|Year : 2018 | Volume
| Issue : 2 | Page : 53-58
Stratification of injuries to the lateral collateral ligament of the ankle using ultrasound: protocol of a prospective, open-label, diagnostic trial and preliminary results
Dan Huang1, Xiu-Zhen He2, Xu-Huan Yang1, Si-Min Peng1, Ying-Xian Wu1
1 Guangzhou Orthopedics Hospital, Guangzhou, Guangdong Province, China
2 Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong Province, China
|Date of Web Publication||18-Jun-2018|
Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, Foshan, Guangdong Province
Source of Support: None, Conflict of Interest: None
Background and objectives: Patients with ankle sprain most commonly experience injuries to the lateral collateral ligament (LCL) complex, which affects the stability and function of the ankle. Early diagnosis of LCL complex injuries is extremely important. In clinical practice, magnetic resonance imaging (MRI) displays the soft tissues of the ankle well, but it is expensive and cannot be used for real-time evaluation. Ultrasound (US) has the advantages of ease of operation, low cost, and real-time capability. Some studies have reported on the stratification of injuries to the LCL complex using US. However, there is controversy regarding the injury grading. The purpose of this study was to investigate the grading of LCL complex injuries (sprain, partial tear, and complete tear) using US.
Design: A prospective, open-label, diagnostic trial.
Methods: Seventy patients with suspected ankle sprain who have an acute ankle sprain history and present with surgical indicators will be scheduled to receive ankle ligament repair surgery in the Guangzhou Orthopedics Hospital, China. On the day after admission, these patients will undergo US and magnetic resonance imaging (MRI) of the injured ankle prior to ankle ligament repair surgery (test group). The contralateral ankle will be included in the control group and will also undergo MRI and US examination prior to surgery. MRI or surgical results will be used as the gold standard for diagnosing LCL complex injuries. The feasibility of stratification of LCL complex injuries (sprain, partial tear, and complete tear) using US will be evaluated.
Outcome measures and preliminary results: The primary outcome measure of this study is the sensitivity of US in the diagnosis of complete LCL complex tear. The secondary outcome measures are the sensitivity of US in the diagnosis of sprain and partial tear of the LCL complex; the specificity, positive predictive value, negative predictive value, accuracy, area under the ROC curve (AUC), and cut-off value of US in the diagnosis of sprain, partial tear, and complete tear of the LCL; and US imaging for the anatomy of the LCL complex. The results of 53 patients with acute ankle sprain included in the preliminary study suggest that there is no significant difference in the type of injuries to the talofibular ligament and calcaneofibular ligament between ultrasound diagnosis results and surgical or MRI findings (P > 0.05).
Discussion: The results of this study will reveal whether US has a higher diagnostic value than MRI in the diagnosis of injuries to the LCL complex.
Ethics and dissemination: This study was approved by Medical Ethics Committee of Guangzhou Orthopedics Hospital, China in May, 2018 (approval No. 2018-05). This study protocol will be performed in strict accordance with the Declaration of Helsinki. The personal information and data of the testing subjects participating in the clinical trials will be confidential and will be protected in accordance with applicable laws and regulations. The study protocol was designed in February 2018. Patient recruitment will begin in August 2018 and end in August 2019. Data collection will begin in August 2018. Data analysis will be performed in December 2019. The study will end in March 2020. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR1800016244). Protocol version: 1.0.
Keywords: ultrasound; ankle; injury to the lateral collateral ligament; stratification; diagnosis; sprain; partial tear; complete tear; sensitivity; specificity; clinical trial
|How to cite this article:|
Huang D, He XZ, Yang XH, Peng SM, Wu YX. Stratification of injuries to the lateral collateral ligament of the ankle using ultrasound: protocol of a prospective, open-label, diagnostic trial and preliminary results. Clin Trials Orthop Disord 2018;3:53-8
|How to cite this URL:|
Huang D, He XZ, Yang XH, Peng SM, Wu YX. Stratification of injuries to the lateral collateral ligament of the ankle using ultrasound: protocol of a prospective, open-label, diagnostic trial and preliminary results. Clin Trials Orthop Disord [serial online] 2018 [cited 2019 Sep 23];3:53-8. Available from: http://www.clinicalto.com/text.asp?2018/3/2/53/233637
| Introduction|| |
Patients with ankle injury most commonly experience injuries to the lateral collateral ligament (LCL) complex, which greatly affects the joint’s stability and function.,,, Early diagnosis of LCL complex injuries is extremely important., In recent years, much progress has been made in the imaging diagnosis of ankle injury [Table 1].,,
|Table 1: Three representative clinical studies regarding imaging diagnosis of ankle sprain published in 2016-2017|
Click here to view
Although magnetic resonance imaging (MRI) is often used in clinical practice and can easily display the condition of the soft tissues, it is expensive and has limitations (for example, magnetic responance scans at inappropriate angle may provide inaccurate information for final diagnosis). US has the advantages of low cost, and real-time imaging.,,, Some studies have reported on grading of injuries to the LCL complex using US. However, there is controversy regarding injury grading.
This study will investigate the value of US in the grading of injuries of the LCL complex of the ankle.
| Methods/Design|| |
A prospective, open-label, diagnostic trial.
Guangzhou Orthopedics Hospital, China
Recruitment will be performed through posters on a bulletin board that is used to advertise for patients in Guangzhou Orthopedics Hospital, China. After being informed of the trial objective and procedure, patients from the clinics and wards interested in participation or their close relatives will contact the project manager through telephone, e-mail, or Wechat. Patients meeting eligibility criteria will be considered for inclusion.
The researchers will treat and regularly follow-up the patients according to treatment plan. During the trial period, the hospital will subsidize the transportation fee, and there will be no charge for registration and laboratory examination.
- Inclusion criteria
Seventy patients with ankle injury receiving treatment in the clinics and wards of Guangzhou Orthopedics Hospital, China and meet all of the following criteria will be considered for inclusion:
- Patients with ankle injury 1-7 days prior
- Age 16-42 years
- Exclusion criteria
Patients who meet one or more of the following conditions will be excluded from this study:
- Interval between MRI and ultrasound examination ex ceeds 3 days
- Ankle infection
- Ankle fracture
The ankle on the non-injured side undergoing MRI examination will be included in the control group.
A self-control design that compares the imaging data between patient’s injured and non-injured (healthy) sides will be used. Randomization and blinding will not be used.
We will use the available US equipment (Konica Minolta Zaiqi Medical Products Co., Ltd., Shanghai, China; 7–14 MHz probe) will be used for magnetic resonance imaging scanner (GE Signa HDX 3.0T®, GE Healthcare, Milwaukee, WI, USA) will be used for MRI examination. MRI or surgical results will be used as the gold standard for diagnosing LCL injuries.
US examination methods
Anterior talofibular ligament (ATFL) of the ankle
The ATFL will be first examined. If permitted, the affected limb will be positioned to fully expose the lateral malleolus. The probe will be first placed on the lateral malleolus The probe will be moved anteriorly to display the talus. Anisotropic artifacts will often appear in the ATFL due to the oblique movement and they will present as a homogeneous banded hyperechoic artifacts. If one end of the probe is slightly lifted and the other end is slightly pressed to make the ligament fibers perpendicular to the acoustic beam to eliminate anisotropic artifacts, then the normal long-axis section of the ATFL will be shown as a continuous, dense fibrous band-shaped hyperechoic structure that extends from the fibula to the talus.
Calcaneofibular ligament (CFL)
The probe will be placed in the oblique coronal section of the lateral malleolus, with its upper edge and the tip of the lateral malleolus on the same level. US examination of the attachment site of the CFL at the lateral malleolus is more difficult because of its concave-shaped course.
Ultrasound and MRI criteria in the grading of LCL complex injuries
MRI criteria : grade I injury: LCL complex sprain, displaying complete ligament and swelling of soft tissue surrounding the ligament; grade II injury: partial tear of the ligament, displaying irregular ligament morphology, complete fiber bundle, and liquid signal in the ligament; grade III injury: complete tear of the ligament, i.e., absence of or broken ligament morphology.
LCL complex injury grade by ultrasound : LCL complex sprain, manifesting as thickened ligament, reduced echo, and good continuity. Partial tear of the ligament: the ligament texture is partially interrupted or thinned, and there is fluid in the surrounding articular cavity. Complete tear of the ligament: completely interrupted ligament, retraction of the stumps, and there is fluid in the sounding articular cavity.
Diagnostic criteria for ligament injury during the surgery
All patients included in this study will undergo surgery for repair of LCL complex injuries. According to the standard anatomical classification issued by the American Medical Association (AMA) (https://www.ama-assn.org/), LCL complex injuries will be graded as follows: grade I: partial or complete rupture of the ATFL, i.e., partial or complete tear of the ligament which are consistent with ultrasound; grade II: partial or complete tear of both ATFL and CFL; grade III: partial or complete tear of ATFL.
Primary outcome measure
The sensitivity (sensitivity = true positives/true positives + false negatives) of US in the diagnosis of complete tear of the LCL complex: True positive rate. It is the percentage of patients in which the LCL complex is completely torn and correctly diagnosed by the diagnostic criteria. Higher sensitivity indicates lower missed diagnosis rate.
Secondary outcome measures
The secondary outcome measures are sensitivity, specificity, positive predicative value, negative predicative value, accuracy, AUC, cut-off value of US and in the diagnosis of sprain and partial tear of the LCL complex as well as US imaging for displaying LCL complex injuries.
-Sensitivity: detection method and criteria are the same as above.
-Specificity (Specificity = true negatives/true negatives + false positives): True negative rate. It is the percentage of patients in which the LCL complex is not injured (healthy side) and is correctly diagnosed as no LCL complex injury. Higher specificity indicates lower missed diagnosis rate.
-Positive predicative value: It is the percentage of patients in which the LCL complex is truly injured among patients with positive results (ligament injury) detected by US. The positive predicative value can reflect the possibility of ligament injury in US results.
-Negative predicative value: It is the percentage of patients in which the LCL complex is truly not injured among patients with negative results (no ligament injury) detected by US.
-Accuracy: The percentage of patients with true positive and negative results detected by US in total number of patients. Higher accuracy represents a higher degree of correctness.
-Area under the ROC curve (AUC): The ROC curve will be plotted with Y-axis showing sensitivity and representing true positive rate and X-axis showing 1-specificity and representing false positive rate. AUC will be 0.5-1.0. AUC is > 0.5 and is closer to 1 indicates better diagnostic accuracy. AUC = 0.5 indicates the diagnosis method is of no significance.
Cut-off value: The optimal threshold for US diagnosis will be selected. The closer the ROC curve is to the upper left corner, the higher the diagnostic accuracy. The point closest to the ROC curve in the upper left corner is the best threshold for the least error, with the lowest total number of false positives and false negatives.
US: The LCL complex morphology will be evaluated using US to identify the three LCL injuries (sprain, partial tear and complete tear).
The adverse reactions occurring during the follow-up period will be recorded. All adverse events-related details (first onset time, severity, and management method) will be recorded and reported to the project manager and the study’s ethics committee within 24 hours.
Seventy patients with ankle sprain who receive surgery for repair of LCL injury in the Guangzhou Orthopedics Hospital, China will be included in this study. These patients will undergo high-frequency ultrasound examination of the ankle. The injured and healthy sides of the ankle will be included as test and control groups, respectively [Figure 1].
Our preliminary results showed that the sensitivity and specificity of high-frequency ultrasound in the diagnosis of LCL injuries were 84% and 93%, respectively. In accordance with clinical experience, we hypothesized that the sensitivity and specificity of high-frequency ultrasound in the diagnosis of LCL injuries will be 85% and 95%, respectively. The permitted error was 10% for both the sensitivity and specificity. Assuming 1-α = 95%, α = 0.05 (one-sided), a final sample size of n = 58 for evaluating the diagnostic sensitivity of high-frequency ultrasound and a final sample size of n = 29 for evaluating the diagnostic specificity of high-frequency ultrasound were calculated using the PASS 11.0 software (PASS, Kaysville, UT, USA). Following the principle of equal sample size in each group, we will require the largest sample size n = 58. Assuming a participant loss rate of 20%, we will require a total sample size of 70.
All data will be statistically processed using the SPSS 20.0 software (IBM, Armonk, NY, USA) following the intention-to-treat principle. Normally distributed measurement data will be expressed as means and standard deviations. Non-normally distributed data will be expressed as lower quartiles (q1), medians, and upper quartiles (q3). Count data and rating data will be expressed as percentages.
Selection of statistical methods
Friedman rank sum test will be used to compare the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of high-frequency ultrasound in the diagnosis of sprain, partial tear and complete tear of the LCL. Paired t test (for normally distributed data) and Wilcoxon Signed-Rank Test (non-normally distributed data) will be used to compare the AUC and cut-off value of high-frequency ultrasound in the diagnosis of LCL injuries of the ankle. SPSS 20.0 software will be used for plotting the ROC curves. An inspection level of α = 0.05 (bilateral) will be considered.
The subjects included in the final analysis are mainly the population assigned to the per protocol set. Per protocol set refers to the set of subjects who meet inclusion and exclusion criteria, complete the study without major protocol deviations, provide effective baseline efficacy and tight enough compliance, and fulfill the case report form.
Data collection and management
Case report forms will be filled by the investigators accurately, completely, and on time. Written records will be transferred to an electronic format by professional staff using a double data entry strategy.
Research data will be statistically analyzed and reported by professional statisticians. A final report will be made by principle investigators and the database will be locked. All data relating to this study will be preserved by Guangzhou Orthopedics Hospital.
Independent Data Monitoring Committee composition
The role and responsibilities of the Independent Data Monitoring Committee relative to the investigators and ethics committee will be identified. The role and responsibilities of the Independent Data Monitoring Committee will be relative to the project steering committee, statisticians, data managers, inspectors, and sponsors.
All imaging physicians participating in this study have a wealth of ultrasound and MRI examination experience.
The study will be performed mainly by professional subject leaders or chief physicians, and senior deputy chief physicians. Data processing and statistical calculations will be completed by statistical professionals.
The monitors will confirm whether the recorded and reported data will be correct, whether case report forms are correctly filled and whether the contents are consistent with original data. Changes in treatment, outbreaks, lost follow-ups, and omissions in each subject should be confirmed and documented.
Compensation to patients
If the clinical trial causes diseases or requires surgeries which are listed on special medical insurance contract and confirmed by the hospital, the patients will receive economic compensations for examination, treatment and nursing.
Ethics and dissemination
The study protocol was approved by Medical Ethics Committee of Guangzhou Orthopedics, China in May 2018 (approval No. 2018-05). The manuscript was prepared in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statements (Additional file 1 [Additional file 1]). The personal information and data of the testing subjects participating in the clinical trials will be confidential and will be protected in accordance with applicable laws and regulations. Anonymized trial data will be published at www.figshare.com.
| Trial Status|| |
Trial design has been completed at the time of submission. Patient recruitment will begin in August 2018. Results of 53 patients with acute ankle sprain included in the preliminary study are reported.
| Preliminary Results|| |
Information of 53 patients included in the preliminary study
These 53 patients with acute ankle sprain, consisting of 31 males and 22 females, aged 16-42 years who received treatment between May 2016 and May 2017 in Guangzhou Orthopedics Hospital, China will be included in this study. All of these patients had a history of trauma caused by falling down stairs (n = 11), traffic accidents (n = 4) and sports (n = 38).
Confirmation of LCL injuries by surgery or MRI
Partial and complete tear of LCL complex were confirmed by surgery, and sprain of LCL complex by MRI. Among 53 patients, 30 had ATFL injuries (complete tear in 30 patients, partial tear in 13 patients, and sprain in 7 patients). Ultrasound examination revealed complete tears of the ATFL in 31 patients, and partial tears in 15 patients. Complete tear was misdiagnosed in one patient by ultrasound as partial tear of the anterior talofibular ligament because the surrounding synovium and soft tissue filled the space left by the complete tear. ATFL was misdiagnosed in one patient by US as partial tear because of anisotropy. Twenty-two patients had ATFL injuries complicated by CFL ligament injuries. These were not identified by US in one patient. No patients had isolated CFL injuries. Twenty-seven patients had anterior tibial ligament injuries. One was not identified by US. Another 18 patients had fibular avulsion fractures, which were not identified by MRI in three patients [Table 2], [Table 3]).
|Table 3: Comparative results of lateral collateral ligament of the ankle between ultrasound and surgery (number of ligaments)|
Click here to view
Comparative analysis of US results and surgical results
As shown in [Table 2], there were no significant differences in the diagnostic results regarding ATFL and CFL between ultrasound and MRI (P > 0.05). Therefore, our preliminary results showed that there were no significant differences in diagnostic results of LCL complex injuries between ultrasound and MRI or surgery.
US imaging results of typical cases are shown in [Figure 2].
|Figure 2: Ultrasound images of lateral collateral ligament injuries.|
Note: (A) Partial tear of anterior talofibular ligament (1 day after sprain of the right ankle); (B) complete tear of anterior talofibular ligament (1 hour after sprain of the left ankle and obvious swelling); (C) sprain of the anterior talofibular ligament complicated by fibular avulsion fracture (3 days after sprain of the right ankle).
Click here to view
| Discussion|| |
Previous contributions and existing problems in this field
The commonly used auxiliary examination methods for the diagnosis of LCL injuries have many shortcomings. It can accurately display LCL complex injuries within a short time by using the healthy limb as the reference, without radiation exposure.,,, Therefore, it is very suitable for being a standard for diagnosing acute ankle injury.
Features of this study
Caution should be made to conclude the diagnosis of complete tear of the LCL complex because ATFL injury is often accompanied by CFL injuries. There is the possibility that ATFL injury often occurs together with lateral malleolar avulsion fracture. This is a tiny fracture and it is not easily visualized on X-ray, but it can be easily detected by ultrasound. Therefore, in this study, we will evaluate the diagnosis of different injuries to ATFL, CFL, and anterior tibial ligament using US.
Limitations of this study
The healthy side imaging data of the same patient will be used as a control. Non-injured control groups will not be used. This may lead to certain error in the evaluation of diagnostic specificity, which will be explored in future trials.
Significance of this study
Findings from this study offer hope for providing clinical evidence that US has a relatively high accuracy in the diagnosis of different injuries to the anterior talofibular ligament, calcaneofibular ligament, and anterior tibiofibular ligament.
Additional file 1: SPIRIT checklist.
DH designed this study and wrote the manuscript. XHY will be responsible for patient recruitment. XZH, SMP, and YXW will be responsible for data collection and analysis. All authors approved the final version of this manuscript.
Conflicts of interest
There are no conflicts of interest.
Institutional review board statement
This study will be performed in strict accordance with the Declaration of Helsinki and relevant applicable ethical requirements. The study protocol was approved by the Ethics Committee of Guangzhou Orthopedics Hospital (approval No. 2018-05).
This study follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.
The statistical methods of this study were reviewed by the biostatistician of Guangzhou Orthopedics Hospital in China.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be available. Study protocol, informed consent, and clinical study report will be available in September 2020. Anonymized trial data will be available indefinitely at http://www.jsxyfy.com.
Checked twice by iThenticate.
Externally peer reviewed.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]