Morphological changes of collagen fibrils in the subsynovial connective tissue in carpal tunnel syndrome

BACKGROUND: Pathologic changes occur commonly in the subsynovial connective tissue in patients with carpal tunnel syndrome. The purposes of this study were to investigate the ultrastructural changes of the subsynovial connective tissue in these patients and compare them with the findings in cadaver controls. METHODS: The diameter and density of collagen fibrils were measured by transmission electron microscopy in specimens of subsynovial connective tissue from ten patients with idiopathic carpal tunnel syndrome and from ten fresh-frozen cadavers of individuals without known symptoms of carpal tunnel syndrome. RESULTS: We noted deformed collagen fibrils with a spiraled appearance in the specimens from the patients. We also observed phagocytosis of elastin fibrils in all of those specimens. These changes were noted only rarely in the cadaver controls. The mean diameter (and standard deviation) of the collagen fibrils was 45.5 +/- 8.0 nm in the control group and 54.8 +/- 15.2 nm in the patient group (p < 0.05). The mean number of collagen fibrils per 0.04 microm2 (density) was 201.38 +/- 48.88 in the control group and 157.08 +/- 54.38 in the patient group (p < 0.05). CONCLUSIONS: These ultrastructural findings suggest that subsynovial collagen in patients with carpal tunnel syndrome is structurally different from that in individuals without carpal tunnel syndrome, but the processes resulting in that abnormal morphology remain to be elucidated.     

Immunolocalization of collagen types in the subsynovial connective tissue within the carpal tunnel in humans.

The tenosynovium within the carpal tunnel consists of a single layer of synovial cells, which lines the bursae within the carpal tunnel, and the subsynovial connective tissue (SSCT), which contains the tendon vasculature and other structural elements. In this study, we used immunogold labeling to localize collagen types within the SSCT in three cadaver specimens and three patients with carpal tunnel syndrome. Positive labeling for collagen types I, III and VI was found with immunoelectron microscopy. Collagen types I and III were codistributed within the SSCT. Type VI was primarily located in microfibrillar structures between collagen bundles, between elastin and collagen bundles and between collagen bundles and cells. There was no difference in the distribution of collagen types when comparing cadaver specimens and carpal tunnel patients.     

The expression of estrogen receptors in the tenosynovium of postmenopausal women with idiopathic carpal tunnel syndrome

The purpose of this study was to investigate estrogen receptor (ER) expression in tenosynovial tissues of postmenopausal woman with idiopathic carpal tunnel syndrome (CTS) to determine whether estrogen contributes to the pathogenesis of this condition. Biopsy samples of tenosynovial tissues were collected from 14 postmenopausal women (mean age; 57, range; 46–69 years) undergoing surgery for idiopathic CTS, and control specimens of tenosynovial tissue were collected from 6 postmenopausal women (mean age; 59, range; 48–68 years) without CTS. Histological and immunohistochemical examinations were performed to determine the distributions of ER‐α and ER‐β in tenosynovial tissues. Histological examinations showed a significant increase in fibroblast cell densities in the specimens from the carpal tunnel syndrome patients. ER‐α and ER‐β immunoreactivities were observed in fibroblasts and in the synovial lining cells of tenosynovial tissues, and these were significantly greater in patients than in controls. This study suggests that the up‐regulations of ERs in the tenosynovial tissue are associated with idiopathic CTS in postmenopausal women. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1469–1474, 2010     

Synovial histology in carpal tunnel syndrome

This study investigates the relationship between idiopathic carpal tunnel syndrome and tenosynovial histology, specifically inflammation. Tenosynovial biopsy specimens from 177 wrists were obtained from patients at carpal tunnel release, and a control group of 19 specimens was also obtained. Inflammation was present in only 10% of the patient specimens and was correlated with only one of the clinical and histologic factors studied, i.e., nerve conduction impairment. Edema, observed frequently (85%), was not correlated with inflammation. Vascular sclerosis was also found consistently (98%) and was correlated with patient age and degree of edema. Edema and vascular sclerosis occurred with significantly greater frequency and severity in the specimens of patients than in the control group. Fibrosis (3%) and synovial hyperplasia (1%) were uncommon findings. It is concluded that tenosynovitis is uncommon in patients undergoing surgery for treatment of idiopathic carpal tunnel syndrome.     

Subsynovial connective tissue is sensitive to surgical interventions in a rabbit model of carpal tunnel syndrome

The most common histological finding in carpal tunnel syndrome (CTS) is non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT) in the tunnel. While the cause of SSCT fibrosis and the relationship of SSCT fibrosis and CTS are unknown, one hypothesis is that SSCT injury causes fibrosis, and that the fibrosis then leads to CTS. We investigated the sensitivity of the SSCT to injuries. Two types of surgical interventions were performed in a rabbit model: A skin incision with tendon laceration and SSCT stretching sufficient to damage the SSCT, and skin incision alone. Twelve weeks after surgery, the rabbit carpal tunnel tissues were studied with immunochemistry for TGF-β receptors 1, 2, and 3, collagen III, and collagen VI. All TGF-β receptors were expressed. The percentages of the TGF-β receptors' expressions were less in the control SSCT fibroblasts than in the fibroblasts from rabbits with surgical interventions. The surgical interventions did not result in any alteration of collagen III expression. However, both surgical interventions resulted in a significant decrease in collagen VI expression compared to the control group. The two surgical interventions achieved similar expression of TGF-β receptors and collagens. Our results provide evidence that the SSCT is sensitive to surgical interventions, even when these are modest. Since SSCT fibrosis is a hallmark of CTS, these data also suggest that such fibrosis could result from relatively minor trauma.     

An analysis of the flexor synovium in idiopathic carpal tunnel syndrome: report of 625 cases.

This study was undertaken to determine the presence or absence of tenosynovitis in persons with idiopathic carpal tunnel syndrome. Eight hundred thirty-five consecutive operations for carpal tunnel syndrome were retrospectively reviewed, and 625 cases of idiopathic carpal tunnel syndrome were identified. Of these 96% (601) had a synovial tissue histologic diagnosis of benign fibrous tissue without inflammation, 4% (23) showed chronic inflammation, and 0.2% (1) revealed evidence of acute inflammation. We believe that tenosynovitis is not a part of the pathophysiologic process in chronic idiopathic carpal tunnel syndrome. Further histologic analysis of the flexor synovium for pathologic changes other than inflammation is needed.     

Oxidative stress in subsynovial connective tissue of idiopathic carpal tunnel syndrome

Ischemic‐reperfusion injury is thought to be a cause of idiopathic carpal tunnel syndrome (CTS). The purpose of this study was to determine whether oxidative stress caused by ischemia‐reperfusion injury in subsynovial connective tissue is associated with idiopathic CTS and its symptoms. Bioptic samples of tenosynovial tissue were collected from 20 idiopathic CTS patients during surgery. Control specimens of tenosynovial tissue were collected from eight non‐CTS patients. Analysis included histological and immunohistochemical examination for the distribution of endothelial nitric oxide synthase (eNOS), nuclear factor (NF)‐κβ, and transforming growth factor (TGF)‐β RI in subsynovial connective tissues. Histological examinations showed a marked increase in fibroblast density and vascular proliferation in specimens from CTS patients. The expressions of eNOS, NF‐κβ, and TGF‐β RI in fibroblasts and vascular endothelial cells of subsynovial connective tissues of patients were significantly higher than in those of controls. A significant positive correlation was found between the subjective symptom severity of CTS, and the immunoreactivities of eNOS and NF‐κβ. This study suggests that oxidative stress in subsynovial connective tissue is related to CTS and its symptoms. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:1463–1468, 2010     

Biochemical evaluation of serum and flexor tenosynovium in carpal tunnel syndrome

In total, 41 consecutive patients with "idiopathic carpal tunnel syndrome" and abnormal electrophysiologic findings who underwent carpal tunnel release were studied prospectively. The focus of this investigation was the evaluation of the levels of specific chemical mediators within the serum and flexor tenosynovium of these patients. Blood was collected from these patients within 1 week prior to carpal tunnel release, and flexor tenosynovium was obtained at time of surgery. Specimens were then analyzed to determine the levels of interleukins 1 and 6, prostaglandin E(2) (PGE(2)), and malondialdehyde bis diethyl acetal. These values were compared to those of controls who had no evidence of carpal tunnel syndrome. A significant increase was noted in the serum malondialdehyde and tenosynovial levels of malondialdehyde, interleukin 6, and prostaglandin PGE(2) compared to controls. The elevated levels of these biologic factors and the absence of interleukin 1 elevation support a noninflammatory ischemia-reperfusion etiology for so-called "idiopathic carpal tunnel syndrome" that causes progressive edema and fibrosis of the tissues within the carpal canal. These findings correlate with previous histopathology reports. We believe that "idiopathic carpal tunnel syndrome" is an "-osis" not an "-itis."     

Mycobacterium tuberculosis-induced carpal tunnel syndrome: management and follow-up evaluation

PURPOSE: To determine the clinical characteristics of 12 patients with Mycobacterium tuberculosis-induced carpal tunnel syndrome. This article also presents our intraoperative findings and surgical treatment results. METHODS: Twelve patients with tuberculosis-induced carpal tunnel syndrome who had surgery during a 10-year period that began in March 1991 were reviewed. The entrance criterion was a positive histologic report of tuberculosis for surgical specimens. The preoperative evaluation leading to diagnosis was reviewed for all patients. Transection of the transverse carpal ligament and complete synovectomy were performed for all patients. After surgery the patients were given an antituberculosis regimen for 1 year and were followed up for an average of 6 years. RESULTS: Twelve cases from a total of 1,180 patients with carpal tunnel syndrome were traced to M tuberculosis involvement of synovial tissue of the flexor tendons. Ten patients had large rice bodies in thick synovial membranes, and in the other 2 patients thick synovial tissue with yellow exudates were observed during surgery. In contrast to tendon involvement with rupture, no direct median nerve involvement was noted. Histopathologic study results of surgical specimens were positive for tuberculosis in all patients. Eight of 10 initial smears showed acid-fast bacillus and all 10 cultures of the specimens were positive for tubercle bacilli. Surgery and antituberculosis therapy were associated with a desirable outcome and sensory disturbance in the median nerve distribution resolved in all patients. Anterior wrist swelling disappeared and there has been no clinical or laboratory evidence of recurrence in all treated patients. CONCLUSIONS: Early diagnosis and surgical treatment combined with antituberculosis medical treatment are important in treating this condition. All patients treated were relieved of symptoms of synovial proliferation at the wrist, with no recurrence of the condition during the follow-up period. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, Level IV.     

Tamoxifen decreases fibroblast function and downregulates TGF(beta2) in dupuytren's affected palmar fascia

BACKGROUND: Dupuytren's contracture is a fibroproliferative disorder that is associated with increased collagen deposition. Isoforms of transforming growth factor beta (TGF(beta)), normally TGF(beta1) and TGF(beta2), are involved in the progressive fibrosis of Dupuytren's disease. It has been suggested that downregulation of TGF(beta) may be useful in the treatment of the condition. Tamoxifen, a synthetic nonsteroidal antiestrogen, is known to modulate the production of TGF(beta). This study examined the role of tamoxifen in decreasing fibroblast function and downregulating TGF(beta2). METHODS: Primary cultures of fibroblasts were obtained from Dupuytren's affected fascia and carpal tunnel affected fascia as a control. Collagen lattices were prepared and populated with the fibroblasts. The fibroblast-populated collagen lattices (FPCL) were then measured for contraction every 24 h for 5 days. Supernatant was obtained from the culture medium following completion of the FPCL portion of the experiment and used for a TGF(beta2) immunoassay. RESULTS: Dupuytren's affected fibroblasts contracted the FPCLs significantly more than carpal tunnel control fibroblasts. Treating the fibroblasts with tamoxifen caused a decreased contraction rate in both Dupuytren's affected fibroblasts and carpal tunnel controls. There was increased TGF(beta2) expression in the Dupuytren's affected fascia group compared to the carpal tunnel control group. Tamoxifen decreased TGF(beta2) expression in Dupuytren's affected fascia group but not in the carpal tunnel control group. CONCLUSION: TGF(beta) appears to be the key cytokine in the fibrogenic nature of Dupuytren's disease. Tamoxifen treatment has been demonstrated to decrease the function of fibroblasts derived from Dupuytren's affected fascia and downregulated TGF(beta2) production in these same fibroblasts. These data suggest a method to manipulate and control Dupuytren's contracture in the clinical setting.     

Carpal canal stenosis in men with idiopathic carpal tunnel syndrome.

The carpal canal and carpal bones of 14 male patients with idiopathic carpal tunnel syndrome and 26 normal male controls were examined by computed tomography. When compared with the controls, there was significant stenosis of the proximal part but not of the distal part of the carpal canal. Carpal canal stenosis is an important etiologic factor in the development of idiopathic carpal tunnel syndrome in males.     

Die Expression von Typ-VI-Kollagen bei der Arthrofibrose Eine immunhistochemische Untersuchung*

Arthrofibrosis is a disabling complication after trauma and surgery due to massive connective tissue proliferation. The etiology and pathogenesis have never been fully understood. A strong immune response may lead to activation and proliferation of fibroblasts with excessive and disordered deposition of matrix proteins. In similar pathological conditions, like lung fibrosis or superficial fibromatoses with fibrotic transformation an increased expression of collagen type VI has been reported. We investigated fibrotic tissue samples taken from 18 patients (average age: 32.7 years), who underwent arthrolysis of the knee joint because of symptomatic arthrofibrosis following ligament injury. The mean interval between trauma and arthrolysis was 13.8 months (range 4-50 months). Tissue samples were taken from the infrapatellar fat pad and intercondylar connective tissue. All samples were stained with HE. The expression of type III and VI collagen was studied immunohistochemically using an immunoperoxidase method for light microscopic visualization. Histologic analysis from patients with arthrofibrosis showed a synovial hyperplasia with cell infiltration and vascular proliferation compared to synovial tissue samples from knee joints without any detectable pathology. Subsynovial an increased deposition of matrix proteins was visible. Type VI collagen was widely distributed as a network subsynovial and around capillary walls. Type III collagen showed a diffuse distribution. Arthrofibrotic tissue is, similar to pathological conditions with fibrotic transformation characterized by an increased expression of collagen type VI. Collagen type VI may play an important role in matrix homeostasis. It serves as an anchoring element between collagen fibers and as a cell binding structure.     

Histopathology of the flexor tendon sheaths and its relevance in idiopathic carpal tunnel syndrome

Compression of the median nerve in the carpal tunnel can be produced by a variety of factors, including fractures, metabolic disturbances, rheumatoid arthritis or anatomical anomalies. When it is not possible to identify a specific cause, the term ”idiopathic carpal tunnel syndrome” is used. Although this disease is very common, its pathophysiology is still unclear. In the past, the presence of a chronic non-specific tenosynovitis around the flexor tendons was postulated but several investigations failed to show any inflammatory reaction in the carpal synovium. In this study, the histology of the flexor tendon sheaths in a group of 50 patients surgically treated for idiopathic carpal tunnel syndrome (ICTS) have been investigated both from the qualitative (histopathology) and quantitative (micrometric evaluation) points of view. Lack of acute or chronic inflammatory cells, connective disorganization, and vascular modifications are the main histological findings which are present in all the specimens, regardless of the patient’s age, the duration of the sensory symptomatology or the severity of the neurological lesion on EMG exam. The carpal synovium in these patients appeared thickened when compared to the specimens obtained from the control group. However, on micrometric evaluation a relationship between synovial thickness and severity of the symptomatology or of the EMG data was not observed. The carpal synovium in ICTS has a consistent histological appearance and is increased in thickness when compared with normal specimens. Received: 18 September 1998 / Accepted: 14 April 1999     

Endoscopic carpal tunnel release in patients receiving long-term hemodialysis

This study evaluated the clinical results of endoscopic carpal tunnel release in carpal tunnel syndrome caused by long-term hemodialysis and compared the results with that of idiopathic carpal tunnel syndrome. Operations were done in 32 patients (60 hands) with idiopathic carpal tunnel syndrome and in eight patients (15 hands) with carpal tunnel syndrome resulting from long-term hemodialysis. There was no significant difference in findings of preoperative evaluations and postoperative clinical results between the two groups, except for a difference with the patient satisfaction score with surgery on a visual analogue scale. The mean satisfaction score was 9.0 at 6 months, 9.3 at 1 year, and 9.5 at the 2-year followup in the group of patients with idiopathic carpal tunnel syndrome. However, in the group of patients with carpal tunnel syndrome resulting from long-term hemodialysis, the mean satisfaction score was 8.5 at 6 months, 8.2 at 1 year, and 6.5 at the 2-year followup. The score began to decrease at an average of 17.2 months after surgery. Long-term hemodialysis related carpal tunnel syndrome showed satisfactory short-term clinical results until approximately 1.5 years after the operation. After that time, the symptoms tended to deteriorate in 50% of the patients who received hemodialysis continuously.     

Idiopathic carpal tunnel syndrome: histologic study of flexor tendon synovium

The histologic lesions in flexor tendon synovium of 21 patients seen initially with idiopathic carpal tunnel syndrome have been studied. The findings were similar in all biopsy specimens and were typical of a connective tissue undergoing degeneration under repeated mechanical stresses.     

Absorptive properties of synovium harvested from the carpal tunnel

Ischemia-induced reperfusion injury seems to play an important role in the pathophysiology of "idiopathic" carpal tunnel syndrome (CTS). The common final pathway in this developmental sequence is thought to be an intermittent increase in interstitial pressure, leading to degenerative changes in the flexor tenosynovium and fibrotic changes in the perineural tissue. We hypothesize that this concurrently leads to alteration in the physical properties of the synovium, leading to its rapid and persistent swelling. A prospective study was conducted on synovial tissue obtained from 27 CTS patients. The in vitro synovial absorption rate of CTS patients was significantly higher in the first hour compared to controls (n = 7). This difference was maintained up to 5-6 h, albeit at a slower rate. Rapid absorption and retention of fluid by the synovium led to increased interstitial pressure and nerve compression, resulting in early and persistent manifestation of symptoms in sensitized patients.     

Carpal tunnel syndrome in black South Africans

The incidence and the aetiology of chronic carpal tunnel syndrome in black South Africans was evaluated. This study showed that the incidence of idiopathic carpal tunnel syndrome was very low in this population group and that most patients who presented with symptoms and signs of chronic carpal tunnel syndrome had a specific pathology. A rare case of tumoral calcinosis causing carpal tunnel syndrome is presented. A case of perineural lipofibroma causing carpal tunnel syndrome is also described.     

Mycobacterium kansaii flexor tenosynovitis presenting as carpal tunnel syndrome

We present a case in which Mycobacterium kansasii flexor tenosynovitis caused the development of carpal tunnel syndrome. The diagnosis was made from synovial tissue specimens taken at the time of operation.     

Trigger wrist due to idiopathic synovial hypertrophy

The phenomenon of "trigger wrist" has been reported several times since 1961, when it was first described (Eifel, 1961). Most of these cases related to patients suffering from "triggering" at the wrist associated with carpal tunnel compression. Below is a hitherto undescribed case of trigger wrist occurring in a fit girl, without carpal tunnel syndrome, due to idiopathic synovial hypertrophy.     

Immunohistochemical localization of collagen VI in arthrofibrosis

Arthrofibrosis is a disabling complication after knee trauma and surgery. Clinically, it is characterized by pain and joint stiffness due to massive connective tissue proliferation. In similar pathological conditions with fibrotic transformation such as lung fibrosis or superficial fibromatoses, an increased expression of collagen type VI has been reported. Collagen VI, which forms a filamentous network, is thought to serve as an anchoring element between collagen I/III fibrils and basement membranes and as a cell binding structure. Collagen VI may also play a contributing role in the pathogenesis of arthrofibrosis. The aim of the present study was therefore to demonstrate the localization and distribution of type VI collagen in arthrofibrotic tissue. Tissue samples from the infrapatellar fat pad and intercondylar synovia of 13 patients suffering from arthrofibrosis were taken at surgery. The expression of type VI collagen was studied immunohistochemically using an immunoperoxidase method for light microscopic visualization. Histologic analysis showed a synovial hyperplasia with inflammatory cell infiltration and vascular proliferation. Compared with normal synovial tissue, type VI collagen was widely distributed as a network subsynovially and around the capillary walls. The results of the present study suggest that dysregulation of collagen VI synthesis could be an important contributing factor in the complex mechanisms of disordered matrix protein deposition leading to arthrofibrosis.