management of stiffness following total knee arthroplasty

COPYRIGHT © 2006 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

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Management of Stiffness Following

Total Knee ArthroplastyBY JAVAD PARVIZI, MD, FRCS, T. DAVID TARITY, BS, MARLA J. STEINBECK, PHD, ROMAN G. POLITI, BS,

ASHISH JOSHI, MD, MPH, JAMES J. PURTILL, MD, AND PETER F. SHARKEY, MD

Introductiontiffness following total knee arthroplasty is a disablingcomplication1-7. Although some predisposing factorshave been identified, in most cases the exact etiology of

the stiffness cannot be discerned. The reported prevalence ofthis complication has ranged widely from 1.3% to 12%1,8-10.The difference in rate may be due in part to varied definitionsof stiffness11. Several factors affecting the postoperative rangeof motion that have been identified include the preoperativerange of motion, contracture of the extensor mechanism andcapsular structure, the preoperative diagnosis, personality ofthe patient, lack of patient compliance with the rehabilitationprotocol, and the patient’s threshold for pain12-18.

Technical factors, such as overstuffing the patellofemo-ral joint, mismatch of the flexion and extension gaps, inac-

curate ligament balancing, component malpositioning, useof oversized components, joint-line elevation, excessivetightening of the extensor mechanism, and underresectionof the patella have also been implicated1,19. Various manage-ment protocols have been proposed to address this compli-cation. This exhibit presents our institutional experiencewith the management of stiffness following total knee ar-throplasty. We report the findings of a case-control studythat was designed to predict the factors responsible for stiff-ness after total knee arthroplasty. In addition, the results ofan ongoing basic-science study attempting to unravel themolecular mechanism of arthrofibrosis following total kneearthroplasty are presented. We also provide the outline ofour current treatment strategy for the management of stiff-ness following total knee arthroplasty.

S

Fig. 1

Demographic distribution of patients in the study and control groups. TKA = total knee arthroplasty, and BMI =

body-mass index.

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THE JOU R N A L OF BO N E & JO I N T SU RG ER Y · JB JS .ORG

VO LUM E 88-A · SU P P L E M E N T 4 · 2006MA N AG E M EN T OF ST I FF N E S S FOL L OW I N G TOT A L KN E E AR T H ROPL A ST Y

Materials and MethodsCase-Control Study

he purpose of this study was to identify factors that pre-dispose patients to stiffness following total knee arthro-

plasty. With use of an institutional computerized database,the outcome of primary total knee arthroplasty performed in

nearly 10,000 patients from 1995 to 2004 was evaluated. Pa-tients with stiffness following total knee arthroplasty, definedas an arc of motion of <90°, or patients requiring a manipula-tion of a prosthetic knee, were identified. The cohort com-prised 112 knees (ninety-eight patients). These knees werematched for the year of surgery and surgeon with a control

T

Fig. 2

Analysis of preoperative and surgical parameters. ROM = range of motion.

Fig. 3

Analysis of radiographic parameters. IS = Insall-Salvati ratio.

Parvizi_00608.fm Page 176 Monday, October 30, 2006 1:55 PM

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group in a 1:2 ratio. The control group consisted of 224 kneesin 186 patients, all of which were confirmed to have an arc ofmotion of >90° at least one year following a total knee arthro-plasty (Fig. 1). Sixteen knees (fifteen patients) from the con-trol group were then excluded on the basis of the lack ofsufficient information, leaving 208 knees in 171 patients forthe final analysis. The clinical and radiographic records of allpatients were examined in detail (Figs. 2 and 3).

Demographic, surgical, and radiographic etiologicalfactors were evaluated. These included age, race, sex, body-mass index, preoperative range of motion, preoperative diag-nosis, intraoperative complications, total operative time, andestimated blood loss. Radiographic variables included patellartilt, Insall-Salvati ratio20, patellar thickness, femoral flexion an-gle, tibial slope, femorotibial angle, and joint-line measure-ments. The results of all interventions, both surgical andnonsurgical, for the treatment of stiffness were also evaluated.

Descriptive statistical correlation with use of univariateanalysis was performed with SAS software (version 9.1; SASInstitute, Cary, North Carolina) to determine the mean, stan-dard deviations, medians, 25% and 95% interquartile range,and the frequency distribution for the demographic variables.Multivariate analysis was performed with use of stepwise lo-gistic regression after adjusting for the potential confounders

to determine the variables that would predict stiffness after to-tal knee arthroplasty.

Results

Of the ninety-eight patients comprising the study group, amanipulation under anesthesia was performed once forninety-three patients and twice for five patients. Fourteen pa-tients underwent revision total knee arthroplasty for stiffness.The etiology of the stiffness following total knee arthroplastyin those patients was deemed to be arthrofibrosis (thirteen pa-tients) and technical error (one patient).

Demographics: Analysis was performed on 320 knees,with 112 knees (35%) in the study group and 208 (65%) in thecontrol group. The average age of the patients was fifty-eightyears (range, forty-seven to sixty-nine years) in the studygroup and sixty-four years (range, fifty-three to seventy-fiveyears) in the control group; the difference was not significant.A majority of the patients in both the study and controlgroups were white and female (Fig. 1). The patients in thestudy group had a slightly lower body weight (p = 0.05) com-pared with the control group, whereas the body-mass indexwas significantly less (p = 0.003) compared with the controls.No significant differences were seen with respect to patientheight. A significantly higher proportion of individuals who

Fig. 4

COX-2 and Bcl-2 immunohistochemistry and TUNEL analysis of tissue from stiff knees (A, D, and

G), knees with aseptic loosening (B, E, and H), and knees with periprosthetic infection (C, F, and

I). (Top row [A, B, and C] shows COX-2 staining; middle row [D, E, and F] shows apoptosis by

means of TUNEL analysis; and bottom row [G, H, and I] shows fluorescently labeled Bcl-2 cells).

Note the absence of apoptotic cells and the corresponding increase in COX-2 and Bcl-2 in the ar-

throfibrotic samples.


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had stiffness were younger compared with the controls (p <0.0001). There was no significant difference in the prevalenceof stiffness between the genders or between races (white andblack) after adjusting for potential confounders.

Clinical History: The diagnosis was degenerative jointdisease for all patients in both groups. With the numbers stud-ied, no significant difference was detected between the groupswith respect to the preoperative range of motion or otherpostoperative complications (p > 0.05). Moreover, no signifi-cant difference was found between the groups with respect tototal operative time (p = 0.52) or estimated blood loss (p =0.86) (Fig. 2).

Radiographic Findings: The patients with stiffness had asignificantly lower patellar length (p = 0.02), increased patellartendon length (p < 0.0001), a lower Insall-Salvati ratio (p <0.0001), decreased femoral component width (p = 0.007), and adecreased femoral-tibial component ratio (defined as the ratiobetween the widths of the femoral and tibial components as de-termined on anteroposterior radiographs) (p = 0.03). No signif-icant difference was identified in other radiographic variables.

Adjusted Analysis: After adjusting for potential con-founders, we performed stepwise logistic regression analysis todetermine the factors predicting stiffness after total knee ar-throplasty. It was found that the age at the time of the totalknee arthroplasty, body-mass index, a higher femoral flexionangle, and the position of the patella were significant predic-tors of stiffness. The odds of developing stiffness increased inindividuals who had total knee arthroplasty performed at ayounger age (odds ratio = 0.87; p = 0.0009), had a lower body-mass index (odds ratio = 0.97; p = 0.01), had an increasedfemoral flexion angle (odds ratio = 0.78; p = 0.02), and hadpatella baja (odds ratio = 3.50; p = 0.0003) prior to or after ar-throplasty (Table I).

Stratification Analysis: Gender-based stratified analysiswas performed to determine the predictors of stiffness in malesand females. We found that age at the time of the index opera-tion, body-mass index, femoral flexion, and patella baja weresignificant predictors of stiffness in females, whereas patella bajawas the only significant predictor for stiffness in males.

The odds of developing stiffness increased in femaleswhen total knee arthroplasty was performed at a younger age(odds ratio = 0.91; p = 0.02) and in those with a lower body-mass index (odds ratio = 0.85; p = 0.02), an increased femoralflexion angle (odds ratio = 0.78; p = 0.04), and patella baja

(odds ratio = 2.87; p = 0.006). The only significant predictor forstiffness in males was patella baja (odds ratio =0.11; p = 0.04).

Basic Science StudyTissue Collection

This multicenter study utilized a standardized tissue-retrievalprotocol allowing collection and analysis of periarticular tis-sues from the knee of patients with arthrofibrosis who wereundergoing revision arthroplasty. Tissues from the same re-gion of the knee from patients with osteoarthritis undergoingprimary knee arthroplasty, or revision arthroplasty for infec-tion, as well as an aseptic indication were used as controls. Tis-sue samples measuring 2 cm3 from ten affected or controlknees were retrieved. Tissue samples were taken from the peri-articular area, which included the suprapatellar, medial gutter,lateral gutter, and infrapatellar regions. The tissue was placedin sterile saline solution and was transferred immediately toour laboratory for detailed analyses. Tissue samples fromother centers were placed on ice and transferred overnight.

Immunohistochemistry: Tissues were fixed in Tissue-TekOCT (Fisher Scientific, Hampton, New Hampshire) freezemedium and sectioned (6 µm), and they were fixed in 4% para-formaldehyde, dehydrated, embedded in paraffin, and sectioned(6 µm). The paraffin sections were dewaxed and rehydrated. En-dogenous peroxidase activity was blocked with 3% H2O2 inmethanol. Prior to incubation with primary antibodies, tissuesections were treated with one of the following: Triton X-100,antigen-retrieval reagent, or proteinase K (0.01 U/mL). Im-munohistochemistry was performed with the antibodies toNF-κB (nuclear transcription factor-kappaB), COX-2 (cyclo-oxygenase-2), Bcl-2, PCNA (proliferating cell nuclear anti-gen), FGF (fibroblast growth factor), TGF-β (transforminggrowth factor-beta), chymase, and type-I collagen. As a nega-tive control for immunohistochemistry, the sections were in-cubated with no primary antibodies. Immunohistochemistryexperiments utilized the DAB Detection Kit (Vector Labora-tories, Burlingame, California) with biotinylated horse anti-mouse IgG or goat anti-rabbit IgG as secondary antibodies.

Histochemical Staining: Sections were stained with al-cian blue to determine proteoglycan content; alizarin red todetermine tissue calcification; hematoxylin and eosin to deter-mine cellularity, vascularization, and inflammatory cell infil-tration; and toluidine blue to determine mast cell numbers.

Image Acquisition and Analysis Images of the stained tissue were observed with use of confocallaser scanning microscopy (FluoView, Olympus, Tokyo, Japan),equipped with a krypton-argon laser. Three randomly selectedareas of the slices were imaged in red and green, with fluores-cence excitations at 488 and 568 nm and fluorescence emissionsat 530 and 590 nm, respectively. Images were analyzed with useof Image-Pro Plus software (Media Cybernetics, Silver Spring,Maryland), and the mean fluorescence intensity of the threerandomly chosen areas in each slice was determined. At leastthree slices per sample were used. Background autofluores-cence was subtracted from the green and red signal.

TABLE I Predisposing Factors for Stiffness Following Total Knee Arthroplasty

Parameter P Value Odds Ratio

Young age at time of total knee arthroplasty

0.0009 0.87

Low body-mass index 0.01 0.97

High femoral flexion 0.02 0.78

Patella baja 0.0003 3.50


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Apoptosis AssayTUNEL (terminal deoxynucleotidyl transferase-mediated dUTPnick end labeling) assay was used to measure the index of apop-tosis. The TUNEL assay takes advantage of the fact that, duringapoptosis, nucleosomes and endonucleases digest genomicDNA into multiple fragments of approximately 200 bp. To mea-sure the fragmented DNA, the nucleotide ends were labeledwith use of the Klenow FragEL Kit (Oncogene Research Prod-ucts, Cambridge, Massachusetts), according to the manufac-turer’s instructions, and the oxidized diaminobenzidine (brownprecipitate) product was visualized by light microscopy. Toimprove detection of TUNEL-positive cells, the cells were notcounterstained.

Measurement of Lipofuscin and Nitrosylated ProteinsDirect measurement of reactive oxygen and nitrogen species(RONS) production in surgical tissues is difficult because ofinadequate assay sensitivity and reproducibility. Moreover, thequantity of RONS detected represents only the amount pro-duced at that specific time-point. To overcome these limita-tions, we measured oxidative products of RONS reactions,namely, nitrosylated proteins and lipofuscin in the tissue sam-ples. Lipofuscin is a highly polymerized molecule that is gen-erated by the oxidation of lipids. It acts as a proinflammatorymediator, and its presence indicates abnormal tissue produc-tion of RONS. The amount of lipofuscin in tissue samples wasdetermined by autofluorescence and by the Schmorl dye lipo-fuscin detection method. Localization, microscopy, and analy-

sis to detect lipofuscin were performed. Immunolocalization,microscopy, and analysis to detect nitrosylated proteins werealso performed. The immunohistochemistry was performedas described above.

Results

The tissue samples from the knees of individuals with ar-throfibrosis demonstrated an increased number of cells ex-pressing the pro-survival factors COX-2 and Bcl-2 and a verylow number of TUNEL-positive or apoptotic cells (Fig. 4). Inaddition, these samples demonstrated an aggressive fibroblas-tic proliferation (Fig. 5, A and B), deposition of type-I col-lagen (Fig. 5, C), and accumulation of abnormal matrixproteins (Fig. 5, D). Furthermore, microvascular hemorrhage(Fig. 5, E), hypervascularity, and excessive numbers of myofi-broblasts and inflammatory cells, in particular mast cells, werefound in the arthrofibrotic tissues. The most compelling ob-servation was that arthrofibrotic tissue contained a number ofRONS products that were not present in the control tissuesamples. The products were localized to regions near rupturedblood vessels and regions of high fibroblast density.

Discussiontiffness following total knee arthroplasty, although fortu-nately rare, can be challenging. In this study, individuals

undergoing total knee arthroplasty at an earlier age were sig-nificantly more likely to have stiffness develop compared withthe control group (p < 0.0009). After adjustment for potential

S

Fig. 5

Immunohistochemical and cellular stains of tissue retrieved from stiff knees (A through E) and control tissues from knees

without stiffness (F through J).Various staining protocols were performed: PCNA (proliferating cell nuclear antigen)-labeled

proliferative cells (A and F), FGF (fibroblast growth factor)-labeled cells (B and G), collagen type-I deposition (C and H), Prus-

sian blue-hemosiderin (D and I), and hematoxylin and eosin (E and J). The images are representative of staining differences

between affected and control samples (×10).


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confounders, a gender-based stratified analysis was performed.Factors predisposing women to stiffness following total kneearthroplasty included a young age at the time of total knee ar-throplasty, a lower body-mass index, a high femoral flexionangle, and the presence of patella baja. Only patella baja was asignificant predictor in males (Table I). An acute awareness ofthese factors during the rehabilitation period may serve to re-duce the development of stiffness following total knee arthro-plasty in selected patients.

The exact pathoetiology of stiffness secondary to arthrofi-brosis following total knee arthroplasty remains elusive. How-ever, aggressive fibroblast proliferation and tissue metaplasiais known to be the trademark of this condition6,21. Alterationsin normal tissue composition, the replacement of matrix withdisordered collagen fibrils, and cellular damage leading to dys-functional repair are observed in other fibrotic tissues22-26. Thehealing response is initiated by the clotting cascade resulting inthe migration of inflammatory cells to the site of injury23-25,27-30.Both the migration of inflammatory cells into the injured tissueand the proliferation of fibroblasts result in the release of cyto-kines, growth factors, and reactive oxygen and nitrogen species(RONS)28,31,32. An excessive accumulation of RONS then drivesinflammatory infiltration and aggressive fibroblast and mast cellproliferation that result in the oxidative modification of periar-ticular tissue, the release of cytokines and growth factors, andthe induction of pro-apoptotic genes, all of which are central tothe pathogenesis of stiffness33-35. Patients with a genetic predispo-sition to this process demonstrate a deficiency in RONS removal(antioxidants) and/or exaggerated RONS production. The pro-duction of RONS and its byproducts may be responsible forvascular hemorrhaging and the release of the iron oxidationproduct hemosiderin (Fig. 5, D) as well as fibroblast and mastcell proliferation. The accumulation of hemosiderin in turn fu-els further release of RONS products (oxidized lipids and ni-trosylated proteins).

The most reactive of the RONS products are singlet oxy-gen, hypochlorous acid, chlorine gas, hydroxyl radicals, andperoxynitrite. Our in vitro studies have revealed that both ma-

ture type-I and type-II collagen are modified by RONS36. Thesechanges may affect the organization of the tissue matrix, alter-ing its mechanical properties as well as preventing normal re-modeling and resolution of the injury response. The expressionof COX-2 activates Bcl-2, a key regulator of the antiapoptoticmachinery, and strongly suggests that cells are not undergoingapoptosis and thereby attenuating the wound-healing response.

These observations strongly suggest an imbalance in thechemical mediators regulating the normal resolution of the in-flammatory and fibroblastic proliferative phases of healing. Weconclude that aggressive periarticular fibrosis and the unre-solved healing process in patients with arthrofibrosis are resultsof an excessive accumulation of RONS and RONS-modified lip-ids and proteins (Fig. 6). Furthermore, we suggest that periar-ticular arthrofibrosis initiated and propagated by RONS willmost likely occur in patients with a genetic predisposition tothis process, that is, individuals with a genetic makeup that re-sults in a deficiency in RONS removal (antioxidants) and/or ex-aggerated RONS production. Treatment modalities with use ofantioxidant treatment are being studied and may have a role inthe management of this challenging condition.

Corresponding author:Javad Parvizi, MD, FRCS925 Chestnut Street, Philadelphia, PA 19107. E-mail address: [email protected]

The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not re-ceive payments or other benefits or a commitment or agreement to pro-vide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

doi:10.2106/JBJS.F.00608

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Fig. 6

An overview of the findings of the study. ROS = reactive oxygen species, and FGF = fibroblast growth factor.


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