers [71] mentioned two cases with possible central vein occlusion. In both patients, who also had a subarachnoid hemorrhage, the drawings could have also represented severe disk edema. Recently, indeed, Henry [57] described the occurrence of pseudotumor cerebri in three pediatric patients (one HbSS, two HbSC).

27.2.5Retinal Hemorrhages, Salmon Patches, Iridescent Spots and Black Sunbursts

Hannon [49] used the term “salmon-pink exudative plaque” for what has been shown to be a round or oval shaped intraor pre-retinal hemorrhage, as distinguished from a more diffuse intravitreal hemorrhage or clearly subhyaloid hemorrhage, presumed due to an acute arteriolar obstruction.

Glistening deposits, refractile and lipid deposits [114], cholesterol deposits [71] and iridescent glistening deposits [19] are terms that have been used to

Fig. 27.2.3. Black sunbursts in a 45-year-old HbSC patient

describe the small crystal-like deposits seen superficially in the retina in sickling patients. They are often observed in association with mottled or pigmented round areas.

The deep retinal plaques of stellate or spiculate pigment dispersion, seen in the midperiphery in sickling patients, were termed “black sunbursts” by Welch et al. [114] (Fig. 27.2.3).

27.2.5.1 Reports

A review of the relevant reports reveals that iridescent spots, salmon patches, retinal hemorrhages, brown patches and black sunbursts (either one of these signs or a combination of them) are noted in two-thirds of either SS, SC or S--thalassemia patients (Table 27.2.2).

Table 27.2.2. Reported frequency retinal hemorrhages, salmon patches, iridescent spots and black sunbursts

n number of patients, Iri. iridescent spots, Hb Hb type, Mott. mottled brown areas, Ret. retinal hemorrhage, BS black sunburst, Sal. salmon patch

a

27.2.5.2 Course

Asdourian et al. [5] observed a retinal hemorrhage gradually turn into a black sunburst lesion. Similarly described was the transformation of a “salmon patch” superficial retinal hemorrhage into a black sunburst-like lesion [110] (Fig. 27.2.4a–d).

Using light microscopy, Romayananda et al. [89] III 27 found hemosiderin-laden macrophages either prere-

tinally, in “schisis cavities” formed by the internal limiting membrane and inner retina, or between the sensory retina and retinal pigment epithelium. In the latter case, there was focal pigment epithelial hypertrophy, hyperplasia and migration. Apparently, a hemorrhage breaking out from a retinal arteriole or capillary can give rise to different ophthalmoscopic signs after its absorption, depending upon its exact location and consequent plane of dissection: from preretinal iridescent spots, via a round or oval schisis cavity with or without iridescent spot or brownish pigment to the deeper retinal and pigment epithelial scar known as the black sunburst patch.

b

27.2.5.3 Relevance to Function

Even when these retinal hemorrhages occasionally break through the internal limiting membrane into the vitreous, they do not interfere with visual acuity, being both small and peripheral.

Although these patches do not by themselves 27 III cause visual loss, they are related to occlusions of small vessels, burst-out hemorrhages and capillary loss. Talbot et al. [105] did show a correlation between the patches and capillary closure in a series

of 96 young children.

Interestingly, despite the fact that these different signs of vaso-occlusion are often accompanied by the loss of retinal perfusion and thus are a factor in the occurrence of proliferative sickle retinopathy (PSR), they are no more common in HbSC patients, where PSR is frequent.

27.2.6Capillary Occlusions of the Posterior Pole

Stevens et al. [101] and Asdourian et al. [6] reported abnormalities in either or both the macula and temporal raphe in 32 % of HbSS patients, 36 % of HBSC patients and 20 % of S-beta-thal patients in 100 consecutive cases. The macular abnormalities consisted of cotton-wool spots, microaneurysm-like dots, dark and enlarged segments of arterioles, hairpin-shaped venular loops, and on fluorescein angiography, of pathological avascular zones (PAZ) and widening and irregularities of the foveal avascular zone (FAZ). In children, Talbot et al. [105] found no pathologic avascular zones in the macular region in 59 HbSS and 37 HbSC patients with ages from 5 to 8 years.

Goldbaum [42] described the retinal depression sign on ophthalmoscopy, which was seen after the disappearance of cotton-wool spots and was thought to result from local thinning after necrosis of an infarcted inner retina.

Transient dark spots, apparently plugged deoxygenated erythrocytes within small surface vessels, were noted on the disk itself in 9 (7 HbSS) of 80 sickle cell patients [44] and in 17 of 74 HbSS patients [19].

27.2.6.1 Natural History

Some patients with cotton-wool spots were observed longitudinally [6]; at these sites, abrupt obstructions in the adjacent arteriole were seen on fluorescein angiography, with subsequent opening and reclosing of the initially non-perfused arteriole. In some cases, the dependent capillaries also reperfused. Venular loops were found to develop adjacent to areas that remained non-perfused.

Marsh et al. [73] observed an inverse relationship

between the number of perimacular capillary abnormalities and the size of the FAZ; they also noted that a small FAZ and a high count of these capillary abnormalities were more common in younger than in older patients, suggesting that perimacular vessel abnormalities represent the early vaso-occlusive phase that may progress to enlargement of the foveal avascular zone.

27.2.6.2Relevance of These Findings to Function

In only three of the patients studied by Stevens and Asdourian, a visual loss in the range of 20/25 to 20/30 could be attributed to a macular cause. One eye in Asdourian’s series had a paracentral scotoma with a deutan defect on the Farnsworth D-15 panel. In only three cases could field defects be related to these lesions by static perimetry. However, using the Farn- sworth-Munsell 100-hue test, Roy et al. [90] demonstrated mild to moderate yellow-blue defects in nearly all 61 eyes of sickle cell patients; there was no correlation with pathologic avascular zones or retinal depression signs. Mild defects were found in onethird of the control subjects.

These results have not shown that these chronic, remodeling small vessel changes cause significant functional loss. Furthermore, there is no mention in the reports concerning elderly sickle cell patients of major visual loss in association with ischemic maculopathy, which would be expected if these changes were progressive.

Interestingly, no specific mention is made in these papers of the coexistence of peripheral retinopathy: apparently, there is no strong correlation between the extent of peripheral non-perfusion and non-per- fusion along the raphe, in spite of the similarities in vasculature in these two regions [101].

27.2.7 Peripheral Vessel Occlusions

Teleangiectasias, beading and dilatations are signs of the mild and moderate stages of peripheral microangiopathy according to Condon et al.’s [19 – 21] classification. Vessel sheathing and silver-wire appearance can be manifestations of obstruction: this has been classified by Condon as the severe stage, and by Goldberg [39] as stage I.

27.2.7.1 Reports

In Condon’s series [19 – 21], there is no apparent difference between HbSS (24 %) and HbSC (31 %) patients in the prevalence of peripheral obstructions; indeed, Talbot [105] noted a greater number of obstructions in HbSS children (Table 27.2.3).

Table 27.2.3. Occurrence of peripheral vessel obstructions

n number of patients, Tele. telangiectasia, Silver. silverwire vessels, Obstr. obstructions, Sheath. sheathing, A-V arteriovenous anastosmosis

27.2.7.2 Natural History

Galinos et al. [40] showed, prospectively, a continuous remodeling of the peripheral retinal vasculature due to successive closures and reopenings of equatorial retinal vessels (see Fig. 27.2.4b, c). Nevertheless, a centripetal (posterior) recession of the peripheral retinal vasculature usually resulted.

Raichand et al. [86], who followed 40 sickling patients with peripheral obstructions and arteriovenous anastosmoses, observed the formation of four sea fans from arteriovenous anastosmoses of these patients. These anastosmoses had been observed to exist for 7 months to 3 years prior to sea fan formation.

27.2.7.3Relevance of These Findings to Function

No loss of visual acuity had resulted from these peripheral occlusions; moreover, no visual field loss had been detected [40]. However, peripheral vessel closure and capillary bed drop-out can be the setting for proliferative sickle retinopathy (see below).

27.2.8 Proliferative Sickle Retinopathy

Retinal and, in rare instances, disk neovascularization in sickling patients have been reported as retinitis proliferans [18, 19, 58] and as sea fans [114]. Some of these cases progressed to vitreous hemorrhage and retinal detachment, thus proving to be a sight-threat- ening variant of sickle retinopathy.

27.2.8.1Classification of Sickle Cell Retinopathy

Lieb et al. [71] proposed that sickle cell retinopathy be classified as stage I when tortuosity and dilatation of the major retinal vessels were observed; and as grade II when accompanied by ischemic areas with

retinal edema, sheathing of peripheral vessels, neo- III 27 vascularization, microaneurysms and peripheral telangiectasis. Grade III comprises retinal hemor-

rhages, iridescent spots and obstruction of small veins. Retinitis proliferans, vitreous hemorrhage and central artery or vein occlusion are grade IV. Lieb et al. felt that the higher the grade of retinopathy, the more severe the systemic clinical course of the patient had been.

Goldberg [45] proposed a classification of proliferative sickle retinopathy that was both clinically useful and pathogenetically logical. According to Goldberg, peripheral arteriolar obstruction constituted stage I. Peripheral arteriovenous anastosmoses, judged to be sequential to the obstructions, were designated stage II (Fig. 27.2.5). Peripheral retinal neovascularization originating from the anastosmoses was called stage III (Fig. 27.2.6). Vitreous hemorrhages from such neovascularizations were called stage IV. Partly tractional, partly rhegmatogenous (due to tears adjacent to sea fans with vitreous traction) detachments were called stage V. The extent of circumferential involvement was quantitated in substages. Condon et al. [19] proposed a subdivision of Goldberg’s stage I, in which arteriolar obstruction constitutes the most advanced abnormality.

27.2.8.2Reports of Proliferative Sickle Retinopathy

Reports pertaining to the occurrence of proliferative sickle retinopathy (PSR) are listed in Table 27.2.4. Only Condon’s [19 – 21], van Meurs’s [108] and obviously Downes’s [30] series have not been selected specifically on the basis of ocular symptoms. PSR was present in 3 – 14 % of the HbSS patients, in 33 – 43 % of the HbSC patients and in 18 % of the Hb- S--thalassemia patients. In the HbSC patients, up to 31 % of these eyes progressed to vitreous hemorrhage and up to 15 % to retinal detachment. With the exception of one case with an exudative detachment [31], all other reported cases of retinal detachment in PSR were either tractional or a combination of tractional and rhegmatogenous.

Table 27.2.4. Reported frequency of proliferative retinopathy in non-treatment series

n number of patients, Hb Hb type, PSR proliferative sickle retinopathy, *(partly) the same patients, StIII Goldberg stage III: retinal neovascularization, StIV Goldberg stage IV: vitreous hemorrhage, StV Goldberg stage V: retinal detachment

27.2.8.3 Non-peripheral Proliferative Lesions

Fig. 27.2.7. A fortunately rare, very active fibrovascular proliferation located near the disk, more resembling proliferative diabetic retinopathy, but as a manifestation of PSR in a 38-year-old HbSC patient

27.2.8.4Natural History of Proliferative Sickle Retinopathy

In patients with PSR, there is a tendency for a slow increase in the extent of neovascularization, as well as in the incidence of vitreous hemorrhage and retinal detachment (Table 27.2.5).

The youngest patient with reported PSR was an 8- year-old boy with HbSC [102]. The prevalence of PSR increased from the age of 15 years [51, 52] to the age of 35 years, after which time a plateau was reached.

Analyzing 114 eyes with PSR, Condon et al. [15, 22, 23] found autoinfarction (Figs. 27.2.8a, b, 27.2.9a, b) and increased neovascularization to occur simultaneously in the same eye in 32 eyes (28 %). PSR was observed to develop (46 eyes) most commonly in patients under the age of 25 years. The most florid growth of neovascularization occurred also in this age group. The average age of patients with autoinfarction alone (11 %) was higher than that of patients with an increase in number of sea fans (30 %).

In Jampol and colleagues series [62], only four of the 22 vitreous hemorrhages interfered with visual acuity. Within this series risk factors for vitreous