HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) CME Test (opens in a new window) Submit a response View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lonergan, G. J. Articles by Abbondanzo, S. L. Search for Related Content PubMed PubMed Citation Articles by Lonergan, G. J. Articles by Abbondanzo, S. L. Related Collections Pediatric Radiology General

Sickle Cell Anemia¹

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).

	Abstract

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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

	LEARNING OBJECTIVES FOR TEST 5

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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.
  

	Introduction

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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.

	Pathophysiology of SCA

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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.

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   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.

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).

View larger version (139K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (169K): [in this window] [in a new window] [Download PPT slide]   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.

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).

	Clinical Presentation of SCA

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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.

	The Lung

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   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.

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).

View larger version (116K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (108K): [in this window] [in a new window] [Download PPT slide]   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.

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).

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   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.

	The Skeletal System

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (98K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   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.

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.

View larger version (145K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (179K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (104K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (115K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (116K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (122K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (102K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (90K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (128K): [in this window] [in a new window] [Download PPT slide]   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.

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).

View larger version (75K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (73K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (74K): [in this window] [in a new window] [Download PPT slide]   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).

View larger version (130K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (124K): [in this window] [in a new window] [Download PPT slide]   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.

	The Brain

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
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).

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (151K): [in this window] [in a new window] [Download PPT slide]   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.

View larger version (120K): [in this window] [in a new window] [Download PPT slide]   Figure 17a.   Chronic infarct in a 19-year-old patient with SCA and longstanding mild left hemiplegia. (a) Axial CT scan of the brain reveals an area of low attenuation in the right frontoparietal region with adjacent gyral atrophy and enlarged extraaxial spaces. (b) On an axial T2-weighted MR image, the same area exhibits high signal intensity and shows enlargement of the regional extraaxial spaces, findings compatible with chronic infarction and atrophy.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 17b.   Chronic infarct in a 19-year-old patient with SCA and longstanding mild left hemiplegia. (a) Axial CT scan of the brain reveals an area of low attenuation in the right frontoparietal region with adjacent gyral atrophy and enlarged extraaxial spaces. (b) On an axial T2-weighted MR image, the same area exhibits high signal intensity and shows enlargement of the regional extraaxial spaces, findings compatible with chronic infarction and atrophy.

Because of the considerable lifelong cognitive and functional impairments that result from stroke, efforts have been directed toward identifying patients at risk for stroke to institute preventive therapy. Transcranial Doppler ultrasonography (US) has emerged as a valuable tool for assessing large cerebral artery flow dynamics. Studies show that elevated velocities in the distal internal carotid artery and proximal middle cerebral artery correlate with an increased risk of stroke (58–60). Although studies vary slightly in the mean velocities that correlate with stroke, generally, velocities greater than 170–200 cm/sec indicate significant risk. Increased velocity in these vessels has been shown to correlate with areas of MR imaging abnormality and vessel narrowing at both conventional and MR angiography (Fig 18) (60–63). Preventive therapy (usually maintenance transfusions on a monthly basis) is now offered to these patients. Screening transcranial Doppler US should begin by the age of 3 years. Patients with two consecutive elevated velocities are offered maintenance transfusion therapy, with the goal of reducing Hb S concentration to 30% or less of the total hemoglobin concentration. Adams et al (51) recently showed that the risk of stroke was 10% per year in children with abnormal results from screening transcranial Doppler US who were not receiving treatment, compared with only one infarction in 63 patients treated with maintenance transfusion during a surveillance period of just under 2 years. It is not known how maintenance transfusions decrease the incidence of stroke. There may be reduced endothelial damage, reduced intravascular sludging of sickled RBCs, or another, as yet undetermined, reason.

View larger version (108K): [in this window] [in a new window] [Download PPT slide]   Figure 18a.   Elevated blood velocities at transcranial Doppler US in a 7-year-old boy with SCA and acute right sensorimotor deficit. (a) Image from a transcranial Doppler evaluation of the proximal left middle cerebral artery demonstrates an elevated velocity of 283.7 cm/sec. (b) MR angiogram of the circle of Willis helps confirm narrowing of the proximal left middle cerebral artery (arrow). (c) Proton density-weighted axial MR image reveals an area of high signal intensity in the left parietal lobe, a finding compatible with an acute infarct. There are a few punctate areas of high signal intensity in the white matter bilaterally, representing lacunar infarcts.

View larger version (85K): [in this window] [in a new window] [Download PPT slide]   Figure 18b.   Elevated blood velocities at transcranial Doppler US in a 7-year-old boy with SCA and acute right sensorimotor deficit. (a) Image from a transcranial Doppler evaluation of the proximal left middle cerebral artery demonstrates an elevated velocity of 283.7 cm/sec. (b) MR angiogram of the circle of Willis helps confirm narrowing of the proximal left middle cerebral artery (arrow). (c) Proton density-weighted axial MR image reveals an area of high signal intensity in the left parietal lobe, a finding compatible with an acute infarct. There are a few punctate areas of high signal intensity in the white matter bilaterally, representing lacunar infarcts.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 18c.   Elevated blood velocities at transcranial Doppler US in a 7-year-old boy with SCA and acute right sensorimotor deficit. (a) Image from a transcranial Doppler evaluation of the proximal left middle cerebral artery demonstrates an elevated velocity of 283.7 cm/sec. (b) MR angiogram of the circle of Willis helps confirm narrowing of the proximal left middle cerebral artery (arrow). (c) Proton density-weighted axial MR image reveals an area of high signal intensity in the left parietal lobe, a finding compatible with an acute infarct. There are a few punctate areas of high signal intensity in the white matter bilaterally, representing lacunar infarcts.

View larger version (131K): [in this window] [in a new window] [Download PPT slide]   Figure 19a.   Moyamoya disease in a 7-year-old girl with SCA. (a) Lateral view from a left common carotid angiogram reveals occlusion of the supraclinoid internal carotid artery and multiple small collateral vessels arising from the distal internal carotid artery and extending into the regions of the basal ganglia and thalamus, giving the classic "puff of smoke" appearance. (b) Sagittal T1-weighted MR image of the left hemisphere helps confirm multiple tiny serpentine areas of signal void (arrows) in the region of the basal ganglia and thalamus, findings that represent the collateral vessels.

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   Figure 19b.   Moyamoya disease in a 7-year-old girl with SCA. (a) Lateral view from a left common carotid angiogram reveals occlusion of the supraclinoid internal carotid artery and multiple small collateral vessels arising from the distal internal carotid artery and extending into the regions of the basal ganglia and thalamus, giving the classic "puff of smoke" appearance. (b) Sagittal T1-weighted MR image of the left hemisphere helps confirm multiple tiny serpentine areas of signal void (arrows) in the region of the basal ganglia and thalamus, findings that represent the collateral vessels.

	The Spleen

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
The spleen possesses a slow, tortuous microcirculation that renders it quite susceptible to congestion, sludging, and polymerization. The culmination of this process is splenic infarction, which progresses over time to functional autosplenectomy. The infarcted spleen is replaced by fibrosis, with calcium and hemosiderin deposition. At 6 months of age, 14% of patients with SCA are asplenic; at 2 years, 58% are asplenic; and by 5 years of age, 94% are asplenic. This has important consequences for infection susceptibility. Patients with SCA are prone to infection with S pneumoniae, H influenzae type B, and Salmonella, Klebsiella, and other encapsulated bacteria when splenic function is compromised. Children with SCA are therefore given prophylactic oral penicillin beginning at 3 months of age and continuing to at least age 5 years. This treatment has been shown to reduce the prevalence of bacterial infection by 84%. They are also given pneumococcal and H influenzae vaccines, beginning between 2 and 5 years of age (5).

Over time, with infarction, the spleen becomes small, dense, and calcified. This calcification may be visible at radiography and CT (Fig 20). It may also take up Tc-99m methylene diphosphonate. The infarcted, fibrotic spleen has low signal intensity, regardless of MR imaging pulse sequence, secondary to ferrocalcinosis (65). As splenic function is lost, uptake of Tc-99m sulfur colloid diminishes and may totally disappear. However, rests of preserved splenic tissue or regrowth of splenic tissue occasionally may be present in older children and adults with SCA (65,66). These areas appear as rounded masses of hypoechoic tissue at US and at CT have attenuation similar to that of normal spleen. They take up Tc-99m sulfur colloid and at MR imaging have characteristics similar to those of normal spleen. These areas exist within an otherwise small and fibrotic spleen, which is echogenic at US, is hyperattenuated at CT, and may take up Tc-99m methylene diphosphonate (65).

View larger version (95K): [in this window] [in a new window] [Download PPT slide]   Figure 20.   Calcified spleen in an 8-year-old girl with SCA. Frontal radiograph of the left upper quadrant reveals a heterogeneously dense spleen, secondary to mottled calcification.

The trigger for sequestration syndrome is unknown; it often follows shortly after or coincides with other SCA complications, especially viral illness, pain crisis, bacteremia, and stroke. About 10%–30% of children will experience an episode of sequestration syndrome, usually between the ages of 6 months and 3 years. The condition tends to recur, and as many as 50% of patients will experience another episode within 2 years. Although it rarely occurs after the age of 8 years, sequestration syndrome has been described in older children and adults; therefore, a spleen larger than expected in any patient with SCA should prompt an evaluation for this possibly life-threatening complication (Fig 21) (5).

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 21a.   Sequestration syndrome with splenic infarction. (a) Frontal radiograph of the upper abdomen obtained after intravenous administration of contrast material shows splenomegaly (an unusual finding) in a 17-year-old patient with SCA (arrow). (b) Coronal US scan of the left upper quadrant in a 3-year-old patient with left upper quadrant pain shows enlargement and heterogeneous echogenicity of the spleen (*). (c) Axial CT image of the same patient as in b, obtained after administration of intravenous and enteric contrast material, helps confirm an enlarged spleen that enhances heterogeneously (arrows). (d) Photograph of the bivalved spleen in a third patient shows areas of congestion and central necrosis.

View larger version (150K): [in this window] [in a new window] [Download PPT slide]   Figure 21b.   Sequestration syndrome with splenic infarction. (a) Frontal radiograph of the upper abdomen obtained after intravenous administration of contrast material shows splenomegaly (an unusual finding) in a 17-year-old patient with SCA (arrow). (b) Coronal US scan of the left upper quadrant in a 3-year-old patient with left upper quadrant pain shows enlargement and heterogeneous echogenicity of the spleen (*). (c) Axial CT image of the same patient as in b, obtained after administration of intravenous and enteric contrast material, helps confirm an enlarged spleen that enhances heterogeneously (arrows). (d) Photograph of the bivalved spleen in a third patient shows areas of congestion and central necrosis.

View larger version (144K): [in this window] [in a new window] [Download PPT slide]   Figure 21c.   Sequestration syndrome with splenic infarction. (a) Frontal radiograph of the upper abdomen obtained after intravenous administration of contrast material shows splenomegaly (an unusual finding) in a 17-year-old patient with SCA (arrow). (b) Coronal US scan of the left upper quadrant in a 3-year-old patient with left upper quadrant pain shows enlargement and heterogeneous echogenicity of the spleen (*). (c) Axial CT image of the same patient as in b, obtained after administration of intravenous and enteric contrast material, helps confirm an enlarged spleen that enhances heterogeneously (arrows). (d) Photograph of the bivalved spleen in a third patient shows areas of congestion and central necrosis.

View larger version (108K): [in this window] [in a new window] [Download PPT slide]   Figure 21d.   Sequestration syndrome with splenic infarction. (a) Frontal radiograph of the upper abdomen obtained after intravenous administration of contrast material shows splenomegaly (an unusual finding) in a 17-year-old patient with SCA (arrow). (b) Coronal US scan of the left upper quadrant in a 3-year-old patient with left upper quadrant pain shows enlargement and heterogeneous echogenicity of the spleen (*). (c) Axial CT image of the same patient as in b, obtained after administration of intravenous and enteric contrast material, helps confirm an enlarged spleen that enhances heterogeneously (arrows). (d) Photograph of the bivalved spleen in a third patient shows areas of congestion and central necrosis.

	The Kidney

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
The kidney in SCA has increased renal plasma flow and increased glomerular filtration rate. These changes are thought to arise from compensatory hypersecretion of prostaglandins with vasodilatory effects. The glomerulus is large and hyperfiltrating and as a result develops glomerulosclerosis (68). By adolescence, the glomerular filtration rate is normal, and by age 40, it is reduced. The glomerulosclerosis may lead to proteinuria (in up to 12% of older children with SCA), nephrotic syndrome (in approximately 4% of patients), and sometimes renal failure (which has been estimated to occur in 4%–18% of patients) (69,70). Renal failure may be treated with hemodialysis or renal transplantation.

The medullary vessels (vasa recta) flow through a hypertonic interstitium, which promotes sickling and vascular obstruction. Capillary obliteration and medullary necrosis and fibrosis result, usually of the papillary tips (and manifest as papillary necrosis, estimated to occur in 15%–36% of patients). Papillary necrosis is usually asymptomatic, although a sloughed papilla may obstruct urinary drainage. The capillary obliteration also interferes with the countercurrent exchange system at the loop of Henle, which markedly reduces the ability of the kidney to concentrate urine throughout life. This condition is seen to a lesser degree in patients with heterozygous Hb SA and is thought to be caused by mild RBC dehydration and sludging occurring in the hypertonic medullary interstitium (70). Vascular injury in the medullary regions adjacent to the collecting system may cause dilatation of regional veins. Hemorrhage from these veins is theorized to account for the occasional bouts of gross hematuria frequently suffered by patients with SCA; these bouts are usually self-limited (71).

At imaging, as many as 50% of patients with SCA have large kidneys, believed to be a result of increased renal blood volume from the anemia (72,73). At US, the kidneys may display normal echogenicity (89% of patients); may be diffusely, mildly echogenic (5%) (Fig 22); or may exhibit increased medullary echogenicity with normal cortical echogenicity (3%) (74). Over time, the kidneys may shrink if renal failure ensues. Papillary necrosis is evident at excretory urography, when rounded collections of contrast material are seen pooling in areas of papillary loss (Fig 23) (75).

View larger version (152K): [in this window] [in a new window] [Download PPT slide]   Figure 22.   Renal involvement in a 3-year-old girl with SCA. Sagittal US scan of the left kidney reveals diffuse mildly increased echogenicity, nearly equal to that of the adjacent spleen. Incidentally noted is splenomegaly, the cause of which was not documented. Asymptomatic splenomegaly is distinctly unusual in SCA at any age; it is more often seen with sickle variants such as Hb SC and Hb SD.

View larger version (142K): [in this window] [in a new window] [Download PPT slide]   Figure 23a.   Papillary necrosis in SCA. (a) Frontal view of the right kidney obtained during excretory urography in a 32-year-old man with SCA shows a small, round collection of contrast material in an area of missing papillary tip (arrow). (b) Photograph of a kidney (bivalved upper pole) from a different patient shows loss of the papillary tips in some upper pole pyramids (arrows).

View larger version (95K): [in this window] [in a new window] [Download PPT slide]   Figure 23b.   Papillary necrosis in SCA. (a) Frontal view of the right kidney obtained during excretory urography in a 32-year-old man with SCA shows a small, round collection of contrast material in an area of missing papillary tip (arrow). (b) Photograph of a kidney (bivalved upper pole) from a different patient shows loss of the papillary tips in some upper pole pyramids (arrows).

	Miscellaneous Disease Manifestations

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figures 24.   Cholelithiasis in SCA. (a) Frontal plain radiograph of the abdomen in a 31-year-old man with SCA reveals rounded opacities in the right upper quadrant, representing gallstones (arrows). (b) Axial US image of the gallbladder in a 10-year-old girl with SCA shows an echogenic, shadowing stone on the dependent side of the gallbladder.

View larger version (157K): [in this window] [in a new window] [Download PPT slide]   Figures 24.   Cholelithiasis in SCA. (a) Frontal plain radiograph of the abdomen in a 31-year-old man with SCA reveals rounded opacities in the right upper quadrant, representing gallstones (arrows). (b) Axial US image of the gallbladder in a 10-year-old girl with SCA shows an echogenic, shadowing stone on the dependent side of the gallbladder.

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figures 25.   Gallbladder sludge in a 3-year-old girl with SCA. Axial US image of the gallbladder reveals material in the gallbladder lumen of intermediate echogenicity, a finding compatible with nonmineralized sludge.

View larger version (140K): [in this window] [in a new window] [Download PPT slide]   Figures 26.   Extramedullary hematopoiesis in a 55-year-old man with SCA. (a) Frontal chest radiograph shows an oval posterior mediastinal mass in the lower left hemithorax (arrow). (b) Photograph of the resected gross specimen reveals a fleshy soft-tissue mass, confirmed histologically as hematopoietic tissue.

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figures 26.   Extramedullary hematopoiesis in a 55-year-old man with SCA. (a) Frontal chest radiograph shows an oval posterior mediastinal mass in the lower left hemithorax (arrow). (b) Photograph of the resected gross specimen reveals a fleshy soft-tissue mass, confirmed histologically as hematopoietic tissue.

Patients with SCA may experience acute retinal artery occlusion with sudden loss of vision in one eye; this typically resolves in several days, although some long-term visual impairment may result (86). Proliferative retinopathy is also common; occasionally this may cause vitreous hemorrhage (87). Orbital compression syndrome may result from infarcts of the osseous walls of the orbit, which develop edema and subperiosteal hematomas (88). Skull infarctions with subperiosteal hematomas have also been implicated in atraumatic causes of epidural hematomas (89). Sensorineural hearing loss is present in 3.5% of children and is common in adults with SCA (90).

Priapism (painful, persistent penile erection) is an unfortunately common complication for male patients with SCA. By the age of 20 years, 89% of male patients will have experienced at least one episode. The average number of episodes is 15.7 per patient, with the average episode lasting just over 2 hours (91). Repeated priapism may result in penile fibrosis and impotence (91,92). The testis may infarct in patients with SCA (93). Curiously, patients with SCA are one-third as likely as the population at large to develop appendicitis. The reason for this is unknown (94).

	Treatment and Prognosis

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
Currently, treatment for SCA most commonly consists of transfusion, with the addition of complication-specific therapy (such as administration of antibiotics for pneumonia). Transfusions are often given on an as-needed basis for many SCA complications. Maintenance transfusions (usually monthly) are advocated for patients at risk of stroke (typically those identified at transcranial Doppler screening as having middle cerebral artery velocities exceeding 170-200 cm/sec). Both methods of transfusion accomplish two goals: reduction in the relative amount of Hb SS and maintenance of therapeutic levels of normal hemoglobin (95). With maintenance transfusion therapy, the goal is to keep the total hemoglobin concentration at 12 g/dL and the Hb SS concentration 30% or less. Such preventive transfusion therapy has been shown to greatly reduce the risk of first and recurrent stroke (51,96,97). Unfortunately, transfusions carry their own considerable risks and are associated with alloimmunization, transfusion reaction, infection (most ominously with hepatitis C and the human immunodeficiency virus), and total body iron overload. In addition, chelation therapy with deferoxamine is arduous (requiring regular injections), and compliance is suboptimal (98).

Another way to reduce the amount of Hb SS is to change the nature of the hemoglobin produced by the patient’s marrow. This may be accomplished by changing the cell population of the patient’s marrow through transplantation. Bone marrow and stem cell (from umbilical cord blood) transplantation are essentially curative of SCA. In each transplantation method, the native marrow is repopulated with normal stem cells (which do not need to match the recipient human leukocyte antigen) or marrow cells (for which human leukocyte antigen matching is necessary), with the end result being production of non–Hb S-containing RBCs. Unfortunately, marrow donor matches and umbilical cord blood donors for SCA patients are not always available (95,99, 100). Ideally, transplantation would be done before a significant complication such as stroke; however, predicting the severity of disease in infancy and early childhood is quite difficult. Criteria for transplantation are therefore not yet established.

An alternative method of reducing the production of Hb SS-containing RBCs is the induction of fetal hemoglobin (Hb F) by the native marrow. This is accomplished by the administration of hydroxyurea. Hydroxyurea, a cytotoxic agent, increases production of Hb F, essentially replacing some of the abnormal ß globin chains and thereby lowering the relative amount of Hb SS. Hb F has been shown to inhibit the polymerization of hemoglobin. Hydroxyurea itself inhibits endothelial adhesion of RBCs, mildly increases overall hemoglobin concentration (thus somewhat alleviating anemia), and mildly suppresses neutrophil production, which may also ameliorate the effects of SCA (10,98,101,102). Hydroxyurea has been shown to decrease the incidence of ACS, painful crises, hemolytic crises, days in the hospital, and transfusion requirements (103). Hydroxyurea is generally well tolerated; however, there is concern of mutagenicity. Hydroxyurea has been used to treat SCA for just over 5 years; the long-term effects are unknown, although no cases of leukemia have been reported to date (98).

The prognosis for patients with SCA continues to improve. Currently, the median survival in the United States for a patient with SCA is 40–50 years. Overall, ACS is the leading cause of death (16). As patients grow to adulthood, end-organ damage to the lungs and kidneys is the major determinant of survival (104). The highest morbidity and mortality exist in the very young. In children, studies performed over the first 10 years of life show that infection (most often with S pneumoniae and H influenzae) is the most common cause of death, followed by sequestration syndrome and cerebrovascular accident. Pain crises and ACS were the most common clinical problems for children in the first 10 years of life (105). Another study suggested three main determinants of an adverse outcome (adverse outcome was defined as death, stroke, frequent pain crises, or recurrent ACS). The determinants were dactylitis before 6 months of age, severe anemia (defined as hemoglobin <7 g/dL), and leukocytosis without infection (106). Many causes of mortality and morbidity in children with SCA are avoidable with adequate antibiotic prophylaxis, early immunization, maintenance transfusion if indicated, and caregiver education. Survival trends continue to improve accordingly. Between 1968 and 1992, death rates in the United States for black children with SCA have decreased by 41% for 1- to 4-year-olds, 47% for 5- to 9-year-olds, and 53% for 10- to 14-year-olds (107).

	Summary

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 
SCA is a hemolytic anemia characterized by the production of abnormal hemoglobin chains that tend to polymerize when deoxygenated, causing distortion of RBC morphology (sickling), with attendant vascular occlusion and ischemia. Many of the complications of SCA are infarctive, including osteonecrosis, ACS, stroke, and renal papillary necrosis. Children with SCA are especially prone to bacteremia and infection. Control of these dreaded complications is improving with advances in prophylactic antibiotic therapy, transfusion therapy, Hb F induction, and bone marrow and stem cell transplantation. The promise of curative marrow replacement gives hope to SCA patients. Continued improvements in stem cell therapy and bone marrow transplantation appear to herald a cure for this dreaded lifelong disease.

	Footnotes

 
Abbreviations: ACS = acute chest disease, Hb S = sickle cell hemoglobin, Hb SA = heterozygous sickle cell hemoglobin, Hb SS = homozygous sickle cell hemoglobin, RBC = red blood cell, SCA = sickle cell anemia

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Departments of the Air Force, Army, or Defense.

	References

Top Abstract LEARNING OBJECTIVES FOR TEST... Introduction Pathophysiology of SCA Clinical Presentation of SCA The Lung The Skeletal System The Brain The Spleen The Kidney Miscellaneous Disease... Treatment and Prognosis Summary References

 

1. Bookchin RM, Lew VL. Pathophysiology of sickle cell anemia. Hematol Oncol Clin North Am 1996; 10:1241-1253.[Medline]
2. Ballas SK. Sickle cell disease: clinical management. Baillieres Clin Haematol 1998; 11:185-214.[Medline]
3. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 1910; 6:517-521.
4. Pauling L, Itano HA, Singer SJ, Wells IC. Sickle-cell anemia: a molecular disease. Science 1949; 110:543-549.[Free Full Text]
5. Lane PA. Sickle cell disease. Pediatr Clin North Am 1996; 43:639-664.[Medline]
6. Davis CJ, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma: the seventh sickle cell nephropathy. Am J Surg Pathol 1995; 19:1-11.[Medline]
7. Aluoch JR. Higher resistance to Plasmodium falciparum infection in patients with homozygous sickle cell disease in western Kenya. N Engl J Med 1997; 317:781-787.[Abstract]
8. Bowman JE, Murray RFJ. Genetic variation in peoples of African origin Baltimore, Md: Johns Hopkins University Press, 1990; 196-201.
9. Wethers DL. Sickle cell disease in childhood. I. Laboratory diagnosis, pathophysiology, and health maintenance. Am Fam Phys 2000; 62:1013-1020.
10. Bunn HF. Induction of fetal hemoglobin in sickle cell disease. Blood 1999; 93:1787-1789.[Free Full Text]
11. Rodgers GP. Overview of pathophysiology and rationale for treatment of sickle cell anemia. Semin Hematol 1997; 34:2-7.[Medline]
12. Ballas SK, Mohandas N. Pathophysiology of vaso-occlusion. Hematol Oncol Clin North Am 1996; 10:1221-1239.[Medline]
13. Mosseri M, Bartlett-Pandite AN, Wenc K, Isner MH, Weinstein R. Inhibition of endothelium-dependent vasorelaxation by sickle erythrocytes. Am Heart J 1993; 126:338-346.[Medline]
14. Hebbel RP, Vercelotti GM. The endothelial biology of sickle cell disease. J Lab Clin Med 1997; 129:288-293.[Medline]
15. Yaster M, Kost-Byerly S, Maxwell LG. The management of pain in sickle cell disease. Pediatr Clin North Am 2000; 47:699-710.[Medline]
16. Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson B. Acute chest syndrome in sickle cell disease: clinical presentation and course—Cooperative Study of Sickle Cell Disease. Blood 1997; 89:1787-1792.[Abstract/Free Full Text]
17. Stark P, Pfeiffer WR. Intrathoracic manifestations of sickle cell disease. Radiology 1985; 25:33-35.
18. Atkins BL, Price EH, Tillyer L, Novelli V, Evans J. Salmonella osteomyelitis in sickle cell disease children in the east end of London. J Infect 1997; 34:133-138.[Medline]
19. Leong CS, Stark P. Thoracic manifestations of sickle cell disease. J Thorac Imaging 1998; 13:128-134.[Medline]
20. Delatte SJ, Hebra A, Tagge EP, Jackson S, Jacques K, Othersen HB. Acute chest syndrome in the postoperative sickle cell patient. J Pediatr Surg 1999; 34:188-191.[Medline]
21. Martin L, Buonomo C. Acute chest syndrome of sickle cell disease: radiographic and clinical analysis of 70 cases. Pediatr Radiol 1997; 27:637-641.[Medline]
22. Quinn CT, Buchanan GR. The acute chest syndrome of sickle cell disease. J Pediatr 1999; 135:416-422.[Medline]
23. Godeau B, Schaeffer A, Bachir D, et al. Bronchoalveolar lavage in adult sickle cell patients with acute chest syndrome: value for diagnostic assessment of fat embolism. Am J Respir Crit Care Med 1996; 153:1691-1696.[Abstract]
24. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease: National Acute Chest Syndrome Study Group. N Engl J Med 2000; 342:1855-1865.[Abstract/Free Full Text]
25. Quinn CT, Buchanan GR. The acute chest syndrome of sickle cell disease. J Pediatr 1999; 135:416-422.
26. Gelfand MJ, Daya SA, Rucknagel DL, Kalinyak KA, Paltiel HJ. Simultaneous occurrence of rib infarction and pulmonary infiltrates in sickle cell disease patients with acute chest syndrome. J Nucl Med 1993; 34:614-618.[Abstract/Free Full Text]
27. Bhalla M, Abboud MR, McLoud TC, et al. Acute chest syndrome in sickle cell disease: CT evidence of microvascular occlusion. Radiology 1993; 187:45-49.[Abstract/Free Full Text]
28. Steinberg B. Sickle cell anemia. Arch Pathol 1930; 9:876-897.
29. Lisbona R, Derbekyan V, Novales-Diaz JA. Scintigraphic evidence of pulmonary vascular occlusion in sickle cell disease. J Nucl Med 1997; 38:1151-1153.[Abstract/Free Full Text]
30. Aldrich TK, Dhuper SK, Patwa NS, et al. Pulmonary entrapment of sickle cells: the role of regional alveolar hypoxia. J Appl Physiol 1996; 80:531-539.[Abstract/Free Full Text]
31. Pelidis MA, Kato GJ, Resar LM, et al. Successful treatment of life-threatening acute chest syndrome of sickle cell disease with venovenous extracorporeal membrane oxygenation. J Pediatr Hematol Oncol 1997; 19:459-461.[Medline]
32. Trant CA, Casey JR, Hansell D, et al. Successful use of extracorporeal membrane oxygenation in the treatment of acute chest syndrome in a child with severe sickle cell anemia. ASAIO J 1996; 42:236-239.[Medline]
33. Powars D, Weidman J, Odom-Maryon T, Niland JC, Johnson C. Sickle cell chronic lung disease: prior morbidity and the risk of pulmonary failure. Medicine 1988; 67:66-76.[Medline]
34. Aquino SL, Gamsu G, Fahy JV, et al. Chronic pulmonary disorders in sickle cell disease: findings at thin-section CT. Radiology 1994; 193:807-811.[Abstract/Free Full Text]
35. Leong MA, Dampier C, Varlotta L, Allen JL. Airway hyperreactivity in children with sickle cell disease. J Pediatr 1997; 131:278-283.[Medline]
36. Deely DM, Schweitzer ME. MR imaging of bone marrow disorders. Radiol Clin North Am 1997; 35:193-212.[Medline]
37. Anand AJ, Glatt AE. Salmonella osteomyelitis and arthritis in sickle cell disease. Semin Arthritis Rheum 1994; 24:211-221.[Medline]
38. Smith JA. Bone disorders in sickle cell disease. Hematol Oncol Clin North Am 1996; 10:1345-1356.[Medline]
39. Keeley K, Buchanan GR. Acute infarction of long bones in children with sickle cell anemia. J Pediatr 1982; 101:170-175.[Medline]
40. Ware HE, Brooks AP, Toye R, Berney SI. Sickle cell disease and silent avascular necrosis of the hip. J Bone Joint Surg Br 1991; 73:947-949.
41. Resnick D, Niwayama G. Osteonecrosis: diagnostic techniques, specific situations, and complications. In: Resnick , eds. Diagnosis of bone and joint disorders. 3rd ed. Philadelphia, Pa: Saunders, 1995; 3495-3515.
42. Frush DP, Heyneman LE, Ware RE, Bissett GS. MR features of soft-tissue abnormalities due to acute marrow infarction in five children with sickle cell disease. AJR Am J Roentgenol 1999; 173:989-993.[Abstract/Free Full Text]
43. Marlow TJ, Brunson CY, Jackson S, Schabel SI. "Tower vertebra": a new observation in sickle cell disease. Skeletal Radiol 1998; 27:195-198.[Medline]
44. Styles LA, Vichinsky EP. Core decompression in avascular necrosis of the hip in sickle-cell disease. Am J Hematol 1996; 52:103-107.[Medline]
45. Weinberg AG, Currarino G. Sickle cell dactylitis: histopathologic observations. Am J Clin Pathol 1972; 58:518-523.[Medline]
46. Babhulkar SS, Pande K, Babhulkar S. The hand-foot syndrome in sickle-cell haemoglobinopathy. J Bone Joint Surg Br 1995; 77:310-312.
47. Stark JE, Glasier CM, Blasier RD, Aronson J, Seibert JJ. Osteomyelitis in children with sickle cell disease: early diagnosis with contrast-enhanced CT. Radiology 1991; 179:731-733.[Abstract/Free Full Text]
48. Burnett MW, Bass JW, Cook BA. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 1998; 101:296-297.[Free Full Text]
49. Overturf GD. Infections and immunizations of children with sickle cell disease. Adv Pediatr Infect Dis 1999; 14:191-218.[Medline]
50. Bonnerot V, Sebag G, de Montalembert M, et al. Gadolinium-DOTA enhanced MRI of painful osseous crises in children with sickle cell anemia. Pediatr Radiol 1994; 24:92-95.[Medline]
51. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5-11.[Abstract/Free Full Text]
52. Preul MC, Cendes F, Just N, Mohr G. Intracranial aneurysms and sickle cell anemia: multiplicity and propensity for the vertebrobasilar territory. Neurosurgery 1998; 42:971-977.[Medline]
53. Moran CJ, Siegel MJ, DeBaun MR. Sickle cell disease: imaging of cerebrovascular complications. Radiology 1998; 206:311-321.[Abstract/Free Full Text]
54. Schaefer PW, Budzik RF, Koroshetz W, Gonzalez RG. Comparison of diffusion MR imaging, routine MR imaging, and CT in hyperacute stroke. Presented at the 35th Annual Meeting of the American Society of Neuroradiology, Toronto, May 18–22, 1997.; :-.
55. Steen RG, Reddick WE, Mulhern RK, et al. Quantitative MRI of the brain in children with sickle cell disease reveals abnormalities unseen by conventional MRI. J Magn Reson Imaging 1998; 8:535-543.[Medline]
56. Steen RG, Langston JW, Ogg RJ, Xiong X, Ye Z, Wang WC. Diffuse T1 reduction in gray matter of sickle cell disease patients: evidence of selective vulnerability to damage?. Magn Reson Imaging 1999; 17:503-515.[Medline]
57. Steen RG, Xiong X, Mulhern RK, Langston JW, Wang WC. Subtle brain abnormalities in children with sickle cell disease: relationship to blood hematocrit. Ann Neurol 1999; 45:279-286.[Medline]
58. Adams RJ, McKie VC, Carl EM, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol 1997; 42:699-704.[Medline]
59. Seibert JJ, Glasier CM, Kirby RS, et al. Transcranial Doppler, MRA, and MRI as a screening examination for cerebrovascular disease in patients with sickle cell anemia: an 8-year study. Pediatr Radiol 1998; 28:138-142.[Medline]
60. Seibert JJ, Miller SF, Kirby RS, et al. Cerebrovascular disease in symptomatic and asymptomatic patients with sickle cell anemia: screening with duplex transcranial Doppler US—correlation with MR imaging and MR angiography. Radiology 1993; 189:457-466.[Abstract/Free Full Text]
61. Adams RJ, Nichols FT, Figueroa R, McKie V, Lott T. Transcranial Doppler correlation with cerebral angiography in sickle cell disease. Stroke 1992; 23:1073-1077.[Abstract/Free Full Text]
62. Kogutt MS, Goldwag SS, Gupta KL, Kaneko K, Humbert JR. Correlation of transcranial Doppler ultrasonography with MRI and MRA in the evaluation of sickle cell disease patients with prior stroke. Pediatr Radiol 1994; 24:204-206.[Medline]
63. Verlhac S, Bernaudin F, Tortrat D, et al. Detection of cerebrovascular disease in patients with sickle cell disease using transcranial Doppler sonography: correlation with MRI, MRA, and conventional angiography. Pediatr Radiol 1995; 25(suppl 1):S14-S19.
64. Drew JM, Scott JA, Chua GT. General case of the day. RadioGraphics 1993; 13:483-484.[Medline]
65. Levin TL, Berdon WE, Haller JO, Ruzal-Shapiro C, Hurlet-Jenson A. Intrasplenic masses of "preserved" functioning splenic tissue in sickle cell disease: correlation of imaging findings (CT, ultrasound, MRI, and nuclear scintigraphy). Pediatr Radiol 1996; 26:646-649.[Medline]
66. Campbell PJ, Olatunji PO, Ryan KE, Davies SC. Splenic regrowth in sickle cell anaemia following hypertransfusion. Br J Haematol 1997; 96:77-79.[Medline]
67. Roshkow JE, Sanders LM. Acute splenic sequestration crisis in two adults with sickle cell disease: US, CT, and MR imaging findings. Radiology 1990; 177:723-725.[Abstract/Free Full Text]
68. Schmitt F, Martinez F, Brillet G, et al. Early glomerular dysfunction in patients with sickle cell anemia. Am J Kidney Dis 1998; 32:208-214.[Medline]
69. Wigfall DR, Ware RE, Burchinal MR, Kinney TR, Foreman JW. Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease. J Pediatr 2000; 136:749-753.[Medline]
70. Pham PT, Pham PC, Wilkinson AH, Lew SQ. Renal abnormalities in sickle cell disease. Kidney Int 2000; 57:1-8.[Medline]
71. Saborio P, Scheinman JI. Sickle cell nephropathy. J Am Soc Nephrol 1999; 10:187-192.[Free Full Text]
72. Walker TM, Beardsall K, Thomas PW, Serjeant GR. Renal length in sickle cell disease: observations from a cohort study. Clin Nephrol 1996; 46:384-388.[Medline]
73. Minkin SD, Oh AS, Sanders RC. Urologic manifestations of sickle hemoglobinopathies. South Med J 1979; 72:23-28.[Medline]
74. Walker TM, Searjeant GR. Increased renal reflectivity in sickle cell disease: prevalence and characteristics. Clin Radiol 1995; 195:566-569.
75. Harrow BR, Sloane JA, Liebman NC. Roentgenologic demonstration of renal papillary necrosis in sickle cell trait. N Engl J Med 1963; 268:969-976.
76. Charlotte F, Bachir D, Nenert M, et al. Vascular lesions of the liver in sickle cell disease: a clinicopathological study in 26 living patients. Arch Pathol Lab Med 1995; 119:46-52.[Medline]
77. Krauss JS, Freant LJ, Lee JR. Gastrointestinal pathology in sickle cell disease. Ann Clin Lab Sci 1998; 28:19-23.[Abstract]
78. Hillaire S, Gardin C, Attar A, et al. Cholangiopathy and intrahepatic stones in sickle cell disease: coincidence or ischemic cholangiopathy?. Am J Gastroenterol 2000; 95:300-301.[Medline]
79. Al-Salem AH, Qaisruddin S. The significance of biliary sludge in children with sickle cell disease. Pediatr Surg Int 1998; 13:14-16.[Medline]
80. Levin TL, Sheth SS, Hurlet A, et al. MR marrow signs of iron overload in transfusion-dependent patients with sickle cell disease. Pediatr Radiol 1995; 25:614-619.[Medline]
81. Siegelman ES, Outwater E, Hanau CA, et al. Abdominal iron distribution in sickle cell disease: MR findings in transfusion and nontransfusion dependent patients. J Comput Assist Tomogr 1994; 18:63-67.[Medline]
82. Gilkeson RC, Basile V, Sands MJ, Hsu JT. Chest case of the day: extramedullary hematopoiesis (EMH). AJR Am J Roentgenol 1997; 169:270-273.
83. James TN, Riddick L, Massing GK. Sickle cells and sudden death: morphologic abnormalities of the cardiac conduction system. J Lab Clin Med 1994; 124:507-520.[Medline]
84. Covitz W, Espeland M, Gallagher D, Hellenbrand W, Leff S, Talner N. The heart in sickle cell anemia: the Cooperative Study of Sickle Cell Disease (CSSCD). Chest 1995; 108:1214-1219.[Abstract/Free Full Text]
85. Acar P, Sebahoun S, de Pontual L, Maunoury C. Myocardial perfusion in children with sickle cell anaemia. Pediatr Radiol 2000; 30:352-354.[Medline]
86. Fine LC, Petrovic V, Irvine AR, Bhisitkul RB. Spontaneous central retinal artery occlusion in hemoglobin sickle cell disease. Am J Ophthalmol 2000; 129:680-681.[Medline]
87. Charache S. Eye disease in sickling disorders. Hematol Oncol Clin North Am 1996; 10:1357-1362.[Medline]
88. Curran EL, Fleming JC, Rice K, Wang WC. Orbital compression syndrome in sickle cell disease. Ophthalmology 1997; 104:1610-1615.[Medline]
89. Resar LM, Oliva MM, Casella JF. Skull infarction and epidural hematomas in a patient with sickle cell anemia. J Pediatr Hematol Oncol 1996; 18:413-415.[Medline]
90. MacDonald CB, Bauer PW, Cox LC, McMahon L. Otologic findings in a pediatric cohort with sickle cell disease. Int J Pediatr Otorhinolaryngol 1999; 47:23-28.[Medline]
91. Mantadakis E, Cavender JD, Rogers ZR, Ewalt DH, Buchanan GR. Prevalence of priapism in children and adolescents with sickle cell anemia. J Pediatr Hematol Oncol 1999; 21:518-522.[Medline]
92. Powars DR, Johnson CS. Priapism. Hematol Oncol Clin North Am 1996; 10:1363-1372.[Medline]
93. Gofrit ON, Rund D, Shapiro A, Pappo O, Landau EH, Pode D. Segmental testicular infarction due to sickle cell disease. J Urol 1998; 160:835-836.[Medline]
94. Antal P, Gauderer M, Koshy M, Berman B. Is the incidence of appendicitis reduced in patients with sickle cell disease?. Pediatrics 1998; 101:98-99.
95. King KE, Ness PM. Treating anemia. Hematol Oncol Clin North Am 1996; 10:1305-1320.[Medline]
96. Buchanan GR, Bowman WP, Smith SJ. Recurrent cerebral ischemia during hypertransfusion therapy in sickle cell anemia. J Pediatr 1983; 103:921-923.[Medline]
97. Adams RJ. Stroke prevention in sickle cell disease. Curr Opin Hematol 2000; 7:101-105.[Medline]
98. Steinberg MH. Management of sickle cell disease. N Engl J Med 1999; 340:1021-1030.[Free Full Text]
99. Kelly P, Kurtzberg J, Vichinsky E, Lubin B. Umbilical cord blood stem cells: application for the treatment of patients with hemoglobinopathies. J Pediatr 1997; 130:695-703.[Medline]
100. Castro O. Management of sickle cell disease: recent advances and controversies. Br J Haematol 1999; 107:2-11.[Medline]
101. Charache S. Mechanism of action of hydroxyurea. Semin Hematol 1997; 34:15-21.[Medline]
102. Vichinsky EP. Hydroxyurea in children: present and future. Semin Hematol 1997; 34:22-29.[Medline]
103. Koren A, Segal-Kupershmit D, Zalman L, et al. Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Pediatr Hematol Oncol 1999; 16:221-232.[Medline]
104. Serjeant GR. Natural history and determinants of clinical severity of sickle cell disease. Curr Opin Hematol 1995; 2:103-108.[Medline]
105. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease: Cooperative Study of Sickle Cell Disease. Blood 1995; 86:776-783.[Abstract/Free Full Text]
106. Miller ST, Sleeper LA, Pegelow CH, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 2000; 342:83-89.[Abstract/Free Full Text]
107. Davis H, Schoendorf KC, Gergen PJ, Moore RM, Jr. National trends in the mortality of children with sickle cell disease: 1968 through 1992. Am J Public Health 1997; 87:1317-1322.[Abstract/Free Full Text]

This article has been cited by other articles:

				S. Martig, B. S. Lippold, A. Oevermann, and G. Ueltschi Polyostotic bone lesions consistent with bone infarction in a horse Vet Rec., March 15, 2008; 162(11): 352 - 353. [Full Text] [PDF]

				D S KUMAR, R P YADAVALI, L A CONCEPCION, and H ANIQ Acute chest pain in a young woman with a chronic illness Br. J. Radiol., March 1, 2008; 81(963): 261 - 263. [Full Text] [PDF]

				V. C. Ejindu, A. L. Hine, M. Mashayekhi, P. J. Shorvon, and R. R. Misra Musculoskeletal Manifestations of Sickle Cell Disease RadioGraphics, July 1, 2007; 27(4): 1005 - 1021. [Abstract] [Full Text] [PDF]

eLetters:

This Article Abstract Figures Only Full Text (PDF) CME Test (opens in a new window) Submit a response View responses Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lonergan, G. J. Articles by Abbondanzo, S. L. Search for Related Content PubMed PubMed Citation Articles by Lonergan, G. J. Articles by Abbondanzo, S. L. Related Collections Pediatric Radiology General