DOI: 10.1148/rg.274065142
RadioGraphics 2007;27:1005-1021
© RSNA, 2007
Musculoskeletal Manifestations of Sickle Cell Disease1
Vivian C. Ejindu, MRCP,
Andrew L. Hine, FRCR,
Mohammad Mashayekhi, FRCR,
Philip J. Shorvon, FRCR, and
Rakesh R. Misra, FRCR
1 From the Department of Radiology, Central Middlesex Hospital, North West London Hospitals NHS Trust, Acton Lane, Park Royal, London NW10 7NS, England (V.C.E., A.L.H., P.J.S.); Department of Radiology, Barnet and Chase Farm Hospitals NHS Trust, London, England (M.M.); and Department of Radiology, Buckinghamshire Hospitals NHS Trust, Wycombe, England (R.R.M.). Presented as an education exhibit at the 2005 RSNA Annual Meeting. Received July 26, 2006; revision requested October 19 and received February 2, 2007; accepted February 16. All authors have no financial relationships to disclose.
Address correspondence to V.C.E. (e-mail: v.ejindu{at}nhs.net).
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Abstract
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Sickle cell disease results from the presence of abnormal ß globin chains within hemoglobin and may be manifested in anemia, vaso-occlusion, and superimposed infection. The gene that causes sickle cell disease is particularly prevalent in populations of African origin; approximately 8% of African Americans and 40% of the members of some African tribes carry the gene for hemoglobin S. Over time, the disease produces various musculoskeletal abnormalities as a result of chronic anemia; these include marrow hyperplasia, reversion of yellow marrow to red marrow, and, occasionally, extramedullary hematopoiesis. Familiarity with the imaging features of sickle cell disease is important for the diagnosis and management of complications. Ischemia and infarction are common complications that may have long-term effects on the growth of bone; these conditions have characteristic radiographic appearances. Infection may be more difficult to identify. Both infection and infarction may occur in muscle and soft tissue alone, without involving bone. However, osteomyelitis must be diagnosed early and treated immediately to prevent bone destruction and deformity; therefore, care must be taken to achieve an accurate diagnosis by identifying or excluding bone involvement. The clinical and radiographic features of acute osteomyelitis may be particularly difficult to distinguish from those of bone infarction. In that context, magnetic resonance (MR) imaging may be useful. At MR imaging, findings of cortical defects, adjacent fluid collections in soft tissue, and bone marrow enhancement are suggestive of infection.
© RSNA, 2007
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LEARNING OBJECTIVES FOR TEST 4
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After reading this article and taking the test, the reader will be able to:- Describe the musculoskeletal manifestations of sickle cell anemia.
- Recognize the imaging features of common musculoskeletal abnormalities in sickle cell anemia.
- Discuss the role of imaging in the diagnosis and management of musculoskeletal complications of sickle cell anemia.
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Introduction
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Sickle cell anemia is one of a group of conditions known as hemoglobinopathies and is characterized by the reduced or abnormal production of a hemoglobin protein. Normal adult blood contains different types of hemoglobin, the most important among these being hemoglobin A (96%–98% of the hemoglobin component). Hemoglobin A has a molecular structure made up of two 
globin and two ß globin chains. The globin chain gene, which lies on chromosome 16, is duplicated on each chromosome; therefore, four genes contribute to chain production. The ß globin gene is found on chromosome 11, and only one copy is present on each chromosome. Sickle cell anemia is an autosomal recessive genetic condition in which a defective form of hemoglobin, hemoglobin S (Hb S), results from a single amino acid substitution (valine for glutamic acid at position 6) in the ß globin gene. Sickle cell disease results when both ß globin genes are abnormal—either homozygous (Hb SS) or heterozygous (ie, combined with other abnormal hemoglobins, such as hemoglobin C [Hb SC] or ß thalassemia [Hb S–thal]). The combination of a sickle ß globin gene with a normal one (Hb SA) results in the sickle cell trait, with no resultant anemia. The presence of Hb S lessens the severity of infection with falciparum malaria, and this benefit helps explain some similarities in the geographic distribution of sickle cell disease and areas where malaria is endemic.
Deoxygenation of Hb S–containing red blood cells results in the aggregation of abnormal hemoglobin molecules into long chains. This irreversible process distorts the red blood cell into a rigid sickle shape. The consequences are obstruction of the microcirculation, ischemia, and infarction. Anemia results from the rapid removal of abnormal red blood cells by the reticuloendothelial system, which reduces the red cell life span to one-tenth its normal duration.
Sickle cell disease is seen in people from the Middle East and the eastern Mediterranean region but is most prevalent in those of African origin: About 8% of African Americans and 40% of the members of some African tribes carry the gene for Hb S. However, only 0.2% of African Americans have sickle cell anemia (Hb SS). Sickle cell anemia causes significant mortality and morbidity, with a decrease of 25–30 years in the average life expectancy.
In this article, the varied musculoskeletal manifestations of this condition are described. These manifestations include intramedullary and extramedullary effects of increased hematopoiesis; sickle cell–related infarction and resultant abnormalities in the growth of bone; infection; and soft-tissue involvement.
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Effects of Intramedullary Marrow Hyperplasia
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Increased red cell destruction and consequent anemia are the main stimuli for the persistence and subsequent expansion of red (hematopoietic) marrow. Red marrow is present throughout the fetal skeleton. After birth, the red marrow undergoes a gradual conversion into yellow or fatty marrow. The process starts in the extremities of the appendicular skeleton and gradually advances into the more central skeletal structure. In a healthy adult, red marrow is present only in the axial skeleton—the spine, sternum, pelvis, ribs, and proximal long bones. As the epiphyses develop and ossify, only yellow marrow is produced in them.
The demand for increased production of red cells in sickle cell anemia stops the conversion to yellow marrow in the peripheral skeleton and leads to the persistence of appendicular red marrow throughout life. In infants with sickle cell disease, red marrow extends to all of the bones. With increasing age, it recedes from the small bones of the extremities (hands and feet) but persists in the ankles, wrists, and shafts of the long bones (1) (Fig 1). The constant stimulation of red cell production leads to the widening of medullary spaces and thinning of cortical bone, which may result in pathologic fractures. Coarsening of the normal trabecular pattern is seen in both the long and the flat bones (Fig 2). Osteopenia also results from this process and may be visible on radiographs.
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Figure 1. Persistent red marrow in a 29-year-old woman. Sagittal T1-weighted MR image of the spine shows low signal intensity indicative of cellular (red) marrow. Vertebral endplate concavity at multiple levels is due to bone softening.
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Figure 2. Effects of intramedullary hyperplasia. Posteroanterior chest radiograph shows a thickened trabecular pattern and loss of corti-comedullary differentiation in the ribs, changes caused by hematopoietic bone marrow. Stage II avascular necrosis in the left humeral head and striation of the intramedullary cavity in the proximal left humerus also are visible.
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Bone marrow expansion is manifested in the skull as a widening of the diploic space with thinning of the inner and outer tables (Fig 3). Osteoporosis of the skull vault may produce a granular appearance on radiographs. Vertical "hair-on-end" striations that project from the outer aspect of the vault also are seen (2). Such striations are due to the prominence of trabeculae and to new bone formation (Fig 4). Although facial bones are not usually involved in marrow expansion in sickle cell disease, involvement of the mandible with osteopenia and coarse trabeculae is relatively common (3).
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Figure 3. Bone marrow expansion within the skull vault. Posteroanterior radiograph obtained in a 12-year-old boy with heterozygous sickle cell disease (Hb SC) demonstrates widening of the medullary cavity with thinning of the inner and outer tables (arrows).
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In the spine, cortical thinning and softening of bone produce a smooth biconcave deformity of the vertebral bodies: Adjacent intervertebral disks compress the endplates, giving the vertebrae the characteristic "fish-mouth" appearance (Figs 1, 5). Vertebral collapse with resultant kyphosis also is seen (1).
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Figure 5. Fish-mouth vertebral deformities. Lateral radiograph of the lumbar spine in a young man shows the effects of bone softening and resultant compression of vertebrae by adjacent intervertebral disks (arrows).
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Extramedullary Hematopoiesis
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Although it is more common in other hemolytic anemias and in sickle variants such as Hb S–thal, extramedullary hematopoiesis occasionally is seen in sickle cell anemia. The most common site is the liver, but the spleen also may be affected, and soft-tissue hematopoietic masses may develop in the thorax (Fig 6), adrenal glands, and skin. Computed tomography (CT) and magnetic resonance (MR) imaging both are used to demonstrate the locations of such masses. Like normal intramedullary hematopoietic tissue, the soft-tissue masses have intermediate signal intensity on both T1-weighted and T2-weighted MR images. Radionuclide imaging with technetium 99m (99mTc)-labeled sulfur colloid also is useful for identifying the hematopoietic nature of focal masses (4).
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Figure 6a. Extramedullary hematopoiesis. T2-weighted coronal (a) and sagittal (b) MR images of the thoracolumbar spine in a 47-year-old woman show a right-sided paravertebral soft-tissue mass (arrow). The mass had intermediate signal intensity on both T1- and T2-weighted images, similar to the signal intensity of normal intramedullary hematopoietic tissue. Vertebral endplate depression due to central infarction also is depicted.
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Figure 6b. Extramedullary hematopoiesis. T2-weighted coronal (a) and sagittal (b) MR images of the thoracolumbar spine in a 47-year-old woman show a right-sided paravertebral soft-tissue mass (arrow). The mass had intermediate signal intensity on both T1- and T2-weighted images, similar to the signal intensity of normal intramedullary hematopoietic tissue. Vertebral endplate depression due to central infarction also is depicted.
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Thrombosis and Infarction of Bone
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Infarction is a debilitating and significant complication of sickle cell disease, and it may occur anywhere in the skeleton. It results directly from the sickling of red blood cells in the bone marrow, which causes stasis of blood and sequestration of cells. Ischemia and tissue hypoxia are the consequences and, in turn, worsen the sickling process. The eventual result is cell death. Infarcts typically occur in the medullary cavities and epiphyses and often are the source of painful bone crises, although they also may be clinically silent and discovered incidentally at radiography (5).
In infants and young children, infarction often occurs in the diaphyses of small tubular bones in the hands and feet. Infarction at these sites is termed sickle cell dactylitis or "hand-foot" syndrome (6) and results from the presence and persistence of red marrow in these regions. Severe pain at such infarcted sites is thought to be precipitated by cold-induced vasoconstriction. Sickle cell dactylitis is common between the ages of 6 months and 2 years but is rare after the age of 6 years because of the regression of red marrow in these areas with increasing age (1).
Children often present clinically with tender and swollen hands and feet, reduction in movement, and fever. This syndrome occurs in approximately half of children with sickle cell anemia (7). Radiographs depict patchy areas of lucency with periosteal reaction. In more severe cases, bone destruction and resultant deformity may be seen (Figs 7, 8).
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Figure 7. Dactylitis in the hands of an infant. Radiograph shows periosteal new bone formation along the diaphyses of the first three metacarpals of the right hand (arrows) and early destructive lesions in the base of the second metacarpal of both hands (arrowheads).
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Figure 8. Dactylitis in the feet of a 1-year-old child. Radiograph shows periosteal new bone formation along the shafts of the metatarsals in the right foot (arrows) and marked destructive changes that may lead to permanent deformity of the fourth metatarsal in the left foot.
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Both in children and in adults, the long bones are commonly affected. Acute infarcts cause osteolysis. Later, intramedullary lucency and sclerosis become evident with a patchy distribution. If cortical bone is also infarcted, subperiosteal new bone may form either through incorporation into existing cortical bone (thickening of the cortex) or through layered deposits along the inner surface of the cortex (causing a laminated, "bone-within-bone" appearance) (1,8) (Fig 9). The appearances of infarction at scintigraphy with 99mTc methylene diphosphonate (MDP) vary with time and may be difficult to interpret if the duration of symptoms is not known at the time of scanning. In the first few days after infarction, decreased or normal radiotracer uptake is seen (Fig 10). Subsequently, revascularization, primarily from periosteal vessels, produces increased uptake that extends with remodeling. The appearance of old bone infarcts depends on whether an adequate blood supply returns to the affected area. In areas of adequate revascularization, the scintigraphic appearance may return to normal after a few months; in contrast, areas of avascular bone are seen as photopenic foci. Knowledge of the varied scintigraphic appearances of infarction is important, particularly if scintigraphy is performed because of clinical indications of acute osteomyelitis.
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Figure 9a. Bone infarction of the tibial diaphyses in a 5-year-old child. (a) Initial lateral radiograph shows periosteal new bone formation along the tibial diaphyses (arrows), particularly in the upper third of the right tibia, with normal bone texture. (b) Lateral radiograph obtained 6 weeks later shows distortion of the bone texture, with incorporation of the region of periosteal reaction into cortical bone and resultant cortical thickening in both tibiae, as well as linear serpiginous areas of sclerosis in the left tibial shaft. These are typical radiographic features of chronic infarction.
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Figure 9b. Bone infarction of the tibial diaphyses in a 5-year-old child. (a) Initial lateral radiograph shows periosteal new bone formation along the tibial diaphyses (arrows), particularly in the upper third of the right tibia, with normal bone texture. (b) Lateral radiograph obtained 6 weeks later shows distortion of the bone texture, with incorporation of the region of periosteal reaction into cortical bone and resultant cortical thickening in both tibiae, as well as linear serpiginous areas of sclerosis in the left tibial shaft. These are typical radiographic features of chronic infarction.
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Figure 10. Infarction in a 12-year-old boy with homozygous sickle cell disease, left tibial pain, and a low-grade fever. Medial (left) and lateral (right) views of the left (L) tibia from late static phase 99mTc MDP scintigraphy show an area of decreased tracer uptake within the proximal shaft (arrowheads), a finding suggestive of infarction. A bone aspirate culture was negative, and the patient underwent conservative treatment. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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Other bones, such as the pelvis, ribs, and spine, may become markedly sclerotic because of medullary infarction as dystrophic medullary calcification occurs and new bone is laid down on infarcted bone (Fig 11). In the spine, MR imaging has good sensitivity for depicting ischemic changes of the vertebral endplates and for demonstrating edema in acute infarction (Fig 12). Infarction of the ribs in patients with sickle cell disease (Fig 13) may contribute to painful chest crises with resultant hypoventilation and pulmonary infiltrates.
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Figure 11. Increased bone density in a 38-year-old man. Anteroposterior radiograph shows patchy sclerosis of the pelvic bone and vertebrae, caused by medullary infarction and dystrophic calcification.
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Figure 12. Vertebral infarction in a 29-year-old woman with back pain. Sagittal T2-weighted MR image of the lumbar spine shows abnormal heterogeneous signal intensity in the L1 and L2 vertebrae.
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Epiphyseal Infarction
Epiphyseal ischemic necrosis in sickle cell anemia is common, frequently seen in the femoral and humeral heads, and more often bilateral than avascular necrosis in other diseases. Lesions quantified on MR images also are larger (9). Patients who are symptomatic typically complain of joint pain and limited movement. About 50% of patients develop avascular necrosis by the age of 35 years (10). The contribution of synovial fluid to epiphyseal nutrition may offer some protection against infarction in children (1), among whom there is a lower prevalence of that complication (27%) (11).
Frequently, initial radiographs appear normal, and the earliest signs of avascular necrosis are seen on MR images (in particular, T2-weighted inversion recovery images), which show regions of high signal intensity indicative of bone marrow edema. Often, a serpiginous double line that consists of a hyperintense inner border and hypointense periphery can be seen at T2-weighted imaging. The "double line" sign results from the high-signal-intensity inflammatory response of bone with granulation tissue, inside the low-signal-intensity reactive bone interface (12).
As osteonecrosis progresses, changes become evident at radiography. Early radiographic signs include lucency and sclerosis within the epiphysis; subsequently, crescent-shaped subchondral lucencies develop; and eventually, depression of the articular surface, collapse, and fragmentation occur (Fig 14). Changes may be seen in the acetabulum of the hip with osteophyte formation. In weight-bearing joints such as the hip, secondary degenerative changes are produced by altered mechanical factors following collapse. Collapse and secondary degenerative changes are less prominent features of osteonecrosis in non-weight-bearing sites such as the humeral head (1). The University of Pennsylvania classification system for femoral avascular necrosis (13) is shown in the Table.
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Figure 14a. (a) Anteroposterior radiograph obtained in a 44-year-old man shows stage IV avascular necrosis in the left hip and a normal right hip. (b, c) Coronal T2-weighted short inversion time inversion recovery MR images show stage I avascular necrosis in the right hip (arrow in b) as well as flattening of the left femoral head (c), a feature that helped confirm the diagnosis of stage IV avascular necrosis.
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Figure 14b. (a) Anteroposterior radiograph obtained in a 44-year-old man shows stage IV avascular necrosis in the left hip and a normal right hip. (b, c) Coronal T2-weighted short inversion time inversion recovery MR images show stage I avascular necrosis in the right hip (arrow in b) as well as flattening of the left femoral head (c), a feature that helped confirm the diagnosis of stage IV avascular necrosis.
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Figure 14c. (a) Anteroposterior radiograph obtained in a 44-year-old man shows stage IV avascular necrosis in the left hip and a normal right hip. (b, c) Coronal T2-weighted short inversion time inversion recovery MR images show stage I avascular necrosis in the right hip (arrow in b) as well as flattening of the left femoral head (c), a feature that helped confirm the diagnosis of stage IV avascular necrosis.
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Growth Effects
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The effects of sickle cell anemia on growth are thought to result from bone infarction. Epiphyseal shortening arises from vascular compromise, which causes damage to the growth plate, slowing or halting cartilage growth and leading to shortened bone (14) (Figs 15, 16).
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Figure 16. Growth disturbance in the distal radius in a 12-year-old girl. Anteroposterior radiograph of the left wrist shows epiphyseal shortening and a cup deformity of the adjacent metaphysis.
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Premature fusion of growth plates often occurs centrally because of the ingrowth of metaphyseal vessels; however, in tibiotalar slant deformity, premature fusion occurs laterally because of local ischemia (1). As a result, slanting of the articular surfaces of the distal tibia and talus is seen (Fig 17). Epiphyseal deformities with cupping of adjacent metaphyses have been described in sickle cell anemia but also may occur in other childhood disorders, such as infection (Fig 16).
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Figure 17. Growth effects. Anteroposterior radiograph of the ankle shows a tibiotalar slant deformity—an angled deformity of the ankle mortise—caused by premature closure of the lateral tibial epiphysis, a condition secondary to ischemia.
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In the spine, endplate depressions of the vertebral bodies are another manifestation of growth disturbance caused by ischemia and infarction. The H-shaped vertebral deformity is thought to be a result of central growth plate infarction. It can be distinguished from marrow hyperplasia by the characteristic sharp steplike appearance of the vertebral endplate (Figs 6, 18). In addition, compensatory lengthening of the vertebrae adjacent to the H-shaped vertebrae may occur; this deformity has been described as "tower" vertebrae (15).
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Figure 18a. H-shaped vertebral deformity. Lateral (a) and anteroposterior (b) radiographs of the thoracic spine show vertebral endplate depressions. The sharp depression due to bone infarction in the central endplate contrasts with the smooth indentation seen in the presence of bone softening.
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Figure 18b. H-shaped vertebral deformity. Lateral (a) and anteroposterior (b) radiographs of the thoracic spine show vertebral endplate depressions. The sharp depression due to bone infarction in the central endplate contrasts with the smooth indentation seen in the presence of bone softening.
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Osteomyelitis and Septic Arthritis
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Bone and joint infections are serious complications of sickle cell disease and important causes of hospitalization. In one study, a relative rate of occurrence of almost 18% was found for osteomyelitis and 7% for septic arthritis (16). The high frequency of infection in patients with sickle cell disease is due to a number of factors. Hyposplenism, which is secondary to infarction in childhood and subsequent fibrosis, is thought to be an important factor, as are impaired phagocytosis and complement dysfunction (17). Infarction and necrosis of medullary bone create a good culture medium for bacterial growth and spread. In addition, multiple hospital admissions may increase the patient’s exposure to certain bacterial pathogens (1). Various Salmonella species—in particular, nontypical serotypes such as S paratyphi B, S enteritidis, S typhimurium, and S choleraesuis—are the most common bacterial pathogens linked to bone and joint infection in sickle cell disease and are thought to be implicated in most cases of osteomyelitis (18). Staphylococcus aureus, the second most common causal organism, is seen in approximately 10% of cases of sickle cell–related osteomyelitis, in contrast to osteomyelitis from other causes, in which it is much more frequently a causal agent. Gram-negative organisms also are implicated, and tuberculous osteomyelitis and arthritis have been reported in sickle cell disease (19,20). Infection is commonly hematogenous in origin. Bacteremia due to Salmonella and other Gram-negative organisms is thought to result from sickling within mesenteric vessels and subsequent gastrointestinal infarction (21). However, the direct spread of infection does occur, often from leg ulcers. As expected, skin commensals, including S aureus and anaerobic organisms, are frequently grown in laboratory cultures in such cases.
Osteomyelitis regularly affects the long bones, but other bones, such as the vertebrae, also may be involved. The clinical manifestations are pain, fever, swelling, and increased inflammatory markers in blood serum. These clinical features are similar to those of painful bone crises, and differentiation of infection from infarction is difficult. However, this diagnostic problem is particularly important because of the need for rapid treatment of septicemia and bone destruction and the desire to avoid unnecessary long-term antibiotic treatment and potential bacterial resistance.
Blood culture is positive in 50% of cases of acute osteomyelitis and is often required to diagnose infection accurately. If infection is not suspected and blood is sampled later in the course of management, cultures usually are unhelpful.
Radiographic features are nonspecific and initially are often normal. The earliest changes may not be evident for 8–10 days; and the radiographic findings of periosteal inflammation, osteopenia, and sclerosis are seen in both infarction and infection (22) (Fig 19).
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Figure 19a. Chronic osteomyelitis. Anteroposterior (a) and lateral (b) radiographs of the left tibia and fibula in an infant show an involucrum that surrounds the shaft of the fibula.
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Figure 19b. Chronic osteomyelitis. Anteroposterior (a) and lateral (b) radiographs of the left tibia and fibula in an infant show an involucrum that surrounds the shaft of the fibula.
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Ultrasonography (US) may be a useful modality, as it is quick, portable, noninvasive, and more acceptable to children. High-resolution US allows characterization of soft-tissue changes, fluid collections, and periosteal reaction and can be targeted at the sites of greatest pain. It also allows guided diagnostic and therapeutic intervention, such as percutaneous drainage (23,24).
Radioisotope imaging provides useful information about acute osteomyelitis. The capability to image the whole skeleton at once gives this modality an advantage over others for the detection of multifocal disease.
Dynamic or triple-phase 99mTc MDP scintigraphy usually shows a combination of increased perfusion, hyperemia, and osteoblastic activity that results in increased uptake during all three phases in areas affected by acute osteomyelitis (Fig 20). Because of the variability of radiotracer uptake patterns in infarction, it may be difficult to differentiate between that and acute osteomyelitis. In such cases, further examination with modalities such as radiolabeled leukocyte imaging is required.
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Figure 20a. Osteomyelitis in a 19-year-old woman with left distal tibial and ankle pain. Anterior views of the lower legs, obtained with 99mTc MDP scintigraphy in the dynamic phase (a), blood pool phase (b), and late static phase (c), show increased tracer uptake in the region of the left ankle (arrowhead), a finding suggestive of infection. In c, a slight uptake asymmetry between the upper tibiae also is visible. This appearance represents infarction of the left tibia (arrow) with remodeling. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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Figure 20b. Osteomyelitis in a 19-year-old woman with left distal tibial and ankle pain. Anterior views of the lower legs, obtained with 99mTc MDP scintigraphy in the dynamic phase (a), blood pool phase (b), and late static phase (c), show increased tracer uptake in the region of the left ankle (arrowhead), a finding suggestive of infection. In c, a slight uptake asymmetry between the upper tibiae also is visible. This appearance represents infarction of the left tibia (arrow) with remodeling. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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Figure 20c. Osteomyelitis in a 19-year-old woman with left distal tibial and ankle pain. Anterior views of the lower legs, obtained with 99mTc MDP scintigraphy in the dynamic phase (a), blood pool phase (b), and late static phase (c), show increased tracer uptake in the region of the left ankle (arrowhead), a finding suggestive of infection. In c, a slight uptake asymmetry between the upper tibiae also is visible. This appearance represents infarction of the left tibia (arrow) with remodeling. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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Radiolabeled leukocyte imaging is performed by using either indium 111 or 99mTc hexamethylpropyleneamine oxime as the radioactive tracer. A focus of infection shows increased uptake, whereas an area of infarction is indicated by photopenia (Fig 21). However, the extensive and often irregular marrow expansion seen in sickle cell disease may cause difficulties in image interpretation. Another scintigraphic method for detecting acute osteomyelitis is bone marrow imaging with the use of 99mTc sulfur colloid. Radionuclide uptake is decreased in infarction and normal in infection. When bone marrow images are compared with radiolabeled leukocyte images, corresponding abnormalities are indicative of infarction; in contrast, normal uptake on marrow images combined with abnormally high uptake on leukocyte images is indicative of osteomyelitis (25).
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Figure 21a. Anterior views of both tibiae (a) and both ankles (b) from 99mTc hexamethylpropyleneamine oxime–labeled leukocyte imaging (same patient as Fig 20). The appearance of increased radiotracer uptake localized to the region of the left (L) ankle (arrowhead in b) supports a diagnosis of infection. The incidentally observed absence of activity in the upper shaft of the left tibia (arrow in a) is indicative of bone infarction. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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Figure 21b. Anterior views of both tibiae (a) and both ankles (b) from 99mTc hexamethylpropyleneamine oxime–labeled leukocyte imaging (same patient as Fig 20). The appearance of increased radiotracer uptake localized to the region of the left (L) ankle (arrowhead in b) supports a diagnosis of infection. The incidentally observed absence of activity in the upper shaft of the left tibia (arrow in a) is indicative of bone infarction. (Images courtesy of Muriel Buxton-Thomas, Nuclear Medicine Department, King’s College Hospital NHS Trust.)
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A comparison of uptake on scintigrams obtained consecutively with 99mTc MDP and with gallium 67 (67Ga) shows more intense uptake in areas of infection on scintigrams obtained with 67Ga than on those obtained with 99mTc MDP. However, the intrinsic properties of 67Ga (eg, multiple photon energy peaks and variable biodistribution) make the method less than ideal. 67Ga scintigraphy does have a role to play in the evaluation of spinal osteomyelitis, because radiolabeled leukocyte imaging is not reliable in this region. However, with an accuracy of 90%, MR imaging is the modality most often used for evaluation of spinal osteomyelitis (26).
MR imaging is an increasingly useful tool for the diagnosis of osteomyelitis in sickle cell disease because it is capable of showing the pathologic changes before they are visible on radiographs. MR imaging has an important role in demonstrating loculated fluid collections with or without sequestra, and cortical defects with fluid collections in adjacent soft tissue.
T1-weighted sequences show fluid collections as low-signal-intensity areas, although care must be taken if fatty marrow is replaced by hematopoietic marrow in these regions. T2-weighted fat-saturated sequences show fluid as an area of high signal intensity within the bone marrow. If a sequestrum is present, it will appear as a central area of low signal intensity. These sequences also are useful for demonstrating the communication of soft-tissue fluid collections with medullary fluid collections through cortical defects. Intravenous gadolinium–enhanced T1-weighted MR imaging has the capability to demonstrate irregular peripheral bone marrow enhancement around a nonenhancing center, which is seen in osteomyelitis (27) (Fig 22). T2-weighted fat-saturated sequences and intravenous gadolinium–enhanced T1-weighted sequences are most useful for differentiating between bone infarction and osteomyelitis.
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Figure 22. Osteomyelitis of the left femur in a 24-year-old patient with sickle cell disease. Axial gadolinium-enhanced T1-weighted fat-suppressed MR image shows heterogeneous marrow enhancement, a rounded low-signal-intensity fluid collection adjacent to the shaft, and enhancement of the soft tissues around the shaft and of the adjacent musculature. The areas of enhancement are likely to be infected. (Reprinted, with permission, from reference 22.)
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Other findings, such as bone marrow edema, fluid collection in adjacent soft tissue, and abnormal gadolinium enhancement of periosteum, muscle, fascia, and fat, also are seen with infarction as well as with osteomyelitis (Figs 23, 24). However, these features are more useful as imaging indicators of the response to antibiotic treatment in an established infection (17).
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Figure 23. Chronic osteomyelitis in a 19-year-old woman with known homozygous sickle cell disease. Coronal T2-weighted inversion-recovery MR image obtained at a follow-up examination shows cortical thickening and medullary high signal intensity in the left femur as well as multiple soft-tissue fluid collections (arrows) that were later found to be abscesses.
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Figure 24a. Acute bone infarction. Axial T2-weighted MR images of the femur in a 13-year-old boy with leg pain. (a) Initial image shows regions of both high and low signal intensity within the medullary cavity and high signal intensity in the vastus intermedius muscle, features that may represent either infarction or infection. Infection was not suspected clinically. (b) Follow-up image obtained after 4 weeks of standard management shows resolution of the area of low signal intensity within the medullary cavity and the area of high signal intensity in the adjacent muscle, a finding indicative of infarction.
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Figure 24b. Acute bone infarction. Axial T2-weighted MR images of the femur in a 13-year-old boy with leg pain. (a) Initial image shows regions of both high and low signal intensity within the medullary cavity and high signal intensity in the vastus intermedius muscle, features that may represent either infarction or infection. Infection was not suspected clinically. (b) Follow-up image obtained after 4 weeks of standard management shows resolution of the area of low signal intensity within the medullary cavity and the area of high signal intensity in the adjacent muscle, a finding indicative of infarction.
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There is no reference standard for diagnosing sickle cell–related osteomyelitis, and even the culture of biopsy specimens is not completely reliable (28). The lack of a reference standard makes a comparison of imaging modalities difficult. Factors such as availability, local expertise, and suitability for the patient affect the choice of imaging modality used. The interpretation of radiologic findings must be part of a careful ongoing multidisciplinary assessment.
Septic arthritis is less common than osteomyelitis. It often arises in conjunction with vaso-occlusion and bone infarction (29). Aseptic joint effusions are relatively common in association with painful bone crises, and needle biopsy with aspiration of fluid from the joint is important in the diagnosis of infection. Both US and MR imaging are useful for identifying possible sites of infection and guiding needle biopsy. The common MR imaging features seen in septic arthritis include perisynovial edema and synovial enhancement after intravenous gadolinium administration. Joint effusion is seen commonly in the large joints (30) (Fig 25). It is thought that sickling of synovial capillaries may increase vulnerability to infarction and reduce the response to antibiotic therapy (1).
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Figure 25a. Septic arthritis in a 19-year-old woman with left-sided hip pain and fever. (a, b) Axial T2-weighted inversion recovery MR images show a left hip effusion (arrow in a) that extends into a multilocular fluid collection adjacent to the anterior margin of the hip (b). Diffuse edema also is visible within the superficial soft tissues lateral to both hips.
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Figure 25b. Septic arthritis in a 19-year-old woman with left-sided hip pain and fever. (a, b) Axial T2-weighted inversion recovery MR images show a left hip effusion (arrow in a) that extends into a multilocular fluid collection adjacent to the anterior margin of the hip (b). Diffuse edema also is visible within the superficial soft tissues lateral to both hips.
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Muscle and Soft-Tissue Involvement
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Painful crises may involve skeletal muscle and soft tissue alone, or they may also involve bone. Vaso-occlusion may occur in muscle and lead to inflammation, edema, and myonecrosis. Fluid collections, hematomas, and fat necrosis may occur in soft tissue. US can demonstrate and help characterize fluid collections and can help identify tissue induration, hematoma, and fat necrosis (23). MR imaging also has good sensitivity for identifying soft-tissue changes that are the sole source of a painful crisis, particularly soon after onset (31). These changes include high signal intensity within muscle and high-signal-intensity fluid collections on T2-weighted images. Ischemic changes are regularly seen in adjacent bone.
Frequently, soft-tissue involvement is seen with bone infection. In osteomyelitis, associated fluid collections that communicate with marrow through cortical defects are seen. Sinus tracts that open out onto the skin are well demonstrated with MR imaging.
Foci of infection may arise in muscle and soft tissue without involving bone. Both US and MR imaging are particularly useful for diagnosis and for assessment of the extent and depth of involvement. MR imaging is principally used to exclude involvement of underlying bone, and US allows diagnosis and therapeutic intervention (Fig 26).
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Figure 26a. Soft-tissue infection in a 52-year-old man with homozygous sickle cell disease and chronic ankle ulceration. (a) Longitudinal high-frequency (12-MHz) US image of the left ankle shows a hypoechoic collection (arrow) with some internal echoes and layering, located approximately 1 cm deep to the Achilles tendon. Thick pus was aspirated from this area with US guidance. (b) Sagittal T1-weighted MR image shows a low-signal-intensity fluid collection within the pre-Achilles fat space (arrow). Areas of intermediate signal intensity due to the persistence of appendicular red marrow in the medullary cavities of the distal tibia and calcaneum (arrowhead) make the assessment of any changes due to bone involvement difficult; therefore, this sequence cannot be used to exclude osteomyelitis. (c) Sagittal T2-weighted inversion recovery MR image shows the high-signal-intensity fluid collection in the pre-Achilles space (arrow) and a small ankle joint effusion. Bone involvement may be excluded on the basis of this image.
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Figure 26b. Soft-tissue infection in a 52-year-old man with homozygous sickle cell disease and chronic ankle ulceration. (a) Longitudinal high-frequency (12-MHz) US image of the left ankle shows a hypoechoic collection (arrow) with some internal echoes and layering, located approximately 1 cm deep to the Achilles tendon. Thick pus was aspirated from this area with US guidance. (b) Sagittal T1-weighted MR image shows a low-signal-intensity fluid collection within the pre-Achilles fat space (arrow). Areas of intermediate signal intensity due to the persistence of appendicular red marrow in the medullary cavities of the distal tibia and calcaneum (arrowhead) make the assessment of any changes due to bone involvement difficult; therefore, this sequence cannot be used to exclude osteomyelitis. (c) Sagittal T2-weighted inversion recovery MR image shows the high-signal-intensity fluid collection in the pre-Achilles space (arrow) and a small ankle joint effusion. Bone involvement may be excluded on the basis of this image.
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Figure 26c. Soft-tissue infection in a 52-year-old man with homozygous sickle cell disease and chronic ankle ulceration. (a) Longitudinal high-frequency (12-MHz) US image of the left ankle shows a hypoechoic collection (arrow) with some internal echoes and layering, located approximately 1 cm deep to the Achilles tendon. Thick pus was aspirated from this area with US guidance. (b) Sagittal T1-weighted MR image shows a low-signal-intensity fluid collection within the pre-Achilles fat space (arrow). Areas of intermediate signal intensity due to the persistence of appendicular red marrow in the medullary cavities of the distal tibia and calcaneum (arrowhead) make the assessment of any changes due to bone involvement difficult; therefore, this sequence cannot be used to exclude osteomyelitis. (c) Sagittal T2-weighted inversion recovery MR image shows the high-signal-intensity fluid collection in the pre-Achilles space (arrow) and a small ankle joint effusion. Bone involvement may be excluded on the basis of this image.
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Leg ulcers, particularly over bony prominences, are common in
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Abstract
LEARNING OBJECTIVES FOR TEST...
