Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score)

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1 Osteoarthritis and Cartilage 19 (2011) 990e1002 Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score) D.J. Hunter y *, A. Guermazi z, G.H. Lo xk, A.J. Grainger {, P.G. Conaghan #, R.M. Boudreau yy, F.W. Roemer zzz y Rheumatology Department, Royal North Shore Hospital, Northern Clinical School, University of Sydney, Sydney, NSW, Australia z Quantitative Imaging Center (QIC), Department of Radiology, Boston University, School of Medicine, Boston, MA, USA x Medical Care Line, Research Care Line, and Houston Health Services Research and Development (HSR&D) Center of Excellence, Michael E. DeBakey Veterans Administration Medical Center, Houston, TX, USA k Department of Medicine, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX, USA { Department of Radiology, Leeds Teaching Hospitals & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK # Section of Musculoskeletal Disease, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK yy Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA zz Department of Radiology, Klinikum Augsburg, Augsburg, Germany article info summary Article history: Received 28 January 2011 Accepted 11 May 2011 Keywords: MRI Knee osteoarthritis Semi-quantitative score Reliability Objective: In an effort to evolve semi-quantitative scoring methods based upon limitations identified in existing tools, integrating expert readers experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the magnetic resonance imaging (MRI) Osteoarthritis Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability. Methods: The MOAKS instrument refines the scoring of bone marrow lesions (BMLs) (providing regional delineation and scoring across regions), cartilage (sub-regional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) scoring. After a training and calibration session two expert readers read MRIs of 20 knees separately. In addition, one reader re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability (calculated using the linear weighted kappa and overall percent agreement). Results: With the exception of inter-rater reliability for tibial cartilage area (kappa ¼ 0.36) and tibial osteophytes (kappa ¼ 0.49); and intra-rater reliability for tibial BML number of lesions (kappa ¼ 0.54), Hoffa-synovitis (kappa ¼ 0.42) all measures of reliability using kappa statistics were very good (0.61e0.8) or reached near-perfect agreement (0.81e1.0). Only intra-rater reliability for Hoffa-synovitis, and interrater reliability for tibial and patellar osteophytes showed overall percent agreement <75%. Conclusion: MOAKS scoring shows very good to excellent reliability for the large majority of features assessed. Further iterative development and research will include assessment of its validation and responsiveness. Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Introduction Magnetic resonance imaging (MRI) semi-quantitative scoring of knee osteoarthritis (OA) has proven to be a valuable method for performing multi-feature joint assessment 1,2. Such approaches * Address correspondence and reprint requests to: D.J. Hunter, Rheumatology Department, Northern Clinical School, Royal North Shore Hospital, University of Sydney, St Leonards, Sydney, NSW 2065, Australia. Tel: ; Fax: address: David.Hunter@sydney.edu.au (D.J. Hunter). score, in a semi-quantitative manner, a variety of features that are currently believed to be relevant to the functional integrity of the knee and/or are potentially involved in the pathophysiology of OA. These articular features include articular cartilage morphology, subchondral bone marrow lesions (BMLs) and cysts, osteophytes, the menisci, the anterior and posterior cruciate ligaments, the collateral ligaments, synovitis, joint effusion, bone attrition, intraarticular loose bodies, and periarticular cysts/bursitis. Several methods for semi-quantitative assessment of knee OA have been developed 3e5. The first of the published instruments, the Whole-Organ MRI Score (WORMS), was developed cognizant of the /$ e see front matter Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi: /j.joca

2 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e potential of MRI to provide a measure of all potentially relevant knee OA structures 4. After identifying some limitations with WORMS 6,7, work was undertaken to develop the Boston Leeds OA Knee Score (BLOKS) 5. Both of these tools are in widespread use in various observational studies and clinical trials. Both WORMS and BLOKS have been widely disseminated and used, although the number of direct comparisons of the two instruments to date was quite limited 5. Recently the validity and reliability of WORMS and BLOKS was compared 8e10. This comparison has been helpful in identifying the relative merits and weaknesses of these instruments with regards to certain features assumed to be most relevant to the natural history of the disease including cartilage, meniscus and BMLs. Both instruments had certain limitations and if one were to use the extant literature on published semi-quantitative scoring instruments the discerning investigator would need to choose from a complex array of measures from these two different instruments. For example, WORMS meniscal scoring method mixes multiple different constructs and for BLOKS, application of the BML scoring system was cumbersome and complex and parts of it seemed redundant. Both of these tools have also undergone unpublished iterations that have made it difficult for the naïve reader to determine the differences between the original instruments description and that which has been used in published research. To facilitate appraisal it is important that iterative developments be made public. A number of large epidemiologic studies and clinical trials are maturing to the point where large scale scoring is commencing, and it is important that iterative evolution of existing instruments occur with past research findings in mind. In an effort to evolve semiquantitative scoring methods based upon limitations identified in existing tools, integrating expert readers experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the MRI OA Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability. Methods Upon recognition of the limitations in existing scoring methods iterations were made to elements of the original instruments. The experts (DJH, AG, GHL, AJG, PGC, FR, DG) involved met to consider the limitations of the existing scoring for each pathological feature: BMLs and meniscal abnormalities were the most important areas for revision. The focus of the current exercise was therefore to refine the scoring of BMLs, to include sub-regional assessment, to omit some areas of redundancy in cartilage and BML scoring, and to refine the elements of meniscal morphology. After consensus was reached on the new definitions, a intra- and inter-rater reliability exercise was undertaken. Fig. 1. Subregional division of the patella in the axial plane. Axial T2w image shows the medial (M) and lateral (L) portions of the patella as divided in MOAKS. Note that the patellar apex is part of the medial subregion (arrow). 1. The patella is divided into two sub-regions, the medial and lateral patella on the axial view (see Fig. 1). The patellar crista (also called apex) is allocated to the medial subregion. 2. The femur is divided into six sub-regions e medial and lateral trochlea, medial and lateral central femur, and the medial and lateral posterior femur. Method of dividing the sub-regions (see Fig. 2): i. Trochlea is defined as the femoral articular surface of the patellofemoral (PF) joint. For the division between the trochlea and central regions, on the sagittal image a line is drawn tangentially to the anterior aspect of the proximal tibia (at the margin of the tibial plateau) until it intersects the femoral surface. The division between the central femur and the posterior femur is a line constructed vertically from the posterior aspect of the tibia. (The rationale for choosing these Description of MOAKS The MOAKS instrument was developed and tested on images obtained on a 3.0 T MRI system with a dedicated peripheral knee coil. Other systems with different field strengths will need to be evaluated. Delineation of subregional divisions OA can affect one or multiple compartments in the knee. In MOAKS the knee is divided into 14 articular sub-regions for scoring articular cartilage and BMLs and in addition the subspinous region is added for BML scoring: Fig. 2. Anatomical delineation of femur into trochlea (T), central (C) and posterior (P) regions on sagittal projection. Sagittal projection depicts delineation of the tibia into anterior, central and posterior sub-regions, which is divided into equal thirds.

3 992 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e1002 Table I Scoring system for BMLs Size of BML (including volume of any associated cysts) by volume No. of BMLs counted % of lesion that is BML (vs cyst) 0: none 0: none 1: <33% of subregional volume 1: <33% 2: 33e66% of subregional volume 2: 33e66% 3: >66% of subregional volume 3: >66% 1. BMLs and Cysts BMLs and cysts e include areas of presumed BML [areas of ill-delineated signal within the trabecular bone that are hypointense on T1-weighted images and hyperintense on T2-weighted fat-suppressed (fs) images] and associated subarticular bone marrow cysts (defined as well-delineated lesions of fluid equivalent signal directly adjacent to the subchondral plate). Fig. 3. Coronal IW image shows anatomical delineation of the tibia into medial, subspinous (SS) and lateral sub-regions. The femur is divided into the medial and lateral femoral condyle. The intercondylar notch is considered to be part of the medial femur. divisions, as opposed to choosing the meniscal boundaries, was the concern that meniscal subluxation and degeneration would introduce variability into this delineation if used). ii. Anterior and posterior tibial margins are defined irrespective of the presence of osteophytes iii. The femoral notch is defined as being part of the medial femur. iv. The superior border of the femur is the physeal line. The posterior border of the trochlea region is the anterior 50% of this region (as measured along the length of the epiphyseal line) (see Fig. 2). 3. The tibia is divided into three medial (anterior, central and posterior) and three lateral (anterior, central and posterior) subregions covered by articular cartilage, and the subspinous subregion [SS-region delineated by the tibial spines (Fig. 3)]. For the anterior, central and posterior divisions the tibia is divided into equal thirds excluding the presence of osteophytes. Special considerations for scoring in any region. If a lesion spans more than one subregion, the lesion needs to be scored in all subregions, especially as the MOAKS system is modified into a volumeoriented approach and not lesional. Also, if a feature occurs within the subspinous region, but extends also into one or more of the medial or lateral tibial sub-regions, the lesion will be scored in the subspinous region but also in the additional tibial sub-regions separately. Description of scoring for individual features Each feature is scored separately. We have chosen a number of commonly recognized features based on their likely relevance to pain and structural damage or progression of OA. The scoring for BMLs and articular cartilage described is by sub-regions as outlined above. Scoring of osteophytes will be performed at defined locations or sites. For each joint morphologic feature, we have listed the number (if there are multiple abnormalities), its location and grade. For BML and cartilage which are scored by region the score is assigned for the region. We have also described preferred pulse sequences to delineate each feature. BMLs will be scored based on the standardized regions outlined previously (p 4e5). Multiple BMLs can occur within each region. Each region will generate a single grade for size inclusive of all BMLs into one score, the number of BMLs per subregion will be counted and % of lesions that is BML as distinct from cyst will be coded (see Table I). a. Each subregion will be graded for BML (including ill-defined lesion and cysts) size in regard to the total volume of the subregion occupied by BML(s) (see Fig. 4). Consequently, a BML in a smaller subregion will be smaller when compared to a BML that is assigned the same grade but is present in a larger subregion, or two BMLs of the same absolute size might be assigned different grades if present in sub-regions with differing volume. b. Percentage of the volume of each BML that is BML (as distinct from cyst) is graded as; grade 0 ¼ none, grade 1 <33%, grade 2 ¼ 33e66% and grade 3 >66%. c. If a cyst is present without an associated BML, then cysts will be scored as a 0 for size % of lesion that is BML. The scoring for size should be identical to that for BMLs (Table I). In contrast, if a BML does not include any portion of a cyst, the % of the lesion that is BML vs cyst score would be 3. d. Do not score marrow signal within osteophytes, however if the lesion extends beyond the osteophyte then it should be scored. Pulse sequences. Suggested pulse sequences to evaluate BMLs are turbo spin-echo (TSE) T2-/intermediate- or proton-density (PD)- weighted fat-saturated or Short TI Inversion Recovery (STIR) sequences in the axial, coronal, and sagittal planes 11. T1-weighted fs images after intravenous administration of a gadolinium-based contrast agent may be used alternatively 12. 3D TSE sequences such as Cube (GE), XETA (extended Echo Train Acquisition) or SPACE (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution, Siemens) might possibly be of use for BML assessment in the future 13e15. Gradient echo-type sequences, even with robust fat suppression or water excitation, are notoriously insensitive to bone marrow abnormalities due to trabecular magnetic susceptibility of T2* effects, which may result in underestimation of the size of noncystic BMLs 16,17. Recent studies have demonstrated that these sequences are also less sensitive in the detection of non-cystic BMLs when using fluid-sensitive fast spin-echo (FSE) sequences as the reference standard 16,18e21. We do not recommend the use of these sequences for scoring BMLs.

4 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e Fig. 4. BML grading. Grade 0 ¼ none, grade 1 <33% of subregional volume, grade 2 ¼ 33e66% of subregional volume and grade 3 >66% of subregional volume. A. Coronal T2 w image shows small grade 1 BML in central subregion of medial tibia. B. A grade 2 BML is depicted in central subregion of medial femur. C. Grade 3 BMLs in the central sub-regions of the medial femur (arrows) and central medial tibia (arrowheads). D. Coronal image shows BML consisting of non-cystic/ill-defined portion (arrowheads) and cystic (arrow) part. 2. Articular cartilage Although many joint structures are affected in OA, articular cartilage is one of the main tissues involved in the disease process. The rationale for the cartilage score was to provide separate scores for the size (i.e., area affected) and depth of cartilage damage in each of the sub-regions. Each articular cartilage region (except the subspinous region) is graded for size of any cartilage loss (including partial and fullthickness loss) as a % of surface area as related to the size of each individual region surface (see Fig. 5) and % of loss in this subregion that is full-thickness loss (Table II and Fig. 5). Description of morphology at individual sites is not to be used to create cumulative scores of the knee as histopathology is unclear and this scale is not necessarily linear. Pulse sequences. Optimal pulse sequences to evaluate cartilage are still undergoing extensive review. We refer to current state-of-the art reviews of imaging of articular cartilage 22. For assessment of early OA commonly used gradient-echo sequences such as spoiled gradient recalled acquisition (SPGR), Fast Low Angle Shot Water Excitation (FLASH), dual echo steady state (DESS) or similar are not suitable as these depict focal defects in an inferior manner when compared to standard T2/IW (Intermediate-Weighted)- or PD (Proton Density)-w fs turbo-spin-echo sequences 23e Osteophytes Osteophytes are osteo-cartilaginous protrusions growing at the margins of osteoarthritic joints from a process that involves endochondral ossification. Previous radiographic studies have highlighted this feature as a hallmark of disease 27. For MOAKS, osteophytes are scored in each of the 12 locations or sites outlined below (Table III) and graded according to size where: Grade 0 ¼ none; Grade 1 ¼ small; Grade 2 ¼ medium; Grade 3 ¼ large. Osteophytes along the trochlea, central and posterior margins of the femoral condyles and tibial plateaus, and along the medial, lateral, superior and inferior margins of the patella. Posterior Table II Delineation of grading for cartilage Size of any cartilage loss (including partial and full-thickness loss) % full-thickness cartilage loss of the region as a % of surface area as related to the size of each individual region 0: none 0: none 1: <10% of region of cartilage surface area 1: <10% of region of cartilage surface area 2: 10e75% of region of cartilage surface area 2: 10e75% of region of cartilage surface area 3: >75% of region of cartilage surface area 3: >75% of region of cartilage surface area

5 994 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e1002 As commonly employed contrast-enhanced sequences are not available in large OA studies due to cost concerns and possible side reactions, a surrogate of signal changes in Hoffa s fat pad has been applied that has been shown on biopsy to represent mild chronic synovitis 32. This abnormality is best described as diffuse hyperintense signal on T2/PD/IW-w fat suppressed sequences within the fat pad. It has to be noted that in addition to synovitis these signal changes could also be attributed to other etiologies such as post-arthroscopic changes or Hoffa s disease 33. Despite this non-specificity these signal changes are referred to as Hoffa-synovitis in MOAKS. i. Hoffa-synovitis score (on sagittal image) (one single score for assessment of degree of hyperintensity in Hoffa s fat pad) based on the region highlighted in Fig. 8. Score is based on size: 0 ¼ normal; 1 ¼ mild, 2 ¼ moderate, 3 ¼ severe. Fig. 5. Grade for size of any cartilage loss as a % of surface area as related to the size of each individual region. Grade 0 ¼ none, grade 1 <10% of region of cartilage surface area, grade 2 ¼ 10e75% of region of cartilage surface area and grade 3 >75% of region of cartilage surface area. (Drawing courtesy of Daichi Hayashi, MD). femoral osteophytes are assessed peripherally and centrally. The larger osteophyte for either, peripheral or central, location will be scored (Fig. 6). a. Size of osteophyte should reflect protuberance (how far the osteophyte extends from the joint) rather than total volume of osteophyte (see Fig. 7). b. Score the largest osteophyte within a given location. Pulse sequences. Optimal pulse sequences to evaluate osteophytes are standard non-fs short echo time (TE)-weighted (preferably T1 over PD) or gradient-echo-type such as SPGR, FLASH, DESS etc. images in the axial, coronal, and sagittal planes. They may also be assessed on fs water-sensitive sequences Hoffa s synovitis and synovitis e effusion Synovitis and effusion are frequently present in OA and in some studies this feature correlated with pain and other clinical outcomes although the literature is conflicting 28e30. Quantitative MRI markers of synovitis include thickness (or volume) of synovial tissue and the rate of synovial enhancement following intravenous injection of contrast material 31. Table III Sites for osteophyte scoring Osteophyte location Slice orientation Anterior femur (trochlea) Medial Sagittal/Axial Lateral Posterior femur Medial Sagittal/Axial Lateral Central femur Medial Coronal Lateral Patella Superior Sagittal Inferior Medial Axial Lateral Tibia Medial Coronal Lateral Pulse sequences. Suggested pulse sequences to evaluate regions for Hoffa-synovitis are T2/IW- or PD-weighted fat-saturated images in the mid-slices of the sagittal plane 28,29. Effusions occur frequently in OA. Recent studies suggest that large synovial effusions may be associated with pain and stiffness in patients with OA 28. It is important to note that effusion (fluid equivalent signal within the joint cavity) on T2/IW/PDw images includes synovitis and effusion 34. Thus, this imaging measure should preferably referred to as effusion-synovitis. Scores (Table IV) should be obtained from axial views (Fig. 9). Paraarticular cysts and ganglia should not be included in this score as they are considered separately. Pulse sequences. True amount of joint effusion may be assessed as intra-articular hypointensity on T1w images after i.v. contrast administration. T2/IW/PDw images show intra-articular hyperintensity that represents a composite of effusion and synovitis Meniscus The meniscus has many functions in the knee, including load bearing, shock absorption, stability enhancement and lubrication 35. Degenerative meniscal lesions such as horizontal cleavages, oblique or complex tears are associated with older age 36. By the time radiographic disease develops, the overwhelming majority of persons have meniscal lesions 36,37. The studies that have explored the relationship between the meniscus and risk of disease progression in OA provide a clear indication of the increased risk inherent with damage to this vital tissue 38,39. Changes in position (also termed subluxation or extrusion) and meniscal morphologic change manifest as tears or loss of substance have both been shown to predispose to cartilage loss. We chose a scoring system that delineated both of these items and provided detail on what the abnormality was and where in the meniscus this occurred. a. Extrusion: Four areas where extrusion is scored: 1. Medial meniscus: Medial extrusion relative to medial tibial margin (coronal image). 2. Medial meniscus: Anterior extrusion (sagittal image) e where extrusion is maximum. 3. Lateral meniscus: Lateral extrusion relative to lateral tibial margin (coronal image). 4. Lateral meniscus: Anterior extrusion (sagittal image) where extrusion is maximum. Grading for extrusion: Grade 0:<2 mm; Grade 1: 2e2.9 mm, Grade 2: 3e4.9 mm; Grade 3: >5 mm.

6 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e Fig. 6. Locations for osteophytes scoring. A. Coronal plane. Osteophytes are scored at the marginal locations of the medial and lateral femur and tibia, respectively (arrowheads). B. Sagittal plane. Osteophytes are scored at the superior and inferior patellar pole (arrowheads). C. Axial plane. Osteophytes are scored at the medial and lateral patella poles (arrowheads), at the anterior medial and lateral femur (black arrows) and the posterior femur medial and lateral (white arrows). Note that there are two locations medially and laterally for osteophytes scoring at the posterior femur, the central and peripheral location. Only the larger osteophyte for either the central or peripheral location will be scored. Note: we wanted to capture anterior extrusion to see if this is independently predictive of cartilage loss/pain/etc. compared with medial or lateral extrusion. For each measurement the reference will be the edge of the tibial plateau (excluding any osteophytes). b. Morphology: (scored on medial and lateral meniscus for the anterior, body and posterior horn). The anterior and posterior horn regions are scored using the sagittal sequences and the body is scored using the coronal sequences. Morphologic features scored: i. Signal (not extending through meniscal surface i.e., not a tear): Y/N. a. Signal is defined as above as compared with tears which are defined as high signal extending to an articular surface on at least two slices. ii. Vertical tear (includes radial and longitudinal tears) e must extend to both the femoral and tibial surfaces: Y/N. iii. Horizontal and radial tear: must extend from the periphery of the meniscus to either a femoral or tibial surface. Y/N. iv. Complex tear: as defined by high signal that extends to both the tibial and femoral surfaces and 3 points on those surfaces). Y/N. v. Root tear (posterior horn): Y/N. vi. Partial maceration: as defined by loss of morphological substance of the meniscus and with or without associated increased signal in the remaining meniscal tissue. Y/N. vii. Progressive partial maceration: Progressive partial maceration as compared to the previous visit. Y/N. viii. Complete maceration: No meniscal substance is visible. Y/N. ix. Meniscal cyst: Y/N. x. Meniscal hypertrophy is defined as definite increase in meniscal volume in given subregion when compared to normal: Y/N. Pulse sequences. Optimal sequences to evaluate menisci are T1, T2w or PD fat-saturated images in both coronal and sagittal planes 40,41. As for BMLs, newly developed 3D FSE sequences might alternatively be used for meniscal assessment Ligaments/tendon Anterior cruciate ligament (ACL) tears will be recorded as either absent or present. Partial tears are infrequent and reportedly prone to poor reliability on interpretation 43. Thus, partial tears are scored as normal in MOAKS. Only definite complete tears will be scored. a. ACL: Score: normal (0)/complete tear (1). i. Associated with BML/cyst at site of insertion or origin?: Y/N. ii. ACL Repair: Y/N.

7 996 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e1002 Fig. 7. Scoring of osteophytes. Grade 0 ¼ none, grade 1 ¼ small, grade 2 ¼ medium and grade 3 ¼ large. A. Grade 1 osteophyte medial femur. B. Grade 2 osteophyte lateral femur. C. Grade 3 osteophyte lateral femur. Size of osteophyte should reflect protuberance (how far the osteophyte extends from the joint) rather than total volume of osteophyte. b. Posterior Cruciate Ligament (PCL): Score: normal (0)/complete tear (1). i. Associated with BML/cyst at site of insertion or origin?: Y/N. c. Patellar tendon: Score: 0: no signal abnormality/1: signal abnormality present. Pulse sequences. Optimal sequences to evaluate the aforementioned ligaments are coronal, axial and sagittal, PD or IW, fat TSE images, while 3D sequences also appear promising 17,44,45. Additional paracoronal T2-w sequences might be helpful to differentiate partial from full-thickness tears Periarticular features a. Pes anserine bursitis e absent/present This is a bursa that lies anterior and inferior to the medial tibial plateau and is a potential source of pain around the knee. If there is increased signal in this bursa, bursitis is scored as being present. b. Iliotibial band (ITB) signal e absent/present The ITB is a strong, dense, broad layer of fascia that is part of the fascia lata. The ITB encases the tensor fasciae lata which helps to steady the trunk on the thigh. 3 / 4 of the gluteus maximus inserts into the iliotibial tract and the distal end inserts at the lateral tibial plateau. High signal between the ITB and the femoral cortex may represent irritation of the ITB and is common in medial OA. However, this is also Table IV Delineation of grading for effusion-synovitis Fig. 8. Hoffa-synovitis. Sagittal T2w image shows grade 2 hyperintense signal changes in Hoffa s fat pad consistent with Hoffa-synovitis. Size of effusion-synovitis 0: physiologic amount 1: small e fluid continuous in the retropatellar space 2: medium e with slight convexity of the suprapatellar bursa 3: large e evidence of capsular distention

8 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e Fig. 9. Effusion-synovitis. Hyperintensity within the articular cavity represents a composite of effusion and synovial thickening that cannot be distinguished from each other in the absence of contrast. Grade 0 ¼ none, grade 1 ¼ small, grade 2 ¼ medium and grade 3 ¼ large. A. Grade 0 effusion-synovitis. Normal intra-articular hyperintensity is depicted. B. Grade 1 effusion-synovitis. C. Grade 2 effusion-synovitis. D. Grade 3 effusion-synovitis. anon-specific finding and often asymptomatic 47. If there is high signal in this structure, ITB signal should be scored as being present. c. Popliteal cyst-absent/present Popliteal cysts are not true cysts and represent fluid in the semimembranosusemedial gastrocnemius bursa. The communication between the joint space and gastrocnemiusesemimembranosus bursa allows intra-articular joint fluid to communicate with this bursa 48. If there is any fluid in this region, this feature should be scored as being present. Pulse sequence. Optimal sequences for evaluating popliteal cysts are PD or T2-weighted axial images. d. Infrapatellar bursa signal e absent/present This is a bursa located inferior to Hoffa s fat pad adjacent to the patellar tendon and is a potential source of pain around the knee. If there is high signal in this bursa, this feature should be scored as being present. e. Prepatellar bursa signal e absent/present This is a bursa that lies anterior to the patella and is a potential source of pain around the knee. High signal anterior to the patella tendon is a very common non-specific finding of often no clinical relevance. True bursitis is characterized by well demarcated fluid equivalent signal within this structure; only then should this feature be scored as being present. f. Ganglion cyst i. Associated with the tibio-fibular joint: present/absent. ii. Associated with PCL and ACL: present/absent. iii. Other: present/absent. Loose bodies: Scale: absent/present. Table V provides a summary of the changes in the new score (MOAKS) from older instruments including BLOKS 5 and WORMS 4. Study images for reliability exercise. The images for the reliability exercise were chosen at random from MRI scans undertaken

9 998 Table V Features that are scored in MOAKS in comparison to the original BLOKS instrument and WORMS score. We used BLOKS as the starting point, and the alterations in MOAKS reflect deviation from BLOKS MRI feature Original BLOKS score Original WORMS score Alteration in MOAKS BML size Score of 0e3 applied for BML volume in nine different articular sub-regions. Each BML within a subregion receives an individual size score. Summed BML size/volume for subregion from 0 to 3 in regard to percentage of subregional bone volume. Modify thresholds from 10 e 85% to 33e66%. Instead of scoring EACH BML, the entire subregion receives one size score based on the threshold listed above. Grade for regions-use same sub-regions as proposed for cartilage e with the addition of the subspinous region. Count no. of lesions. BML % area Score of 0e3 applied for % surface area adjacent to subchondral plate. e Omitted from new scoring system. % of lesion BML rather than cyst Cartilage 1 Score of 0e3 for % of lesion that is BML as distinct from cyst. Score of 0e3 for size of loss and % of loss in region that is full thickness. Summed cyst size/volume for subregion from 0 to 3 in regard to percentage of subregional bone volume. Subregional approach: Scores from 0 to 6 depending on depth and extent of cartilage loss. Intrachondral cartilage signal additionally scored as present/absent. No change. Further subdivision of the medial and lateral tibial region into anterior, central and posterior and subdivision of the weight-bearing femur into central and posterior. Cartilage 2 Extent of any cartilage loss at specified points. e Omitted from new scoring system. Osteophyte Score of 0e3 applied for osteophyte size in Score of 0e7 applied for osteophyte size at No change. 12 locations. 16 sites. Synovitis Score of 0e3 applied for synovial volume. Combined effusion/synovitis score. Score of 0e3 applied to signal changes in Hoffa s fat pad. Feature renamed as Hoffa-synovitis Effusion Score of 0e3 applied for size of effusion. Score of 0e3 applied for size of effusion. Feature renamed to Effusion-synovitis Scoring parameters are unchanged. Meniscal extrusion Score of 0e3 applied for amount of Not scored. No change. extrusion in four locations. Meniscal signal Scored as present or absent in six regions. Not scored. No change. Meniscus tear Type of tear or degenerative process scored as present or absent in six regions. Anterior horn, body, posterior horn scored separately in medial/lateral meniscus from 0 to 4: Add meniscal hypertrophy, partial maceration and progressive partial maceration. 1: minor radial or parrot beak tear 2: non-displaced tear or prior surgical repair 3: displaced tear or partial resection 4: complete maceration/destruction or complete resection. Ligaments Presence/absence of tear. Presence/absence of tear. No change. Periarticular features Presence/absence. Presence/absence. No change. D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e1002

10 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e Table VI The reliability for reading of MOAKS features (weighted kappa and percent agreement) MOAKS feature Region Intra-rater Inter-rater Weighted kappa (95%CI) Percent agreement Weighted kappa (95%CI) Percent agreement Cartilage area Femoral 0.92 (0.77e1.00) (0.27e0.98) 0.80 Tibial 0.73 (0.47e1.00) (0.05e0.67) 0.70 Patella 0.71 (0.43e0.99) (0.42e0.99) 0.75 Cartilage depth Femoral 0.95 (0.85e1.00) (0.60e0.98) 0.80 Tibial 0.83 (0.69e0.96) (0.52e0.94) 0.75 Patella 0.92 (0.82e1.00) (0.72e0.98) 0.80 BML size Femoral 0.85 (0.69e1.00) (0.69e0.95) 0.80 Tibial 0.76 (0.55e0.98) (0.86e1.00) 0.95 Patella 1.00 (1.00e1.00) (0.74e1.00) 0.85 Subspinous 0.79 (0.60e0.99) (0.57e0.94) 0.75 BML, %cyst Femoral 0.57 (0.18e0.95) (0.40e1.00) 0.90 Tibial 0.50 (0.23e0.97) (0.46e1.00) 0.85 Patella 0.88 (0.73e1.00) (1.00e1.00) 1.00 Subspinous 0.70 (0.36e1.00) (0.36e0.93) 0.75 BML, no. of lesions Femoral 0.84 (0.68e1.00) (0.64e0.92) 0.75 Tibial 0.54 (0.30e0.77) (0.62e1.00) 0.85 Patella 0.90 (0.77e1.00) (0.82e1.00) 0.90 Subspinous 0.80 (0.63e0.97) (0.51e0.93) 0.75 Meniscus morphology Medial 1.00 (1.00e1.00) (0.89e1.00) 0.95 Lateral 0.91 (0.77e1.00) (0.86e1.00) 0.95 Meniscal extrusion Medial 0.82 (0.67e0.98) (0.46e0.86) 0.60 Lateral 0.89 (0.75e1.00) (0.67e0.91) 0.80 Osteophytes Femoral 0.64 (0.36e0.92) (0.58e1.00) 0.95 Tibial 0.70 (0.50e0.91) (0.24e0.74) 0.55 Patella 0.84 (0.67e1.00) (0.39e0.89) 0.65 Hoffa-synovitis e 0.42 (0.14e0.70) (0.47e0.93) 0.75 Effusion-synovitis e 0.90 (0.78e1.00) (0.52e0.92) 0.70 within the National Institutes of Health (NIH) OA Initiative (OAI, The OAI is a multi-center, longitudinal, prospective observational study of knee OA. The overall aim of the OAI is to develop a public domain research resource to facilitate the scientific evaluation of biomarkers for OA as potential surrogate endpoints for disease onset and progression. The OAI database provides an unparalleled state-of-the-art database showing both the natural progression of the disease and information on imaging and biochemical biomarkers and outcome measures. From 329 participants in the OAI Progression subcohort within OAI Group C (those enrolled through 4/30/2005) with MRI performed on both knees at baseline, all knees with K&L grade 2 or 3 were identified (n ¼ 339). A 2 2 factorial design was formed incorporating the factors of side (left vs right knee) and Kellgren and Lawrence (KL) grade (2 or 3). For subjects with both knees having K&L grade 2 or 3, only one knee was randomly selected for potential inclusion. The final 2 2 factorial random sample of 20 knees for the reliability study included five randomly selected knees in each of the four cells. A computerized uniform random number between 0 and 1 was assigned to each knee, sorted, then the five knees in each cell with the lowest assigned numbers comprised the randomly selected knees in each cell (e.g., n ¼ 5 of 90 knees in cell left knee with K&L grade ¼ 3 were randomly selected, etc.). MRI acquisition. MRI of both knees was performed on 3 T systems (Siemens Trio, Erlangen, Germany). MRIs were acquired with a USA Instruments (USAI) quadrature transmit/receive knee coil. The coronal IW 2D turbo spin-echo, a sagittal 3D DESS sequence, coronal and axial multiplanar reformations of the 3D DESS and a sagittal IW fs FSE sequence were used for scoring MOAKS. Details of the full OAI pulse sequence protocol and the sequence parameters have been published in detail recently 49. The sagittal T2 mapping and coronal 3D T1-weighted Fast Low Angle Shot Water Excitation (FLASH WE) sequences were not used for semiquantitative assessment. Assessment of reliability. After an initial training and calibration session on 10 cases that were not included in the reliability exercise, two expert readers with 10 and 8 years experience in semiquantitative MRI assessment of knee OA respectively, (AG, FR) independently read MRIs of the 20 knees from the OAI. In addition, one reader (FR) re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability [calculated using the linear weighted kappa (95% confidence interval (CI))] and the percent agreement of the scoring exercise. Results The reliability of the instrument was assessed on 20 subjects with a mean age of 57.8 years [standard deviation (SD) 9.8] and a mean body mass index (BMI) of 31.4 kg/m 2 (SD 5.0). Fifty-five percent (n ¼ 11) were female. Of the 20 knees that were assessed their Kellgren and Lawrence Grades were K&L ¼ 2 in 10 knees, K&L ¼ 3 in 10 knees. The reliability for the features described above is reported in Table VI. With the exception of inter-rater reliability for tibial cartilage surface area (kappa ¼ 0.36), tibial osteophytes (kappa ¼ 0.49) and intercondylar synovitis (kappa ¼ 0.49); and intra-rater reliability for tibial BML number of lesions (kappa ¼ 0.54), infrapatellar synovitis (kappa ¼ 0.42) and intercondylar synovitis (kappa ¼ 0.57) all measures of reliability were very good (0.61e0.8) or reached near-perfect agreement (0.81e1.0) according to the criteria developed by Landis and Koch 50. The low prevalence of certain features in certain sub-regions may have adversely affected the kappa results hence the percent agreement was also calculated. The majority of features were scored with overall percent agreement above 75% for both, the intra- and inter-reader exercise. Only intrarater reliability for Hoffa-synovitis (55%), and inter-rater reliability for tibial (55%) and patellar (65%) osteophytes showed overall percent agreement <75%.

11 1000 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e1002 Discussion The structural determinants of mechanical dysfunction and pain in arthritis are presently not well understood, but probably involve a multitude of interactive pathways characterized by changes in structure and function of the whole joint 51. The current practice of monitoring only a few of these features (usually radiographicallyassessed joint-space narrowing and osteophytes) provides only a restricted view of the disease process and lessens the utility of such assessments. Semi-quantitative MRI scoring will continue to provide important insights into the etiopathogenesis of disease as well as structureefunction relationships. As new insights continue to develop the field, this scoring instrument, used to assess structural change in knee OA will similarly need to evolve. This report provides data on the reliability of structural features scored using MOAKS: a semi-quantitative scoring instrument for MRI assessment of knee OA that builds on the prior experiences of BLOKS and other semi-quantitative scoring tools. The MOAKS instrument refines the scoring of BMLs (providing regional delineation and scoring across regions), cartilage (subregional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) and subluxation scoring. In addition we decided to omit some areas of redundancy including the second cartilage scoring method that was part of the original BLOKS instrument and assessed cartilage at defined locations in a specific image and also omitted BML adjacency to subchondral plate scoring. The timing of this work is relevant as large scale scoring exercises are about to commence in a number of studies including the OAI. Importantly, the measurement properties (including construct and predictive validity and the responsiveness) of these modifications will need to be assessed to ensure their credibility. The reliability of most of the features that were scored in this exercise was substantial or almost perfect agreement according to Landis and Koch criteria 50. Some of the features however had only moderate agreement when using kappa statistics including intrarater reliability for femoral and tibial cystic portions of BMLs, count of tibial BMLs, and Hoffa-synovitis, and inter-rater reliability for tibial cartilage area and tibial osteophytes. For some of these features low frequencies of non-zero scores are accountable for these kappa values. Overall percent agreement was good to perfect for almost all features. Some of the features listed are exploratory in nature and warrant further investigation, including measures of meniscal extrusion. The magnitude of the meniscal extrusion is the same that we have previously used in BLOKS and that has been used in prior analyses 39,52,53. The extent of analysis in the research literature describing the importance of anterior or posterior extrusion is limited. In our previous analyses anterior extrusion has been associated with an increased risk of cartilage loss 39. In conclusion, we have refined an existing scoring instrument and assessed its reliability. MOAKS demonstrates reasonable reliability. Further iterative development and research will include assessment of its validation and responsiveness for use in both clinical trials and epidemiological studies. This will allow determination of the significance of specific features to determine if there are subsets that can be consolidated or eliminated to simplify the instrument. Contributions DJH conceived and designed the study, drafted the manuscript and takes responsibility for the integrity of the work as a whole, from inception to finished article. All authors contributed to acquisition of the data. All authors critically revised the manuscript and gave final approval of the article for submission. Conflict of interest statement The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. David Hunter receives research or institutional support from AstraZeneca, DonJoy, Lilly, Merck, NIH, Pfizer, Stryker and Wyeth. Ali Guermazi receives research or institutional support from NIH and GE Healthcare. He is consultant to MerckSerono, Stryker, Genzyme and Novartis. He is President of BICL (Boston Imaging Core Lab), LLC, a company providing radiologic image assessment services. Frank Roemer is shareholder of Boston Imaging Core Lab (BICL) LLC., a company providing radiologic image assessment services. Other authors declared no conflict of interest. Acknowledgments Dr Hunter is supported by an Australian Research Council Future Fellowship. We would like to acknowledge the support of Dr Daniel Gale who contributed to BLOKS and the initial development of MOAKS. References 1. Hunter DJ, Zhang W, Conaghan PG, Hirko K, Menashe L, Reichmann WM, et al. Responsiveness and reliability of MRI in knee osteoarthritis: a meta-analysis of published evidence. Osteoarthritis Cartilage 2011;19:589e Hunter DJ, Zhang W, Conaghan PG, Hirko K, Menashe L, Li L, et al. Systematic review of the concurrent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage 2011;19:557e Kornaat PR, Ceulemans RY, Kroon HM, Riyazi N, Kloppenburg M, Carter WO, et al. MRI assessment of knee osteoarthritis: knee osteoarthritis scoring system (KOSS)einter-observer and intraobserver reproducibility of a compartment-based scoring system. Skeletal Radiol 2005;34:95e Peterfy CG, Guermazi A, Zaim S, Tirman PF, Miaux Y, White D, et al. Whole-organ magnetic resonance imaging score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage 2004;12:177e Hunter DJ, Lo GH, Gale D, Grainger AJ, Guermazi A, Conaghan PG. The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston Leeds Osteoarthritis Knee Score). Ann Rheum Dis 2008;67:206e Hunter D, Conaghan P, Peterfy C, Bloch D, Guermazi A, Woodworth T, et al. Responsiveness, effect size, and smallest detectable difference of magnetic resonance imaging in knee osteoarthritis. Osteoarthritis Cartilage 2006;14(Suppl 1):112e5. 7. Conaghan P, Tennant A, Peterfy C, Woodworth T, Stevens R, Guermazi A, et al. Examining a whole-organ magnetic resonance imaging scoring system for osteoarthritis of the knee using Rasch analysis. Osteoarthritis Cartilage 2006;14(Suppl 1): 116e Lynch JA, Roemer FW, Nevitt MC, Felson DT, Niu J, Eaton CB, et al. Comparison of BLOKS and WORMS scoring systems part I. Cross sectional comparison of methods to assess cartilage morphology, meniscal damage and bone marrow lesions on knee MRI: data from the osteoarthritis initiative. Osteoarthritis Cartilage 2010;18:1393e401.

12 D.J. Hunter et al. / Osteoarthritis and Cartilage 19 (2011) 990e Felson DT, Lynch J, Guermazi A, Roemer FW, Niu J, McAlindon T, et al. Comparison of BLOKS and WORMS scoring systems part II. Longitudinal assessment of knee MRIs for osteoarthritis and suggested approach based on their performance: data from the osteoarthritis initiative. Osteoarthritis Cartilage 2010;18:1402e Hunter DJ, Zaim S, Mosher TJ. What semi-quantitative scoring instrument for knee OA MRI should you use? Osteoarthritis Cartilage 2010;18:1363e Roemer FW, Frobell R, Hunter DJ, Crema MD, Fischer W, Bohndorf K, et al. MRI-detected subchondral bone marrow signal alterations of the knee joint: terminology, imaging appearance, relevance and radiological differential diagnosis. Osteoarthritis Cartilage 2009;17:1115e Roemer FW, Khrad H, Hayashi D, Jara H, Ozonoff A, Fotinos-Hoyer AK, et al. Volumetric and semiquantitative assessment of MRI-detected subchondral bone marrow lesions in knee osteoarthritis: a comparison of contrast-enhanced and non-enhanced imaging. Osteoarthritis Cartilage 2010;18: 1062e Ristow O, Steinbach L, Sabo G, Krug R, Huber M, Rauscher I, et al. Isotropic 3D fast spin-echo imaging versus standard 2D imaging at 3.0 T of the kneeeimage quality and diagnostic performance. Eur Radiol 2009;19:1263e Welsch GH, Zak L, Mamisch TC, Paul D, Lauer L, Mauerer A, et al. Advanced morphological 3D magnetic resonance observation of cartilage repair tissue (MOCART) scoring using a new isotropic 3D proton-density, turbo spin echo sequence with variable flip angle distribution (PD-SPACE) compared to an isotropic 3D steady-state free precession sequence (True-FISP) and standard 2D sequences. J Magn Reson Imaging 2011;33: 180e Kijowski R, Davis KW, Woods MA, Lindstrom MJ, De Smet AA, Gold GE, et al. Knee joint: comprehensive assessment with 3D isotropic resolution fast spin-echo MR imagingediagnostic performance compared with that of conventional MR imaging at 3.0 T. Radiology 2009;252:486e Guermazi A, Kwok C, Hannon M, Moore C, Jakicic J, Green S, et al. Subchondral bone marrow lesions of the knee: a comparison of semiquantitative assessment of fatsuppressed intermediate-weighted fast spin echo (IW) and double echo steady state (DESS) sequences at 3T. Osteoarthritis Cartilage 2009;17(Suppl 1). Ref Type: Abstract. 17. Peterfy CG, Gold G, Eckstein F, Cicuttini F, Dardzinski B, Stevens R. MRI protocols for whole-organ assessment of the knee in osteoarthritis. Osteoarthritis Cartilage 2006;14(Suppl A):A95eA111 [Review] [32 refs]. 18. Kijowski R, Blankenbaker DG, Woods MA, Shinki K, De Smet AA, Reeder SB. 3.0-T evaluation of knee cartilage by using three-dimensional IDEAL GRASS imaging: comparison with fast spin-echo imaging. Radiology 2010;255:117e Kijowski R, Blankenbaker DG, Klaers JL, Shinki K, De Smet AA, Block WF. Vastly undersampled isotropic projection steady-state free precession imaging of the knee: diagnostic performance compared with conventional MR. Radiology 2009;251:185e Yoshioka H, Stevens K, Hargreaves BA, Steines D, Genovese M, Dillingham MF, et al. Magnetic resonance imaging of articular cartilage of the knee: comparison between fat-suppressed three-dimensional SPGR imaging, fat-suppressed FSE imaging, and fat-suppressed three-dimensional DEFT imaging, and correlation with arthroscopy. J Magn Reson Imaging 2004;20:857e Duc SR, Koch P, Schmid MR, Horger W, Hodler J, Pfirrmann CW. Diagnosis of articular cartilage abnormalities of the knee: prospective clinical evaluation of a 3D waterexcitation true FISP sequence. Radiology 2007;243:475e Gold GE, Chen CA, Koo S, Hargreaves BA, Bangerter NK. Recent advances in MRI of articular cartilage. AJR Am J Roentgenol 2009;193:628e Roemer FW, Kwoh CK, Hannon MJ, Crema MD, Moore CE, Jakicic JM, et al. Semiquantitative assessment of focal cartilage damage at 3T MRI: A comparative study of dual echo at steady state (DESS) and intermediate-weighted (IW) fat suppressed fast spin echo sequences. Eur J Radiol Mohr A, Roemer FW, Genant HK, Liess C. Using fat-saturated proton density-weighted MR imaging to evaluate articular cartilage. AJR Am J Roentgenol 2003;181:280e Stahl R, Luke A, Ma CB, Krug R, Steinbach L, Majumdar S, et al. Prevalence of pathologic findings in asymptomatic knees of marathon runners before and after a competition in comparison with physically active subjects-a 3.0 T magnetic resonance imaging study. Skeletal Radiol 2008;37:627e Masi JN, Sell CA, Phan C, Han E, Newitt D, Steinbach L, et al. Cartilage MR imaging at 3.0 versus that at 1.5 T: preliminary results in a porcine model. Radiology 2005;236:140e Altman RD, Hochberg M, Murphy WAJ, Wolfe F, Lequesne M. Atlas of individual radiographic features in osteoarthritis. Osteoarthritis Cartilage 1995;3(Suppl A):3e Hill CL, Gale DG, Chaisson CE, Skinner K, Kazis L, Gale ME, et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. Journal of Rheumatology 2001;28:1330e Hill CL, Hunter DJ, Niu J, Clancy M, Guermazi A, Genant H, et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis 2007;66:1599e Roemer FW, Zhang Y, Niu J, Lynch JA, Crema MD, Marra MD, et al. Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study. Radiology 2009;252: 772e Loeuille D, Rat AC, Goebel JC, Champigneulle J, Blum A, Netter P, et al. Magnetic resonance imaging in osteoarthritis: which method best reflects synovial membrane inflammation? Correlations with clinical, macroscopic and microscopic features. Osteoarthritis Cartilage 2009;17:1186e Fernandez-Madrid F, Karvonen RL, Teitge RA, Miller PR, An T, Negendank WG. Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn Reson Imaging 1995;13:177e Roemer FW, Guermazi A, Zhang Y, Yang M, Hunter DJ, Crema MD, et al. Hoffa s fat pad: evaluation on unenhanced MR images as a measure of patellofemoral synovitis in osteoarthritis. AJR Am J Roentgenol 2009;192:1696e Roemer FW, Kassim JM, Guermazi A, Thomas M, Kiran A, Keen R, et al. Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI. Osteoarthritis Cartilage 2010;18:1269e Seedhom BB, Dowson D, Wright V. Proceedings: functions of the menisci. A preliminary study. Annals of the Rheumatic Diseases 1974;33: Englund M, Guermazi A, Gale D, Hunter DJ, Aliabadi P, Clancy M, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 2008;359: 1108e15 [see comment]. 37. Bhattacharyya T, Gale D, Dewire P, Totterman S, Gale ME, McLaughlin S, et al. The clinical importance of meniscal tears demonstrated by magnetic resonance imaging in