CHAPTER 7 Nuclear Medicine Imaging With an Emphasis on Spinal Infections
PET AND SPECT
The gamma camera or SPECT camera is a camera that is able to detect scintillations (flashes of light) produced when gamma rays, resulting from radioactive decay of single photon emitting radioisotopes, interact with a sodium iodide crystal at the front of the camera. The scintillations are detected by photomultiplier tubes, and while the areas of crystal seen by tubes overlap, the location of each scintillation can be computed from the relative response in each tube.1 The energy of each scintillation is also measured from the response of the tubes, and the electrical signal to the imaging computer consists of the location and photon energy. In front of the crystal resides a collimator which is made of lead and usually manufactured with multiple elongated holes (parallel-hole collimator). The holes allow only gamma rays that are traveling perpendicularly to the crystal face to enter. The gamma photons absorbed by the crystal therefore form an image of the distribution of the radiopharmaceutical distribution in front of the camera. By rotating the camera around the patient and acquiring images at different angles, tomographic images, or SPECT images, can be generated through the use of specific reconstruction algorithms.2
As with SPECT, PET relies on computerized reconstruction procedures to produce tomographic images, but by means of indirectly detecting positron emission.3 Positrons, when emitted by radioactive nuclei, will combine with an electron from the surroundings and annihilate it. Upon annihilation, both the positron and the electron are then converted to electromagnetic radiation in the form of two high-energy photons which are emitted 180 degrees away from each other. It is this annihilation radiation that can be detected externally and is used to measure both the quantity and the location of the positron emitter. Simultaneous detection of two of these photons by detectors on opposite sides of an object places the site of the annihilation on or about a line connecting the centers of the two opposing detectors. At this point, mapping the distribution of annihilations by computer is conducted. If the annihilation originates outside the volume between the two detectors, only one of the photons can be detected, and since the detection of a single photon does not satisfy the coincidence condition, the event is rejected. Since radioisotopes suitable for PET have a short half-life (e.g. 110 min for 18F), an on-site cyclotron is needed for production of such isotopes.4
RADIOPHARMACEUTICALS AND METHODOLOGY
99mTc-MDP/HDP
Bone scintigraphy makes use of 99mTc-labeled organic analogues of pyrophoshate which are characterized by P-C-P bonds and predominantly absorb at kinks and dislocation sites on the surface of hydroxyapatite crystals. The most commonly used diphosphonate agents are 99mTc hydroxyethylene diphosphonate (99mTc HDP) and 99mTc methylene diphosphonate (99mTc MDP). The major physiologic determinants of bone uptake of these phosphate agents are the rate of bone turnover and blood flow, and the bone surface area involved.5 When performed for osteomyelitis, the study is usually done in three or four phases. Three-phase bone imaging consists of a dynamic imaging sequence, the flow or perfusion phase, followed immediately by static images of the region of interest, which is the blood-pool or soft-tissue phase. The third, or bone phase, consists of planar static images of the area of interest, acquired 2–4 h later. SPECT is performed when deemed necessary by the nuclear medicine physician. The usual injected dose for adults is 740–925 MBq (20–25 mCi) of 99mTc-MDP. The normal distribution of this tracer, by 3–4 h after injection, includes the skeleton, genitourinary tract, and soft tissues.6
67Ga
67Ga-citrate has been used for localizing infection for more than three decades. 67Ga, which is cyclotron produced, emits 4 principal rays suitable for imaging: 93, 184, 296, and 388 keV. Several factors govern uptake of this tracer in inflammation and infection. When injected intravenously, 67Ga binds primarily to transferrin a β-globulin responsible for transporting iron. Increased blood flow and increased vascular membrane permeability associated with inflammation/infection result in increased delivery and accumulation of transferrin-bound 67Ga at inflammatory foci. At the site of infection or inflammation, 67Ga can then bind to lactoferrin, which is present in high concentrations in inflammatory foci, attach to leukocytes, or may be directly taken up by bacteria. Siderophores, low molecular weight chelates produced by bacteria, have a high affinity for 67Ga. The siderophore–67Ga complex is presumably transported into the bacterium, where it remains until phagocytosed by macrophages.7 Imaging is usually performed 18–72 h after injection of 185–370 MBq of 67Ga-citrate. The normal biodistribution of 67Ga, which can be variable, includes bone, bone marrow, liver, genitourinary and gastrointestinal tracts, and soft tissues.7
Radiolabeled leukocytes
Neutrophils concentrate in large numbers, up to 10% of the total number of neutrophils per day, at sites of infection. Their accumulation is stimulated by the presence of lactoferrin, local neutrophil secretions, and chemotactic peptides. Several techniques for in vitro radiolabeling of isolated leukocytes have been reported; the most commonly used procedures make use of the lipophilic compounds 111In-oxyquinoline (oxine) and 99mTc hexamethyl propyleneamine oxine (HMPAO).8 The lipophilic oxine binds bi- and trivalent ions such as 111In. Following diffusion of 111In-oxine across the cell membrane, 111In is released from oxine, which leaves the cell and binds intracellularly. HMPAO forms a small neutral lipophilic complex with 99mTc that readily crosses the cell membrane and changes into a secondary hydrophilic complex that is trapped in cells. The radiolabeling procedure takes about 2–3 h. The usual dose of 111In-labeled leukocytes is 10–18.5 MBq (300–500 μCi); the usual dose of 99mTc-HMPAO-labeled leukocytes is 185–370 MBq (5–10 mCi). A total white count of at least 2000/mm3 is needed to obtain satisfactory images. Usually, the majority of leukocytes labeled are neutrophils, and hence the procedure is 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.9 At 24 h after injection, the usual imaging time for 111In-labeled leukocytes, the normal distribution of activity is limited to the liver, spleen, and bone marrow. The normal biodistribution of 99mTc-HMPAO-labeled leukocytes is more variable. In addition to the reticuloendothelial system, activity is also normally present in the genitourinary tract, large bowel (within 4 h after injection), blood pool, and occasionally the gallbladder.10 The interval between injection of 99mTc-HMPAO-labeled leukocytes and imaging varies with the indication; in general, imaging is usually performed within a few hours after injection.
99mTc-labelled antibodies
Considerable effort has been devoted to developing in vivo methods of labeling leukocytes using peptides and antigranulocyte antibodies/antibody fragments. One method makes use of a murine monoclonal IgG1 (Granuloscint; CISBio International) that binds to non-specific cross-reactive antigen-95 present on neutrophils. Studies generally become positive by 6 h after injection; delayed imaging at 24 h may increase lesion detection.11 Another agent that has been investigated is a murine monoclonal antibody fragment of the IgG1 class that binds to normal cross-reactive antigen-90 present on leukocytes (LeukoScan; Immunomedics). Sensitivity and specificity of this agent range from 76% to 100% and from 67% to 100%, respectively.12
18F FDG
18Fluorodeoxyglucose is a fluorinated glucose analogue that, like glucose, passes through the cell membrane. Following subsequent phosphorylation by glucose-6-hexokinase it is trapped within the cell.13–15 Although FDG PET is reported to be a sensitive and specific technique in oncological imaging, it is well known that inflammatory and infectious lesions can cause false-positive results.16 Various types of inflammatory cells such as macrophages, lymphocytes, and neutrophil granulocytes as well as fibroblasts have been shown to avidly take up FDG, especially under conditions of activation. It even appears that on autoradiography, the FDG distribution in certain tumors is highest in the reactive inflammatory tissue, i.e. the activated macrophages and leukocytes surrounding the neoplastic cells.7,8
INFECTION OF THE SPINE
Vertebral infection represents 2–4% of all cases of osteomyelitis and its incidence is increasing.17 In order to prevent clinically significant consequences which include neural compromise and late spinal deformities, early diagnosis and prompt treatment are essential. Causative pyogenic microorganisms in decreasing order of frequency are Staphylococcus aureus, Streptococcus and Pneumococcus and Gram-negative bacteria.18 Tuberculous spondylitis is an important form of nonpyogenic granulomatous infection. The routes of spinal infection include hematogenous spread, postoperative infections, direct implantation during spinal punctures, and spread from a contiguous focus.
Acute osteomyelitis and spondylodiscitis
The combination of physical examination and biochemical alterations in combination with three-phase bone scanning, and especially MRI, have a high sensitivity (>90%) for the detection of acute osteomyelitis and spondylodiscitis.19–21 Accordingly, in the absence of complicating factors, the added value of scintigraphic imaging techniques will be limited. Nevertheless, FDG PET especially may have a role in doubtful cases, albeit rarely. For instance, it may play a role in differentiating spondylodiscitis from erosive degenerative disc disease, a condition occasionally displaying a false-positive MRI and bone scan findings.20,22–24 When confronted with a negative PET scan in this clinical situation, infection can be excluded.
Chronic osteomyelitis
Patients with chronic osteomyelitis may present with a variety of symptoms, including localized bone and joint pain, erythema, swelling, fevers, night sweats, etc. Laboratory tests, such as leukocyte count, estimated sedimentation rate, and C-reactive protein can be helpful in diagnosis but lack sensitivity and specificity in low-grade infections.25–28 C-reactive protein is also useful for gauging response to therapy.
Many imaging modalities have been proposed for the noninvasive evaluation of chronic osteomyelitis.29 Radiographs are helpful in the diagnosis and staging of the patient. However, changes are often subtle. Conventional radionuclide scans can also be useful in the diagnosis but do not aid in preoperative planning of resection. Combined three-phase bone scintigraphy and leukocyte scan has a good clinical accuracy (79–100%) when considering the peripheral skeleton;19,30–35 however, its accuracy decreases (1) in low-grade chronic infections(lower sensitivity);25,27 (2) in the presence of periskeletal soft tissue infection due to the limited resolution of conventional nuclear imaging (lower sensitivity and specificity); (3) in the central skeleton due to the presence of normal bone marrow and the possibility of so-called ‘cold lesions’ (lower sensitivity and specificity);24,31–35 and (4) after trauma or surgery due to the presence of ectopic hematopoietic bone marrow (lower specificity). To avoid false-positive studies due to ectopic bone marrow, the combination of leukocyte scanning with bone marrow scanning (99mtechnetium sulfur colloid) has been proposed.36 Congruency between leukocyte and bone marrow scanning indicates the presence of bone marrow, while the presence of a positive leukocyte scan and negative marrow scan suggests the presence of infection. Using this technique, diagnostic accuracy of up to 96% has been reported. In the vertebral column, a combination of bone and gallium scan has been proposed to improve both sensitivity and specificity.37 However, the need for two or even three (bone scan/leukocyte scan/bone marrow scan or bone scan/gallium scan) techniques is not practical, adds to the cost and patient radiation dose, and is time consuming.
Computed tomography is used to identify a sequestered infection and for preoperative resection planning. Similarly, MRI is useful for surgical planning because it delineates intraosseous and extraosseous involvement. CT and MRI are, however, of limited value in the presence of metallic implants as well as for discriminating between edema and active infection after surgery.21,29,30
Overall, in spite of the available armamentarium of imaging modalities, clinicians are often confronted with an indeterminate diagnosis and the clinical strategy adopted is often limited to a ‘wait and see’ policy or empirical antibiotic treatment.25,38,39 Accordingly, novel imaging modalities with a very high accuracy for identification of sites of chronic osteomyelitis are of major interest. Several authors have addressed the value of FDG PET for this purpose. Guhlman et al. studied 51 patients suspected of having chronic osteomyelitis in the peripheral (n=36) or central (n=15) skeleton prospectively with static FDG PET imaging and combined 99mTc-antigranulocyte Ab/99mTc-methylene diphosphonate bone scanning within 5 days.40 Obtained images were evaluated in a blinded and independent manner by visual interpretation, which was graded on a five-point scale of two observers’ confident diagnosis of osteomyelitis. Receiver operating characteristic (ROC) curve analysis was performed for both imaging modalities. The final diagnosis was established by means of bacteriologic culture of surgical specimens and histopathologic analysis (n=31) or by biopsy and clinical follow-up over 2 years (n=20). Of 51 patients, 28 had osteomyelitis and 23 did not. According to the unanimous evaluation of both readers, FDG PET correctly identified 27 of the 28 positives and 22 of the 23 negatives (IS identified 15 of 28 positives and 17 of 23 negatives, respectively). On the basis of ROC analysis, the overall accuracy of FDG PET and immunoscintigraphy in the detection of chronic osteomyelitis were 96%/96% and 82%/88%, respectively.
Kälicke et al. evaluated the clinical usefulness of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) in acute and chronic osteomyelitis and inflammatory spondylitis.41 The study population comprised 21 patients suspected of having acute or chronic osteomyelitis or inflammatory spondylitis. Fifteen of these patients subsequently underwent surgery. FDG PET results were correlated with histopathological findings. The remaining six patients, who underwent conservative therapy, were excluded from any further evaluation due to the lack of histopathological data. The histopathological findings revealed osteomyelitis or inflammatory spondylitis in all 15 patients: seven patients had acute osteomyelitis and eight patients had chronic osteomyelitis or inflammatory spondylitis. FDG PET yielded 15 true-positive results. However, the absence of negative findings in this series may raise questions concerning selection criteria.
De Winter et al. reported on 60 patients suffering from a variety of suspected chronic orthopedic infections.42 In this prospective study, the presence or absence of infection was determined by surgical exploration in 15 patients and long-term clinical follow-up in 28 patients. As opposed to the study by Guhlmann et al., patients with recent surgery were not excluded. Considering only those patients with suspected chronic osteomyelitis, FDG PET was correct in 40 of 43 patients. There were three false-positive findings, 17 true-negative findings, and no false-negative findings. This resulted in a sensitivity of 100%, a specificity of 85%, and an accuracy of 93%. Two of three false-positive findings occurred in patients who had been operated on recently (6 weeks and 4 months, respectively).
Zhuang et al. studied the accuracy of FDG PET for the diagnosis of chronic osteomyelitis.43 Twenty-two patients with possible osteomyelitis (5 in the tibia, 5 in the spine, 4 in the proximal femur, 4 in the pelvis, 2 in the maxilla, and 2 in the feet) that underwent FDG PET imaging and in whom operative or clinical follow-up data were available were included for analysis. The final diagnosis was made by surgical exploration or clinical follow-up during a 1-year period. FDG PET correctly diagnosed the presence or absence of chronic osteomyelitis in 20 of 22 patients but produced two false-positive results, respectively two cases of recent osteotomies, resulting in a sensitivity of 100%, a specificity of 87.5%, and an accuracy of 90.9%. It is, however, unclear from their report in how many patients histopathologic or microbiologic studies were available.
Chako et al. retrospectively analyzed the accuracy of FDG PET for diagnosing infection in a large population of patients and in a variety of clinical circumstances, including suspicion of chronic osteomyelitis in 56 patients.44 Final diagnosis was made on the basis of surgical pathology and clinical follow-up for a minimum of 6 months. Among the patients suspected of having chronic osteomyelitis, the accuracy was 91.2%.
CONCLUSION
Although limited, available data on FDG PET for imaging of the spine are promising, displaying a higher accuracy for diagnosing osteomyelitis when compared to other imaging modalities for this purpose, including conventional nuclear medicine examinations. For instance, in the study by Guhlman et al., comparing the combination of bone scan and leukocyte scan with FDG PET, the latter proved significantly more accurate for the diagnosis of osteomyelitis in the central skeleton. The fact that FDG PET is not disturbed by the presence of metallic implants and is able to differentiate between scar tissue and active inflammation constitutes a major advantage when compared to CT and MRI. As opposed to radiolabeled leukocytes or radiolabeled antibodies, FDG is likely to penetrate easier and faster in lesions than cellular tracers or antibodies.45 Aside from the potential for higher sensitivity, taking into account available data, a negative PET scan virtually rules out osteomyelitis.42,44
Initially, it was thought that the specificity of FDG PET for detection of infection of the spine may be limited by the fact that this tracer also accumulates in benign lesions and tumors. More recent papers, however, focusing on fractures, hemangioma, Paget’s disease, and endplate abnormalities of and in the spine, tend to contradict this hypothesis. Following traumatic fracture or surgical intervention, bone scintigraphy reveals a positive result for an extended period of time, up to 2 years post-fracture, posing a challenge when evaluating patients for superimposed infection or for possible malignancy. Similarly, acute fracture or recent surgical intervention of the bone may cause increased FDG accumulation. However, available results suggest that FDG uptake patterns following fracture differ amongst various bones. In a series of 17 patients by Schmitz et al., MRI demonstrated a vertebral compression fracture generating from osteoporosis in 13 cases.46 In 12 of these 13 cases, PET scans were categorized as true negative. Comparable results were obtained by Zhuang et al. in a retrospective study assessing the pattern and time course of abnormal FDG uptake following traumatic or surgical fracture.47 Out of 10 patients with a documented fracture of the spine (interval between confirmation of the fracture and time of PET scanning, 24 days and 45 months), none displayed increased FDG uptake. Importantly, in other bone structures, if positive, uptake proved normal by a maximum of 3 months after fracture or surgical intervention of the bone. Accordingly, based on currently available data, there should be normal FDG uptake at spine fractures either initially or by a maximum of 3 months post-fracture. Bhargava et al. reported on a case of vertebral Paget’s disease showing normal FDG uptake and intense osteoblastic activity on the bone scan.48 Bybel et al. performed FDG PET to stage a nasopharyngeal carcinoma and found hypometabolic regions in multiple thoracic vertebrae.49 These corresponded to multiple hemangiomas as evidenced by MRI. These findings are in sharp contrast to those reported by Hatayama et al. in 16 patients with histopathologically documented hemangiomas of the extremities.50 In these authors’ experience, all 16 lesions examined by PET displayed FDG accumulation with standardized uptake values ranging from 0.7 to 1.67. Stumpe et al. performed prospectively FDG PET in 30 consecutive patients with substantial endplate abnormalities found during MR imaging of the lumbar spine.51 The sensitivity and specificity for differentiation of degenerative from infectious endplate abnormalities were 50% and 96% for MRI versus 100% and 100% for FDG PET. Finally, in most patients, a thorough medical history makes the presence of tumor unlikely, and sterile inflammations such as chronic polyarthritis, vasculitis, and tumors often appear at sites or show distribution patterns that are suggestive of these diseases.
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