When a patient with Charcot neuroarthropathy presents with an acutely symptomatic limb, joint or a non-healing wound, the differential diagnosis always includes infection. Bone and joint infections are naturally associated with a high degree of potential morbidity. This potential morbidity is significantly increased when there is a delay in diagnosis or when the diagnosis is missed altogether. Therefore, validating a definitive diagnosis of infection and clarifying when it involves bone is essential to providing appropriate and timely treatment. Nuclear medicine leukocyte imaging (NMLI) allows prompt confirmation of the presence of infection and identifies the location of a focus of infection when it exists.1 In addition, these studies have a predictable appearance in the face of an active Charcot arthropathy without infection. Given the limb threatening consequences of an infected Charcot joint, using NMLI allows one to differentiate between Charcot and osteomyelitis.2 Clinicians can repeat NMLI after the completion of antibiotic therapy in order to rule out the complication of indolent infection. In the absence of infection, these imaging studies provide supplemental data to support the pursuit of an alternative diagnosis in the differential list. A Brief Overview Of The History Of Nuclear Imaging Nuclear medicine imaging techniques for identifying and isolating infection have been used since the 1950s. Gallium was one of the first isotopes used to localize infections and other pathologic processes. This agent binds with transferrin, an iron bound protein found within the cytoplasm of white blood cells (WBCs). An intravenous injection of gallium citrate provides an in vivo labeling of leukocytes and bacterial organisms, which allows one to identify inflammatory processes.1 Since the introduction of gallium imaging for infection, research has brought about the development of alternate, radiolabeled WBC studies to enhance the specificity and imaging quality of these exams. In 1976, indium-oxine leukocyte Imaging (111In-Oxine-WBC imaging) came to the forefront and has since enjoyed a large degree of clinical usage.3-18 Indium will delineate leukocyte accumulation, providing a “faithful mirror” of WBC activity within 24 hours. Over time, the 111In-Oxine-WBC imaging has earned its place in the study of both acute and chronic infectious processes. Indium imaging, like gallium, suffers from inherently poor imaging characteristics as it emits dual high-energy alpha rays to produce its images. This results in poor spatial resolution and a low target to background ratio. This technique often requires a minimum of 24 hours to localize within an area of WBC accumulation. Depending on the differential diagnosis, one may obtain serial imaging at four to six hours, 24 hours, 48 hours and 72 hours. In cases of positive uptake, the region of isotope localization will become more discrete as time progresses due to the combined effect of the physical and biologic half-life of the compound. Improved localization occurs over time as a result of lowered background radiation and an improvement in target to background ratio. At the time, this was the best imaging agent available for the noninvasive investigation of infection. However, indium leukocyte imaging has remained a primary imaging agent for localization of infectious processes despite the agent’s poor imaging characteristics and low spatial resolution. Interest in nuclear medicine imaging rejuvenated in the late 1980s as a new and improved radiolabeled white cell technique came to the forefront. In 1986, technetium-99m hexamethyl propylene amine oxime (Tc-HMPAO), under the trade name Ceretec, was developed for cerebral perfusion imaging using the isotope technetium. The excellent imaging characteristics of the isotope 99mTc significantly enhanced nuclear medicine tomography in cerebral imaging. It was later discovered that the agent, HMPAO, has a high affinity and avidity in labeling to white blood cells. Technetium is a very “photogenic” isotope due to its low energy of emission and short half-life. In other words, technetium has favorable imaging characteristics, providing improved spatial resolution in imaging that is not achievable using either indium or gallium. Combining technetium with HMPAO creates a chemical compound that has both high affinity and avidity to leukocytes, and produces images with improved spatial resolution. One can best appreciate this improvement in resolution when comparing Tc-HMPAO directly to other infection imaging agents such as gallium citrate and indium-oxine-leukocyte compounds. By using technetium, there is an increased specificity of radiolabeled WBC imaging and an overall improvement in technique. Tc-HMPAO imaging has proven to have great utility in some of the most complicated and challenging of infectious conditions.19-47 This includes both the evaluation and management of postoperative infection, and differentiating osteomyelitis from adjacent soft tissue infection.48 What You Should Know About Magnetic Resonance Imaging All imaging techniques used to identify infection are judged based upon their respective sensitivity and specificity. The data on NMLI varies dramatically in the current literature.49 Many would argue that magnetic resonance imaging (MRI) is the best modality for the diagnostic challenge of identifying osteomyelitis as it will predictably show a decreased signal in T-1 images and increased signal on T-2 images in the face of a degenerative inflammatory process in bone.50-58 The sensitivity of MRI for infection is reportedly between 94 to 100 percent while the specificity for infection is commonly reported between 69 to 96 percent. Unfortunately, other conditions that distort normal anatomy (such as the case of coincident Charcot neuroarthropathy and infection) will confound the reading of MRI. It is extremely important to note that Charcot neuroarthropathy, in an active state, will show a very similar MRI pattern to osteomyelitis. The mixed lytic and resorptive destruction that occurs in bone due to infection is indistinguishable from the destruction that one would see in actively progressive neuropathic disease on a MRI.2,11,50,51 Can Combining Imaging Techniques Enhance Diagnostic Capabilities? Differentiating between a Charcot foot and infection is among the most important diagnostic challenges in lower extremity pathology. It is important to understand that one cannot make a definitive diagnosis of osteomyelitis from a routine bone scan or by using any NMLI agent. The definitive diagnosis of osteomyelitis still requires the gold standard of bone biopsy. However, one should consider using combination imaging with NMLI as it is a valuable noninvasive adjunct in differentiating between a Charcot foot and infection. When an 111Indium-Oxine-WBC study identifies a focus of infection, there is no structural detail to the images. While this imaging modality allows one to easily appreciate an accumulation of WBCs, the study by itself cannot pinpoint the specific location of the accumulation. The combination of an indium-white blood cell image and a routine bone scan (99mTc-MDP) provides more specific identification of leukocyte accumulation. The combination imaging technique uses the structural information provided by 99mTc-MDP for plotting out regions of leukocyte accumulation as identified by the 111In-Oxine-WBC scan.11-15,48-49,59,61-62 A side by side comparison of these studies optimizes interpretation of the data set. In general, one can use the 99mTc MDP bone scan, specifically the third phase bone image, to seek structural information that allows mapping of the precise location of WBC accumulation when compared to an 111In-Oxine-WBC scan. Researchers have demonstrated that correlation in two or more orthogonal planes is important when attempting to differentiate infectious processes that occur in or adjacent to areas of sterile inflammation, as one may see in active arthropathy or acute neuropathic disease states.10 Combination imaging to differentiate soft tissue infection from osteomyelitis has been repeatedly suggested in the literature to enhance the specificity and sensitivity of nuclear medicine leukocyte studies. The overall sensitivity of NMLI has been reported to range between 75 percent and 100 percent while the specificity ranges from 70 percent to 100 percent.11,49 Pertinent Pointers On Interpreting NMLI Specific recommendations regarding how to interpret the combination of 99mTc-MDP and 111In-oxine or 99mTc leukocyte images include grading the intensity of uptake, congruence of intensity and congruence of the size of the region of leukocyte uptake in comparison to that of the unaffected contralateral limb. Combination imaging allows for cross comparison that further delineates the specific location of pathology and provides skeletal mapping of white cell accumulation that is helpful in preparing for bone biopsy procurement.8,11,15,62 To interpret radiolabeled leukocyte studies appropriately, it is important to understand disease states other than infection that prompt leukocyte accumulation in order to predict when a false positive image may result. Alternately, understanding those conditions that do not prompt leukocyte accumulation will help to narrow the differential diagnosis further in the face of a negative leukocyte scan. The radionuclide leukocyte study will remain negative in the presence of severe degenerative arthritis, migratory polyarthritis, metastatic bone disease and aseptic necrosis. A mild increased uptake has been reported in the presence of closed fracture, delayed union or non-union of bone and total joint implant arthroplasty.9,10 Clinical conditions ranging from heterotopic bone formation and myositis ossificans to fulminant rheumatoid arthritis and active neuropathic disease can prompt sterile inflammatory reactions that may result in false positive studies. In the face of active Charcot neuroarthropathy, an increased area of uptake in the four-hour 111Indium-Oxine-WBC image will correlate with plain radiographic changes that are consistent with the acute Charcot flare.11 One may see a subsequent “washout” phenomenon in these patients, occurring between the four-hour and 24-hour images that Schauwecker has described previously in the literature.2 In the absence of infection, this abnormal uptake and subsequent washout phenomenon in active neuroarthropathy is presumably due to the development of hematopoietically active bone marrow that accompanies active Charcot arthropathy.15,49 This active marrow is believed to be the result of the fracture repair process that accompanies the destructive changes and remodeling typified in the Charcot joint. The conversion of fatty marrow to hematopoietically active marrow may be due to increased cytokine activity. When there is a concomitant area of infection, clinicians will not see the washout phenomenon but will see an area of persistent increased intensity that delineates the focus of white cell activity and infection in delayed imaging. This is a scintigraphic finding that helps differentiate active Charcot neuroarthropathy from osteomyelitis.2 The washout phenomenon can be subtle and is important to discern when planning for a bone biopsy procedure. Understanding this phenomenon is integral to an accurate interpretation of leukocyte imaging in clinical conditions that involve Charcot neuroarthropathy and the risk of coincident infection. In the face of a “burned out” Charcot arthropathy, affected joints will have an increased area of intensity on 99mTc-MDP bone scan but will not prompt leukocyte accumulation on the NMLI. In the case of active Charcot neuroarthropathy and existing coincident infection, the infection will be clearly delineated by a positive leukocyte scan that will persist in serial imaging beyond 24 hours. When Combination Imaging Can Be Helpful For Chronic Diabetic Ulcers And Septic Joints When a chronic, non-healing diabetic ulceration exists, combination imaging is vital to determine if an underlying infection is present as a wound will not heal over infected soft tissue or bone. In these cases, it is most important to discriminate between an infected ulceration and an underlying osteomyelitis.14,49,63,64 When performing a radionuclide leukocyte scan in the face of ulceration, keep in mind that drainage due to wound exudates into dressing materials will contain isotope-labeled leukocytes.64 This will distort the area of interest as the radioactivity present in wound drainage can amplify the degree of uptake one sees in the region of interest. Clinicians can avoid this technical error by having the patient perform a dressing change immediately prior to imaging. This will minimize the accumulation of radionuclide within dressing materials and prevent misinterpretation of the image data. The negative impact that a draining ulcer has on such imaging has been documented and previously reported in the literature.64 In the case of a septic joint, one should obtain serial NMLI approximately two weeks after the completion of antibiotic therapy. Doing so helps confirm the absence of residual infectious activity. Keep in mind that a bone scan performed after treatment of a septic joint will be negative as there is no residual bone remodeling or hyperemia as opposed to what you would see in a bone scan after treatment for bone infection. After treating osteomyelitis, one can see bone remodeling and hyperemia on a bone scan for greater than one year’s time in many cases. Therefore, a negative 99mTc-MDP scan after treatment of a septic joint will rule out the presence of an indolent inflammatory process. Key Steps For Preventing Imaging Errors Technical errors in performing radionuclide leukocyte labeling procedures may occur at every step of the process so it is important to understand the methods and statistical strategies involved in such work. In general, a radiolabeled leukocyte compound is viable for use when a 90 percent tag or greater is confirmed by the nuclear medicine pharmacy. This is then logged on the patients’ prescription for the isotope. An insufficient label is apt to provide a poor quality exam as the target to background ratio is severely hindered by an increased background radiation or low percentage label. This increase in background radiation is due to the large amount of unbound isotope circulating free within the vascular compartment. When one encounters a negative study, it is prudent to check the prescription log to ensure the test was performed properly (i.e. >90 percent labeling efficiency of isotopes and leukocytes for imaging). Another source of error in imaging is infiltration of the isotope at the sight of injection. Since extremely small concentrations of isotope are used, even a partial infiltration of an injected dose will compromise the data set. Performing imaging of the injection site routinely can help rule out false negative studies. In Conclusion The differential diagnosis of infection in association with Charcot neuroarthropathy is an important clinical challenge commonly encountered by physicians and surgeons specializing in the lower extremity. Infection often recurs even after amputation or successful treatment of infected ulcerations. Commonly, leukocyte counts, erythrocyte sedimentation rate and blood cultures are of nominal value in these cases. Plain radiography often shows soft tissue edema without signs of bone demineralization until 40 to 50 percent of the bone matrix is lost. As such, very early Charcot neuroarthropathy, stage “0” Charcot, presents with little change on plain radiographs. Clinical practice has determined NMLI is helpful in differentiating conditions that mimic bone infection such as septic arthritis and acute exacerbation of Charcot neuroarthropathy. While the interpretation of NMLI studies is chiefly the responsibility of the radiologist, the ordering physician should have a good working knowledge of the goals of the studies and how these images are to be interpreted and clinically correlated. This should include a thorough understanding of conditions that are associated with an increased leukocyte accumulation and those that are not. With this understanding, the clinician can better predict when a false positive or false negative result is possible. This allows better prognostication for the patient and an improved clinical approach to the pathology. Systemic diseases often manifest with pathology in the lower extremity. Complicated medical conditions such as diabetes, chronic renal failure, coronary artery disease, peripheral vascular disease and others are compounded by the threat of infection and are among the most challenging clinical scenarios. When these perplexing cases present, there should be a meeting of the minds among the surgical specialist, infectious disease specialists, radiologists and general practitioners to determine an appropriate method for obtaining a definitive diagnosis. In general, we safeguard patients by ruling out the diagnosis that carries with it the highest risk of morbidity. The consensus is that infection of soft tissue and bone carries a high degree of morbidity, and accordingly merits prompt identification and treatment. In the event infection is ruled out, one can modify the differential diagnosis accordingly based upon the clinical severity. When NMLI studies are negative and serologic values remain at or return to normal, clinicians can anticipate an uneventful clinical recovery. An obvious weakness in protocols requiring radioisotope labeling of white blood cells presents is diagnosing patients who suffer from generalized neutropenia. Neutropenia directly impacts the total number of cells available for labeling, thus this condition will diminish the overall quality of the exam in a proportion that is consistent to the degree of neutropenia. This physiologic manifestation occurs in a number of disease states, including diabetes. One can implement antibiotic therapy prior to imaging in these cases without affecting leukocyte labeling or interfering with imaging leukocyte accumulation. Dr. Judge is certified in foot, ankle and reconstructive rearfoot and ankle surgery by the American Board of Podiatric Surgery. She is a Fellow of the American College of Foot and Ankle Surgeons and is a Certified Nuclear Medicine Technologist. Dr. Judge is the Director of Externship Programs at Saint Vincent Charity Hospital in Cleveland. Ms. Kelty is certified in nuclear medicine technology by the Nuclear Medicine Technology Certification Board and is a Radioimmunotherapy Liaison to IDEC Pharmaceuticals Corporation.
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