MAGNETIC RESONANCE

Relationship of 3D meniscal morphology and positionwith knee pain in subjects with knee osteoarthritis: a pilotstudy

Andrea Wenger & Martin Englund & Wolfgang Wirth &

Martin Hudelmaier & Kent Kwoh & Felix Eckstein &

for the OAI Investigators

Received: 13 May 2011 /Revised: 6 July 2011 /Accepted: 1 August 2011 /Published online: 14 August 2011# European Society of Radiology 2011

AbstractObjectives To explore whether quantitative, three-dimensionalmeasurements of meniscal position and size are associatedwith knee pain using a within-person, between-knee studydesign.Methods We studied 53 subjects (19 men, 34 women) fromthe Osteoarthritis Initiative, with identical radiographic OAgrades in both knees, but frequent pain in one and no painin the other knee. The tibial plateau and menisci wereanalyzed using coronally reconstructed double echo steady-state sequence with water excitation (DESSwe) MRI.Results The medial meniscus covered a smaller proportion ofthe tibial plateau (−5%) and displayed greater extrusion of the

body (+15%) in painful than in painless knees (paired t-test; p<0.05). The external margin of the lateral meniscus showedgreater extrusion of the body in painful knees (+22%; p=0.03),but no significant difference in the position of its internalmargin or tibial coverage. Medial or lateral extrusion ≥3 mmwas more frequent in painful (n=23) than in painless knees(n=12; McNemar’s test; p=0.02). No significant associationwas observed between meniscal size and knee pain.Conclusions These data suggest a relationship betweenextrusion of the meniscal body, as measured with quanti-tative MRI, and knee pain in subjects with knee OA.Further studies need to confirm these findings and theirclinical relevance.Key Points& Meniscal segmentation provides quantitative measures

of meniscal size/position& Between-knee, within-person approaches can explore

potential sources of knee pain& Meniscal extrusion may be a potential source of knee

pain

Keywords Meniscus . Extrusion . Pain . Kneeosteoarthritis . Magnetic resonance imaging

Introduction

The menisci are known to distribute loads, reduce friction,and protect the articular cartilage during joint loading [1].Knee osteoarthritis (OA) is a whole-joint disorder involvingmultiple articular tissues such as cartilage, subchondralbone, ligaments, muscle and the menisci [2].

Meniscal lesions are highly prevalent in the general(healthy) population [3]. Meniscal tears and meniscectomy

A. Wenger (*) :W. Wirth :M. Hudelmaier : F. EcksteinInstitute of Anatomy & Musculoskeletal Research,Paracelsus Medical University (PMU),Strubergasse 21,A5020 Salzburg, Austriae-mail: andrea.wenger@pmu.ac.at

M. EnglundDepartment of Orthopedics, Lund University,Lund, Sweden

M. EnglundClinical Epidemiology Research & Training Unit,Boston University School of Medicine,Boston, MA, USA

W. Wirth :M. Hudelmaier : F. EcksteinChondrometrics GmbH,Ainring, Germany

K. KwohDivision of Rheumatology and Clinical Immunology,University of Pittsburgh and VA Pittsburgh Healthcare System,Pittsburgh, PA, USA

Eur Radiol (2012) 22:211–220DOI 10.1007/s00330-011-2234-z

both predispose to the onset of knee OA, probably becauseof the loss of biomechanical functions [4–7]. Conversely,knee OA may lead to degenerative meniscal damage thatmay accelerate the disease process [8]. Meniscal tears areknown to be associated with structural progression (increasedcartilage loss) of kneeOA [9–11] and with meniscal extrusion[12–14], defined as a difference ≥3 mm between the externalmeniscal margin and that of the tibial plateau. Meniscalextrusion also is also common in knees without OA [15].

Although traumatic meniscal tears are often painful,degenerative lesions appear not directly associated withsymptoms [3, 16, 17]. Some studies reported a significantassociation between MRI-graded meniscal tears and pain[18], but others did not [19, 20]. To date, no study hasconfirmed a relationship between meniscal extrusion andpain [18, 20], although extrusion may mechanically stressthe pain-sensitive joint capsules [21, 22] and pain-sensitiveexternal portions of the meniscus [23].

As pain perception is subjective and varies widely acrosssubjects, relationships between structural alterations andpain are difficult to establish [24]. A between-knee, within-person study design has been advocated to circumvent thischallenge and provides additional benefits of eliminatingconfounding by other person-related factors such as age,sex, body mass index (BMI), genetics, etc. [24, 25]. Asmeniscal extrusion and size are difficult to evaluateobjectively by scoring, interest has emerged in developingquantitative measurement technology using MRI [26–29].

To explore the relationship between pain and quantitativemeasures of the meniscus [29] in knees with the same gradeof radiographic OA (rOA), we thus applied a within-person,between-knee study design, using clinical and imaging datafrom the Osteoarthritis Initiative (OAI). Specifically, weexplored whether knees with frequent pain display greatermeniscal extrusion (primary hypothesis), and whether kneeswith frequent pain display differences in meniscal sizecompared with contra-lateral knees with no pain (secondaryhypothesis). With the awareness that OA pain is multifac-torial and that no single (imaging) feature can explain thepresence and absence of pain, the current study is meant toprovide a contribution to understanding whether or notmeniscal extrusion is one of many factors that is related toosteoarthritic knee pain.

Materials and methods

Study design and sample selection

The selection of OAI study subjects that matched thecriteria of the current study design was performed usingbaseline and 12 months follow-up clinical and radiographicdata (public-use data set 0.2.2 and 1.2.1). The study

rationale and general inclusion criteria for the OAI (e.g.age 45–79, presence of symptoms and/or knee rOA or riskfactors for developing knee OA) are publicly available(http://oai.epi-ucsf.org/datarelease/) [25].

The radiographic grading used for participant selectionrelied on the fixed-flexion radiographs obtained at baseline.Calculated Kellgren–Lawrence grades (cKLG) were de-rived by centrally certified readers [30, 31]. Knees withdefinite osteophytes and grade 0 OARSI-JSN were classi-fied as cKLG2; knees with definite osteophytes andOARSI-JSN grade 1 and 2 were classified as cKLG3 [32].

Subjects were selected as follows:

& Presence of definite rOA and identical cKLG (cKLG2or cKLG3) in both knees at baseline.

& Frequent pain (grade 2 = pain on most days of a monthin the past 12 months) in one knee, and no pain (grade 0 =no pain in the past 12 months [any pain, aching orstiffness]) in the other knee at baseline. Knees withfrequent pain are termed “painful” and knees with nopain “painless” throughout the study.

& Maximal change of symptom status at 12 months’follow-up in either knee to infrequent pain (grade 1 =pain in past 12 months, but not on most days of themonths), to avoid subjects having more frequent pain inthe formerly painless knee than in the frequently painfulknee.

Of 4796 OAI participants, 56 fulfilled the above criteria.In two cases, MR images were not available; one case wasexcluded because of complete destruction/maceration of themedial meniscus.

MR image data

The image analysis relied on the public-use MR image dataset 0.E.1. acquired at 3T (Magnetom Trio, SiemensHealthcare Erlangen, Germany) using a quadraturetransmit-receive knee coil (USA Instruments, Aurora, OH,USA) [33, 34]. The quantitative meniscal analysis wasperformed using the double oblique coronal multi-planarreconstructions of the sagittal double echo steady-statesequence with water excitation (Fig. 1, corMPR DESSwe,reconstructed slice thickness = 1.5 mm, in-plane resolution0.37 mm×0.7 mm interpolated to 0.37 mm×0.37 mm) [35,36]. Two-dimensional coronal intermediate-weighted turbospin-echo (IW.TSE) images (slice thickness = 3 mminterpolated to 1.5 mm, in-plane resolution 0.37 mm×0.46 mm) were used to assist in the delineation of thesurfaces in the corMPR DESSwe sequence [33]. The IW.TSE was also used to determine lesion scores of themenisci [37] by two experienced musculoskeletal radiol-ogists in consensus (see acknowledgement) blinded toclinical status of the knees [37].

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Quantitative meniscal analysis

All segmentations were performed by one reader (A.W.)previously trained using image data from the healthy OAIreference cohort and published series of anatomical kneejoint sections and corresponding MR images [38, 39].Manual segmentation was performed using specialised

software (Chondrometrics GmbH, Ainring, Germany)[29]. The reader was blinded both to pain and cKLG statusof the knees during the segmentation of the below tissueboundaries (Fig. 2):

& the articulating surface area of the tibial condyles: Inregions of cartilage coverage, the cartilage surface was

Fig. 1 Central images ofcontra-lateral knees of a studyparticipant. The right medialmeniscus (a, painful knee)shows greater extrusion than theleft (b, painless knee), with themedial joint capsule beingstretched (arrows). The medialmeniscus in the right knee alsoshows a complex tear

Fig. 2 3D reconstruction of themedial and lateral meniscus –measures are indicated schemat-ically. Femoral (FA), tibial (TA)and external (EA) area of themedial and lateral meniscus,respectively are shown in theupmost picture. Extrusion (mEx.Max) is defined as a ≥3 mmoverlap of the meniscus over thetibial plateau (ACdAB) andreflecting the area of themeniscus that is not adjacent tothe tibial plateau (TA.Uncov).The distance from the externalmargin of the tibial plateau tothe inner margin of the meniscus(OvD = overlap distance)reflects the computed area of thetibial plateau covered bymeniscus (ACdAB.Cov)

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segmented, and in regions of cartilage denudation, thedenuded subchondral bone (dAB). This segmentedsurface was termed ACdAB, as suggested in a previousreport [29, 40]. Osteophyte surfaces were not includedin ACdAB.

& the tibial area of the medial meniscus and lateralmeniscus, i.e. the area of the meniscus facing the tibialplateau

& the femoral area of the medial and lateral meniscus,facing the femoral articulating surface

& the external area of the medial and lateral meniscus,representing the meniscal boundary facing the joint capsule

To avoid inconsistencies in the segmentation, images ofthe contra-lateral knee were horizontally flipped and theknee segmented first was uploaded as a reference. Seg-mentation started anteriorly and ended posteriorly using thefirst/last image in which both the tibial cartilage and themenisci could be reliably identified. Quantification ofanterior or posterior extrusion of the meniscus is notpossible using coronal images, but requires a sagittalimaging protocol [9].

Internally towards the intercondylar region, the bordersof the menisci were defined by the margin of the tibialcartilage surfaces, because of the missing intrinsic anatom-ical demarcation between the menisci and the transverseand meniscofemoral ligaments. Segmentations were qualitycontrolled by a second reader (F.E.), with adjustments beingmade by consensus.

Computation of three-dimensional morphometric outcomes

Three-dimensional reconstructions of the segmented surfaceswere performed for each compartment [29]. Coverage ofthe tibial plateau by the meniscus (ACdAB.Cov) wasdetermined in absolute (mm2) and relative units (%).Meniscal size was determined by computing the meniscalsurfaces, volume, mean (Th.Me) and maximum thickness(Th.Max, = height), and the mean (Wid.Me) and maxi-mum width (Wid.Max) of both menisci (Fig. 2) [9].Meniscal bulging (Bul.Me) was defined as the averagedistance between the external area and the surfaceconnecting the intersection of tibial and external andfemoral and external area, (Fig. 2).

Meniscal position relative to the tibial plateau wasdetermined as the absolute and relative area of the tibialarea not covering the tibial plateau (TA.Uncov/p). Themean (mEx.Me) and maximum extrusion (mEx.Max) weredetermined as the average and maximal distance betweenthe external area of the meniscus and the external margin ofthe ACdAB (Fig. 2). Positive values indicate an “external”position of the external margin of the meniscus (i.e. towardsthe capsule) compared with the external margin of the

ACdAB, whereas negative values indicate an “internal”position. The distance between the internal margin of themeniscus (i.e. intersection of the tibial and femoral area)and the external border of the tibial plateau was determinedas the mean (OvD.Me) and maximum overlap distance(OvD.Max; Fig. 2). The extrusion and overlap distancewere also computed for the central five images and for themost central image.

Statistical analyses

Primary analyses focused on measures of meniscal position-ing. Differences for continuous outcomes were evaluatedusing a paired two-tailed t-test. McNemar’s test was used tocompare the proportion of knees with extrusion ≥3 mm inpainful vs. painless knees. A two-tailed p-value <0.05 wasconsidered to be statistically significant. Differences betweencKLG2 and cKLG3 strata were evaluated in sensitivityanalyses. Because sets of correlated quantitative outcomeswere interpreted in conjunction rather than in isolation in thispilot study, no adjustment for multiple comparisons wasperformed.

To estimate intra-reader reliability, image data of fourparticipants were analysed again several weeks later. Theroot mean square (RMS) standard deviation across theparticipants was computed as described previously [41].Test-retest data of the quantitative measures of the medialmeniscus are given in Table 1, and those for the lateralmeniscus in Table 2.

Results

Demographic, clinical and semi-quantitative meniscal data

Of 53 participants in this sample, 19 were men and 34women. The mean±SD age was 62.7±9.4 years, bodyheight 1.67±0.10 m, body weight 83.8±15.7 kg, and BMI29.9±4.9. Twenty-two participants displayed cKLG2 inboth knees and 31 cKLG3 bilaterally. At 1-year follow-up,12 participants still displayed grade 2 vs. grade 0 pain incontra-lateral knees, 12 participants grade 2 vs. grade 1, 14grade 1 vs. grade 0, and 15 grade 1 vs. grade 1. At baseline,the painful knees displayed greater pain intensity (numer-ical rating scale = 3.7±2.6) than contra-lateral painlessknees (0.8±2.3), with 10 corresponding to the worst painthe subject can imagine. The total WOMAC score wasgreater in the frequently painful (15.9±13.3) than in thepainless knees (6.3±10.7).

Twenty-six (49%) of the painful and 28 (53%) of thepainless knees had a grade 3 lesion of the medial meniscus,with average±SD scores of 1.4±0.9 and 1.3±0.8, respec-tively. Nine (17%) of the painful and 6 (11%) of the

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painless knees had a grade 3 meniscal lesion of the lateralmeniscus, with the average score of 0.8±1.0 in painful and0.5±0.8 in painless knees.

Quantitative results in the medial femorotibial compartment

The area of the tibia covered by the medial meniscuswas significantly smaller in painful than in painlessrOA knees (41±10% vs. 44±7%; p=0.04; Table 1), butno significant difference in the size of the medialmeniscus was observed between contralateral knees(Table 1). The relative area of the meniscus not coveringthe tibial plateau was significantly (p=0.03) greater inpainful (19±12%) than in painless knees (16±9%).Analysis of the central slice (p=0.04) and the central five

slices (p=0.02) showed significantly larger extrusionvalues for painful versus painless knees. The distancebetween the internal margin of the medial meniscus andthe external margin of the tibial plateau tended to besmaller in painful than in painless knees (−5 to −12%),but differences were only borderline significant (p=0.05 to0.10). Whereas 19 out of 53 knees with frequent pain (36%)showed a mean extrusion ≥3 mm in the central five slices ofthe medial meniscus, this was the case for only 12 out of 53knees without pain (23%) (p=0.02).

Quantitative results in the lateral femorotibial compartment

The size of the tibia and the proportion covered by thelateral meniscus was similar in painful versus painless

Table 1 Morphometric measures for the medial meniscus in the painful versus contra-lateral painless knees with the same radiographic knee OAstatus (calculated Kellgren-Lawrence grade 2 or 3) as well as test-retest results (n=53)

Medial Meniscus Mean±SD painful knees Mean±SD painless knees Mean Diff% pain vs. no pain t-test (paired) RMS SD

Tibial plateau coverage

ACdAB [mm²] 1108±205 1112±209 −0.5 0.622 15.0

ACdAB.Cov [mm²] 451±121 480±107 −6.3 0.044 22.0

ACdAB.Covp [%] 41.2±9.73 43.5±7.13 −5.4 0.042 1.72

Meniscal size and signal

Tibial area [mm²] 538±116 557±113 −3.8 0.139 16.3

Femoral area [mm²] 618±130 640±139 −3.8 0.162 12.1

External area [mm²] 385±100 387±99.5 −1.2 0.779 8.16

Th.Me [mm] 2.57±0.460 2.56±0.416 0.4 0.732 0.037

Th.Max [mm] 6.70±1.31 6.88±1.47 −2.7 0.276 0.472

Volume [mm³] 2085±690 2133±675 −2.9 0.477 37.9

Wid.Me [mm] 8.45±1.28 8.66±1.16 −2.5 0.186 0.236

Wid.Max [mm] 15.2±2.54 15.6±2.26 −1.8 0.235 0.750

Bul.Me [mm] 0.535±0.153 0.527±0.146 −0.9 0.781 0.114

Meniscal position

TA.Uncov [mm²] 99.2±66.6 89.9±61.0 10.1 0.183 4.41

TA.Uncovp [%] 18.8±12.0 15.9±9.18 18.3 0.029 1.81

mEx.Me [mm] 2.65±1.71 2.50±1.30 5.3 0.441 0.409

mEx.Max [mm] 6.85±1.55 6.66±1.64 3.6 0.422 1.17

mEx.Cent [mm] 2.56±1.45 2.21±1.09 15.5 0.038 0.415

mEx.Cent5 [mm] 2.64±1.46 2.28±1.05 15.7 0.024 0.443

OvD.Me [mm] −9.57±2.32 −10.1±1.81 −5.0 0.068 0.450

OvD.Max [mm] −3.03±1.95 −3.47±1.49 −11.7 0.062 0.639

OvD.Cent [mm] −4.48±2.57 −4.95±1.95 −9.3 0.104 0.696

OvD.Cent5 [mm] −4.67±2.53 −5.22±1.94 −10.4 0.046 0.802

SD: standard deviation; Diff(%): difference in percent; RMS SD: root mean square standard deviation; ACdAB: area of cartilage surface includingdenuded areas of subchondral bone; ACdAB.Cov: area of cartilage surface covered with meniscus; ACdAB.Covp: area of cartilage surfacecovered with meniscus in percent; Th.Me: mean thickness of the meniscus; Th.Max: maximal thickness of the meniscus; Wid.Me: mean width ofthe meniscus; Wid.Max: maximal width of the meniscus; Bul.Me: mean bulging of the meniscus; TA.Uncov: tibial area of the meniscus notcovering the tibial plateau; TA.Uncovp: tibial area of the meniscus not covering the tibial plateau in percent; mEx.Me: mean external extrusion;mEx.Max: maximal external extrusion; mEx.Cent: extrusion in the most central slice; mEx.Cent5: extrusion in the central five slices reflecting themeniscal body; OvD.Me: mean overlap distance; OvD.Max: maximal overlap distance; OvD.Cent: overlap distance in the most central slice;OvD.Cent5: overlap distance in the central five slices reflecting the meniscal body

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rOA knees (Table 2). There was a trend towards a greatermeniscal size in painful than in painless knees (+1 to +4%),but this was only significant for the maximum width(p=0.03; Table 2). The relative area of the meniscus notcovering the tibial plateau was significantly (p<0.001)greater in painful (8±9%) than in painless knees (4±5%),and so was the mean extrusion distance for the entirelateral meniscus (p<0.001), the central slice (p=0.02),and the central five slices (p=0.03; Table 2). The distancebetween the internal margin of the lateral meniscus andthe external margin of the tibial plateau was similar inpainful versus painless knees. Whereas 4 out of a total of53 knees with frequent pain (8%) showed a meanextrusion ≥3 mm in the central five slices of the lateralmeniscus, none of the knees without pain displayed anextrusion ≥3 mm (p=0.13).

Quantitative results across the medial and lateral meniscus,and per cKLG strata

A significantly greater proportion of the painful (n=23;43%) than of the painless knees (n=12; 23%) had ≥3 mmextrusion (p=0.02) in the five central slices. Sensitivityanalyses revealed that smaller quantitative differencesbetween painful and painless knees were seen in KLG2than in KLG3 knees (data not shown). Within the cKLG3strata, 17 of the painful knees (55%) showed a meanextrusion ≥3 mm (central 5 slices) of either the medial orlateral meniscus, and only 2 (7%) of the painless knees (p=0.001). Within the cKLG2 strata, 6 (27%) of the painfulknees showed a mean extrusion ≥3 mm in the medial orlateral compartment compared with 2 (9%) of the painlessknees (p=0.29).

Table 2 Morphometric measures for the lateral meniscus in the painful versus contralateral painless knees with the same radiographic knee OAstatus (calculated Kellgren-Lawrence grade 2 or 3) as well as test-retest results (n=53)

Lateral Meniscus Mean±SD painful knees Mean±SD painless knees Mean Diff% pain vs. no pain t-test (paired) RMS SD

Tibial plateau coverage

ACdAB [mm²] 943±199 952±202 −0.8 0.423 35.6

ACdAB.Cov [mm²] 527±124 533±111 −1.4 0.631 27.6

ACdAB.Covp [%] 56.3±8.07 56.3±5.50 −0.6 0.987 1.56

Meniscal size and signal

Tibial area [mm²] 552±113 544±111 1.0 0.401 18.8

Femoral area [mm²] 631±134 617±128 1.7 0.207 17.8

External area [mm²] 379±100 368±82.5 2.8 0.151 10.2

Th.Me [mm] 2.64±0.401 2.59±0.349 1.5 0.225 0.077

Th.Max [mm] 6.88±1.39 6.77±0.940 1.4 1.400 0.132

Volume [mm³] 2157±672 2073±601 3.6 0.123 55.9

Wid.Me [mm] 9.14±1.29 9.03±1.25 1.0 0.466 0.229

Wid.Max [mm] 13.3±1.98 12.8±1.84 3.4 0.026 0.560

Bul.Me [mm] 0.520±0.222 0.506±0.121 3.6 0.642 0.137

Meniscal position

TA.Uncov [mm²] 44.7±54.0 21.5±26.6 101 0.002 19.0

TA.Uncovp [%] 8.00±9.38 3.92±4.63 97.7 0.003 4.07

mEx.Me [mm] −0.843±2.48 −1.84±1.74 −48.1 0.001 1.11

mEx.Max [mm] 8.02±1.87 7.95±1.95 1.5 0.778 0.644

mEx.Cent [mm] 1.48±1.12 1.15±0.485 25.0 0.020 0.506

mEx.Cent5 [mm] 1.46±1.10 1.15±0.442 22.3 0.026 0.424

OvD.Me [mm] −14.7±2.81 −14.9±2.59 −1.2 0.392 1.37

OvD.Max [mm] −8.01±2.70 −8.25±2.55 −2.2 0.491 0.750

OvD.Cent [mm] −9.10±3.45 −9.05±2.83 1.6 0.913 0.805

OvD.Cent5 [mm] −9.40±3.13 −9.43±2.63 0.2 0.935 0.798

Abbreviations are the same as in Table 1

Please note that a “negative” value for extrusion corresponds to an internal position of the external border of the meniscus compared with theexternal border of the tibial plateau (i.e. intrusion). The less negative values in the painful knees reflect a more external position of the meniscusthan in painless knees. Note that whereas the entire lateral meniscus shows an intrusion, on average, the meniscal body (i.e. the central five slices;mEx.Cent5) shows extrusion compared with the tibia

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Discussion

In this study, we found a smaller proportion of the medialtibial plateau to be covered by the medial meniscus inpainful than in painless OA knees. Also the medialmeniscus displayed more extrusion in painful knees,reflected in a greater uncovered meniscal surface, and agreater extrusion distance. Meniscal lesion scores, on theother hand, were similar in painful and painless knees.Laterally, the external border of the meniscus was also in amore “extruded” position in painful knees but no significantdifferences were noted in the position of its internal border(but a trend towards a somewhat larger size and width).

Limitations of this study are the modest sample size (n=53), and that a large number of participants was required (i.e.4796) for case selection, as the approach chosen required aspecific combination of features. Because correlated meas-ures of extrusion and size were not corrected for multipletesting, the results need to be interpreted with caution. Aparticularity of the study, however, is the use of a within-person, between-knee study design that eliminates person-specific confounders and other differences in pain perceptionbetween individuals [24, 25]. This approach has been shownto be more effective in revealing a relationship between painand structural alterations (in radiographs) than across-subjectanalysis approaches [24]. Because this design does notcontrol for knee-specific differences, we additionally limitedthe analysis to subjects who displayed the same radiographicstage of knee OA in both knees. However, potential forconfounding by other structural features (e.g. bone marrowlesions) remains.

Quantitative measurements generally rely on a highspatial resolution. This was provided by the DESSwe whichalso has been previously validated for quantitative cartilagemeasurement [35, 36, 42, 43]. As IW- or T2-weighted TSEsequences are commonly used for evaluating meniscallesions, we additionally used IW.TSE images to assist thereadings of the DESSwe [44, 45] and to facilitate thesegmentation process, particularly in situations of unclearcontrast. A limitation is that only a coronal MPRorientation of the DESSwe was used, whereas sagittalimages are required [9] to establish whether anterior andposterior extrusion is correlated with pain frequency.Further, MRIs were acquired without weight-bearing,whereas the meniscus has its primary biomechanicalfunction during load bearing. However, a recent studyshowed that there were only minimal differences in themorphology and position of the meniscus between non-weight-bearing and weight-bearing [46], for MR imagesacquired with and without use of a loading device [47].Finally, this study is limited by its observational nature andthe lack of inclusion of extended semi-quantitative scores[48, 49] for the menisci, subchondral bone, cartilage,

ligaments and the synovium. Yet, to our knowledge, thisis the first study to explore whether novel quantitative,three-dimensional measures of meniscal extrusion andmeniscal size differ between painful and painless kneeswith rOA. These measures may potentially provide a moreobjective and sensitive evaluation of complex geometricfeatures that are challenging to evaluate based on subjectivegrading, as minute structural changes may extend overseveral image slices. Further studies, involving a face-to-face comparison, will have to confirm whether quantitativemeasures of extrusion provide additional (or more sensi-tive) information in relation to commonly employed scoringmethods [48]. The quantitative outcomes computed fromthe tibial surface and meniscal segmentation are notintended to replace semi-quantitative scoring of the menis-cus. Instead, they should be considered as a complimentaryassessment of tibial coverage, meniscal size and meniscalposition, which provide challenges in the subjective scoringof 2D images. Also, given its cost and complexity, themethod is targeted at research studies exploring the patho-physiology of knee OA, but not at clinical diagnostics. Toour knowledge, this is the first study to show a significantrelationship between pain frequency and meniscal position,whereas previous studies relying on semi-quantitativescores were unable to detect this association [18–20].

In our study, the number of meniscal tears was similar inpainful versus painless knees, so that side differences inpain frequency are probably not explained by lesions. Thisis in agreement with previous observations that degenera-tive meniscal tears are not directly associated withsymptoms [3, 16, 17]. A recent paper, however, describeda relationship between meniscal extrusion and bone marrowlesions (BMLs), potentially due to less mechanical protec-tion by the meniscus [50]. BMLs have been associated withpain status and have been discussed as a potential source ofpain [49, 51, 52]. Also, meniscal extrusion may causebulging and mechanical stretching of the joint capsule,which is richly innervated with pain fibres [21, 22] and/ormechanical stress on the external aspect of the meniscus,which is also richly innervated [23]. Interestingly, therelationship between pain and extrusion was more obviousin cKLG3 than in cKLG2 knees, with extrusion ≥3 mmbeing rare in cKLG2 knees. Boxheimer et al. [53] foundthat meniscal displacement of ≥3 mm (between differentknee positions) was strongly associated with complexmeniscal tears and collateral ligament lesions, and studyparticipants with displaceable meniscal tears had signifi-cantly more pain than did patients with non-displaceablemeniscal tears, independent of the concomitant kneeabnormalities. However, given the cross-sectional natureand the explorative character of our study, we can onlyspeculate about the relationship of meniscal extrusion andknee pain. If the current findings can be replicated, further

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studies will have to explore whether meniscal extrusion iscausing pain, whether it is involved in mediating pain, orwhether it is simply an “innocent bystander” in thisrelationship.

In conclusion, this is to our knowledge the first study todescribe a relationship between meniscal extrusion (mea-sured quantitatively and in 3D) and the frequency of kneepain. Extrusion of ≥3 mm (in the central five slices) wasmore frequent in painful than in contra-lateral painlessknees, and more frequent in cKLG3 than in cKLG2 knees.Further studies will have to confirm these findings and willhave to explore whether and to what extent meniscalextrusion is involved in the causation or mediation of kneepain in OA.

Acknowledgements We thank Iris Nöbauer and Siegfried Trattnigfrom the Magnetic Resonance Centre of Excellence at the MedicalUniversity Vienna, Austria for providing the semi-quantitativemeniscal readings (Crues and Lotysch lesion scores). Katja Bloecker,Richard Frobell and Martina Sattler (Institute of Anatomy &Musculoskeletal Research, Paracelsus Medical University Salzburg,Austria) are thanked for their help with establishing the reading rulesfor meniscal segmentation and with selecting the participants from theOAI data base. Also, we thank the OAI participants, OAI investigatorsand OAI Clinical Center’s staff for generating the publicly availableimage data set.

The study and image acquisition was supported by the OAI(contract nos. N01-AR-2-2258; N01-AR-2-2259; N01-AR-2-2260;N01-AR-2-2261; N01-AR-2-2262) funded by the National Institutesof Health and conducted by the OAI Study Investigators. Privatefunding partners include Pfizer, Inc.; Novartis PharmaceuticalsCorporation; Merck Research Laboratories; and GlaxoSmithKline.Private sector funding for the OAI is managed by the Foundation forthe National Institutes of Health. This manuscript has received theapproval of the OAI Publications Committee based on a review of itsscientific content and data interpretation.

The image analysis was supported by funds from ParacelsusMedical University (PMU Forschungsfond). Dr. Englund is supportedby the Swedish Research Council, the Faculty of Medicine, LundUniversity, and the Royal Physiographic Society in Lund and Dr.Kwoh by grant AR054731. Felix Eckstein is CEO and co-owner ofChondrometrics GmbH; he also provides consulting services toMerckSerono, Novartis and Sanofi Aventis. Wolfgang Wirth is co-ownerof Chondrometrics GmbH.

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