AJR 2004; 183:989-994
© American Roentgen Ray Society
Radiographic and MRI Features of Deferiprone-Related Arthropathy of the Knees in Patients with ß-Thalassemia
Christian J. Kellenberger1,2,
Markus Schmugge3,
Traudel Saurenmann3,
Lin Di Gennaro3,
Stefan W. Eber3,
Ulrich V. Willi1 and
Paul S. Babyn2
1 Department of Diagnostic Imaging and Radiology, University Children's
Hospital, Steinwiesstrasse 75, Zurich CH-8032, Switzerland.
2 Present address: Department of Diagnostic Imaging, The Hospital for Sick
Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
3 Division of Haematology and Immunology, University Children's Hospital, Zurich
CH-8032, Switzerland.
Received December 1, 2003;
accepted after revision May 14, 2004.
Presented at the 39th Annual Congress of the European Society of Paediatric
Radiology, Bergen, Norway, 2002.
Address correspondence to C. J. Kellenberger.
Abstract
OBJECTIVE. This study was undertaken to describe the radiographic
and MRI appearances of arthropathy of the knees in 14 patients with
ß-thalassemia major undergoing chelation therapy with deferiprone
(L1).
MATERIALS AND METHODS. All available radiographs and MRI studies of
the knees in 14 ß-thalassemia major patients (mean age, 16.3 years; age
range, 7–33 years) undergoing chelation therapy with L1 were
retrospectively assessed for changes in the synovium, cartilage, and bone.
Imaging findings and signs of knee arthropathy were correlated with chelation
therapy and average serum ferritin concentration.
RESULTS. Nine (64%) of the 14 patients developed arthralgia of the
knees during treatment with L1. Abnormal imaging findings were present in all
symptomatic and two asymptomatic patients (12/14, 86%) and included joint
effusion, subchondral bone irregularity, and patellar beaks. Additional MRI
findings were thickening and enhancement of the synovium; hypointense bands in
the synovium; irregularly thickened epiphyseal and articular cartilage
overlying subchondral bone defects; and, on T2-weighted sequences,
hyperintense articular cartilage lesions. The degree of knee symptoms at the
time of imaging did not reflect the severity of cartilage and subchondral bone
changes.
CONCLUSION. Radiologic changes can be seen in L1-related arthropathy
and should be recognized. MRI of the knees should be considered in symptomatic
children and young adults with thalassemia undergoing L1 chelation therapy for
iron overload.
Introduction
The thalassemias are inherited anemias caused by mutations in the 
-
or ß-hemoglobin gene that affect the synthesis of hemoglobin.
Beta-thalassemia major requires regular blood transfusion, which is
complicated by iron overload
[1]. Iron chelation therapy is
essential to prevent visceral and cardiac toxicity, and several agents are now
available [2]. Deferiprone
(L1), an orally active iron chelator, has been in clinical use for several
years. Some toxic side effects of L1 therapy have been recognized including
agranulocytosis, gastrointestinal symptoms, and arthropathy
[3–8].
The most common clinical problem associated with L1 therapy is arthropathy
that mainly involves the knees
[6]. The imaging findings of
this arthropathy have not been well described. In a recent review, all toxic
side effects of L1 therapy were considered reversible, controllable, and
manageable [2]. However, we
noted previously unreported destructive-appearing changes in the knees of a
patient who had been treated with L1. This finding led us to investigate all
our patients treated with L1 for iron chelation. Our objective in this report
is to describe the radiographic and MRI appearances of L1-related arthropathy
of the knees.
Materials and Methods
All patients who underwent L1 therapy between 1991 and 2002 at our
institution were retrospectively evaluated. Treatment with L1 and this
retrospective study were approved by the institutional ethics board. The study
group consisted of 14 transfusion-dependent ß-thalassemia major patients
(six females, eight males; mean age at the time of initial knee imaging, 16.3
years; age range, 7–33 years). They had undergone regular blood
transfusions since a mean age of 2.5 years (range, 2 months–6 years).
Chelation therapy was initiated at a mean age of 8.2 years (range, 3–17
years); nine patients received subcutaneous deferoxamine before L1 therapy.
Chelation with L1 was started at a mean age of 11.2 years (range, 3–24
years), and L1 was given for a mean duration of 5.9 years (range, 11
months–10.5 years). The daily dose of L1 ranged between 35 and 75 mg/kg
of body weight. The average serum ferritin concentration observed during L1
treatment ranged between 1,422 and 6,571 mg/L (mean, 3,346 mg/L). The presence
of arthralgia, joint swelling or effusion (or both), and limited joint motion
was assessed by patient interview and physical examination at regular clinical
visits during and after L1 treatment and at the time of MRI.
Imaging initially consisted of radiographs in patients with joint symptoms.
Serial MRI studies and radiographs of both knees were obtained to better
define arthropathy in six patients who had experienced an episode of severe
pain. Because abnormalities were found in these six patients, the asymptomatic
patients also underwent bilateral knee radiography in search for potential
changes due to L1 treatment.
MRI was performed on a 2-T system (Tomikon S200, Bruker) in 13 patients and
on a 1.5-T system (Gyroscan ACS NT, Philips) in one patient. The MRI
examination included a variety of sequences. T1-weighted spin-echo and
T2-weighted RARE or turbo spin-echo sequences were available for all patients.
T1-weighted fat-suppressed 2D or 3D spoiled gradient-echo imaging for
cartilage evaluation was performed in at least one study in five of six
patients. Gadolinium-enhanced T1-weighted spin-echo sequences with fat
saturation had been performed as part of both studies in four and as part of
the initial study in one patient.
Knee images were reviewed by two pediatric radiologists in consensus. The
radiographs were assessed for the presence of joint effusion, joint space
narrowing, bone joint surface irregularities and protrusions, and metaphyseal
or physeal abnormalities. Mineralization and tubulation of the distal femora
and proximal tibiae were assessed, and any other abnormality was noted.
The MR images were evaluated for changes in the synovium, cartilage, bone,
and soft tissues. Any abnormal finding was subjectively graded, on the basis
of the observers' experience, as mild, moderate, or severe. A joint effusion
was graded as mild when the suprapatellar recess was minimally distended, as
moderate when the suprapatellar recess was moderately distended (> 1 cm),
and as severe when marked distention of the suprapatellar recess and
additional posterior distention of the joint space were present.
The synovium was assessed for thickening, altered signal, and enhancement.
Synovial thickening was graded as mild when the joint capsule was slightly
thicker than normal (> 2 mm), as moderate when it was moderately thickened
(> 5 mm), and as severe when there was marked and nodular thickening (>
1 cm). Epiphyseal, physeal, and articular cartilage were assessed for altered
thickness and signal changes along with irregularities of subchondral bone and
bone marrow signal. Abnormalities of cartilage were graded as mild when three
or fewer lesions were present, as moderate when there was more extensive
multifocal involvement, and as severe when involvement was diffuse. Any other
abnormal finding was noted.
Data concerning the L1 therapy and iron overload—including the age of
the patient at the start of regular blood transfusions and chelation therapy,
the dosage and duration of chelation therapy with L1 and deferoxamine, and the
average serum ferritin concentration—were compared between symptomatic
and asymptomatic patients on L1 therapy and between patients with and without
subchondral bone changes. Data are presented as means ± SDs.
Statistical analysis was performed with the two-tailed Student's t
test assuming unequal variances using Excel (Microsoft). A p value of
less than 0.05 was considered statistically significant.
Results
Clinical Findings
Of the 14 patients treated with L1, four never experienced any joint
symptoms and one had mild knee pain before L1 therapy. Nine patients (64%)
developed bilateral knee pain 8 months–2.6 years after starting L1
treatment (mean, 1.6 years). Knee pain was mild and only present after
exercise in two patients, whereas seven patients (50%) experienced several
episodes of severe knee pain accompanied by limited motion, swelling,
effusion, and warmth on clinical examination. These arthritislike episodes
occurred after an increase of the L1 dose from 50 to 75 mg/kg per day in four
patients, usually improved after temporary interruption of L1 therapy, but
eventually led to discontinuation of L1 therapy in four patients (29%). Six of
seven symptomatic patients who discontinued L1 therapy (four because of
arthropathy, two because of increasing ferritin concentration, and one because
of pregnancy) did not experience any further joint symptoms; however, the
remaining patient still had knee pain and effusions 6 months after L1 therapy
was stopped.
Besides experiencing involvement of the knees, all 10 symptomatic patients
also had episodes of similar, but usually less severe, symptoms of the ankles
(n = 5), wrists (n = 4), fingers (n = 3), elbows
(n = 2), feet (n = 2), shoulders (n = 1), and back
(n = 1).
Synovial biopsy, performed in one symptomatic patient after the initial MRI
study (patient 2 in Tables 1
and 2), revealed focal
proliferation of synovial lining cells and numerous vessels. Hemosiderin was
present in macrophages and synovial lining cells. No cellular infiltrate was
seen to suggest an inflammatory process.
Radiographic Changes
Radiographs of the knees showed abnormal changes characterized as mild,
moderate, or severe imaging findings in 12 (86%) of the 14 patients (Figs.
1A,
1B,
2A,
2B,
2C,
2D,
3A,
3B,
3C,
3D). The radiographic findings
of each patient are listed in Table
1. Joint effusions of varying severity on serial studies were
present in eight patients (57%). Bone abnormalities were present in 11
patients (79%), including subchondral bone changes and patellar beaks.
Irregular flattening of the subchondral bone was present in nine patients
(64%); it involved the femoral condyles in all nine patients (Figs.
1A,
1B,
2A,
3A, and
3B), the tibial plateau in
three patients (Fig. 3A), and
the patella in two patients (Fig.
3B). A broad beak of the superior patellar pole was seen in four
patients (Figs. 1B and
3B). In two patients who had
been started on L1 therapy in adulthood, the only finding was a more pointed
patellar beak, as seen in cases of early osteoarthritis of the femoropatellar
joint.
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Fig. 1A. —18-year-old man with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 5 in Tables
1 and
2). Mild radiographic changes
were detected. Patient had experienced several episodes of severe knee pain
with swelling that eventually led to discontinuation of L1 therapy. Frontal
radiograph of left knee shows mild irregular subchondral cortical flattening
of femoral condyles (arrows).
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Fig. 1B. —18-year-old man with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 5 in Tables
1 and
2). Mild radiographic changes
were detected. Patient had experienced several episodes of severe knee pain
with swelling that eventually led to discontinuation of L1 therapy. Lateral
radiograph of left knee reveals broad patellar beak (arrowhead) in
addition to irregularities of subchondral bone (arrows).
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Fig. 2A. —10-year-old boy with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 6 in Tables
1 and
2). Moderate radiographic and
severe MRI changes were seen at initial study. Patient had moderate knee pain
at time of initial imaging, and subsequent episodes of severe arthralgia led
to discontinuation of L1 therapy. Lateral radiograph of right knee shows
moderate irregular subchondral cortical flattening of femoral condyles.
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Fig. 2B. —10-year-old boy with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 6 in Tables
1 and
2). Moderate radiographic and
severe MRI changes were seen at initial study. Patient had moderate knee pain
at time of initial imaging, and subsequent episodes of severe arthralgia led
to discontinuation of L1 therapy. Sagittal T2-weighted RARE image (TR/TE,
3,496/100) of right knee shows joint effusion and multiple focal
high-intensity lesions confined to articular cartilage (arrow). Bone
marrow signal is low, which is consistent with iron deposition.
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Fig. 2C. —10-year-old boy with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 6 in Tables
1 and
2). Moderate radiographic and
severe MRI changes were seen at initial study. Patient had moderate knee pain
at time of initial imaging, and subsequent episodes of severe arthralgia led
to discontinuation of L1 therapy. Sagittal T2-weighted RARE image (3,496/100)
of right knee shows hypointense bands outlining infrapatellar fat pad
(arrowheads), which is consistent with synovial hemosiderin
deposition, and irregular thickening of synovial membrane
(arrow).
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Fig. 2D. —10-year-old boy with ß-thalassemia major who was
receiving chelation therapy with L1 (patient 6 in Tables
1 and
2). Moderate radiographic and
severe MRI changes were seen at initial study. Patient had moderate knee pain
at time of initial imaging, and subsequent episodes of severe arthralgia led
to discontinuation of L1 therapy. Sagittal contrast-enhanced T1-weighted
spin-echo image (624/20) obtained with fat saturation of right knee reveals
intense enhancement of thickened synovium (arrows).
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Fig. 3A. —16-year-old boy with ß-thalassemia major 4 years after
chelation therapy with L1 and 4 years after bone marrow transplantation
(patient 1 in Tables 1 and
2). Severe radiographic and MRI
findings were noted on follow-up imaging. Patient was asymptomatic at that
time but previously had severe arthralgia during L1 treatment that resolved
after discontinuation of L1. Frontal radiograph of left knee shows irregular
subchondral cortical flattening of femur and tibia (arrows).
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Fig. 3B. —16-year-old boy with ß-thalassemia major 4 years after
chelation therapy with L1 and 4 years after bone marrow transplantation
(patient 1 in Tables 1 and
2). Severe radiographic and MRI
findings were noted on follow-up imaging. Patient was asymptomatic at that
time but previously had severe arthralgia during L1 treatment that resolved
after discontinuation of L1. Lateral radiograph of left knee better reveals
depth of subchondral bone lesions (arrows), which also involve
patella, and shows broad beak of superior pole of patella
(arrowhead).
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Fig. 3C. —16-year-old boy with ß-thalassemia major 4 years after
chelation therapy with L1 and 4 years after bone marrow transplantation
(patient 1 in Tables 1 and
2). Severe radiographic and MRI
findings were noted on follow-up imaging. Patient was asymptomatic at that
time but previously had severe arthralgia during L1 treatment that resolved
after discontinuation of L1. Sagittal intermediate-weighted turbo spin-echo
image (TR/TE, 3,099/16) of left knee reveals thickened articular cartilage
extending into subchondral bone defects (arrows). Synovium
(arrowheads) is mildly thickened and hypointense.
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Fig. 3D. —16-year-old boy with ß-thalassemia major 4 years after
chelation therapy with L1 and 4 years after bone marrow transplantation
(patient 1 in Tables 1 and
2). Severe radiographic and MRI
findings were noted on follow-up imaging. Patient was asymptomatic at that
time but previously had severe arthralgia during L1 treatment that resolved
after discontinuation of L1. Axial T2-weighted turbo spin-echo image
(1,912/60) obtained with fat saturation shows irregular articular surface,
irregular thickness, and heterogeneous signal increase of articular cartilage
(arrowheads) of right knee.
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Additional findings included a small ossific density in the articular
cartilage of the medial femoral condyle in one patient, prominent growth
recovery lines in two patients, and coarse radiolucent striations in the
distal femoral metaphysis in one patient. The metaphyses otherwise appeared
normal, and the growth plates were not widened. The bone changes appeared to
persist over time in any patient who underwent serial radiography and were
present at follow-up in five patients imaged 15–67 months (mean, 37
months) after termination of L1 treatment.
MRI Changes
Six boys underwent serial MRI knee examinations, with the first study done
at an age of 9–18 years (mean age, 13.8 years) and the second study done
9–26 months (mean, 16 months) later. The MRI findings are summarized in
Table 2. Joint effusions (Figs.
2B,
2C,
2D) were present in all
patients initially, and follow-up studies showed improvement in five patients.
On T2-weighted sequences, part of the synovial joint surface was outlined by
hypointense bands (Figs. 2C and
3C) in all patients and was
most conspicuous in the region of the infrapatellar fat pad. The synovium was
diffusely thickened (Fig. 2C)
in five patients and showed intense enhancement
(Fig. 2D) in four of the five
patients who had undergone gadolinium-enhanced sequences. These synovial
abnormalities did not significantly change over time. The epiphyseal and
articular cartilage appeared irregularly thickened in four patients with areas
of signal isointense relative to cartilage extending into defects of the
subchondral bone (Figs. 3C and
3D). In three patients, the
articular cartilage showed irregular high signal on T2-weighted sequences
(Fig. 3D), with multiple
distinct foci of very high signal in one patient
(Fig. 2B). In two patients, the
chondral signal changes partially improved in the second study. Bone marrow
signal was consistent with varying degrees of siderosis
(Fig. 2B).
Correlation of Symptoms, Imaging Findings, and Chelation Therapy
The two patients with normal findings on radiographs were asymptomatic. All
patients with joint effusion were symptomatic; however, two symptomatic
patients did not have a joint effusion. Two of the nine patients with
subchondral bone changes had never experienced any knee symptoms. The amount
of joint effusion seen on serial MRI studies tended to reflect the degree of
knee symptoms at the time of imaging, but the severity of cartilage and
subchondral bone changes did not (Table
2). The patients with subchondral bone changes had been started on
L1 therapy at a younger mean age (8.62 ± 2.51 years) than those without
subchondral bone changes (15.70 ± 7.49 years), but this difference did
not reach statistical significance (p = 0.096). Patients who
developed knee symptoms had been started on chelation therapy at a
significantly older mean age (9.68 ± 3.39 years) than the asymptomatic
patients (5.52 ± 2.42 years) (p = 0.036). The duration of L1
therapy, cumulative dose of L1, and average serum ferritin concentration did
not correlate with the presence of symptoms or subchondral bone changes.
Discussion
Arthropathies and bone deformities are well known to occur in patients with
thalassemia major and have been attributed to the disease or to its therapy.
Before the introduction of chelation therapy, hypertransfused patients were
prone to develop a distinctive osteoarthropathy, possibly caused by
hemosiderosis, abnormalities of calcium metabolism, parathyroid hormone
regulation, vitamin D function, or localized problems due to marrow expansion
[9–11].
Ankles were more frequently involved than knees, and radiographic changes
included osteopenia, widened medullary spaces, thin cortices with coarse
trabeculations, and evidence of microfractures. Joint surface irregularities,
as seen in our patients, have not, to our knowledge, been reported
[9,
11].
After the introduction of deferoxamine for iron chelation therapy,
thalassemia patients were noted to develop metaphyseal abnormalities and
vertebral changes that can resemble spondylometaphyseal dysplasia
[12–17].
Deferoxamine appears to interfere with enchondral ossification and can result
in growth failure. In the knees, radiographic abnormalities of deferoxamine
toxicity include metaphyseal widening, sclerotic longitudinal trabeculations,
irregularity of the metaphyseal zone with sclerotic and radiolucent cystic
areas, and growth plate widening
[12–16].
On MRI, a spectrum of morphologic changes involving the distal femoral
metaphysis, epiphysis, and physeal cartilage have been reported, but changes
of epiphyseal or articular cartilage have not, to our knowledge, been
described [18,
19].
L1 has been evaluated in clinical trials since 1987 and has recently been
registered for clinical use in India and Europe
[2]. The most common clinical
problem associated with L1 treatment is arthropathy of large joints
[6]. Bilateral knee involvement
is most frequent, but ankles, hips, shoulders, elbows, wrists, and small
joints of the hands and feet can also be affected
[3,
5,
20,
21]. The clinical syndrome
consists of musculoskeletal stiffness; joint pain; and, in severe cases, joint
swelling and effusion as seen in our patients.
The radiographic findings of L1-related arthropathy have been mentioned
only briefly in the literature. Apart from joint effusions, minor degenerative
changes have been reported in the patellofemoral joint in one patient
[21]. In a trial performed in
India, radiographs of affected knee joints were reported to show no
significant findings except increased joint space in four cases, whereas
chondromalacia was mentioned in the description of four of five patients
studied with MRI but was not further specified
[20]. In another trial,
radiography, MRI, and radioisotope scanning were considered noncontributory
[7]. In contrast to the
findings in these reports, imaging of the knees revealed abnormal
findings—including abnormalities of the synovial membrane, epiphyseal
and articular cartilage, and subchondral bone—in 86% of our patients
treated with L1. Joint effusions, of varying degrees in serial studies, were
evident in all but two symptomatic patients. The synovium was thickened and
showed intense enhancement in four of the five patients who underwent
gadolinium-enhanced MRI. Hypointense bands outlining parts of the synovial
joint surface on T2-weighted sequences were seen in all MRI studies. Synovial
biopsy in one patient, showing hemosiderin in macrophages and cells lining the
synovium, suggests that these hypointense bands represent hemosiderin
deposition in the synovial membrane. Epiphyseal and articular cartilage
abnormalities, seen in four of the six patients examined with MRI, included
irregular thickening with subchondral extension and high-signal lesions on
T2-weighted sequences. Bone abnormalities were more conspicuous on radiographs
than on MR images and included irregular flattening of the subchondral bone
and patellar beaks. The subchondral irregularities involved the femoral
condyles and, in severe cases, the tibial plateau and patella. Subchondral
bone changes were present not only in symptomatic patients but also in two
asymptomatic patients. The bone abnormalities were unchanged over time and did
not improve in those patients imaged after the termination of L1 treatment.
The long-term sequelae are uncertain, but the damage to articular cartilage
and the deformity of subchondral bone may lead to premature osteoarthritis.
The fact that no typical findings of thalassemic osteoarthropathy or
deferoxamine toxicity were observed in our patients suggests that the
irregularities of subchondral bone and the changes of epiphyseal and articular
cartilage are associated with L1-related arthropathy.
The incidence of L1-related arthropathy was higher in our series than in
other clinical trials (range, 13–38.5%)
[8,
20]. Sixty-four percent of our
patients developed knee pain during L1 treatment, and 50% experienced several
episodes of knee pain with swelling, effusion, and warmth on clinical
examination. This high incidence in our series could be related to the fact
that our patients began to receive L1 at a younger age and were treated for a
longer duration than those patients in most trials
[3,
5,
7,
8,
20]. In addition, our patients
had a considerable iron load because of the relatively late onset of chelation
therapy and initially low dose of L1. Previous reports have suggested that
arthropathy is more frequent in patients who are more heavily iron-loaded
[8,
21] and who receive larger
doses of the drug (100 mg/kg per day)
[4]. We noted exacerbation of
symptoms after an L1 dose increase in four patients. The symptoms have been
reported to resolve spontaneously in most patients after temporary
discontinuation of the drug or after dose reduction
[5,
8,
20]. The symptoms may even
resolve during continued drug administration without dose reduction
[3,
5,
21]. In our series, symptoms
usually improved after temporary discontinuation of L1. However, recurrent
episodes of severe knee pain and arthritislike symptoms eventually led to
termination of L1 therapy in four (29%) of the 14 patients in our study, which
is higher than has been reported in adults (13%)
[7].
The cause of L1-related arthropathy is not known
[6]. It has been hypothesized
that the arthropathy is due to a toxic effect of L1 mediated by free radicals,
resulting from formation of 1:1 or 1:2 L1–iron complexes rather than the
usual inert 1:3 complexes [6,
21], which is especially
likely at low concentrations of L1 relative to iron
[22]. The iron stores in
tissue were increased in most of our patients, and this finding has previously
been noted in patients with L1-related arthropathy
[4,
8,
20,
21]. Synovial biopsy,
performed in one of our patients and in three patients of another series
[21], has shown iron
deposition and proliferation of synovial lining cells without evidence of an
inflammatory or allergic reaction. These histologic findings are similar to
those in thalassemic osteoarthropathy and arthropathy secondary to
transfusional siderosis [9,
23,
24], but the changes of
epiphyseal cartilage and subchondral bone observed in patients with L1-related
arthropathy remain unique. The reasons that L1 predominantly affects
epiphyseal cartilage and deferoxamine affects the growth plate of metaphyseal
ossification remain unclear.
Although the small sample size and retrospective design are limitations to
our study, we had sufficient information to describe the imaging features of
L1-related arthropathy. Because the reported MRI findings are based only on
studies performed in patients who had an episode of severe arthralgia, MRI
abnormalities may potentially also have been present in less symptomatic or
asymptomatic patients, and this should be assessed in future studies. Because
of the small number of patients and large SD of the evaluated parameters of
chelation therapy, potentially significant differences between patients with
and without symptoms or subchondral bone changes may have not been detected.
The only parameter to estimate iron overload available in our
patients—the average serum ferritin concentration—does not
represent the true body iron load, and a correlation to the amount of
intraarticular iron has not been described
[1]. Systematic investigation
of the body iron load by liver biopsy and of the intraarticular amount of iron
by joint aspiration and synovial biopsy is needed to further evaluate the role
of iron in the pathogenesis of L1-related arthropathy.
In conclusion, radiologic changes can be seen in patients with L1-related
arthropathy and should be recognized. Although clinical symptoms may be mild
or resolve after discontinuation of the drug, structural damage to cartilage
and subchondral bone may be present and seems to persist. MRI is helpful in
evaluating synovial and cartilaginous changes. Investigation of symptomatic
children should include knee radiography and MRI. Long-term studies with set
protocols are needed to evaluate pathogenesis and outcome.
Acknowledgments
We thank Rahim Moineddin for his help with the statistical analysis.
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Abstract
Introduction
