Genicular Artery Embolization with Imipenem/Cilastatin for Pigmented Villonodular Synovitis of the Knee: A Case Report

Abstract

Background: Pigmented villonodular synovitis (PVNS) is a rare, proliferative disorder of the synovium that predominantly affects the knee. Traditional treatment involves surgical resection; however, the high recurrence rates have prompted the exploration of alternative, minimally invasive treatments. This case report presents the novel use of genicular artery embolization (GAE) with imipenem/cilastatin as a therapeutic intervention. Case presentation: We present a case of a 52-year-old male with a 5-month history of progressive left-knee pain and swelling. Magnetic resonance imaging (MRI) suggested PVNS, which was confirmed through synovial biopsy. Because of concerns about surgical recovery and recurrence risk, the patient opted for GAE with imipenem/cilastatin over traditional synovectomy. This technique, employing the antibiotic’s anti-angiogenic and anti-inflammatory properties, was administered under local anesthesia without complications. Results: Post-procedural assessments demonstrated rapid and sustained symptom relief. At the 1-month follow-up, the patient’s Visual Analog Scale (VAS) pain score decreased from 7/10 to 3/10, and their Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36 health survey scores indicated significant functional improvement. By the 6-month follow-up, the VAS had reached 0/10; the KOOS value reflected near-complete functional recovery; and MRI confirmed reduced synovial hypertrophy and absence of recurrence. No complications were observed. Discussion: GAE with imipenem/cilastatin shows potential as an effective alternative to surgery for PVNS, particularly in patients at risk of surgical complications or recurrence. While the preliminary findings are promising, the limitations include the case’s single-subject design and the need for extended follow-up to determine long-term outcomes and recurrence rates. Further studies comparing GAE with traditional surgical approaches are needed to assess its broader applicability in PVNS management. Conclusion: GAE with imipenem/cilastatin offers a promising, minimally invasive approach for PVNS, providing significant symptom relief and functional recovery with minimal complications. Although long-term studies are needed, this technique could serve as a viable alternative for patients with PVNS, especially those contraindicated for surgery.

1. Introduction

Pigmented villonodular synovitis (PVNS) is a synovial joint disorder characterized by the overgrowth of the synovium and the accumulation of hemosiderin-laden macrophages, often causing joint effusion, pain, and progressive destruction of the surrounding bone and cartilage. It refers to a subtype of tenosynovial giant cell tumors (TGCTs) that diffusely affect the soft tissue lining of joints and tendons [1]. It often affects a single joint, leading to swelling, pain, and reduced mobility. The symptoms usually develop gradually, which, combined with the rarity of PVNS, can make it difficult to distinguish from other rheumatologic conditions. As a result, diagnosis may be delayed, and by the time PVNS is identified, there is often visible joint damage and functional impairment. Early recognition is, therefore, essential to help prevent progression and preserve joint function [2]. Diagnosing PVNS requires a detailed clinical evaluation supported by additional diagnostic tests. On physical examination, the affected joint may appear swollen with noticeable effusion. Early X-rays can appear normal or may show reduced joint space, signs of osteoarthritis, or, in advanced cases, bone erosion. MRI can occasionally reveal synovial thickening. Joint aspiration often yields fluid with significant inflammatory markers and is frequently bloodstained. In synovial fluid samples, sediment from the synovial villi may be observed [3]. Ultimately, a definitive diagnosis is confirmed via a tissue biopsy obtained through arthroscopy or open surgery, allowing histological examination, which typically reveals synovial hyperplasia [4].

PVNS typically affects the knee in over 80% of cases, and its treatment often involves surgical removal of the affected synovium [5]. However, PVNS has a high recurrence rate even after surgery [6], which can lead to repeated procedures and eventual osteoarthritis in the end stage [7].

Traditional treatment modalities include total or subtotal synovectomy through arthroscopy or open surgery [8], and, in severe cases, radiotherapy [9,10]. Due to the high recurrence rate and associated morbidity of traditional techniques, novel, less invasive treatments are being explored. Genicular artery embolization (GAE) is an alternative treatment option for osteoarthritis [11,12,13]; and hemarthrosis [14] and could potentially be an option for PVNS by reducing the blood supply to the hypervascular synovium. GAE with imipenem/cilastatin is the most widely used technique with a low rate of adverse effects [13].

Imipenem/cilastatin, a broad-spectrum β-lactam antibiotic, has demonstrated not only its well-known antimicrobial properties but also significant anti-angiogenic and anti-inflammatory effects, which could be beneficial in treating PVNS [15,16]. Preclinical studies have shown that imipenem/cilastatin can modulate key inflammatory pathways and inhibit angiogenesis, both of which are central to the pathogenesis of PVNS. Specifically, imipenem/cilastatin has been found to downregulate pro-inflammatory cytokines and reduce the formation of new blood vessels, potentially addressing the hypervascularity and inflammation that characterize PVNS [17]. Clinical observations further support these findings, suggesting that imipenem/cilastatin can reduce the levels of pro-inflammatory cytokines, which play a key role in the progression of PVNS-associated inflammation [18]. These properties indicate that imipenem/cilastatin may offer a novel therapeutic approach to managing the disease, complementing or even enhancing the effects of other treatments such as GAE.

2. Case Presentation

A 52-year-old male presented with a 5-month history of progressive left-knee pain. The patient had no history of trauma or significant comorbidities. Physical examination revealed significant left-knee swelling, reduced range of motion, and tenderness. Magnetic resonance imaging (MRI) revealed a significant synovial irregular thickening with joint effusion (bone marrow edema and loss of articular cartilage), raising suspicion for PVNS. A weight-bearing knee X-ray also revealed knee osteoarthritis grade II Kellgren–Lawrence (Figure 1). The patient underwent an ultrasound-guided synovial biopsy, which confirmed the diagnosis of pigmented villonodular synovitis. The lesion was classified as a diffuse type, affecting a significant portion of the synovium.

The patient was informed of the traditional treatment options, including arthroscopic [19,20] or open synovectomy. However, due to concerns about post-operative recovery and the risk of recurrence, the patient refused surgical intervention. After a multidisciplinary team consultation, the novel technique of genicular artery embolization using imipenem/cilastatin was proposed as an alternative. The patient consented to the procedure after being informed about the potential risks and benefits.

The embolization was performed under local anesthesia. A percutaneous superficial femoral artery approach was utilized to access the genicular arteries supplying the synovium of the knee. Under fluoroscopic guidance, selective catheterization of the medial and lateral genicular arteries was performed with a microcatheter, TruSelect 0.021” 105 cm (Boston Scientific). Once the vessels were identified, imipenem/cilastatin was injected into the vascular supply of the affected area (Figure 2). Imipenem/cilastatin, traditionally used as an antibiotic, was selected due to its recently identified (temporary embolic agent) anti-angiogenic and anti-inflammatory properties, which could limit neovascularization and synovial hyperplasia while reducing the risk of ischemia compared with traditional embolic agents such as polyvinyl alcohol (PVA) particles or microspheres [21].

The procedure was well tolerated, with no immediate complications. The patient was discharged on the evening of the procedure in a day hospital regimen, with non-steroid anti-inflammatory drugs (NSAIDs) prescribed for pain management.

Follow-up visits were scheduled to monitor clinical improvement and assess the need for additional interventions. We collected preoperative VAS [22], SF-36 [23], and KOOS values [24], and these assessments were repeated at 1, 3, and 6 months post-procedure. A post-procedural MRI was also performed at 6 months (Figure 3).

3. Results

Before the procedure, the patient’s preoperative VAS score was 7 out of 10, indicating significant pain levels, while their KOOS values demonstrated substantial functional impairment. The baseline KOOS values were approximately 42 for pain, 45 for symptoms, 40 for activities of daily living (ADL), 30 for sport and recreation, and 35 for quality of life. These scores highlight the patient’s notable discomfort and limited ability to engage in daily activities and recreational pursuits, alongside a reduced overall quality of life. The baseline SF-36 score reflected similarly poor health, with a physical functioning score around 45, role limitations due to physical health at 40, bodily pain at 38, and general health at 42, indicating a significant impact on overall wellbeing. These initial findings emphasize the patient’s compromised physical state and the high level of pain that affected their general health.

At the 1-month follow-up, the patient reported marked pain relief, with the VAS score decreasing to 3 out of 10. The KOOS values showed significant improvement across all areas, with pain increasing to 65, symptoms to 62, ADL to 68, sport and recreation to 50, and quality of life to 55. The greatest improvement was seen in the KOOS ADL domain (an increase of 28 points) and pain (23 points), while the least improvement was in sport and recreation (20 points). These enhancements suggest improved mobility, reduced pain, and an ability to engage more effectively in daily life and recreational activities, with a noted improvement in the patient’s perceived quality of life. The SF-36 scores also improved, with physical functioning rising to 60, role limitations to 55, bodily pain to 65, and general health to 58. In SF-36, the most notable improvement was seen in bodily pain (27 points) and the least in role limitations (15 points). The improvements in these SF-36 scores reflect a better overall physical and mental health status, with diminished physical limitations and bodily pain, indicating that the patient’s condition had improved beyond just pain relief, positively impacting their general quality of life and psychological wellbeing.

By the 3-month follow-up, the VAS score had further decreased to 1 out of 10, indicating near-complete pain relief. The KOOS values continued to improve, with pain at 80, symptoms at 78, ADL at 85, sport and recreation at 70, and quality of life at 75. The KOOS domains with the most significant improvements at this stage were ADL (17 points) and quality of life (20 points), while sport and recreation showed a moderate increase (20 points). These scores indicate a marked increase in the patient’s functional status, demonstrating the ability to comfortably manage everyday activities, participate in sport and recreational activities, and experience enhanced quality of life. Correspondingly, the SF-36 scores showed physical functioning at 75, role limitations at 70, bodily pain at 85, and general health at 72, reflecting a considerable recovery in the patient’s quality of life and functional status. SF-36 bodily pain and physical functioning saw the largest gains (20 and 15 points, respectively), while role limitations again improved the least (15 points). These trends suggest that the patient was less hindered by pain and physical limitations, with notable improvements in general health perceptions.

At the 6-month follow-up, the patient remained symptom free, with a VAS score of 0 out of 10. The KOOS values reflected sustained improvement, with pain at 95, symptoms at 92, ADL at 96, sport and recreation at 88, and quality of life at 90. In the KOOS domains, the greatest gains by this stage were seen in ADL (96, a near-complete restoration of functional capacity), while the sport and recreation score, though improved to 88, showed a slightly lower increase compared with the other domains. This level of improvement in the KOOS values indicates nearly complete restoration of the patient’s functionality and an absence of residual symptoms, pointing to a strong recovery in quality of life. The SF-36 scores were similarly high, showing physical functioning at 90, role limitations at 88, bodily pain at 95, and general health at 90. In SF-36, bodily pain and physical functioning remained the highest, at 95 and 90 points, respectively, while role limitations reached 88, slightly lower than other domains. These sustained high scores across multiple dimensions underscore that the patient experienced a comprehensive recovery, with minimal limitations in physical functioning, low pain levels, and high perceptions of general health (

Table 1. Progression of VAS, KOOS, and SF-36 values from preoperative to 6-month follow-up (Pre-OP: preoperative, FUP: follow-up).

Time Point	VAS Score	KOOS Pain	KOOS Symptoms	KOOS ADL	KOOS Sport/Recreation	KOOS Quality of Life	SF-36 Physical Functioning	SF-36 Role Limitations	SF-36 Bodily Pain	SF-36 General Health
Pre-OP	7/10	42	45	40	30	35	45	40	38	42
1-Month FUP	3/10	65	62	68	50	55	60	55	65	58
3-Month FUP	1/10	80	78	85	70	75	75	70	85	72
6-Month FUP	0/10	95	92	96	88	90	90	88	95	90

). No complications, such as infections, ischemic injuries, or nerve damage, were reported.

These results indicate that, over time, the most substantial improvements in the KOOS values were consistently seen in pain and ADL domains, while sport and recreation showed more moderate yet significant gains. In SF-36, bodily pain and physical functioning showed the most notable improvements, while role limitations demonstrated the least change across all follow-up stages (Figure 4). While long-term follow-up is needed to assess the durability of these outcomes, these initial results appear highly promising, reflecting significant improvements in both the patient’s subjective experience of health and objective functional abilities over the course of recovery.

In conclusion, an MRI at this stage demonstrated a significant reduction in synovial hypertrophy and joint effusion, with no evidence of recurrence or ischemic complications. These findings align with the observed clinical outcomes, highlighting an enhanced functional recovery and the absence of post-operative complications.

4. Discussion

The standard treatment for PVNS has long been surgical resection of the synovium, but the recurrence rates can be as high as 40% [6]. Several therapeutic alternatives have been proposed in the literature, but many of these serve as adjuvant treatments to surgery or in cases of post-surgical recurrence.

Radiotherapy may be used as a supplement of a surgical treatment, especially in diffuse forms and recurrence [25]. Radiation doses of 20–50 Gy are supplied in 15–25 fractions, starting with the period of 6–8 weeks following the surgery [26]. Combined manual lymphatic drainage and Kinesio taping may be an effective approach for relieving post-operative pain and edema in patients with PVNS [27]. Nevertheless, first-line non-surgical alternatives are essential for those patients who decline or are ineligible for surgical intervention.

A treatment with anti-TNF (tumor necrosis factor) antibodies has been suggested. After applying monoclonal antibody (infliximab), there was a gradual improvement in clinical symptoms, decrease in pain, and, thus, avoided or delayed bone and joint destruction. Among patients treated with this method, despite minor changes in MR examination after applying medicine, histopathological examination confirms a significant decrease in number of synovial membrane macrophages [28].

Radiosynoviorthesis (RSO), also known as radionuclide synovectomy, has introduced a novel paradigm in the management of knee synovitis. RSO involves the intra-articular infusion of a radioisotope into the affected joint, aiming to deactivate the inflammatory stimulus originating from the synovial membrane [29].

Selective embolization has emerged as a potential treatment for various joint diseases by targeting hypervascularized tissue [30,31]. The use of imipenem/cilastatin as an embolic agent is novel, as its known anti-angiogenic and anti-inflammatory properties may contribute to sustained synovial suppression while offering a safer profile in terms of ischemic complications compared with other embolic materials [32].

Imipenem/cilastatin’s role in inhibiting inflammatory processes [15] in PVNS makes it an appealing choice for embolization. By reducing blood supply and curbing inflammatory activity [16], GAE with imipenem/cilastatin could effectively prevent synovial re-proliferation and lower the risk of recurrence seen with surgical approaches. This approach was inspired by Bemporad’s successful application of arterial embolization in the treatment of temporomandibular joint (TMJ) inflammation, with the TMJ being a similarly vascularized joint, demonstrating the potential of this technique in controlling joint inflammation with minimal risk of ischemia [33].

This case highlights the potential benefits of GAE for patients with PVNS, particularly those who decline surgery. Additionally, GAE may offer a rational approach for patients deemed inoperable due to comorbidities or other contraindications to surgical intervention. By effectively reducing symptoms and improving joint function, GAE serves as a viable alternative for symptom management and quality-of-life enhancement in patients who cannot undergo surgery.

The early outcomes from this case suggest that the procedure is safe and effective [34,35], though larger clinical trials and long-term follow-up studies are needed to validate its use as a primary treatment. Given the procedure’s minimally invasive nature and lack of associated symptoms, we are continuing follow-up monitoring to determine whether a re-treatment could be performed in the event of symptom recurrence. This approach may further support the feasibility of GAE as a sustainable option for managing PVNS over the long term.

Despite the promising early outcomes demonstrated in this case, several limitations remain that warrant consideration. First, the findings are based on a single case, and therefore, the generalizability of these results is limited. Without larger-scale studies or randomized controlled trials, it is challenging to draw definitive conclusions about the effectiveness and safety of GAE with imipenem/cilastatin as a primary treatment for PVNS. Additionally, while the 6-month follow-up showed sustained symptom relief and functional improvement, longer-term follow-up is essential to determine the durability of these results and to assess for potential late-onset complications or recurrence.

Another limitation pertains to the imaging techniques used for post-procedural assessment. Although MRI provides valuable insight into changes in synovial hypertrophy and joint effusion, it may not fully capture subtle functional improvements or potential microscopic recurrence [36]. Further studies incorporating advanced imaging methods, such as dynamic contrast-enhanced MRI or PET imaging [37], could enhance our understanding of the synovial response to GAE and aid in detecting early signs of relapse.

The choice of imipenem/cilastatin as an embolic agent, while novel and seemingly effective in this case, lacks extensive research specific to PVNS. The anti-angiogenic and anti-inflammatory properties of imipenem/cilastatin need further validation in this context, as alternative embolic agents may yield different outcomes in terms of ischemia risk and synovial suppression. Moreover, GAE was performed in a single, highly vascularized joint, and the results may differ for PVNS located in other joints [38] or for patients with varying degrees of disease severity.

Lastly, the minimally invasive nature of GAE with imipenem/cilastatin presents an appealing option [17], but it is still uncertain whether this approach can provide results comparable with or superior to surgical options in the long term. Therefore, continued follow-up and additional clinical trials are necessary to better define the role of GAE in the standard treatment protocol for PVNS, particularly in relation to traditional surgical approaches and other non-surgical treatments.

Imipenem/cilastatin, while showing promise as an embolic agent for PVNS, raises concerns regarding antimicrobial resistance (AMR) when used outside of its primary antibiotic role. As a broad-spectrum β-lactam antibiotic, imipenem is vital in treating multidrug-resistant infections [39]. However, its use for non-infectious purposes, like embolization, may lead to resistance by exerting selective pressure on microbial populations. This could reduce its effectiveness in treating infections and potentially limit its use in PVNS treatment [40]. Compared to other therapies like surgical approaches or non-surgical options such as anti-TNF monoclonal antibodies, GAE with imipenem/cilastatin presents a unique benefit–risk profile, balancing anti-inflammatory and anti-angiogenic effects with the risk of resistance [40]. Long-term studies are needed to assess its safety and the potential impact of AMR on its use as a viable treatment option for PVNS.

5. Conclusions

The genicular artery embolization technique using imipenem/cilastatin presents a promising, minimally invasive treatment option for PVNS, but there is room for improvement, and further research is needed to optimize its application. One area of focus could be the development of advanced embolic agents with enhanced anti-inflammatory and anti-angiogenic properties while minimizing the risk of ischemic complications. Additionally, the use of advanced imaging modalities, such as dynamic contrast-enhanced MRI or PET imaging, may allow for more precise monitoring of the synovial response and earlier detection of potential microscopic recurrences. Further research should also include randomized controlled trials to directly compare GAE with traditional surgical approaches and other non-surgical treatments to better understand its long-term efficacy and safety. Expanding the application of GAE to joints beyond the knee could also be an avenue for exploration, as it may broaden the scope of its use in PVNS and other hypervascularized conditions. Lastly, identifying clear patient selection criteria would help target those who would benefit most from this procedure, potentially improving clinical outcomes and reducing the recurrence rate. By addressing these areas, GAE could become an even more viable and effective alternative in the management of PVNS.