Radionuclide imaging of musculoskeletal infection

NUCLEAR MEDICINE: INFECTION AND INFLAMMATION

Radionuclide imaging of musculoskeletal infection

Christopher J. Palestro^I,II,*; Charito Love^III

^IProfessor of Nuclear Medicine and Radiology, Albert Einstein College of Medicine, Bronx, New York

^IIChief Division of Nuclear Medicine and Molecular Imaging, North Shore Long Island Jewish Health System, Manhasset and New Hyde Park, New York, [e-mail]

^IIIResearch Scientist, Division of Nuclear Medicine and Molecular Imaging, North Shore Long Island Jewish Health System, Manhasset and New Hyde Park, New York

ABSTRACT

Radionuclide imaging studies are routinely used to evaluate patients suspected of having musculoskeletal infection. Three-phase bone imaging is readily available, relatively inexpensive, and very accurate in the setting of otherwise normal bone. Labeled leukocyte imaging should be used in cases of "complicating osteomyelitis" such as prosthetic joint infection. This test also is useful in clinically unsuspected diabetic pedal osteomyelitis as well as in the neuropathic joint. It is often necessary, however, to perform complementary bone marrow imaging, to maximize the accuracy of labeled leukocyte imaging. In contrast to other regions in the skeleton, labeled leukocyte imaging is not useful for diagnosing spinal osteomyelitis. At the moment, gallium is the preferred radionuclide procedure for this condition and is a useful adjunct to magnetic resonance imaging. FDG-PET likely will play an important role in the evaluation of musculoskeletal infection, especially spinal osteomyelitis, and may replace gallium imaging for this purpose.

Key words: Musculoskeletal infection, osteomyelitis, bone scintigraphy, labeled leukocytes, gallium, FDG-PET

RESUMO

Estudos através de imagens com o uso de radionuclídeos são rotineiramente usadas para avaliar pacientes suspeitos de terem infecção músculo-esquelética. A imagem óssea em tridimensional é facilmente avaliável, relativamente de baixo custo, e muito precisa na localização de alterações ósseas. Imagem com leucócito marcado poderia ser usada nos casos de "osteomielite com complicações" tais como infecção prostética articular. Esse teste também é útil na não suspeita clinica de osteomielite associada ao pé diabético tanto quanto nas junções neuropáticas. É sempre necessário, por outro lado, realizar imagem complementar da medula óssea para aumentar a precisão da imagem com leucócito marcado. Em contraste com outras regiões no esqueleto, imagem com leucócito marcado não é útil para diagnosticar osteomielite da coluna vertebral. Até agora, o gálio é o radionuclídeo preferido para essa condição e é um adicional utilizável para imagem por ressonância magnética. FDG-PET igualmente será importante na avaliação de infecção músculo-esquelética, especialmente osteomielite espinhal, e pode substituir o gálio para esse propósito.

INTRODUCTION

The diagnosis of musculoskeletal infection can be clinically challenging and imaging procedures are routinely performed as part of the diagnostic workup. Although there are several radionuclide tests from which to choose, it is important to realize that no one test is optimal for every situation. This article reviews the principles, indications, and limitations of radionuclide imaging studies available for diagnosing musculoskeletal infection.

Radionuclide Imaging Procedures

Three-Phase Bone Scintigraphy

Bone scintigraphy is performed with technetium-99m labeled diphosphonates, usually methylene diphosphonate (MDP), the uptake of which depends on blood flow and the rate of new bone formation. The three-phase bone scan consists of the flow or perfusion phase, acquired immediately after tracer injection, followed immediately by an image of the region of interest, the blood pool or soft-tissue phase. The third, or bone, phase consists of images performed two to four hours later. The classic appearance of osteomyelitis is focal hyperperfusion, focal hyperemia, and focal bone uptake (Fig. 1). Bone scintigraphy is widely available, relatively inexpensive, easily performed and rapidly completed, and extremely sensitive. With an accuracy of more than 90%, 3-phase bone scintigraphy is the nuclear medicine test of choice for diagnosing osteomyelitis in bones not affected by underlying conditions (Maurer et al., 1981; Schauwecker, 1992; Palestro and Torres, 1997). Abnormalities on bone scans, however, reflect the rate of new bone formation in general and not infection specifically. Consequently tumors, 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 (Schauwecker, 1992; Palestro and Torres, 1997).

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 of gallium by certain bacteria has been observed in-vitro. Siderophores, small molecular weight chelates produced by bacteria, have a high affinity for gallium. The siderophore-gallium complex is presumably transported into the bacterium, where it remains until phagocytosed by macrophages. Although some gallium is transported bound to leukocytes, it is important to note that even in patients with few or no circulating leukocytes, this agent can detect infection with good sensitivity. Imaging is usually performed 18-72 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% (Fig. 2). The less than ideal imaging characteristics of gallium and the need for two isotopes with multiple imaging sessions over several days are additional disadvantages to the procedure (Hoffer, 1980; Palestro, 1994).

In-Vitro Labeled Leukocytes

A variety of in-vitro leukocyte labeling techniques have been used; the most commonly employed procedures make use of indium-111 oxyquinolone (oxine) or technetium-99m-HMPAO (exametazime). A total circulating white count of at least 2000/uL is needed to obtain satisfactory images. The majority of white cells labeled usually are 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 (Fineman et al., 1989; Palestro et al., 1991; Palestro et al., 1992; Love and Palestro, 2004; Vicente et al., 2005).

Labeled leukocyte imaging is the radionuclide procedure of choice for diagnosing so-called complicating osteomyelitis (Palestro and Torres, 1997). Although they do not usually accumulate at 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, generally assumed to be confined to the axial and proximal appendicular skeletons, actually is quite 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. Thus it is not always possible to determine if an area of activity on a labeled leukocyte image represents infection or atypically located, but otherwise normal, marrow and it is often necessary to perform technetium-99m sulfur colloid bone marrow imaging (Fig. 3) (Palestro et al., 2006). Both leukocytes and sulfur colloid accumulate in the bone marrow; leukocytes also accumulate in infection, sulfur colloid, however, does not (Feigin et al., 1976). 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 (Fig. 4) (Palestro et al., 2006). The overall accuracy of combined leukocyte/marrow imaging is approximately 90% (Mulamba et al., 1983; King et al., 1990; Palestro et al., 1990; Palestro et al., 1991; Seabold et al., 1991; Palestro et al., 1992; Achong et al., 1994; Palestro et al., 1998; Joseph et al., 2004; Love et al., 2004).

In-Vivo Labeled Leukocyte Imaging

There are significant limitations to the in-vitro leukocyte labeling procedure. It is labor intensive, not always available, and involves direct handling of blood products. Considerable effort, therefore, has been devoted to the search for in-vivo methods of labeling leukocytes, including peptides and antigranulocyte antibodies (Love and Palestro, 2003). None of these in-vivo methods, which have met with mixed results, are approved for use in the United States.

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 uptake of FDG is related to the cellular metabolic rate as well as to the number of glucose transporters available (Bell et al., 1993; Pauwels et al., 1998; Zhuang and Alavi, 2002). Activated inflammatory cells, such as neutrophils, lymphocytes, monocytes, and macrophages, demonstrate increased expression of glucose transporters and in inflammatory conditions, the affinity of these glucose transporters for deoxyglucose may be increased by cytokines and growth factors (Kubota et al., 1992; Pauwels et al., 1998; Mochizuki et al., 2001; Paik et al., 2004).

FDG-PET has several potential advantages over conventional nuclear medicine tests. Results are available within 30-60 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 hematopoietically active marrow. Degenerative bone changes usually show only faintly increased FDG uptake compared to osteomyelitis. FDG-PET images are not affected by metallic implant artefacts and have a distinctly higher spatial resolution than images obtained with single photon emitting tracers. Finally FDG is less expensive then the combinations of radiolabeled leukocyte/bone marrow/bone scan multimodality imaging techniques (Gemmel et al., 2006).

Several studies support the value of FDG for diagnosing musculoskeletal infection but prospective investigations focused on particular indications are necessary to accurately define its role in musculoskeletal infection (Guhlmann et al., 1998; Sugawara et al., 1998, Kalicke et al., 2000; De Winter et al., 2001; Schiesser et al., 2003).

Radiolabeled Antibiotics

An interesting approach to diagnosing musculoskeletal infection makes use of radiolabeled antibiotics Presumably the radiolabeled antibiotic is 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 (Sonmezoglu et al., 2001; Sarda et al., 2002; De Winter et al., 2004; Gemmel et al., 2004). At the present time, this agent is available only on an investigational basis.

Indications

Spinal osteomyelitis

Spinal osteomyelitis, which has a predilection for the elderly, may result from bacteremia or direct inoculation of bacteria into the spine. Usually confined to the vertebral body and intervertebral disc, the posterior elements are involved in up to twenty percent of cases (Love et al., 2000). Magnetic resonance imaging (MRI) with an accuracy of about 90% is the imaging procedure of choice for diagnosing spinal osteomyelitis (Modic et al., 1985). It permits early diagnosis of infection, and provides direct visualization of the spinal cord, subarachnoid space, extradural soft tissues, and spinal column, without intrathecal contrast. There are limitations to this test, however. 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 on MRI. The test is sensitive to motion and patients who cannot remain still may not be suitable candidates for imaging. In patients with certain implants, such as pacemakers and cardiac valves, the test is contraindicated. In these situations, as well as when MRI is nondiagnostic, or at odds with the clinical impression, 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 imaging is useful for detecting the abscesses that often accompany this entity (Lisbona et al., 1993; Palestro and Torres, 1997; Hadjipavlou et al., 1998; Love et al., 2000). There are data that suggest that if gallium tomography, or SPECT, is performed, the bone scan is not needed (Fig. 5) (Love et al., 2000).

FDG-PET is a promising alternative to bone and gallium imaging for diagnosing spinal osteomyelitis (Fig. 6). 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 (Stumpe et al., 2002). One group of investigators reported that FDG-PET was superior to MRI in 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 (Gratz et al., 2002).

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. Among 30 patients without implants, there were 2 false positive results: both in patients who had undergone surgery less than six months prior to imaging. Among 27 patients with spinal implants, there were six false positive results. Sensitivity, specificity and accuracy were not significantly different between the group of patients that had surgery within 6 months before the FDG-PET and the group who had surgery more than 6 months before FDG-PET imaging. 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; the negative predictive value, 100%, was excellent (De Winter et al., 2003).

In contrast to other sites in the skeleton, labeled leukocyte imaging is not useful for diagnosing spinal osteomyelitis as 50% or more of all cases appear as areas of nonspecific decreased or absent activity (photopenia) on white cell images. This photopenia is associated with numerous conditions, besides infection, including tumor, infarction and Paget's disease (Palestro et al., 1991).

Diabetic Foot Infections

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 (Palestro and Tomas, 2000).

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. In many cases however, more advanced imaging is needed and either labeled leukocyte imaging or MRI can be performed (Fig. 7). A meta-analysis of the literature with determination of weighted averages for each modality showed that radiographs had a weighted average sensitivity of 54% and 80% specificity, three-phase bone scan had an average of 91% sensitivity and 46% specificity, labeled white cell studies had 88% sensitivity and 82% specificity, and MR imaging had 92% sensitivity and 84% specificity (Wrobel and Connolly, 1998).

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 (Palestro and Tomas, 2000).

The dramatic bony changes of the Charcot joint invariably result in a positive three-phase bone scan even in the absence of infection (Palestro and Tomas, 2000). Labeled leukocyte accumulation in the uninfected neuropathic joint also occurs, but this problem can be overcome by performing complementary bone marrow imaging (Fig. 8) (Palestro et al., 1998).

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. 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 (Newman et al., 1991; Newman et al., 1992; Palestro et al., 1998; Palestro and Tomas, 2000).

There are too few data available at the present time to assess the role of FDG-PET in diabetic foot infections (Keidar et al., 2005).

Prosthetic Joint Infection

Some complications of joint replacement surgery, such as dislocation and fracture, are readily diagnosed and treated. Differentiating infection from aseptic loosening is more difficult, however, because the clinical presentation of, and the histopathologic changes in, both entities are remarkably similar (Love et al., 2001).

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, unsuccessful, attempts at phagocytosis, which in turn stimulate proinflammatory cytokine and proteolytic enzyme secretion 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 (Love et al., 2001).

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 three months, another third within one year, and the remainder more than one year after surgery. Histopathologically, the inflammatory reaction accompanying the infected prosthesis is similar to that present in aseptic loosening, with one important difference: neutrophils, which are usually absent in aseptic loosening, are invariably present in infection (Love et al., 2001).

Differentiating aseptic loosening from infection is extremely important because the treatment of these two entities is very 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 (Love et al., 2001).

Nonspecific markers of inflammation such as the erythrocyte sedimentation rate and C-reactive protein level may be elevated in both loosening and infection. Plain radiographs are neither sensitive nor specific and cross-sectional imaging modalities, such as CT and MRI, can be limited by hardware induced artifacts (Love et al., 2001). 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% (Fehring and Cohen, 1996; Lachiewicz et al., 1996; Cheung et al., 1997).

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. The current imaging procedure of choice for evaluating suspected joint replacement infection is combined leukocyte/marrow imaging with an overall accuracy ranging from 88%-98% (Mulamba et al., 1983; Palestro et al., 1990; Palestro et al., 1991; Joseph et al., 2001; Love et al., 2004). 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. Because the success of labeled leukocyte imaging is directly dependent on the presence of a neutrophil response, 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 (Fig. 9) (Love et al., 2004).

The role of FDG-PET in the evaluation of painful lower extremity joint prostheses has been extensively investigated (Van Acker et al., 2001; Zhuang et al., 2001; Chacko et al., 2002; Manthey et al., 2002; Vanquickenborne et al., 2003; Love et al., 2004; Stumpe et al., 2004).

Although initial reports suggested that FDG-PET 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 (Love et al., 2004; Stumpe et al., 2004). This is not surprising when one considers that inflammation, often intense, 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. Thus, both aseptic loosening and infection are characterized by increased periprosthetic activity on FDG-PET 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. The synovial lining of joints is highly vascular and lacks protective basement membrane. Entry of bacteria causes an influx of inflammatory cells and secretion of cytokines and proteolytic enzymes all geared towards elimination of organisms as well as neutralization of bacterial endotoxins. Unfortunately, these very same inflammatory responses also destroy synovium and cartilage. Thus, early diagnosis is of utmost importance.

Radionuclide studies are of limited value in the evaluation of septic arthritis. The classic presentation of acute arthritis on 3-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, moreover, are not mutually exclusive, and bone scan findings consistent with septic arthritis do not exclude and can potentially mask an underlying osteomyelitis (Palestro, 1994). Neither gallium nor labeled leukocyte imaging reliably separate infectious from noninfectious arthritis. Labeled leukocyte imaging can be positive in rheumatoid arthritis, acute gouty arthritis, and pseudogout (Coleman et al., 1982; Uno et al., 1986; Palestro et al., 1990; Palestro et al., 1992).

CONCLUSIONS

A wide range of radionuclide imaging modalities is available for the evaluation of clinically suspected musculoskeletal infection. 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. Labeled leukocyte imaging also is 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. FDG-PET likely will play an important role in spinal infections.

Received: July 21, 2007;

Revised: August 01, 2007;

Accepted: August 5, 2007.

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*

Author for correspondence

Publication Dates

• Publication in this collection
  12 Mar 2008
• Date of issue
  Sept 2007

History

• Accepted
  05 Aug 2007
• Reviewed
  01 Aug 2007
• Received
  21 July 2007