NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

PEDIATRIC MUSCULOSKELETAL RADIOLOGY

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NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE Techniques and Applications Helen R. Nadel, MD, FRCPC, and Moira E. Stilwell, MD, FRCPC

Most clinicians are aware of the exquisite sensitivity but nonspecificity of nuclear medicine techniques. The many advances in instrumentation, computer hardware and software, and the introduction of new radiopharmaceuticals have contributed to an improvement in detection and diagnosis of musculoskeletal disease in children. Scintigraphy remains a useful tool, but is often underused by radiologists who do not appreciate the benefits that scintigraphic techniques have to offer in the diagnosis of pediatric bone conditions. Dualenergy x-ray absorptiometry (DEXA) is also a newer technique that is beginning to be used in the pediatric and adolescent age group. The value of these diagnostic techniques is discussed and illustrated with case examples.

in some instances but is only helpful in the presence of adequate localizing clinical factors. Time delay of hours is undesirable when confronted with a child suspected of having musculoskeletal sepsis. The use of bone scintigraphy in the assessment of musculoskeletal abnormalities is based on increased sensitivity in detecting abnormalities before other diagnostic imaging techniques. The pitfall of bone scintigraphy is its lack of specificity. There must be close correlation of scintigraphic findings with those of other imaging modalities and history and physical findings in the evaluation of an individual patient. This helps further characterize scan findings from the three general areas of tumor, trauma, and infection, which can be diagnosed on musculoskeletal scintigraphy.

GENERAL PRINCIPLES TECHNICAL CONSIDERATIONS

Thirty percent to 50% of bone calcium must be lost before differences in bone density are appreciated radiographically. Periosteal new bone formation requires 7 to 10 days before it can be visualized on a radiograph. Subtle detection of fluid in a joint or elevation of periosteum can be detected with ultrasound

The managed care model of ”family-centered care” often requires what has been a mainly adult patient general nuclear medicine department to perform scintigraphic techniques in children. Technical considerations concerning care of the child, immobili-

From the Department of Radiology, Children’s and Women’s Health Centre of British Columbia; and Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada

RADIOLOGIC CLINICS OF NORTH AMERICA

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VOLUME 39 NUMBER 4 JUL,Y 2001

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zation, dosing of radiopharmaceuticals, and instrumentation are of major importance. It is routine in many dedicated pediatric nuclear medicine departments to allow parents or siblings to remain in the imaging room to provide a sense of security and safety for the child. Similarly, the patient is allowed to hold a favorite toy or a prized possession and parents are instructed to bring such items with them for the test. Children are often most worried about the needle required for the injection. Many nuclear medicine departments now routinely use the application of topical anesthetic creams as part of the preparation for the examination.% Immobilization techniques to gain patient support in pediatric studies can vary from wrapping the patient to the use of sedation and general anest h e ~ i a . For 4 ~ neonates ~~~ to age 2, it may suffice to hold the patient in place, deprive sleep, and feed the child while on the imaging table. Papoose techniques for bundling and entertainment including television, movies, music, or stories can be used to immobilize children older than 4 to 5 years of age. The cooperation of an older child can often be obtained if the procedure is carefully explained to them and their parents. Children between the ages of 2 and 5, or who are mentally retarded or have severe attention deficit problems, are more likely to require sedation. The accepted standard for conscious sedation in pediatrics has been set out by the Committee on Drugs of the American Academy of pediatric^,^ although many other guidelines and references to this can be found in the literature.6, The correct dosing for administration of radiopharmaceuticals to children is available in standard pediatric nuclear medicine texts and can be based on either body surface area or the weight of the child relative to adult dosage.38,63 It is important to have some knowledge of what the absorbed dose is for standard musculoskeletal scintigraphic examinations in children. This enables the physician to give appropriate risk assessment when explaining the procedures to parents or an adolescent-aged patient.58

A polyphosphate, such as methylene diphosphonate (MDP) labeled with technetium 99m (Tc 99m) is the main radiopharmaceutical used for musculoskeletal imaging. Scanning is usually performed as a three-phase bone scan with immediate blood flow and blood pool imaging of the site of symptoms obtained after injection, followed by delayed imaging 1.5 to 2 hours later. It is important that the children are well hydrated to have optimum visualization; but we do not usually require continuous intravenous infusion. Proper positioning is important in pediatrics particularly in young infants, and although children are smaller it does not imply that more of a child can be imaged on a single scintigraphic view. In fact, examinations take longer in children and infants because of the requirement of joint-to-joint images for detailed assessment. Although the new gamma camera systems often allow whole-body passes it is often necessary to supplement these images with magnified spot views or even pinhole imaging. Image magnification either with camera zoom, computer magnification, or collimation is essential when performing scintigraphic examinations in children. Magnification is either optical with collimation or electronic. Optical magnification uses either a pinhole or converging collimator, enlarges the image, and improves overall system resolution. Electronic magnification makes the image bigger without altering overall system resolution (Fig. 1). The capability for single photon emission CT (SPECT) imaging is essential in pediatric scintigraphy. SPECT allows for improved image contrast and hence improved diagnostic accuracy. It is helpful in localizing and further defining most musculoskeletal abnormalities to include the extremities and is essential when assessing a child with the clinical problem of back pain (Figs. 2 and 3). Multiple head detector gamma camera systems are becoming more available in pediatric centers. The advantages of these systems include increased resolution and sensitivity and decreased time of examination in a child.

Figure 1. Normal bone scan images in children of varying ages. A, A single spot view of almost the whole body in this infant is obtained without zoom or magnification and is not of optimal diagnostic quality. Anterior (/eft) and posterior (right). 6, Repeat images of the thorax with magnification are of better diagnostic quality, confirming that the examination is normal in this infant. C, Scintigraphic views of the knees of two 6-year-olds. The normal examination is on the left with sharp nonglobular linear appearing increased epiphyseal plate activity. Image on the right is symmetrical metaphyseal increased activity that is caused by involvement with neuroblastoma or other marrow-involving tumors. Poor positioning also can sometimes cause this appearance.

Figure 1. See legend on opposite page

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Figure 2. Normal bone scan images of the knees in a 12-year-old boy. A, Planar views and 6,single photon emmission computed tomographic (SPECT) image: top row: transaxial, middle row: sagittal, bottom row: coronal.

NUCLEAR MEDICINE TOPICSIN PEDIATRIC MUSCULOSKELETALDISEASE

Figure 3. A 14-year-old gymnast with back pain. A, The planar images suggest increased activity over the lower lumbar spine (arrow). Note that the tibia and fibula can be visualized as individual bones. B, SPECT maximum intensity projection (MIP) images (transverse [left],sagittal [middle], coronal [righa confirm that the spine is normal and that the right-sided projected activity seen on the planar images is the ectopic right kidney (arrow).

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Correlative imaging is essential to state of the art practice of pediatric nuclear medicine. Computer multimodality image fusion programs are becoming available and more sophisticated. These allow comparison of different isotope scintigraphic studies or serial studies in the same patient or comparison of scintigraphy with other imaging modalities, such as CT, MR imaging, and positron emission tomography (PET) for better correlation of anatomy and function. New combined gamma camera and CT devices allowing direct anatomic and physiologic correlation are also being manufactured and will have further impact on the care of the pediatric patient. CONGENITAL AND DEVELOPMENTAL SYNDROMES

It is important to be able to recognize subtle developmental variants that may mimic disease. Bone scintigraphy does not diagnose syndromes in children, but certain syndromes may have characteristic appearances that should be able to be recognized on the scan images (Figs. 4 to 6). INFECTION AND INFLAMMATION

To diagnose an inflammatory process correctly as being caused by either osteomyelitis, septic arthritis, or cellulitis, a three-phase MDP bone scan with blood flow, blood pool, and delayed imaging is recommended. Occasionally, the flow phase may not be necessary; however, it is mandatory to obtain images in at least two phases.=,36, 65 Early phase images including blood flow and blood pool images show the distribution of soft tissue hyperemia. All three inflammatory processes demonstrate hyperemia and all three can coexist. Hyperemia caused by septic arthritis characteristically involves both sides of the infected joint symmetrically. In both cellulitis and septic arthritis, delayed bone images may be normal or show a mild increase in bone uptake, or some persistence of soft tissue activity in a diffuse pattern without focal localization of the radiopharmaceutical on the delayed phase in bone. Occasionally the three-phase bone scan can help to identify subtle soft tissue abnormalities without bony involvement. This requires careful attention to all three phases of the scan and correlation

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with appropriate clinical findings and other imaging studies (Fig. 7). Classically, osteomyelitis shows focal hyperemia on the blood flow and blood pool images with focal delayed increased uptake in bone on the delayed images. Some children presenting with acute virulent onset of disease, including high fever, rapid onset of symptoms, and severe bone pain, may have cold bone lesions with decreased uptake in bone on the initial imaging study delayed views.43,48,49 Delayed cold bone scans usually, however, show evidence of increased hyperemia in the blood flow and blood pool phase of the study at the margins of the inflammatory process (Fig. 8). Regardless, all bone scans are positive by the end of the first week, considerably earlier than radiographic change is seen. The accuracy of the bone scan is approximately 9001’0. 4,51 Whenever possible, it is ideal to obtain the bone scan before a joint aspiration, because the aspiration procedure itself may cause some bone reaction and increased activity on the scan images. There are some reports in the literature that suggest that aspiration of a bone or joint may not cause the scintigraphic study to be abnormal in all cases.13, This can be somewhat variable depending on the technique of the person performing the aspiration and there may be less reactive change on the scintigraphic examination if the scan is performed within a few hours of aspiration (Fig. 9). Another potential pitfall of early scintigraphic evaluation in the assessment of possible infection can be encountered if there is increased joint pressure. This can cause a transient photopenic joint on the scan because of the inability of the radiopharmaceutical to reach the site of infection (Fig. Because the bone scan may not become positive until 48 to 72 hours after the onset of infection, an early scan may be equivocal. The addition of specific inflammatory radiopharmaceutical imaging with gallium 67 or labeled white cells with Tc 99m hexamethylpropyleneamine increases the sensitivity in those patients in whom there is a convincing clinical suspicion of osteomyelitis. Sometimes a repeat bone scan in 48 to 72 hours after the first scan may confirm the diagnosis and provide less of a radiation burden to the child. Imaging with indium 111oxine-labeled white blood cells is not recommended in children because of its high radiation burden.20 Neonatal osteomyelitis was once thought to be assessed poorly with bone scintigraphy.s Text continued on page 630

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 4. Benign bone lesions with mild increased activity on bone scan. A, Anteroposterior (AP) and lateral views of the knees showing identifying increased activity (arrows) in a benign osteochondroma of the medial and posterior aspect of the right knee. B, Three-phase bone-scan images of a benign bone cyst in the medial aspect of the left proximal femur. The arrow identifies the activity on the delayed view (lower right) with no apparent hyperemia on the blood flow (fop three rows) and blood pool images (lower left).

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Figure 5. See legend on opposite page

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 5. Benign bone lesions with marked increased activity on bone scan. Two children with fibrous dysplasia. Mono-ostotic fibrous dysplasia in skull. Planar whole body (arrows) (A) and tomographic (B)images of the skull demonstrate intense focal increased activity in the single lesion in the skull. No additional lesions are found. Illustration continued on following page

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Figure 5 (Continued). C, Polyostotic fibrous dysplasia in a child with multiple lesions involving the left lower extremity. The intense abnormal increased activity and the unilateral involvement are typical findings in this disease.

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 6. The scintigraphic appearance of two syndromes. A, Gaucher’s disease. Note intense abnormal symmetric increased activity in the extremities with undertubulation of the femora. The differential diagnosis of the scan appearance would include infection or neoplasm. The increased activity can be caused by bone infarction. B, Multiple hereditary osteochondromas or diaphyseal aclasia. Note the skeletal deformities throughout the bone scan caused by the osteochondromas.

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Figure 7. This 9-year-old boy presented with severe back pain that was difficult to localize clinically. The posterior blood pool image (A) shows hyperemia in the region of the left sacroiliac joint (arrow). The delayed posterior planar image (B) shows only mild asymmetry of the left sacroiliac joint (arrow) as compared with the right, and SPECT did not identify focal activity in bone. A CT scan was performed, which showed a left iliacus abscess.

Careful attention to technique with appropriate magnification spot views, however, can result in extremely accurate images (Fig. 11). The age or size of the patient alone should not be a deterrent to perform skeletal scintigraphy2,l2 Aigner et a12 assessed 20 neonates and found that scintigraphy had a 90% sensitivity for detection of focal skeletal involvement. The scans demonstrated localized hyperperfusion with abnormalities on immediate blood flow and blood pool phases, and either hot or photopenic lesions on delayed scans. They also found scintigraphy helpful in follow-up. The reduction and resolution of the focal hyperperfusion was the best sign of adequate response to antibiotic treatment. The corollary, persistence or recurrence of hyperperfusion, indicated a failed response to the rap^.^ Back pain is an uncommon symptom in childhood and vertebral scintigraphy with SPECT can be a sensitive means of assessing this area. Three-phase bone scan can localize the area of abnormality, which then can be assessed further with other imaging modalities, such as CT and MR imaging. This technique also visualizes infection of the intervertebral disk space (diskitis), a specific inflammatory process that occurs in children.

The usual pattern is delayed bone scan uptake in the vertebrae on either side of the affected disk space; however, in adolescents, the increase in uptake may affect only a single end plate (Fig. 12). SPECT is essential in the assessment of back pain. The differential diagnosis of acute back pain may be spondylolysis, in which SPECT imaging is also specific, with focal involvement of the pars interarticularis area best seen on the tomographic images (Fig. 13). CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS

Chronic recurrent multifocal osteomyelitis (CRMO) is a fascinating and distinct variant of osteomyelitis that occurs in children and adolescents. Its peak incidence is at age 14 years and it is more common in girls.61Its cause remains unknown, although an infectious agent is suspected. Attempts to isolate a specific pathogen have proved unsuccessful. The clinical features include recurrent attacks of infection at multiple sites in the skeleton that are self-limited and eventually resolve after a few years of an unpredictable clinical course. The diagnosis is based on clinical, imaging,

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 8. This 5-year-old girl clinically had cellulitis in her right leg. The bone scan was performed to assess for osteomyelitis. A, The immediate blood flow (left) and blood pool (right) images show marked hyperemia in the entire right leg. B, The delayed whole body views show intense increased activity along the shaft of the entire tibia. The increased activity is so intense that the right fibula and left leg activity is not well visualized because of all the counts coming from the right tibia. There is a medial and posterior area (arrow) that is more photopenic. Anterior (left). Posterior (right). Illustration continued on following page

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Figure 8 (Continued). C, Twenty-four-hour image (right) compared with standard 2-hour-delayed image (left) shows persistence of focal activity in the tibia and clearance from the soft tissues, thereby confirming the presence of osteomyelitis of the tibia in association with the cellulitis. In cellulitis alone, the 24-hour image would not show focal increased bony activity. The bone scan findings identify hot and cold osteomyelitis and associated cellulitis.

Figure 9. This 12-year-old boy complained of left knee pain without the history of trauma or the presence of fever. Initial radiographs were normal. Three-phase bone scan identifies hyperemia on blood flow (A) and blood pool (B)images and delayed (C) increased activity in the left knee (arrows). An aspiration of the left knee joint was performed at an outside hospital the previous day before the bone scan. No pus was aspirated and no growth was obtained on the culture. No treatment was given as the symptoms improved rapidly. Follow-up radiographs were normal. The abnormality seen on scintigraphy is presumed to be caused by the aspiration. 0,Right and left lateral views.

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 10. This 3-year-old boy presented with fever and left hip pain. A, Blood pool images show hypoemia in the region of the left hip (arrow). 6,The delayed images show a photopenic area in the left femoral head region (arrow). There is the suggestion that the left hip joint (right) is slightly wider than the right (left).Ultrasound examination confirmed the presence of fluid in the left hip joint. Because of the presence of fluid in the joint, focal increased bony activity caused by osteomyelitis could be obscured because the radiopharmaceuticalcannot be delivered to the bone. The joint was aspirated after the scan. Follow-up radiographs did not show bone destruction suggestive of osteomyelitis. The findings are in keeping with septic arthritis or synovitis and the patient was treated with the appropriate antibiotic course.

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Figure 11. Neonatal osteomyelitis. This 4-week-old infant was not using her left arm. Initial radiographs were normal. A, There is hyperemia noted in the proximal left humeral metaphysis on blood pool images (arrow). B, There is focal increased bony activity in the same location on the delayed views (arrow). Therapy was instituted for osteomyelitis, and subsequent follow-up radiographs identified focal metaphyseal lucency confirming the diagnosis.

and pathologic findings. Common clinical presentations are pain with or without swelling. Fever and constitutional symptoms may or may not occur. The white blood cell count is usually normal. Symptoms may be present from weeks to months.52, Radiographic appearances vary and have been described to include mixed lytic and sclerotic lesions, purely sclerotic lesions, and destr~ction.'~ Any part of the skeleton may be involved. Most common sites include the metaphyseal portions of the long bones, medial ends of the clavicles, face, spine, pelvis, and upper e ~ t r e m i t i e sThe . ~ ~ lesions seem close to the growth plates but do not transgress them.52Periosteal reaction may or may not be present on radiographs. Antibiotics have no impact on the clinical course of this disease, although some studies indicate that systemic steroids may provide mild benefit. Although CRMO and conventional osteomyelitis share a common histopathologic feature, namely chronic inflammation, they are different in important ways. Typically, a predisposing cause is not found for CRMO in contrast to conventional osteomyelitis. CRMO does not generally involve the formation of sequestra or sinuses. Bone scintigraphy has a number of advan-

tages in CRMO including the ability to demonstrate the multifocal nature of this entity. Scintigraphy can demonstrate both symptomatic foci and asymptomatic foci (Figs. 14 and 15). The findings on scintigraphy at typical sites are similar to that for conventional osteomyelitis. A three-phase abnormality is the hallmark at active sites, but nonactive sites may not show abnormal activity. The differential diagnosis is, however, nonspecific based on the scintigraphic findings alone and can include primary musculoskeletal neoplasm and Langerhans cell histiocyt~sis.'~ TRAUMA

Toddler's fracture most commonly affects the tibia and is usually diagnosed by radiographs. Occasionally, the radiographs are equivocal, or the stress injury may involve less commonly affected bony structures, such as fibula or small bones of the feet. Bone scintigraphy may correctly and quickly pinpoint the cause of the pain before radiographic change may be present in a young child who presents with acute joint or limb pain in the absence of symptoms to suggest infection (Fig. 16).

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 12. Diskitis in a 14-year-old girl with Crohn’s disease who presented with back pain. A, There was hyperemia on the posterior blood pool images (arrow). 6,The delayed phase identified a similarly located subtle abnormality in the lumbar spine (arrows). C,The MIP SPECT images (transverse [/eft] sagittal [middle], coronal [right]) clearly demonstrated contiguous involvement in two lumbar spine vertebral bodies with intervening disk (arrows). Although renal abnormalities should not be diagnosed on a bone scan, if there is concern regarding renal abnormality, this should be correlated with ultrasound. The right kidney had pooling of activity in the collecting system on blood pool and delayed images. Ultrasound examination confirmed pelvicaliectasis. The inflammatory mass associated with the diskitis and vertebral osteomyelitis was also likely contributing to the renal obstruction.

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Figure 13. A, Increased activity in the left L5 pars interarticularis, which is best identified on the SPECT imaging (arrows) (fop row: transaxial, middle row: sagittal, boffom row: coronal). Illustration continued on opposite page

In a young child presenting with acute hip pain, bone scintigraphy may be helpful to detect avascularity of the femoral head caused by Legg-Calvk-Perthes disease long before radiographic change occurs. A timely diagnosis allows early immobilization in an attempt to lessen the development of potential complications. The scintigraphic classification of the stages of the disease described by Conway et all6 can provide prognostic information that may affect therapy. In older children presenting with acute hip pain, the bone scan may show subtle findings that suggest the diagnosis of slipped capital femoral epiphysis. Once this diagnosis is suspected the patient is treated as an acute fracture and no longer allowed to weight bear. In addition, if there are associated complications, such as avascular necrosis of the femoral head or chondrolysis, the scintigraphic study may be helpful for these diagnoses (Fig. 17). The role of scintigraphy in the management of the suspected case of child abuse is to provide a quick assessment for defining and characterizing the extent and severity of

trauma that is complimentary to other radiologic investigation^.^^ The major advantages of bone scintigraphy are its increased sensitivity (25% to 50%) in detecting evidence of soft tissue and bone trauma, and in the documentation of specific and characteristic sites of abuse, such as in the ribs or the diaphyses of the extremities (Fig. 1 8 ) . 1 6 r 6 0 The authors find scintigraphy particularly helpful in young infants when subtle areas of bony injury may either be too early to detect on radiographs or completely healed areas may be radiographically normal. In both of these instances the bone scan may show areas of increased activity. REFLEX SYMPATHETlC DYSTROPHY

Reflex sympathetic dystrophy (RSD) is the pain syndrome that has various clinical forms, precipitating factors, localizations, physiopathologic hypotheses, and diagnostic criteria. It was first described as early as 186439 in US Civil War soldiers who had suffered gunshot wounds that affected peripheral

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

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Figure 13 (Continued). B, Planar imaging only shows faint increased activity in the area of spondylolysis.

nerves and developed a subsequent persistent burning pain and progressive trophic changes in the affected limb. Because of the persistent pain the term cuusulgiu was applied.53RSD is now used to encompass all variants of the syndrome, which include pain, hyperesthesia, vasomotor disturbances, and dystrophic changes that usually improve with sympathetic denervation. Trauma is the most common precipitating factor in the pain syndrome. The trauma may be acute or may also be remote by months or longer from the onset of the pain symptoms. Driessens et all8 quoted a 1%risk of developing post-traumatic RSD but also stated that some say the percentage may be as high as 5%. Other causes may include malignancy, infection, cervical osteoarthritis, tendonitis, peripheral neuropathy, myocardial infarction,

herniated disks, use of barbiturates and antituberculous drugs, and psychological stress to name but a Clinically, three stages are described in RSD: (1) acute, (2) dystrophic, and (3) atrophic, which vary in the degree of the progressive trophic changes. The duration of the stages is variable from weeks to years.53Most often the diagnosis is a clinical one. Conventional radiographs may be normal or show the nonspecific finding of osteopenia with or without associated soft tissue swelling. Symptoms in children may be the same as in adults, or they often present with what seems to be arthritis.34Children, however, may present with RSD in the absence of a defined antecedent event or the pain can be misdiagnosed as having a psychiatric ca~se.'O,~~ The diagnosis may often be delayed in chil@

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Figure 14. See legend on opposite page

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 15. A 15-year-old boy with pain in the low back sacral area. Planar bone scan (A) and SPECT MIP (B) images (leffto righf; transaxial, sagittal, coronal). There is focal intense increased activity in the region of the sacrum. CT scan showed bilateral symmetric mixed sclerotic and lytic changes involving the upper sacrum. No organism was grown on biopsy and the presumed diagnosis is CRMO.

Figure 14. This 8-year-old girl presented with an elevated erythrocyte sedimentation rate (ESR) and pain in her left ankle. A, Her initial whole body bone scan was negative. B, On a repeat scan 4 months later because of persistence of symptoms in her ankle, whole body blood pool images demonstrate hyperemia in the left ankle and right wrist. C,On the whole body delayed images there is focal abnormal increased activity in the same areas of hyperemia (arrowheads). Note also the increased activity in the ischiopubic synchondroses greater on the left (arrow) than the right, which is a developmental variant. No radiographic abnormality was identified in the left ankle or right wrist. The presumed diagnosis is chronic recurrent multifocal osteomyelitis (CRMO).

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Figure 16. This 14-month-old infant presented with refusing to weight bear. Radiographs were negative. Blood pool image (A) showed hyperemia, and the delayed image (B) showed increased activity in the mid- to distal tibia (arrows) consistent with an occult toddler’s fracture. Subsequent follow-up radiographs confirmed subtle healing fracture.

dren and inappropriate therapy instituted because children often have fewer of the trophic changes seen in ad~1ts.l~ RSD should be considered in a child who presents with a painful extremity with marked tenderness about a joint and a lack of laboratory and clinical findings.56 The three-phase bone scan can play an important role in diagnosis of this syndrome because there are often few if any other radiologic modalities that show an abnormality. The classic RSD scintigraphic appearance includes intense periarticular activity in an involved extremity on the delayed phase of the scan preceded by hyperemia in a similar distribution on the immediate postinjection blood flow and blood pool phases of the scan.33Some authors make a distinction of pseudodystrophy resulting from disuse and which may have decreased activity on scintigraphy from true RSD. This ”cold variant’’ has been called ”les formes froides” by the French.lBThis cold variant is the more common form seen in the pediatric population.” In contrast to RSD in adults, adolescent girls are affected more commonly, and have involvement of mainly the lower limb in up to 70% of cases.” Scintigraphic findings in the cold variant of RSD include photopenic abnormalities on the delayed scan and hypoemia on the immediate blood flow and blood pool phase. The abnormality can be recognized in children who have open epiphyses by the incongruence of the involved epiphyseal activity compared with remote ipsilateral and contralateral epiphyseal plate activity (Fig. 19).37 Pathophysiology of RSD is believed to be multifactorial. Earliest theories have described reverberating circuits in internuncial neuron pools of the spinal cord. Others pro-

posed the pain is caused by activation of sensory fibers by sympathetic efferents. Because not just peripheral nerve damage but minor trauma can be causative for RSD others proposed that minuscule peripheral nerve twigs could be damaged in soft tissue injury and form artificial synapses. Based on experimental evidence in nerve injury it has been suggested that abnormal firing of peripheral nerves because of increased sensitivity could be causative.17 Treatment has varied over the years. Although mainly supportive, sympathetic blockade can help relieve symptoms, particularly in adults. In children, the use of steroids, physical therapy, transcutaneous nerve stimulation, and supportive and psychological care have all been Aggressive analgesic therapy has been used for therapy including the use of opioids and nerve blocks. This syndrome is often mentioned in the anesthesia literature when discussing chronic pain relief and its Because it has a more benign and clinical course in children, sympathetic blockade is not often performed. MUSCULOSKELETAL TUMOR IMAGING AND THERAPEUTIC RESPONSE ASSESSMENT

Scintigraphic examinations can be used for staging, metastatic work-up, surveillance follow-up, therapeutic response assessment, and treatment of musculoskeletal tumors in children. Musculoskeletal tumors that are routinely evaluated include osteogenic sarcoma, Ewing’s sarcoma, rhabdomyosarcoma, neuroblastoma, and lymphoma, and occasionally leukemia. These tumors can be evaluated with standard bone scanning agents, such as

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 17. A 14-year-old boy had a left slipped capital femoral epiphysis (SCFE), which was pinned. Because of the marked degree of slip posteriorly and medially, there was concern for the vascularity of the femoral head. Three-phase images demonstrate hypoemia on the blood pool images (A, arrows) and photopenia in the region of the left femoral head on the AP and frog lateral pinhole views (B, arrowheads) consistent with avascular necrosis. These additional delayed views better delineate the abnormality than the whole body images (C).

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Figure 18. Six-week-old infant with suspected nonaccidental injury. Blood pool whole body (A) and oblique (B) images (RAO [left], LAO [right]) demonstrate hyperemia in the costochondral cartilage area on the left (arrows). C,The delayed SPECT MIP images (transverse [Ieff], sagittal [rnidd/e], coronal [right]) confirm increased activity in this area. No abnormality was noted on chest radiograph. RAO = right anterior oblique; LAO = left anterior oblique.

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

Figure 19. Cold reflex sympathetic dystrophy (RSD) in a 9-year-old girl who experienced pain in her right ankle after running. Initial radiographs were normal. A, There is hypoemia on blood pool images of the right lower extremity. B, The entire right lower extremity is relatively photopenic compared with the left on delayed whole body images. The involved epiphyseal plates are decreased in activity compared with the other noninvolved epiphyseal plate activity. Follow-up radiographs demonstrated osteopenia of the ankle.

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MDP. Tumor-specific radiopharmaceuticals, such as gallium 67, thallium 201, Tc 99m sestamibi, metaiodobenzylguanidine, octreotide, and PET imaging using 2-[fluorine-l8]-fluoro2-deoxy-D-glucose (FDG), have led to new approaches to the management of these tumors in children. Strontium 89 and samarium 153 are being evaluated for pediatric use in 50 the treatment of painful bone meta~tases.'~, Primary malignant bone tumors, such as osteogenic sarcoma, Ewing's sarcoma, and rhabdomyosarcoma involving bone, appear as intense tracer uptake on skeletal scintigraphy with Tc 99m MDP standard bone scans. In osteogenic sarcoma there may also be soft tissue extension of the tumor detected. Rarely, some malignant lesions appear photopenic. MDP scintigraphy is still the appropriate way to survey the skeleton for extent of disease including metastatic or multifocal disease including skip lesions. An extended pattern of diffuse increased uptake can occur in other bones in the same extremity as the lesion, particularly in the adjacent joints. This is believed to reflect hyperemia or altered gait. In osteogenic sarcoma, pulmonary metastases are more common than bone metastases. Pulmonary metastases can show uptake of Tc 99m bone-seeking radiopharmaceuticals, but the sensitivity for uptake is much less than the sensitivity for metastatic disease detected with CT scan. Increased Tc 99m MDP activity not caused by metastatic disease may be found after amputation of a lower limb and fitting of a prosthesis at various sites to include the stump tip, in the ipsilateral hip joint and sacroiliac joint, in the soft tissues surrounding the prosthesis, and diffusely in the entire limb because of altered biomechanical stress. Allograft limb reconstruction following limb-sparing surgery for osteogenic sarcoma shows persistent increased Tc 99m activity at the junction of the allograft and normal bone. Persistently decreased Tc 99m MDP activity is seen in the graft cortical bone and variable uptake is noted at the periphery of the graft. Persistent intense activity at an amputation site after 6 months usually sigrufies recurrent disease. The flare phenomenon as a cause for increased MDP bone activity can be seen in osteogenic sarcoma. The introduction of the use of colony-stimulating factors to reduce myelotoxicity in patients on chemotherapy has been noted to cause a pattern of nonspecific increased activity in the axial skeleton or juxtaarticular areas on MDP bone scintigraphy.28,59

Histologic response assessment is one of the best predictors of overall survival in tumors, such as osteosarcoma and Ewing's sarcoma.24,41,46 Good histologic responders may have an overall survival of approximately 90%, whereas poor histologic responders may only have a 50% survival rate. This assessment is made on the histologic specimen at the time of definitive surgery, either limb salvage or amputation after a course of neoadjuvant chemotherapy. Thallium 201 and Tc 99m sestamibi have been used as surrogate markers for the noninvasive assessment of histologic response in osteogenic sarcoma. The most important factor in the use of scintigraphy for histologic response assessment and detection of residual tumor is the determination of baseline tumor avidity for the specific radiopharmaceutical. The determination of baseline tumor avidity is best performed at the time of initial staging for all suspected tumors to minimize the influence of tissue distortion and inflammation after biopsy or surgery. Histologic tumor response assessment relies on the finding of a decrease in thallium uptake between pretreatment and post-treatment scans to indicate good tumor histologic response. Poor tumor histologic response shows persistence of abnormal radiopharmaceutical uptake (Fig. 20). Scintigraphic tumor response can be assessed visually, and with semiquantitative ratios. A visual grading system to compare lesion uptake with cardiac uptake can be used. Lesions are assessed for the pattern of activity whether margins are focal or diffuse in uptake, whether the uptake pattern within the lesion is homogeneous or donut, and if the extent of involvement is in bone alone or involves both bone and soft tissue. Semiquantitative methods using region-of-interest methods for calculation of tumor to nontumor ratios are routinely performed. Both thallium 201 and sestamibi accumulate in metastatic lesions of osteogenic sarcoma. These varying patterns may also relate to response but multicenter trials are still ongoing to determine a correlation. The mechanisms of localization of thallium 201 and Tc 99m sestamibi are very different. Thallium 201 and Tc 99m sestamibi may be useful for assessing tumor histologic response in primary and metastatic bone and soft tissue tumors with both showing accumulation in viable tumor, but less so in inflammatory conditions and not appreciably in necrotic tissue. Thallium 201 has a multifactorial mechanism

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Figure 20. Thallium scintigraphy in two children with osteogenic sarcoma. The upper row are images showing a good response to neoadjuvant chemotherapy as assessed by thallium scintigraphy on two different occasions. One examination was performed at the time of diagnosis prechemotherapy (left)and then repeated just before definitive surgery (right) after neoadjuvant chemotherapy. The prechemotherapy images show intense TI-201 activity in the tumor in the distal right femur. The presurgical images show decrease in TI-201 activity. Tumor ratios listed below their respective images show a decrease on the two examinations. The bottom row of images are examples of a poor thallium response to neoadjuvant chemotherapy in a child with osteogenic sarcoma of the distal left femur. Note the persistence of thallium activity in the tumor and increase in tumor ratio between prechemotherapy and presurgical thallium scans.

of tumor localization primarily based on an active ATPase energy-dependent sodium-potassium pump. In contrast to thallium, uptake of Tc 99m sestamibi is not mediated by the Na-K ATPase-dependent pump, but by a process of passive diffusion across the cell membrane. The equilibrium intracellular concentration of sestamibi has also been found to be inversely related to the degree of expression of P-glycoprotein, and hence a marker for multidrug resistance.a The clinical signifi-

cance of this finding relative to uptake patterns in musculoskeletal neoplasms has not been validated. Thallium 201 activity is seen normally in choroid plexus of lateral ventricles, eyes, salivary glands, thyroid, heart, liver, stomach, large bowel, kidneys, testes, and uniform muscle uptake in all muscle group^.^ Rapid blood clearance and rapid tumor uptake occur after the intravenous injection of both thallium 201 and Tc 99m sestamibi. Tc 99m

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sestamibi activity is seen in choroid plexus, lacrimal glands, salivary glands, thyroid, heart, lungs, liver, gallbladder, bowel, spleen, kidneys, and skeletal muscle.66Sestamibi has minimal bone marrow uptake that is not seen with thallium, faster excretion by the liver through the hepatobiliary system, and more intestinal and renal uptake. Because of the increased renal uptake more urinary bladder activity may be a problem when assessing pelvic tumors. In the presence of pulmonary congestion thallium but not sestamibi is seen in lungs because of diffusion into the extravascular space.’ An 18-FDG-PET may also be helpful in monitoring tumor histologic response. In tumors treated with combined radiotherapy and hyperthermia, well-defined regions of absent uptake developed within responsive tumors, correlating pathologically with necrosis. Following treatment, a peripheral rim of 18-FDG accumulation has been found to correlate pathologically with the formation of a fibrous pseudocapsule. In tumors treated with chemotherapy, 18-FDG accumulation decreased more homogeneously throughout the tumor in responsive cases. 18-FDG uptake has been shown to reflect more accurately viable metabolically active tumor. PET may also detect metastatic foci, but occasionally nonspecific uptake not caused by malignant disease may show increased uptake on a whole-body PET scan.21,31 MDP bone scintigraphy in Ewing’s sarcoma is important in initial staging of the tumor and for following patients after therapy. Scintigraphy at presentation commonly shows intense uptake of radiopharmaceutical in the lesion. The uptake is usually homogenous (in contrast to osteogenic sarcoma, which may be patchy) with poorly defined margins. Ewing’s sarcoma may show metastases at diagnosis. Skeletal metastases developing before or at the same time as pulmonary metastases can be detected by bone scintigraphy. Soft tissue and pulmonary metastatic disease of Ewing’s sarcoma are not detected on MDP bone scintigraphy. MDP uptake can be affected by nonspecific factors other than tumor activity. There may be marked decrease in uptake 3 to 4 months after treatment with radiation therapy. Intense focal uptake at tumor site within 3 to 4 months after treatment may be caused by tumor recurrence or complications, such as infection or pathologic fracture. An MDP bone scan of primary lesion site provides little information to predict long-

term survival or disease progression in patients with nonmetastatic Ewing’s sarcoma. Scintigraphy with thallium 201 more reliably shows histologic tumor response. Ewing’s sarcoma exhibits similar findings to osteogenic sarcoma on thallium 201 scintigraphy. Pretreatment uptake of thallium 201 is found in all extremity tumors. Because of splanchnic uptake, pelvic tumors may have equivocal uptake. The use of SPECT and imaging the pelvis soon after injection to decrease the effect of splanchnic uptake improve sensitivity. Because there is not often surgical resection of the primary site, thallium may potentially provide more specificity for the presence of viable tumor compared with follow-up bone scintigraphy. Metastatic disease can be seen with thallium 201 but sensitivity is not available as yet in any large pediatric series. As with osteogenic sarcoma, some work is progressing with the use of PET imaging in children with Ewing’s sarcoma. Ewing’s sarcoma FDG-PET has been reported in one case to be more sensitive than skeletal scintigraphy in detecting bone marrow metastasis. In followup, FDG-PET was better in the assessment of response to therapy.55 The staging and noninvasive response assessment in rhabdomyosarcoma is challenging because of its multifocal behavior. The tumors often accumulate Tc 99m MDP because of hypervascularity. Local bony involvement can be distinguished with 95% accuracy. Bone scans alone, however, do not detect soft tissue involvement by primary and metastatic disease in all cases. Thallium 201 tumor scintigraphy can be helpful in soft tissue tumors for assessment of primary and metastatic disease and response to therapy. Mild to marked thallium 201 uptake in rhabdomyosarcoma has been described in child ~ e nSerial . ~ ~ scans with assessment of change in tumor ratios can be helpful with assessing treatment response. FDG-PET has been reported to have some success in distinguishing benign soft tissue masses from malignant lesions of soft tissue sarcoma.27FDG-PET relative uptake is found to correlate with the grade of tumor with high-grade lesions having higher uptake. Some difficulty is reported in discriminating low-grade malignant uptake from benign lesion uptake. PET scanning in soft tissue tumors may eventually play a role in the assessment of nondiagnostic biopsy results by localizing the highest metabolically active site for biopsy or surgical excision. Some nonspecificity of uptake can occur

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

with uptake of FDG in granulation and fibrous tissues. Because of the low yield of MDP bone scintigraphy and unknown yield of tumor-specific radiopharmaceuticals, such as thallium 201 in head and neck rhabdomyosarcoma, the routine use of scintigraphy is not recommended and should be tailored to the clinical symptoms.

PEDIATRIC BONE MINERAL DENSITY AND OSTEOPOROSIS

During childhood and adolescence, the attainment of optimal peak bone mass is of paramount importance and is acknowledged to be an important factor for future bone health. Bone development and mineralization is an elaborate process with multiple requirements: adequate nutrition including protein for osteoid formation; calcium and vitamin D for calcification-ossification and muscle mass; physical activity for remodeling; and hormonal modulation by thyroid, parathyroid, gonadal, pituitary, and growth h0rmones.5~ Optimal bone mass may not be achieved when one or more of these factors is disrupted. There is increasing interest in the topic of bone mineralization in young patients and how it can be assessed best in health and coexisting illness or disease. It is important to remind practitioners of the many diseases and illnesses affecting skeletal growth and development that can also cause osteopenia or osteoporosis. Causes of decreased bone mineral density (BMD) in children are as follows: Gastrointestinal and hepatic intestinal diseases Celiac disease Inflammatory bowel disease Liver disease Cholestatic disease Hepatitis C-associated osteosclerosis Transplantation Gastrectomy Endocrine Graves’ disease Hypothalamic amenorrhea Primary and secondary amenorrhea Diabetes Anorexia nervosa Genetic and metabolic Turner’s syndrome Down syndrome

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Cystic fibrosis Phenylketonuria Malignancy Leukemia Lymphoma Solid tumors Drugs Steroids Cyclosporine Anticonvulsants Chemotherapy Chronic Rheumatic Diseases Juvenile systemic lupus erythematosus Juvenile rheumatoid arthritis Juvenile diabetes mellitus Developmental Idiopathic scoliosis Meningomyelocele Tarsal coalition Constitutional growth delay Transplantation Osteoporosis is characterized by a reduction in bone mass per unit volume, is associated with fragility fractures, and is a major cause of morbidity in late adult life. Osteopenia is taken to refer to a lesser amount of bone loss and is a risk factor for insufficiency fracture and development of subsequent osteoporosis. It is well known that conventional radiographs are insufficient for assessment of bone mineralization because a decrease of up to 40% may be required before change is noticeable. Current noninvasive techniques are used to quantify bone mineral content where qualitative bone abnormalities are generally not present. Although currently DEXA is the most widely used technique for measuring BMD and can estimate bone mass and bone strength, it does not have the ability to assess material properties of a bone; nor does it offer morphologic information about the presence of microfracture or structural damage. The use of qualitative ultrasound may be promising in this regard. Qualitative ultrasound does not measure BMD per se but measures other indices including speed of sound expressed in meters per second and broadband ultrasound attenuation measured in decibels per megahertz. A DEXA has acceptable dosimetry for use in children with the entrance skin dose measured at less than 5 mrem. This is approximately one tenth of the dose received for a chest r a d i ~ g r a p hScanning .~~ time is approximately 3 to 8 minutes to assess L1-L4 depending on the age of the child. Although

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soft tissue thickness in children is variable and less than in adults it has no significant effect on BMD measurements. At this time, central DEXA is viewed as the most desirable measuring device for BMD because of acceptable radiation dose; relatively low cost per examination; and ability to measure sites at risk for fracture including the spine, hip, and total body. Two parameters in BMD must be understood: T-score and Z-score. These are standardized scores that provide a common scale for the purposes of comparison of BMD results. The T-score is the number of standard deviations a patient’s BMD is above or below sex-matched mean reference value of young adults’ BMD. The T-score is a comparison with mean peak bone mass. The peak-adult BMD follows a bell-shaped normal distribution curve. This value helps determine the BMD value that is desirable for that specific patient. The Z-score is defined as the number of standard deviations that a patient’s BMD is above or below age-, sex-, and ethnicitymatched mean reference value. This score helps determine the expected BMD for an individual patient. The T-score can be used for the assessment of fracture risk in postmenopausal women. Z-scores are not used for this fracture risk assessment in the postmenopausal adult female population but can help determine if secondary causes for low BMD need to be identified. Because fracture risk is not the pertinent issue in the childhood population, T-score evaluation is not relevant in children. When evaluating a child’s BMD, the Z-score may be used if there is an appropriate reference data base to determine how an actual individual BMD compares with the expected BMD. Conversion factors exist for assessment of bone mineral measurements taken on different manufacturers’ scanning devices. It is important when evaluating bone density measurements as compared with a published database that the value used for the comparison is corrected for the same device and the precision of the scan device. The use of standardized scores is limited by differences in manufacturer’s reference data. To this end, international standardization has been adopted to recommend appropriate cross-calibration between the three major manufacturers of bone densitometry devices. Standardized posteroanterior spine (L2-L4) BMD (sBMD) results expressed in units of milligram per centimeter squared are derived

from the manufacturers’ measured BMD figures in units of gram per centimeter squared corrected according to the following formula? X 1.07551; Hologic: sBMD = 1000IBMDHologic Lunar: sBMD = 1000[BMDL-, X 0.95221; Norland: sBMD = 1000IBMDNorlmd x 1.07611 For the total hip standardized BMD equations are: X 1.0881; Hologic: sBMD = 1000 [BMDHolOgic Lunar: sBMD = 1000[BMDL,,, X 0.9791; x 1.0121 Norland: sBMD = 1000[BMD,,,,,,

Even with conversion to sBMD there is an estimate error of 2% to 5%, requiring greater changes in BMD before an interval change is considered statistically significant. The smallest change in BMD that can be regarded as statistically significant is dependent on the precision error of the scanner on which the measurement is made. The precision error is calculated for a specific densitometer when setting up a bone density laboratory and again when changes are made to the technology staff or equipment.26These institutionspecific precision error values for a densitometer should be available to the physician who is reporting the bone density examination and should be taken into account when evaluating serial examinations in an individual patient. Densitometry measurements by DEXA in children are confounded by the fact that this technique uses areal measures (gram per centimeter squared); increases in BMD in growing children may mainly be caused by increase in the size of bones; or bone size in itself may be an independent variable of bone strength. Boot et all1 found that height, calcium intake, and physical activity had no significant effect on spinal volumetric BMD, whereas these factors did affect spinal BMD. They postulated that the changes are caused by changes in bone size. Assessment of both bone size and bone volume (gram per cubic centimeter) is important when both are changing but volumetric data are difficult to obtain because of the higher radiation dose involved in quantitative CT. Volumetric BMD assessed in grams per cubic centimeter is assessed by quantitative CT. It is possible that peripheral quantitative CT may provide helpful information. Also, it may be more difficult to detect small changes in BMD when skeletal growth is rapid.30 Normative databases for children are available for hip, spine, and total body. Accuracy

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE

for each site measured should be known on each machine and for each technologist who performs the examination. For a change on serial measurements to be considered significant it should exceed 2.77% times the established precision error (International Society for Clinical Densitometry, unpublished data). Generally, accuracy and precision are greater when more sites are measured. This may be impractical in children who are old enough to cooperate and where spine measures may be adequate. Young children under the age of 9 or so may be better served by whole-body measurements because small areas at the hip, spine, and so forth may limit accuracy and precision. Also, low levels of calcification or ossification may make determination of margins or regions of interest difficult. Previously, the lengthy scanning times required for DEXA measurements of the lumbar spine and femoral neck made this an impractical study to perform in very young children. An additional disadvantage is decreased precision in young subjects because of decreased density and small bone size making measurements technically more difficult. Currently available units offer faster examinations and allow determination of total body calcium, which is also an important parameter in children. The expected rates of change should be factored into the decision of significance of serial measurements. These may be extrapolated from normal data growth curves for healthy children but expected rate of loss because of coexisting illness and other risk factors may not be known. Rates of bone loss are expected to be more rapid. Six-month monitoring intervals may be reasonable. Recommendations for pharmacologic intervention in children have not yet been established. It is not yet known whether bone loss rates vary widely during illness or treatment in children; nor how much they vary from child to child during the same illness or treatment. Nevertheless, serial measurements are important for following the natural history of disease and therapy. Recognition of osteopenia in the young population is a remaining challenge in the field of bone densitometry. At this time, there are no universally accepted normative databases for the assessment of bone development in children and adolescents. Care must be taken in applying databases that are complicated by factors described previously. Baseline BMD value determinations in children with significant coexisting problems or dis-

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eases should be undertaken and followed at regular intervals. Spacing of examination intervals depends on methodology used, expected results, and the effect of these determinations on management. In children with multifactorial risks, measures should be correlated with other important indicators of growth and maturation. The Z-score at which intervention should be undertaken is not defined for all ages and all conditions. More long-term studies are needed to understand fully the effect of steroid use on BMD and long-term fracture risk in children. Although many groups and subgroups of children and adolescents are at risk for osteoporosis and osteopenia, it is not clear which groups are at risk on a limited as opposed to a progressive basis. Institutions that treat ill children are taking a closer look at the issue of osteopenia and failure to achieve peak bone mass. Diminished bone mass in children is a cause for clinical concern and warrants evaluation, intervention, and where possible prevention. Currently, DEXA provides an acceptable method for measuring BMD in children. Further long-term evaluation of children who are healthy and children who are at risk for future osteoporosis is likely to prove valuable. References 1. Abdel-Dayem HM, Scott AM, Macapinlac HA, et al: Role of T1-201 chloride and Tc 99m sestamibi in tumor imaging. In Freeman LM (ed): Nuclear Medicine Annual. New York, Raven Press, 1994, pp 181-234 2. Aigner RM, Fueger GF, Vejda M: Follow-up of osteomyelitis of infants with systemic serum parameters and bone scintigraphy. Nuklearmedizin 35:116, 1996 3. Aigner RM, Fueger GF, fitter G: Results of threephase bone scintigraphy and radiography in 20 cases of neonatal osteomyelitis. Nucl Med Commun 1720, 1996 4. Alazraki NP: Radionuclide imaging in the evaluation of infections and inflammatory disease [review]. Radiol Clin North Am 31:783, 1993 5. American Academy of Pediatrics Committee on Drugs: Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 89:1110, 1992 American Academy of Pediatrics Committee on Drugs: Reappraisal of lytic cocktail/demerol, phenergan, and thorazin (DPT) for the sedation of children. Pediatrics 95:598, 1995 American College of Emergency Physicians: Use of pediatric sedation and analgesia. Ann Emerg Med 29:834, 1997 Ash J, Gilday DL: The futility of bone scanning in neonatal osteomyelitis: Concise communication. J Nucl Med 21:417, 1980

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9. Atkins HL, Budinger TF, Lebowitz E, et al: Thallium201 for medical use. Part 3: Human distribution and physical imaging properties. J Nucl Med 18:133, 1977 10. Blau EB: Reflex sympathetic dystrophy syndrome in children. Wisconsin Medical Journal 83:34, 1984 11. Boot A, De RIdder MAJ, Pols HAP, et al: Bone mineral density in children and adolescents: Relation to puberty, calcium intake, and physical activity. J Clin Endocrinol Metab 8257, 1997 12. Bressler EL, Conway JJ, Weiss SC: Neonatal osteomyelitis examined by bone scintigraphy. Radiology 152685, 1984 13. Canale ST, Harkness RM, Thomas PA, et al: Does aspiration of bones and joints affect results of later bone scanning? J Pediatr Orthop 523, 1985 14. Charron M, Brown M, Rowland P, etal: Pain palliation with strontium-89 in children with metastatic disease [see comments]. Med Pediatr Oncol 26:393, 1996 15. Chow LT, Griffith JF, Kumta SM, et al: Chronic recurrent multifocal osteomyelitis: A great clinical and radiologic mimic in need of recognition by the pathologist. APMIS 107369, 1999 16. Conway JJ, Collins M, Tanz RR, et al: The role of bone scintigraphy in detecting child abuse. Semin Nucl Med 23:321, 1993 17. Devor M Nerve pathophysiology and mechanisms of pain in causalgia. J Auton Nerv Syst 7371, 1983 18. Driessens M, Dijs H, Verheyen G, et al: What is reflex sympathetic dystrophy? Acta Orthop Belg 65902, 1999 19. Forster RS, Fu FH: Reflex sympathetic dystrophy in children: A case report and review of the literature. Orthopedics 8:475, 1985 20. Gainey MA, Siege1 JA, Smergel EM, et al: Indium111 labeled white blood cells: Dosimetry in children. J Nucl Med 29:689, 1988 21. Garcia R, Kim EE, Wong FC, et al: Comparison of fluorine-18-FDG PET and technetium-99m-MIBI SPECT in evaluation of musculoskeletal sarcomas. J Nucl Med 371476, 1996 22. Genant HK, Grampp S, Gluer CC, et al: Universal standardization for dual x-ray absorptiometry: Patient and phantom cross-calibration results. J Bone Miner Res 9:1503, 1994 23. Gilday D, Paul D, Paterson J: Diagnosis of osteomyelitis in children by combined blood pool and bone imaging. Radiology 117331, 1975 24. Glasser DB, Lane JM, Huvos AG, et a1 Survival, prognosis, and therapeutic response in osteogenic sarcoma: The Memorial Hospital experience. Cancer 69:698, 1992 25 Glastre C, Braillon P, David L, et a1 Measurement of bone mineral content of the lumbar spine by dual energy x-ray absorptiometry in normal children: Correlations with growth parameters. J Clin Endocrinol Metab 70:1330, 1990 26. Gluer CC, Blake G, Lu Y, et al: Accurate assessment of precision errors: How to measure the reproducibility of bone densitometry techniques. Osteoporos Int 5:262, 1995 27. Griffeth LK, Dehdashti F, McGuire AH, et a1 PET evaluation of soft-tissue masses with fluorine-18 fluoro-2-deoxy-D-glucose. Radiology 182:185, 1992 28. Herrlin K, Willen H, Wiebe T: Flare phenomenon in osteosarcoma after complete remission. J Nucl Med 36:1429, 1995 29. Howman-Giles R, Uren RF, Shaw PJ: Thallium-201 scintigraphy in pediatric soft-tissue tumors. J Nucl Med 36:1372, 1995

30. lohnston CC Jr, Miller JZ, Slemenda CW, et al: Calcium supplementation and increases in BMD in children. N Engl J Med 32782, 1992 31. lones DN, McCowage GB, Sostman HD, et al: Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET. J Nucl Med 371438,1996 32. Kleinman P K Diagnostic Imaging of Child Abuse. St. Louis, Mosby, 1998 33. Kozin F, Soin JS, Ryan LM, et al: Bone scintigraphy in the reflex sympathetic dystrophy syndrome. Radiology 138:437, 1981 34. Laxer RM, Allen RC, Malleson PN, et al: Technetium 99m-methylene diphosphonate bone scans in children with reflex neurovascular dystrophy. J Pediatr 106:437, 1985 35. Mandell GA, Harcke HT, Bowen JR, et al: Transient photopenia of the femoral head following arthrography. Clin Nucl Med 14397, 1986 36. Maurer A, Chen C, Camargo E, et a1 Utility of threephase skeletal scintigraphy in suspected osteomyelitis. J Nucl Med 22:941, 1981 37. McEachem AM, Nadel H R Reflex sympathetic dystrophy: Characteristic findings in children [abstract]. Pediatr Radiol 29:941, 1999 38. Miller JH, Gelfand MJ: Pediatric Nuclear Imaging. Philadelphia, WB Saunders, 1994 39. Mitchell SW, Morehouse GR, Keen WW: Gunshot Wounds and Other Injuries of Nerves. New York, JB Lippincott, 1864 40. Nadel H R Nuclear oncology in children. In Freeman LM (ed): Nuclear Medicine Annual. New York, Raven Press, 1996, p 143 41. ODonoghue JP, Powe JE, Mattar AG, et a1 Threephase bone scintigraphy: Asymmetric patterns in the upper extremities of asymptomatic normals and reflex sympathetic dystrophy patients. Clin Nucl Med 18:829, 1993 42. Oud CF, Legein J, Everaert H, et al: Bone scintigraphy in children with Dersistent Dain in an extremitv. suegesting a1gone;rodystroihy. Acta Ortho;’ Berg 65:364, 1999 43. Pennington WT Photopenic bone scan osteomyelitis: A clinical perspective. J Pediatr Orthop 19:695, 1999 44. Picci P, Rougraff BT, Bacci G, et al: Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing’s sarcoma of the extremities. J Clin Oncol 11:1763, 1993 45. Pintelon H, Jonckheer MH, Piepsz A: Paediatric nuclear medicine procedures: Routine sedation or management of anxiety? Nucl Med Commun 15:664,1994 46. Provisor AJ, Ettinger LJ, Nachman JB, et al: Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children’s Cancer Group. J Clin Oncol 15:76, 1997 47. Resnick D, Niwayama G: Osteomyelitis, septic arthritis, and soft tissue infection: Mechanisms and situations. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, ed 3. Philadelphia, WB Saunders, 1995 48. Rosovsky M, FitzPatrick M, Goldfarb CR, et al: Bilateral osteomyelitis due to intraosseous infusion: Case report and review of the English-language literature. Pediatr Radiol 2472, 1994 49. Rosovsky M, Goldfarb CR, Finestone H, et al: ”Cold spots” in pediatric bone imaging. Semin Nucl Med 24:184, 1994 50. Samarium-153 lexidronam for painful bone metastases. Med Lett Drugs Ther 39:83, 1997

NUCLEAR MEDICINE TOPICS IN PEDIATRIC MUSCULOSKELETAL DISEASE 51. Schauwecker DS: The scintigraphic diagnosis of osteomyelitis [review]. AJR Am J Roentgenol 158:9, 1992 52. Schuster T, Bielek J,Dietz HG, et al: Chronic recurrent multifocal osteomyelitis (CRMO). Eur J Pediatr Surg 6:45, 1996 53. Schwartzman RJ, McLellan TL: Reflex sympathetic dystrophy. Arch Neurol44555, 1987 54. Sherazi Z , Gordon I: Quality of care: Identification and quantification of the process of care among children undergoing nuclear medicine studies. Nucl Med Commun 17363,1996 55. Shulkin BL, Mitchell DS, Ungar DR, et al: Neoplasms in a pediatric population: 2-[F-18]-fluoro-2-deoxy-Dglucose PET studies. Radiology 194495, 1995 56. Silber TJ, Majd M: Reflex sympathetic dystrophy syndrome in children and adolescents. Am J Dis Child 142:1325, 1988 57. Southard RN, Morris JD, Mahan JD, et al: Bone mass in healthy children: Measurement with quantitative DXA. Radiology 179:735, 1991 58. Stabin MG, Gelfand MJ: Dosimetry of pediatric nuclear medicine procedures. Q J Nucl Med 42:95,1998 59. Stokkel MP, Valdes Olmos RA, Hoefnagel CA, et a1 Tumor and therapy associated abnormal changes on bone scintigraphy: Old and new phenomena. Clin Nucl Med 18:821, 1993

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60. Sty JR, Wells RG: Child abuse: Extraosseous abdominal bone imaging uptake. Clin Nucl Med 19:1011, 1994 61. Tan BS, Nayanar V, Mansberg R, et al: Two cases of chronic recurrent multifocal osteomyelitis: Radiological and scintigraphic findings. Australas Radio1 40:437, 1996 62. Traughber PD, Manaster BJ, Murphy K, et al: Negative bone scans of joints after aspiration or arthrography: Experimental studies. AJR Am J Roentgenol 146:87, 1986 63. Treves S T Pediatric Nuclear Medicine. Berlin, Springer, 1995 64. Turpin S, Taillefer R, Lambert R, et al: “Cold” reflex sympathetic dystrophy in an adult. Clin Nucl Med 21:94, 1996 65. Tuson CE, Hoffman EB, Mann MD: Isotope bone scanning for acute osteomyelitis and septic arthritis in children. J Bone Joint Surg Br 76:306, 1994 66. Wackers FJT, Berman DS, Maddahi J, et al: Technetium-99m hexakis 2-methoxyisobutyl isonitrile: Human biodistribution, dosimetry, safety, and preliminary comparison to thallium-201 for myocardial perfusion imaging. J Nucl Med 30:301, 1989 67. Weiss S Sedation of pediatric patients for nuclear medicine procedures [review]. Semin Nucl Med 23:190, 1993

Address reprint requests to Helen R. Nadel, MD, FRCPC Division of Nuclear Medicine Department of Radiology Children’s and Women’s Health Centre of British Columbia 4480 Oak Street Vancouver, BC Canada V6H 3V4 e-mail: [email protected]