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Vascular Pathologic Changes in the Flexor Tenosynovium (Subsynovial Connective Tissue) in Idiopathic Carpal Tunnel Syndrome

Posted on: Saturday, 6 November 2004, 03:00 CST

Abstract

We used the Verhoeff-van Gieson stain method to identify histopathology and to localize elastin in the subsynovial connective tissue of the tendon sheath (SSCT) of the middle finger flexor digitorum superficialis (FDS) within the carpal tunnel in 10 carpal tunnel syndrome (CTS) patients and 10 control cadaver specimens. Normal SSCT stained for elastin abundantly around blood vessels and within vessel walls. The typical pathologic findings of CTS patients SSCT included vascular proliferation, vascular hypertrophy, and vascular obstruction with wall thickening. There was a decreased amount of elastin in the blood vessel walls and around the vessels in the CTS patients as well. The changes in the carpal tunnel patients were particularly remarkable in that the patients were younger than the controls, yet showed findings more characteristic of chronic degeneration.

2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Introduction

Carpal tunnel syndrome (CTS) is the most frequently encountered peripheral compressive neuropathy [30]. There are many risk factors for CTS, with highly repetitive work suspected in many cases of otherwise idiopathic CTS [1-3,48,51,53].

The intrasynovial tendons of the hands and feet have parietal and visceral synovial sheaths that form a closed compartment that contains synovial fluid for lubrication. In extrasynovial tendons, such as Achilles tendon, there is a peritendinous sheet of paratenon composed of loose fibrillar tissue, which functions as an elastic sleeve, permitting free movement of the tendon against the surrounding tissue [10,26,27]. The structure of the flexor tenosynovial organization within the carpal tunnel is neither typically intrasynovial nor typically extrasynovial in nature. The gliding mechanism of the flexor tendons in the carpal tunnel, the subsynovial connective tissue (SSCT), appears instead to be a hybrid of the intrasynovial and cxtrasynovial mechanisms (Fig. 1).

The histological features of the flexor tendon sheath in idiopathic CTS typically reveal a non-inflammatory fibrous connective tissue [19,41,47], with thickening of the tendon sheath, fibrosis, edema, thickening of vessels walls, intimai hyperplasia, and thrombosis. These findings support the view that pressure in the carpal tunnel and ischemia are important factors in the etiology of idiopathic CTS [23,40,41,44].

Elastin has an unanticipated regulatory function during arterial development, controlling proliferation of smooth muscle and stabilizing arterial structure. A disruption of elastin synthesis results in subendothelial proliferation of smooth muscle, and may contribute to obstructive arterial disease such as atherosclerosis [4,8,28,35,49]. These findings are similar to those seen in idiopathic CTS, but we are unaware of any previous studies of elastin in patients with CTS.

The purpose of this study was, therefore, to examine the vascular changes of the subsynovial connective tissue in patients with idiopathic CTS, compared with cadaver specimens as control, especially with regard to the amount and localization of elastin.

Fig. 1. Structure of subsynovial connective tissue. (A) Intrasynovial tendon (SM: synovial membrane; SF: synovial fluid), (B) extrasynovial tendon (PT: paratenon), (C) flexor tendons in carpal tunnel (SSCT: subsynovial connective tissue).

Materials and methods

We performed a retrospective chart review on patients who had subsynovial connective tissue sent to our Department of Laboratory Medicine and Pathology during carpal tunnel release between January 1999 and December 2001 at the Mayo Clinic, Rochester, MN. Exclusion criteria included a history of diabetes, glucose intolerance, thyroid disease, rheumatoid arthritis, osteoarthrosis, degenerative joint disease, flexor tendinitis, gout, hemodialysis, BMI > 30, sarcoidosis, amyloidosis, peripheral nerve disease, or traumatic injuries to the ipsilateral arm. The first 10 consecutive patients with idiopathic (i.e., meeting the same exclusion criteria) CTS undergoing carpal tunnel release surgery and having had a synovial biopsy in the same time period were included in the research study. The medical history of each patient was abstracted from the patients' charts to identify idiopathic CTS. The tissue obtained during surgery included the subsynovial sheet of the flexor digitorum profundus tendons in all cases. All patients had a subsynovial connective tissue histological diagnosis of non- inflammatory fibrous tissue. The control group consisted of 10 fresh frozen cadavers from which subsynovial connective tissue of the middle finger FDS in the carpal tunnel was obtained. A chart review was performed on each member in the control group, in order to be sure the individual met the same exclusion criteria and in addition did not have an antemortem diagnosis of CTS. In order to have a close age match as possible with the patient group we selected the youngest cadavers available, the mean age of the patient group and control group was 59.4 and 75.0 years, respectively.

Staining methods

The subsynovial connective tissue was formalin-fixed and paraffinembedded. Five m sections were made by our Department of Laboratory Medicine and Pathology. The sections were stained for light microscopy by the Verhoeff-van Gieson method, which shows elastin fibers as black,1 smooth muscle as yellow, and collagen as red [46].

Quantitative morphometric analysis

The analytical method was identical to that developed and utilized by Dass et al. [13]. A normal objective lens (4) was used to capture the whole histological cross-section. This involved constructing a montage of the tissue section from several restricted subfields. Images were captured using a standard 625-line charge coupled device (CCD) camera attached to an Eclipse E400 light microscope (Nikon, Japan). On construction of the montage, it was noticed that fluctuations in light intensity from the microscope, combined with the variable sensitivity of the camera's photodiodes, gave rise to images of different light intensities and patterns. This was accounted for by subtracting a blank reference image taken from a section-free region of the microscope slide. Real time images were grabbed, digitized, and displayed directly on a monitor. Montages were reconstructed using the image-editing program Adobe Photoshop 6.0. Image analysis and processing were performed using Scion image analytic software. Image processing was used to optimize the signal to noise ratio.

For each patient montage, eight sites, including vessels in each case, were photographed under 10 magnification, by one person not related with this study, and one image of the eight was then selected randomly for analysis. Quantification of elastin entailed thresholding, i.e. separating pixels into groups of similar characteristics. In this case the similar characteristic was the color of the elastin stain, which fell within a narrow range of pixel shades. Finally, it was necessary to define the cropped area. The area occupied by elastin fibers was expressed as a percentage of the entire cropped area (Fig. 2). The same procedure was repeated three times and the three results were summed, and the mean used for statistical analysis.

Under 10 magnification, vessel number per unit area was calculated. In order to calculate mean thickness of vessel walls, five vessels in each case were selected randomly for measurement, and the mean value was calculated.

Statistical analysis

The information was entered into a database and statistical analysis was done with the software program SSPS, version 10.0 for windows (SPSS Inc., Chicago, IL, USA). The subjects were compared using t-tests for continuous variables. All statistical tests were two-sided and p-values of less than 0.05 were considered significant. Results are reported as mean SD unless otherwise indicated.

Results (histology and pathology)

In the normal SSCT, elastin was distributed unevenly between collagen fibers in the extracellular matrix of the SSCT. Elastin was abundant around blood vessels and within vessel walls (Fig. 3).

The typical pathologic findings of CTS SSCT were vascular proliferation, vascular hypertrophy and vascular obstruction with wall thickening. There was a decreased amount of elastin in blood vessel walls and around the vessels (Fig. 4).

The mean number of vessels per unit area (0.00155 mm^sup 2^) was 0.15 0.10 in the control group and 0.36 0.12 in the CTS group (p = 0.002, two-tail, paired). The mean thickness of blood vessels was 18.90 3.68 m in the control group and 38.10 20.60 m in the CTS group (p = 0.023, two-tail, paired). The mean elastin density within vessels was 0.18 0.04 in the control group and 0.10 0.03 (p = 0.001, two-tail, paired) in the CTS group. The mean elastin density around vessels was 0.23 0.04 in the control group and 0.15 0.04 in the CTS group (p = 0.002, two-tail, paired).

The reddish color intensity of stained collagen fibers was decreased in the CTS SSCT compared to controls. In general, the more severe the vascular hypertrophy and obstruction, the less elastin noted within and around blood vessels (Fig. 4).

Discussion

Carpal tunnel syndrome is a constellation of symptoms associated with \localized impairment of the median nerve function at the wrist. The median nerve impairment is associated with elevated pressure within the carpal tunnel, which results in mechanical compression and local ischemia [20-22,37,50-52,55]. Thickening of the synovial lining of the tendons that share the carpal tunnel with the median nerve increases the volume of tissue and the mechanical pressure within the carpal tunnel [2]. The combination of ischemic changes and mechanical contact pressure over time lead to changes in the myelin sheath and occasionally result in injury to the axon that can be detected on neurophysiologic testing such as standard nerve conduction studies [41,55].

Fig. 2. Quantitative morphomctric analysis. (A) Whole image before color extraction for elastin (black: elastin, yellow: vessel, red: collagen), (B) cropped image after color extraction for elastin in vessels, (C) cropped image including vessel and SSCT around vessel after color extraction for elastin.1

Fig. 3. Histology of normal SSCT. (A) Whole image of SSCT showing uneven distribution of elastin, (B) lesser amount of elastin in non- vascular site, (C) larger amount of elastin within and around vessels.

The histopathologic findings of the flexor tendonosynovium in CTS patients include an absence of inflammation, alterations in collagen fiber size and organization, thickening of the tendon sheath, fibrosis, edema, thickenings of vessel walls, intimai hyperplasia, and atherosclerotic change [19,36,41]. It is not known whether these tenosynovial changes arise first, and then compress the nerve, or arise in response to some external factor that affects tenosynovium and nerve independently.

Fig. 4. Pathology in patient SSCT. (A) Increased number of vessels, (B) decreased elastin within and around vessels, obstructed lumen of vessels and thickened vessel wall, (C) decreased reddish color intensity of stained collagen.

In mammals, elastin is synthesized by smooth muscle cells, fibroblasts, vascular endothelial cells, chondrocytes, and mesothelial cells [14]. Elastin is almost always codistributed with collagen as a protein providing tensile strength, and the relative proportions of elastin and collagen, as well as their physical arrangement, determine the mechanical properties of most connective tissues [14].

Under normal conditions, elastin turnover is minimal and elastin- producing cells such as fibroblasts and smooth muscle cells appear to have the potential of degrading both newly synthesized and insoluble elastin [14,34,43]. Degradation of insoluble elastin is usually mediated by inflammatory cells, and can have major pathologic consequences. Hypoxia is one regulator of tropoelastin gene expression and decreases tropoelastin mRNA stability [6].

Elastin is a potent autocrine regulator of vascular smooth muscle cell activity. Elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non- integrin, heterotrimeric G-protein-coupled pathway. Elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells [28]. The disruption of the elastin matrix leads to defective arterial morphogenesis. Lack of elastin can lead to dissection of arteries and an obstructive arterial disease such as atherosclerosis, which results from subendothelial cell proliferation and reorganization of smooth muscle [28,35]. Hypoxia downregulates tropoelastin gene expression [6]. In addition, smooth muscle cells produce metalloproteinases that have the capacity to degrade elastin [43]. Elastin is known as a potent autocrine regulator of vascular smooth muscle cell activity and this regulation is important for preventing fibrocellular pathology [28].

In idiopathic CTS, though there is no infiltration of inflammatory cells in the SSCT, we observed that elastin was decreased around and within vessels. This can be explained by either increased elastolysis of smooth muscle cells, decreased elastogenesis of elastin producing cells under the chronic hypoxic condition known to be present in CTS [36,41,55], or a combination of the two. The intimai hypertrophy and thickened vessel walls seen in the SSCT of our patients with idiopathic CTS are similar to those seen in atherosclerosis [7,35,49]. In short, the histopathology of CTS includes features characteristics of chronic hypoxia and degeneration, and supports theories of etiology which might promote such conditions locally [1-3,5,31,33,48,51,53]. This chronic hypoxic condition would in turn induce proliferation of fibroblasts, vascular remodeling and smooth muscle cell proliferation [11,12,15- 17,24-25,39,54], all of which are seen in the histopathology of CTS [2,19,29,36,38,41, 44,45],

There are many reports that highly repetitive work is associated with an increased incidence of idiopathic CTS and that vascular changes happen commonly in the SSCT of idiopathic CTS [2,3,9,18,32,42,51,53]. However, until now a plausible link between the putative physical cause and the observed vascular histopathology was not clear. We believe that chronic hypoxia, with the cascade of effects on elastin and perhaps other matrix macromolecules, may be that link. Moreover, to the extent that the structural changes in the tenosynovium induced by hypoxia have the effect of increasing fibrosis and decreasing vascularity, they may lead to a greater susceptibility to future ischemic episodes. This could establish a vicious cycle of tenosynovial ischemia and reperfusion, in response to ever decreasing levels of inciting trauma, with resulting alterations in tenosynovial bulk and material properties, which could well secondarily affect the physical environment and vascularity of the median nerve. In such a case, which we believe is supported by our observations here, the critical pathophysiology of idiopathic CTS might lie in the flexor tcnosynovium, with the nerve affected secondarily as a result of the changes in the vascularity and physical properties of the tenosynovium.

The strengths of this study lie in its systematic evaluation of the vascular pathology and elastin distribution in CTS patients and unaffected controls. The weaknesses relate to the small and non- random patient sample, and the fact that we did not study any markers of elastin synthesis or degradation. We also did not study any other factors that might be present in the SSCT of CTS patients. Finally, we only sampled the SSCT of one of the nine tendons within the carpal tunnel, and did not systematically assess the SSCT of the other tendons, not the related adventitial tissue around the median nerve. While one may argue that our cadaver controls are less appropriate than living controls, we would counter that any biopsies taken incidental to non-carpal tunnel surgery in the region of the wrist would be complicated by selection bias, based on whatever the indication was, other than carpal tunnel syndrome, for the surgery in the area of the wrist, and that the solicitation of healthy volunteers to submit to an open biopsy of the carpal tunnel raises ethical concerns. Ethically, we do not believe that the incremental quality of information would be worth the cost and risk, even assuming that volunteers could be found. And we further believe that, scientifically, cadaver specimens with no history of wrist trauma or disease are better controls than patients whose carpal tunnels are opened because of some other disease or injury in the wrist, that happens not to be CTS.

In conclusion, we have observed changes in vascular morphology and clastin distribution in the SSCT of patients with CTS that suggest that the condition is not exclusively a pathology of nerve, and, indeed, that the nerve changes may be a result rather than a cause of these changes. The hypothesis we propose here should be tested by further research on the SSCT in CTS, including investigations of metabolic changes in the cells of the SSCT, changes in activity of matrix metalloproteinases, changes in intracellular organelles, changes in other extracellular matrix macromolecules in the SSCT, and changes mechanical properties and permeability of the SSCT. In addition, animal models should be developed to test this hypothesis further, by attempting to create nerve compression by inducing pathology in the tenosynovium.

Acknowledgements

This study was funded by grants from NIH(NIAMS) and Mayo Foundation.

1 For interpretation of colors, the reader is referred to the web version of this article.

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Oh Jinrok(a), Chunfeng Zhao(a), Peter C. Amadio(a),* Kai-Nan An(a), Mark E. Zobitz(a), Lester E. Wold(b)

a Orthopedic Biomechanics Laboratory, Mayo Clinic, Rochester, MN 55905, USA

b Department of Pathology, Mayo Clinic, Rochester, MN 55905, USA

* Corresponding author. Tel.: +1-507-284-2806/538-2806; fax: +1- 507-284-5539.

E-mail address: pamadio@mayo.edu (P.C. Amadio).

Copyright Journal of Bone and Joint Surgery, Inc. Nov 2004

Source: Journal of Orthopaedic Research

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