**5.1 Osteomyelitis**

Osteomyelitis is defined by infection localized to bone. It can occur as a result of hematogenous seeding, contiguous spread of infection to bone from adjacent soft tissues and joints, or direct inoculation of infection into the bone as a result of trauma or surgery (Lalani, 2011). Three-phase bone scan with 99mTc-hydroxymethylene diphosphonate or Tc-99m-MDP has long been used as the standard method for the detection of osteomyelitis (Gotthard et al., 2010), and positive focally increased uptake on all three phases (**Fig. 2**) is usually seen (Love et al., 2003).

Fig. 2. Three-phase bone scan: Focally increased uptake on all three phases in a patient with osteomyelitis of the right great toe.

In contrast, in the setting of cellulitis there is increased activity only in the first two phases and normal or mild diffuse increased activity in the third phase (Brown et al., 1993; Horwich, 2011). Radiographic studies do not show any change for at least 1- 2 weeks after initial infection, contrary to the three-phase bone scan where imaging of the infection can be seen in the first 24 - 48 hours of the infection (Díaz & De haro, 2005). Bone scintigraphy has a high sensitivity exceeding 80% and a limited specificity reaching up to 50% (Gotthard et al., 2010, as cited in Hakim et al., 2006; Palestro et al., 2002). The limited specificity can be explained by uptake of the radiopharmaceutical at all sites of increased bone metabolism irrespective of the underlying cause. Other conditions such as tumors, fractures, joint neuropathy may mimic osteomyelitis at three-phase bone scintigraphy. To improve specificity, complementary imaging with gallium-67 (67Ga) citrate (for spinal infection) or indium-111-labelled autologous leukocytes (for the appendicular skeleton) is often performed (Love et al., 2003).

Gallium scans utilize the affinity of gallium-67 to acute phase reactants (lactoferrin, transferrin, and others) to demonstrate areas of inflammation that may be related to infection (Horwich, 2011). Intense uptake on 67Ga bone scintigraphy in two adjacent vertebrae with loss of the disc space is highly suggestive of spinal osteomyelitis (Palestro & Torres, 1997). This method is quite sensitive and more specific than three-phase bone scan (Horwich, 2011; as cited in Palestro, 1991; Tumeh, 1986). It is typically performed 24 hours following inyection and therefore should be reserved for patients who are clinically stable and do not require prompt

Nuclear Medicine in Musculoskeletal Disorders: Clinical Approach 105

and nuclear medicine methods are used for the diagnosis or a preliminary investigation of infectious arthritis, the definitive diagnostic test is the identification of bacteria in the synovial fluid aspiration (Díaz & De haro 2005). Though, some joints are difficult to examine. As in the osteomyelitis, there is an increased uptake on all three phases of threephase bone scan (El-Maghraby et al., 2006). The hallmark of septic arthritis is symmetrical uptake in both sides of the joint (Díaz & De haro, 2005). However, a positive scintigraphy has a low specificity. The differential diagnosis is made more accurate when the osteoarticular scintigraphy is combined with gallium citrate or more commonly radiolabelled leukocyte or immunoglobulins. In the presence of septic arthritis, these agents demonstrate activity patterns of diffuse nature in the soft tissue in and around the joint with no focal abnormality in bone. However, this can be difficult to ascertain without demonstration of exactly where bone lies in relation to the soft tissue infection and may need combined imaging. Rosenthall et al have shown that a combined study does raise the sensitivity for the detection of septic arthritis from 54% with TC-99m-MDP alone to 84% for combined 67Ga/Tc-99m-MDP scanning (El-Maghraby et al., 2006; as cited in Rosenthall et al., 1982). Another combination is the labelled leukocytes/Tc-99m-MDP combined study, which is reported to be more specific than a 67Ga/Tc-99m-MDP study and produces fewer equivocal results (El-Maghraby et al., 2006; as cited in Tehranzadeh et al., 2001; Chengazi & O'Mara, 2003). For disc space infections, although the bone scan is often positive, gallium scintigraphy is the preferred method. Indium-111(111In)-leukocytes have been shown to be of limited value in the diagnosis of disc space infection; although some authors feel that the labelled white cell scan can be of benefit especially if the cold (photon deficient) lesions are

Cellulitis is a soft tissue infection. The scan shows intense uptake in the first two phases of the study with diffuse extra-osseous activity, while the final image is normal after 2-4 hours. The presence of other processes that stimulate osteoblastic reaction, as in cases of suspected osteomyelitis in areas with trauma, surgery or arthritis, complicates the interpretation of the scintigraphic image which is completely non specific. Combined studies with different radiotracers such as 67Ga, 111In-leukocytes or 99mTc-HM-PAO improve the sensitivity and specificity, although MRI remains as gold standard technique (Díaz & De Haro, 2005).

Prosthetic joint replacement is a common procedure and most patients have excellent results, but 20% of them develop pain during the follow-up. It may be secondary to infection, aseptic loosening or heterotopic bone formation (El-Maghraby et al., 2006). Differentiate betweeen loosening and infection is often a difficult problem, especially because clinical signs and symptoms, laboratory tests and radiographies are insensitive, nonspecific, or both. Crosssectional imaging modalities are hampered by artifacts produced by the prosthetic devices. Radionuclide imaging is not affected by the presence of metallic hardware and is therefore useful for evaluating the painful prosthesis (Love et al., 2001). Negative scintigraphic study rules out septic or aseptic loosening. Both conditions, however, may show increased tracer uptake in bone scans, but the pattern and site of uptake may help to differentiate each other. In aseptic loosening, focal localized uptake at the tips is seen, whereas in the infection diffuse intense uptake will be seen in the three phases of bone scan. The sensitivity for bone scan in infection is relatively high, ranging from 70% to 100% but the specificity is variable ranging

considered diagnostic of disc space infection (Brown et al., 1993).

**5.3 Cellulitis** 

**5.4 Painful joint replacement** 

imaging results for urgent management decisions. Gallium not only enhances the specificity of the diagnosis but provides information about surrounding soft tissue infection (Palestro & Torres, 1997). If gallium scan is negative, it effectively excludes the diagnosis of osteomyelitis (Horwich, 2011; as cited in Pineda, 2006). A gallium scan can be performed concurrently with a technetium labelled three-phase bone scan, and the information gathered may be more useful than that of either examination alone (Horwich, 2011; as cited in Tumed, 1986). Both radionuclides can be injected at the same time and the scintigraphic images can be obtained three to four hours after injection, while gallium images will be obtained up to 24 hours later (Horwich, 2011). This combination is probably the best nuclear medicine tool for the evaluation of vertebral osteomyelitis (Palestro & Torres, 1997).

Labelled leukocyte imaging is a good alternative in the evaluation of osteomyleitis, but is of little value in vertebral osteomyelitis because this entity often presents as a non specific photopenic defect (Gotthard et al., 2010; as cited in Van Der Bruggen et al., 2010). But, in the diabetic foot diagnosis, labelled leukocyte imaging alone is sufficient to determine the presence of osteomyelitis in the forefoot. In the midfoot and hindfoot it may be necessary to combine leukocyte scintigraphy with others radiotracers to precisely localize the infection (Palestro & Torres, 1997). The combined imaging approach of 99mTc-colloid bone marrow/labelled-leukocyte scanning enhances the sensitivity and specificity above 90%, avoiding the problem of physiologic uptake into bone marrow. Because in osteomyelitis bone marrow is replaced by the infectious process, bone marrow imaging will be negative whereas leukocyte scanning in the same location will be positive (Gotthardt et al., 2010, as cited in Palestro et al., 2006).

In chronic osteomyelitis the specificity of Tc-99m-MDP bone scans is very low even with active exacerbation because positive uptake also occurs with the healing process (El-Maghraby et al., 2006). Other false negative results are possible in areas of relative ischemia, since radiotracer may not be adequately delivered to the target site (Horwich, 2011). 67Ga combined with Tc-99m-MDP allows identification of active chronic osteomyelitis. Discordance between 67Ga and Tc-99m-MDP with more intense 67Ga or different distribution is highly specific at 80-100% (El-Maghraby et al., 2006). 18F-FDG-PET is a promising modality for imaging musculoskeletal infection and might play an important role in the evaluation of chronic osteomyelitis and spinal infection (Strobel & Stumpe, 2007). The specificity for spinal infection drops only if patients underwent surgery less than 6 months before PET and if osteosynthetic material is present (Gotthardt et al., 2010; as cited in De Winter et al., 2003). However, because MRI may not be an option in patients with metallic implants in situ, PET currently is the most sensitive imaging modality in the evaluation of such patients (Gotthardt et al., 2010; as cited in De Winter et al., 2003). Furthermore, in cases of severe defenerative disk disease with oedema-like changes in the endplates and the adjacent discs, MRI can give false-positive results (Gotthardt et al., 2010; as cited in Palestro et al., 2006). Other tracers for diagnosing spinal osteomyelitis are also under investigation, including radiolabelled antibiotics and antifungical tracers (Gemmel et al., 2006).

#### **5.2 Septic arthritis**

Septic arthritis is the infection of the synovial tissues. It often occurs as a result of hematogenous seeding and less often by direct inoculation as a result of trauma or surgery (Díaz & De haro, 2005). Although it may occur at any age, it is most common in children under 3 years. Over 90% of cases are mono-articular (El-Maghraby et al., 2006). The most commonly involved joints are the hips and the knees (Díaz & De haro, 2005). Despite MRI and nuclear medicine methods are used for the diagnosis or a preliminary investigation of infectious arthritis, the definitive diagnostic test is the identification of bacteria in the synovial fluid aspiration (Díaz & De haro 2005). Though, some joints are difficult to examine. As in the osteomyelitis, there is an increased uptake on all three phases of threephase bone scan (El-Maghraby et al., 2006). The hallmark of septic arthritis is symmetrical uptake in both sides of the joint (Díaz & De haro, 2005). However, a positive scintigraphy has a low specificity. The differential diagnosis is made more accurate when the osteoarticular scintigraphy is combined with gallium citrate or more commonly radiolabelled leukocyte or immunoglobulins. In the presence of septic arthritis, these agents demonstrate activity patterns of diffuse nature in the soft tissue in and around the joint with no focal abnormality in bone. However, this can be difficult to ascertain without demonstration of exactly where bone lies in relation to the soft tissue infection and may need combined imaging. Rosenthall et al have shown that a combined study does raise the sensitivity for the detection of septic arthritis from 54% with TC-99m-MDP alone to 84% for combined 67Ga/Tc-99m-MDP scanning (El-Maghraby et al., 2006; as cited in Rosenthall et al., 1982). Another combination is the labelled leukocytes/Tc-99m-MDP combined study, which is reported to be more specific than a 67Ga/Tc-99m-MDP study and produces fewer equivocal results (El-Maghraby et al., 2006; as cited in Tehranzadeh et al., 2001; Chengazi & O'Mara, 2003). For disc space infections, although the bone scan is often positive, gallium scintigraphy is the preferred method. Indium-111(111In)-leukocytes have been shown to be of limited value in the diagnosis of disc space infection; although some authors feel that the labelled white cell scan can be of benefit especially if the cold (photon deficient) lesions are considered diagnostic of disc space infection (Brown et al., 1993).
