(Radiographics. 2001;21:971-994.)
© RSNA, 2001
Sickle Cell Anemia1
Gael J. Lonergan, Lt Col, USAF, MC,
David B. Cline, MAJ, MC, USA and
Susan L. Abbondanzo, MD
1 From the Department of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (G.J.L.); Departments of Radiologic Pathology (G.J.L.) and Hematopathology (S.L.A.), Armed Forces Institute of Pathology, 14th St and Alaska Ave NW, Bldg 54, Rm M-121, Washington, DC 20306-6000; and Department of Radiology, Walter Reed Army Medical Center, Washington, DC. Received December 15, 2000; revision requested December 28 and received January 26, 2001; accepted February 7. Address correspondence to G.J.L. (e-mail: lonergan@afip.osd.mil).
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Abstract
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Sickle cell anemia (SCA) is a disease caused by production of abnormal hemoglobin, which binds with other abnormal hemoglobin molecules within the red blood cell to cause rigid deformation of the cell. This deformation impairs the ability of the cell to pass through small vascular channels; sludging and congestion of vascular beds may result, followed by tissue ischemia and infarction. Infarction is common throughout the body in the patient with SCA, and it is responsible for the earliest clinical manifestation, the acute pain crisis, which is thought to result from marrow infarction. Over time, such insults result in medullary bone infarcts and epiphyseal osteonecrosis. In the brain, white matter and gray matter infarcts are seen, causing cognitive impairment and functional neurologic deficits. The lungs are also commonly affected, with infarcts, emboli (from marrow infarcts and fat necrosis), and a markedly increased propensity for pneumonia. The liver, spleen, and kidney may experience infarction as well. An unusual but life-threatening complication of SCA is sequestration syndrome, wherein a considerable amount of the intravascular volume is sequestered in an organ (usually the spleen), causing vascular collapse; its pathogenesis is unknown. Finally, because the red blood cells are abnormal, they are removed from the circulation, resulting in a hemolytic anemia. For the patient with SCA, however, the ischemic complications of the disease far outweigh the anemia in clinical importance.
Index Terms: Sickle cell disease (SS, SC), 10.651, 40.214, 40.651, 60.651, 76.651, 77.651, 81.651
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LEARNING OBJECTIVES FOR TEST 5
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After reading this article and taking the test, the reader will be able to:
- Describe the pathophysiology of hemoglobin and red blood cells in sickle cell anemia.
- Define the imaging features of the common sequelae of sickle cell anemia.
- Describe the role of imaging in the diagnosis and evaluation of suspected complications of sickle cell anemia.
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Introduction
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Sickle cell anemia (SCA) is a hemolytic anemia characterized by abnormally shaped (sickled) red blood cells (RBCs), which are removed from the circulation and destroyed at increased rates, leading to anemia. Of greater clinical importance, the sickled RBCs cause vascular occlusion, which leads to tissue ischemia and infarction. The underlying abnormality in the RBC of SCA is the presence of abnormal sickle cell hemoglobin (Hb S), which, when deoxygenated, becomes relatively insoluble and forms aggregates with other hemoglobin molecules within the RBC. These aggregates develop into long chains, which distort the RBC into a sickled shape and impair flow through vessels. In addition, the deformed RBCs tend to adhere to endothelium, worsening vascular occlusion, ischemia, and the likelihood of tissue infarction. For the vast majority of patients with SCA, the vaso-occlusive complications of the disease are much more clinically troublesome than is the anemia, which is usually well tolerated (1,2).
The first published account of SCA was by Herrick in 1910 (3), who described the clinical and hematologic manifestations of the disease in a 20-year-old dental student from Grenada. Later, Pauling et al (4) determined that a point mutation in the gene coding the ß chain of the hemoglobin molecule resulted in a single amino acid substitution (valine for glutamic acid) in the ß globin chain, which, when present on both chromosomes in a patient, resulted in sickle cell hemoglobin or Hb S. When a patient possesses two sickle cell hemoglobin genes (Hb SS), sickle cell anemia results; a heterozygote patient (with one normal and one sickle cell ß globin chain) is designated Hb SA. Thus, SCA was the first disease determined to have a molecular basis (4). This single amino acid substitution leads to a complex array of abnormal hemoglobin chain interactions, RBC cell membrane permeability changes, endothelial adhesion, vascular occlusion, and increased hemolysis (5).
The term sickle cell disease applies to all patients with at least a single Hb S chain and one other abnormal ß globin chain, which may be another sickle cell ß chain (in which case the patient is homozygous Hb SS and by definition has sickle cell anemia), Hb SC, or one of the thalassemias (Hb S-thal). There are also other, much less common abnormal ß globin chains, which may combine with a sickle cell ß chain to produce rarer forms of sickle cell disease, such as Hb SD. Overall, Hb SS accounts for 60%–70% of the cases of sickle cell disease in the United States and has the severest clinical manifestations of any of the sickle cell disease variants (5). Sickle cell trait (the heterozygous Hb SA, with one abnormal sickle gene designated S and one normal hemoglobin gene designated A) is for the most part a benign condition, with no propensity for vaso-occlusive complications. Sickle cell trait is associated with an increased risk of a rare renal tumor, medullary carcinoma (6). The importance of sickle cell trait lies with its implications for genetic counseling (5). Notably, Hb S appears to reduce susceptibility to malaria (Plasmodium falciparum infection) in a dose-dependent manner; a patient with homozygous Hb SS is more resistant to malaria infection than is a patient with heterozygous Hb SA (7).
SCA is the most common single gene disorder in black Americans, affecting about one in 375 blacks in the United States. Approximately 0.15% of the black population in the United States is afflicted with SCA, and just under one in 12 Americans of African descent has heterozygous sickle cell trait. SCA is prevalent in other ethnic groups as well, including those from Mediterranean area countries, Turkey, the Arabian peninsula, and the Indian subcontinent. It may be seen in people of Spanish descent and those from the Caribbean, South America, and Central America (8,9).
This article reviews the pathophysiology of SCA, with emphasis on the major organs affected by the disease. The radiologic and pathologic findings of the various manifestations of SCA are described and illustrated. To complete the review of SCA, prognosis and treatment options are also discussed.
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Pathophysiology of SCA
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The normal human hemoglobin molecule consists of four globin chains: two 
chains and two ß chains. When the and ß chains are normal, this is abbreviated Hb A. Abnormal hemoglobin is designated by the type of abnormality in the globin chain. For example, the presence of one sickle cell (S) ß chain and one C ß chain is abbreviated Hb SC. Homozygous sickle cell disease is designated Hb SS. Abnormal hemoglobin, such as Hb SS, is usually the result of an abnormality in the ß (not ) chains.
The ß globin chain is coded on the short arm of chromosome 11. Sickle cell hemoglobin (Hb S) is formed when the amino acid valine is substituted for glutamic acid at the sixth position of the ß chain; this is the result of a point mutation in the gene coding for ß globin synthesis. This single amino acid substitution has far-reaching effects on hemoglobin interactions, RBC morphology, and hemodynamics. The Hb S ß chain, with valine at the sixth position, has an unusual propensity to bind with other Hb S chains (contained in other hemoglobin molecules within the RBC) when deoxygenated. The basic structural unit that results is a twisted, ropelike structure composed primarily of two complete hemoglobin molecule strands, with binding between the ß chains (Fig 1). This process is referred to as polymerization. The result is a strand of relatively rigid, polymerized hemoglobin molecules. Onto this basic polymer, other hemoglobin molecules may also polymerize, leading to large polymer strands. These rigid strands distort the RBC into a variety of elongated shapes and decrease its deformability (10). This sets the stage for vascular obstruction (Fig 1) and hemolysis.
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Figure 1. Diagrams illustrate the pathophysiology of SCA. A shows a hemoglobin molecule composed of two chains and two sickle ß chains. In B, the hemoglobin molecules bind together across ß chains, forming a strand of hemoglobin molecules. In C, other hemoglobin molecules bind to the strand, creating a large polymer. In D, the RBC is distorted by the rigid polymers within into an elongated, sickle shape. In E, the sickled RBCs obstruct small vascular channels.
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Polymerization is an ongoing process in SCA. Its extent depends on a number of factors, with the most important being the rate and extent of deoxygenation, the hemoglobin concentration in the cell (the higher the hemoglobin concentration, the more readily polymerization will occur), the intracellular hemoglobin composition (the presence and percentage of other hemoglobin variants, such as fetal hemoglobin [Hb F], which may inhibit polymerization), pH, and temperature. An individual RBC may undergo episodes of partial polymerization when deoxygenated, which may then reverse after reoxygenation. Cycles of deoxygenation and reoxygenation, with polymer formation, continue throughout the life of the RBC in SCA (1,10).
Polymerization is responsible for the sickled or banana shape of RBCs in SCA (Fig 2). Polymerization also causes a nonselective increase in membrane cation permeability to sodium, potassium, magnesium, and calcium. When these cations enter the RBC (down their concentration gradient), several cell membrane transport systems are activated, with the important cumulative effect being the egress of water. This leads to RBC dehydration (forming a "dense" RBC). RBC dehydration in turn increases the hemoglobin concentration in the cell, which tends to accelerate polymerization during the next episode of deoxygenation and leads to more dehydration. The end result of multiple episodes of polymerization (which is reversible) and dehydration (which is not fully reversible) is a dense, irreversibly sickled cell. When oxygenated, an irreversibly sickled cell may contain no polymer but is nonetheless distorted in shape and will contribute to vaso-occlusion (1,10,11).
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Figure 2. Sickled RBCs in SCA. High-power photomicrograph (original magnification, x100; hematoxylin-eosin stain) of a spleen tissue sample shows sickled RBCs (arrows) in the vascular sinuses.
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Deformability of individual RBCs is necessary for normal RBC passage through the smallest of vascular channels. Cellular dehydration leads to increased viscosity of the RBCs, with resultant decreased deformability of Hb S cells, even when oxygenated. The membrane of Hb SS RBCs is also abnormal in a variety of ways, contributing to abnormal deformability. Finally, deoxygenation profoundly alters deformability through its induction of polymerization. These features make negotiation of the microvasculature difficult, if not impossible, for many Hb SS RBCs (Fig 3) (12).
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Figure 3. Vascular sinus congestion with Hb SS RBCs. Medium-power photomicrograph (original magnification, x40; hematoxylin-eosin stain) of a spleen tissue sample shows congestion of the vascular sinuses with Hb SS RBCs.
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RBCs in SCA also appear to have an increased binding affinity for vascular endothelium. The degree of affinity correlates strongly with the severity of clinical disease. Several molecular interactions are likely to contribute to this endothelial affinity. One is a surface complex on reticulocytes that binds to endothelium. Another mechanism is a complex present on both reticulocytes and endothelium that binds thrombospondin (secreted by activated platelets). Several other plasma proteins, perhaps increased in times of stress, promote adhesion of Hb SS RBCs to vascular endothelium, which worsens vaso-occlusion (10,12). It has also been shown that adherent sickled RBCs inhibit vasorelaxation (13).
Finally, it has long been known that the macrovasculature of patients with SCA may develop intimal hyperplasia. This creates irregular areas of endoluminal narrowing, which likely worsen vaso-occlusion by promoting thrombosis. This process has been documented in the cerebral and splenic vascular beds (14).
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Clinical Presentation of SCA
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Newborn screening programs in 41 states and the District of Columbia detect SCA by using hemoglobin electrophoresis, isoelectric focusing, high-performance liquid chromatography, or DNA analysis. Solubility testing (Sickledex) is no longer commonly used, as it detects only Hb SS and may miss other ß globin variants such as Hb SC. Newborn screening enables prompt diagnosis, institution of parental education, and prophylactic penicillin administration to reduce the risk of life-threatening bacteremia (5,7).
Acute, painful vaso-occlusive crises are the most common, and earliest, clinical manifestations of SCA. Half of all patients with SCA experience a painful crisis by 4.9 years of age. The pain is usually described as bone pain, although crises may involve virtually any organ. They are presumed to be caused by microvascular occlusion with subsequent tissue ischemia. In young children, vaso-occlusive crises most commonly manifest as dactylitis, a painful swelling of the hands, fingers, feet, and toes (15). Other problems in SCA include osteomyelitis, osteonecrosis, splenic infarct, splenic sequestration, acute chest syndrome, stroke, papillary necrosis, and renal insufficiency. This article reviews the clinical disease processes that result from SCA from an organ-based approach.
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The Lung
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The lung is a common site of involvement in SCA. Injuries range from acute processes, such as pneumonia and acute chest syndrome (ACS), to chronic entities, such as pulmonary fibrosis. Pulmonary complications constitute the second leading cause of hospitalization (after acute pain crises) and are now the leading cause of death for patients with SCA (16).
Pneumonia is much more common in children with SCA than in the unaffected pediatric population. It is estimated that children with SCA are 100 times more susceptible to developing pneumonia than other children, and they have a 30% recurrence rate (17). Impaired immune status, a result of functional asplenia and other abnormalities in the immune process, render the patient with SCA prone to infection, which most frequently manifests as pneumonia (5,18). Preventing this frequent, recurrent, and sometimes life-threatening complication is the goal of daily oral penicillin prophylaxis, begun by age 3 months and continued to at least 5 years of age (5,7). Pneumonia in SCA is most commonly caused by Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcus aureus, Chlamydia pneumoniae, and Salmonella organisms (19). The clinical manifestations are cough and fever, typical of pneumonia in the general population. A corresponding consolidation on chest radiographs helps confirm the diagnosis (Fig 4) (19). Pneumonia may lead to ACS.
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Figure 4a. Pneumonia in a 3-year-old patient with SCA. (a) Frontal chest radiograph shows a right pleural effusion (arrow). (b) Lateral chest radiograph shows subtle consolidation of the posterior lung base (arrow). (c) Chest computed tomographic (CT) scan acquired the following day helps confirm right lower lobe pneumonia and right pleural effusion, as well as revealing a small area of airspace disease in the posterior left lower lobe.
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Figure 4b. Pneumonia in a 3-year-old patient with SCA. (a) Frontal chest radiograph shows a right pleural effusion (arrow). (b) Lateral chest radiograph shows subtle consolidation of the posterior lung base (arrow). (c) Chest computed tomographic (CT) scan acquired the following day helps confirm right lower lobe pneumonia and right pleural effusion, as well as revealing a small area of airspace disease in the posterior left lower lobe.
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Figure 4c. Pneumonia in a 3-year-old patient with SCA. (a) Frontal chest radiograph shows a right pleural effusion (arrow). (b) Lateral chest radiograph shows subtle consolidation of the posterior lung base (arrow). (c) Chest computed tomographic (CT) scan acquired the following day helps confirm right lower lobe pneumonia and right pleural effusion, as well as revealing a small area of airspace disease in the posterior left lower lobe.
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The term acute chest syndrome describes an acute pulmonary illness, characterized by a new pulmonary consolidation and some combination of fever, chest pain, and signs of pulmonary compromise such as cough, dyspnea, and tachypnea. The cause of ACS is not fully understood, and there have been many causative agents identified, including infection and fat emboli; frequently, the underlying cause is not discovered in individual patients (5). ACS may progress to respiratory distress syndrome and death. The severity of the clinical symptoms distinguishes ACS from the clinically milder pneumonia. Because ACS may be caused by pneumonia, the two entities may constitute a continuum.
ACS is the second leading cause of hospitalization in patients with SCA, after painful crises. It accounts for 25% of deaths in patients with SCA and is currently the single leading cause of death in SCA. Children are more prone than adults to develop ACS (50% of all children will experience at least one episode of ACS), but adults have a higher mortality rate (4.3%) than do children (1.8%) (16). ACS is also a common postoperative complication in patients who have undergone general anesthesia and may be seen in up to 10% of these patients (20).
ACS may best be conceptualized as a common clinical manifestation of many different pathologic processes. One of the first recognized causes of ACS was bacterial pneumonia, especially from S pneumoniae, S aureus, H influenzae, Klebsiella organisms, and various viral and other agents. It is estimated that 2%–40% of ACS is associated with bacterial pneumonia. In children, bacteremia is a more common cause of ACS than in adults (bacteremia was documented in 14% of infants with ACS compared with just 1.8% of those over the age of 10 years in one large study) (16). Nonetheless, studies vary widely in reported incidence (16,21,22). Bacteremia, discovered in approximately one-third of fatal cases in one study, appears to correlate with a worse outcome, especially in adults (16).
Another common cause of ACS is theorized to be infarcting bone with resultant pulmonary fat emboli. Bronchoalveolar lavage studies have shown the presence of fat in pulmonary macrophages in up to 60% of adult ACS cases (23). This correlates with the oft-noted clinical history of SCA patients admitted with pain crises who later develop ACS during the same hospitalization. It is thought that the pain crisis indicates infarcting bone marrow, with subsequent embolization to the lungs and development of ACS (16,24,25). Rib infarction is also theorized to cause ACS because of pain and resultant hypoventilation (with the possible additional feature of fat emboli) (26).
Pulmonary vascular occlusion may also lead to ACS. Pulmonary thrombosis has been demonstrated at autopsy, and microvascular occlusion has been shown at thin-section CT in ACS (27,28). Segmental pulmonary artery occlusion has also been noted with perfusion scintigraphy during an episode of ACS (29). Pulmonary vascular occlusion may be a component of all cases of ACS and may even initiate ACS, as regional hypoxia leads to pulmonary vasoconstriction, sickling, and endothelial adhesion (30). Other factors linked to ACS include opioid use, pulmonary edema, and parvovirus B19 (the latter may cause bone marrow infarction and lead to fat emboli) (22).
The radiographic finding necessary for the diagnosis of ACS is single or multiple areas of pulmonary consolidation (Fig 5). However, 30%–60% of patients have no initial radiographic abnormality, often because they are admitted for another reason (usually for pain crises), and subsequently develop ACS (21,22,24). Abnormal chest radiographs show middle and lower lobe airspace disease more commonly than upper lobe disease. Pleural effusions are frequent and do not help differentiate infectious from noninfectious causes of ACS. One study noted that noninfectious consolidations in children tended to clear much more rapidly than infectious consolidations (21). The majority (70%) of patients with ACS are hypoxic (oxygen saturation <90%, as measured by pulse oximetry) (22).
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Figure 5a. Acute chest syndrome in an 8-year-old patient with SCA who presented with severe cough, chest pain, and fever. (a) Portable frontal chest radiograph shows consolidation of the left lower lobe, left pleural effusion, and a smaller area of consolidation in the right lung base. The child’s clinical status worsened to respiratory failure and death despite maximal therapy. (b) Photograph of the coronally sectioned lungs shows dark peripheral areas in both lungs, findings consistent with infarct, and central, red areas of recent pulmonary hemorrhage and vascular congestion. The child died from a combination of pulmonary infarction and hemorrhage, resulting in respiratory failure.
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Figure 5b. Acute chest syndrome in an 8-year-old patient with SCA who presented with severe cough, chest pain, and fever. (a) Portable frontal chest radiograph shows consolidation of the left lower lobe, left pleural effusion, and a smaller area of consolidation in the right lung base. The child’s clinical status worsened to respiratory failure and death despite maximal therapy. (b) Photograph of the coronally sectioned lungs shows dark peripheral areas in both lungs, findings consistent with infarct, and central, red areas of recent pulmonary hemorrhage and vascular congestion. The child died from a combination of pulmonary infarction and hemorrhage, resulting in respiratory failure.
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Treatment consists of hydration, transfusion, supplemental oxygen, and analgesia. Incentive inspirometry to improve atelectasis, antibiotic therapy for suspected infection, and steroids may also be used (22). Mechanical ventilation was needed in 13% of patients in one study (24). In severe cases, extracorporeal membrane oxygenation has been used successfully (31,32). The mean hospital stay is 7 days for adults and 4 days for children (16).
Repeated episodes of pulmonary insults such as ACS and pneumonia may lead to chronic pulmonary disease, which may ultimately prove fatal, in the patient with SCA. Chronic pulmonary disease occurs in approximately 4% of patients (19). At histologic evaluation, chronic lung disease in SCA consists of pulmonary fibrosis (usually focal), pleural scarring, adhesions, and pulmonary arteriolar intimal hyperplasia, with resultant pulmonary hypertension (22,33). At radiography, a fine reticular pattern representing generalized fibrosis is seen in the lungs (Fig 6) (19). At CT, typical findings include septal thickening, dilated secondary pulmonary lobules, traction bronchiectasis, and architectural distortion. Despite CT abnormalities, pulmonary function testing may be normal in patients with chronic lung disease (34). In children with SCA, a marked increase in airway hyperreactivity, which is typically asymptomatic, has been noted at pulmonary function testing (in 73% of patients) (35).
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Figure 6. Chronic lung disease in an asymptomatic 14-year-old boy with SCA. Chest radiograph shows a fine reticular pattern throughout both lungs and cardiomegaly (a result of the anemia). Partially visualized is a flattened, irregular, right humeral head (arrow), an appearance indicative of osteonecrosis.
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The Skeletal System
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The skeletal system of patients with SCA is remarkable for its lifelong preservation, and frequent expansion, of red (cellular) marrow. In healthy individuals, red marrow converts to yellow (fatty) marrow during childhood, with the transition beginning in the distal regions of the appendicular skeleton and moving to the more proximal regions. This process begins soon after birth, and by the 2nd decade of life, red marrow residua persist in the pelvis, sternum, ribs, and vertebrae. The epiphyses are fat-containing throughout life. In patients with SCA, most of their marrow space tends to be preserved as red marrow (Fig 7), sometimes even in their epiphyses. Expansion of the medullary space (due to increased hematopoietic demands from the anemia) may be especially evident in the skull, where a hair-on-end appearance may result from diploic space widening (Fig 8). Persistence of red marrow may make detection of marrow abnormality, such as infarction and infection, difficult (36).
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Figure 7. Persistent red marrow in a 7-year-old girl with SCA. Sagittal T1-weighted MR image of the spine shows heterogeneous low signal intensity in the cellular (red) marrow and H-shaped vertebrae (arrows).
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Figure 8a. Marrow expansion of the skull in a 12-year-old boy with SCA. (a) Collimated Water view of the skull shows striated appearance of the skull caused by diploic space widening and trabecular prominence. (b) Axial CT image (bone window) of the upper skull helps confirm diploic space widening and trabecular prominence. (c) Sagittal T1-weighted MR image of the brain shows diploic space widening with intermediate-signal-intensity material, representing red marrow (*). Note the sparing of the occipital bone (arrows), which contains no marrow elements.
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Figure 8b. Marrow expansion of the skull in a 12-year-old boy with SCA. (a) Collimated Water view of the skull shows striated appearance of the skull caused by diploic space widening and trabecular prominence. (b) Axial CT image (bone window) of the upper skull helps confirm diploic space widening and trabecular prominence. (c) Sagittal T1-weighted MR image of the brain shows diploic space widening with intermediate-signal-intensity material, representing red marrow (*). Note the sparing of the occipital bone (arrows), which contains no marrow elements.
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Figure 8c. Marrow expansion of the skull in a 12-year-old boy with SCA. (a) Collimated Water view of the skull shows striated appearance of the skull caused by diploic space widening and trabecular prominence. (b) Axial CT image (bone window) of the upper skull helps confirm diploic space widening and trabecular prominence. (c) Sagittal T1-weighted MR image of the brain shows diploic space widening with intermediate-signal-intensity material, representing red marrow (*). Note the sparing of the occipital bone (arrows), which contains no marrow elements.
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Skeletal complications of SCA include infarction and osteomyelitis. Both of these problems are assumed to be caused by the congested, cellular marrow found throughout much of the skeletal system of patients with SCA. This cellular marrow impedes blood flow, which enhances stasis, regional hypoxia, and sickling. Infarction may result. These same processes render the marrow susceptible to pathogens because normal defense is impaired; osteomyelitis may result (37,38).
Bone infarction is estimated to be at least 50 times more common than osteomyelitis in SCA, at least in children (39). Infarction typically occurs in the medullary cavity and the epiphysis, and it has been described in essentially every marrow-containing bone. Bone marrow infarction is thought to be the underlying cause of most pain crises in SCA, and, as mentioned, may result in fat emboli and ACS. Ischemia rapidly causes pain, even before infarction is manifested; therefore, radiographs obtained early during pain crises often appear normal. Patients with SCA are also prone to silent infarction, and the discovery of osteonecrosis may be an incidental finding (40).
Infarction manifests over time (which often takes months), first with an ill-defined zone of radiolucency, which subsequently develops arclike subchondral and intramedullary lucent areas, with patchy lucent and sclerotic areas. A peripheral rim of sclerosis is often seen, especially with medullary bone infarcts (Fig 9). At CT, an infarct initially manifests as disruption of the normal trabecular architecture and may be difficult to detect. As infarction progresses, it appears as circular areas of decreased attenuation. MR imaging is likely the most sensitive radiologic form of investigation, as it may show abnormality as soon as a few days after the ischemic insult. Infarction appears as an area of high signal intensity on T2-weighted and inversion recovery images (41). Abnormal periosteal signal intensity and soft-tissue changes may also be seen at MR imaging, making differentiation between infarction and osteomyelitis difficult (Fig 10) (42). Over time, these areas will become low signal intensity on all MR images (regardless of pulse sequence) as fibrosis and sclerosis replace the infarcted region.
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Figure 9a. Medullary bone infarcts in SCA. (a) Frontal radiograph of the right shoulder in a 22-year-old patient shows an area of patchy sclerosis and radiolucency. (b) Sagittal fat-suppressed T1-weighted magnetic resonance (MR) image of the right hip in a 19-year-old patient, obtained after intravenous injection of contrast material, shows multiple irregular areas of high signal intensity forming a rim around central areas of lower signal intensity, representing enhancement in areas of maturing medullary infarct. Note the high-signal-intensity regions in the medial acetabular wall, also representing infarct (arrowheads).
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Figure 9b. Medullary bone infarcts in SCA. (a) Frontal radiograph of the right shoulder in a 22-year-old patient shows an area of patchy sclerosis and radiolucency. (b) Sagittal fat-suppressed T1-weighted magnetic resonance (MR) image of the right hip in a 19-year-old patient, obtained after intravenous injection of contrast material, shows multiple irregular areas of high signal intensity forming a rim around central areas of lower signal intensity, representing enhancement in areas of maturing medullary infarct. Note the high-signal-intensity regions in the medial acetabular wall, also representing infarct (arrowheads).
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Figure 10a. Acute infarct with extraosseous soft-tissue abnormality in a 24-year-old man with SCA who presented with acute thigh pain. (a) Coronal T1-weighted MR image of the left femur shows heterogeneous abnormal signal intensity throughout the lower diaphysis extending to the articular surface, as well as surrounding soft-tissue edema. There are also areas of low signal intensity in the tibial plateau indicating infarct. (b) Coronal inversion recovery MR image of the same area shows heterogeneous high signal intensity of the lower shaft (including condyles), with considerable high signal intensity of the edematous soft tissue surrounding the femur.
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Figure 10b. Acute infarct with extraosseous soft-tissue abnormality in a 24-year-old man with SCA who presented with acute thigh pain. (a) Coronal T1-weighted MR image of the left femur shows heterogeneous abnormal signal intensity throughout the lower diaphysis extending to the articular surface, as well as surrounding soft-tissue edema. There are also areas of low signal intensity in the tibial plateau indicating infarct. (b) Coronal inversion recovery MR image of the same area shows heterogeneous high signal intensity of the lower shaft (including condyles), with considerable high signal intensity of the edematous soft tissue surrounding the femur.
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Treatment is generally supportive and includes administration of analgesics, hydration, and antibiotics if coexistent infection is suspected. In the spine, infarction may appear as a central, square-shaped endplate depression, resulting from microvascular endplate occlusion and subsequent overgrowth of the surrounding portions of the endplate. This appearance is seen in approximately 10% of patients, but it is essentially pathognomonic for SCA and has been called the Lincoln log or H-shaped vertebra deformity (Fig 11) (19). Overgrowth in height of at least one adjacent vertebral body has been noted in adults with infarcted vertebral bodies (43).
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Figure 11. H-shaped vertebrae in a 15-year-old patient with SCA. Lateral radiograph of the thoracolumbar junction demonstrates classic boxlike endplate depressions from osteonecrosis of the vertebral endplate.
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Epiphyseal infarction in SCA has a predilection for the proximal humeri and proximal femora, although any bone may be involved. SCA is the most common cause of osteonecrosis of the hip in children, and approximately half of all patients with SCA will develop epiphyseal osteonecrosis by the age of 35 years (44). Initially, the patient has pain, but radiographs appear normal. At this time, T2-weighted and inversion recovery MR images may show high signal intensity in the marrow, representing marrow edema resulting from ischemia. Subsequent radiographs show some mottled attenuation of the epiphysis, subchondral lucent areas, and, finally, flattening of the articular surface (Fig 12). Over time, osteoarthritis with joint space narrowing, articular surface sclerosis, and osteophytosis may occur. In weight-bearing joints such as the hip, joint replacement may be necessary (36). Bed rest is recommended for osteonecrosis, and core decompression has been reported to be effective in improving the outcome in younger (
21 years) SCA patients with early osteonecrosis (44).
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Figure 12a. Osteonecrosis of the femoral head in SCA. (a) Frontal radiograph of the right hip in an 11-year-old girl with SCA shows mottled attenuation of the proximal femoral epiphysis and slight irregularity of the articular surface. (b) Coronal T1-weighted MR image of a 10-year-old patient shows flattening and heterogeneous signal intensity of the femoral head, findings compatible with advanced osteonecrosis with sclerosis and collapse. The area of high signal intensity likely represents some normal fatty marrow in the epiphysis. (c) Photograph of a sectioned femoral head from a third patient shows an oval area of sclerosis (curved arrows) and subchondral fracture (straight arrow), both typical of osteonecrosis.
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Figure 12b. Osteonecrosis of the femoral head in SCA. (a) Frontal radiograph of the right hip in an 11-year-old girl with SCA shows mottled attenuation of the proximal femoral epiphysis and slight irregularity of the articular surface. (b) Coronal T1-weighted MR image of a 10-year-old patient shows flattening and heterogeneous signal intensity of the femoral head, findings compatible with advanced osteonecrosis with sclerosis and collapse. The area of high signal intensity likely represents some normal fatty marrow in the epiphysis. (c) Photograph of a sectioned femoral head from a third patient shows an oval area of sclerosis (curved arrows) and subchondral fracture (straight arrow), both typical of osteonecrosis.
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Figure 12c. Osteonecrosis of the femoral head in SCA. (a) Frontal radiograph of the right hip in an 11-year-old girl with SCA shows mottled attenuation of the proximal femoral epiphysis and slight irregularity of the articular surface. (b) Coronal T1-weighted MR image of a 10-year-old patient shows flattening and heterogeneous signal intensity of the femoral head, findings compatible with advanced osteonecrosis with sclerosis and collapse. The area of high signal intensity likely represents some normal fatty marrow in the epiphysis. (c) Photograph of a sectioned femoral head from a third patient shows an oval area of sclerosis (curved arrows) and subchondral fracture (straight arrow), both typical of osteonecrosis.
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Dactylitis, or hand-foot syndrome, is the term used to describe painful, swollen hands and feet accompanied by fever. It is most often seen in children younger than 4 years of age and is very uncommon after 7 years of age. Dactylitis is often the first clinical manifestation of SCA. At histopathologic evaluation, there is extensive infarction of the marrow, medullary trabeculae, and the inner layers of cortical bone, as well as subperiosteal new bone formation and periosteal elevation (45). At radiography, the hands and feet initiallyappear normal. Within 10 days of the onset of symptoms, periostitis with subperiosteal new bone is typically evident (Fig 13). There is also cortical thinning, irregular attenuation of the medullary spaces, and an overall moth-eaten appearance of the involved bones of the hands and feet. Treatment is conservative, with administration of analgesics, hydration, and empiric antibiotics if coexistent infection is suspected (46).
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Figure 13a. Hand-foot syndrome (dactylitis) associated with SCA. (a) Frontal radiograph of the right foot in a 3-year-old girl shows thick periostitis and subperiosteal new bone along the metatarsal shafts. (b) Photograph of the same patient’s right foot shows generalized soft-tissue swelling of the dorsum of the foot and bullous changes of the skin. (c) Radiograph of the left hand in a 1-year-old patient who presented with painful swelling shows milder changes of dactylitis, manifested by swelling of the index finger soft tissues and periostitis along the third through fifth metacarpal shafts.
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Figure 13b. Hand-foot syndrome (dactylitis) associated with SCA. (a) Frontal radiograph of the right foot in a 3-year-old girl shows thick periostitis and subperiosteal new bone along the metatarsal shafts. (b) Photograph of the same patient’s right foot shows generalized soft-tissue swelling of the dorsum of the foot and bullous changes of the skin. (c) Radiograph of the left hand in a 1-year-old patient who presented with painful swelling shows milder changes of dactylitis, manifested by swelling of the index finger soft tissues and periostitis along the third through fifth metacarpal shafts.
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Figure 13c. Hand-foot syndrome (dactylitis) associated with SCA. (a) Frontal radiograph of the right foot in a 3-year-old girl shows thick periostitis and subperiosteal new bone along the metatarsal shafts. (b) Photograph of the same patient’s right foot shows generalized soft-tissue swelling of the dorsum of the foot and bullous changes of the skin. (c) Radiograph of the left hand in a 1-year-old patient who presented with painful swelling shows milder changes of dactylitis, manifested by swelling of the index finger soft tissues and periostitis along the third through fifth metacarpal shafts.
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Osteomyelitis is a serious complication of SCA. It is most common in the diaphyseal region of bone in this patient population and most often found in the femur, tibia, and humerus (47). Patients with SCA and osteomyelitis present with pain, fever, erythema, and an elevated white blood cell count. The most commonly encountered organism is Salmonella (especially the nontypical serotypes S typhimurium, S enteritidis, S choleraesuis, and S paratyphi B), followed by S aureus. Among non-SCA patients, S aureus is the most common cause of osteomyelitis, but Salmonella organisms were shown to be at least two times more common than S aureus in a recent review of the world literature. In the United States, Salmonella organisms were five times more common than S aureus. The remainder of the causative organisms are usually gram-negative enteric bacilli (18,37,48). It is theorized that tiny infarctions in the gastrointestinal tract lead to Salmonella (and other enteric gram-negative) bacteremia and ultimately to osteomyelitis. In addition, diminished hepatic clearance of portal bacteremia, interference with macrophage bacterial phagocytosis, and abnormalities of the complement system and opsonization may all contribute to increased exposure and susceptibility to Salmonella and other enteric pathogens (37,49).
Osteomyelitis, although much less common than infarction, may be difficult to discriminate from infarction, even with clinical, laboratory, and radiologic information. Both may manifest with pain, fever, swelling, erythema, and a mildly elevated white blood cell count. Imaging is often requested to help determine the likelihood of osteomyelitis. Radiographic findings of periostitis and osteopenia are nonspecific and may be seen with both infarction and infection. These signs may progress to sclerosis (Fig 14). CT may depict subperiosteal abscess and fluid collections once thought to be diagnostic of osteomyelitis, although these findings may be seen with infarction as well (42,47). MR imaging is the preferred modality for evaluating marrow. Osteomyelitis demonstrates abnormally elevated signal intensity in the marrow on T2-weighted and inversion recovery images. The edges of this abnormal-signal-intensity area are typically ill-defined. The most sensitive and specific pulse sequence is T1 weighted, performed with fat saturation after administration of gadolinium-based contrast material (Fig 15). In cases of osteomyelitis, the areas of abnormal enhancement are almost always infected (36).
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Figure 14a. Salmonella osteomyelitis in a 10-year-old boy with SCA. (a) Initial frontal radiograph obtained at onset of lower shin pain and fever is normal. (b) Radiograph acquired 7 days later shows mottled attenuation of the lower tibial shaft and diffuse periostitis of the lower half of the diaphysis. (c) Repeat frontal radiograph obtained 5 weeks after the onset of symptoms shows generalized sclerosis of the lower tibial diaphysis with an area of central lucency, likely representing subacute or chronic abscess (arrow).
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Figure 14b. Salmonella osteomyelitis in a 10-year-old boy with SCA. (a) Initial frontal radiograph obtained at onset of lower shin pain and fever is normal. (b) Radiograph acquired 7 days later shows mottled attenuation of the lower tibial shaft and diffuse periostitis of the lower half of the diaphysis. (c) Repeat frontal radiograph obtained 5 weeks after the onset of symptoms shows generalized sclerosis of the lower tibial diaphysis with an area of central lucency, likely representing subacute or chronic abscess (arrow).
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Figure 14c. Salmonella osteomyelitis in a 10-year-old boy with SCA. (a) Initial frontal radiograph obtained at onset of lower shin pain and fever is normal. (b) Radiograph acquired 7 days later shows mottled attenuation of the lower tibial shaft and diffuse periostitis of the lower half of the diaphysis. (c) Repeat frontal radiograph obtained 5 weeks after the onset of symptoms shows generalized sclerosis of the lower tibial diaphysis with an area of central lucency, likely representing subacute or chronic abscess (arrow).
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Figure 15a. Osteomyelitis of the left femur in a 24-year-old patient with SCA. (a) Axial T1-weighted MR image acquired after intravenous injection of gadolinium-based contrast material shows heterogeneous enhancement of the marrow cavity, a rounded low-signal-intensity area adjacent to the shaft that is nonenhancing (representing a fluid collection), and enhancement of the soft tissues around the shaft and of the adjacent musculature. The areas of enhancement are likely infected. (b) Axial inversion recovery MR image obtained slightly lower in the femur shows high signal intensity surrounding a lower-signal-intensity area in the marrow cavity (likely representing early involucrum formation) and heterogeneous high signal intensity in the soft tissues of the lower thigh that represents edema.
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Figure 15b. Osteomyelitis of the left femur in a 24-year-old patient with SCA. (a) Axial T1-weighted MR image acquired after intravenous injection of gadolinium-based contrast material shows heterogeneous enhancement of the marrow cavity, a rounded low-signal-intensity area adjacent to the shaft that is nonenhancing (representing a fluid collection), and enhancement of the soft tissues around the shaft and of the adjacent musculature. The areas of enhancement are likely infected. (b) Axial inversion recovery MR image obtained slightly lower in the femur shows high signal intensity surrounding a lower-signal-intensity area in the marrow cavity (likely representing early involucrum formation) and heterogeneous high signal intensity in the soft tissues of the lower thigh that represents edema.
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Unfortunately, marrow infarction may have a very similar appearance at MR imaging, with areas of abnormal high signal intensity on T2-weighted and inversion recovery images and regional enhancement (Fig 10). Thus, the differentiation of infection from marrow infarction at MR imaging may not be possible (42,50). Soft-tissue abnormalities such as edema and abnormal enhancement of periosteum, muscle, deep fascia, and subcutaneous fat were once thought to indicate osteomyelitis; unfortunately, the same soft-tissue abnormalities may also be seen with infarction (42,50). Studies of scintigraphic evaluation with various combinations of technetium-99m methylene diphosphonate, gallium-67, and Tc-99m sulfur colloid have failed to produce definitive results. In conclusion, imaging alone does not yet allow reliable and accurate differentiation of osteomyelitis from infarction (37,42,50).
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The Brain
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Stroke, atrophy, and cognitive impairment are major consequences of SCA. Approximately 25% of all patients with SCA will have a neurologic complication over their lifetime; 11% of these complications will occur by age 20 years (51,52). Many children will experience "silent infarction" (defined as absence of clinical symptoms with MR imaging findings of infarct). Silent infarction is twice as common as clinical infarction and may occur in up to 22% of children by 12 years of age. Other, less common problems include intraparenchymal and subarachnoid hemorrhage and aneurysm.
Infarction in patients with SCA is usually ischemic. Ischemia is believed to result from sickled cells in the cerebral vessels, with resultant RBC adherence, intimal damage, intimal hyperplasia, and endoluminal narrowing. Endoluminal narrowing increases flow and turbulence, leading to more endothelial damage. Narrowed vessels are more prone to adherence of sickled cells, delayed transit time, and sludging, all of which increase the likelihood of distal ischemia (53). Embolic and thrombotic strokes are unusual (33,53).
Infarcts, both silent and clinical, are best detected with MR imaging. Infarcts in patients with SCA tend to occur in the white matter (Fig 16) and at the peripheral supply zones of the anterior cerebral and middle cerebral arteries (33,53). Acute infarcts (ie, those imaged within the first 7 days after onset) exhibit low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Between approximately 1 week and 1 month after onset, the infarcts become just slightly hypointense on T1-weighted images and remain high signal intensity on T2-weighted images. The chronic infarct exhibits low signal intensity on T1-weighted images and high signal intensity on T2-weighted images, developing better-defined margins and signs of focal atrophy (Fig 17). At CT, infarcts demonstrate low-attenuation areas, becoming better defined and manifesting evidence of atrophy with time. Diffusion-weighted imaging has been shown to demonstrate infarction as soon as 6 hours after the insult (53,54).
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Figure 16a. Silent white matter infarct in an 18-year-old woman with SCA. (a) Axial proton density-weighted MR image of the brain shows two irregular but well-defined areas of high signal intensity. (b) Axial T2-weighted MR image helps confirm well-defined high-signal-intensity areas that represent chronic infarcts.
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Figure 16b. Silent white matter infarct in an 18-year-old woman with SCA. (a) Axial proton density-weighted MR image of the brain shows two irregular but well-defined areas of high signal intensity. (b) Axial T2-weighted MR image helps confirm well-defined high-signal-intensity areas that represent chronic infarcts.
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Abstract
LEARNING OBJECTIVES FOR TEST...
