Verena Festen Schrier

Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy. It involves increased intra-carpal tunnel pressure and subsequent neuropathy of the median nerve distal to the carpal tunnel. CTS is hallmarked by tingling and numbness of predominantly the thumb, index, and long finger, but can progress to a more severe stage involving muscle weakness and irreversible nerve damage. Decisions concerning the type of treatment are made based mostly on disease severity, but currently, in part due to the complexity of the pathophysiology, there are limited treatment predictors available to help guide this decision. In this dissertation, we looked into CTS by exploring the role of connective tissue in idiopathic CTS, by describing the role of ultrasound in the prediction of clinical outcome, and by assessing potential targets for improving treatment.

Part I CTS pathophysiology and the role of connective tissue

Increased carpal tunnel pressure is a hallmark of CTS, but in the majority of cases, the cause of this increase is unclear. In the first part of this thesis, we described the complexity of CTS pathophysiology and the association with high-force and high-frequent finger motions. One area of research has indicated a prominent role for the subsynovial connective tissue (SSCT) in the carpal tunnel. The review in Chapter 2 details the overall mechanical and anatomical changes of the median nerve as well as the SSCT. CTS patients show increased fibrosis in the SSCT, making it less flexible and more prone to additional damage with prolonged shear stress during finger and hand motion. We describe a hypothetical model in which initial damage to the SSCT leads to a self-sustaining feedback loop of continuing and increasing damage and fibrosis. Although it is a hypothetical model, this can function as the starting point to increase our understanding of CTS pathology and support the development of targeted therapies, for example to prevent additional SSCT fibrosis.

In Chapter 3, we build on this by assessing the chronological development of the SSCT in a rabbit model. Using scanning electron microscopy, we observed and non-quantitatively compared the architecture from fetal to young adults. We found that the SSCT starts out as a solid and dense structure surrounding the flexor tendons, but after a few weeks after birth splits into a multilayered system interconnected by collagen fibrils. Although a causal relation could not be tested, this change coincided with the young rabbits showing weight-bearing movements and could thus imply an adaptive response to loading. This finding could be of clinical relevance considering the prevention of further SSCT damage, as seen in CTS patients, by stimulating the adaptive response (e.g., by splinting).

Part II (Dynamic) Ultrasound in the clinical assessment of the CTS patient

In the second part of this thesis, the central topic was the added value of ultrasound (US) in CTS patient care. The static measurement of the cross-sectional area of the nerve has been the primary topic of studies published so far, but increased interest has also developed for dynamic assessments. Both in transverse as well as longitudinal planes, the median nerve, the flexor tendons, and the SSCT can be visualized using standard brightness-mode ultrasound. CTS patients show decreased nerve motion compared to controls, and dynamic assessment might thus hold valuable information for the prognosis.

Recently, a speckle tracking algorithm, enhanced with a singular value decomposition filter to reduce noise from background signals, was validated to track flexor tendon and SSCT motion with finger flexion and extension. Chapter 4 assessed the reliability of these measurements in twenty-two CTS patients as well as sixteen healthy controls. Intra- and inter-class correlation coefficients for both groups were good to excellent. Higher reliability was found for tendon tracking compared to the SSCT. We concluded that speckle tracking with SVD can reliably analyze longitudinal excursion of these carpal tunnel structures.

Directly following these findings, speckle tracking was applied to a clinical CTS cohort of 90 patients in Chapter 5 to test the association between relative SSCT movement (shear index) and CTS severity. An increase in shear index was found (equals a decrease in SSCT movement) with increasing CTS severity as quantified by neuroconductive tests. There was no association present when categorizing severity with patient-reported symptom scores or with clinical outcome after surgery. Limitations of this study included the overall good response to surgery, complicating discrimination between responders and non-responders.

The measurements described in chapters 4 and 5 were based on the (relative) movement in the longitudinal plane. More commonly, US acquisitions are done in the transverse plane since this is more practical and allows for the quantification of the cross-sectional area of the nerve. It is known that nerve area decreases after intervention, but currently, less is known about the changes in nerve dynamics or the correlation with clinical outcome. In Chapter 6 we describe a prospectively followed CTS cohort of 85 patients. After surgery, the median nerve decreased significantly in size and moved more in dorsal direction. Although a larger nerve area at baseline was significantly associated with better functional scores, this was not found for symptomatic relief. Additionally, none of the dynamic baseline parameters showed an association with clinical outcome.

As the final chapter in part II, we presented a novel US technique in Chapter 7. This study was designed to assess the usability of shearwave elastography in the carpal tunnel context. Elastography was compared to a classic lab-based indentation test while measuring under incremental longitudinal nerve stress, with different probe orientations and positions. Compared to the indentation test, elastography showed a statistically comparable increasing pattern of elasticity. No significant interference of the osseous structures was found. However, we did find a lower elasticity when measuring the nerve in the transverse plane compared to a longitudinal assessment. This is relevant since in clinical practice and some of the studies published so far, measurements were done only in the transverse plane.

Part III Improving CTS treatment outcome

The current guidelines recommend treating CTS with either splinting, a local steroid injection, and/or surgical intervention based on the clinical presentation sometimes in conjunction with electrophysiological results. Surgery is seen as the only definitive solution since studies have shown that injections in the majority of patients only provide temporary relief. The usage and role in CTS treatment of injections, therefore, remains a topic of debate. To improve clinical outcome after injection, the procedure is now also done under ultrasound guidance. Hydrodissection is an injection technique in which, while ultrasound-guided, anatomical planes are created by targeting the injection between the nerve and the transverse carpal ligament and around the nerve. Some studies indicate a beneficial effect of this technique, but so far it has not yet been compared with standard clinical practice. In Chapter 8 we used a double-blinded, randomized pilot study to show equal satisfaction rates for those with and without hydrodissection therapies. Both groups showed symptomatic and functional improvement after one and six months, but in the preliminary data no clinical superiority was found.

In Chapter 9 we discussed a new surgical approach as an alternative to the classic transverse carpal ligament release. We describe an US-guided carpal tunnel release in which an abrasive thread is looped around transverse carpal ligament thereby allowing the surgeon to divide the ligament without the open approach. The main advantages include minimal damage to surrounding tissue and short recovery periods while the required expertise with the US forms the main challenge. Future studies are necessary to fully assess the added clinical value.

Improved clinical outcome can also be approached by studying pre-therapeutic patient satisfaction. In Chapter 10, we describe a CTS database study in which we show that higher experience scores were associated with better symptom and function scores post-surgery. Despite the lack of a causal relation, this does indicate that there is an interplay between patient experience and what we are currently using as outcomes to determine the success of a surgery.

Finally in Chapter 11, we again looked at patient-reported outcomes, but this time we focused on the question of whether type of treatment (i.e., surgery or injection) would alter the minimum score necessary for patients to be satisfied after treatment. Even when corrected for baseline severity, patients who underwent injection required less improvement to reach the minimal clinically important difference threshold than those who underwent surgery. These results are directly relevant for researchers designing future studies with these instruments and, on a larger scale, the results infer that patient-reported outcomes are prone to external factors unknown to us.