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Magnetic resonance imaging as a noninvasive means for quantitating the dimensions of articular cartilage in the human knee.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 1, January 2004, pp 5–9
DOI 10.1002/art.11495
© 2004, American College of Rheumatology
EDITORIAL
Magnetic Resonance Imaging as a Noninvasive Means for Quantitating the
Dimensions of Articular Cartilage in the Human Knee
Laurie D. Hall
The report by Cicuttini and colleagues in this
issue of Arthritis & Rheumatism (1) is an important
demonstration of the substantial progress investigators
have made in developing magnetic resonance imaging
(MRI) methods for measuring the dimensions of human
articular cartilage, particularly in the knee (2–4). Importantly, the findings reported by Cicuttini et al indicate
the utility of MRI in monitoring osteoarthritis (OA)–
related loss of knee cartilage during a 2-year period.
While the most ergonomically efficient method for
deriving the key parameters for assessing disease progression from scans is an open question, the good news
is that the studies by Cicuttini and others are attracting
the attention of a growing number of research groups, as
well as of consortia sponsored by government (5) and
individual pharmaceutical companies (6). The diverse
needs and interests of those groups will ensure that a
wide range of methods will become available, each
optimized for a specific purpose.
Among clinical and radiographic techniques to
evaluate the articular joint, MRI occupies a unique
position, as highlighted in Table 1. While a major focus
of MRI is the articular cartilage, the same 3-dimensional
(3-D) MRI scans that are used to visualize the articular
cartilage also provide information about the joint as a
“complete organ,” since the scans reveal all of the major
soft tissues within the joint capsule (meniscal disks,
ligaments) and those surrounding it (tendons, musculature, vasculature); depending on the protocol used, the
cortical and trabecular bone can also be assessed.
The study by Cicuttini and colleagues (1) and
earlier investigations of cartilage (7–11) explore one
facet of the data available from this powerful technique.
In evaluating the utility of MRI, Cicuttini et al used data
from a study of 117 patients with radiographically evident OA, who underwent MRI scanning at study entry
and 2 years later. Although all scans were acquired using
the sagittal orientation, they were transformed to the
coronal plane prior to measurements (see below). The
boundaries of the cartilage were determined manually
using a defined set of rules; since that approach is
laborious and subject to observer error, it is a testament
to the training of the investigators that the interobserver
coefficients of variation (CVs) were only 2–3% (1).
Indeed, a main purpose of their study was to demonstrate that, in the future, substantial time could be saved
if measurement of only the volume of the tibial cartilage
is used for assessment of disease progression. Thus, they
investigated the correlations between cartilage volumes
in the separate compartments of the knee. Their finding
of a strong correlation between changes in femoral
cartilage volume and changes in tibial cartilage volume
in the medial and lateral tibiofemoral joints led to their
suggestion that measurement of tibial cartilage will
suffice for monitoring disease progression.
Cicuttini and coworkers discuss several aspects of
their study that reflect their original decision to acquire
the scans with the sagittal orientation (1). In such scans,
however, it can be difficult to define the cartilage
boundaries; hence, as indicated above, they reformatted
the original data into the coronal orientation prior to
volume measurement. Clearly, in addition to the work
involved, this reformatting can introduce a source of
error which could be eliminated in future studies. For
interpretation of the existing data, the authors compared
tibial cartilage volumes calculated from the original
sagittally oriented scans with those from the reformatted
coronal scans. With the latter, the lateral tibial volume
was systematically overestimated by 3.5% and the medial volume underestimated by 3.8%. Importantly, the
authors argue that, for studies of clinical progression, it
Laurie D. Hall, PhD, DSc: University of Cambridge School of
Clinical Medicine, Cambridge, UK.
Address correspondence and reprint requests to Laurie D.
Hall, PhD, DSc, Herchel Smith Laboratory for Medicinal Chemistry,
University of Cambridge School of Clinical Medicine, Robinson Way,
Cambridge CB2 2PZ, UK. E-mail: ldh11@hslmc.cam.ac.uk.
Submitted for publication June 23, 2003; accepted in revised
form October 13, 2003.
5
6
HALL
Table 1. Summary of the strengths and weaknesses of 4 methods for assessing osteoarthritic damage to
the human knee
Method
Strengths/weaknesses
Clinical rheumatologic assessment
Radiographic measurement of joint space
Not suitable for assessing early damage
Measures late-stage damage
Does not measure cartilage quality
Invasive
Views joint as a complete organ
Visualization of soft tissues (cartilage, meniscal disks,
tendons, ligaments)
Visualization of bone (cortical and trabecular)
Visualization of surroundings (musculature,
vasculature)
Arthroscopy
Magnetic resonance imaging
is the rate of cartilage change that matters rather than
the absolute volume, and that the rates derived from
reformatted scans are similar to those from the sagittal
MRI (10).
The database used by Cicuttini and colleagues is
a valuable resource and, regardless of whether others
will wish to use this specific measurement protocol, the
take-home message is certainly that further MRI studies
of OA progression should be encouraged. In this context, it is important to consider the substantial progress
made by the 2 other groups referenced in the report by
Cicuttini et al, namely Peterfy and colleagues in the US
(2) and Eckstein and colleagues in Germany (3); both of
these groups continue to be very active (12,13). In
common with Cicuttini and coworkers, those investiga-
tors acquired water-only 3-D scans from which they
derived measurements of a range of cartilage dimensions, including volume and thickness.
While space does not permit a detailed appraisal
of their many studies, it is important to note that
Eckstein et al have demonstrated that repeated measurements can be made by different independent observers, with remarkably small CVs. Clearly, this reproducibility of measurement results obtained by different
operators is extremely important in assessing OA damage and its progression, as well as measuring quantitatively the efficacy of any pharmaceutical treatment. In
that context, a recent publication (6) from a collaborative group provides evidence of the precision with which
repeated measurements can be made with the aid of
Figure 1. Computer visualization and measurement of the femoral articular cartilage, as derived from a 3-dimensional
magnetic resonance imaging scan of the knee of a 57-year-old man. Left, Both the external and internal surfaces of the cartilage
and the interface with the cortical bone; total volume is calculated to be 13.16 ml. Right, The same scan data following
computer-based “punch biopsy” of a specified region (black rectangle) are shown; the calculated volume of the “biopsy
specimen” is 0.14 ml.
EDITORIAL
7
Figure 2. Left, Two-dimensional magnetic resonance imaging scan of the distal interphalangeal (DIP) joint of a healthy 23-year-old man, measured
at 2.4T, slice thickness 1.0 mm, in-plane resolution 0.075 ⫻ 0.15 mm. All of the major structures are clearly seen, including details of the architecture
of the trabecular bone. Importantly, the surface cartilage (sc) is clearly defined by a line of low signal intensity between the high intensity from
synovial fluid (sf) and the rest of the cartilage. Right, Sagittal and coronal scans of 2 DIP joints of an osteoarthritis (OA) patient, measured using
a protocol in which the signal from the lipid in the bone marrow is suppressed (same scanning parameters as used for the image on left). The upper
pair of scans is from a joint in which the effect of age is demonstrated by the loss of clear-cut signal from the surface cartilage. The lower pair is
from a joint with advanced OA damage, which clearly shows a substantial osteophyte and focal loss of the adjacent articular cartilage. ip ⫽
interphalanx; sms ⫽ synovial membrane support; ac ⫽ articular cartilage; sus ⫽ subungual space; dp ⫽ distal phalanx; fdp ⫽ flexor digitorum
profundus; vp ⫽ volar plate.
computer software. That study included data from 10
healthy young volunteers plus 8 randomly selected OA
patients and is perhaps the most detailed investigation of
its kind, clearly demonstrating the overall robustness of
the MRI method when used by a carefully trained team.
Given the current status of MRI measurements
of knee cartilage, it is relevant to question how this
methodology might best be used for monitoring clinical
efficacy in pharmaceutical trials. In addition to the
problems associated with individual measurements,
there are two important issues related to such trials. The
first is the need for repeated measurements over a
period of months, and possibly years, which in turn
necessitates methodology by which repeated measurements of the same cartilage regions can be made. The
second is the innate variability of cartilage dimensions
between individual subjects. Furthermore, it is not obvious how best to incorporate data from age-matched
controls. Among other approaches, one solution to all
three of these problems may be the use of MRI as a form
of “noninvasive punch biopsy”(4). While utilizing the
same basic 3-D MRI scan techniques, this approach
differs in the method used to assess cartilage dimensions. Thus, software is used to measure the volume of
many small regions of cartilage selected by inspection of
the first scan from each patient (Figure 1). Some of
those cover regions that exhibit clinical damage or are
known statistically to be prone to wear and damage;
others are intentionally located remote from such areas
and are to be used as the “age-matched controls.”
In “noninvasive punch biopsy,” the settings of the
software defining each of those spatially localized regions can be used to measure the same regions in each of
the series of 3-D MRI scans acquired during the overall
duration of a trial. This procedure necessitates coregistration of each of these subsequent scans with the
original, using technology that is available in a variety of
forms. The report by Kshirsagar et al (4) amply demonstrates the technical feasibility of this approach: in 4
repeated measurements of 4 separate regions of cartilage, the CV was 2%. More recent developments by this
author in the Herchel Smith Laboratory have further
8
enhanced the ergonomics of this approach such that all
parts of the measurements are now automated. That
automation has substantially improved the overall precision and reproducibility of the measurements: remarkably, in normal subjects and those with early-stage
damage, repeated measurements can be made with CVs
of essentially 0. It remains to be seen how well this
methodology performs for monitoring damaged regions
during clinical trials. Nevertheless, the approach demonstrates the potential for effectively using local regions
of undamaged cartilage in the subjects’ damaged knee as
“age-matched controls” against which either progression
of damage, or repair, can be assessed.
What of the future? It is clear that the pioneering
work of several investigative groups has, at long last, now
started to attract many other researchers from a diverse
range of backgrounds, some of whom are forming
consortia to tackle a complex area that requires integration of the disparate skills of interdisciplinary teams. It is
also clear that it is important to create a substantial
database of MRI scans, which could facilitate understanding of the etiologic relationships between clinical
assessments and radiologic findings in patients with OA.
Indeed, such comparisons alone will provide muchneeded information on the clinical diagnosis of OA.
Furthermore, measurements from scans repeated over a
period of years will provide unique insight into the
progression of OA; at present, no other method can
provide such knowledge.
In considering the future of MRI studies, it is
important to note the large commitment to this endeavor made by the National Institutes of Health (NIH)
(5). The NIH will support the acquisition of 4 new MRI
scanners that will be used in identical protocols over a
period of 5 years to create a huge database of knee MRI
scans. Importantly, each subject in this study will also be
assessed clinically and by standard radiographic measurements. Given the present knowledge about MRI
scanning protocols, it is likely that the quality of the
scans will be state-of-the-art. It is important that future
improvements in image measurement software be accommodated within the program and that the scan data
be made widely available to other researchers. Although
the precise scanning and measurement protocols have
not yet been determined, the overall objectives of the
program were discussed at 2 meetings organized by the
NIH and are described on the NIH Web site (5).
The use of MRI in studies of the etiology and
clinical course of OA will likely expand, especially as
HALL
new technology is developed and refined, and applied
even to small joints. Indeed, as shown in studies in this
laboratory (14) and others, MRI can now provide sufficiently high spatial resolution to visualize cartilage damage in finger joints (Figure 2), specifically the distal
interphalangeal joint. Furthermore, with MRI protocols,
it is possible to quantitatively assess structural properties
of articular cartilage with precision and to distinguish
OA-damaged cartilage from that of clinically normal
“age-matched controls,” using 2 parameters referred to
as the “spin-spin relaxation time” (T2 value) and the
“magnetization transfer rate.” These parameters reflect
the interactions of water molecules with collagen and
proteoglycan and enable quantitation of the local concentrations of all 3 species. Although much further work
is needed before widespread clinical application of MRI
can be achieved, the future of this technology appears
very bright, given its potential to provide an unparalleled
picture of the joint in OA. Hopefully this picture, which
will be richer and more detailed than anything before,
will lead to both new understanding of the disease and
new approaches to treatment.
REFERENCES
1. Cicuttini FM, Wluka AE, Wang Y, Stuckey SL. Longitudinal study
of changes in tibial and femoral cartilage in knee osteoarthritis.
Arthritis Rheum 2004;50:94–7.
2. Peterfy CG, van Dijke CF, Janzen EL, Gluer CC, Namba R,
Majumdar S, et al. Quantification of articular cartilage in the knee
with pulsed saturation transfer subtraction and fat-suppressed MR
imaging: optimization and validation. Radiology 1994;192:485–91.
3. Eckstein F, Schnier M, Haubner M, Priebsch J, Glaser C,
Englmeier KH, et al. Accuracy of cartilage volume and thickness
measurements with magnetic resonance imaging. Clin Orthop
1998;352:137–48.
4. Kshirsagar AA, Watson PJ, Tyler JA, Hall LD. Measurement of
localised cartilage volume and thickness of human knee joints by
computer analysis of 3D images. Invest Radiol 1998;289:299–33.
5. National Institute of Arthritis and Musculoskeletal and Skin
Diseases. Osteoarthritis Initiative. URL: www.niams.nih.gov/ne/oi/
imaging.htm.
6. Raynauld J-P, Kauffmann C, Beaudoin G, Berthiaume M-J, de
Guise JA, Bloch DA, et al. Reliability of a quantification imaging
system using magnetic resonance images to measure cartilage
thickness and volume in human normal and osteoarthritic knees.
Osteoarthritis Cartilage 2003;11:351–60.
7. Cicuttini F, Forbes A, Morris K, Darling S, Bailey M, Stuckey S.
Gender differences in knee cartilage volume as measured by
magnetic resonance imaging. Osteoarthritis Cartilage 1999;7:
265–71.
8. Jones G, Glisson M, Hynes K, Cicuttini F. Sex and site differences
in cartilage development: a possible explanation for variations in
knee osteoarthritis in later life. Arthritis Rheum 2000;43:2543–9.
9. Cicuttini FM, Wluka AE, Stuckey SL. Tibial and femoral cartilage
changes in knee osteoarthritis. Ann Rheum Dis 2001;60:977–80.
EDITORIAL
10. Wluka AE, Stuckey S, Snaddon J, Cicuttini FM. The determinants
of change in tibial cartilage volume in osteoarthritic knees. Arthritis Rheum 2002;46:2065–72.
11. Cicuttini FM, Wluka A, Forbes A, Wolfe R. Comparison of tibial
cartilage volume and radiologic grade of the tibiofemoral joint.
Arthritis Rheum 2003;48:682–8.
12. Peterfy CG. Imaging of the disease process. Curr Opin Rheumatol
2002;14:590–6.
9
13. Eckstein F, Muller S, Faber SC, Englmeier KH, Reiser M, Putz R.
Side differences of knee joint cartilage volume, thickness, and
surface area, and correlation with lower limb dominance: an
MRI-based study. Osteoarthritis Cartilage 2002;10:914–21.
14. Hodgson RJ, Barry MA, Carpenter TA, Hall LD, Hazleman BL,
Tyler JA. Magnetic resonance imaging protocol optimisation for
evaluation of hyaline cartilage in the distal interphalangeal joint of
fingers. Invest Radiol 1995;30:522–31.
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