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Cardiac amyloidosis is often preceded by orthopedic manifestations such as carpal tunnel syndrome, and 10% of patients who underwent idiopathic carpal tunnel release surgery will have biopsy-confirmed amyloid deposits in the tenosynovial sheath. Trigger finger is also commonly reported in patients with amyloidosis and involves the same tendon sheath as carpal tunnel syndrome, but the prevalence of amyloid deposition is unclear. This prospective cross-sectional study enrolled 100 patients aged ≥50 years at the time of surgery for idiopathic trigger finger. Patients underwent release surgery, and a sample of the tenosynovium of the affected finger was excised, stained with Congo red, and subtyped with mass spectrometry if amyloid was demonstrated. Further cardiac evaluation was performed in patients with amyloid deposition. Of the 100 patients (mean age 65.5 ± 8.1 years) enrolled, only 2 demonstrated amyloid deposits on Congo red staining. One patient with previous proteinuric kidney disease had fibrinogen A α-chain amyloidosis, and the other patient had untyped amyloidosis. Neither patient had cardiac involvement. A total of 13 of the 100 patients underwent concomitant carpal tunnel release surgery, and 2 of these patients had amyloid deposits in the carpal tunnel with "false-negative" samples from the trigger finger tenosynovium. In conclusion, biopsy during trigger finger release surgery demonstrated a 2% yield for amyloidosis, which is significantly lower than the previously published yield of 10% during carpal tunnel release surgery. This observation has important implications for the development of diagnostic algorithms to screen patients for amyloidosis during orthopedic operations., Competing Interests: Disclosures Dr. Sperry is a consultant for Alnylam Pharmaceuticals Inc. and Pfizer Inc. Dr. Hanna, has served on advisory boards for Alnylam Pharmaceuticals Inc., Eidos, Akcea Therapeutics, and Pfizer Inc. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Transthyretin-derived amyloid deposition is commonly found in intercarpal ligaments of patients with senile systemic amyloidosis. However, the frequency of transthyretin-derived amyloid deposits in ligaments of other tissues remains to be elucidated. This study aimed to determine the frequency of amyloid deposition and the precursor proteins of amyloid found in orthopedic disorders. We studied 111 specimens from patients with carpal tunnel syndrome (flexor tenosynovium specimens), rotator cuff tears (rotator cuff tendon specimens), and lumbar canal stenosis (yellow ligament specimens). To identify amyloid precursor proteins, we used immunohistochemical staining with antibodies that react with transthyretin, immunoglobulin light chain, amyloid A protein, and β(2)-microglobulin. By means of Congo red staining, we identified 47 (42.3%) amyloid-positive samples, 39 of which contained transthyretin-derived amyloid (18 flexor tenosynovium specimens, 5 rotator cuff tendon specimens, and 16 yellow ligament specimens). Genetic testing and/or clinical findings suggested that all patients with transthyretin amyloid deposits did not have familial amyloidotic polyneuropathy. The occurrence of amyloid deposition in those tissues depended on age. These results suggest that transthyretin-derived amyloid deposits may occur more frequently in various ligaments and tendons than originally expected. In the future, such amyloid deposits may aid determination of the pathogenesis of ligament and tendon disorders in older patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A 50 year young farmer presented with clinical features of bilateral carpal tunnel syndrome and generalized lymphadenopathy including paratracheal and retroperitoneal lymphodes. The histological diagnosis confirmed primary amyloidosis of lymphnodes. Presentation of primary amyloidosis as lymphnodal mass with deposition of amyloid in carpal tunnel is extremely rare and can only be diagnosed by histochemistry. The clinical response to drugs is variable and needs surgical intervention for decompressive therapy which can improve the symptoms of carpal tunnel syndrome.

Background: In 1997, Stoppini et al reported that monoclonal antibody specific to the C-terminal 92-99 of beta(2)-microglobulin (beta(2)m) had been capable of inhibiting fibrillogenesis of beta(2)m in vitro. Meanwhile, recent studies have indicated that an acidifying procedure can unfold conformation of the precursor protein, leading to fibril formation of beta(2)m as well as a transthyretin., Methods: We thus prepared monoclonal antibody specific to the C-terminal 92-99 (mAb 92-99), and investigated its reactivity in plasma ultrafiltrate and amyloid tissues from 18 hemodialysis patients with dialysis-related amyloidosis (DRA)., Results: beta(2)m extracted from ultrafiltrate showed no reaction for mAb 92-99, whereas acidified beta(2)m from ultrafiltrate showed a reaction for mAb 92-99. Similarly, a homogenate of carpal amyloid tissues showed a strong reaction for mAb 92-99 on immunoblotting. Immunohistochemical study showed also a distinct staining for mAb 92-99 in 7 Congophilic specimens from DRA patients. More interestingly, staining for mAb 92-99 could be found in most, though not all, non-Congophilic tissues., Conclusion: This study demonstrates that the monoclonal antibody specific to the C-terminal 92-99 of beta(2)m can detect the conformational intermediate in amyloidogenesis of beta(2)m ex vivo, and demonstrates that an unfolded beta(2)m at C-terminal could be found not only in Congophilic area but even in non-Congophilic area as well.

This is the second report of transthyretin (TTR) amyloidosis in a patient who had ATTR Tyr114His diagnosed by mass spectrometry and gene analysis. This case had some clinical features that differed from those of the first reported cases. The patient, 73-year-old man, complained of generalized cutaneous tubercula that had started at age 68. These tubercula gradually increased in size and became generalized. He felt a slight numbness in his extremities. Clinical and electrophysiological examinations revealed that he had bilateral carpal tunnel syndrome (CTS), whereas there was no clear evidence of sensory and/or motor polyneuropathy. Autonomic symptoms were not present. Biopsy studies revealed that both his tuberculum and his sural nerve contained TTR-related amyloid. In his sural nerve, amyloid deposits were observed mainly in the perineurium, not in the endoneurium, and there was no significant depletion of myelinated fibers. The features of this patient were clinically characterized by generalized cutaneous amyloid deposits and late-onset CTS with a lack of overt polyneuropathy and autonomic dysfunction. The unique clinical features in this case seemed to be consistent with the distribution of amyloid deposits.

Background: beta2-microglobulin (beta2m) is considered to be the amyloidogenic precursor in dialysis-related amyloidosis (DRA, Abeta2M amyloidosis). beta2m modified with advanced glycation end products (AGE) may be an important factor in the pathogenesis of DRA. The presence of AGE in beta2m-positive amyloid deposits and surrounding macrophages has been demonstrated by immunohistochemical techniques in light microscopy., Methods: In order to better define the localization of beta2m and AGE in amyloid deposits and in cells, carpal tunnel connective tissues obtained from surgical specimens in six patients with DRA were studied by immunohistochemistry and electron microscopy, using the avidine-biotine complex and immunogold staining procedures, respectively. A polyclonal rabbit anti-human beta2m and two monoclonal mouse anti-AGE antibodies [AG-1 anti-imidazolone and AG-10 anti-N(epsilon)-carboxymethyl-lysine] enabled us to label their respective antigens at the optical and ultrastructural level., Results: with both techniques, extracellular amyloid deposits strongly reacted with anti-beta2m and anti-AGE antibodies, although the immunoreactivity of beta2m was more intense. Macrophage-like synovial cells (CD-68 positive) surrounding amyloid deposits were also immunoreactive for beta2m and AGE, which were detected in lysosomes and in intracellular fibrillar material. Anti-AGE reactivity was also evident in collagenous structures in the absence of beta2m or amyloid deposits, supporting the proposal that AGE modification of collagen might have pathogenic relevance in the development of DRA., Conclusions: The co-localization of AGE and beta2m, both intra- and extra-cellularly, in amyloid fibrils was confirmed by immunoelectron microscopy; however, the positivity of collagen to anti-AGE antibodies and a different pattern of intracellular localization suggest that molecules other than beta2m may also be modified by AGE and may be involved in the pathogenesis of DRA.

Objective: To determine the prevalence of amyloid deposits among patients with carpal tunnel syndrome (CTS) receiving dialysis, and to investigate the factors associated with amyloid and non-amyloid CTS., Methods: Subjects for this prospective study were dialysis patients who underwent surgery for CTS in the same surgical unit between 1989 and 1997. CTS was diagnosed from clinical and electromyographic (EMG) findings. Systematic standard radiographs and laboratory data were also obtained. Surgical investigations included systematic macroscopic examination and biopsy of the epineurium, flexor retinaculum, synovium, and flexor tendon sheaths. Samples were stained for amyloid and examined by plain and polarized light microscopy, immunohistochemistry, and electron microscopy., Results: Forty-one samples from 30 patients (11 bilateral cases) were examined. Amyloid deposits were found in 26 samples from 18 patients (7 M, 11 F). Fifteen samples from 12 patients (3 M, 9 F) showed no amyloid deposits. Amyloid CTS was statistically significantly associated with arthralgia and longterm dialysis [mean 13.3 (range 5.5-23) vs 7.5 yrs (range 3 mo-14 yrs)] in non-amyloid CTS. Flexor tenosynovitis and carpal bone erosion occurred more frequently in amyloid CTS. There were no statistically significant differences between the 2 groups in clinical, laboratory or EMG findings, type of dialysis membrane, or frequency of ipsilateral fistula. Only amyloid CTS was recurrent., Conclusion: Amyloid deposits were confirmed microscopically in 63.4% of patients. The relatively large number of cases of non-amyloid CTS without signs of dialysis associated arthropathy suggests that CTS is not a satisfactory criterion for diagnosis of dialysis arthropathy or beta2-microglobulin amyloidosis unless the presence of amyloid has been confirmed or duration of dialysis treatment has been at least 15 years.

Background: The occurrence of various arthropathies including carpal-tunnel syndrome (CTS) in dialysis-associated amyloidosis, a condition caused by the deposition of beta 2 microglobulin (beta 2MG), has been emphasized for several years. We attempted to analyse the pathogenesis of CTS in haemodialysis-associated amyloidosis (HA)., Methods: The expression of cell adhesion molecules and inflammatory cytokines in tenosynovial tissues was determined by using both reverse-transcriptase polymerase chain reaction (RT-PCR) and immunostaining., Results: There was a marked expression of ICAM-1, VCAM-1, E-selectin mRNAs together with increased mRNA expression of inflammatory cytokines (IL-1 beta, TNF alpha, IL-6 and MCP-1) in proliferating synovial tissues. ICAM-1 was expressed not only on vascular endothelial cells, but also on synovial cells. In contrast, both VCAM-1 and E-selectin were exclusively expressed on endothelial cells. Mononuclear cells bearing CD13, CD14, CD33 and HLA-DR with macrophage-like morphology were accumulated in the perivascular area and expressed VLA-4, LFA-1 and Mac-1. Moreover, synovial lining cells, vascular endothelial cells and infiltrated mononuclear cells expressed chemokines such as MCP-1 and MIP-1 alpha., Conclusions: These data suggest that upregulated expression of inflammatory cytokines and adhesion molecules promotes activation and infiltration of macrophages causing CTS in haemodialysis-associated amyloidosis patients.

The carpal tunnel syndrome (CTS) is the most frequent clinical symptom of dialysis-related amyloidosis. We examined CTS by ultrasound imaging and correlation between CTS and bone amyloidosis was sought. One hundred and forty-two wrists of 71 hemodialysis (HD) patients and 28 of 14 normal volunteers (group 1) were studied. Patients on HD were divided into 4 groups based on HD duration: Group 2, less than 5 years; group 3, 5-10 years; group 4, 10-15 years; and group 5, more than 15 years. The frequency of CTS increased gradually with HD duration: 0% in group 2, 35.3% in group 3, 36.4% in group 4 and 74.1% in group 5. The thickness of the palmar radiocarpal ligament (PRL), corresponding to the posterior wall of the carpal tunnel was significantly greater in groups 4 (p < 0.05), and 5 (p < 0.05) than in group 1 (2.25 +/- 1.30 and 3.11 +/- 1.02 in group 4 and 5 vs 1.15 +/- 0.34 mm in group 1); and the width of the carpal tunnel (CT) was significantly larger in group 5 than in group 1 (6.92 +/- 1.78 in group 5 vs 5.53 +/- 1.48 mm in group 1, p < 0.05). Wrists operated on for CTS had significantly increased PRL and CT compared to the control group and patients without CTS. Patients with CTS had wider PRL than the control and HD patients without CTS. Cystic radiolucent lesions (CRL) of carpal bones characteristic of bone amyloidosis were noted in 15 of 71 HD patients. The thickness of PRL and width of CT in HD patients with CRL exceeded those in patients without CRL. These data indicated that ultrasonographic findings of wrists were closely correlated with the degree of CTS and CRL. The usefulness of ultrasonographic evaluation of PRL thickness and CT width in the evaluation of dialysis-related amyloidosis should be evaluated.

Histological examination of surgical specimens from 98 patients with carpal tunnel syndrome revealed amyloid deposits in 12% of the cases. Amyloid was located in the flexor retinaculum and to the same extent in the tenosynovium. Serial sections of the material containing amyloid deposits demonstrated that examination of only one level would detect solely 90% of the amyloid-positive cases. In one single case amyloid deposits were considered extensive enough to cause compression of the median nerve and thus could have played a role in the pathogenesis of the carpal tunnel syndrome. In 8 of the 12 cases the patients' histories proved no correlation to preexisting diseases. In our opinion, an individual disposition may promote amyloid deposits as a response to local and chronic irritation. It is noteworthy that the mean age in the amyloid-positive group (70 years) is significantly higher than in the amyloid-negative cases (55 years).

beta 2-microglobulin amyloidosis is a major complication in chronic hemodialysis patients. Destructive arthropathy, spondylarthropathy, and carpal tunnel syndrome are clinical manifestations of beta 2M amyloid depositions within the joints, intervertebral discs, and tendon sheets. We have investigated the prevalence of beta 2M amyloidosis associated radiological joint lesions in a population of 175 patients on chronic hemodialysis. In 32 of 175 patients the diagnosis of amyloidosis arthropathy and spondylarthropathy was made by radiomorphological criteria. These 32 patients were asked about rheumatic symptoms (localisation and character of pain, synovitis, carpal tunnel syndrome, influence of dialysis membrane on pain) and examined clinically. Bilateral pain of the shoulders or wrists was complained by most of the patients. 24 of the 32 patients had signs of secondary hyperparathyroidism besides beta 2M-amyloidosis. 29 patients had a carpal tunnel syndrome, 23 of whom had to be operated. beta 2M-amyloid was histochemically demonstrated in all of these 23 cases. Renal transplantation led to immediate pain relief in 3 out of 3 patients, a change of the dialysis membrane (high-flux membrane) improved chronic pain in the majority of patients.

Carpal tunnel syndrome developed in six patients receiving long-term (12 to 17 years) hemodialysis. Biopsy specimens of tendons and synovial-tendon sheaths showed deposition of eosinophilic hyalin material exhibiting many properties of amyloid. However, this material did not react with antibodies to known amyloid proteins, except for the P component. On electron microscopy, the material consisted of fine filaments, 9 to 10 nm thick, that showed a marked tendency to parallel alignment and arrangement in bundles. The same material was found in arterioles of the rectum in three of four patients who were examined. We suggest that this material represents a previously undescribed type of amyloid. Its deposition may be due to the effects of long-term hemodialysis, or to the long-term uremic state, and may pose a potential problem to dialyzed patients.

Amyloid deposits in the temporal artery were observed 40 years ago, but the presence of vascular ischemic symptoms in patients with amyloidosis has been infrequently recognized. We examined 22 patients who had typical jaw claudication with biopsy-proven primary amyloidosis. In none was vasculitis a contributing cause of the claudication. However, two patients were misdiagnosed initially as having temporal arteritis and polymyalgia rheumatica and were treated with corticosteroids, which resulted in significant toxicity. Subsequent temporal artery biopsy revealed extensive amyloid deposits in both patients. Jaw claudication was associated with other ischemic vascular symptoms, such as arm or calf claudication. The median survival for the subset of patients with amyloidosis and jaw claudication was 42 months, and that for the entire group of patients with amyloidosis was 12 months. Appropriate staining of temporal artery biopsy specimens is necessary for the correct diagnosis in such cases.

In this investigation of the etiology of amyloid-associated arthropathy in hemodialysis (HD) patients, determination of whether amyloid deposition triggered the formation of the cystic radiolucent bone lesions was attempted. The relationship between these lesions in carpal bones and carpal tunnel syndrome (CTS) was studied by radiography and tomography, and one of the carpal bones, the os capitatum, was examined histologically at autopsy. The mean number of cystic radiolucent lesions in carpal bones of the 21 patients with CTS was significantly greater than that in the 43 patients without CTS. On tomograms, cystic radiolucent lesions of carpal bones had interconnections with joint spaces. Inflammatory fibrous granulation tissue, with or without amyloid deposits, was found in the cystic lesions. It was concluded that cystic radiolucent lesions in carpal bones of patients on HD was related to CTS, and that synovitis and subsequent chronic inflammation were responsible. Thus, amyloid deposits did not trigger the formation of such lesions.

Twenty-six non-randomized patients with carpal tunnel syndrome are presented. It is documented that three out of four patients may be diagnosed pre-operatively by five or more clinical parameters. All patients were screened for amyloidosis in biopsies from the carpal tunnel. One patient presented amyloid deposits in the transversal carpal ligament. The importance of macro- and microscopic findings in the carpal tunnel inclusive local amyloidosis for the pathogenesis of the carpal tunnel is discussed. It is concluded that provided systemic amyloidosis is not suspected, screening for amyloidosis may have diagnostic interest, however without therapeutic consequences and therefore unnecessary.

Since 1975, various entrapment neuropathies have been reported in patients undergoing periodic haemodialysis, the most frequent being the carpal tunnel syndrome. Ten patients on chronic haemodialysis developing 15 carpal tunnel syndromes (5 unilateral and 5 bilateral) are reported. Various causes for the renal failure were present and clinical signs of the carpal tunnel syndrome developed at a late stage. The arteriovenous fistula required for extrarenal epuration was antebrachial and of the laterolateral type, except in one case when it was lateroterminal. The carpal tunnel syndrome was always on the same side as the fistula, developing at a later stage on th contralateral side in the 5 cases of bilateral disorders. Lesions were severe, in 11 of the 15 cases. Some patients noted fluctuations in pain symptoms during haemodialysis, either improving or becoming worse. Gross pathological findings during operation (13 cases) were tenosynovitis with epineural hypervascularisation on the opposite side. In 9 cases, however, atypical hypertrophic tenosynovitis was observed. Histological examination in 12 cases demonstrated typical tenosynovitis in 3 patients, but granulomatous tenosynovitis with amyloid deposits was reported in 9 patients. Lesions were bilateral in 2 cases thus present, on the side opposite to the fistula. Ultrastructural study confirmed the amyloid nature of the deposits in 3 cases, the microfibrillary appearance (80 to 100 A) being characteristic of amyloid substance. This rare complication does not represent a common carpal tunnel syndrome, and three mechanisms may be involved in its induction : peripheral uraemic neuropathy, haemodynamic modifications resulting from the antebrachial arteriovenous shunt, and amyloid formation in the flexor synovial sheaths. In the latter case, the type of amyloid disease may be a primary systemic amyloidosis not previously detected, or an elective amyloid process localised to the tenosynovial and periarticular tissues.