Ludo Schropp

DUTCH SUMMARY (Translated)

Introduction
Thoracic outlet syndrome (TOS) is characterized by positional compression of the neurovascular bundle at the level of the thoracic outlet. This bundle consists of the brachial plexus, the subclavian vein, and the subclavian artery. Depending on the affected structure, three forms are distinguished: neurogenic (NTOS), venous (VTOS), and arterial TOS (ATOS). Compression can occur in three anatomical compartments: the costoclavicular space (between the first rib, clavicle, and the anterior scalene muscle), the scalene triangle (between the anterior scalene muscle, middle scalene muscle, and the first rib), or the retro-pectoralis minor space (behind the pectoralis minor muscle). Anatomical variations, hypertrophic muscles, and bony abnormalities, such as a cervical rib, can narrow these spaces and contribute to symptomatology. TOS is a rare condition that mainly occurs in young, active adults between twenty and fifty years old.

In VTOS, repeated compression of the subclavian vein in the costoclavicular space leads to endothelial damage, intravascular fibrosis, stenosis, and in some cases, thrombosis. Clinically, this manifests as swelling, pain, and discoloration of the affected arm. When only positional compression is present, it is referred to as McCleery syndrome; with accompanying acute thrombosis, it is called Paget-Schroetter syndrome or effort thrombosis. Diagnostics focus on demonstrating both intravascular thrombosis and extrinsic compression. Treatment is aimed at recanalization (anticoagulation, catheter-directed thrombolysis, venoplasty) and thoracic outlet decompression (first rib resection and scalenectomy), possibly combined with venous reconstruction.

Primary upper extremity deep vein thrombosis (pUEDVT) involves thrombosis without a 'secondary' cause, such as thrombosis arising from catheters, pacemaker wires, or malignancy. pUEDVT is further subdivided into idiopathic thrombosis and thrombosis caused by compression in VTOS. Due to the lack of good prospective multidisciplinary studies on pUEDVT, there are no uniform diagnostic strategies and treatment guidelines. Treatment varies from conservative anticoagulation therapy to invasive thrombolysis followed by surgical decompression of the thoracic outlet, often entirely dependent on local expertise and the preference of the treating specialty. There are roughly two views on the origin and treatment of a pUEDVT. First, the 'interventionalist' view: if no secondary cause for the thrombosis is present, the thrombosis is considered a VTOS-associated thrombosis, and treatment consists of rapid recanalization and decompression to remove the cause of the thrombosis. Opposite this is the 'observational' view, where a pUEDVT is considered an idiopathic thrombosis and is treated with anticoagulation, with a search for a mechanical cause of the thrombosis only in extreme cases.

In ATOS, compression of the subclavian artery causes stenosis, aneurysm formation, and thrombus formation with distal embolization, resulting in ischemic complaints of the hand or arm. This compression is caused in the vast majority of cases by an anatomical variant, often a cervical rib or fused first and second ribs. Treatment consists of restoring arterial patency through endovascular and surgical techniques and decompression of the subclavian artery by resection of the compressing structures. Of the three subvariants, ATOS is the least common. The loss of arterial pulsations when assuming different positions is not equivalent to the diagnosis of ATOS; for this, an intraluminal problem (stenosis, aneurysm, thrombus) must actually be present.

Part I – Evaluation of current treatment strategies and innovative diagnostic techniques
In Chapter 2, a systematic literature review investigates the optimal timing for thoracic outlet decompression (TOD) after thrombolysis in VTOS-associated pUEDVT. A distinction is made between early (within two weeks) and delayed surgery. Although the available studies are characterized by low methodological quality, small populations, and inconsistent definitions, early TOD seems as safe and effective as delayed surgery. Since early decompression stops the cascade of damage to the vessel, we consider this treatment strategy most appropriate.

Chapter 3 focuses on arterial and venous stents in the thoracic outlet, an anatomically dynamic area where stents are extra vulnerable. In this multicenter series of 26 patients, a high percentage of failing stents is seen, especially when no TOD has been performed (60 – 73% symptomatic stent failure). An additional literature review supports these findings, despite significant methodological limitations in existing studies. Therefore, the conclusion is that stent placement in the thoracic outlet should only be considered in extreme cases, where adequate TOD prior to stent placement must be a requirement.

In Chapter 4, the potential role of botulinum toxin (BTX) as a diagnostic and therapeutic tool in TOS is investigated. Although BTX injections into the scalene muscles induce atrophy and can theoretically provide compression reduction, high-quality evidence is lacking. The included studies, including only one RCT, use different criteria for neurogenic TOS and report heterogeneous outcomes. In these studies, some patients seem to benefit therapeutically from BTX; however, no conclusions could be drawn. No studies have investigated the diagnostic value of BTX in NTOS or the therapeutic and diagnostic value in vascular TOS.

Chapter 5 introduces intravascular ultrasound (IVUS) as a tool in the diagnosis and treatment of VTOS. In ten patients, IVUS proves valuable for detecting narrowing, intraluminal abnormalities (such as thrombus, trabeculae, and broken valves), and for assessing the necessity and subsequent adequate positioning of stents. Although IVUS is costly, it can offer potential added value in selected cases.

Barriers in current literature
The available pUEDVT literature consists almost exclusively of retrospective, monocenter, and monodisciplinary studies. The quality of evidence is strongly limited by three important factors: Strong selection bias, especially in invasively treated patients; A lack of uniform diagnostic criteria for VTOS-associated UEDVT; The lack of standardized outcome measures, particularly patient-reported outcomes.
As a result, existing cohorts are heterogeneous and difficult to compare, and there is no basis for evidence-based guidelines and thus evidence-based treatment of the patient.

Part II – Harmonization of future pUEDVT research
In the second part of this thesis, three important initiatives are described, all aimed at reducing bias induced by the three factors mentioned above.

In Chapter 6, a standardized method to measure vascular compression in the thoracic outlet on dynamic CT and MRI scans is described. The intra- and inter-observer reliability of this method is tested in this study. The measurement protocol applied to dynamic CT appears more reliable than MRI. This measurement protocol combined with CT can be used to describe a cohort of pUEDVT or vascular TOS patients and to use transparent inclusion and diagnostic criteria. Whether the measured degree of compression actually correlates with the development of complaints or venous thrombosis remains to be investigated.

In Chapter 7, the pUEDVT-specific research protocol for the ThoRacic OutleT Syndrome (TROTS) registry is introduced. This multicenter, multidisciplinary registry brings together vascular surgeons, internists, and vascular medicine specialists and offers the possibility to track 'real-world data' on patients to build a representative, prospective cohort of pUEDVT patients. The TROTS registry aims to provide a strong basis for future research and a platform for developing unambiguous diagnostic criteria and treatment recommendations.

In Chapters 8 and 9, a new score for post-thrombotic syndrome of the arm is developed: the Upper Extremity Post-Thrombotic Syndrome score (UE-PTS). This score, established through an international multidisciplinary expert panel, combines clinical symptoms, physical characteristics, and a validated functional outcome measure (DASH score). The UE-PTS is intended as a uniform, reproducible outcome measure for future pUEDVT research. Before it can be applied in clinical practice, validation within a pUEDVT cohort is required.

CONCLUSION
The studies in this thesis show the limitations of the current literature but simultaneously offer new insights and tools for progress, specifically for uniforming and standardizing pUEDVT research. Pure 'unbiased' inclusion of patients, harmonized reproducible diagnostic criteria, and the use of validated outcome measures are the essence. The initiatives presented in this thesis, including the TROTS registry, can provide the foundation and network needed to work toward high-quality evidence and evidence-based treatment for patients with pUEDVT and TOS.