Conventional Tomography

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with breakdown of skin and subcutaneous tissue

Data from Resnick D, Niwayama G. Osteomyelitis, septic arthritis and soft tissue infection: mechanisms and situations. In: Resnick D, editor. Diagnosis of bone and joint disorders. 3rd edition. Philadelphia: WB Saunders; 1995. p. 2335.

Data from Resnick D, Niwayama G. Osteomyelitis, septic arthritis and soft tissue infection: mechanisms and situations. In: Resnick D, editor. Diagnosis of bone and joint disorders. 3rd edition. Philadelphia: WB Saunders; 1995. p. 2335.

bone scan. This examination is readily performed after injection of 25 mCi of methylene diphosphonate. The patient is imaged with a nuclear medicine gamma camera. The initial or flow phase is acquired at a rate of 2 seconds per frame, followed by blood pool phase images approximately 5 to 10 minutes after injection. Delayed static images of the area of interest are performed 3 hours after injection. Abnormal findings for osteomyelitis typically include increased flow activity, blood pool activity, and positive uptake on 3-hour images. The intensity of uptake becomes more focal and intense at the area of interest, and when positive on all three phases is highly sensitive for osteomyelitis (73% to 100% sensitivity) [40-43]. In a recent metaanalysis the pooled sensitivity reached 61% but the specificity was the lowest (25%) compared with leukocyte scintigraphy and MRI [44].

This technique has high sensitivity for osteomyelitis and can differentiate cellulitis from osteomyelitis reliably when no complicating conditions are present. Cellulitis is only positive on the first two phases and has a normal (not increased) uptake on the 3-hour images. The specificity for osteomyelitis decreases, however, when other conditions are present simultaneously. These include recent trauma, surgery, placement of orthopedic devices, or diabetes [45-47]. In these conditions the specificity of a three-phase bone scan decreases; most reports are between 73% and 79% but have been reported as low as 38%. These complicating conditions may cause a positive bone

Sinography Chronic Osteomyelitis

Fig. 10. Sinography. Chronic osteomyelitis. A small flexible catheter was placed within a cutaneous opening (arrow). Retrograde opacification of a sinus tract confirmed the communication with an abscess in the midportion of the tibia.

scan but the findings are of lower specificity. Further imaging generally is required to assess more accurately possible osteomyelitis in these conditions.

Gallium scan

Infection also has been identified by injection of 5 mCi of gallium [48]. The mechanisms that favor the increased uptake of radiogallium are not

Conventional Tomography
Fig. 11. Conventional tomography of the spine in a patient who has S aureus endocarditis. A lateral tomogram of L4-L5 region shows a large osteolytic area involving the disc space and contiguous vertebral bodies, with surrounding sclerosis (arrow).

fully understood, but are probably related to gallium attachment to serum proteins, particularly transferrin produced by leucocytes and siderophores produced by infected microorganisms. This product has improved specificity compared with the three-phase bone scan alone [46,49]. Imaging typically is performed 48 hours after injection but occasionally can be performed at 24 hours. Gallium has occasional false positives from fractures and tumor uptake, and has marked excretion through the gastrointestinal tract. Although more specific than a three-phase bone scan, image quality suffers slightly compared with a three-phase bone scan and takes longer. Alternatively, the bone scan has the relative advantage of being very sensitive and, if negative, effectively excludes the diagnosis of osteomyelitis. The reported sensitivity for gallium scan has ranged from 25% to 80%, with a specificity of 67% [50-52].

A gallium scan can be obtained in conjunction with technetium (Tc) scan in the same patient, and the information that is obtained may be more useful than that of either examination alone [53]. After administration of Tc agents, scans can be obtained within a few hours, documenting the presence of an inflammatory process; optimal scanning with gallium, however, may necessitate a delay of 10 to 24 hours. Gallium scans may reveal abnormal accumulation in patients who have active osteomyelitis when Tc scans reveal decreased activity ("cold" lesions) or perhaps normal activity. Furthermore, gallium accumulation seems to correlate more closely with activity in cases of osteomyelitis than does Tc uptake [53].

White blood cell scan

The white blood cell scan (WBCS) was done originally with Indium111-la-beled white blood cells and more recently with 99mTc hexamethylpropylene-amine oxime (HMPAO)-labeled white cells [54]. The indium product has a higher radiation dose to the patient, takes 24 hours to perform, and the images have extensive noise. This product was available in clinical trials earlier than the HMPAO WBCS with a reported sensitivity of more than 90% and a specificity of 78% [50]. This technique was shown to be useful in complicated and uncomplicated patients. Similar sensitivity and specificity were found with the HMPAO technique. In an effort to improve the specificity of bone imaging, complementary scintigraphy may be performed using autologous poly-morphonuclear neutrophils (PMN) labeled with 99mTc HMPAO. The diagnosis relies in the congruent spatial distribution of the images in both methods. In some instances, however, there is an uncommon scintigraphic pattern represented by absence of uptake of 99mTc HMPAO PMN. In a retrospective study by Galp^rine and coworkers [55], 17 cases of cold 99mTc HMPAO PMN scintigraphy but with positive 99Tc HMDP and proven bacterial orthopedic infected hardware were analyzed. All the patients had a cold image over the hip and the causative agent was Staphylococcus. There is no reasonable explanation for the phenomenon; the authors suggest that in the case of cold HMPAO in conjunction with positive HMDP, the former should be considered as a false negative and require further study. The advantages of the Tc WBCS that make it preferable for clinical use include same day study and result, lower radiation dose, and better image quality and resolution.

All these studies require withdrawal of 50 mL of blood and separation of the white cell component from the rest of the blood with radiolabeling of the white blood cells. After reconstitution of the radiolabeled cells in saline, the cells are reinjected into the patient. Labeled leukocyte studies by in vitro method using mIn-oxine, 99mTc HMPAO, and 99mTc-stannous colloid have the inherent limitation of personnel safety: risks of infection and cross-contamination. To overcome these problems, attempts have been made to target leukocytes directly by in vivo labeling techniques. There are several receptors present on the leukocytes and the granulocytes that can be targeted with suitable ligands, such as monoclonal antibodies, antibody fragments, or peptides. Currently there is ongoing investigation under these categories with anti-NCA90-Fab (Leukoscan), murine MoAb IgG1 (Granuloscient; CISBio International), anti-CD15 antigen (Neutrospect, 99mTc-fanolesomab; LeuTech), and the receptor-binding agent DPC-11870 that targets the leukotriene B4 receptor, which is abundantly expressed in the granulocyte cell surface [56].

The main advantage of the WBCS, however, is the marked improvement in specificity compared with bone scans, particularly when complicating conditions are superimposed. The specificity increases to 80% to 90% when compared with the bone scan. Several authors have reported a loss of sensitivity of leukocyte scintigraphy when imaging chronic osteomyelitis in the axial skeleton. The nonspecific uptake of labeled leukocytes has been suggested to be attributable to the presence of hematopoietic bone marrow in the axial skeleton. The decreased uptake of labeled cells in infections of the axial skeleton is poorly understood, but microthrombotic occlusion and inflammatory compression of the blood vessels may prevent labeled cells from reaching the site of infection. The sensitivity of leukocyte scintigraphy decreased from 84% to 21% for chronic osteomyelitis in the axial skeleton [44].

A drawback of nuclear medicine is its limited spatial resolution with less ability to clearly delineate areas of complex anatomy, such as the foot and ankle. The circulatory compromise that predisposes individuals to distal extremity infection also may limit the delivery of isotopes distally. Although three-phase bone scintigraphy has an accuracy of 90% or greater for the diagnosis of osteomyelitis in otherwise normal bone, the specificity of the test decreases in the setting of preexisting conditions, such as fracture, presence of orthopedic hardware, and neuropathic joint disease [42]. Nuclear medicine can image patients who have prostheses without interference from artifact. Another advantage of nuclear medicine over other imaging modalities is that pediatric patients rarely require sedation, children can be scanned more than once after the injection of the radiopharmaceutical, and multiple foci of disease can be demonstrated [57].

Radiolabeled antibiotics

The use of radiolabeled antibiotics is fast emerging as a promising diagnostic test for the detection of infective lesions because of their specific binding to the bacterial component [58]. The main advantage of these agents may be the differentiation between infection and sterile inflammatory lesions [59,60]. The normal Infecton (ciprofloxacin labeled with Tc-99m) image shows high uptake by the kidneys with excretion to the urinary bladder, moderate uptake by the liver and spleen, and no uptake by bone or bone marrow [61]. In a population of 102 patients who had various infections undergoing an Infecton scan, the authors reported an overall sensitivity and specificity of the method of 83% and 91%, respectively [61]. More recently, Malamitsi and coworkers [62] evaluated 45 patients who had known or suspected bone infection with Infecton scans. Almost all were also subjected to a three-phase 99mTc-methylene diphosphonate bone scan and most of them to a 99mTc-human polyclonal immunoglobulin scan, in addition to a gal-lium-67-citrate scan, plus CT or MRI or both. The sensitivity and specificity of Infecton scintigraphy were found to be 97.2% and 80%, respectively, with positive and negative predictive values of 94.6% and 88.9% [62]. Siaens and coworkers [63] investigated the differences and advantages of 99mTc-enrofloxacin versus Infecton in a murine model of musculoskeletal infections, their results showing less uptake of Infecton by normal tissue.

Labeled immunoglobulins

A Tc-99m-labeled murine immunoglobulin M monoclonal antigranulo-cyte antibody that binds to human polymorphonuclear leukocyte CD15 antigens has been evaluated. The initial report is promising, with possibly better diagnostic results than other techniques, initial sensitivity of 91%, and specificity of 70% [42]. Rubello and coworkers [64] performed 253 Leu-koscan examinations in a group of 220 consecutive patients who had suspected bone infections. The examination was performed by acquiring early (Protocol A = 4 h) and delayed (Protocol B = 18-24 h) planar images. The radiotracer uptake intensity in the infected site was graded using a four-point visual scale compared with the contralateral body region in the case of the peripheral skeleton or the nearest vertebrae in the case of spondylodis-citis. Sensitivity was equal in both protocols (84.2%) but specificity was higher in delayed images (85.7% versus 76.2%). In patients who had an early high uptake Leukoscan intensity, further delayed images appear unnecessary for the purpose of diagnosing infection. In contrast, in patients who have an early mild Leukoscan uptake intensity only, delayed imaging seems to be recommended for improving specificity.


Streptavidin, a 65-kDa protein, accumulates at sites of inflammation and infection as a result of increased capillary permeability. In addition to being used by bacteria for their growth, biotin forms a stable, high-affinity noncova-lent complex with avidin. Lazzeri and coworkers [65] explored the usefulness of this technique for the detection of early vertebral osteomyelitis in a series of 55 patients. Thirty-two of the patients underwent MRI and 24 underwent CT scan. DTPA-conjugated biotin was radiolabeled by incubating 500 mg of DTPA-biotin with 111 MBq of 111In-chloride. Two-step scintigraphy was performed by first infusing 3 mg streptavidin intravenously, followed 4 hours later by 111In-biotin. Imaging was begun 60 minutes later. Strepta-vidin/111In-biotin scintigraphy was positive in 32 of 34 patients who had spinal infection (94.12% sensitivity) and negative in 19 of 21 patients who did not have infection (95.24% specificity). The sensitivity for MRI and CT were 54.17% and 35.29% with a specificity of 75% and 57.14%, respectively. The only false positive result observed with streptavidin/111In-biotin scintigraphy corresponded to the site of a spinal malignancy. These results suggest that streptavidin/111In-biotin scintigraphy is an efficacious method for the detection of vertebral osteomyelitis in the first 2 weeks after the onset of symptoms.

More than 400,000 hip and knee arthroplasties are performed annually in the United States. Differentiating infection from aseptic loosening, the most common cause of joint arthroplasty failure, is extremely important because the management of these two conditions differs markedly. Bone marrow imaging with a combination of 111In-labeled leukocytes and 99mTc sulfur colloid has an accuracy of more than 90% and is the preferred radionuclide procedure for diagnosing prosthetic joint replacement infection [66,67].

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  • sarah
    Can gallium scans have false positives?
    8 years ago

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