Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

BACKGROUND: Non-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR. CONCLUSION: Subsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival

Force-plate analysis-of-gait at long-term follow-up after surgical stabilization and hyaluronic acid/doxycycline treatment of stifle arthritis in dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: Data represent mean ± standard deviation. n = 8 dogs; NS – not significant (<i>p</i>>0.05).</p

Contralateral cranial cruciate ligament (CrCL) survival.

<p>Kaplan-Meier plot for contralateral CrCL survival in three large populations of client-owned dogs. Overall median survival was 2.59 years. There was no significant difference in ligament survival between groups (<i>p</i> = 0.57). Complete – dogs that experienced contralateral CrCLR during the study period; Censored – dogs that did not experience contralateral CrCLR during the study period.</p

Photomicrographs of stifle synovium from dogs with unilateral cranial cruciate ligament rupture and a contralateral stable stifle.

<p>(<b>A</b>) Unstable stifle of a five-year-old neutered male Golden Retriever. Proliferation of the synovial intima with villus formation can be seen. Widening of intima (arrows) and infiltration of the intima and sub-intima with mononuclear inflammatory cells can also be seen. (<b>B</b>) Unstable stifle of a five-year-old Chesapeake Bay Retriever. TRAP⁺ mononuclear cells (arrows) were identified in synovial villi in the intima and sub-intimal tissues. (<b>C</b>) Stable stifle from a six-year-old neutered male Golden Retriever. Proliferation of the synovial intima can also be seen, with accumulation of mononuclear inflammatory cells within the intima and the sub-intimal tissues (arrows). A,C – Hematoxylin and eosin stain; B – histochemical stain for tartrate-resistant acid phosphatase (TRAP). A – bar = 500 µm; B – bar = 200 µm; C – bar = 100 µm.</p

Relative expression of immune response genes in synovial fluid from unstable index and stable contralateral stifles of dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: TCR Vβ - beta chain of the canine T cell receptor; TRAP – tartrate-resistant acid phosphatase; IL – interleukin; IFN – interferon; TNF – tumor necrosis factor. Data represent median (range). Median values in bold indicate that gene expression is significantly different from the peripheral blood mononuclear cell internal control (<i>p</i><0.05).</p><p>*<i>p</i><0.05,</p><p>**<i>p</i><0.01 versus contralateral stifle.</p>##<p><i>p</i><0.01 versus same tissue at diagnosis. n = 15–16 at diagnosis, n = 14–15 at 10 week recheck, n = 5–7 at 1 year recheck.</p

Synovial inflammation in the unstable index and stable contralateral stifles of dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: Synovitis was scored subjectively using arthroscopy using a compartmental numerical rating scale (NRS, score range 0–24) and a visual analogue scale (VAS). Histologic sections of synovium were also subjectively graded for inflammation and numbers of TRAP⁺ mononuclear cells using a visual analogue scale; severity scores ranged from 0 (no inflammation) to 100 (could not be more severely inflamed). NS – not significant.</p

Tibial plateau angle (TPA) and age influence contralateral cranial cruciate ligament (CrCL) survival over time in dogs diagnosed with unilateral CrCL rupture.

<p>(<b>A</b>) Increasing TPA was associated with decreased contralateral CrCL survival, whereas increasing age at diagnosis was associated with increased contralateral CrCL survival (<b>B</b>). However, these effects appear minor, as the slope of the regression lines is small and data points are widely scattered.</p

Bacterial load in the unstable index and stable contralateral stifles of dogs with unilateral cranial cruciate ligament rupture.

<p><b>Note</b>: Data represent median (range). Bacterial load represents estimated 16S rRNA amplicon number using universal primers and real-time PCR.</p><p>*<i>p</i><0.05 versus contralateral joint.</p>##<p><i>p</i>≤0.01 versus same tissue at diagnosis. (n = 13 to 16 dogs per group).</p

Contralateral cranial cruciate ligament (CrCL) survival after post-operative treatment with provisional disease-modifying therapy.

<p>Kaplan-Meier plot for contralateral CrCL survival in a population of client-owned dogs treatment with oral doxycycline after TPLO stabilization of unilateral CrCLR. Arthroscopic examination and associated lavage of the contralateral stable stifle, together with intra-articular hyaluronic acid and oral doxycycline did not significantly influence CrCL survival (<i>p</i> = 0.87). Complete – dogs that experienced contralateral CrCLR during the study period; Censored – dogs that did not experience contralateral CrCLR during the study period.</p