orthopedic pathology lower extremities

Orthopedic Pathology of the Lower Extremities: Scintigraphic Evaluation in the Thigh, Knee, and Leg

Elba C.S.C. Etchebehere, Mauricio Etchebehere, Reinaldo Gamba, William Belangero, and Edwaldo E. Camargo

Radionuclide imaging (RI) of the osseous and nonosse- ous structures of the thigh, knee, and leg provide important diagnostic and prognostic information upon which the orthopedic surgeon can base treatment planning and management decisions. 99mTc-MDP scintigraphy is essential in overuse injuries such as stress fractures and shin splints. RI is important in assessing complications of trauma. It is the only imaging modality able to assess the magnitude of physeal stimulus caused by femoral fractures and to predict a favorable or unfavorable outcome of leg length by semiquantitative analysis; SPECT imaging can detect and locate decreased metabolism associated with posttraumatic closure of the physeal plate to predict growth arrest and deformities. Three-phase bone imaging (TPBI) is essential to differentiate hypervascular from

avascular nonunions and fol low delayed union. In osteonecrosis of the knee, bone scintigraphy precedes radiograph changes even in stage I of the disease. 9~"Tc-MDP and sSmTc-HIG imaging are powerful tools in determining the outcomes of osteoarthritis and rheumatoid arthritis, respectively. Bone scintigraphy can also detect chronic ligament and acute and chronic meniscal lesions. The combined use of TPBI, gallium-67 citrate imaging, and indium-111 or sSmTc-HMPAO labeled leukocytes is important to diagnose and differentiate acute from chronic osteomyelitis, and to detect infected knee prostheses. Thallium-201 chloride imaging and 9SmTc-sestamibi imaging have an important role in the assessment of tumor response to chemotherapy and in the quantification of tumor viability. Copyright �9 1998 by W.B. Saunders Company

B ECAUSE OUR LOWER extremities are used in almost all activities of daily living, it is not

surprising that they are so often involved in such a wide range of traumatic and stress-related injuries. This report describes the scintigraphic findings in problems of the thigh, knee, and leg, but will also emphasize the clinical and radiologic imaging correlates that the referring orthopedist must consider.

OVERUSE INJURIES OF THE FEMORAL, TIBIAL, AND FIBULAR SHAFTS

Shin Splints

The American Medical Association's Standard Nomenclature of Athletic Injuries defined "'shin splint" in 1966 as "pain and discomfort in the leg from repetitive running on hard surfaces, a forcible use of the foot flexors; diagnosis should be limited to musculotendinous inflammation excluding fracture and ischemic disorders." BaW suggested that shin splints should be used generically, but this is not widely accepted. Other terminologies such as medial tibial syndrome and medial tibial stress syndrome are currently being used as synonymous of shin splint. 2"4 Common sites of exercise-induced tibial pain are the posteromedial and anterolateral aspects of the leg, corresponding to the posterior and anterior compartments, respectively. The "soleus" and the "flexor digitorum longus" muscles are major contributors to shin splint, while the "tibialis posterior" contributes little to the occur-

rence of shin splints. 5 Radiographic findings in patients with shin splint are normal.

Three phase radionuclide bone imaging (TPBI) findings are characterized by normal blood flow and blood pool and linear, faint tracer uptake in the posteromedial 6 or anterolateral aspects of the tibial cortex on delayed images (Fig 1A). The normal blood pool correlates with the lack of periosteal inflammation on histopathology while the increased metabolic activity in the radionuclide delayed images is due to disruption of the periosteum (Sharpey's fibers), with new bone formation. 6 Pa- tients with normal scintigrams are more likely to exhibit compartment syndrome while an abnormal scintigram is more likely to represent shin splint. 7 Compartment pressures are not elevated in shin splint. Fasciotomy usually does not improve pain in these patients and therefore is not indicated 2,3,8,9 except in rare circumstances. 4

Stress Fractures

Stress fracture is an overuse injury caused by muscle forces acting together with bending and

From the Division of Nuclear Medicine, Department of Radiology, and Department of Orthopedics and Traumatology, Campinas State UniversiD' (UNICAMP), Campinas, Brazil.

Address reprint requests to Elba C.S.C. Etchebehere, MD, Servis de Medicina Nuclear, Hospital das CKnicas da UNICAMP, Caixa Postal 6142, 13081-970 Campinas, Brazil.

Copyright �9 1998 by W.B. Saunders Company 0001.2998/98/'2704-000458.00/0

Seminars in Nuclear Medicine, Vol XXVIII, No 1 (January), 1998: pp 41-61 41

42 ETCHEBEHERE ET AL

Fig 1. An athlete complaining of pain in the left leg and tenderness in the right leg. (A) 2-hour delayed images showed, in the anterior view, a faint line of increased tracer uptake in the distal third of the right tibial diaphysis which corresponded to a shin splint and a focal, fusiform and intense tracer uptake in the mid third of the left t ibial diaphysis which corresponded to a stress fracture. (B) The lateral view was best for demonstrating the transverse extent of the stress fracture, which in this case corresponded to a grade II bone involvement (20-40%).

impact forces on a bone not adapted to the loading. 6,1~ Stress fractures of the tibia and fibula occur primarily in young athletes, especially runners, ballet dancers, and military recruits, with location related to type of strain. In a group of 700 military recruits with stress fractures, Morris and Blicken- staff 11 found that 17% of the fractures occurred in the tibia (usually proximal third, posteromedial aspect) and only 1% in the fibula. Female athletes with a history of oligomenorrhea 1~ and women with restrictive eating patterns are more prone to stress fractures. 12 In ballet dancers, these frature tend to be more common in the middle third of the tibia and in runners in the distal fibula just above the ankle. The clinical course usually begins with an insidious soreness in the leg, only during exercise. After a while the pain increases and begins to occur after regular walking and even at night. Physical examination will disclose tenderness over the site of the fracture.

Radiographs in the first 2 to 4 weeks of onset of the symptoms may appear normal l~ when TPBI is already diagnostic. 6,13 Later in the course of the injury, radiographs may demonstrate a narrow radiolucent line involving one or both cortices, then evolving to periosteal and endosteal thickening. These radiographic changes show evidence of

fracture repair rather than the fracture itself. A radiolucent cortical fracture line is usually not seen. The later radiographic appearance may be mislead- ing, especially in the pediatric group, and differen- tiation from osteomyelitis, osteoid osteoma, bone malignancy is imperative.

Increased radionuclide bone activity occurs early in the course of a stress fracture, and as it heals, activity diminishes and finally disappears. An experimental study inducing stress fractures in the tibial diaphyses of 31 rabbits demonstrated that at the sites of positive bone scans, microscopic damage was already present. 14

A scintigraphic staging (I to V) for stress fractures as an aid to patient management has been proposed by Zwas et al. 15 In stage I there is a small, thin, linear, localized area of mild radiotracer activity, confined to the bone cortex, corresponding to minimal periosteal reaction with less than 20% bone involvement. Stage II fractures extend further along the cortical bone, characterized by moderate linear tracer uptake compromising between 20% and 40% of the width of the bone, representing moderate periosteal reaction (Figs 1A and 1B). Stage III fractures involve the medullary bone and are characterized by a moderate, wide, fusiform, tracer uptake occupying 40% to 60% of the width

SCINTIGRAPHIC EVALUATION OF THE LOWER EXTREMITIES 43

of the bone. Stage IV fractures appear as an area of markedly increased radiotracer uptake occupying 60% to 80% of the width of the bone. Stage V fractures, or complete stress fracture, involve the entire width of the bone and are characteristically transcortical-medullary fusiform lesions with intense tracer uptake. Radiographic changes can be found in lesions classified as stages III or higher, some in stage II and none in stage 1.13 Nonatheletic repetative biomechanical loading from any cause can lead to stress fractures. ~6 Multiple diaphyseal sclerosis (Ribbing's disease), a rare disorder of the long bones, may simulate the radiographic and scintigraphic findings of stress fracture, chronic infection, and bone-forming neoplasia.17 The radiographs usually show benign-appearing endosteal and periosteal cortical thickening and linear radionuclide uptake confined to the shaft of all involved bones. Clinical studies using magnetic resonance imaging (MRI) for the diagnosis, grading, and management of stress fractures have been controver- sial. ]8d9 Large series to determine the value added of MR/ and then to compare the efficacy and outcomes with bone scintigraphy which remains the imaging standard of reference have not been done. As Piffanelli et al 2~ clearly stated " . . . three-phase bone scintigraphy yields objective in- format ion. . , where clinics and radiology are often negative . . . . allows differential diagnosis between soft tissue lesions and bone fractures even at an early stage and allows the resumption of sports activity to be planned."

COMPLICATIONS OF TRAUMA

Assessment of Physeal Stimulus Caused by Femoral Fractures

Femoral shaft fractures usually occur in the middle third of the diaphysis and are the result of violent force and, in children, may also occur by child abuse or be secondary to metabolic bone disease. The surgeon must be aware of complications such as angular and rotational deformities and discrepancy of limb length which is the most common management problem in these children. On average, the magnitude of the overgrowth of the fractured femur is about 6.9 mm, but it is less prominent in children under 4 and above 7 years of age. 21 Overgrowth is difficult to predict 22,23 and the surgeon manages these fractures with superimposi- tion of fragments in order to maintain limb lengths within 1 cm of each other. Three phase bone

scintigraphy plays an important role in the prediction of possible growth complications.

The growth acceleration following fracture is caused by stimulation of the epiphyseal growth plate, which has been documented in our laboratory by three phase bone scintigraphy. 24 In the first 24 hours that follow a fracture of the femoral shaft, there is normal blood flow and activity in the delayed images to the entire femur, including the fractured site. After the first 24 hours blood flow and activity in the delayed images start to increase at the fracture site as well as in the distal end growth plate of the fractured femur. We have found that when blood flow and activity in the delayed images of the distal end growth plate of the fractured femur persist high for up to 12 months, the overgrowth occurs and the outcome is favorable (leg lengths will be equal). In contrast, when there is little or no increased activity in the distal end growth plate of the fractured femur the patient usually has an unfavorable outcome. Activity at the fracture site in the delayed images usually de- creases before a decline of the activity of the ipsilateral distal end growth plate can be detected. After approximately 18 months, activity in the distal end of the growth plate is normal . 24

In our laboratory, these studies for evaluation of epiphyseal growth plate stimulation are interpreted by visual and semiquantitative analyses. The latter consists of calculating the ratio of the geometric means of the activities of the distal epiphyseal plates of the fractured and the contralateral femurs. The mean and standard deviation of the ratio fractured femur/contralateral femur in a group of 20 patients was 1.185 -+ 0.14, significantly higher than in a control group (1.013 +_ 0.14; P < 0.01). 24

In 80% of the patients the ratio was higher than 2.58 standard deviations above the mean of the control group. The visual analysis consistently demonstrates increased activity in the 10 minute equilibrium image and increased tracer uptake in the 2-hour delayed images of the distal growth plate of the fractured femurs (Fig 2). With information about the prognosis of the fracture, the orthopedic surgeon can alter the course of management of the child with unfavorable scintigraphic findings.

Posttraumatic Premature Closure of the Physeal Plate

Injury involving the growth plate may cause disruption of epiphyseal vessels which affects the


Fig 2. A 9 year-old boy with fracture of the mid-third of the right femoral diaphysis. Three-phase bone scintigraphy showed increased blood pool (left image) and diffuse delayed tracer (right image) uptake in the distal growth plate of the right femur which corresponded to the overgrowth stimulus secondary to the fracture, The ratio fractured femur / contralateral femur was 1.27. The boy had normal femoral compensation,

resting cartilage and the zone of proliferation. A bridge of fibrous tissue may then develop across the physis and subsequently be replaced by bone and impair longitudinal growth. 25 Approximately 15% of all fractures in children involve the physis. Damage to the growth cartilage is a major problem to the orthopedic surgeon because it may occur during the trauma itself or during reduction. Despite a perfect anatomical reduction, angular deformity, one of the most common complications of physeal fractures, 26 may develop. Early diagnosis and management of physeal growth impairment is an ongo- ing orthopedic challenge. Salter and Harris 27 have classified physeal injuries into types I through V, according to the mechanism of injury (Fig 3). In some injuries, such as types I and II, growth usually is not impaired, whereas in types III through V, growth impairment may occur. 26 The challenge of diagnostic imaging modalities is to detect early vascular changes that precede bone bridge formation. 28 Gross abnormalities are quite obvious on plain radiographs, but subtle damage to the physis is only recognized much later, when growth arrest has already occurred. Computerized tomography (CT) is useful for late surgical management. 28

TBPI plays an important role in the early detection and semiquantitative analysis of vascular abnormalities and physeal dysfunction. 29 Symmetrical positioning with anterior and posterior data acquisi- tion is required. Normal growth plates demonstrate homogeneous distribution of blood flow and radiotracer uptake. Immediately after injury to the

growth plate, increased blood flow, and radiotracer uptake may be present. Complete closure of the physis is characterized by reduction of blood flow and radiotracer uptake. Bone SPECT imaging plays an important role in the detection of closure in the central portion of the growth plate. The coronal views in particular increase the sensitivity for detection of reduction of metabolism and help the orthopedic surgeon to predict growth arrest and deformities (Fig 4).

MRI images provide superb anatomical information of the growth plates. MRI is indicated to detect fractures and vascular abnormalities after acute trauma when radiographs are normal, and to give information on the size, location, and shape of bony bridges for preoperative planning and treatment. The use of Gd-DTPA in experimental studies has been shown to enhance regions of the physis where there is no bone formation, while bone bridge maturation shows decreased Gd-DTPA accumula- tion3 8

Delayed Union and Nonunion Fractures

Union is considered delayed when healing has not advanced at the average rate for the location

I ' r iPE I ! TYPE Ul

physis

epiphysis

••u• t t t

crushing force

Fig 3. Salter-Harris types of injuries. Type I: complete separation of epiphysis from shaft through the hypertrophic cell zone of the growth plate; no bone is actually fractured and the periosteum may remain intact. Type I1: fracture extends partially across the deep layer of the growth plate and partially through the metaphysis, remaining a triangular portion of the metaphysis attached to epiphyseal fragment. Type II1: intraarticular fracture through the epiphysis across the deep zone of the physis to the periphery; open reduction and fixation are often necessary. Type IV: fracture line extends from the articular surface through the epiphysis, physis and metaphysis. If the fractured segment is not perfectly realigned with open reduction then osseous bridge may occur resulting in partial growth arrest. Type V: a severe crushing force is transmitted across the epiphysis to the growth plate. Radio- graphic diagnosis is difficult since displacement may not occur. Growth plate may be damaged resulting in partial growth arrest and angular deformity,


Fig 4. A 10-year-old boy with fracture of the left femoral diaphysis and a Salter-Harris type I lesion in the proximal 9rowth plate of the left tibia. (A) Planar images showed focally increased tracer uptake in the mid third of the left femur correspondin 9 to the fractured site and markedly increased diffuse tracer uptake in the distal 9rowth plate of the femur corresponding to overgrowth stimulus secondary to the fracture. Note the apparently normal diffuse and symmetric tracer uptake in the proximal growth plate of the left tibia, where the Salter-Harris lesion occurred. (B) SPECT images cleady demonstrated decreased metabolism in the medial portion of the proximal growth plate of the left tibia. Note the homogeneous and intense uptake seen in the distal 9rowth plate of the left femur due to overgrowth stimulus. This patient had normal femoral compensation, with deformity.

B

and type of flacture) ~) In the Io\~er extremities. w,'eight bearing in a ~ alking cast accelerates lulioi1. but after 4 to ! 2 weeks of conserx atix e treauucm, iF the fracture is still ununited, a decision must be made to consider treatment of a nonunion fracture.>

Nonunion fractures have been defined as estab- lished when a minimum of 9 months have elapsed since injury and the fracture shows no visible

progression off healing for 6 montl>, Tho final

~,tatus of a nimunion fracture is the formation of a pseudarthrt>,i,. There are t~ o main types of pseudarthrosis el nonunion~: h) per\ascular (h>pertro-

phic) Lind a\ ascular (atrophic). In h) per\ascular pseudarthrosis the ends of the fragment~ are hyper- \ ascular and capable of a biologic reaction. TBPI ,,viii demonstrate increased blood flow. blood pool.


and radiotracer uptake in the fragments (Fig 5). These findings usually lead to a simpler treatment with stable fixation of the fragments. In contrast, in avascular pseudarthrosis, the ends lack blood, are inert and thus, incapable of a biologic reaction. In avascular pseudarthrosis TPBI will reveal reduced blood flow, blood pool, and radiotracer uptake in the fragments. This type of pseudarthrosis requires longer treatment for consolidation, using extemal fixation or decortication and bone grafting for healing. In a retrospective analysis of 77 patients treated for nonunion fractures, hypervascular nonunions of the femur healed after 9.5 months on the

average while for the tibia, the healing process took 10 months on the average. The duration of treatment of avascular nonunions was much longer and required up to 20 months for the femur and 16 months for the tibia. 31 Because of the frequency of severe open tibial fractures, the tibia is the most frequent site of nonunion. In a review by Green et al, 32 76% of 72 nonunions of the tibial shaft occurred after open fractures and 56% were infected.

If infection is present, the complexity of treatment of nonunion fractures increases. The nuclear physician must keep this problem in mind, since TPBI will demonstrate a marked increase in blood

Fig 5. Hypervascular pseudarthrosis of the right tibia with typical focally increased blood flow (A), blood pool (B) and increased radiotracer uptake (C) at the fracture site. This pattern resembles that of an infection, and, therefore, labeled leukocytes would be indicated should infection be suspected.


flow and in the 2-hour delayed images in both types of infected pseudarthrosis and in noninfected hypervascular pseudarthrosis. Therefore, careful differential diagnosis must be made when infection is suspected. A gallium-67 citrate scintigraphy increases the likelihood of infection if the gallium-67 uptake exceeds that of [Tc-99m] MDP. 33 However, the most specific tracers for infection are labeled leukocytes. In a study of 102 sites of delayed unions or nonunions by Nepola et a134 tO determine whether the diagnosis of osteomyelitis was possible using combined [Tc-99m] MDP and labeled leukocytes, they found a negative predictive rate of 94% and a positive predictive rate of 70%. The false-positive results occurred at metaphyseal sites adjacent to a joint, where there was posttraumatic arthropathy, at the site of a failed arthrodesis, and at the site of unstable delayed union or nonunion.

THE ACUTE AND CHRONIC PAINFUL KNEE

Osteonecrosis

Idiopathic osteonecrosis of the knee is a common cause of knee pain in older patients, usually occurs in women (3:1) over the age of 60 in the medial femoral condyle, and is unilateral. It may also occur in the lateral condyle, tibial plateau, patella, and be bilateral in fewer than 20% of the patients. 35 Patients usually complain of pain of sudden onset especially at night, well localized in the medial aspect of the knee. On physical examination, there is effusion, muscle contracture, and motion impairment with difficulty bending the knee due to pain. Its etiology still remains unknown. Increased size of marrow fat cells has been observed in patients on corticosteroids, which leads to a decrease in blood flow and an increase in bone pressure, especially in areas such as the condyle where the compartment is not expandable.

Histopathology demonstrates death of a segment of the weight bearing portion of a condyle, with subchondral fracture and collapse. Radiographi- cally, five stages of osteonecrosis have been de- scribed according to the histopathologic progression of the disease. 36 Stage I, which may last for as long as 3 months, is characterized by normal radiographs while the articular cartilage shows only slight discoloration. Stage II is characterized by an area of slight flattening of the condyle which corresponds to an impending subchondral fracture. Stage III shows an area of radiolucency with distal

sclerosis, corresponding to necrosis without sequestration. Stage IV is characterized by a calcified plate (sequestration). Finally, in stage V, there is narrowing of the joint space and a degenerative process involving the entire articular compartment. Therefore, osteonecrosis of the knee, as in the hip, is an important and underestimated cause of osteoarthritis.

In stage I, radiographs are normal, at the same time TPBI is already markedly abnormal. 36 There is normal or slightly increased focal blood flow and focal and markedly increased tracer uptake in the 2-hour delayed images only in the affected condyle, 37 since arthritic changes have not yet been developed in the knee compartment (Fig 6). Unlike osteonecrosis of the hip, increased uptake will be present in the early phase, and rarely will the nuclear physician find decreased activity in the condyle. 38 Radiocolloid uptake may also be present, reflecting phagocytic activity at the necrotic lesion. 39 With progression of the disease, TPBI findings further reflect the development of osteoarthritis. SPECT imaging may be abnormal before planar imaging. 4~ Especially when focal uptake may be part of a systemic or a polyostotic process, whole body imaging is helpful. 41 MRI is also useful in the detection and preoperative evaluation of osteonecrosis of the knee 42-46 providing good anatomic detail of lesion extent.

Osteochondritis Dissecans

Osteochondritis dissecans is the most common source of loose bodies in the knee. This entity is characterized by a segment of cartilage that together with subchondral bone separates from an articular surface. The separation of the bony fragment may be partial or complete. The lesion is usually located in the medial femoral condyle, but may also occur in the lateral femoral condyle, lateral tibial condyle or the patellofemoral compartment. 47-5~ It occurs three times more often in males than in females, usually in young adults and in children under 12 years of age. The true etiology is probably multifactorial. 5~ The ischemic theory has not gained wide acceptance because the lower end of the femur has a rich blood supply. The accessory centers of ossification theory is based on the fact that males are more prone to osteochondritis dissecans than females because the fusion of accessory ossification centers, which are less resistant to


Fig 6. Patient with osteonecrosis of the right medial femoral condyle. (A) Radiograph of the right knee performed 3 weeks after the onset of symptoms was normal. The patient was submitted shortly after to three-phase bone imaging. (B) Blood pool phase showed a faint focal area of increased radioactivity in the medial aspect of the right knee, (C) 2-hour delayed images showed a focal area of intense increased uptake in the right medial femoral condyle.

trauma, occurs around 10 years of age in males and 4 years of age in females. The traumatic theory seems more appealing because many authors report previous trauma of various intensities in most patients (40% to 60%) with osteochondritis dissecans. Detachment of bony fragments that occur secondary to hemoglobinopathy, previous steroid therapy, postrenal transplant and Caisson's disease is caused by osteonecrosis and differs from osteochondritis dissecans because in the latter, the segment separates from a vascularized normal bone. This leads to the belief that joint trauma is the most important etiologic factor of osteochondritis dissecans. When the lesion occurs before epiphy-

seal closure there is a favorable outcome, while in adults the outcome is less favorable.

TPBI is used for diagnosis when radiographs are equivocal and to add prognostic information for treatment planning. 52,54 In combination with radiographs, three phase bone scintigraphy has a high diagnostic rate with a sensitivity of 90%. 5z A scintigraphic classification of osteochondritis dissecans from stages 0 to IV has been proposed. This classification has been correlated with radiographs, symptoms, stability of the lesion, and has prognostic implication. 53,54

In stage 0 radiographs as well as three-phase bone imaging are normal.


In stage I radiographs show a characteristic osteochondritis dissecans defect but three-phase bone imaging is still normal, the patient is symptom- free, and the lesion is usually stable.

In stage II three-phase bone scintigraphy demonstrates focal increased uptake at the site of the osteochondritis dissecans, normally seen in the medial aspect of the medial femoral condyle, and the patient complains of pain and local tenderness. Stage II lesions can either be stable or unstable. Increased activity in the blood pool image has high sensitivity (100%) and specificity (83%) for identifying unstable lesions.

In stage III bone scintigraphy demonstrates increased blood flow, blood pool, and uptake in the 2-hour delayed images not only at the site of the osteochondritis dissecans, but also in the femoral condyle, around the lesion.

In stage IV the scintigraphic appearance of the lesion is similar to that seen in stage III, with increased uptake in the juxtaarticular tibial plateau. Both stages III and IV lesions are usually unstable.

Bone scintigraphy findings have prognostic implication. Cahill and Berg 54 noted that under conservative management, when the patient is compliant and restricting activities to a symptom-free level, scintigraphic staging will go from III to I. If conservative treatment fails the scintigraphic staging will remain the same or increase. The sensitivity of scintigrams gives the orthopedic surgeon a better estimate of the activity of the lesion. MR/is also a useful imaging modality in the evaluation of osteochondritis dissecans and is able to determine its real diameter and cartilage changes. 55 MRI arthrography with Gd-DTPA increases the rate of correct diagnosis of osteochondritis dissecans to 93%. The mechanical stability of the lesion can be determined by bone scintigraphy as well as MRI. ~4

Osteoarthritis

The arthritic pathologies can be classified broadly as inflammatory and noninflammatory joint diseases. We will focus on the two basic arthritic diseases: osteoarthritis (a degenerative noninflammatory joint disease) and rheumatoid arthritis (inflammatory diffuse connective tissue joint disease). Osteoarthritis is a degenerative noninflammatory joint disease characterized by a complex response of joint tissue to aging complicated by factors such as obesity, change of gait patterns over the years, 56

repeated knee bending, occupational joint stress, joint trauma, and probably higher bone mass. 57.58 In the knee, osteoarthritis is basically attributable to mechanical events. The knee compartment may have a focal increase in pressure leading to cartilage changes, destroying the cartilage and then the bone. Bone destruction begins slowly and is further delayed by new bone formation. Pain is not significant until the bone is exposed in the articular surface. 59

Synovitis is a secondary phenomenon that may occur in osteoarthritic patients. In the acute phase of the inflammation there is hyperemia and a diffuse concentration of polymorphonuclear leukocytes in the synovial stroma. In the chronic phase, the cellular infiltrate consists basically of lympho- cytes with associated vascular changes such as venous distension, capillary obstruction, and peri- vascular hemorrhage. The edematous proliferating synovium, referred to as the pannus (granulation tissue), protrudes into the joint cavity. These histopathologic findings are important for the understand- ing of the scintigraphic patterns encountered with different radiotracers in the osteoarthritic patient.

Radiographic signs reflect anatomic changes, and only secondarily can be used to infer clinical effect. 6~ Bone scintigraphy is more sensitive in detecting the disease in its early phase, determining the relative activity of the process, and assessing disease progression, because bone activity correlates with biochemical evidence of increased matrix turnover (Fig 7). 65 Different patterns of scintigraphic abnormalities have been reported to reflect various aspects of the disease process of osteoarthritis. For example, an increase in the blood pool phase has been correlated with knee pain. 66 In 2-hour delayed images, bone scintigraphy may exhibit many different patterns of uptake which sometimes can be correlated with anatomic changes: a diffusely increased tracer accumulation correlates with pain and osteophyte formation on radiographs; a linear tracer uptake in the joint correlates with subchondral bone sclerosis on radiographs; and focal increased and intense subchondral bone activity correlates with severe radiographic changes. 67 When there is not increased uptake on delayed imaging, Dieppe et a168 found that patients did not have progression of the disease, meaning that bone scintigraphy had a strong negative predictive value.


A

Fig 7. Patient with osteoarthritis. (A) 2-hour delayed image in the anterior view showed increased radiotracer uptake in the left patella. (B) The lateral view clearly revealed the uptake in the femoral-pateliar compartment, corresponding to knee osteoarthritis.

MRI can be used to detect subchondral changes. It detects tricompartmental involvement, and evalu- ates meniscal and ligament disease related to osteoarthritis. 69 Synovial thickening observed on MR/is synonymous of synovitis and these findings have correlated well with synovial membrane bi-

opsy. 7~ McAlindon et a171 found that certain MR/ and scintigraphic findings correlated well. When total knee arthroplasty is being considered, the nuclear physician must keep in mind that patients with active osteoarthritis will have synovitis which makes the exclusion of infection somewhat prob- lematic. TPBI will demonstrate increased blood pool and radiotracer uptake because the joint has an intense inflammatory response, making it difficult to answer the question of whether or not bacterial infection is present. The use of labeled leukocytes in patients with synovitis also poses a problem, because inflamed synovium will also have intense leukocyte accumulation giving a false positive result. 12 The diagnosis of knee infection even in the early phase osteoarthritis may be difficult since synovitis may be present. Technetium-99m labeled nonspecific polyclonal human immunoglobulin (99mTc-HIG) concentrates in the inflamed synovial tissue. De Bois et al73 have investigated the mechanism of uptake of 99mTc-HIG in the synovium of knee joints of rats with arthritis and found that 99mTc-HIG binds to the extracellular matrix proteins in the inflamed synovial tissue. 99mTc-HIG has been useful in clinical practice, especially in patients with rheumatoid arthritis.

Unlike osteoarthritis, rheumatoid arthritis is a systemic disease with immune disturbance and positive tests for rheumatoid factor and elevated acute phase markers, while osteoarthritis is a local disease with little systemic upset. Pain and progres- sive joint damage lead to increasing disability. Histopathology is characterized by a generalized and rapid enzymatic attack on the entire cartilage, to which focal mechanical changes may be added, because the cartilage is weakened by the aggres- sion. In patients with rheumatoid arthritis, bone scintigraphy demonstrates increased diffuse uptake on both sides of the joint which precedes radiographic changes and helps to assess treatment efficacy. 74 Labeled leukocytes are a sensitive index for monitoring rheumatoid arthritis response to intraarticular steroid injection. 75 Although nonspecific for rheumatoid arthritis, 99mTc-HIG can evaluate disease activity, the degree and extent of joint inflammation, and seems to perform better than clinical scores. 76 In the majority of studies compar- ing 99mTc-HIG, 99rnTc-labeled leukocytes, and 99mTc-nanocoloid in the assessment of patients with rheumatoid arthritis, 99mTc-HIG imaging was more


sensitive in the assessment of severity and localiza- tion of the initial phases of the disease. 7728 In a study of 47 patients with arthralgia, de Bois et a179 reported a positive predictive value of 88% and a negative predictive value of 97% for 99mTc-HIG. In comparison to bone scintigraphy, 99mTc-HIG is more useful in identifying active inflammation in the joints of patients with chronic rheumatoid arthritis because bone scintigrams show increased tracer uptake in joints both with and without current inflammation, and cannot distinguish between the two. 8~

Ligament Tear

The cruciate ligaments are the most important stabilizers of the knee. Ligament injuries are common in the younger population and are usually caused by trauma related to sports practice. The anterior cruciate ligament (ACL) is the most common cruciate ligament affected by trauma. When a knee sustains a cruciate lesion, it probably under- goes degenerative changes, sl-83 MRI is the method of choice for diagnosing cruciate rupture. Scintigra- phy can be helpful when MRI is not possible to perform, not available, not conclusive or when the conclusions are not supported by the physical examination.84, 85

Since the demonstration by Collier et a186 of the advantages of SPECT over conventional planar imaging in the diagnosis of ACL lesions, the nuclear physician can no longer rely on planar images to diagnose them. 85,86 The initial blood pool phase may be slightly increased reflecting osteoarthritic changes. 86 Chronic ruptures are demonstrated by a focal activity at the medial aspect of the posterior portion of the lateral femoral condyle (the ACL femoral insertion), but both ends of the ACL attachments may also show increased focal activity. Scintigraphy can also detect associated injuries such as posterior cruciate injuries, medial and lateral meniscal tears, and collateral ligament rupture and additional more subtle bone injuries. 85-87

Dorchak et al 9~ have demonstrated that bone scintigraphy was abnormal in 92% of the knees with chronic and symptomatic ACL deficits but radiograph correlated with the scintigraphic changes only when they were moderate or severe. Scintigra- phy is able to show the metabolic consequences of both early ACL rupture and the chronic secondary changes to the joint. When the medial meniscus

remains competent in the presence of an ACL lesion, increased tracer uptake will be present in the lateral compartment since there is increased stress in that compartment. Bone scintigraphy is also a useful method in evaluating and monitoring ACL reconstruction by evaluating the restoration of bone homeostasis. 90.91

Meniscal Tear

The menisci are fibrocartilagenous structures that bear 50% of the load transmitted across the knee joint, spreading the load and minimizing the point of contact in the articular cartilage. They are also considered as secondary stabilizers of the normal knee and, more importantly, of the ligament- deficient knee. 92,93 The vertical longitudinal and vertical transverse types of trauma are the main causes of symptomatic meniscal tears. 94

Bone scintigraphy can be helpful in diagnosing meniscal tears when MRI cannot be performed or is equivocal. The acute meniscal tear can be detected with a sensitivity of 88% by bone SPECT imaging as demonstrated by Murray et al. 95 They pointed out to the high negative predictive value of bone SPECT imaging in these cases, making it a useful, inexpensive, and noninvasive screening method for acute knee pain. The acute medial meniscal tear is characterized in the planar images as an intense focal accumulation of radiotracer in the medial aspect of the knee. SPECT images will demonstrate, particularly in the transverse slices, a grossly increased semilunar-shaped tracer accumulation at the border of the tibial and femoral articular surfaces. Chronic meniscal tears are more difficult to distinguish scintigraphically from articular damage or synovitis secondary to meniscal tear. 86

OSTEOMYELITIS

Osteomyelitis is a bone inflammation caused by an infecting organism. It can be acute, subacute, or chronic according to the duration of the symptoms and exogenous or hematogenous depending on the origin of the organism. Exogenous osteomyelitis may be secondary to an exposed fracture, postsurgical, or caused by a contiguous infection.

In acute hematogenous osteomyelitis diagnosis may be difficult to establish because of lack of radiograph changes in the first 10 days and because the especially susceptible very young patients do not cooperate for imaging. TPBI can locate and


diagnose early infection with high sensitivity. 96 It is especially important to distinguish septic arthritis from osteomyelitis with articular involvement or to differentiate soft tissue infection from osteomyelitis. Scintigraphy is also the best method to demonstrate multiple sites of osteomyelitis. 97

TBPI reveals 96 markedly increased blood flow, increased blood pool, and more focal more intense tracer uptake in the 2-hour delayed images at the site of acute infection. In the absence of an acute fracture, only very aggressive bone tumors, such as osteosarcoma and very active metabolic diseases, such as Paget's disease, will show the intense three phase uptake similar to that seen in acute osteomyelitis. The combined use of gallium-67 citrate and three-phase bone scintigraphy increases the accuracy and specificity (93%) in the diagnosis of osteomyelitis. 98 The use of gallium-67 citrate, 111in_ or 99mTc-HMPAO-labeled leukocytes, or 99mTc-

HIG should be restricted to situations in which the diagnosis of osteomyelitis is equivocal, such as when the bone has been previously affected by other conditions.

Kaps and Georgi 99 found in a rabbit model that leukocyte imaging becomes negative when inflammation evolves from the acute to the chronic phase. They also found that false-negative images are primarily because of marked medullary necrosis, reduced concentration of granulocytes within the necrosis, and extended medullary fibrosis with reduction of blood flow. These pathologic findings are similar to the stages of osteomyelitis in humans and allow the prediction of the result of the leukocyte scintigram.

Chronic osteomyelitis is occasinally difficult to diagnose. At the site of radiographic chronic osteomyelitis, focally increased blood flow, increased blood pool, and increased tracer uptake in the 2-hour delayed image represents active disease with high probability, while negative TPBI practi- cally excludes the disease. 1~176 When TBPI does not demonstrate diagnostic findings in a previously violated bone with chronic osteomyelitis, then 67Ga or labeled leukocytes scintigrams should be performed. The probability of active chronic osteomyelitis will approach 100% when 99mTc-MDP and 67Ga images have been performed sequentially and the uptake of 67Ga exceeds that of the 99mTc-MDP. 101

Implant surgery should be avoided in areas of acute osteomyelitis. Therefore, before the orthope-

dic procedure, any suspected infection must be investigated. E1 Esper et al a~ studied the use of labeled leukocyte scintigraphy with 99mTc-HMPAO in patients with suspected osteomyelitis related to an orthopedic device and found a sensitivity of 83% and a specificity of 100%. These authors concluded that labeled leukocytes should be performed to exclude chronic osteomyelitis when there is no preexisting strong suspicion based on clinical, biologic, and radiologic signs. The demonstration of infection with labeled leukocytes allows the surgeon to select the adequate procedure to be performed (Fig 8).

MRI has a high sensitivity I~ in detecting osteomyelitis and is able to distinguish between soft tissue infection and osteomyelitis with excellent anatomical definition. 1~ Its restrictions are related to the presence of metallic implants and age (young children usually have to be sedated). MRI cannot detect multiple sites of osteomyelitis and often findings are nonspecific.

KNEE PROSTHESIS

After total knee arthroplasty, many complications such as loosening and infection, embolism, delayed wound healing, hematomas, fractures, nerve palsy, avulsions, subluxations, dislocations, and breakage may occur. The nuclear physician may help the orthopedic surgeon when loosening, infection, refracture, or other superimposed osseous traumatic lesion is suspected.

Loosening is a time-related phenomenon. The majority of knee prostheses are cemented and osteolysis may occur at the bone cement surface leading to loosening, especially of the tibial compo- nent. Bone remodeling will then begin in response to the osteolysis. Infection may also lead to loosening. The orthopedic surgeon will suspect loosening when pain is present.

Deep infection represents perhaps the most severe complication of total knee arthroplasty. The incidence of infection after total knee arthroplasty may be as high as 12%. The deep or periprosthetic infection may be either early, defined as occuring within 3 months of surgery, or late. Symptoms of early infection include prolonged pain, swelling, inflammation, fever, and are not difficult to recog- nize. Late infection is much more common, devel- ops usually from a hematogenous spread of micro- organisms, and recognition may be more difficult.


A

t ! !: t}

B

C D

R i,

t

8 �9 ii

g*

Fig 8. A6~-year -~dpa t ien tw i tha to ta l l e f t kneepros thes is fo r14yearsandmeta l l i c imp lan ts in the r igh tkneewassubmi t - ted to three-phase bone scintigraphy to rule out infection for placement of total right knee prosthesis, He had been symptom-free for 6 months. Three-phase bone imaging showed (A) intense increased blood f low to the right knee and (B) increased blood pool activity in the right knee. (C) 2-hour delayed images showed a focal, intense increased uptake in the right knee and absence of uptake in the metallic implants and in the total left knee prosthesis. (D) Leukocyte imaging wi th 99mTc-HMPAO revealed a focal, intense increased uptake in the right knee and a linear, intense tracer uptake around all the metallic implants in the same knee. Total right knee arthroplasty was deferred. The total left knee prosthesis was interpreted as normal.

Any painful prosthesis for which a cause is not readily apparent should be considered infected until proven otherwise. Knee infection may be present without radiographic signs of loosening. Radiographic diagnosis of infection is only possible at an advanced stage of loosening when large areas of radiolucency are visible on the radiographs. The diagnosis of an infected total knee

prosthesis based on fluid aspiration is also difficult. When the infection is obvious (usually early infections) the amount of fluid is sufficient for an accurate diagnosis. In late, subclinical infection, the amount of fluid in the prosthetic knee joint is minimum or absent and the diagnosis difficult.

After total knee arthroplasty, TPBI demonstrates increased blood flow and increased tracer uptake


A B

D

C

Fig 9. A 17-year-old girl wi th pain in her right thigh. (A) The radiograph showed a dense, calcified, homogeneous lesion, possibly contiguous with the bone. (B) An MRI revealed a round lesion surrounded by edema and there was no conclusion as to the type of lesion. (C) Bone scintigraphy, in the anterior projection, revealed a focal, round area of increased activity which, in the lateral projection (D), showed no contact wi th the femur.

around the prosthesis, with a photopenic area that corresponds to the prosthesis itself. Increased blood flow will persist as long as there is an inflammatory reaction to surgery, and may last for as long as 6

months and then decline (Fig 8). Unlike hip prosthesis, increased bone uptake may be seen normally for several years after total knee prosthesis) 05,1~ The diagnosis of infection or loosening


E F

Fig 9. {cont'd). (E) The lesion was thought to be benign, and this was confirmed wi th ~mTc-sestamibi. Ten minutes after injection a focal area of tracer uptake in the right thigh was visualized. (F) Images performed 2 hours after sestamibi injection revealed reduction of uptake in the lesion, supporting the concept that the lesion was benign. Our diagnosis was myositis ossificans, confirmed by histopathology.

with TPBI should not be attempted before the first postsurgical year. Although TPBI may have a high sensitivity (100%) for detecting infection and loosening of knee prosthesis, specificity and accuracy are not optimal (64% and 73%, respectively), my

Other radiopharmaceuticals may be used to identify infected knee prosthesis prior to or after completion of 1 year of surgery. Labeled leukocytes, with indium-Ill or with technetium-99m, have high sensitivity (70-100%), specificity (86- 100%), and accuracy (91-93%) in the diagnosis of infected knee prostheses, m7,1~ Flivik et aP ~ have proposed the use of 99mTc-nanocolloid for bone marrow scintigraphy with the advantage of being easier to handle than labeled leukocytes, eliminat- ing potential risks involved with blood handling. They found a lower specificity (84%) than with labeled leukocytes but higher sensitivity (94%) and accuracy (87%). They postulate that the difference in sensitivity and accuracy is probably because of the mechanisms of distribution of these tracers: while labeled leukocytes are mainly attracted to places of acute inflammation, nanometer-sized col- loids find their way into the extravascular space regardless of the duration and etiology of the inflammatory process. White blood cell scintigraphy with monoclonal antibodies has been found to have similar diagnostic accuracy as labeled white blood cells with indium-ll 1 or technetium-99m,

with the advantage of being easier to perform and relatively a\ ailable. ~l~ The combined use of radiopharmaceuticals improves sensitivity, specificity, and accuracy in the diagnosis of total knee prosthesis infection. The use of labeled leukocyte scintigraphy combined with 99mTc-sulfur colloid bone marrow imaging will improve the accuracy significantly (95%). m When infection is present leukocyte uptake will occur, but sulfur colloid will not accumu- late in the infected area. Therefore, infection pro- duces incongruent images with these two tracers.

In a patient with pain and normal bone scintigraphy after total knee arthroplasty, the likelihood of loosening or infection will be very low. Therefore, scintigraphy is a very useful tool in establishing the need for revision surgery in total knee replacement. u2

TUMOR VIABILITY

Tumor Imaging

In our practice, radiotracers are used to evaluate the aggressiveness of a lesion, tumor viability following chemotherapy, the presence of distant metastases and, therapeutically, to palliate pain in patients with bone metastases. Our orthopedic surgeons rely on plain radiographs to establish the appropriate differential diagnosis for most primary bone neoplasms. Bone scintigrams in our practice


are not used for diagnosis because they lack specificity. Often the complaints of a patient are related to a minor traumatic event and the surgeon must be aware of the discrepancy between the magnitude of the trauma and the intensity and duration of the pain even if the radiographs are normal. When clinical and laboratory findings are discrepant, the patient is referred to our laboratory for three-phase bone scintigraphy to evaluate the presence and the aggressiveness of a lesion. An example of this is myositis ossificans, a benign bone lesion which can bear resemblance to paros- teal osteosarcoma on plain radiographs (Fig 9). Three-phase bone scintigraphy is the second diagnostic tool used to help in the differential diagnosis,

Fig 10. Patient with osteosarcoma of the distal diaphysis of the left femur. (A) sSmTc-sestamibi images performed before chemotherapy showed diffusely increased heterogeneous uptake in the distal diaphysis of the left femur, which corresponded to the tumor. SgmTc-MDP bone scintigraphy performed 5 days after the 9SmTc-sestamibi study showed markedly increased tracer uptake at the tumor site. (B) 9SmTc-sestamibi images performed after chemotherapy revealed markedly reduced uptake at the site of the lesion, while ggmTc-MDP bone scintigraphy performed after chemotherapy did not reveal any significant change. Quantitative analysis of the SSmTc- sestamibi images revealed 98% necrosis, which correlated with histopathology.

especially since cost versus benefit is an important issue. We do not recommend the use of three-phase bone imaging in the short-term follow-up of patients with malignant bone tumors because of the "flare up" response to chemotherapy or the remodeling process, secondary to surgical trauma.

In our practice, bone scintigraphy can detect early relapse, before patients have clinical symptoms or a positive radiograph or CT scan. 113 In our practice, scintigrams are performed on patients with malignant bone tumors during the staging phase and also yearly. Oncologists believe that after 4 years the detection of relapse is less probable. Thallium-201 and 99mTc-sestamibi play an important role in the evaluation of bone tumor

SCINTIGRAPFIIC EVALUATION OF THE LOWER EXTREMITIES 57

Fig 11. A 19-year-old girl was submitted to resection of the left scapula due to Ewing's sarcoma. Three years after surgery she developed a lump on her back. (A) Bone scintigraphy revealed diffusely increased tracer uptake in the eighth left posterior rib. Note the absence of the left scapula. (B) m"Tc-sestamibi (posterior view) revealed (arrow) diffusely increased tracer uptake in the same region, and therefore viable tumor in the eighth left posterior rib.

viability and quantification of tumor necrosis following preoperative chemotherapy. J l4,~ is Patients with high-grade sarcomas of bone and soft tissue have been submitted to thallium-201 scintigraphy before and after chemotherapy and their findings corn-

pared to the histopathological response. Fifteen out of 16 patients showed good correlation between scintigraphy and histopathology.116 In a study of 30 patients with high-grade osteosarcoma, Ohtomo et a11~7 found a high correlation between thallium-201 uptake and the histoiogic tumor grades (P < 0.0001). Rosen et al, 1Is in a group of 24 patients with osteosarcoma and 3 with malignant fibrous histiocytoma, found that sequential thallium-201 scintigraphy correlated with the degree of tumor necrosis and identified poor response within 2 weeks after the initiation of treatment. These findings, especially when tumor necrosis is less than 90%, can prompt an early change in preoperative chemotherapy and facilitate limb salvage surgery (Fig 10). 119

In our laboratory, patients with primary bone tumors (malignant and benign) and soft tissue sarcomas are submitted to a whole body imaging with 99mTc-sestamibi. Patients with equivocal bone scintigraphy are also submitted to 99mTc-sestamibi whole body imaging to determine whether or not a lesion is aggressive and, therefore, probably malignant (Fig 11). If 99mTc-sestamibi imaging shows little or no uptake, a benign tumor is more likely. If there is markedly increased uptake or a "dough- nut" sign there is a high probability of an aggressive, malignant tumor.

The role of Nuclear Medicine in the evaluation of osteosarcoma and Ewing's sarcoma seems now defined: bone scintigrams are useful in the evaluation of distant metastasis while thallium 201 and 99mTc-sestamibi are best for following the respose to therapy.

Other diagnostic methods, such as color Doppler flow images, are being investigated for detection of the effect of chemotherapy on bone sarcomas and compared to contrast-enhanced MRI and three- phase bone scintigraphy.120 Although color Doppler flow analysis can accurately monitor the effect of chemotherapy on bone sarcomas with no radiation exposure and at low cost, the quantification of tumor necrosis is not possible.

Acknowledgment

The authors are indebted to Monica N.S. Barbosa, MD for her help in organizing patient data and to the nuclear technologists Teresa Vallini, Daniela S. Bartholo, and Juliana A. Pereira for their technical assistance.


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