Which assessments are used to analyze active knee stability after an anterior cruciate ligament injury to determine readiness to return to sports?

Background Adequate neuromuscular control of the knee for active joint stability could be one element to prevent secondary injuries after an anterior cruciate ligament (ACL) injury, either treated conservatively or surgically. However, it is unclear which measurements should be used to assess neuromuscular control of the knee for a safe return to sports (RTS). Purpose To summarize assessments for neuromuscular control of the knee in athletes after an ACL injury to decide upon readiness towards a successful return to sports (RTS). Study design Systematic review, level of evidence 4 Methods This systematic review followed the guidelines of Preferred Reporting of Items for Systematic Reviews and Meta-analyses (PRISMA) and has been listed in PROSPERO (CRD42019122188). The databases MEDLINE/PubMed, EMBASE, CINAHL, Cochrane Library, Physiotherapy Evidence Database (PEDro), SPORTDiscus and the Web of Science were searched from inception until March 2019. The search was updated with e-mail alerts from the searched databases until December 2019 and yielded to studies identifying assessments using electromyography (EMG) for neuromuscular control during dynamic activities in patients with an ACL rupture or repair. All included articles were assessed for risk of bias with a modified Downs and Black checklist. Results A total of 1178 records were identified through database search. After screening for title, abstract and content regarding in- and exclusion criteria, 31 articles could be included for analysis. Another six articles could be included from hand search of reference lists of the included articles, resulting in a total of 37 articles. Surface EMG was used in all studies as method to assess neuromuscular control. However, there was a wide range of tasks, interventions, muscles measured, and outcomes used. Risk of bias was medium to high due to an unclear description of participants and prior interventions, confounding factors and incompletely reported results. Conclusions Despite a wide range of EMG outcome measures for neuromuscular control, none was used to decide upon a safe RTS in adult patients after an ACL injury. Clinical relevance Future studies should aim at finding valid and reliable assessments for neuromuscular control to judge upon readiness towards RTS. Key words: anterior cruciate ligament, assessment, active knee stability, neuromuscular control, return to sports


Introduction
It is known that patients with ACL reconstruction show altered kinematics and kinetics 27 -these 132 changes are referred to neuromuscular adaptations due to altered sensorimotor control. 25 133 These changes in sensorimotor control are caused by altered afferent inputs to the central 134 nervous system due to the loss of the mechanoreceptors of the native (original) ACL. 79,99 135 Furthermore, patients with a deficient ACL show different neuromuscular strategies during 136 walking 81 , depending on the functional activity level and being copers (sufficient knee stability) 137 or non-copers (suffering from giving-way episodes). Three-dimensional kinetics and kinematics provide some data to judge upon quality of active 147 knee stability ("dynamic valgus"), however, give only little insight in neuromuscular control. In 148 addition, the currently suggested RTS criteria do not seem to be adequate to assess 149 neuromuscular control of the knee joint to judge upon a safe RTS or even competition. 150 Consequently, meaningful, reliable, valid and accurate diagnostic tools for patients with an 151 Therefore, the first aim of this systematic review was to summarize the scientific literature 158 regarding assessments for neuromuscular control in patients with an ACL injury (either treated 159 surgically or conservatively). The second aim is to analyze whether these assessments for 160 neuromuscular control were used to decide upon readiness for RTS in these patients. 161

Design, protocol and registration 163
This systematic review was planned, conducted and analyzed according to the guidelines of 164 Preferred Reporting of Items for Systematic Reviews and Metaanalyses (PRISMA) 49 and 165 followed the recommendations of Cochrane group. 33 166 The protocol for this systematic review was registered beforehand in the International 167 prospective register of systematic reviews (PROSPERO) from the National Institute for Health 168 Research NHI (https://www.crd.york.ac.uk/PROSPERO/index.php#index.php) and got the 169 registration number CRD42019122188. The search protocol can be accessed via 170 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=122188. 171

Eligibility criteria 172
To define the relevant key words for the literature search, the PICOS 83 strategy was used as 173 follows (Table1): 174 assessments for neuromuscular control of lower limb muscles using EMG as method, original 182 articles published in peer-reviewed, scientific journals, available as full texts, written in English, 183 German, French, Italian or Dutch without any restriction regarding publication date or year 184 could be included. Exclusion criteria were studies with model-driven approaches, animals, 185 cadavers, comparisons of surgical techniques, passive or non-functional tasks (such as 186 isokinetic measurements for strength and isometric muscle activity), editorials, conference 187 abstracts, book chapters, theses, systematic reviews and meta-analyses. 188

Information sources 189
The search was effectuated in the electronic databases MEDLINE/PubMed, EMBASE,190 CINAHL, Cochrane Library, Physiotherapy Evidence Database (PEDro), SPORTDiscus and 191 in the Web of Science. Furthermore, a hand search was done using the reference lists of 192 included articles to identify additional and potentially eligible articles that had been missed in 193 the electronic database search. To ensure new articles matching the search terms, e-mail 194 alerts were established from each of the databases if possible. 73 The hits from these two 195 additional sources were also screened for eligibility applying the same criteria as for the articles 196 from the database search. 197

Search 198
The search was executed based on the inclusion and exclusion criteria in all of the seven 199 activity OR onset OR offset OR on-off-pattern OR pre-activity OR latency OR reflex response)). 215

Study selection 216
All hits obtained by the database searches were downloaded to the Rayyan reference 217 management platform (rayyan.qcri.org). Prior to screening, duplicates were removed. Parallel 218 to these steps, the obtained hits were also inserted into EndNote (Clarivate Analytics, 219 Philadelphia, USA) and duplicates removed. Two authors (AB and IK) screened title and 220 abstract of the records, one by using the software EndNote (Clarivate Analytics, Philadelphia, 221 USA) and the other one with the help of the free software "rayyan". 61 If in-or exclusion of the 222 record was unclear, the full text was read, and in-/exclusion criteria were applied. Two authors 223 (IK, AB) independently decided upon in-or exclusion of all studies; if their decisions did not 224 match, discussion took place until consensus was achieved. If consensus would not have been 225 achieved, a third author (IB or HB) would have finally decided upon in-or exclusion of the 226 record in question; however, this was not necessary. score) were rated as being of medium quality, and total scores below 13 were rated as being 234 of low methodological quality, high risk of bias respectively. As the aim of this systematic 235 review was to summarize the applied measures for neuromuscular control, the methodological 236 quality of the included studies was of secondary interest. Therefore, no study was excluded 237 due to a low total score in the risk of bias assessment. 238

Data collection process 239
After final decision of all studies, data extraction for each eligible study was performed by the 240 first author (AB) with predefined Microsoft® Excel (Microsoft Corporation, Redmond WA, USA) 241 spreadsheet. As all included studies were available as full texts and the provided data were 242 enough for the systematic review, no authors had to be contacted in order to obtain or confirm 243 data. The first author (AB) extracted necessary information from each article describing the 244 study design, groups measured and their characteristics, the tasks to be fulfilled by all 245 participants, and all assessments or methods used to evaluate neuromuscular control. 246 Furthermore, the use of the chosen assessment for neuromuscular control was judged whether 247 it was used as tool to clear the participants for RTS. The second author (IK) controlled the 248 extracted data at random. 249 250 Results systematic review, study protocol), unclear or inadequate outcome, healthy participants or 260 without ACL injury. Details about every step of the search are illustrated in the following 261 flowchart (Fig.1). 262 Insert Figure 1 about here.   conservative, or healthy controls), the remaining three studies made a comparison between 282 The number of included, adult participants with ACL injury varied from N = 1 98 to a maximum 285 of N = 70 39 with a wide range of described physical activity from "normal" 13 , "regular" 46 , "active 286 in at least one sport" 38 , TAS of minimal 3 84 , minimal 2h/week 1,2

294
Abbreviations: ACLD = anterior cruciate ligament deficiency (conservative/non-surgical treatment); ACLR = anterior cruciate 295 ligament reconstruction/repair (surgery); BPTB = bone-patella-tendon-bone technique for ACLR; Level I: sports are described as 296 jumping, pivoting and hard cutting sports; Level II sports: also involve lateral motion, but with less jumping or hard cutting than 297 level I; n.a. = not applicable; n.s. = not stated; RTA = return to activity (return to participation); RTS = return to sports; RTP = return All included studies used surface EMG as method to assess neuromuscular control and 301 provided EMG-related variables such as peak and mean amplitudes, timing and peak of 302 muscle activity, preparatory and reactive muscle activity, on-and offset of muscular activation, 303 co-activation/co-contraction ratios, asymmetry index.  . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

344
The aim of this systematic review was to summarize the scientific literature regarding 345 assessments for neuromuscular control in patients with an ACL injury (either treated surgically 346 or conservatively). The second aim was to analyze whether these assessments for 347 neuromuscular control were used to decide upon readiness for RTS in these patients. 348 There were a lot of factors in the study population which could have an influence on 349 neuromuscular control: 350

Influence by type of comparison (intra-versus inter-subject) 351
The use of the contralateral, non-injured leg in intra-subject comparison, without a "real" control 352 group 57,67 may lead to an overestimation of the neuromuscular performance in the ACL-353 reconstructed or -injured leg. After ACL reconstruction, functional performance is often 354 expressed with the Lower Limb Symmetry Index (LSI). 3,91 However, the LSI may overestimate 355 the time point of RTS ACL surgery, and therefore lead to an increased risk for secondary 356 injury. 95 In acutely injured ACL patients, intra-individual comparison showed bilateral 357 consequences during stair ascent and indicates an alteration in the motor program (''pre-358 programmed activity''). 16 In addition, in case of a case-controlled study design, the subjects in 359 the control group should be matched to the ACL participants regarding age, body mass, height, 360 activity level and leg dominance. 361 Influence by level of activity and fatigue 362 mental demands of playing sport". 14 Furthermore, impairment measures are also poorly related 371 to participation. 74 It is therefore recommended to search for a standardized assessment close 372 to the injury mechanism. 373

Influence by sex 374
Not all included studies reported findings of mixed groups separately by gender. Some did not 375 even state the sex of the participants. This could partly be explained by the date of publication 376 as gender difference in ACL patients has not been in the focus of research 20 years before. 377 But nowadays, a lot of facts concerning females are known: Female athletes are more likely 378 to suffer from an ACL injury 93 than men: their increased risk is probably multifactorial. However, 379 several studies indicate that hormonal factors play a role 8,32,71,80,97 contributing to an increased 380 laxity of ligaments in the first half of the menstrual cycle. The higher risk for females to suffer 381 from an ACL injury can be explained by motion and loading of the knee joint during 382 performance. 31 The ligament dominance theory says that female athletes typically perform 383 movements in sports with a greater knee valgus angle than men. Therefore, the amount of 384 stress on the ACL in these situations is higher because there is a high activation of the 385 quadriceps despite limited knee and hip flexion, greater hip adduction and a large knee 386 adduction moment. 69,70 Moreover, females typically land with an internally or externally rotated 387 tibia 52 , leading to an increased knee valgus stress due to greater and more laterally orientated 388 ground reaction forces. 82 A systematic review and meta-analysis 86 reported equal results in 389 women and men for outcomes such as anterior drawer, Pivot-Shift and Lachman test, hop 390 tests, quadriceps or hamstring testing, International Knee Documentation Committee (IKDC) 391 knee examination score and loss of range of motion. However, female patients showed inferior, 392 statistically significant subjective and functional outcomes such as laxity, revision rate, Lysholm 393 score, TAS and incidence of not returning to sports. 394

Influence by treatment 395
The included studies reported different treatment options (surgical reconstruction with different 396 graft types, conservative treatment). Depending on the classification of the participants in 397 copers and non-copers, the results in neuromuscular control may differ from a population of 398 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
(which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10.1101/2020.03.05.20031617 doi: medRxiv preprint ACL-reconstructed (ACL-R) participants. Therefore, all researchers who worked with copers 399 and non-copers made intra-and inter-group comparisons without an ACL-R group. A 400 Cochrane review revealed low evidence for no difference in young, active adults after two and 401 five years after the injury, assessed with patient-reported outcomes. However, many 402 participants with conservative treatments remain symptomatic (non-copers with unstable knee) 403 and therefore, later opt for ACL surgery. 51 Furthermore, the choice of graft would influence the 404 neuromuscular control of measured muscles due to the morbidity of the harvesting site of the 405 graft (hamstrings e.g.). 406

EMG variables 407
The provided EMG-related variables were in accordance to the ones mentioned in a systematic 408 review searching for knee muscle activity in ACL-deficient (ACLD) patients and healthy 409 controls during gait. 81 Another study summarized and quantitatively analyzed muscle onset 410 activity prior to landing in patients after ACL injury 88  If the researchers mentioned the procedures for collecting EMG data, they referred to 416 standardized applications and guidelines such as SENIAM. 30 417

Return to sports (RTS) 418
Regarding the determination of RTS after ACL reconstruction, there is some evidence for the 419 use of functional performance tests, which had also been widely used in the included studies. 420 Multiple functional performance measures -a battery including strength and hop tests, quality 421 of movement and psychological tests 92 -might be more useful for the determination of RTS 422 than a single performance measure. 4 However, it is still unclear, which measures should be 423 used to bring athletes safely back to RTS with a low risk of a second ACL injury. 92 Currently 424 used RTS criteria may be suboptimal at reducing the risk of a second ACL injury. 44  . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not peer-reviewed)
The copyright holder for this preprint . https://doi.org/10.1101/2020.03.05.20031617 doi: medRxiv preprint patient-reports, clinical examination, thigh circumference, ligamentous stability, range of 427 motion, effusion and performance-based criteria. Recovery of neuromuscular function was 428 mentioned to be important because of the existing connection between the variables time since 429 surgery and the risk for re-injury of the knee joint but adequate assessment procedures to 430 assess neuromuscular function are still a matter of debate. 24 431 Limitations 432 The sample size of all the studies was quite low, however providing reasonable sample size 433 calculations and depending on the variable investigated, the results were acceptable. 434 Furthermore, the more restrictive the inclusion criteria for the participants, the more 435 homogeneous the intervention and the control groups were, but the more challenging the 436 recruitment process was, leading to smaller groups to be investigated. 437 The used assessment for the risk of bias, the Downs and Black checklist 20 (in a former used, 438 modified form 62,73 is designed for randomized and non-randomized controlled studies, 439 however, the latter score lower in some items, get lower total scores and therefore a worse 440 overall rating of the methodological quality. Despite this disadvantage, we decided to use the 441 modified checklist as we could assess all the study designs included in the presented 442 systematic review. 443 444

445
Despite a wide range of assessments for neuromuscular control, none was used to decide 446 upon a safe RTS. Additional studies are needed to define readiness towards RTS by assessing 447 neuromuscular control in adult ACL patients. Clinicians should be aware of LSI problems (non-448 injured side is affected, probably not a good reference, pre-surgery/-injury scores would be 449 perfect but not realistic in recreational athletes, probably in professional sports) and that 450 physical performance batteries do not reflect neuromuscular control needed for a safe RTS. 451 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not peer-reviewed)
The copyright holder for this preprint . https://doi.org/10.1101/2020.03.05.20031617 doi: medRxiv preprint More research is needed to find a reliable and valid, EMG-related variable to assess 452 neuromuscular control in a standardized situation, close to the injury mechanism and as sport-453 specific as possible. 454 455

Conflict of interest 456
All authors declare to have no conflict of interest. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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750
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(which was not peer-reviewed)
The copyright holder for this preprint . https://doi.org/10.1101/2020.03.05.20031617 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.