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Knee cartilage assessment with MRI (dGEMRIC) and subjective knee function in ACL injured copers: a cohort study with a 20 year follow-up
Osteoarthritis and Cartilage 22 (2014) 84e90
Knee cartilage assessment with MRI (dGEMRIC) and subjective knee function in ACL injured copers: a cohort study with a 20 year follow-up P. Neuman y *, H. Owman y, G. Müller z, M. Englund yx, C.J. Tiderius y, L.E. Dahlberg y y Department of Orthopaedics, Clinical Sciences, Malmö, Lund University, Sweden z Department of Radiology, Clinical Sciences, Malmö, Lund University, Sweden x Clinical Epidemiology Research & Training Unit, Boston University School of Medicine, Boston, MA, USA
a r t i c l e i n f o
s u m m a r y
Article history: Received 27 January 2013 Accepted 22 October 2013
Objective: To assess knee cartilage quality and subjective knee function, 20 years after injury in anterior cruciate ligament (ACL) injured copers. Method: We examined 32 knees using delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC), 20 years after a complete ACL tear. Only subjects who had coped with the ACL injury without ACL reconstruction (ACLR), and who presented without radiographic signs of osteoarthritis (OA) at an earlier 16-year follow-up, were included in this study. The quality of the central weightbearing parts of the medial and lateral femoral cartilage was estimated with dGEMRIC (T1Gd). These results were compared with corresponding results in 24 healthy individuals, and with the subjects’ selfreported subjective knee function using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Results: The values of T1Gd in the medial and lateral femoral cartilage of the study group (mean (95% CI)), were 404 (385e423) and 427 (399e455) ms, not statistically different from those of the healthy reference group (P ¼ 0.065 and 0.31). The subjective knee function 20 years after the injury, according to the five domains of the KOOS score, was good, with a mean score of 90 11. Values of T1Gd for the medial femoral cartilage were correlated with the KOOS subgroup QOL (P ¼ 0.021, Pearson correlation). Conclusions: Subjects who have managed to cope with their ACL injury for 20 years with sustained good subjective knee function also seem to have knee cartilage of good quality, with T1Gd values not very different from a healthy reference group. Ó 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Osteoarthritis Knee Anterior cruciate ligament injury Meniscus injury MRI dGEMRIC
Introduction Osteoarthritis (OA) is the most common form of arthritis, and has enormous implications in terms of personal suffering and costs to society1,2. According to the World Health Organization, OA is among the top ten conditions in the global burden of disease3. The knee is one of the joints most frequently affected by OA4. About 25% of individuals over 55 years of age have significant knee pain, and half of these show radiographic changes associated with OA5. Risk factors for knee OA are clearly multifactorial6. An anterior cruciate ligament (ACL) injury is one of the best documented risk factors for developing knee OA7e10. ACL injuries are common among young
* Address correspondence and reprint requests to: P. Neuman, Department of Orthopaedics, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: 4640336689; Fax: 46-40336200. E-mail address: [email protected] (P. Neuman).
athletes involved in sports requiring knee pivoting and cutting movements11,12. It has been estimated that OA develops in about 50% of subjects with ACL tears 10e20 years after injury8,10,13e15. According to the literature, meniscal injuries and meniscectomy are other well documented risk factors for the development of knee OA following ACL injury9,10,15. The gold standard in the diagnosis of OA is currently radiography. However, radiography is limited by insensitivity to early degenerative changes. Cartilage degeneration due to OA is not visible by radiography until decades after the onset of the disease, when the changes in cartilage are beyond repair16,17. Furthermore, there is only a weak association between radiographic signs of knee OA and symptoms18. There is evidence that new quantitative MRI techniques can be used to assess the loss of macromolecules such as glycosaminoglycans (GAGs) in cartilage during the early stages of OA19. There are also indications that there is a better correlation between results obtained with these new quantitative MRI
1063-4584/$ e see front matter Ó 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.joca.2013.10.006
P. Neuman et al. / Osteoarthritis and Cartilage 22 (2014) 84e90
techniques and symptoms, than between radiographic or routine MRI findings and symptoms20,21. The depletion of GAGs from articular cartilage is one of the first observable effects of the OA disease process22. GAGs are highly negatively charged sugar chains that are covalently bound to proteins, forming large aggregating proteoglycans23. It has been shown that delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is a valid, reliable and non-invasive contrast-enhanced MRI technique that can be used to estimate the relative GAG content in articular cartilage in a clinical setting24. A long relaxation time, T1Gd, is consistent with high cartilage GAG content. Results from dGEMRIC have already made valuable contributions to clinical research on early changes in the cartilage matrix. For example, it has been shown that it is able to discriminate between high and low cartilage quality in the knees of different groups of patients; lower cartilage quality being found in subjects with a lower level of physical activity following an ACL injury or a partial meniscectomy, and in those with a higher BMI or lower thigh muscle strength25e28. In knees at risk of developing OA, dGEMRIC values at baseline have been shown to be predictive of radiographic signs of knee OA 6 years later29. The aim of the present study was to evaluate knee cartilage quality 20 years after ACL injury, in a group of individuals who had not been treated with ACL reconstruction (ACLR) and in whom there was no radiographic evidence of overt OA, using dGEMRIC. This group of ACL copers was selected with the objective of determining whether the dGEMRIC method could be used to detect early changes in cartilage due to OA, before the cartilage degenerates too much to be repaired, as is the case when OA changes are visible on plain radiography. As ACLR changes the cartilage homeostasis, ACL reconstructed individuals were not included30. We hypothesized that dGEMRIC would show inferior cartilage quality in this study subgroup, compared to that in healthy reference subjects, and that we would find an association between the subjects’ self-reported subjective knee function and the knee cartilage quality assessed using dGEMRIC.
Method Subjects One hundred consecutive patients referred to the Department of Orthopaedics, Lund, Skåne University Hospital, between February 1985 and April 1989 for acute ACL injury, were recruited to the study. Both short-term and long-term follow-ups were planned for this cohort, which was treated with early neuromuscular knee rehabilitation without primary ACLR. We have previously shown that these subjects had a favorable outcome 16 years after injury regarding functional performance and thigh muscle strength31, subjective knee function32, and knee laxity33. The prevalence of tibiofemoral (TF) and/or patellofemoral (PF) OA was also low9,34. Forty subjects from the 100 described above satisfied the following inclusion criteria for 20 year post-injury dGEMRIC imaging: NACLR and no radiographic OA (grade 1) 16 years post-injury (Fig. 1). Three subjects suffered from claustrophobia and could not complete the dGEMRIC examination. Four subjects declined to participate due to lack of time and logistic problems. One patient could not be contacted. The eight subjects who were not included did not differ from those included in the study group regarding patient characteristics, concomitant meniscal and chondral knee injuries or radiographic changes. Thus, 32 participants (M:F ¼ 17:15, aged 35e 61, mean 45 years) were examined with dGEMRIC and questionnaires (Fig. 1). The Local Ethics Committee approved the study, and written informed consent was obtained from all participants. The dGEMRIC values obtained from the participants were compared with those in a healthy reference group described previously28, comprising 24 individuals without any knee symptoms or previous knee injuries, examined with the same dGEMRIC protocol as that used in the present study. The individuals in the reference group were matched with the study participants regarding level of physical activity, and consisted of 14 men and 10 women with a mean age of 25 years and similar BMI to the group with acute ACL injury at inclusion (Table I).
1985-1989 inclusion Acute ACL tear, n = 100 Loss to follow-up, n = 6 16-year follow-up N = 94, NACLR = 72, ACLR = 22, bilat = 6, X-ray = 79, KOOS = 94 Not included, n = 60
Declined to participate, n = 4. Could not be contacted, n = 1.
85
Invited to 20-year follow-up: NACLR subjects with least radiographic OA changes at X-ray 16 years after injury and a Kellgren and Lawrence grade 1, n = 40 Could not perform MRI because of claustrophobia, n = 3 Included in 20-year follow-up, n = 32 dGEMRIC and KOOS
Fig. 1. Flowchart showing the inclusion of participants in the study.
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Table I Characteristics of the study group, the healthy reference group and subjects not included in the present study
Men, n Age, years (mean SD) BMI, kg/m2 (mean SD)
Study sample at baseline (at injury) n ¼ 32
Study sample at 20-year follow-up n ¼ 32
Healthy reference group dGEMRIC n ¼ 24
Subjects not included at baseline (at injury) n ¼ 68
Subjects not included in 16-year follow-up n ¼ 62
17 (53%) 25 6.4 23.2 3.1
17 (53%) 45 6.6 25.3 3.5
14 (58%) 25 0 22.5 2.3
41 (60%) 26 8.0 24.5 2.6
38 (61%) 42 8.1 26.8 4.5
Radiography
Self-reported knee function
Standing anteroposterior radiographs were obtained 15.7 years (mean; range 11e19 y) after the ACL injury using a standardized knee position with both knees at 20 flexion and weight bearing, using a General Electric Prestige 2 on a tilt table (film-focus distance 1.5 m). A fluoroscopically positioned X-ray beam was used to optimize medial tibial plateau alignment. All radiographs were independently read en masse within a period of 2 days by two observers blinded to the clinical details9. Joint space narrowing (JSN) and osteophytes were graded on frontal images using a 4point scale (range 0e3, 0 ¼ no evidence of JSN or bony change), according to the OA Research Society International atlas35. The inter-rater reliability (kappa statistic) was k ¼ 0.78 for JSN and k ¼ 0.52 for osteophytes. The maximum discrepancy in grading between the readers was 1. In such cases, the radiographs were reread and consensus was reached. Radiographic TF OA was considered present if any of the following criteria was fulfilled in any of the two TF compartments: JSN grade 2 or higher, the sum of the two marginal osteophyte scores from the same compartment 2, or grade 1 JSN in combination with grade 1 osteophyte in the same compartment. This definition approximates grade 2 knee OA based on the Kellgren and Lawrence scale36.
The Knee Injury and Osteoarthritis Outcome Score (KOOS Swedish version LK 1.09, www.koos.nu) is a 42-item selfadministered, knee-specific questionnaire based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)40,41. KOOS comprises five subscales: pain, other symptoms, function in daily living (ADL), function in sport and recreation (sport/rec) and knee-related quality of life (QOL). A score from 0 to 100 is calculated for each subscale, 100 representing the best result. Subjects were instructed to complete the KOOS questionnaire by considering their injured knee at the time of dGEMRIC 20 years after injury. The KOOS has been found to be valid, reliable and responsive at follow-up after ACL injury and in subjects with knee OA41,42. KOOS results were compared to those of a populationbased postal survey of random inhabitants in southern Sweden with a similar age range as the current cohort (n ¼ 158, age 35e54 years, 51% women)43. The Tegnér score (range 0e10) was used to assess the individual’s level of physical activity at the time of dGEMRIC44. Grade 10 represents highly demanding knee activities such as professional soccer or American football, and 0 represents no physical activity due to being on sick leave or having a disability pension. Grade 4 represents non-competitive activities such as jogging, bicycling and cross-country skiing.
MRI Statistical analysis P-values for comparisons of continuous data (T1Gd) were calculated using Student’s t test. T1Gd sub-analysis of individuals with or without meniscus surgery and of individuals with grade 0 or 1 OA changes were calculated using Student’s t test. The Pearson correlation was used to test for correlations between KOOS and dGEMRIC T1Gd values. No adjustment for age was made for T1Gd as dGEMRIC does not correlate with age45. All tests were two-
500
P = 0.31
P = 0.065
ACL Ref
ACL Ref
Lat
Med
450 T1Gd (ms)
Subjects were investigated with dGEMRIC 20.6 years (mean; range 18e23) after the injury, using a standard 1.5 T MRI system with a dedicated knee coil (Magnetom Vision; Siemens Medical Solutions, Erlangen, Germany). Initially, Gd-DTPA2 (MagnevistÒ, Schering AG, Berlin, Germany) was injected at a dose of 0.3 mmol/ kg body weight. To optimize the uptake of Gd-DTPA2 into the cartilage subjects exercised by walking up and down stairs for approximately 10 min, starting 5 min after injection. Post-contrast imaging of the cartilage was performed 2 h after the injection. Central parts of the weight-bearing lateral and medial femoral cartilage were identified, and quantitative relaxation time calculations were performed in a 3 mm thick sagittal slice on each condyle, using sets of six turbo inversion recovery images with different inversion times: TR ¼ 2000 ms, TE ¼ 15 ms, FoV 120 120 mm2, matrix ¼ 256 256, TI ¼ 50, 100, 200, 400, 800 and 1600 ms. A full-thickness region of interest (ROI) in the cartilage was examined in the central parts of the medial and lateral femoral weight-bearing cartilage between the center of the tibial plateau and the rear insertion of the meniscus, as described previously37. T1Gd was calculated using the mean signal intensity from each ROI as input to a three-parameter fit38. dGEMRIC images were analyzed by one individual (HO) using the MATLAB-based Mokkula software developed by Eveliina Lammentausta, University of Kuopio, Finland. ROIs were drawn without any knowledge of per-operative findings or surgical treatment39. None of those examined had to be excluded due to motion artifacts in the MRI images (defined as having > 12% of the ROI pixels above a T1Gd value of 1300 ms).
400 350 300
Fig. 2. Mean T1Gd values (with 95% confidence intervals) for the lateral (lat) and medial (med) femoral cartilage in the study cohort (ACL injury) (n ¼ 32), and the healthy reference group (n ¼ 24).
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tailed, and P 0.05 was considered to denote statistical significance. The statistical analysis was performed with SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Results are given as the mean 1 SD (95% CI), unless otherwise stated. Results dGEMRIC results The values of T1Gd in the group that had suffered an ACL injury were not significantly different from those in the healthy reference group, medially or laterally. The value of T1Gd medially in the injured group was 404 53 (385e423) ms vs 428 38 (412e444) ms in the reference group (P ¼ 0.065). The corresponding values laterally were 427 79 (399e455) vs 445 41 (428e462) ms (P ¼ 0.31) (Fig. 2). No difference was observed in T1Gd obtained for the combination of medial and lateral femoral cartilage (bulk mean) in a subgroup analysis between subjects with radiographic signs of OA (grade 1 osteophyte or grade 1 JSN) and in subjects without osteophytes or JSN, values being 415 70 (380e450) ms and 412 38 (392e432) ms respectively (P ¼ 0.85). All subjects included in this study had a Kellgren and Lawrence grade 1. The values of T1Gd in medial femoral cartilage in subjects with (n ¼ 3) and without (n ¼ 29) a major medial meniscal injury (partial meniscectomy) were 384 48 (329e439) ms and 407 53 (387e 427) ms, respectively (P ¼ 0.48). The values in lateral femoral cartilage in subjects with (n ¼ 10) and without (n ¼ 22) a major lateral meniscal injury were 410 105 (344e476) ms and 435 65 (407e463) ms, respectively (P ¼ 0.41). T1Gd was not related to BMI, the Tegnér activity score, age or sex (data not shown). Self-reported knee function The results obtained from the KOOS questionnaire for the study group, consisting of patients who had not undergone ACLR, were better than or similar to those obtained for the reference group43. The scores obtained for the reference group were (mean SD): pain 88 18, symptoms 88 16, ADL 89 19, sport/rec 78 29, and QOL 81 24. The corresponding scores for the study group (n ¼ 32) were: pain 95 10, symptoms 92 11, ADL 98 4, sport/ rec 86 20, and QOL 81 20 (Fig. 3). The P-values obtained for the
100
Mean KOOS
80 60 40 20 0 Pain
Symtoms
ADL
Sport
QOL
Fig. 3. Mean KOOS for each subscale (with 95% confidence intervals) for the study sample (ACL injury) -C- (n ¼ 32) and a random population-based reference group -B(n ¼ 158)43. The ACL injury group had significantly higher (better) scores for the pain and ADL subscales than the reference group, P ¼ 0.03 and P ¼ 0.008, respectively.
87
five subscales were: 0.034 (pain), 0.18 (symptoms), 0.0084 (ADL), 0.14 (sport/rec), and 1.0 (QOL). KOOS increased with improving knee cartilage quality estimated with dGEMRIC, although the only association that was statistically significant was that between the QOL subscale and the quality of the medial femoral cartilage. Pearson correlations between the five KOOS subgroups and values of T1Gd obtained from the medial femoral cartilage were: P ¼ 0.090 (pain), P ¼ 0.17 (symptoms), P ¼ 0.058 (ADL), P ¼ 0.35 (sport/rec), and P ¼ 0.021 (QOL). The corresponding Pearson correlations for the lateral femoral cartilage were: P ¼ 0.72 (pain), P ¼ 0.74 (symptoms), P ¼ 0.90 (ADL), P ¼ 0.19 (sport/rec), and P ¼ 0.40 (QOL). Discussion This study of 32 subjects who had sustained an acute ACL injury, who were treated without ACLR and who showed no overt knee OA on radiography 16 years after injury did not show any statistically significant differences in knee cartilage T1Gd values (used as a measure of cartilage quality), 20 years after the ACL injury, compared to a healthy reference group. This group of ACL copers was selected with the objective of determining whether the dGEMRIC method could be used to detect early changes in cartilage due to OA, before the cartilage degenerates too much to be repaired, as is the case when OA changes are visible on plain radiography. We expected to find lower cartilage quality (i.e., lower T1Gd values) in the study group, and were surprised to find that the values did not differ significantly from those of a healthy reference group. We decided to compare T1Gd values with a healthy reference group which resembled the study group (age and activity level) just before the time of the ACL injury. An alternative would have been to compare T1Gd values with an age-adjusted study group without any previous knee injury but according to previous findings on the dGEMRIC method we believe that we then would have been required to include more individuals to discern any statistical significant difference between the groups. Previously particularly low values of T1Gd have been observed in ACL injured subjects with a concomitant meniscus injury46. One reason for not finding a lower cartilage quality (i.e., lower T1Gd values) in the current study may be the small number of subjects (three) that had undergone medial meniscectomy, a well-known risk factor for the development of OA9,47e49. A second reason that might explain why these copers appear to have good knee cartilage quality 20 years after their ACL injury is the unique treatment they received in the original study50, where: all subjects were identified early after their knee injury; the individual pattern of knee injury was established and respected during the rehabilitation process; meniscus lesions were sparingly treated with meniscectomy; subjects were closely monitored, treated and educated by a competent physiotherapist to achieve functional knee stability, increased neuromuscular function and avoid giving-way of the knee; subjects initially (first year after injury) lowered their activity level. This treatment is different from how the acutely ACL injured patient is generally treated today, reflected in the previous study, in which the average follow-up time after ACL tear was 2 years and half of the study subjects were ACL reconstructed46. Although it’s hard to draw any solid conclusions from a comparison between this 20 year and a 2 year follow-up in two different cohorts, it is interesting to note that higher values of T1Gd were observed in this study. This may indicate that, if treated correctly, knee cartilage may have the potential to improve slowly over a period of several years after a severe knee injury. Thirdly, a selection bias could also to some extent explain why these copers appear to have good knee cartilage quality 20 years after their ACL injury as non copers that were subsequently ACL reconstructed (25%) were not included. Twenty
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years after their ACL injury, the injured subjects in the present study had T1Gd values similar to those in a healthy reference group. This finding is in line with other aspects of knee function reported in previous studies on this cohort of well-functioning ACL deficient copers9,31e34. Moreover, the injured group was found to have better KOOS results than a randomly selected age-matched group. Longer follow-up of these individuals is needed to investigate development of knee OA in later years. On a group level, higher or equal KOOS values were observed for the current cohort compared to the reference group, suggesting that the group as a whole seem to be content with their injured knee. On a subscale level, only an association between QOL and T1Gd was found. This is interesting as QOL together with sport/rec seem to be the most sensitive subscale with regards to ACL injury according to the Swedish ACL Register (www.aclregister.nu). All other subscales show results in line with numerous previous studies where the association between structural cartilage changes and symptoms has been weak. Several studies have reported good agreement between cartilage GAG content and T1Gd values37,51,52. A short T1Gd has also been reported to be a feature of early-stage knee and hip OA19,20,29,53e55. However, we found no correlation between T1Gd and discrete radiographic knee changes (grade 1, Kellgren and Lawrence) in the present study. The primary objective of this study was not to investigate associations between radiography and the dGEMRIC method, but to determine whether dGEMRIC was able to detect changes in the cartilage in a cohort at risk of developing OA. Knee radiography was actually performed 4e5 years prior to the dGEMRIC investigation, but we nevertheless believe that the study group still had well-functioning knees, without overt OA with gross cartilage defects. It may be argued that the study group was too small to allow any firm conclusions to be drawn. However, the results of previous studies performed by our group suggest that only a limited number of subjects is needed to detect statistically and clinically significant differences using dGEMRIC19,25,27e29,37,39,46,56. This is mainly due to the low variability of the T1Gd values measured in the examined cohorts. Furthermore, it is not feasible to include the larger numbers of subjects required for multivariable modeling in dGEMRIC studies due to the high cost involved, the shortage of MRI capacity, and difficulties in scheduling subjects for examination. Between reference subjects (n ¼ 24) and ACL injured subjects (n ¼ 32), we only had a post hoc power of 82% and 36% to detect a difference of 24 ms medially and 18 ms laterally in T1Gd values from the femoral cartilage, with alpha set at 0.05. As the difference in T1Gd in previous studies has been approximately 50 ms the power a priori was close to 100% for the medial and lateral femoral cartilage. The actual T1Gd differences between the two groups were very small and would probably not be clinically relevant, even if observed in a larger cohort. We examined the central weight-bearing cartilage of the medial and lateral femoral condyles because this is most commonly affected by early degenerative changes in cartilage57. Others have argued that more information can be obtained by studying the whole volume of the knee cartilage58, but we preferred to use the same MRI protocol as in our previous studies19,25,27e29,37,39. Fleming et al. found similar T1Gd values in femoral and tibial cartilage in subjects who had sustained ACL injuries26. This study, on a group of subjects that had sustained an ACL injury, and who were not treated with ACLR, shows that it is possible to maintain a good subjective knee function and good cartilage quality up to 20 years after injury. This is a very encouraging finding that may be important when counseling recently injured subjects who are prepared to abstain from pivoting sports, and who are willing to undergo neuromuscular knee rehabilitation
without ACL surgery. In conclusion, our results show that subjects who have managed to cope with their ACL injury for 20 years, with good subjective knee function, also seem to have a good cartilage quality, as their T1Gd values were not very different from a healthy reference group. Authors’ contribution Paul Neuman: contributed to and critically commented on the design of the study; recruited patients to the study; collected and assembled data; analyzed and interpreted data; critically revised the article and wrote the manuscript. Henrik Owman: contributed to conception and design; calculated dGEMRIC values; assembled and analyzed data; critically revised the article. Gunilla Müller: commented on the study design; analyzed and interpreted data; provided technical MRI support and read the diagnostic MRI images; critically revised the article. Martin Englund: contributed to and critically commented on the design of the study; collected and analyzed data from radiography; critically revised the article. Carl Johan Tiderius: contributed to conception and design of the study; analyzed and interpreted data; critically revised the article. Leif Dahlberg: contributed to conception and design of the study; analyzed and interpreted data; critically revised the article. Role of the funding source Supported by grants from The Swedish Research Council, Governmental funding of clinical research within the NHS (National Health Services), Skåne County Council’s Research and Development Foundation, Swedish National Centre for Research in Sports, King Gustaf V’s 80-year Fund, The Crafoord Foundation, The Swedish Rheumatism Association, The Alfred Österlund Foundation, The Herman Järnhardt Foundation, The Greta and Johan Kock Foundation and The Skåne University Hospital Funds. Conflict of interest The authors have no conflict of interest and this manuscript has not been submitted elsewhere. Acknowledgments We appreciate the help of Jan-Åke Nilsson for statistical guidance and Pernilla Carlsson for preparation of the manuscript. References 1. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 2006;20:3e25. 2. Moskowitz RW. The burden of osteoarthritis: clinical and quality-of-life issues. Am J Manag Care 2009;15:S223e9. 3. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367: 1747e57. 4. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137e62. 5. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60:91e7. 6. Nuki G. Osteoarthritis: a problem of joint failure. Z Rheumatol 1999;58:142e7.
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26. Fleming BC, Oksendahl HL, Mehan WA, Portnoy R, Fadale PD, Hulstyn MJ, et al. Delayed Gadolinium-Enhanced MR Imaging of Cartilage (dGEMRIC) following ACL injury. Osteoarthritis Cartilage 2010;18:662e7. 27. Tiderius CJ, Olsson LE, Nyquist F, Dahlberg L. Cartilage glycosaminoglycan loss in the acute phase after an anterior cruciate ligament injury: delayed gadolinium-enhanced magnetic resonance imaging of cartilage and synovial fluid analysis. Arthritis Rheum 2005;52:120e7. 28. Tiderius CJ, Svensson J, Leander P, Ola T, Dahlberg L. dGEMRIC (delayed gadolinium-enhanced MRI of cartilage) indicates adaptive capacity of human knee cartilage. Magn Reson Med 2004;51:286e90. 29. Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahlberg LE. Association between findings on delayed gadoliniumenhanced magnetic resonance imaging of cartilage and future knee osteoarthritis. Arthritis Rheum 2008;58:1727e30. 30. Frobell RB, Le Graverand MP, Buck R, Roos EM, Roos HP, Tamez-Pena J, et al. The acutely ACL injured knee assessed by MRI: changes in joint fluid, bone marrow lesions, and cartilage during the first year. Osteoarthritis Cartilage 2009;17:161e7. 31. Ageberg E, Friden T. Normalized motor function but impaired sensory function after unilateral non-reconstructed ACL injury: patients compared with uninjured controls. Knee Surg Sports Traumatol Arthrosc 2008;16:449e56. 32. Kostogiannis I, Ageberg E, Neuman P, Dahlberg L, Friden T, Roos H. Activity level and subjective knee function 15 years after anterior cruciate ligament injury: a prospective, longitudinal study of nonreconstructed patients. Am J Sports Med 2007;35:1135e43. 33. Neuman P, Kostogiannis I, Friden T, Roos H, Dahlberg LE, Englund M. Knee laxity after complete anterior cruciate ligament tear: a prospective study over 15 years. Scand J Med Sci Sports 2012;22:156e63. 34. Neuman P, Kostogiannis I, Friden T, Roos H, Dahlberg LE, Englund M. Patellofemoral osteoarthritis 15 years after anterior cruciate ligament injury e a prospective cohort study. Osteoarthritis Cartilage 2009;17:284e90. 35. Altman RD, Hochberg M, Murphy Jr WA, Wolfe F, Lequesne M. Atlas of individual radiographic features in osteoarthritis. Osteoarthritis Cartilage 1995;3(Suppl A):3e70. 36. Kellgren JH, Lawrence JS. Radiological assessment of osteoarthrosis. Ann Rheum Dis 1957;16:494e502. 37. Tiderius CJ, Olsson LE, de Verdier H, Leander P, Ekberg O, Dahlberg L. Gd-DTPA2)-enhanced MRI of femoral knee cartilage: a dose-response study in healthy volunteers. Magn Reson Med 2001;46:1067e71. 38. Kingsley PB, Ogg RJ, Reddick WE, Steen RG. Correction of errors caused by imperfect inversion pulses in MR imaging measurement of T1 relaxation times. Magn Reson Imaging 1998;16:1049e55. 39. Tiderius CJ, Tjornstrand J, Akeson P, Sodersten K, Dahlberg L, Leander P. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC): intra- and interobserver variability in standardized drawing of regions of interest. Acta Radiol 2004;45: 628e34. 40. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833e40. 41. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee Injury and Osteoarthritis Outcome Score (KOOS) e development of a self-administered outcome measure. J Orthop Sports Phys Ther 1998;28:88e96.
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42. Roos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes 2003;1:64. 43. Paradowski PT, Bergman S, Sunden-Lundius A, Lohmander LS, Roos EM. Knee complaints vary with age and gender in the adult population. Population-based reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS). BMC Musculoskelet Disord 2006;7:38. 44. Tegner Y, Lysholm J. Rating systems in the evaluation of knee ligament injuries. Clin Orthop Relat Res 1985:43e9. 45. Dahlberg LE, Lammentausta E, Tiderius CJ, Nieminen MT. In vivo monitoring of joint cartilage e lessons to be learned by delayed gadolinium enhanced magnetic resonance imaging of cartilage. Eur Muscoskel Rev 2012;7:58e62. 46. Neuman P, Tjornstrand J, Svensson J, Ragnarsson C, Roos H, Englund M, et al. Longitudinal assessment of femoral knee cartilage quality using contrast enhanced MRI (dGEMRIC) in patients with anterior cruciate ligament injury e comparison with asymptomatic volunteers. Osteoarthritis Cartilage 2011;19:977e83. 47. Fairbank TJ. Knee joint changes after meniscectomy. J Bone Joint Surg Br 1948;30B:664e70. 48. Englund M, Lohmander LS. Risk factors for symptomatic knee osteoarthritis fifteen to twenty-two years after meniscectomy. Arthritis Rheum 2004;50:2811e9. 49. Englund M, Roos EM, Lohmander LS. Impact of type of meniscal tear on radiographic and symptomatic knee osteoarthritis: a sixteen-year followup of meniscectomy with matched controls. Arthritis Rheum 2003;48:2178e87. 50. Zatterstrom R, Friden T, Lindstrand A, Moritz U. Early rehabilitation of acute anterior cruciate ligament injury e a randomized clinical trial. Scand J Med Sci Sports 1998;8:154e9.
51. Bashir A, Gray ML, Hartke J, Burstein D. Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magn Reson Med 1999;41:857e65. 52. Juras V, Bittsansky M, Majdisova Z, Szomolanyi P, Sulzbacher I, Gabler S, et al. In vitro determination of biomechanical properties of human articular cartilage in osteoarthritis using multi-parametric MRI. J Magn Reson 2009;197:40e7. 53. Lammentausta E, Kiviranta P, Toyras J, Hyttinen MM, Kiviranta I, Nieminen MT, et al. Quantitative MRI of parallel changes of articular cartilage and underlying trabecular bone in degeneration. Osteoarthritis Cartilage 2007;15:1149e57. 54. Nojiri T, Watanabe N, Namura T, Narita W, Ikoma K, Suginoshita T, et al. Utility of delayed gadolinium-enhanced MRI (dGEMRIC) for qualitative evaluation of articular cartilage of patellofemoral joint. Knee Surg Sports Traumatol Arthrosc 2006;14:718e23. 55. Williams A, Sharma L, McKenzie CA, Prasad PV, Burstein D. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: findings at different radiographic stages of disease and relationship to malalignment. Arthritis Rheum 2005;52:3528e35. 56. Tiderius C, Hori M, Williams A, Sharma L, Prasad PV, Finnell M, et al. dGEMRIC as a function of BMI. Osteoarthritis Cartilage 2006;14:1091e7. 57. Boegard T, Rudling O, Petersson IF, Sanfridsson J, Saxne T, Svensson B, et al. Postero-anterior radiogram of the knee in weight-bearing and semiflexion. Comparison with MR imaging. Acta Radiol 1997;38:1063e70. 58. McKenzie CA, Williams A, Prasad PV, Burstein D. Threedimensional delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) at 1.5 T and 3.0 T. J Magn Reson Imaging 2006;24: 928e33.
Knee cartilage assessment with MRI (dGEMRIC) and subjective knee function in ACL injured copers: a cohort study with a 20 year follow-up P. Neuman y *, H. Owman y, G. Müller z, M. Englund yx, C.J. Tiderius y, L.E. Dahlberg y y Department of Orthopaedics, Clinical Sciences, Malmö, Lund University, Sweden z Department of Radiology, Clinical Sciences, Malmö, Lund University, Sweden x Clinical Epidemiology Research & Training Unit, Boston University School of Medicine, Boston, MA, USA
a r t i c l e i n f o
s u m m a r y
Article history: Received 27 January 2013 Accepted 22 October 2013
Objective: To assess knee cartilage quality and subjective knee function, 20 years after injury in anterior cruciate ligament (ACL) injured copers. Method: We examined 32 knees using delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC), 20 years after a complete ACL tear. Only subjects who had coped with the ACL injury without ACL reconstruction (ACLR), and who presented without radiographic signs of osteoarthritis (OA) at an earlier 16-year follow-up, were included in this study. The quality of the central weightbearing parts of the medial and lateral femoral cartilage was estimated with dGEMRIC (T1Gd). These results were compared with corresponding results in 24 healthy individuals, and with the subjects’ selfreported subjective knee function using the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. Results: The values of T1Gd in the medial and lateral femoral cartilage of the study group (mean (95% CI)), were 404 (385e423) and 427 (399e455) ms, not statistically different from those of the healthy reference group (P ¼ 0.065 and 0.31). The subjective knee function 20 years after the injury, according to the five domains of the KOOS score, was good, with a mean score of 90 11. Values of T1Gd for the medial femoral cartilage were correlated with the KOOS subgroup QOL (P ¼ 0.021, Pearson correlation). Conclusions: Subjects who have managed to cope with their ACL injury for 20 years with sustained good subjective knee function also seem to have knee cartilage of good quality, with T1Gd values not very different from a healthy reference group. Ó 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Osteoarthritis Knee Anterior cruciate ligament injury Meniscus injury MRI dGEMRIC
Introduction Osteoarthritis (OA) is the most common form of arthritis, and has enormous implications in terms of personal suffering and costs to society1,2. According to the World Health Organization, OA is among the top ten conditions in the global burden of disease3. The knee is one of the joints most frequently affected by OA4. About 25% of individuals over 55 years of age have significant knee pain, and half of these show radiographic changes associated with OA5. Risk factors for knee OA are clearly multifactorial6. An anterior cruciate ligament (ACL) injury is one of the best documented risk factors for developing knee OA7e10. ACL injuries are common among young
* Address correspondence and reprint requests to: P. Neuman, Department of Orthopaedics, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: 4640336689; Fax: 46-40336200. E-mail address: [email protected] (P. Neuman).
athletes involved in sports requiring knee pivoting and cutting movements11,12. It has been estimated that OA develops in about 50% of subjects with ACL tears 10e20 years after injury8,10,13e15. According to the literature, meniscal injuries and meniscectomy are other well documented risk factors for the development of knee OA following ACL injury9,10,15. The gold standard in the diagnosis of OA is currently radiography. However, radiography is limited by insensitivity to early degenerative changes. Cartilage degeneration due to OA is not visible by radiography until decades after the onset of the disease, when the changes in cartilage are beyond repair16,17. Furthermore, there is only a weak association between radiographic signs of knee OA and symptoms18. There is evidence that new quantitative MRI techniques can be used to assess the loss of macromolecules such as glycosaminoglycans (GAGs) in cartilage during the early stages of OA19. There are also indications that there is a better correlation between results obtained with these new quantitative MRI
1063-4584/$ e see front matter Ó 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.joca.2013.10.006
P. Neuman et al. / Osteoarthritis and Cartilage 22 (2014) 84e90
techniques and symptoms, than between radiographic or routine MRI findings and symptoms20,21. The depletion of GAGs from articular cartilage is one of the first observable effects of the OA disease process22. GAGs are highly negatively charged sugar chains that are covalently bound to proteins, forming large aggregating proteoglycans23. It has been shown that delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is a valid, reliable and non-invasive contrast-enhanced MRI technique that can be used to estimate the relative GAG content in articular cartilage in a clinical setting24. A long relaxation time, T1Gd, is consistent with high cartilage GAG content. Results from dGEMRIC have already made valuable contributions to clinical research on early changes in the cartilage matrix. For example, it has been shown that it is able to discriminate between high and low cartilage quality in the knees of different groups of patients; lower cartilage quality being found in subjects with a lower level of physical activity following an ACL injury or a partial meniscectomy, and in those with a higher BMI or lower thigh muscle strength25e28. In knees at risk of developing OA, dGEMRIC values at baseline have been shown to be predictive of radiographic signs of knee OA 6 years later29. The aim of the present study was to evaluate knee cartilage quality 20 years after ACL injury, in a group of individuals who had not been treated with ACL reconstruction (ACLR) and in whom there was no radiographic evidence of overt OA, using dGEMRIC. This group of ACL copers was selected with the objective of determining whether the dGEMRIC method could be used to detect early changes in cartilage due to OA, before the cartilage degenerates too much to be repaired, as is the case when OA changes are visible on plain radiography. As ACLR changes the cartilage homeostasis, ACL reconstructed individuals were not included30. We hypothesized that dGEMRIC would show inferior cartilage quality in this study subgroup, compared to that in healthy reference subjects, and that we would find an association between the subjects’ self-reported subjective knee function and the knee cartilage quality assessed using dGEMRIC.
Method Subjects One hundred consecutive patients referred to the Department of Orthopaedics, Lund, Skåne University Hospital, between February 1985 and April 1989 for acute ACL injury, were recruited to the study. Both short-term and long-term follow-ups were planned for this cohort, which was treated with early neuromuscular knee rehabilitation without primary ACLR. We have previously shown that these subjects had a favorable outcome 16 years after injury regarding functional performance and thigh muscle strength31, subjective knee function32, and knee laxity33. The prevalence of tibiofemoral (TF) and/or patellofemoral (PF) OA was also low9,34. Forty subjects from the 100 described above satisfied the following inclusion criteria for 20 year post-injury dGEMRIC imaging: NACLR and no radiographic OA (grade 1) 16 years post-injury (Fig. 1). Three subjects suffered from claustrophobia and could not complete the dGEMRIC examination. Four subjects declined to participate due to lack of time and logistic problems. One patient could not be contacted. The eight subjects who were not included did not differ from those included in the study group regarding patient characteristics, concomitant meniscal and chondral knee injuries or radiographic changes. Thus, 32 participants (M:F ¼ 17:15, aged 35e 61, mean 45 years) were examined with dGEMRIC and questionnaires (Fig. 1). The Local Ethics Committee approved the study, and written informed consent was obtained from all participants. The dGEMRIC values obtained from the participants were compared with those in a healthy reference group described previously28, comprising 24 individuals without any knee symptoms or previous knee injuries, examined with the same dGEMRIC protocol as that used in the present study. The individuals in the reference group were matched with the study participants regarding level of physical activity, and consisted of 14 men and 10 women with a mean age of 25 years and similar BMI to the group with acute ACL injury at inclusion (Table I).
1985-1989 inclusion Acute ACL tear, n = 100 Loss to follow-up, n = 6 16-year follow-up N = 94, NACLR = 72, ACLR = 22, bilat = 6, X-ray = 79, KOOS = 94 Not included, n = 60
Declined to participate, n = 4. Could not be contacted, n = 1.
85
Invited to 20-year follow-up: NACLR subjects with least radiographic OA changes at X-ray 16 years after injury and a Kellgren and Lawrence grade 1, n = 40 Could not perform MRI because of claustrophobia, n = 3 Included in 20-year follow-up, n = 32 dGEMRIC and KOOS
Fig. 1. Flowchart showing the inclusion of participants in the study.
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Table I Characteristics of the study group, the healthy reference group and subjects not included in the present study
Men, n Age, years (mean SD) BMI, kg/m2 (mean SD)
Study sample at baseline (at injury) n ¼ 32
Study sample at 20-year follow-up n ¼ 32
Healthy reference group dGEMRIC n ¼ 24
Subjects not included at baseline (at injury) n ¼ 68
Subjects not included in 16-year follow-up n ¼ 62
17 (53%) 25 6.4 23.2 3.1
17 (53%) 45 6.6 25.3 3.5
14 (58%) 25 0 22.5 2.3
41 (60%) 26 8.0 24.5 2.6
38 (61%) 42 8.1 26.8 4.5
Radiography
Self-reported knee function
Standing anteroposterior radiographs were obtained 15.7 years (mean; range 11e19 y) after the ACL injury using a standardized knee position with both knees at 20 flexion and weight bearing, using a General Electric Prestige 2 on a tilt table (film-focus distance 1.5 m). A fluoroscopically positioned X-ray beam was used to optimize medial tibial plateau alignment. All radiographs were independently read en masse within a period of 2 days by two observers blinded to the clinical details9. Joint space narrowing (JSN) and osteophytes were graded on frontal images using a 4point scale (range 0e3, 0 ¼ no evidence of JSN or bony change), according to the OA Research Society International atlas35. The inter-rater reliability (kappa statistic) was k ¼ 0.78 for JSN and k ¼ 0.52 for osteophytes. The maximum discrepancy in grading between the readers was 1. In such cases, the radiographs were reread and consensus was reached. Radiographic TF OA was considered present if any of the following criteria was fulfilled in any of the two TF compartments: JSN grade 2 or higher, the sum of the two marginal osteophyte scores from the same compartment 2, or grade 1 JSN in combination with grade 1 osteophyte in the same compartment. This definition approximates grade 2 knee OA based on the Kellgren and Lawrence scale36.
The Knee Injury and Osteoarthritis Outcome Score (KOOS Swedish version LK 1.09, www.koos.nu) is a 42-item selfadministered, knee-specific questionnaire based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)40,41. KOOS comprises five subscales: pain, other symptoms, function in daily living (ADL), function in sport and recreation (sport/rec) and knee-related quality of life (QOL). A score from 0 to 100 is calculated for each subscale, 100 representing the best result. Subjects were instructed to complete the KOOS questionnaire by considering their injured knee at the time of dGEMRIC 20 years after injury. The KOOS has been found to be valid, reliable and responsive at follow-up after ACL injury and in subjects with knee OA41,42. KOOS results were compared to those of a populationbased postal survey of random inhabitants in southern Sweden with a similar age range as the current cohort (n ¼ 158, age 35e54 years, 51% women)43. The Tegnér score (range 0e10) was used to assess the individual’s level of physical activity at the time of dGEMRIC44. Grade 10 represents highly demanding knee activities such as professional soccer or American football, and 0 represents no physical activity due to being on sick leave or having a disability pension. Grade 4 represents non-competitive activities such as jogging, bicycling and cross-country skiing.
MRI Statistical analysis P-values for comparisons of continuous data (T1Gd) were calculated using Student’s t test. T1Gd sub-analysis of individuals with or without meniscus surgery and of individuals with grade 0 or 1 OA changes were calculated using Student’s t test. The Pearson correlation was used to test for correlations between KOOS and dGEMRIC T1Gd values. No adjustment for age was made for T1Gd as dGEMRIC does not correlate with age45. All tests were two-
500
P = 0.31
P = 0.065
ACL Ref
ACL Ref
Lat
Med
450 T1Gd (ms)
Subjects were investigated with dGEMRIC 20.6 years (mean; range 18e23) after the injury, using a standard 1.5 T MRI system with a dedicated knee coil (Magnetom Vision; Siemens Medical Solutions, Erlangen, Germany). Initially, Gd-DTPA2 (MagnevistÒ, Schering AG, Berlin, Germany) was injected at a dose of 0.3 mmol/ kg body weight. To optimize the uptake of Gd-DTPA2 into the cartilage subjects exercised by walking up and down stairs for approximately 10 min, starting 5 min after injection. Post-contrast imaging of the cartilage was performed 2 h after the injection. Central parts of the weight-bearing lateral and medial femoral cartilage were identified, and quantitative relaxation time calculations were performed in a 3 mm thick sagittal slice on each condyle, using sets of six turbo inversion recovery images with different inversion times: TR ¼ 2000 ms, TE ¼ 15 ms, FoV 120 120 mm2, matrix ¼ 256 256, TI ¼ 50, 100, 200, 400, 800 and 1600 ms. A full-thickness region of interest (ROI) in the cartilage was examined in the central parts of the medial and lateral femoral weight-bearing cartilage between the center of the tibial plateau and the rear insertion of the meniscus, as described previously37. T1Gd was calculated using the mean signal intensity from each ROI as input to a three-parameter fit38. dGEMRIC images were analyzed by one individual (HO) using the MATLAB-based Mokkula software developed by Eveliina Lammentausta, University of Kuopio, Finland. ROIs were drawn without any knowledge of per-operative findings or surgical treatment39. None of those examined had to be excluded due to motion artifacts in the MRI images (defined as having > 12% of the ROI pixels above a T1Gd value of 1300 ms).
400 350 300
Fig. 2. Mean T1Gd values (with 95% confidence intervals) for the lateral (lat) and medial (med) femoral cartilage in the study cohort (ACL injury) (n ¼ 32), and the healthy reference group (n ¼ 24).
P. Neuman et al. / Osteoarthritis and Cartilage 22 (2014) 84e90
tailed, and P 0.05 was considered to denote statistical significance. The statistical analysis was performed with SPSS for Windows, version 20.0 (SPSS Inc., Chicago, IL, USA). Results are given as the mean 1 SD (95% CI), unless otherwise stated. Results dGEMRIC results The values of T1Gd in the group that had suffered an ACL injury were not significantly different from those in the healthy reference group, medially or laterally. The value of T1Gd medially in the injured group was 404 53 (385e423) ms vs 428 38 (412e444) ms in the reference group (P ¼ 0.065). The corresponding values laterally were 427 79 (399e455) vs 445 41 (428e462) ms (P ¼ 0.31) (Fig. 2). No difference was observed in T1Gd obtained for the combination of medial and lateral femoral cartilage (bulk mean) in a subgroup analysis between subjects with radiographic signs of OA (grade 1 osteophyte or grade 1 JSN) and in subjects without osteophytes or JSN, values being 415 70 (380e450) ms and 412 38 (392e432) ms respectively (P ¼ 0.85). All subjects included in this study had a Kellgren and Lawrence grade 1. The values of T1Gd in medial femoral cartilage in subjects with (n ¼ 3) and without (n ¼ 29) a major medial meniscal injury (partial meniscectomy) were 384 48 (329e439) ms and 407 53 (387e 427) ms, respectively (P ¼ 0.48). The values in lateral femoral cartilage in subjects with (n ¼ 10) and without (n ¼ 22) a major lateral meniscal injury were 410 105 (344e476) ms and 435 65 (407e463) ms, respectively (P ¼ 0.41). T1Gd was not related to BMI, the Tegnér activity score, age or sex (data not shown). Self-reported knee function The results obtained from the KOOS questionnaire for the study group, consisting of patients who had not undergone ACLR, were better than or similar to those obtained for the reference group43. The scores obtained for the reference group were (mean SD): pain 88 18, symptoms 88 16, ADL 89 19, sport/rec 78 29, and QOL 81 24. The corresponding scores for the study group (n ¼ 32) were: pain 95 10, symptoms 92 11, ADL 98 4, sport/ rec 86 20, and QOL 81 20 (Fig. 3). The P-values obtained for the
100
Mean KOOS
80 60 40 20 0 Pain
Symtoms
ADL
Sport
QOL
Fig. 3. Mean KOOS for each subscale (with 95% confidence intervals) for the study sample (ACL injury) -C- (n ¼ 32) and a random population-based reference group -B(n ¼ 158)43. The ACL injury group had significantly higher (better) scores for the pain and ADL subscales than the reference group, P ¼ 0.03 and P ¼ 0.008, respectively.
87
five subscales were: 0.034 (pain), 0.18 (symptoms), 0.0084 (ADL), 0.14 (sport/rec), and 1.0 (QOL). KOOS increased with improving knee cartilage quality estimated with dGEMRIC, although the only association that was statistically significant was that between the QOL subscale and the quality of the medial femoral cartilage. Pearson correlations between the five KOOS subgroups and values of T1Gd obtained from the medial femoral cartilage were: P ¼ 0.090 (pain), P ¼ 0.17 (symptoms), P ¼ 0.058 (ADL), P ¼ 0.35 (sport/rec), and P ¼ 0.021 (QOL). The corresponding Pearson correlations for the lateral femoral cartilage were: P ¼ 0.72 (pain), P ¼ 0.74 (symptoms), P ¼ 0.90 (ADL), P ¼ 0.19 (sport/rec), and P ¼ 0.40 (QOL). Discussion This study of 32 subjects who had sustained an acute ACL injury, who were treated without ACLR and who showed no overt knee OA on radiography 16 years after injury did not show any statistically significant differences in knee cartilage T1Gd values (used as a measure of cartilage quality), 20 years after the ACL injury, compared to a healthy reference group. This group of ACL copers was selected with the objective of determining whether the dGEMRIC method could be used to detect early changes in cartilage due to OA, before the cartilage degenerates too much to be repaired, as is the case when OA changes are visible on plain radiography. We expected to find lower cartilage quality (i.e., lower T1Gd values) in the study group, and were surprised to find that the values did not differ significantly from those of a healthy reference group. We decided to compare T1Gd values with a healthy reference group which resembled the study group (age and activity level) just before the time of the ACL injury. An alternative would have been to compare T1Gd values with an age-adjusted study group without any previous knee injury but according to previous findings on the dGEMRIC method we believe that we then would have been required to include more individuals to discern any statistical significant difference between the groups. Previously particularly low values of T1Gd have been observed in ACL injured subjects with a concomitant meniscus injury46. One reason for not finding a lower cartilage quality (i.e., lower T1Gd values) in the current study may be the small number of subjects (three) that had undergone medial meniscectomy, a well-known risk factor for the development of OA9,47e49. A second reason that might explain why these copers appear to have good knee cartilage quality 20 years after their ACL injury is the unique treatment they received in the original study50, where: all subjects were identified early after their knee injury; the individual pattern of knee injury was established and respected during the rehabilitation process; meniscus lesions were sparingly treated with meniscectomy; subjects were closely monitored, treated and educated by a competent physiotherapist to achieve functional knee stability, increased neuromuscular function and avoid giving-way of the knee; subjects initially (first year after injury) lowered their activity level. This treatment is different from how the acutely ACL injured patient is generally treated today, reflected in the previous study, in which the average follow-up time after ACL tear was 2 years and half of the study subjects were ACL reconstructed46. Although it’s hard to draw any solid conclusions from a comparison between this 20 year and a 2 year follow-up in two different cohorts, it is interesting to note that higher values of T1Gd were observed in this study. This may indicate that, if treated correctly, knee cartilage may have the potential to improve slowly over a period of several years after a severe knee injury. Thirdly, a selection bias could also to some extent explain why these copers appear to have good knee cartilage quality 20 years after their ACL injury as non copers that were subsequently ACL reconstructed (25%) were not included. Twenty
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years after their ACL injury, the injured subjects in the present study had T1Gd values similar to those in a healthy reference group. This finding is in line with other aspects of knee function reported in previous studies on this cohort of well-functioning ACL deficient copers9,31e34. Moreover, the injured group was found to have better KOOS results than a randomly selected age-matched group. Longer follow-up of these individuals is needed to investigate development of knee OA in later years. On a group level, higher or equal KOOS values were observed for the current cohort compared to the reference group, suggesting that the group as a whole seem to be content with their injured knee. On a subscale level, only an association between QOL and T1Gd was found. This is interesting as QOL together with sport/rec seem to be the most sensitive subscale with regards to ACL injury according to the Swedish ACL Register (www.aclregister.nu). All other subscales show results in line with numerous previous studies where the association between structural cartilage changes and symptoms has been weak. Several studies have reported good agreement between cartilage GAG content and T1Gd values37,51,52. A short T1Gd has also been reported to be a feature of early-stage knee and hip OA19,20,29,53e55. However, we found no correlation between T1Gd and discrete radiographic knee changes (grade 1, Kellgren and Lawrence) in the present study. The primary objective of this study was not to investigate associations between radiography and the dGEMRIC method, but to determine whether dGEMRIC was able to detect changes in the cartilage in a cohort at risk of developing OA. Knee radiography was actually performed 4e5 years prior to the dGEMRIC investigation, but we nevertheless believe that the study group still had well-functioning knees, without overt OA with gross cartilage defects. It may be argued that the study group was too small to allow any firm conclusions to be drawn. However, the results of previous studies performed by our group suggest that only a limited number of subjects is needed to detect statistically and clinically significant differences using dGEMRIC19,25,27e29,37,39,46,56. This is mainly due to the low variability of the T1Gd values measured in the examined cohorts. Furthermore, it is not feasible to include the larger numbers of subjects required for multivariable modeling in dGEMRIC studies due to the high cost involved, the shortage of MRI capacity, and difficulties in scheduling subjects for examination. Between reference subjects (n ¼ 24) and ACL injured subjects (n ¼ 32), we only had a post hoc power of 82% and 36% to detect a difference of 24 ms medially and 18 ms laterally in T1Gd values from the femoral cartilage, with alpha set at 0.05. As the difference in T1Gd in previous studies has been approximately 50 ms the power a priori was close to 100% for the medial and lateral femoral cartilage. The actual T1Gd differences between the two groups were very small and would probably not be clinically relevant, even if observed in a larger cohort. We examined the central weight-bearing cartilage of the medial and lateral femoral condyles because this is most commonly affected by early degenerative changes in cartilage57. Others have argued that more information can be obtained by studying the whole volume of the knee cartilage58, but we preferred to use the same MRI protocol as in our previous studies19,25,27e29,37,39. Fleming et al. found similar T1Gd values in femoral and tibial cartilage in subjects who had sustained ACL injuries26. This study, on a group of subjects that had sustained an ACL injury, and who were not treated with ACLR, shows that it is possible to maintain a good subjective knee function and good cartilage quality up to 20 years after injury. This is a very encouraging finding that may be important when counseling recently injured subjects who are prepared to abstain from pivoting sports, and who are willing to undergo neuromuscular knee rehabilitation
without ACL surgery. In conclusion, our results show that subjects who have managed to cope with their ACL injury for 20 years, with good subjective knee function, also seem to have a good cartilage quality, as their T1Gd values were not very different from a healthy reference group. Authors’ contribution Paul Neuman: contributed to and critically commented on the design of the study; recruited patients to the study; collected and assembled data; analyzed and interpreted data; critically revised the article and wrote the manuscript. Henrik Owman: contributed to conception and design; calculated dGEMRIC values; assembled and analyzed data; critically revised the article. Gunilla Müller: commented on the study design; analyzed and interpreted data; provided technical MRI support and read the diagnostic MRI images; critically revised the article. Martin Englund: contributed to and critically commented on the design of the study; collected and analyzed data from radiography; critically revised the article. Carl Johan Tiderius: contributed to conception and design of the study; analyzed and interpreted data; critically revised the article. Leif Dahlberg: contributed to conception and design of the study; analyzed and interpreted data; critically revised the article. Role of the funding source Supported by grants from The Swedish Research Council, Governmental funding of clinical research within the NHS (National Health Services), Skåne County Council’s Research and Development Foundation, Swedish National Centre for Research in Sports, King Gustaf V’s 80-year Fund, The Crafoord Foundation, The Swedish Rheumatism Association, The Alfred Österlund Foundation, The Herman Järnhardt Foundation, The Greta and Johan Kock Foundation and The Skåne University Hospital Funds. Conflict of interest The authors have no conflict of interest and this manuscript has not been submitted elsewhere. Acknowledgments We appreciate the help of Jan-Åke Nilsson for statistical guidance and Pernilla Carlsson for preparation of the manuscript. References 1. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol 2006;20:3e25. 2. Moskowitz RW. The burden of osteoarthritis: clinical and quality-of-life issues. Am J Manag Care 2009;15:S223e9. 3. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367: 1747e57. 4. Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137e62. 5. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60:91e7. 6. Nuki G. Osteoarthritis: a problem of joint failure. Z Rheumatol 1999;58:142e7.
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