Transcatheter embolisation in chronic musculoskeletal disorders

Abstract

Chronic musculoskeletal conditions affect millions of patients worldwide resulting in disability, reduced quality of life, and have a profound economic impact on the individual and society. Current treatment strategies fail patients who have not responded to conservative management but are not surgical candidates. Over the last decade, transcatheter embolisation has emerged as a potential treatment for these difficult to treat patients. By exploiting pathological neovascularisation within conditions such as knee osteoarthritis, adhesive capsulitis, and tendinopathy, embolisation has been used to improve patients’ pain and function. This review explores the rationale for musculoskeletal transcatheter embolisation, illustrating the technique, and latest evidence for the most common procedures.

Introduction

Chronic musculoskeletal (MSK) disorders such as osteoarthritis (OA), tendinopathy, and enthesopathy affect millions of patients worldwide. The dominant symptom of these conditions is chronic pain, reducing patient’s quality of life and imposing a significant financial burden on healthcare systems and society alike.

The National Institute for Health and Care Excellence (NICE) in the UK advocates an initial conservative management strategy in the treatment of chronic musculoskeletal disorders with lifestyle modification, physiotherapy, and analgesia. If this fails, then consideration of surgical intervention is recommended. ¹ Unfortunately, there is not a reliable surgical option for all chronic MSK disorders. Furthermore, surgery may not be indicated in mild-to-moderate stages of disease and patients may have a preference for non-surgical options. Joint replacement surgery, whilst being the definitive treatment for osteoarthritis, is less favoured in young patients with a relatively increased long-term risk of prosthetic mechanical wear and loosening, whereas elderly patients with co-morbidities may not be suitable surgical candidates. ² Unfortunately there are a large number of patients who have failed conservative treatments, but are not surgical candidates. Trans-catheter embolisation (TCE) is an emerging, minimally invasive treatment for chronic musculoskeletal disorders that has the potential to help this challenging patient cohort.

TCE has garnered interest over the past decade through the early success of genicular artery embolisation (GAE) in the treatment of knee osteoarthritis. ³ TCE is now being investigated in the treatment of other musculoskeletal conditions such as shoulder pain, tendinopathy, and chronic back pain. This review explores the rationale for MSK TCE, illustrates the technique, and latest evidence for the most commonly performed procedures.

Scientific rationale

There is emerging evidence that chronic musculoskeletal disorders are associated with an inflammatory process. Inflammatory mediators release cytokines such as vascular endothelial growth factor (VEGF) inducing neo-angiogenesis. The formation of pathological blood vessels supplying inflamed hypervascular tissue is postulated to contribute to ongoing inflammation, cartilage and osseous destruction in a self-perpetuating cycle. End nerve-fibres also grow alongside these abnormal blood vessels contributing to pain. ^4–6 The pathological neo-angiogenesis manifests on angiographic imaging as abnormal neo-vessels with a hyperaemic blush and/or early venous drainage. The rationale of TCE in chronic MSK disorders is to exploit these abnormal blood vessels as an embolisation target (Figure 1).

Figure 1.

The descending genicular artery was cannulated revealing hyperaemia of the medial knee compartment (a), which was embolised with maintenance of the normal osseous inflow arteries “pruning”.

Transcatheter embolisation is a well-established interventional radiology procedure for many indications such as the treatment of acute bleeding and tumours. In MSK TCE, microcatheters are used to select and deliver embolic agents to the pathological hyperaemic area at the site of a patient’s pain. Embolisation in chronic MSK conditions was first described by Okuno et al to treat tendinopathy and enthesopathy. ⁷ Several investigators have since utilised the technique in a range of different locations. Whilst most research to date has focused on genicular artery embolisation in patients with knee osteoarthritis, research is ongoing into the use of TCE for shoulder adhesive capsulitis, tendinopathy, enthesopathy, myalgia and facet joint arthropathy.

Diagnostic imaging

Diagnostic imaging is vital in the pre-procedural, intraprocedural and post-procedural assessment of patients considered for TCE. Plain radiographs, ultrasound (US) and magnetic resonance imaging (MRI) are commonly performed in the pre-procedural work-up of patients with chronic MSK conditions. For osteoarthritis, plain radiographs are used to assess OA severity, whereas doppler US and contrast-enhanced MRI are used to assess for tissue hyperaemia and synovitis. Pre-procedural cross-sectional imaging is crucial to exclude other causes of chronic MSK pain. MRI is the most common modality as it enables excellent soft tissue resolution, and exclusion of pathology that will not benefit from TCE, for example meniscal injury in patients being considered for GAE which warrants an alternative treatment strategy. There is emerging evidence that pre-procedural imaging can predict TCE treatment failure that may aid in patient selection. ⁸ Patients with bone marrow lesions, meniscal injury, and severe OA are associated with less favourable clinical outcomes with GAE. ⁹

Digital subtraction angiography (DSA) is the mainstay of intraprocedural imaging for defining the arterial anatomy and guiding selective embolisation. The cessation of the hyperaemic blush has been predominantly utilised as the end-point of TCE which can be identified real-time on angiography. A recent report has described the novel application of intraprocedural contrast-enhanced ultrasound to visualise synovial hyperaemia in knee which may aid in the reduction of radiation dose. ¹⁰ Cone-beam rotational computed tomography (CBCT) can be used during TCE to obtain three-dimensional arterial anatomy, confirming the target vessel, and aiding minimisation of non-target embolisation.

MRI is emerging as a useful modality to assess treatment response in TCE. The semi-quantitative Whole-Organ MRI Score (WORMS) is a validated scoring method used to compare the imaging appearance of the knee pre- and post-GAE treatment. ¹¹ Two studies reported a significant reduction in synovitis post-GAE, in keeping with the proposed hypothesis of targeting pathological hyperaemia. ^12,13

Procedural technique

Following appropriate patient work-up and selection, TCE is performed in a dedicated interventional angiography suite, usually as a day-case procedure under local anaesthetic or conscious sedation. Standard ultrasound-guided femoral arterial access is obtained. Smaller arteriotomies can be performed with a three or 4 French introducer-sheath to reduce access complications. An appropriate sized base-catheter is navigated under fluoroscopic guidance to the arterial territory of interest. DSA is utilised at this stage to define the vascular anatomy and guide selective cannulation. Microcatheters, ranging in size between 1.7 and 2.4 French, are used for selective cannulation of the pathological vessels and positioned in the artery at the site from which embolisation is to be performed. CBCT can then be performed to assess microcatheter position and ensure no aberrant arterial anastomoses or significant osseous or cutaneous branch supply which may result in non-target embolisation. Unlike other embolisation procedures, the embolisation end point for MSK TCE and particularly for GAE predominately involves the cessation of the hyperaemic blush rather than obtaining native vessel stasis in a technique coined ‘pruning embolisation’.

Several particulate embolic agents have been utilised in MSK TCE. Imipemen/cilastatin sodium (IPM/CS), an antibiotic, forms small (40–75 µm) particles in contrast suspension but is slightly water soluble, effectively dissolving with time in the blood stream. ¹⁴ Imipemen/cilastatin sodium provides a short-term embolic effect in MSK TCE with its transient nature, which has seen it used in a number of end-organ territories such as the hands and feet, without ischemic complications. Unfortunately, IPM/CS is not suitable for patients with allergic/hypersensitivity reactions or those receiving valproic acid due to drug interaction. Imipemen/cilastatin sodium is also not currently licensed for use as an embolic agent in the United Kingdom, Europe and North America. Permanent embolic agents including 90–180 µm polyvinyl alcohol, 75–100 µm Embozene (Varian Medical), and 100–300 µm Embospheres (Merit Medical) have been more widely utilised in the Western world. The latter two have been used in a number of MSK TCE trials. ^12,13,15

There is currently insufficient evidence to recommend the use a certain embolic agent or particle size in MSK embolisation. A recent GAE meta-analysis, of the small number of available studies, showed no significant difference in pain improvement when comparing IPM/CS and Embozene. ³ The embolic data in shoulder adhesive capsulitis is more limited. The majority of studies utilise IPM/CS but there is a trend for lower complication rates with temporary embolisation. Coil embolisation has not been investigated in MSK TCE but is generally avoided. In GAE, the genicular arteries provide important osseous blood supply and it is hypothesised that the combination of permanent particles and coils could result in osteonecrosis. Furthermore, the genicular arteries provide essential collateral networks to maintain distal blood flow in peripheral vascular disease, which is a potentially important future consideration.

Osteoarthritis of the knee

Osteoarthritis affects one in ten people in the United Kingdom, with knee osteoarthritis being the most prevalent. ¹⁶ The genicular arteries supply the knee synovium, hypothesised to perpetuate the cycle of inflammation, pain and synovitis through neovascularity in osteoarthritis.

Genicular artery embolisation in the treatment of knee OA is the most widely researched MSK TCE technique. Okuno et al evaluated GAE in 95 knees of 72 patients with mild to moderate osteoarthritis using 75 µm IPM/CS or 100 µm Embozene. ¹² Clinical success at six months was 86.3%, defined as a 50% reduction in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores; a disease-specific questionnaire of pain, stiffness and functional limitation in knee osteoarthritis. Balga et al reported a clinical success rate of 80% at six months in 20 patients treated with 75 µm–100µm Embozene, albeit with a lower defined success criteria of 18% reduction in WOMAC scores. ¹⁵ Landers et al demonstrated a treatment response at 12 month follow-up in six of ten patients with mild to moderate osteoarthritis treated with IPM/CS or 90–180 µm of polyvinyl alcohol particles. ¹⁷ Little et al demonstrated significant improvement in visual analogue scale (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) scores at 12 month follow-up in 38 patients with mild to moderate osteoarthritis following GAE with 100–300 µm Embospheres. ¹³ Notably, six patients were not embolised due to a potentially risk of non-target embolisation or absence of a hyperaemic target intraprocedurally. This highlights the importance of genicular arterial anatomy. A recent study compared cadaveric dissection with angiographic data from GAE, revealing a number of important arterial anastomoses that need to be identified in order to perform safe and effective GAE. ¹⁸

The majority of investigational treatment has been conducted in mild to moderate osteoarthritis and their remains debate whether GAE has a role in severe disease. A retrospective review of GAE using IPM/CS in 12 patients with severe osteoarthritis demonstrated an initial improvement in pain in the first month but gradual return of symptoms to baseline severity at 3 months. ¹⁹ On the other hand, a prospective study by Padia et al demonstrated a clinical success rate of 68% at 12 months, defined as a 50% reduction criteria in WOMAC scores, in 40 patients including 16 subjects with severe osteoarthritis. ²⁰ The role of GAE in severe disease as such remains to be fully elucidated.

The current evidence for GAE is predominately limited to cohort studies or case series (level IV evidence). A recent randomised controlled study has been performed in 21 patients assigned to undergo GAE or a sham placebo procedure. ²¹ At 1 month, patients in the placebo arm crossed over to the GAE arm. This is the first study to address the placebo effect in GAE, reporting a significant improvement in pain and disability in patients undergoing GAE compared to placebo.

Genicular artery embolisation has demonstrated a good safety profile thus far. The most common embolisation-specific adverse event is transient skin discoloration from non-target cutaneous embolisation. Padia et al reported seven cases of self-resolving, focal (<1 cm) skin ulceration using 100 µm Embozene for GAE. However, following application of an ice pack to the skin of subsequent patients to induce temporary vasoconstriction of cutaneous vessels, no further cutaneous complications occurred. ²⁰ In terms of osseous complications, Padia et al reported two cases of asymptomatic<2 cm bone infarcts and Bagla et al reported two cases of bone marrow oedema on follow-up MRI. ^15,20 Little et al has shown post-procedural bone attrition on MRI but on further interrogation this was thought to be related to patients with a higher BMI which is known in itself to progress osteoarthritis. ¹³ Importantly, no significant cases of osteonecrosis have been reported in the literature. Two cases of transient plantar paraesthesia have occurred using 75 µm Embozene, presumed due to non-target embolisation of the median plantar nerve with no further cases occurring following a change to a larger embolic size. ¹⁵ The application of an ice pack, use of temporary or larger particles (≥100 µm), and interrogation of non-target supply with CBCT are likely to reduce significant complications following GAE.

Shoulder adhesive capsulitis

Adhesive capsulitis of the shoulder is characterised by pain and stiffness at the shoulder joint with significant restriction in range of motion. The diagnosis is made clinically but MRI is often utilised to exclude other pathologies and demonstrates features suggestive of the condition including thickening of the coracohumeral ligament, thickening of the joint capsule and synovial enhancement at the rotator interval. ²² Correspondingly, pathological vascularity and inflammation has been demonstrated at the rotator interval suggesting a role for transcatheter embolisation. ²³ Neo-vessels arising from branches of the axillary or subclavian artery are targeted for embolisation using the aforementioned techniques.

Okuno et al performed a prospective pilot study in seven patients with pharmacologically resistant adhesive capsulitis demonstrating a significant improvement in pain and range of motion at a mean follow-up of ten months. ²⁴ A subsequent prospective study by Okuno et al in 25 patients demonstrated a clinical success rate of 84%, defined as a 50% improvement in VAS scores and elimination of the need of pain medication at 3 months. ²⁵ Furthermore, 88% of patients were completely pain free at 12 months follow-up. Ciampi-Dopazo et al reported significant improvement in nocturnal pain, activity-related pain and range of motion in 9 patients treated with TCE combined with intensive physiotherapy. ²⁶ Reproducible findings have been reported by Martinez et al in a prospective study of 40 patients demonstrating significant improvement in pain and range of motion at 6 months including the absence or minor residual pain in 92.5% of patients at 12 month follow-up. ²⁷ The aforementioned studies have all been performed with IMP/CS with no embolisation-specific adverse events apart from transient peri-procedural pain and one-day fever in one study. ²⁵ In a retrospective series of fifteen patients with shoulder pathology including nine with adhesive capsulitis, Gremen et al used 100–250 µm Embozene particles with modest success; mean pain scores significantly improved at six month follow-up overall but only two patients had a 50% reduction in pain. ²⁸ Adverse events were all self-resolving in this study with Embozene; eight patients with pain, two with paraesthesia, two with skin necrosis and one with marrow oedema. A recent multicentre study of twenty patients with adhesive capsulitis using HydroPearl (Terumo Interventional Systems), a tightly calibrated permanent embolic, demonstrated a significant improvement in pain and function at 6 month follow-up. ²⁹ Transient skin discolouration was reported but otherwise no major adverse events occurred.

Tendinopathy and enthesopathy

Transcatheter embolisation has also been used to treat tendinopathy and enthesopathy in the shoulder, elbow, hip, knee and foot. In a prospective series by Okuno et al, seven patients were treated with IPM/CS for patellar tendinopathy, rotator cuff tendinopathy, plantar fasciitis, lateral epicondylitis, iliotibial band syndrome or Achilles insertion tendinopathy. ⁷ Significant improvement in pain scores were demonstrated at 4 months follow-up. Apart from self-limiting subcutaneous haemorrhage in one patient, no embolisation-specific adverse events occurred. Iwamoto et al treated 24 patients with lateral epicondylitis using IPM/CS demonstrating significant improvement in pain, function and degree of tendinosis on MRI in 22 patients available at two year follow-up, with no embolisation-specific adverse events. ³⁰ Notably, eight patients underwent a second procedure during this period indicating a role of TCE as staged or repeat procedure when necessary. A retrospective study by Hwang et al utilised 40–120 µm Embospheres or IPM/CS to treat 15 cases of shoulder or elbow tendinopathy in 13 patients. ³¹ Clinical success, defined as a 50% reduction in pain scores and discontinuation of pain medication at 4 months follow-up, was demonstrated in 73% of patients. Self-resolving skin erythema occurred in one patient treated with Embospheres. Lee et al treated 14 cases of medial epicondylitis with IPM/CS or gelatin sponge demonstrating a clinical success rate of 85.7% at six months follow-up, defined as a 70% improvement in Quick-DASH scores, a measure of patient symptoms and functionality, at six month follow-up. ³² The aforementioned study by Gremen et al has also utilised Embozene in the treatment of nine patients with shoulder tendinobursitis. ²⁸

Trapezius myalgia

Transcatheter embolisation has also been utilised as a novel treatment of shoulder or neck pain as a result of trapezius myalgia. In a retrospective series by Shibuya et al, 42 patients with trapezius myalgia were treated with IPM/CS. ³³ Abnormal neovascularisation and early venous drainage identified on angiography was used to target the transverse cervical artery, suprascapular artery, or circumflex scapular artery feeding the trapezius muscle. Clinical success was 71.4%, defined as a 50% improvement in Brief Pain Inventory (BPI) score at six months follow-up. No embolisation-specific adverse events occurred.

Back pain

More recently, Fujiwara et al investigated transcatheter embolisation as a novel treatment for chronic low back pain resistant to conservative management. ³⁴ Fourteen patients with back pain relating to lumbar or sacroiliac joint arthropathy were treated with IPM/CS. The target vessels including the lumbar, iliolumbar, sacral and gluteal arteries determined anatomically depending on the level of the facet joint pain on clinical examination. Anterior segmental medullary arteries were recognised and avoided to prevent spinal cord infarction. Embolic agent was administered incrementally into the target vessel if an evoked patient response occurred at the site where they usually experienced their symptoms. Embolic was administered until the patient’s evoked response attenuated or near-stasis of the target vessel. Significant improvement in pain and disability scores were noted up to two years follow-up. Apart from an evoked pain response, no embolisation-specific adverse events occurred.

The future: Considerations and developments

There is emerging evidence for transcatheter embolisation as a novel treatment in chronic MSK disorders. Most of the research has been conducted in knee osteoarthritis but there is also evidence for the shoulder and few reports for use in the elbow, foot and back. Studies have elucidated repeatable findings; embolisation is technically achievable with a good safety profile and has the potential to improve patients’ pain and function.

The current evidence for MSK embolisation predominately stems from small, single cohort studies with relatively short-term follow-up. There is an irrefutable need to validate these findings through randomised controlled trials.

The assessment of pain is extremely complex and warrants careful consideration. Patient function, perceived quality of life, and neuropsychological factors need to be considered in order to assess the multiple complex elements that constitute chronic pain perception. Several outcomes measures of pain and functionality have been used, albeit heterogeneously, in the literature including the Visual analogue scale scores (VAS), Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores. The VAS is a simple method for assessing pain, but is limited by its lack of temporal evaluation in addition to appraisal of quality of life and function. KOOS and WOMAC are validated questionnaires that assess pain, and function, providing a more complete evaluation of symptoms. Future studies are needed to establish the Minimum Clinically Important Difference (MCID) for specific MSK TCE procedures. The MCID is the clinical response at which the patient experiences a significant benefit such that they may return to normal activities of daily living and have a sustained improvement in quality of life.

Appropriate patient selection is paramount when offering alternative novel therapies. Future research into patient factors and imaging features are needed to further refine patient selection pre-procedurally. There is already evidence available that certain imaging features on MRI are associated with less favourable outcomes in GAE as described earlier. Pre-procedural prognostic factors are required to be identified for TCE procedures outside of the knee.

Musculoskeletal embolisation has so far demonstrated a good safety profile. Complications predominately relate to non-target cutaneous embolisation but are predominately transient with no lasting sequalae. A variety of embolic agents have been employed but the optimal choice of embolic is yet to be determined. The literature suggests there is a trend for a safer profile using a temporary embolic or larger particle size (≥100 µm). Large multicentre trails comparing the outcomes and adverse features related to permanent and temporary embolic agents would provide further insight to optimise embolic options. Research appears to be already underway into the use of novel temporary embolic agents, besides IPM/CS, that may be used in MSK embolotherapy (NCT04951479).

The risk associated with radiation exposure is a further factor that needs consideration in the safety profile of MSK embolisation, particularly as these procedures are generally performed in a younger population. Whilst radiation dose is influenced by operator and patient specific factors, the approximate effective dose for genicular artery embolisation for example, is under 30 Gray/cm². This is considered lower than that encountered in other non-musculoskeletal trans-arterial embolisation procedures already in established practice. ³⁵ Nevertheless, radiation should be controlled to minimise the risk to patients. The novel use of intraprocedural ultrasound to visualise synovial hyperaemia, described previously in this article for GAE, may play a role in other areas of MSK embolotherapy as an alternative to digital subtraction angiography to delineate procedural endpoints.

The cost effectiveness of musculoskeletal trans-arterial embolisation requires further study. There are currently no studies comparing embolisation and alternative interventional techniques within the management of chronic MSK conditions, it is therefore impossible to make definitive conclusions regarding cost effectiveness. Percutaneous delivered drug therapies such as intraarticular corticosteroid and hyaluronic acid injections in knee osteoarthritis are inevitably cheaper and have been shown to be cost effective. However, these treatments have also been shown to only provide a short-term symptomatic relief, thus requiring repeated treatments. ^36,37 The aim of MSK embolotherapy is to provide intermediate to long term symptomatic relief, and is offered in patients who have already tried and failed to respond to conservative therapies. Furthermore MSK embolotherapy may potentially prevent future surgical treatments, such as knee replacement surgery for GAE, which would have a profound economic benefit. Within our practice, the estimated procedural cost for genicular artery embolisation is approximately £2,680 compared to £8,238 for a total knee replacement. Future research is evidently warranted to elucidate the cost effectiveness of these novel MSK embolotherapy procedures against other medical and surgical therapies. The Genicular Artery Embolisation for Knee Osteoarthritis II (GENESISII) trial plans to perform a health economic cost effectiveness analysis of GAE versus other treatment modalities for moderate knee OA, which will provide further insight into cost effectiveness.

Musculoskeletal embolotherapy is an exciting cutting-edge development with interventional radiology again leading the way to explore new avenues to benefit patients and improve their quality of life. The evidence for transcatheter embolisation thus far is very promising. We eagerly await the results of level I data to be able to include MSK TCE in the treatment armamentarium of chronic musculoskeletal disorders.