Advantages of Diagnostic Nuclear Medicine
Part 2: Cardiac and Other Nonmusculoskeletal Disorders
Carlos E. Jimenez, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 27 - NO. 13 - DECEMBER 1999
This is the second of two articles on radionuclide imaging in sports medicine. The first, on musculoskeletal injuries, appeared in November.
In Brief: Advances in nuclear medicine have improved the detection and localization of very small abnormalities. Radionuclide imaging of myocardial perfusion is very useful for detecting coronary artery disease in patients who have an ambiguous presentation, such as those with chest pain syndrome and a nondiagnostic exercise test. Scintigraphy is also useful for diagnosing pulmonary thromboembolism, hyperthyroidism, testicular torsion, and fevers of unknown origin. In addition, improvements in positron-emission tomography and imaging with isotope-labeled monoclonal antibodies now permit detection and staging of prostate and brain malignancies and diagnosis of infections such as osteomyelitis.
For physically active patients, nuclear imaging techniques are probably used most often to diagnose and classify musculoskeletal injuries (see "Advantages of Nuclear Medicine, Part 1: Musculoskeletal Disorders," November, page 45). However, these techniques also can be very useful in evaluating active patients for common nonmusculoskeletal disorders such as coronary artery disease (CAD) and hyperthyroidism. Scintigraphic techniques may expedite diagnosis—a welcome advantage for an anxious patient.
New radionuclide agents and nuclear medicine techniques such as single-photon-emission computed tomography (SPECT) have enhanced image contrast resolution, resulting in improved detection and localization of very small abnormalities, especially in the heart. SPECT images can be viewed in a three-dimensional dynamic rotating format on computer monitors, facilitating the demonstration of pertinent findings. Even with the advent of high-resolution anatomic studies such as magnetic resonance imaging (MRI) and computed tomography (CT), nuclear imaging studies continue to be very effective for assessing certain diseases. Nuclear imaging's strengths lie in the ability to provide early physiologic information by demonstrating abnormalities in blood perfusion or metabolic activity in tissue.
Imaging for Coronary Artery Disease
Myocardial infarction remains the leading cause of death in the United States, and 48% of men and 63% of women who die suddenly from acute coronary events have no prior signs or symptoms of CAD (1). Regular aerobic exercise promotes cardiovascular fitness and lowers the risk of cardiac disease, but intense physical exertion can kill patients who have underlying cardiac disease. For this reason, the American College of Sports Medicine recommends exercise stress testing (EST) for older patients (over 40 years for men, over 50 years for woman) and for those with multiple cardiac risk factors who are planning to start a vigorous exercise program (2). But because of its high rate of false-negative and false-positive results, conventional EST has significant limitations for diagnosing occult CAD. These limitations have been the impetus for using nuclear imaging techniques to detect CAD.
Myocardial ischemia. Myocardial perfusion scintigraphy employs an intravenous radiopharmaceutical to reveal the distribution of blood flow in the myocardium. The technique can identify areas of reduced blood flow associated with myocardial obstruction or scarring. Perfusion defects that are observed on the stress images but not on the resting images are referred to as reversible defects and suggest ischemia. Persistent defects seen on both the resting and stress images are referred to as fixed defects and are consistent with scarring.
This technique is most commonly used to evaluate patients who have an intermediate likelihood of CAD; these include asymptomatic patients with a positive EST, patients with atypical chest pain, those with typical angina and a negative EST, and those whose EST is nondiagnostic because of left ventricular hypertrophy, left bundle branch block, Wolff-Parkinson-White syndrome, or nonspecific ST-T changes on the ECG. Myocardial perfusion scintigraphy is also commonly used to assess the completeness of vascularization after bypass surgery or coronary angioplasty and as a prognostic indicator in patients with known coronary disease.
Several protocols have been developed for rest and stress myocardial perfusion imaging with either thallium-labeled or technetium-99m-labeled agents (sestamibi and tetrofosmin); the protocols have sensitivities that range from 70% to 95% and specificities that range from 60% to 90%. Each method has distinct advantages and disadvantages (3). More important, however, is perfusion imaging's value in predicting cardiac death and myocardial infarction in patients with and without known CAD (4,5). In a study of 5,183 patients referred for nuclear imaging stress testing, those with normal scans were at low risk for cardiac death (0.5%/yr) and myocardial infarction (0.3%/yr) over a follow-up period of about 2 years when compared with patients who had abnormal scans. Patients who had worse scan abnormalities had significantly higher rates of infarction and death (6).
The main difference among all the myocardial perfusion radionuclide protocols is in their ability to identify reversible perfusion defects. Currently, the SPECT dual-isotope approach, with a resting thallium study and Tc 99m sestamibi or tetrofosmin stress images, permits optimal evaluation when the primary concern is ruling out myocardial ischemia (figure 1). The 140 keV energy of the technetium-labeled agents is ideal and permits simultaneous ECG-gated image acquisition, which gives additional information about left ventricular ejection fraction, regional myocardial wall motion, wall thickening, and potential artifacts. Improvements in computer technology now can correct for patient motion and soft-tissue attenuation, thus reducing artifacts and improving procedure specificity.
Left bundle branch block. One group that deserves particular attention is asymptomatic active patients who are found to have new-onset left bundle branch block (LBBB) during a routine exam. In the Framingham study (7), onset of LBBB increased the incidence of cardiovascular mortality by a factor of three to four. On the other hand, LBBB is also seen in apparently normal hearts, and these patients do not have a higher incidence of cardiac death. Thus, the coexistence of CAD and LBBB implies a significant risk, creating the need for an accurate noninvasive test to detect CAD in asymptomatic patients who have LBBB.
The usual tests are not suitable for these patients. ST-segment changes during exercise electrocardiography are nondiagnostic for ischemia in patients with LBBB unless ischemia is severe. Exercise myocardial perfusion imaging is also not practical because of its high likelihood of recording artifactual, reversible septal-perfusion defects, which are indistinguishable from images caused by stenosis of the left anterior descending coronary artery (8). (Proposed mechanisms to explain this heart-rate-dependent artifact include prolonged compression of the septal perforators, reduced diastolic flow, small-vessel CAD, septal fibrosis, and wall motion artifact.)
Resting myocardial perfusion radionuclide testing with coronary vasodilators (dipyridamole or adenosine) is the preferred noninvasive diagnostic modality for this population because of its superior accuracy and much lower incidence of artifactual reversible perfusion defects (9).
Chest pain. Nuclear perfusion cardiac imaging has had a major impact on patients who present to an emergency department with acute chest pain and a normal or nondiagnostic ECG. Studies reveal that 3% to 6% of patients discharged from emergency rooms with the diagnosis of noncardiac chest pain did, in fact, have an acute myocardial infarction. Much infarction-related damage could have been prevented if these patients had been recognized (10).
Injection of Tc 99m sestamibi causes immediate binding of the isotope inside the myocardial cells without any subsequent redistribution. Patients can be injected with the tracer when they are experiencing chest pain, but the imaging can be delayed up to several hours while they are treated and stabilized. The images obtained will reflect the pattern of myocardial perfusion at injection. Patients who have chest pain and abnormal perfusion images likely have myocardial ischemia or infarction. They are usually admitted to the hospital unless prior clinical information or images suggest that the event is not acute. On the other hand, a normal Tc 99m sestamibi study in a patient complaining of chest pain essentially excludes myocardial ischemia or unstable angina.
A multicenter study (10) with this protocol in the emergency room revealed that myocardial perfusion nuclear imaging reduced the rate of myocardial infarction from 1.8% to 0.1% in patients discharged with chest pain. Compared with the era before the protocol was started, there were fewer hospital admissions and fewer cardiac catheterizations performed in patients without obstructive coronary artery disease.
Assessing Other Disorders
Acute pulmonary thromboembolism. Acute pulmonary thromboembolism (PE) is a common disease with nonspecific clinical findings, high mortality, and significant morbidity. Various estimates put the incidence of PE in the United States at more than 650,000 per year, with more than 100,000 deaths (11). Among athletes, risk factors for PE include oral contraceptive use, inherited hypercoagulation disease (eg, protein C or S deficiency), and immobilization (eg, prolonged bed rest) due to musculoskeletal injury or a disabling illness.
Pulmonary angiography is still the standard for diagnosing PE, but it is costly, invasive, not readily available, and fraught with its own morbidity and mortality risks. Currently, the most widely used noninvasive diagnostic test for PE is ventilation/perfusion (V/Q) lung scanning (12). This test can be performed easily, quickly, and without discomfort or morbidity for patients. Because of the technique's high sensitivity, a normal or near-normal perfusion scan effectively excludes the diagnosis of PE. On the other hand, a scan showing two or more large unmatched ventilation/perfusion lung segments is extremely specific for PE (figure 2) and warrants starting anticoagulation therapy without seeking angiographic confirmation.
Unfortunately, V/Q scans most often demonstrate a low or intermediate probability of PE. In patients who have a high pretest clinical probability but have an indeterminate V/Q scan, other imaging procedures, such as Doppler ultrasound of the lower extremities, pulmonary angiography, or pulmonary spiral CT scanning, may be required to diagnose a thrombotic process. A nondiagnostic V/Q scan can be helpful in other ways, however. For example, during pulmonary angiography, it can direct the angiographer to suspicious areas, thus shortening the procedure and reducing the radiation exposure.
Hyperthyroidism. Nuclear imaging can also be helpful in diagnosing primary hyperthyroidism, a syndrome caused by excess thyroid hormone secretion and commonly seen in active people. It produces signs and symptoms that include tachycardia, tremors, weight loss, gastrointestinal disturbances, nervousness, heat intolerance, sweating, fatigue, muscle weakness, exophthalmos, amenorrhea, and osteoporosis. The differential diagnosis includes Graves' disease, hyperfunctional adenoma, toxic multinodular goiter, subacute thyroiditis from a postviral syndrome, postpartum thyroiditis, and exogenous thyroid hormone abuse (eg, for weight control) (13,14). In some instances, the symptoms can mimic overtraining syndrome or chronic fatigue (15). Suspected hyperthyroidism is confirmed primarily with serum immunoassays for thyroid-stimulating hormone (TSH) and "free" thyroxine (FT4). In primary hyperthyroidism, TSH levels are decreased and the FT4 levels elevated or normal; however, a single abnormal thyroid function test cannot readily discriminate among all the causes of hyperthyroidism.
A thyroid scan with 24-hour radioiodine uptake (RAIU) determination is very useful in identifying the cause when it is not clear from the history, physical examination, and laboratory tests. In the United States, the normal range for a 24-hour RAIU is between 10% and 30% of the amount administered, but a patient with Graves' disease will have a 24-hour RAIU that is greater than 30% and a scan that shows an enlarged thyroid gland with homogeneous tracer uptake. Scans of a patient with subacute or postpartum thyroiditis will exhibit a near-zero radioiodine uptake and a minimal thyroid gland visualization on the scan. This contrasts with a scan of a patient with a single hyperfunctional autonomous thyroid nodule; it will show an intense region of focal uptake within the nodule, suppressed uptake to the rest of the gland, and a 24-hour RAIU that is typically elevated or in the high-normal range. Finally, the characteristic scintigraphic appearance of a toxic multinodular goiter shows heterogenous tracer uptake with various focal cold and hot areas of different sizes, and an RAIU that is elevated.
The clinical importance of distinguishing among different causes of hyperthyroidism is enormous since the treatment varies according to the condition. For instance, radioactive iodine 131 (131 I) therapy for managing a patient with Graves' disease is usually between 10 and 15 mCi, but a patient with a toxic autonomous thyroid nodule commonly requires a higher 131 I dose for effective treatment, about 20 to 29 mCi. In contrast, patients whose hyperthyroidism is due to thyroiditis are given only supportive therapy and do not require isotope therapy.
Testicular pain. Testicular scintigraphy has often been used successfully to diagnose causes of acute scrotal pain, particularly in children and adolescents. Its utility lies in its ability to differentiate acute testicular torsion from inflammation, most commonly due to epididymitis. When performed by an experienced physician, scintigraphy has a sensitivity and specificity greater than 90% for acute torsion. When color Doppler ultrasound was compared with scintigraphy in patients who had acute scrotal syndromes and indeterminate clinical presentation, their sensitivities were comparable, but scintigraphy had a greater specificity (16).
In patients who have testicular torsion that is within a few hours of onset, scintigraphy will demonstrate decreased flow and uptake in the involved testicle. In acute epididymitis, on the other hand, scintigraphy demonstrates increased flow and focal uptake in the affected epididymal region with or without testicular involvement (epididymo-orchitis).
It is particularly important to diagnose testicular torsion expeditiously because delay in surgical repair results in testicular infarction. About 90% of an ischemic gonad will survive if detorsion is performed within 6 hours, but survival decreases rapidly after that. Management of epididymitis is mainly noninvasive.
Fever of undetermined origin. Fever of undetermined origin is a challenging medical condition because of the extensive differential diagnosis, which includes chronic infections, neoplasm, connective tissue disorders, drug reactions, and granulomatous diseases. Infections and neoplasm account for as much as two thirds of all causes of fever of undetermined origin. Among young athletes, the most likely causes are mycobacterium infections, viral infections (including cytomegalovirus and Epstein-Barr virus), lymphoma, and sarcoidosis. When the patient has unremitting fever and no localizing signs, imaging with gallium- or indium-labeled white blood cells has been useful for uncovering the offending process (17).
Radiolabeled monoclonal antibodies. Recently, various radiolabeled monoclonal antibodies directed against specific tumor or leukocyte cell-surface antigens have been developed to uncover small pathologic processes in sick patients after an unremarkable anatomic imaging work-up (18,19). Monoclonal agents that are approved by the US Food and Drug Administration (FDA) and have seen increasing clinical use include indium-111 capromab pendetide (ProstaScint) and arcitumomab (Cea-Scan). The former is being used for detecting the spread of prostate cancer in patients who have rising prostate-specific antigen levels, especially in the lymph nodes, where metastases often go undetected by other diagnostic imaging tests. Arcitumomab is a technetium-99m-labeled antibody fragment that is used in imaging and staging recurrent colorectal cancer in patients with rising levels of carcinoembryonic antigen, a phenomenon seen in 70% of colorectal cancer patients.
Another antibody, sulesomab (Leukoscan), targets the white blood cells associated with an acute infection. It is a technetium-labeled antibody that has been approved for the detection of osteomyelitis and marketed in Europe for about 2 years. This tracer can be prepared in about 5 minutes, and the nuclear images can be obtained as early as 30 minutes after injection for the detection of infectious focus. Sulesomab is awaiting FDA approval in the United States. A phase 3 trial conducted by the Leukoscan Appendicitis Clinical Trial Group (19) showed that among 141 children and adults presenting with suspected acute, atypical appendicitis, the sensitivity and specificity of imaging with sulesomab were 91% and 92%, respectively.
Positron emission tomography. While positron emission tomography (PET) has long been used by researchers to characterize the functional state of many diseases, new developments have revolutionized its clinical role. These include greater availability of positron isotopes, the ability to image positron isotopes with special adaptations to conventional dual-headed gamma cameras, and increasingly available reimbursement.
The radioisotope used most frequently in PET imaging is F-18 fluorodeoxyglucose (FDG). This positron radiotracer tracks glucose metabolism and is highly accurate in detecting and staging several malignancies. Some well-accepted indications for FDG-imaging PET include the evaluation of suspected pulmonary malignancies that are indeterminate by anatomic imaging, determining myocardial viability, grading brain tumors, and differentiating recurrent tumor from scar after therapy for colorectal and brain malignancies. New data support indications for PET imaging that promise to expand its future clinical role, particularly in oncology and musculoskeletal conditions, as improved technology continues to decrease protocol cost.
A Broadening Role
New isotopic imaging agents and advances in technological equipment are broadening the role of nuclear medicine in evaluating active patients to detect prevalent diseases such as CAD, hyperthyroidism, and pulmonary thromboembolism. The strength of scintigraphy lies in its ability to provide early physiologic demonstration of abnormalities in perfusion and metabolism that cannot be readily measured by the high-resolution radiologic studies.
The opinions or assertions presented here are the private views of the author and are not to be construed as official or as reflecting the views of the US Department of the Army or Department of Defense.
Dr Jimenez is a major in the US Army Medical Corps and deputy commander for clinical services in the primary care clinic at Fort Buchanan, Puerto Rico. He is also an assistant professor of radiology and nuclear medicine at the Uniformed Services University of the Health Sciences, Bethesda, Maryland. Dr Jimenez is a diplomate of the American Boards of Internal Medicine and Nuclear Medicine and has a certificate of added qualifications in sports medicine. Address correspondence to Carlos E. Jimenez, MD, Army Health Clinic, PO Box 34000, Bldg 21, Fort Buchanan, Puerto Rico 00934; address e-mail to [email protected].