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
