Imaging of musculoskeletal infections

Best Practice & Research Clinical Rheumatology Vol. 20, No. 6, pp. 1197e1218, 2006 doi:10.1016/j.berh.2006.08.009 available online at http://www.sciencedirect.com

10 Imaging of musculoskeletal infections Christopher J. Palestro*

MD

Professor of Nuclear Medicine and Radiology, Albert Einstein College of Medicine, Chief of Nuclear Medicine, Long Island Jewish Medical Center Division of Nuclear Medicine, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040, USA

Charito Love

MD

Research Scientist Division of Nuclear Medicine, Long Island Jewish Medical Center, New Hyde Park, New York, USA

Theodore T. Miller

MD

Associate Professor of Radiology, New York University School of Medicine, Chief, Division of Musculoskeletal Imaging Department of Radiology, North Shore University Hospital and Long Island Jewish Medical Center, Manhassett, New York, USA

Imaging procedures are routinely used to evaluate patients suspected of having musculoskeletal infection. Radiographs should be performed whenever musculoskeletal infection is suspected. Even when not diagnostic, radiographs are useful. They provide an anatomic overview of the region of interest, including pre-existing conditions that could influence the selection and interpretation of subsequent procedures. Magnetic resonance imaging (MRI) is sensitive, provides superb anatomic detail, does not use ionizing radiation, and is rapidly completed. This technique is especially valuable for septic arthritis, spinal osteomyelitis, and diabetic foot infections. Among the radionuclide procedures, three-phase bone imaging is readily available, and very accurate in unviolated bone. Labeled leukocyte imaging should be used in cases of ‘complicating osteomyelitis’ such as prosthetic joint infections. This test is also useful in unsuspected diabetic pedal osteomyelitis and the neuropathic joint. Gallium imaging is a useful adjunct to MIR in spinal infection. 18F-2-fluoro-2-deoxy-D-glucose positron emission

* Corresponding author. Tel.: þ1 718 470 7081; Fax: þ1 718 831 1147. E-mail address: [email protected] (C.J. Palestro). 1521-6942/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.

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tomography (FDG-PET) will likely play an important role, especially in the evaluation of spinal infection. Key words: musculoskeletal infection; osteomyelitis; magnetic resonance imaging; ultrasonography; computed tomography; radiographs; bone scintigraphy; labeled leukocytes; gallium; FDG-PET.

The diagnosis of musculoskeletal infection can be clinically challenging, and imaging procedures are routinely performed as part of the diagnostic work-up. Although there is a plethora of imaging tests from which to choose, no single test is optimal for every situation, and each patient is best served with an individualized approach. This article reviews the principles, indications, and limitations of the various morphologic and functional imaging studies available for diagnosing musculoskeletal infection.

PROCEDURES Morphologic imaging Radiography Relatively inexpensive and readily available, radiographs should routinely be the initial imaging procedure performed in all patients suspected of having musculoskeletal infection. The earliest radiographic changes of osteomyelitis are soft-tissue swelling and blurring of adjacent fat planes, which may take several days to become apparent after the onset of infection. Approximately 10 days after the onset of infection, radiographs may demonstrate lysis of medullary trabeculae, focal loss of cortex, and periosteal reaction (Figure 1).1 The sensitivity of plain radiography ranges from 43% to 75%, and the specificity from 75% to 83%. Though helpful when positive, a negative study does not exclude osteomyelitis. In patients with violated bone, moreover, radiographs are non-specific, being diagnostic in as few as 3e5% of culture-positive cases.2 Even when they are not diagnostic, radiographs are useful. They provide an anatomic overview of the region of

Figure 1. Osteomyelitis of the fourth toe. Radiograph shows destruction of the cortical and trabecular bone of the proximal phalanx (black arrow) and soft tissue swelling (white arrows).

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interest and any pre-existing conditions that could potentially influence both the selection and interpretation of subsequent procedures. Magnetic resonance imaging Advantages of magnetic resonance imaging (MRI) are the superb anatomic detail it reveals (including the ability to evaluate both bone and adjacent soft tissue), its lack of ionizing radiation, and its rapid completion. Disadvantages of MRI are its occasional inability to distinguish infectious from reactive inflammation, and difficulty imaging sites with metallic instrumentation such as joint prostheses. The earliest finding of acute osteomyelitis on MRI is an alteration of the normal marrow signal intensity, which can be appreciated as early as 1e2 days after the onset of infection. Due to inflammatory edema, which is the hallmark of acute infection, the signal intensity of marrow decreases on T1-weighted sequences and increases on fatsuppressed T2-weighted sequences, reflecting the free water content of the inflammatory exudate. The margins of the abnormal signal are usually ill-defined. Periosteal reaction and adjacent soft-tissue edema subsequently develop and are apparent on MRI earlier than on radiographs (Figure 2). In routine uncomplicated situations there is little need for contrast, since the signal abnormality is seen as well on a fatsuppressed T2-weighted sequence as it is with a post-contrast T1-weighted sequence. Intravenous gadolinium contrast is most useful for evaluating soft tissue abscesses and for distinguishing synovial thickening from synovial fluid.3

Figure 2. Osteomyelitis of the proximal fibula. A coronal fat-suppressed T2-weighted magnetic resonance image of the leg of a child shows high signal intensity in the proximal shaft of the fibula (F), with surrounding high-signal-intensity soft-tissue edema and periosteal reaction (arrows). Note the normal low signal intensity in the adjacent normal tibia (T).

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MRI has a 100% negative predictive value for excluding osteomyelitis; if the marrow is completely normal on all pulse sequences, infection can be reliably excluded. The positive predictive value of MRI, or its ability to differentiate osteomyelitis from other causes of abnormal marrow signal intensity (such as neuropathic arthropathy and ‘reactive marrow edema’), is not as high. Reactive marrow edema is non-infectious edema that occurs in bone marrow adjacent to a site of soft-tissue infection or even adjacent to another focus of osteomyelitis. The exact pathogenesis is unknown but it is thought to represent a type of vasogenic hyperemia. The signal intensity of reactive marrow edema can mimic that of osteomyelitis and it can be enhanced with gadolinium contrast agents, thus causing false-positive results.4 Computed tomography and ultrasonography Computed tomography (CT) and ultrasonography (US) are also used to evaluate acute osteomyelitis, but are not mainstream imaging modalities. CT features of acute osteomyelitis are increased density of the normal fatty medullary canal as it is replaced by infectious edema, blurring of fat planes, and eventually periosteal reaction and loss of cortex.5,6 Although CT may show these changes earlier than plain radiographs, it is less desirable than MRI because of decreased soft-tissue contrast as well as exposure to ionizing radiation. In many places in the world US is more readily available than MRI, and is the next imaging modality employed after radiography. Sonographically, acute osteomyelitis is characterized by the presence of a subperiosteal abscess.7 Advantages of US are that it is rapidly performed, does not use ionizing radiation, and does not require sedation of small children. US is useful in regions that are complicated by orthopedic instrumentation and which therefore might not be well seen with MRI or CT, or in patients in whom MRI is contraindicated. Disadvantages of US are that it is operator-dependent and can have false-negatives and false-positives. US cannot image past the cortex of a bone, and therefore early osteomyelitis that has not yet produced a subperiosteal abscess may not be appreciated. Power Doppler sonography will eventually show hyperemia around the periosteal abscess, but may not do so in the first few days of abscess formation.8 Conversely, a soft-tissue abscess that is adjacent to bone but is not truly subperiosteal may be misinterpreted as osteomyelitis. Finally, complex anatomic regions such as the wrist or foot can be difficult to evaluate with US. Functional (radionuclide) imaging tests Three-phase bone scintigraphy Bone scintigraphy is performed with technetium-99m-labeled diphosphonates, usually methylene diphosphonate (MDP). Tracer uptake is dependent on blood flow and the rate of new bone formation. When used for suspected osteomyelitis, a three-phase bone scan should be performed. The three-phase bone scan consists of the flow or perfusion phase, which is acquired immediately after tracer injection, followed immediately by an image of the region of interest, which is the blood pool or soft-tissue phase. The third or bone phase consists of images performed 2e4 hours later. The classic appearance of osteomyelitis on three-phase bone imaging is focal hyperperfusion, focal hyperemia, and focal bone uptake (Figure 3). Bone scintigraphy is widely available, relatively inexpensive, easily performed, and rapidly completed. The test is extremely sensitive and can be positive within 2 days after the onset of symptoms.

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Figure 3. Osteomyelitis of the right calcaneus. Posterior images show focal hyperperfusion on the flow phase (left), focal hyperemia on the blood pool phase (middle) and focal bony uptake on the bone phase (right). This is the classic presentation of osteomyelitis on three-phase bone scintigraphy.

With an accuracy of more than 90%, three-phase bone scintigraphy is the nuclear medicine test of choice for diagnosing osteomyelitis in bones not affected by underlying conditions.9e11 Abnormalities on bone scans reflect the rate of new bone formation in general and not infection specifically. Consequently fractures, orthopedic hardware, and the neuropathic joint can all result in a positive three-phase bone scan in the absence of infection, and in these circumstances, because of decreased specificity, the bone scan is less useful.10,11 Gallium scintigraphy Several factors govern uptake of this tracer in inflammation and infection. About 90% of circulating gallium is in the plasma and nearly all of it is transferrin-bound. Increased blood flow and increased vascular membrane permeability result in increased delivery and accumulation of transferrin-bound gallium at inflammatory foci. Gallium also binds to lactoferrin, which is present in high concentrations in most infections. Direct uptake by certain bacteria has been observed in vitro. Siderophores, low-molecular-weight chelates produced by bacteria, have a high affinity for gallium. The siderophoree gallium complex is presumably transported into the bacterium, where it remains until phagocytosed by macrophages. Some gallium may be transported bound to leukocytes. Gallium imaging is usually performed 18e72 hours after injection and is often performed in conjunction with radionuclide bone imaging. Although reliable when clearly positive or negative, the study is frequently equivocal, and the overall accuracy of bone/gallium imaging ranges between about 60% and 80% (Figure 4). The less-thanideal imaging characteristics of gallium and the need for two isotopes with multiple imaging sessions over several days are additional disadvantages of the procedure.12,13 In-vitro labeled leukocytes The development of methods to radiolabel leukocytes that migrate to sites of infection was a significant milestone in the evolution of radionuclide techniques for imaging infection. A variety of in-vitro leukocyte-labeling techniques have been used; the most commonly employed procedures make use of the lipophilic compounds indium-111 oxyquinolone and technetium-99m-HMPAO. The radiolabeling procedure takes about 2e3 hours. A total white count of at least 2000/mL is needed to obtain satisfactory images. The majority of leukocytes labeled are usually neutrophils, and the procedure is therefore most useful for identifying neutrophil-mediated inflammatory processes such as bacterial infections. The procedure is less useful for those illnesses in which the predominant cellular response is other than neutrophilic, such as tuberculosis.14e17 Labeled leukocyte imaging is the radionuclide procedure of choice for diagnosing so-called complicating osteomyelitis.11 Although they do not usually accumulate at

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Figure 4. Equivocal bone/gallium study. The distribution and relative intensity of activity around the left total knee replacement is nearly identical on the bone (left) and gallium (right) images. Although bone/gallium imaging is reliable when clearly positive or negative, the large number of equivocal results (up to 30%) is a significant limitation to this procedure.

sites of increased bone mineral turnover in the absence of infection, labeled leukocytes do accumulate in the bone marrow. The normal distribution of hematopoietically active bone marrow in adults is generally assumed to be confined to the axial and proximal appendicular skeletons. In fact, the ‘normal’ distribution of hematopoietically active bone marrow is variable. Systemic diseases such as sickle-cell and Gaucher disease produce generalized alterations in marrow distribution, while fractures, orthopedic hardware, and the neuropathic joint cause localized alterations. The normal distribution of hematopoietically active marrow in children varies with age. Consequently, it may not be possible to determine whether an area of activity on a labeled leukocyte image represents infection or atypically located but otherwise normal marrow. As a result it is often necessary to perform technetium-99m sulfur colloid marrow imaging.18 Both labeled leukocytes and sulfur colloid accumulate in the bone marrow; leukocytes also accumulate in infection, sulfur colloid, however, does not.19 The combined study is positive for infection when activity is present on the labeled leukocyte image without corresponding activity on the sulfur colloid marrow image (Figure 5).19 The overall accuracy of combined leukocyte/marrow imaging is approximately 90%.20e29 In-vivo labeled leukocyte imaging There are significant limitations to the in-vitro labeled leukocyte procedure. It is laborintensive, not always available, and involves direct handling of blood products. Considerable effort has therefore been devoted to the search for in-vivo methods of labeling leukocytes, including peptides and antigranulocyte antibodies.30 BW 250/183 (Granuloscint CISBio International, Gif sur Yvette, France) is a murine monoclonal IgG1 immunoglobulin that binds to the NCA-95 antigen present on leukocytes. About 10% of the injected activity is neutrophil-bound at 45 minutes post injection, with 20% of the activity circulating freely in the blood. Studies performed

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Figure 5. (A) Infected right hip prosthesis. The labeled leukocyte image (left) is unremarkable. However, when reviewed together with the marrow image (right), the abnormal leukocyte activity in the right hip region (arrow) is easily appreciated. (B) Left femoral fracture with orthopedic hardware. Radiograph (left) demonstrates orthopedic hardware in the left femur. On the labeled leukocyte image (middle) there is irregularly increased uptake in the distal left femur and proximal left tibia, which could be due to infection. The distribution of activity on the corresponding marrow image (right) is virtually identical to that on the labeled leukocyte image. This indicates that the findings on the labeled leukocyte image are due to marrow, not to infection.

with this agent generally become positive by 6 hours after injection; however delayed imaging at 24 hours has been recommended to increase lesion detection. Sensitivity for osteomyelitis ranges from 69% in the hips to 100% for in the lower leg and ankle, probabyly reflecting easier detection with decreasing marrow distally.31 A significant disadvantage of this agent is the high incidence of dose-dependent human antimurine antibody (HAMA) response, which ranges from less than 5% in patients receiving a single dose of the antibody to more than 30% in patients receiving repeated injections.30 While clinical reactions may occur, the most important effect of HAMA is that it can invalidate results of repeat imaging by altering the pharmacokinetics of the agent, resulting in both false-positive and false-negative tests. This agent is not available in the United States. Sulesomab (Leukoscan Immunomedics, Morris Plains, New Jersey, USA) is a 50-kD fragment antigen-binding (Fab’) portion of a murine monoclonal antibody of the IgG1 class that binds to the NCA-90 antigen on leukocytes.32 An advantage of this antibody fragment is the lack of HAMA response. The mechanism of uptake, in addition to binding to circulating neutrophils, includes crossing permeable capillary membranes and binding of the fragment to leukocytes already present at the site of infection.33 Clinical results have been variable. In one investigation of patients with suspected musculoskeletal infection, the sensitivity, specificity, and accuracy of the test were

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90e93%, 85e89%, and 88e90% respectively.34,35 In another series, however, the sensitivity, specificity, and accuracy were 76%, 84%, and 78% respectively.36 In one series of diabetic patients with suspected pedal osteomyelitis, the agent was reported to be 100% sensitive and 100% specific.35 Another group of investigators, however, reported an 80% sensitivity and a 67% specificity in this population.36 This agent is not available in the United States. 99m Tc-fanolesomab (NeutroSpec, Palatin Technologies, Cranberry, New Jersey, USA) is a murine M-class immunoglobulin that binds to the CD15 antigen expressed on human neutrophils, eosinophils and lymphocytes. The antibody binds to neutrophils in greater proportion than to any other cell type. Binding increases proportionately with increasing numbers of circulating neutrophils, and is up-regulated with neutrophil activation. Fanolesomab binds to circulating neutrophils, which eventually migrate to the focus of infection, as well as to neutrophils and neutrophil debris containing CD-15 receptors already sequestered in the focus of infection.37 In clinical trials this agent accurately diagnosed osteomyelitis in the appendicular skeleton.38,39 A phase-II study was undertaken to assess the accuracy of fanolesomab for diagnosing osteomyelitis and to compare it with labeled leukocyte imaging and three-phase bone scintigraphy.38 Bone scintigraphy was sensitive (100%) but not specific (38%). Fanolesomab was sensitive (91%), moderately specific (69%), and comparable to labeled leukocytes (91% sensitivity, 62% specificity). In another investigation, 25 diabetic patients with pedal ulcers underwent fanolesomab, labeled leukocyte, and three-phase bone imaging. The sensitivity, specificity, and accuracy of fanolesomab alone were 90%, 67%, and 76%, respectively, comparable to the values obtained with labeled leukocyte imaging alone (80%, 67%, and 72%) and significantly more specific than three-phase bone imaging.39 99m Tc-fanolesomab was approved for clinical use in the United States in 2004. In December 2005 it was withdrawn from the United States market as a result of post-marketing reports of serious and life-threatening cardiopulmonary events following administration. Onset of these events generally occurred within minutes after injection and included two deaths attributed to cardiopulmonary failure within 30 minutes after injection. Additional cases of serious cardiopulmonary events e including cardiac arrest, hypoxia, dyspnea and hypotension e required resuscitation with fluids, vasopressors, and oxygen. The precise explanation for these events has not yet been elucidated. Currently 99mTc-fanolesomab is not available anywhere and its future is uncertain. FDG-PET Fluorine-18- fluorodeoxyglucose (FDG) is transported into cells via glucose transporters, and is phosphorylated to 18F-2’-FDG 6-phosphate but is not metabolized. The degree of cellular uptake of FDG is related to the cellular metabolic rate and to the number of glucose transporters.40e42 Activated inflammatory cells e such as neutrophils, lymphocytes, monocytes, and macrophages e demonstrate increased expression of glucose transporters, and in inflammatory conditions the affinity of glucose transporters for deoxyglucose presumably is increased by various cytokines and growth factors.41,43e45 FDG-PET has several potential advantages over conventional nuclear medicine tests. Results are available within 30e60 minutes of tracer administration. Normal bone marrow has only a low glucose metabolism under physiological conditions, which may facilitate the distinction of inflammatory cellular infiltrates from hematopoietic

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marrow. Degenerative bone changes usually show only faintly increased FDG uptake compared to infection. FDG-PET images are not affected by metallic implant artifacts and have a distinctly higher spatial resolution than images obtained with single photon emitting tracers. Finally, FDG is less expensive than the combinations of radiolabeled leukocyte/bone marrow/bone scan multimodality imaging techniques.46,47 There have been several studies confirming the utility of FDG for diagnosing musculoskeletal infection.48e53 In a retrospective study of patients with a history of fractures or orthopedic intervention, FDG-PET results were compared with the results of bone scans, radiographs, CT and MRI, as well as surgical pathology.52 In patients with fractures or surgery within 3 months prior to FDG-PET, only 6/14 patients had abnormally increased FDG uptake. In the group of patients with fractures or surgery more than 3 months prior to FDG-PET, only one showed abnormally increased uptake; this patient had biopsy-proven osteomyelitis at the fracture site. In a subgroup of nine patients with recent spinal compression fractures or spinal surgery, all scans were negative, even in the three patients in whom the interval between the fracture and FDGPET imaging was brief. In another series, none of four patients with fractures 4e12 months old had false-positive results.50 In another study, reactive changes in aseptic fracture non-union showed only faint uptake that could be clearly distinguished from osteomyelitis.48 These initial reports about the value of FDG imaging for diagnosing osteomyelitis are encouraging; nevertheless extensive investigations focused on specific indications are still needed to accurately define the role of this tracer in musculoskeletal infection. Radiolabeled antibiotics Antibiotics localize in foci of infection, and may be taken up and metabolized by microorganisms. A novel approach to diagnosing infection makes use of radiolabeled antibiotics, which have none of the disadvantages of the in-vitro-labeled white cell or antigranulocyte antibody procedures. Presumably, the radiolabeled antibiotic would be incorporated and metabolized by the bacteria present in the infectious focus, resulting in accurate and specific localization of the infection. The most extensively studied of these compounds is technetium-99m-ciprofloxacin (Infecton, DraxImage, Kirkland, Quebec Canada). Published results have been variable, however.54e57 At the present time, this agent is available only on an investigational basis. INDICATIONS Spinal osteomyelitis Spinal, or vertebral, osteomyelitis, which accounts for less than 10% of all cases of osteomyelitis and has a predilection for the elderly, may result from bacteremia or direct inoculation of bacteria into the spine. Though usually confined to the vertebral body and intervertebral disc, the posterior elements are involved in up to 20% of cases.58 MRI, with an accuracy of approximately 90%, is the imaging procedure of choice for diagnosing spinal osteomyelitis.59 MRI permits early diagnosis of infection and provides direct visualization of the spinal cord, subarachnoid space, extradural soft tissues, and spinal column. MRI is more sensitive than radiographs and CT for early detection of vertebral infection. The initial MRI appearance of spinal osteomyelitis is that of marrow edema in adjacent vertebrae and endplates. Typically, there is also high signal intensity within the disc on T2WI images and loss of the intranuclear cleft. Eventually the

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vertebral endplates are destroyed (Figure 6). Both pyogenic and tuberculous spondylitis can have associated paravertebral and epidural abscesses, and gadolinium contrast should be administered to help distinguish abscess from non-drainable phlegmon. Unlike pyogenic abscesses, tuberculous abscesses may calcify, and the calcification is best appreciated on radiographs or CT. MRI is not without limitations. Severe degenerative disc disease, with edema-like granulation changes in the endplates and in the superior and inferior aspects of the disc, can mimic infection. However, if the patient has been complaining of pain for several weeks to months and the MRI shows no evidence of endplate destruction or paravertebral or epidural abscess, the process is more likely to be non-infected degeneration than pyogenic. CT is useful for evaluating the endplates in equivocal cases to determine whether there is frank destruction. CT also is helpful for guiding percutaneous biopsy. MRI is sensitive to motion, and patients who are unable to remain still for the examination may not be suitable candidates for imaging. The test is contraindicated in patients with certain implants, such as pacemakers and cardiac valves. In patients in whom MRI cannot be performed or is not diagnostic, nuclear medicine studies are a useful alternative. The current radionuclide procedure of choice for diagnosing spinal osteomyelitis is combined bone/gallium imaging, with results comparable to those of MRI. In addition to enhancing the specificity of the bone scan, gallium is useful for detecting the abscesses that often accompany this entity.11,58,60,61 There are data to suggest that if gallium tomography, or single photon emission CT (SPECT), is used the bone scan is not needed (Figure 7).58 FDG-PET is a promising alternative to bone and gallium imaging for diagnosing spinal osteomyelitis (Figure 8). Although most published series are small, FDG-PET appears to be as accurate as gallium imaging for diagnosing spinal osteomyelitis. It may be especially useful for distinguishing true infectious spondylodiscitis from severe granulation-type degenerative disc disease, a differentiation that is not always easily made with MRI.62 One group of investigators reported that FDG-PETwas superior to MRI in

Figure 6. Vertebral osteomyelitis. Sagittal T1-weighted MRI (left) shows low-signal-intensity marrow edema (white arrows) in the endplates on either side of the disc and focal destruction of the endplates (black arrows). Sagittal fat-suppressed T2-weighted MRI (right) shows high-signal-intensity marrow edema (white arrows) in the endplates on either side of the disc and focal destruction of the endplates (black arrows). Note also the high-signal-intensity edema within the disc itself.

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Figure 7. Vertebral osteomyelitis. Initial magnetic resonance imaging (MRI, not shown) was not diagnostic and gallium imaging (left) was performed. Intense uptake is present in the lower lumbar spine (arrow). Repeat MRI with contrast (right) shows enhancement of the L3/L4 vertebrae and the prevertebral and epidural tissues. Gallium is a useful adjunct to MRI in suspected spinal osteomyelitis.

patients who had a history of surgery and suffered from high-grade infection in combination with paravertebral abscess formation and in those with low-grade spondylitis or discitis.63 In 57 patients, including 27 with metallic hardware, suspected of having spinal infection after spinal surgery, the sensitivity, specificity, and accuracy of FDG-PET were 100%, 81%, and 86%, respectively. The positive predictive value was 65%, and the negative predictive value was 100%. Among 30 patients without spinal implants, there

Figure 8. Coronal 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) image, from the same patient as shown in Figure 7, demonstrates intensely increased activity in the lower lumbar spine (arrow), similar to the abnormality present on the gallium image. The intense activity to the left of the spine is due to FDG accumulation in the left kidney (arrowhead). FDG-PET is a useful adjunct to MRI in suspected spinal osteomyelitis. Same-day imaging and superior image resolution are advantages of this technique compared to gallium.

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were two false-positive scans; both occurred in patients who had undergone surgery within 6 months prior to imaging. Among 27 patients with spinal implants, there were six false-positive results; these were not related to recent surgery. Sensitivity, specificity and accuracy were not significantly different between the subgroup that had surgery within 6 months of the FDG-PET and the subgroup with surgery more than 6 months prior to FDG-PET. The specificity was 65% in the group with spinal implants and 92% in the group without. The overall accuracy (86%) of FDG-PET in this prospective study was good, and the negative predictive value (100%) was excellent. The authors concluded that postoperative spinal infection can be excluded when the FDG-PET study is negative.64 In contrast to other sites in the skeleton, labeled leukocyte imaging is not useful for diagnosing spinal osteomyelitis. Although increased uptake is virtually diagnostic, 50% or more of all cases of vertebral osteomyelitis present as areas of decreased or absent activity (photopenia) on white cell images. This photopenia is not specific for vertebral osteomyelitis, and is associated with numerous other conditions, including tumor, infarction and Paget’s disease.65 Diabetic foot infections Diabetes mellitus affects about 5% of the US population.31 The most common complication in the diabetic forefoot is the mal perforans ulcer, accounting for more than 90% of all cases of diabetic pedal osteomyelitis. Many patients with pedal osteomyelitis present without systemic illness and lack obvious clinical signs and symptoms other than the ulcer, and imaging studies are often used to confirm the diagnosis.66 Radiographs should be the initial imaging study performed because they may provide the diagnosis and because they give an overview of the anatomy and any underlying complicating structural changes. Previous radiographs are helpful in order to determine whether any of the abnormalities seen on the current radiographs are acute, suggesting infection. In many cases, however, more advanced imaging is needed, and either labeled leukocyte imaging or MRI can be performed (Figure 9). A metaanalysis of the literature with determination of weighted averages for each modality showed that radiographs had a weighted average sensitivity of 54% and 80% specificity,

Figure 9. Diabetic pedal osteomyelitis. Sagittal T1-weighted magnetic resonance imaging (MRI) (left) shows destruction of the midfoot with a low-signal-intensity abscess (open arrow) and low-signal-intensity marrow edema (closed arrows). Sagittal fat-suppressed T2-weighted image (right) shows the high-signal-intensity abscess (open arrow) and high-signal-intensity marrow edema (closed arrows).

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three-phase bone scan had an average of 91% sensitivity and 46% specificity, labeled white cell studies had 88% sensitivity and 82% specificity, and MRI had 92% sensitivity and 84% specificity.67 Approximately 5% of diabetics with neuropathy develop a neuropathic or Charcot joint, usually involving the tarsal or tarsometatarsal joints. The most common radiographic finding is a Lisfranc fracture-dislocation with eburnation and fragmentation of the tarsometarsal joints. Ultimately, massive bony sclerosis, osteophytosis, frank destruction of bones and joints, and osseous debris occur. It can be difficult to distinguish the destruction of neuro-arthropathy from that of superimposed infection, although foci of lysis within a sclerotic bone suggest infection.66 On MRI, the neuropathic joint is characterized by disorganized destruction, dislocation, marrow edema, effusion, and loss of bone and joint definition, and it is not always possible to distinguish the edema of the neuropathy from that of osteomyelitis. Secondary signs such as adjacent abscess, ulcer, or sinus tract, and cortical destruction suggest that the marrow edema is infectious.68e71 The dramatic bony changes of the Charcot joint invariably result in a positive threephase bone scan even in the absence of infection.66 Labeled leukocyte accumulation in the uninfected neuropathic joint does occur, but this problem can be overcome by performing radionuclide marrow imaging (Figure 10).72 Despite the myriad of available procedures, diagnosing complications of the diabetic foot is challenging. For pedal osteomyelitis the most useful studies are MRI and labeled leukocyte scintigraphy. Besides availability and experience, the information desired will govern the choice of imaging study to be performed. MRI has the obvious advantages of providing excellent anatomic detail and resolution of both bones and soft tissues, which is necessary for surgical planning. Labeled leukocyte imaging may be more sensitive for detecting clinically unsuspected pedal osteomyelitis and is useful for monitoring response to medical therapy and evaluating the neuropathic joint.66,72e74 There are too few data available at present to assess the role of FDG-PET in diabetic foot infections.75 Prosthetic joint infection Nearly 500,000 hip and knee arthroplasties are performed annually in the United States, and it is estimated that by the year 2030 this number may exceed 700,000. Some complications of joint replacement surgery, such as dislocation and fracture,

Figure 10. Charcot (neuropathic) joint. Radiograph (left) demonstrates increased bone density in the tarsal bones and metatarsal bone bases, as well as Lisfranc deformity and soft tissue swelling. Superimposed infection cannot be excluded. Labeled leukocyte image (middle) demonstrates increased activity in the neuropathic joint. The marrow image (right) is similar in appearance to the labeled leukocyte image, and the combined study is negative for infection.

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are readily diagnosed and treated. Differentiating infection from aseptic loosening is more difficult, however, because the clinical presentation of e and the histopathologic changes in e both entities are remarkably similar.76 A significant number of cases of aseptic loosening are due to an inflammatory/ immune reaction against the prosthesis itself. A synovial-like pseudomembranous structure develops at the cement/bone interface. The cellular composition of the pseudomembrane is varied: histiocytes are seen most frequently (95% of specimens), followed by giant cells (80%), and lymphocytes and plasma cells (25%). Neutrophils are present in less than 10% of the cases. Particulate debris, produced by component wear and fragmentation, presumably attracts and activates tissue phagocytes present around the prosthesis. This debris is impervious to regular enzymatic destruction, leading to repeated but unsuccessful attempts at phagocytosis. These ongoing attempts at phagocytosis stimulate secretion of proinflammatory cytokines and proteolytic enzymes that damage bone and cartilage and activate immune cells. The heightened inflammatory response leads to osteolysis, resulting in loss of supporting osseous tissues and, eventually, prosthetic loosening.76 The rate of infection following primary implantation is about 1% for hip and 2% for knee prostheses. The rate of infection following revision surgery is somewhat higher: about 3% for hip and 5% for knee replacements. About one third of these infections develop within 3 months, another third within 1 year, and the remainder more than 1 year after surgery. Histopathologically, the inflammatory reaction accompanying the infected prosthesis is similar to that present in aseptic loosening, with one important difference: neutrophils, usually absent in aseptic loosening, are invariably present in infection.76e78 Differentiating aseptic loosening from infection is extremely important because the treatment of these two entities is different. The patient with an aseptically loosened device usually undergoes a single-stage revision arthroplasty requiring only one hospital admission. The treatment of the infected prosthesis is more complicated, requiring a two-stage procedure; the infected prosthesis is removed, the patient receives a course of antimicrobial therapy, and eventually undergoes a revision arthroplasty.76 The useful diagnostic test must be sensitive and specific. A test that is sensitive but not specific leads to multiple expensive operations in patients in whom a single intervention may have sufficed. The specific, but insensitive, test also results in additional surgical intervention, because undiagnosed infection will cause any revision implant to fail. Non-specific markers of inflammation e such as the erythrocyte sedimentation rate and C-reactive protein level e may be elevated in both loosening and infection.76 Joint aspiration with gram stain and culture is considered the definitive diagnostic test; its sensitivity, however, is variable, ranging from 28% to 92%. Its specificity is more consistent, ranging from 92% to 100%.79e81 Plain radiographs are neither sensitive nor specific, and cross-sectional imaging modalities such as CT and MRI are limited by hardware-induced artifacts.76 Radionuclide imaging, which reflects physiologic rather than anatomic changes and is not affected by metallic hardware, plays an important role in the evaluation of prosthetic joint infection. Bone scintigraphy is very sensitive but not at all specific, and it should be used only as a screening test. The current imaging procedure of choice for evaluating suspected joint replacement infection is combined leukocyte/marrow imaging with an overall accuracy in the range 88e98%.20,21,23,28,29 Although inflammation may be present in both the infected and aseptically loosened device, neutrophils, which are invariably present in infection, are usually absent in aseptic loosening. The success of labeled leukocyte imaging is highly dependent on the presence of

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a neutrophil response, and this critical histological difference between infection and aseptic loosening accounts for the high sensitivity and specificity of leukocyte/marrow imaging for diagnosing prosthetic joint infection (Figure 5A).29 The role of FDG-PET in the evaluation of painful lower-extremity joint prostheses has been extensively investigated.29,82e87 Although initial reports suggested that FDGPET could accurately identify the infected joint prosthesis, recent studies are less encouraging. FDG-PET is not capable of distinguishing the aseptically loosened from the infected prosthesis.29,87 This is not surprising when one considers that inflammation e often intense e is present in both aseptic loosening and infection. In contrast to labeled leukocyte imaging, there is no preferential imaging of neutrophil-mediated inflammatory processes with FDG-PET. Thus, both aseptic loosening and infection are characterized by increased periprosthetic activity on FDG studies. Septic arthritis Infectious organisms can reach the joint either through direct inoculation, hematogenous spread, or contiguous spread from an adjacent intra-articular site of osteomyelitis. Radiographically, the earliest signs of septic arthritis are soft-tissue swelling and blurring of fat planes about the joint, followed by joint distention due to effusion and synovial thickening. Periarticular osteopenia also eventually develops, and early in the course of pyogenic arthritis, joint space narrowing occurs due to proteolytic enzymes released by the white-cell exudate which destroy the articular cartilage. In tuberculous arthritis, the main radiographic features are marked periarticular osteopenia with relative preservation of the joint space until late in the disease, because the chronic inflammatory exudate of tuberculosis lacks the cartilage-destroying proteolytic enzymes. US and MRI are excellent for the evaluation of the suspected septic joint, and will show changes before radiography. The presence of a joint effusion does not necessarily indicate a septic joint. This is particularly true for children, in whom a systemic viral infection can cause a transient but painful reactive sterile synovitis. In large joints such as the hip and knee, absence of a joint effusion or synovial thickening excludes a septic joint with a high degree of certainty. This is not the case, however, for small joints.88,89 US is especially useful in children since it can be performed quickly and does not require sedation. US demonstrates a joint effusion as an anechoic or a mildly heterogeneous hypoechoic fluid collection. Depending on the acuteness of the process, power Doppler may or may not show hyperemia in the surrounding synovium (Figure 11).90,91 A disadvantage of US is that it cannot evaluate the underlying bony structures, and therefore may miss an early osteomyelitis. MRI is useful for evaluating both the joint and the underlying bony structures. Distinguishing joint fluid from thickened synovium is best done using intravenous gadolinium contrast. Although there is overlap, pyogenic synovitis tends to be thick and irregular, while tuberculous synovitis tends to be thin and smooth. Radionuclide studies are of limited value in the evaluation of septic arthritis. The classic presentation of acute arthritis on three-phase bone scintigraphy consists of hyperperfusion and hyperemia of the joint on early images, with increased activity limited to the articular surfaces of the involved bones on delayed images. This presentation is associated with both septic and aseptic arthritis. Osteomyelitis and acute arthritis are not mutually exclusive, and bone-scan findings consistent with septic arthritis do not

1212 C. J. Palestro et al

Figure 11. Septic arthritis of the hip. Longitudinal power Doppler sonogram of a child’s hip (left) shows the anechoic effusion (E) and the bright hyperemia of the distended joint capsule and surface of the cortex (arrows). Femoral head (FH) is normal. Longitudinal power Doppler sonogram of the contralateral, asymptomatic, hip (right) shows no effusion, minimal background hyperemia and a normal femoral head (FH).

exclude e and can potentially mask e an underlying osteomyelitis.1 Neither gallium nor labeled leukocyte imaging reliably separates infectious from non-infectious arthritis. Labeled leukocyte imaging can be positive in rheumatoid arthritis, acute gouty arthritis, and pseudogout (Figure 12).92e95 SUMMARY A wide range of imaging modalities is available for the evaluation of clinically suspected musculoskeletal infection. Relatively inexpensive and ubiquitously available,

Figure 12. Rheumatoid arthritis of the wrist. There is diffusely increased labeled leukocyte activity in the right wrist (arrow) of a patient with rheumatoid arthritis. This uptake pattern is indistinguishable from that seen in septic arthritis.

Imaging of musculoskeletal infections 1213

radiographs should be the initial imaging procedure performed in all patients suspected of having musculoskeletal infection. Even when not diagnostic, radiographs are valuable because they provide an anatomic overview of the region of interest and any pre-existing conditions that could potentially influence both the selection and interpretation of subsequent procedures. If additional imaging studies, beyond radiographs, are necessary, their selection should be governed by the indication and availability. Magnetic resonance imaging is exquisitely sensitive, provides superb anatomic detail, does not use ionizing radiation, and is rapidly completed. This technique is especially valuable for septic arthritis, spinal osteomyelitis, and diabetic foot infections. It is less useful in the evaluation of orthopedic hardware because hardware-induced artifacts degrade image quality. Among the various radionuclide procedures, three-phase bone imaging accurately diagnoses infection in unviolated bone. Labeled leukocyte imaging is the radionuclide procedure of choice in cases of ‘complicating osteomyelitis’, and is the imaging procedure of choice for prosthetic joint infection. Unlike MRI or CT, this procedure is not hindered by the presence of metallic hardware. Labeled leukocyte imaging is also useful in unsuspected diabetic pedal osteomyelitis, for monitoring response to treatment in these patients, and for evaluating the neuropathic joint. Gallium imaging is a useful adjunct to MRI in spinal infection. Although data are just emerging, FDG-PET likely will play an important role, especially in spinal infections.

Practice points  radiographs should be the initial imaging procedure performed in the work-up of musculoskeletal infection  MRI provides exquisite anatomic detail, is extremely sensitive, does not use ionizing radiation, and is especially useful for diagnosing spinal osteomyelitis, diabetic pedal osteomyelitis, and septic arthritis  three-phase bone scintigraphy is readily available, easily performed, very sensitive, and accurately diagnoses osteomyelitis in unviolated bone; in the presence of trauma, orthopedic hardware, neuropathic joint, etc, it is useful only as a screening test  labeled leukocyte imaging is the radionuclide procedure of choice for diagnosing complicating osteomyelitis. To maximize accuracy, complementary marrow imaging must often be performed. This test is especially useful for diagnosing prosthetic joint infection, unsuspected pedal osteomyelitis in diabetics, and for evaluating the neuropathic joint  labeled leukocyte imaging is not useful for diagnosing spinal osteomyelitis  gallium imaging is a useful adjunct to MRI in spinal osteomyelitis  FDG-PET appears to be a promising alternative to gallium imaging for spinal osteomyelitis, but is not useful for prosthetic joint infection  ultrasound is useful in suspected septic arthritis  radionuclide studies are of limited value in septic arthritis

1214 C. J. Palestro et al

Research agenda  both MRI and labeled leukocyte imaging are used for evaluating diabetic foot infections, but intra-individual comparisons between these two tests are lacking; a prospective comparison in the same population would help establish the appropriate indications for each of them  a prospective investigation of FDG-PET and gallium in suspected spinal osteomyelitis should be performed to confirm the value of FDG-PET in this entity  while the diagnostic value of the imaging tests reviewed in this paper have been investigated, few data are available on their value for monitoring response to treatment

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