Chronic Pain Following Unicompartmental Knee Arthroplasty: A Narrative Review and Illustrative Case Report on Genicular Artery Embolization Using Imipenem/Cilastatin

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

1. Does unilateral knee condyle surgery always result in contralateral condyle pain? What is the incidence of contralateral condylar pain? Is the pain more likely to occur on the affected side or the contralateral side? It is recommended to expand the content in the review section by comparing the pain profiles of the affected condyle and the contralateral condyle at various time points following unilateral knee joint condylar surgery, followed by a detailed presentation of the clinical case.
2. The evidence level of this study is inherently limited due to its nature as a single case report, which precludes the establishment of causal relationships or generalizability. This limitation is characteristic of case reports in general.
3. Selection bias: The cases were selectively chosen based on specific criteria—mechanical causes were excluded, and all exhibited vascular hyperplasia—thereby limiting the generalizability of the findings to the broader population of patients with chronic pain following unicompartmental knee arthroplasty (UKA).
4. Lack of Quantitative Vascular Assessment: Postoperative follow-up utilized only ultrasound, precluding objective, quantitative comparison of vascular parameters before and after the procedure (such as with dynamic contrast-enhanced MRI).

Author Response

We thank the Reviewer for the constructive and insightful comments, which have significantly improved the clarity, structure, and scientific rigor of the manuscript. Below, we provide a detailed point-by-point response. All changes have been incorporated into the revised manuscript as indicated.

Reviewer Comment 1

Does unilateral knee condyle surgery always result in contralateral condyle pain? What is the incidence of contralateral condylar pain? Is the pain more likely to occur on the affected side or the contralateral side? It is recommended to expand the content in the review section by comparing the pain profiles of the affected condyle and the contralateral condyle at various time points following unilateral knee joint condylar surgery, followed by a detailed presentation of the clinical case.

Response

We thank the Reviewer for this insightful comment. In response, we have substantially expanded the review section by adding a dedicated subsection entitled “Pain Distribution after Unilateral Unicompartmental Knee Arthroplasty”, in which we clarify that unilateral condylar surgery does not inevitably result in contralateral condylar pain. We discuss the relative rarity and limited quantification of true contralateral pain and emphasize that postoperative pain is more commonly localized to the ipsilateral non-resurfaced compartment. The temporal evolution of pain distribution (early, mid-term, and late postoperative phases) is also addressed.

In addition, to strengthen the conceptual continuity between the narrative review and the clinical case, we have added a new section entitled “6. Rationale for the Illustrative Case”, placed immediately before the Case Presentation. This section synthesizes the key pathophysiological concepts discussed in the review and explicitly explains the rationale for presenting the clinical case as an illustrative example of vascular-driven pain following unicompartmental knee arthroplasty.

Reviewer Comment 2

The evidence level of this study is inherently limited due to its nature as a single case report, which precludes the establishment of causal relationships or generalizability. This limitation is characteristic of case reports in general.

Response

We agree with the Reviewer and have explicitly addressed this limitation. A revised Limitations section has been added to the Discussion, clearly stating that the study represents a single case report, does not allow causal inference, and should be interpreted as hypothesis-generating rather than confirmatory. We have also reviewed the Conclusions to ensure that language implying causality or generalizability has been avoided.

Reviewer Comment 3

Selection bias: The cases were selectively chosen based on specific criteria—mechanical causes were excluded, and all exhibited vascular hyperplasia—thereby limiting the generalizability of the findings to the broader population of patients with chronic pain following unicompartmental knee arthroplasty (UKA).

Response

We thank the Reviewer for this observation. The issue of selection bias has now been explicitly addressed in the revised Limitations section. We clarify that the case was intentionally selected after exclusion of mechanical failure, infection, and radiographic disease progression, and based on imaging evidence of synovial hypervascularization. While this approach limits generalizability, we explain that it was necessary to isolate a clinical scenario in which a vascular-driven pain mechanism was most likely to be present. We now emphasize that the findings should be interpreted within the context of a highly selected subgroup of patients.

Reviewer Comment 4

Lack of Quantitative Vascular Assessment: Postoperative follow-up utilized only ultrasound, precluding objective, quantitative comparison of vascular parameters before and after the procedure (such as with dynamic contrast-enhanced MRI).

Response

We agree with the Reviewer and have incorporated this point into the Limitations section. We now acknowledge that postoperative imaging follow-up relied on power Doppler ultrasound, which does not allow quantitative assessment of vascular changes. The absence of advanced quantitative imaging modalities, such as dynamic contrast-enhanced MRI, is explicitly recognized as a limitation that restricts mechanistic interpretation. We also highlight that future studies should include standardized quantitative vascular imaging to better correlate perfusion changes with clinical outcomes.

Reviewer 2 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

Several improvements have been made to the full text (both the review and case) in comparison to the first version of the paper. 

I found a notable reduction in overstatement, adherence to the CARE checklist, and in general a more clear description of the topic. 

I still believe that a narrative review design may be too limited for the purpose, but I understand the authors response on this and accept it as reasonable. 

However, even if a proper RoB analysis is not possible and would not be suitable for this design I would ask authors to report the main limitations and caveats emerging from the assessed papers. 

Author Response

We thank the Reviewer for the positive evaluation of the revised manuscript and for acknowledging the improved clarity, reduced overstatement, and adherence to the CARE checklist.

In response to the Reviewer’s suggestion, we have added a dedicated section (Section 9: Limitations) to the manuscript. In this section, we explicitly discuss the main limitations and caveats emerging from the assessed literature, including small sample sizes, lack of control groups, heterogeneity in patient selection and outcome measures, limited quantitative vascular imaging, and short follow-up durations.

We believe that the addition of this section provides a more transparent and balanced appraisal of the existing evidence and strengthens the overall interpretation of both the narrative review and the illustrative case.

Round 2

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

agree to publish

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has problems with consistency and structure. The review part is not clear. Authors call it a narrative review but also describe it like a systematic review. The search method is written in detail, but the numbers are missing, and the text does not explain well which studies were finally included. This makes the review look confusing. The writing has many language issues. Sentences are too long, ideas are repeated, and some words are used in a strange way. There are small grammar mistakes, name spelling mistakes, and different spellings for the same medical terms - please revise the entire work. The introduction also repeats ideas and has too much background that is not needed. The case report and the discussion miss important details. The implant type, alignment, exact doses are not clearly described. The follow up scores are not explained well, and the discussion moves away from the main topic and repeats information. The limitations of the study are weak, and some formal parts of the manuscript (figures, ethics text, references, template details) are incomplete.

Author Response

We thank the Reviewer for the constructive comments, which have helped us to improve the clarity, structure, and completeness of the manuscript. All suggested points have been carefully addressed. A summary of the revisions is provided below.

Reviewer Comment 1

The review part is not clear. It is described as both narrative and systematic.

Response:
We have revised the manuscript to clearly define the review as a narrative, non-systematic review. All terminology and descriptions suggestive of a systematic review have been removed, and the search strategy section has been simplified accordingly.

Reviewer Comment 2

The search method is detailed, but numbers and study selection are missing.

Response:
As the review is now explicitly narrative, numerical study selection and flowchart reporting are not applicable. The revised text clarifies that representative literature from the last 25 years was used to provide contextual and clinical insight rather than a quantitative synthesis.

Reviewer Comment 3

The writing has language issues, repetitions, and inconsistencies.

Response:
The manuscript has undergone thorough language revision. Long sentences were shortened, repetitions removed, terminology standardized, and spelling and grammatical errors corrected throughout the text.

Reviewer Comment 4

The introduction is repetitive and contains excessive background.

Response:
The Introduction has been substantially shortened and refocused on persistent pain after unicompartmental knee arthroplasty (UKA). General background information has been reduced, and the study aim is now clearly stated.

Reviewer Comment 5

The case report lacks technical details (implant type, alignment, doses).

Response:
The Case Presentation has been expanded to include implant type, postoperative alignment, procedural details, and the exact dose and administration of Imipenem/Cilastatin, improving clarity and reproducibility.

Reviewer Comment 6

Follow-up scores are not well explained.

Response:
Outcome measures are now better contextualized, with clearer interpretation of changes in VAS, WOMAC, KOOS, and SF-36 scores over follow-up.

Reviewer Comment 7

The discussion is repetitive and moves away from the main topic.

Response:
The Discussion has been restructured and shortened, with removal of redundant content and a stronger focus on UKA-specific implications and the novelty of genicular artery embolization in this setting.

Reviewer Comment 8

The limitations are weak.

Response:
The Limitations section has been strengthened and clarified, explicitly addressing the single-case design, lack of a control group, limited imaging follow-up, and uncertainty regarding long-term outcomes.

Reviewer Comment 9

Some formal parts of the manuscript are incomplete.

Response:
All formal sections have been revised and completed.

Reviewer 2 Report

Comments and Suggestions for Authors

This article combines narrative review and single case report to explore the vascular-inflammatory mechanism of persistent lateral pain after medial unicompartmental knee arthroplasty (UKA), and reports the clinical outcome of knee artery embolization (GAE) using Imipenem/Cilastatin (IPM/CS) for the first time. The topic focuses on the "postoperative pain without clear mechanical or infectious causes", which is novel and has potential clinical value. However, the article has obvious deficiencies in evidence level, methodological description, ethical compliance, and argument balance.
1. This article is a "narrative review + case report", not "original research". Delete the misleading words such as "therapeutic potential" in the title, abstract, and keywords that imply high-level evidence.
2. Although the databases and keywords are listed, no search formula, time range, and flowchart for screening (PRISMA flow) are provided. The method for assessing the risk of bias of included studies (such as Newcastle-Ottawa Scale) is not explained.
3. The results are only 1 case, which cannot rule out the placebo effect. It is recommended to add a preliminary series of at least 3-5 consecutive cases to verify feasibility and replicability.
4. The X-ray and CT in Figures 1 and 2 do not indicate window width/level, slice thickness, and lack of postoperative 12-month imaging comparison. It is recommended to supplement.
5. Table 1 only lists absolute values. An "Minimum Clinically Important Difference (MCID)" column should be added and the source of the used MCID threshold (such as WOMAC pain 9 points) should be indicated.
6. The spelling errors such as "De Sntis" and "imipenem/cystatin" occur multiple times. Please proofread the entire text.
7. The first time abbreviations appear, they should be fully spelled out, such as PDUS and MCIC.

Author Response

We sincerely thank the Reviewer for the careful and insightful evaluation of our manuscript. We appreciate the constructive comments, which have helped us to substantially improve the clarity, methodological transparency, and scientific rigor of the paper. Below we provide a point-by-point response.

Comment 1

This article is a "narrative review + case report", not "original research". Delete misleading terms such as "therapeutic potential".

Response:
We agree with the Reviewer. The manuscript does not aim to present high-level evidence or original experimental research. Accordingly, we have revised the title, abstract, keywords, and conclusions, removing potentially misleading terms such as “therapeutic potential”.
The revised wording consistently frames the manuscript as a narrative review combined with a single illustrative case report, emphasizing hypothesis generation rather than therapeutic validation.

Comment 2

No search formula, time range, PRISMA flowchart, or risk-of-bias assessment is provided.

Response:
We acknowledge this limitation. Given the narrative (non-systematic) nature of the review, a PRISMA flowchart and formal risk-of-bias tools (e.g., Newcastle–Ottawa Scale) were not initially included.
To improve transparency, we have:

• Explicitly stated that this is a narrative review and not a systematic review.

• Clarified that formal risk-of-bias assessment was not performed, as per narrative review methodology.

This clarification has been added to the Search Strategy and Selection Criteria section.

Comment 3

One case cannot exclude placebo effect. Add at least 3–5 consecutive cases.

Response:
We fully agree that a single case cannot rule out placebo effects or establish reproducibility. Unfortunately, at the time of submission, only one eligible and fully documented case meeting strict inclusion criteria (post-UKA pain, exclusion of mechanical/infectious causes, refusal of revision surgery, and complete 12-month follow-up) was available.
We have therefore:

• Explicitly acknowledged this limitation in the Discussion and Conclusions.

• Avoided causal or efficacy claims.

• Reframed the case as a proof-of-concept and hypothesis-generating observation.

We are currently collecting additional cases and plan to report a consecutive case series in a future study.

Comment 4

Imaging lacks window/level, slice thickness, and 12-month postoperative comparison.

Response:
We agree. The figure captions have been expanded to include CT slice thickness and imaging parameters, and this information has been added to the text.
Regarding 12-month imaging, no new CT was clinically indicated due to symptom improvement and absence of red flags. This has now been explicitly stated as a limitation, and Power Doppler ultrasound follow-up has been clarified.

Comment 5

Table 1 lacks MCID values and sources.

Response:
Thank you for this valuable suggestion. We have:

• Added a Minimum Clinically Important Difference (MCID) column to Table 1.

• Cited established MCID thresholds (e.g., WOMAC pain ≈ 9–12 points; KOOS ≈ 8–10 points).

• Clarified in the caption and Methods that observed changes exceeded MCID values, while explicitly stating that clinical relevance does not imply efficacy in a single-case design.

Comment 6

Spelling errors (e.g., “De Sntis”, “imipenem/cystatin”).

Response:
We apologize for these errors. The entire manuscript has undergone thorough linguistic and technical proofreading, and all spelling inaccuracies and nomenclature inconsistencies have been corrected (e.g., De Santis, Imipenem/Cilastatin).

Comment 7

Abbreviations should be spelled out at first use.

Response:
We agree and have ensured that all abbreviations are fully spelled out at first mention, including PDUS, MCID/MCIC, and others, in accordance with journal guidelines.

Reviewer 3 Report

Comments and Suggestions for Authors

The study titled “Chronic Pain Following Unicompartmental Knee Arthroplasty: Current Management and the Therapeutic Potential of Genicular Artery Embolization Utilizing Imipenem/Cilastatin” aims to analyze the mechanisms, diagnostic work-up, and current treatments for chronic pain after unicompartmental knee arthroplasty (UKA), and to explore genicular artery embolization (GAE) with Imipenem/Cilastatin as a novel minimally invasive option.

The paper highlights that chronic pain after knee arthroplasty affects a substantial proportion of patients and is often unrelated to clear mechanical failure or infection, with synovial inflammation and pathological neovascularization emerging as important drivers of persistent pain after UKA.

The main objective is to review existing evidence on the pathophysiology, diagnosis, and management of chronic post-UKA pain and to propose GAE using Imipenem/Cilastatin as a targeted vascular intervention for patients not suitable for revision surgery.

Considering the aim of the paper, I'm not entirely sure that the chosen design is appropriate. While I do not have issues with narrative review, they are usually applied as a review design aimed at qualitatively synthesizing current knowledge on a topic, a well-established topic and knowledge. The authors here are actually trying to present a novel therapeutic approach, but scientific evidence doesn't appear strong enough for this. Moreover, many references are older than 5 years, a condition that reduce even more the strength of the review. 

About the case presentation: I suggest the authors to use the CARE checklist in order to improve reporting. 

My suggestion is to withdraw the review, maybe switching to a systematic review design. 

On the other hand, the case report could be presented after applying the CARE checklist. It would be important to avoid overstating claims in this case, considering the study design. 

Thank you for giving me the opportunity to review this paper. 

Author Response

We thank the Reviewer for the careful evaluation of our manuscript. Below we address each comment point by point.

1. Study design and use of a narrative review

Comment:
The narrative review may not be appropriate given the novelty of the proposed approach.

Response:
The manuscript does not aim to validate a new therapy. The narrative review is intended as an exploratory and hypothesis-generating overview of chronic post-UKA pain, focusing on vascular-inflammatory mechanisms. The manuscript has been revised to clearly state this intent and to remove any language implying therapeutic effectiveness.

2. Novel therapeutic approach and strength of evidence

Comment:
The scientific evidence supporting the proposed intervention appears weak.

Response:
We agree. The described intervention is now presented strictly as an illustrative example. The case report is descriptive, and no causal or efficacy claims are made. Limitations related to single-case design, placebo effects, and spontaneous improvement are explicitly discussed.

3. Age of the cited literature

Comment:
Many references are older than 5 years.

Response:
Older references were intentionally included when addressing foundational biomechanical and pathophysiological mechanisms that remain valid. Where possible, more recent studies have been added, particularly in sections related to genicular artery embolization and post-arthroplasty pain.

4. Case presentation and reporting quality

Comment:
The case report should improve reporting and avoid overstatement.

Response:
The case presentation has been revised to improve clarity and transparency, with expanded diagnostic work-up, rationale for intervention, structured follow-up, and explicit discussion of limitations. All evaluative or promotional language has been removed.

5. Suggestion to withdraw the review or convert it to a systematic review

Comment:
The review should be withdrawn or converted into a systematic review.

Response:
The current literature on genicular artery embolization in post-UKA pain is scarce and heterogeneous, making a systematic review methodologically inappropriate. We believe that an exploratory narrative review combined with an illustrative case report is a suitable approach at this stage.