John I. Loewenstein,
Demetrios Vavvas
ANEMIA
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Key Features |
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Fundus findings in anemia may include hemorrhages, cotton wool spots, and retinal edema. The hemorrhages are typically superficial and flame shaped, but they may also have a white center (Figs 170.1 and 170.2). Rarely, preretinal or vitreous hemorrhage or a macular star may occur. The retinal vessels are usually normal, although pale arterioles and dilated veins may be seen.[1] Fluorescein angiography may reveal an increased retinal transit time.
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FIGURE 170.1 Intraretinal hemorrhages and cotton wool spots in a case of severe anemia. |
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FIGURE 170.2 Intraretinal hemorrhages, white-centered hemorrhage, and cotton wool spots in a case of aplastic anemia. |
Vision is not affected unless there are changes at the macula, and such changes are unusual. Retinopathy resolves with treatment of the underlying anemia.
The picture as a whole is suggestive, but not diagnostic, of anemia. It usually is not possible to determine the type of anemia from the fundus findings. Some authors feel that white-centered hemorrhages are more common in pernicious anemia than in other types of anemia[2]; others state that a picture of numerous preretinal hemorrhages, together with white-centered hemorrhages, is characteristic of aplastic anemia,[3] but systematic quantitative studies have not been undertaken. Two case reports link moderately severe iron deficiency anemia and retinal arterial occlusive events.[4,5] With only two cases, it is difficult to prove causality. One case of Fanconi anemia, a rare chromosomal abnormality, has been reported with widespread vasculopathy, including areas of central and peripheral leakage, areas of nonperfusion and neovascularization.[6] Angioid streaks have been reported to occur with familial dyserythropoietic anaemia type III.[7] Anemia associated with malaria has been reported to have high incidence of retinopathy, but cerebral malaria without anemia can also have fundus changes, and the severity of fundus changes may be a predictor of worse outcome.[8]
There is controversy in the literature regarding the most important factors related to the prevalence of retinopathy in anemia. Age, sex, type of anemia, hematocrit values, and platelet counts have all been invoked, but only a few quantitative studies have been performed. Foulds[3] studied 30 cases of pernicious anemia. He found retinopathy in all patients with a hemoglobin concentration of less than 5 g/dL, in one-third of patients with a hemoglobin concentration of 5-6 g/dL, and in no patients with a hemoglobin concentration of greater than 6 g/dL. On this basis, he states that retinopathy is most likely associated with a hemoglobin concentration of less than 6 g/dL. Wise and colleagues[1] stated that a hemoglobin concentration of 2.5 g/dL or less is usually associated with retinopathy. Merin and Freund[9] studied 89 patients with anemia in Africa. The majority of their patients had anemia secondary to nutritional deficiency and hookworm infestation. None of their patients with a hemoglobin level greater than 8 g/dL had retinopathy, whereas 46% of those with a hemoglobin concentration of less than 8 g/dL showed hemorrhages or 'exudates', or both. Aisen and associates[10] examined 35 anemic patients and 35 age- and sex-matched controls. Twenty percent of the anemic patients had hemorrhages or cotton wool spots, but there was no correlation with the hematocrit value. Rubenstein and co-workers[11] studied two groups of patients with anemia. Group 1 consisted of 67 patients, each having a hemoglobin concentration of less than 12 g/dL or a platelet count of less than 100000, or both. A variety of diseases was present in this group, including many cases of leukemia. Some of the leukemic patients were receiving chemotherapy. It was demonstrated in these patients that, for a given platelet level, a lower hematocrit value was more likely to be associated with retinal hemorrhages. Similarly, for a given hemoglobin concentration, more severe thrombocytopenia was more likely to be associated with retinal hemorrhage. The data for group 1 are summarized in Table 170.1.
TABLE 170.1 -- Data for Group 1 in Rubenstein and Co-Workers' Study
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Platelets/mm2 |
Hemoglobin g/dL |
Patients (n) |
Patients with Retinal Hemorrhage |
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<50 000 |
<8 |
10 |
7 |
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8-12 |
14 |
5 |
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>12 |
1 |
0 |
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50 000-100 000 |
<8 |
7 |
3 |
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8-12 |
8 |
2 |
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>12 |
5 |
0 |
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>100 000 |
<8 |
19 |
2 |
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8-12 |
3 |
0 |
Data from Rubenstein RA, Yanoff M, Albert DM: Thrombocytopenia, anemia, and retinal hemorrhage. Am J Ophthalmol 1968; 65:435.
Group 2 consisted of 123 hemophiliacs and 42 patients with Cooley's anemia. All patients in this group had a hemoglobin concentration of less than 8 g/dL at some point in the course of disease, but none had thrombocytopenia. No patient in this group had retinal hemorrhages. Not all members of group 2 had a dilated fundus examination by an ophthalmologist, whereas all members of group 1 did have such an evaluation. It is therefore possible that the number of retinal hemorrhages in the patients in group 2 was underestimated. Since many leukemic patients were included in group 1, it is not possible to determine from their data whether the relationship among anemia, thrombocytopenia, and retinopathy holds true for nonleukemic cases. Holt and Gordon-Smith[12] examined a large number of patients with a variety of blood diseases. They studied 33 patients with leukemia and found that 18 of them had retinopathy, which was more likely with increasing anemia and thrombocytopenia. These authors did not report platelet levels in their other cases of anemia, but they did give the impression that the combination of anemia and thrombocytopenia was more likely to yield retinopathy. They found that more profound anemia was required to produce cotton wool spots than was required to produce hemorrhages.
Carraro and associates[13] studied 226 consecutive patients with anemia alone, thrombocytopenia alone or both. They excluded patients with leukemia, diabetes and hypertension and liver cirrhosis. All patients had dilated eye exams by ophthalmologists. Most common fundus findings were superficial flame-shaped or discrete hemorrhages. There were few patients with subhyaloid hemorrhages and one with disk edema. As a whole, 28% of the patients had retinopathy findings. Among patients with both anemia and thrombocytopenia the incidence of retinopathy ranged from ~10% with the presence of mild anemia and thrombocytopenia and increased to 100% in the presence of combined severe anemia and severe thrombocytopenia. In severe anemia (less than 8 g/dL) only, 70% of patients had retinopathy findings, and in severe or very severe thrombocytopenia alone (<50 × 109/L), 45% of patients (four of nine) had retinopathy findings.
Merin and Freund,[9] in their study of anemia in Africa, could fid no cases of retinopathy in children, despite very low hemoglobin levels. This has led to speculation that age is a factor in the prevalence of retinal abnormalities in anemia. Aisen and associates,[10] however, could not confirm a correlation between age and retinopathy in their population. These two studies also suggested that hemorrhages and cotton wool spots in anemia were more common in males than in females. Aisen and associates subjected this hypothesis to statistical analysis and failed to fid significance despite the trend. The Carraro et al study,[13] which is the largest and most carefully performed to date, failed to fid an association between age or sex and retinopathy in multivariate analysis. They did not, however, include children.
In summary, a precise level of anemia at which retinal abnormalities will occur cannot be given. Several studies have shown that prevalence of retinopathy increases with severity of anemia. Retinal abnormalities in anemia without accompanying thrombocytopenia are less common, unless the anemia is profound. The combination of thrombocytopenia and anemia makes retinopathy more likely. Young children may be less likely to show retinal changes with anemia, unless it is caused by leukemia.
Venous tortuosity may be a feature of anemic retinopathy,[10] but there is no correlation with the hematocrit value.[14]
The pathophysiology of retinopathy in anemia is poorly understood. It is possible that dilatation of retinal vessels occurs as a response to retinal hypoxia in profound anemia. The resulting increase in transmural pressure, or perhaps the hypoxia itself, may damage vascular walls. Thrombocytopenia might contribute by retarding healing. This scheme might explain vascular leakage that produces hemorrhage and edema. Cotton wool spots are infarcts of the nerve fiber layer of the retina. It is possible that they are produced by relative hypoxia in anemia; vascular spasm might explain their focal nature.
LEUKEMIA
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Key Features |
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The fundus in leukemia may show venous dilatation, tortuosity, and irregularity, and vessels may show abnormal color and sheathing. Flame, white-centered, preretinal and vitreous hemorrhages; cotton wool spots; and leukemic infiltrates may occur (Figs 170.3 to 170.5). The latter appear as white clumps or masses in the retina. Microaneurysms, venous occlusions, and neovascularization are sometimes seen, typically in chronic leukemia. Serous detachment of the retina may occur as a result of choroidal infiltration.[15-17]
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FIGURE 170.3 Large leukemic infiltrate. |
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FIGURE 170.4 (a) Intraretinal and preretinal hemorrhages in a case of acute lymphatic leukemia. Right eye. (b) Left eye of the patient in (a). |
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FIGURE 170.5 (a) Retinal vascular dilatation and tortuosity in a case of secondary polycythemia. Right eye. (b) Left eye of the patient in (a). |
In general, the presence of retinal abnormalities in leukemia has not been well correlated with the white cell count. Autopsy studies show a high agonal white cell count in patients with leukemic infiltration,[18]but the relationship between the white cell count and infiltration was difficult to demonstrate in most clinical studies. A recent study of leukemic patients in Malaysia however, demonstrated an association between hemorrhages with white centers and the white blood count, whereas hemorrhages without white centers were found to correlate with low platelet counts.[19]
The anemia, thrombocytopenia, and hyperviscosity that may accompany leukemia probably account for many of the retinal findings. Retinal hemorrhages are likely the result of anemia and thrombocytopenia. As discussed in the section on anemia, for a given platelet level, a lower hematocrit value is more likely to be associated with retinal hemorrhages.[11,12] Similarly, for a given hemoglobin level, more severe thrombocytopenia is more likely to be associated with retinal hemorrhage. A prospective study of retinopathy in leukemia by Guyer and colleagues[20] as well as a study by Reddy and Jackson[19] demonstrated significantly lower platelet counts in patients with retinal hemorrhages in comparison with those without such lesions, regardless of the type of leukemia. In these studies, patients with acute lymphocytic leukemia and retinal hemorrhages showed lower hematocrit levels than did those without retinal hemorrhages. This relationship was not demonstrated in patients with myeloid leukemia. In patients with acute nonlymphocytic leukemia, the presence of anemia was related to the presence of white-centered hemorrhages in Guyer's study[20] but not in Reddy and Jackson's.[19]Hemorrhages (with or without white centers) and cotton wool spots were more common in adults than in children in Guyer's study but not in Reddy and Jackson's. There was no correlation between fundus findings and mean leukocyte counts in Guyer's study. Karesh and co-workers,[21] in a prospective evaluation of the fundi of patients with myeloid leukemia, demonstrated significantly lower platelet counts in patients with retinopathy than in those without fundus lesions. They found no difference in hematocrit levels and white cell counts in groups with and without retinopathy. They did not do a separate analysis for different types of retinal lesions. Most of their patients with retinopathy had retinal hemorrhages.
Venous dilatation, tortuosity, and irregularity seen in leukemia may be caused by a combination of anemia and hyperviscosity. Venous occlusions are likely to result from hyperviscosity. Cotton wool spots are caused by occlusion of precapillary arterioles, but the reason for these occlusions in leukemia has not been established. Ischemia secondary to anemia, direct occlusion by leukemic cells, occlusion by platelet-fibrin aggregates, or sludging resulting from hyperviscosity may all be factors. In their prospective study, Guyer and colleagues[20] did not fid an association between hematologic variables and cotton wool spots.
Microaneurysms are seen in cases of chronic leukemia and may be related to hyperviscosity.[22,23] In Jampol and colleagues'[23] study of 25 patients with chronic leukemia, eight individuals had microaneurysms.
Neovascularization may also be seen in cases of chronic leukemia.[24] It is usually accompanied by capillary closure.[25] The white centers of some hemorrhages seen in leukemia may consist of leukemic cells and debris, platelet-fibrin aggregates, or septic emboli.[26]
The prevalence of retinal involvement in leukemia varies widely in the literature. Almost all studies suffer from their retrospective nature and a variety of selection biases. Schachat and associates[27]performed a prospective ophthalmic study of patients with newly diagnosed leukemia. A summary of the prevalence of retinal findings in their patients is given in Table 170.2. They found a 5% prevalence of visual loss caused by vitreoretinal disease in those patients in whom a reliable acuity determination was possible. Another prospective study of 288 patients found similar results, with about a third of the patients showing retinal findings. A low percentage (~ 1.5%) had neuro-ophthalmic findings. Ocular findings were more common in adults than in children (50% vs 16%) and more prevalent in myeloid leukemia versus lymphoid (40% vs 30%).[28] Karesh and co-workers[21] prospectively evaluated the fundi of patients with myeloid leukemia and found that 53% of their subjects had retinopathy. Five of 53 patients in their study had visual loss in one or both eyes related to macular hemorrhage.
TABLE 170.2 -- Prevalence of Retinal Findings in Schachat and Associates' Study
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Retinal Finding |
Myeloid Patients (%) |
Lymphoid Patients (%) |
Total Affected (%) |
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Intraretinal hemorrhage |
33 |
13 |
24 |
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Cotton wool spot |
24 |
6 |
16 |
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White-centered hemorrhage |
13 |
8 |
11 |
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Central vein occlusion |
7 |
0 |
4 |
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Vitreous hemorrhage |
4 |
0 |
2 |
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Leukemic infiltrate |
3 |
From Schachat AP, Markowitz JA, Guyer DR, et al: Ophthalmic manifestations of leukemia. Arch Ophthalmol 1989; 107:697. Copyright 1989, American Medical Association.
Alterations in the retinal pigment epithelium caused by leukemia have been reported by several authors.[29-32] The appearance is one of pigment clumping or a reticular pattern of pigment change. Pathologic examination demonstrates leukemic infiltration of the choroid and retina, with destruction and hyperplasia of the pigment epithelium.
There are reports of bilateral central serous retinopathy in acute lymphocytic leukemia as well as other serous retina detachments.[15-17,33] It is difficult to know whether the central serous retinopathy cases represented a chance occurrence of two conditions, a manifestation of leukemia, or were limited presentations of serous retinal detachment secondary to infiltration of the choroid. Kuwabara and Aiello[34]described the pathologic findings in a case of leukemic miliary nodules of the retina.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that can cause leukemia. The virus is endemic in southwest Japan, some Caribbean countries, sub-Saharan Africa, and parts of the Middle East. It has been seen in Melanesia, the southeastern United States, and South America. Transmission of the virus is similar to that of human immunodeficiency virus.
Infection with HTLV-1 may produce several clinical pictures.[35] The most common are transverse myelopathy and leukemia/lymphoma. It may also produce pulmonary alveolitis, Sjögren's syndrome, and polymyositis.
About 10% of patients with transverse myelopathy and HTLV-1 infection have a pigmentary retinopathy.[36,37] Some of these cases show a progressive, widespread retinal degeneration indistinguishable from retinitis pigmentosa. The electroretinogram in these cases is markedly abnormal. Other patients have a sectoral or regional atrophy of the retina and choroid that is nonprogressive. Fukushima and associates[38] demonstrated that T cells responsive to HTLV-1-infected cells are cross-reactive with retinal antigens, suggesting a possible mechanism for the retinal degeneration.
Retinal infiltration similar to that seen in large-cell lymphoma may occur with HTLV-1 leukemia/lymphoma. Kumar and colleagues[39] described such a patient who presented with deep retinal and subretinal infiltrates. Chorioretinal biopsy demonstrated large atypical mononuclear cells located primarily in the retinal pigment epithelium, but focally involving the neurosensory retina.
HTLV-1 infection has been associated with anterior uveitis, vitreous infiltration, and uveitis with retinal perivasculitis.[40,41] Evidence that the virus may be causative of these forms of uveitis is presented in two studies. Nakao and co-workers[42] demonstrated that 41% of patients with nonspecific uveitis had positive titers to HTLV-1, compared with ~23% of patients with other ocular disorders. The latter percentage did not differ significantly from the general population in this endemic area.
Mochizuki and associates[43] found a 35% seroprevalence of HTLV-1 in nonspecific uveitis patients in an endemic area, versus 16% in patients attending the eye clinic who did not have uveitis. The typical clinical picture included iritis, midvitreous inflammation, and retinal vasculitis. In this study, proviral DNA was detected by polymerase chain reaction in inflammatory cells from the anterior chambers of seven of nine seropositive patients with uveitis. The inflammatory cells from patients with other forms of uveitis were tested, and none were positive.
A mother and son who were both infected with HTLV-1 developed white-yellow intraretinal lesions and vitreous opacities without vitreous cells or anterior uveitis. The lesions did not respond to systemic steroid administration, but later resolved spontaneously.[44]
Cotton wool spots and Cytomegalovirus infection of the retina have also been reported with this virus.[40] A comprehensive review of the ocular findings in HTLV-1 can be found in Buggage.[45]
POLYCYTHEMIA
Foulds[2] pointed out that whole-blood viscosity is considerably influenced by the number of red cells present. He found that clinical signs of hyperviscosity begin with a hematocrit value greater than 50%. Wise and colleagues[1] noted that there is a linear relationship between viscosity and hematocrit value up to a hematocrit of 50%. When the level is greater than this, viscosity increases exponentially with the rising hematocrit value. Blood flow in retinal vessels is typically laminar, and Foulds noted that this may be responsible for the proportionality of whole-blood viscosity to the shear rate; thus, whole-blood viscosity is greater when blood flow is slower, and hyperviscosity, therefore, results in greater changes in the venous system.
In polycythemia, the fundus typically shows dark, dilated, tortuous veins (Figs 170.6 and 170.7). The disk is usually hyperemic and swollen, intraretinal hemorrhages are frequently seen, and there may be retinal edema. Central or branch vein retinal occlusions may occur. Patients may lose vision because of retinal edema or vein occlusion. Abnormalities are almost always present in both eyes; the patient with a central vein occlusion in one eye and a normal fellow eye rarely has underlying polycythemia.
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FIGURE 170.6 (a) Retinal vascular dilatation and tortuosity, with intraretinal hemorrhage, in a case of hyperviscosity due to dysproteinemia. Right eye. (b) Left eye of the patient in (a). There is disk hyperemia in addition to vascular dilatation, tortuosity, and intraretinal hemorrhage. |
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FIGURE 170.7 (a) Waldenström's macroglobulinemia with venous dilatation and beading, as well as intraretinal hemorrhage. Right eye. (b) Left eye of the patient in (a). |
Bilateral vein occlusion in polycythemia secondary to Eisenmenger syndrome has been reported.[46] However, primary polycythemia is more likely to produce retinopathy than is secondary polycythemia, probably because of higher red cell counts and hyperviscosity in the former.[1] Treatment will reverse most of the findings unless venous occlusion has occurred.
DYSPROTEINEMIAS
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Key Features |
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Dysproteinemia that results in hyperviscosity of the serum from a variety of causes can produce a dramatic retinopathy.[47] Carr and Henkind[47] reported similar retinal findings in cases of hyperviscosity caused by cryomacroglobulinemia, hypergammaglobulinemia, Waldenström's macroglobulinemia, chronic lymphoctyic leukemia with macroglobulinemia, and multiple myeloma with hyperglobulinemia. Waldenström's macroglobulinemia may be the most likely dysproteinemia to produce retinopathy, possibly because the large size of the protein molecules in this condition lead to very high viscosity levels.[1]Holt and Gordon-Smith,[12] however, found no correlation between total serum protein and retinopathy in their series. Rather, they thought that the presence of retinopathy correlated with the degree of anemia found in their patients. They noted that their patients, as well as others reported in the literature with Waldenström's macroglobulinemia and retinopathy, exhibited severe anemia.
In retinopathy of dysproteinemia, the retinal veins are dark, dilated, and tortuous; intraretinal hemorrhages and cotton wool spots are seen; and the disk is hyperemic. The retinal hemorrhages may be of the superficial flame or deep punctate type and extend to the periphery. Retinal edema may occur. Central or branch vein retinal occlusion may be found, as in polycythemia. Visual loss may be due to vascular occlusion or retinal edema. Abnormalities are usually found bilaterally.
Retinal microaneurysms may be seen in more chronic cases.[48] Exudative retinal detachment has been described in multiple myeloma.[49,50] Neovascularization of the retina or iris with vitreous hemorrhage or neovascular glaucoma can occur. Fibrous proliferation has been described.
Retinopathy may be reversible with treatment of the underlying disease if frank vein occlusion has not occurred.[51]
More recently a paraneoplastic retinopathy in a patient with Waldenström's macroglobulinemia has been reported with findings of deteriorating vision, declining electroretinogram and presence of serum antibodies against photoreceptor proteins.[52]
Cases of serous detachment of the retinal pigment epithelium and neurosensory retina have been reported in patients with paraproteinemia.[53-55] The relationship of the paraproteinemia to development of these serous leaks is uncertain since patients were on steroids.
Purtscher-like retinopathy picture has also been reported in hepatitis C-associated cryoglobulinemia.[56]
HEMORRHAGIC DISORDERS
The retina is not typically involved in hemorrhagic disorders unless there is ocular trauma. Thrombocytopenia is an exception, particularly if there is accompanying anemia (as described earlier). Idiopathic thrombocytopenic purpura rarely results in retinopathy.[7] Thrombotic thrombocytopenic purpura may cause retinal hemorrhages and serous retinal detachment; the relative roles of thrombosis, hypertension, and renal disease in producing the retinal findings are uncertain.[57,58] Fundus appearance compatible with Purtscher's retinopathy has been reported in patients with thrombotic thrombocytopenic purpura.[59]
APPROACH TO THE PATIENT WITH RETINAL HEMORRHAGES OF UNKNOWN CAUSE
The patient who presents with retinal hemorrhages can be a diagnostic dilemma, as the list of conditions involved in the differential diagnosis is long. The first task is to decide whether the hemorrhages are intraretinal, subretinal, or preretinal. Intraretinal hemorrhages are of two types: dot and blot, and flame. Dot and blot hemorrhages are located deep in the retina and are confied by the anteroposterior orientation of the rods and cones, bipolar cells, and Müller's cells. When viewed end-on through the ophthalmoscope, they appear as round, red dots or somewhat larger round 'blots'. Flame hemorrhages are located in the superficial retina and are confied by the mediolateral, arcing orientation of the nerve fiber layer. When viewed with the ophthalmoscope, they are flame shaped, with feathery borders. Flame hemorrhages tend to occur mainly in the posterior portion of the retina. In the periphery, hemorrhages appear as dots and blots regardless of their level in the retina.[60] Intraretinal hemorrhages occur in a wide variety of disorders, including many systemic diseases and retinal venous occlusions. Subretinal hemorrhages are amorphous in shape and are deep to the retinal vessels. These hemorrhages occur in trauma or with subretinal neovascularization (e.g., from age-related maculopathy). Preretinal hemorrhages may also be amorphous, or they may be boat shaped, with a horizontal upper border and a curved lower border (caused by settling of red cells). These hemorrhages cover retinal vessels. Preretinal hemorrhages occur with retinal neovascularization (e.g., in diabetic retinopathy or sickle cell disease), vitreous detachment or retinal breaks, and trauma. Occasionally, they are seen in other disorders (e.g., vein occlusion without neovascularization, leukemia, or subarachnoid hemorrhage).
Bilateral intraretinal hemorrhages pose the greatest challenge to the differential diagnosis. Unilateral intraretinal hemorrhages are most frequently due to venous occlusive disease. Bilateral findings suggest systemic disease as the cause. The distribution of the hemorrhages may be helpful. If they occur mainly in the posterior fundus, systemic disease is likely. Extension to the far periphery suggests venous occlusive disease. Confiement to the peripapillary retina suggests optic nerve disease (including papilledema). Accompanying findings may be helpful in the differential diagnosis. Venous dilatation suggests obstructed flow, which may be due to venous occlusion or hyperviscosity. Microaneurysms are the hallmark of diabetic retinopathy, but they occur with hypertension, venous occlusion, leukemia, and other disorders. They are, however, a sign of chronicity. Arteriolar narrowing and sclerotic changes suggest systemic hypertension. Flame hemorrhages are more frequent in hypertension, with dot and blot lesions more common in diabetes, but both lesions occur in either disorder as well as in vein occlusion and retinopathy associated with blood disorders. Cotton wool spots or white-centered hemorrhages often accompany retinal hemorrhages, and they may be seen in so many disorders that they are of little help in the differential diagnosis. A thorough medical history, general physical examination, complete blood count, and blood glucose determination will reveal the cause of bilateral, posterior intraretinal hemorrhages in the majority of cases. Study of serum protein levels may be useful when hyperviscosity is suspected. Fluorescein angiography may be useful in demonstrating subtle abnormalities of the retinal and choroidal vasculature.
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