Introduction: Amyloidosis are systemic conditions and carpal tunnel syndrome (CTS) precedes the principal systemic complications and can be used as an early marker. Our objective was to determine the frequency of amyloid deposition in idiopathic CTS and its systemic impact. Methods: We retrospectively evaluated patients with CTS between September 2019 to January 2020. Samples from the anterior carpal ligament were pathologically evaluated and amyloid deposition was confirmed by apple-green birefringence on polarized light using Congo red stain. When amyloid was detected we performed genetic testing for transthyretin variants (ATTRv), immunofixation electrophoresis in serum and urine for light chains and multidisciplinary evaluation. Results: Thirty consecutive patients were included, 19 women, 11 men, mean age 70 years old (range 42 - 89 years). We identified 3 patients (10%) with amyloid deposits (mean age: 78.6 years, 2 men, 1 woman). Genetic testing for ATTRv and light chains studies were negative. During follow-up: The first patient required aortic valve replacement. The second patient developed progressive cardiac failure with syncopal episodes, atrioventricular block and atrial fibrillation and required a pacemaker and anticoagulation. The third patient had unexplained chronic edemas. The cardiac evaluation in all 3 patients revealed left ventricular hypertrophy and myocardial uptake (Perugini Score > 2) in their nuclear bone scintigraphies with technetium pyrophosphate. Two patients were treated with tafamidis and one patient died due to refractory cardiac insufficiency. Discussion: Our findings underline the importance of investigating amyloidosis in idiopathic CTS. The identification of deposits allows early diagnosis of cardiac amyloidosis leading to timely intervention and treatment.
Atroshi, I. (1999) Prevalence of Carpal Tunnel Syndrome in a General Population. JAMA, 282, 153-158. https://doi.org/10.1001/jama.282.2.153
[3]
Afshar, A., Sohrabi, S., Tabrizi, A., Kazemi-Sufi, S. and Abbasi, A. (2022) Frequency of Amyloid Deposition in Idiopathic Carpal Tunnel Syndrome. Journal of Hand Surgery (European Volume), 47, 768-769. https://doi.org/10.1177/17531934221085542
[4]
Ladefoged, B., Clemmensen, T., Dybro, A., Hartig-Andreasen, C., Kirkeby, L., Gormsen, L.C., et al. (2022) Identification of Wild-Type Transthyretin Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome Surgery (CACTuS). ESC Heart Failure, 10, 234-244. https://doi.org/10.1002/ehf2.14173
[5]
Donnelly, J.P., Hanna, M., Sperry, B.W. and Seitz, W.H. (2019) Carpal Tunnel Syndrome: A Potential Early, Red-Flag Sign of Amyloidosis. The Journal of Hand Surgery, 44, 868-876. https://doi.org/10.1016/j.jhsa.2019.06.016
[6]
Bishop, E., Brown, E.E., Fajardo, J., Barouch, L.A., Judge, D.P. and Halushka, M.K. (2018) Seven Factors Predict a Delayed Diagnosis of Cardiac Amyloidosis. Amyloid, 25, 174-179. https://doi.org/10.1080/13506129.2018.1498782
[7]
Maurer, M.S., Hanna, M., Grogan, M., Dispenzieri, A., Witteles, R., Drachman, B., et al. (2016) Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). Journal of the American College of Cardiology, 68, 161-172. https://doi.org/10.1016/j.jacc.2016.03.596
[8]
Maurer, M.S. and Ruberg, F.L. (2018) Early Diagnosis of Cardiac Amyloidosis by Carpal Tunnel Surgery. Is It All in the Wrist? Journal of the American College of Cardiology, 72, 2051-2053. https://doi.org/10.1016/j.jacc.2018.09.003
[9]
Jablecki, C.K., Andary, M.T., Floeter, M.K., Miller, R.G., Quartly, C.A., Vennix, M.J., et al. (2002) Practice Parameter: Electrodiagnostic Studies in Carpal Tunnel Syndrome [RETIRED]. Report of the American Association of Electro-Diagnostic Medicine, American Academy of Neurology and the American Academy of Physical Medicine and Rehabilitation. Neurology, 58, 1589-1592. https://doi.org/10.1212/wnl.58.11.1589
[10]
Perugini, E., Guidalotti, P.L., Salvi, F., Cooke, R.M.T., Pettinato, C., Riva, L., et al. (2005) Noninvasive Etiologic Diagnosis of Cardiac Amyloidosis Using 99m Tc-3,3-Diphosphono-1,2-Propanodicarboxylic Acid Scintigraphy. Journal of the American College of Cardiology, 46, 1076-1084. https://doi.org/10.1016/j.jacc.2005.05.073
[11]
Gioeva, Z., Urban, P., Rüdiger Meliss, R., Haag, J., Axmann, H., Siebert, F., et al. (2012) ATTR Amyloid in the Carpal Tunnel Ligament Is Frequently of Wildtype Transthyretin Origin. Amyloid, 20, 1-6. https://doi.org/10.3109/13506129.2012.750604
[12]
Abe, R., Katoh, N., Takahashi, Y., Takasone, K., Yoshinaga, T., Yazaki, M., et al. (2020) Distribution of Amyloidosis Subtypes Based on Tissue Biopsy Site—Consecutive Analysis of 729 Patients at a Single Amyloidosis Center in Japan. Pathology International, 71, 70-79. https://doi.org/10.1111/pin.13041
[13]
Aldinc, E., Campbell, C., Gustafsson, F., Beveridge, A., Macey, R., Marr, L., et al. (2023) Musculoskeletal Manifestations Associated with Transthyretin-Mediated (ATTR) Amyloidosis: A Systematic Review. BMC Musculoskeletal Disorders, 24, Article No. 751. https://doi.org/10.1186/s12891-023-06853-5
[14]
Yamada, T., Takashio, S., Arima, Y., Nishi, M., Morioka, M., Hirakawa, K., et al. (2020) Clinical Characteristics and Natural History of Wild-Type Transthyretin Amyloid Cardiomyopathy in Japan. ESC Heart Failure, 7, 2829-2837. https://doi.org/10.1002/ehf2.12884
[15]
Nakagawa, M., Sekijima, Y., Yazaki, M., Tojo, K., Yoshinaga, T., Doden, T., et al. (2016) Carpal Tunnel Syndrome: A Common Initial Symptom of Systemic Wild-Type ATTR (ATTRwt) Amyloidosis. Amyloid, 23, 58-63. https://doi.org/10.3109/13506129.2015.1135792
[16]
Kyle, R.A., Gertz, M.A. and Linke, R.P. (1992) Amyloid Localized to Tenosynovium at Carpal Tunnel Release: Immunohistochemical Identification of Amyloid Type. American Journal of Clinical Pathology, 97, 250-253. https://doi.org/10.1093/ajcp/97.2.250
Tojo, K., Tsuchiya-Suzuki, A., Sekijima, Y., Morita, H., Sumita, N. and Ikeda, S. (2010) Upper Limb Neuropathy Such as Carpal Tunnel Syndrome as an Initial Manifestation of ATTR Val30met Familial Amyloid Polyneuropathy. Amyloid, 17, 32-35. https://doi.org/10.3109/13506121003619369
[19]
Sekijima, Y., Uchiyama, S., Tojo, K., Sano, K., Shimizu, Y., Imaeda, T., et al. (2011) High Prevalence of Wild-Type Transthyretin Deposition in Patients with Idiopathic Carpal Tunnel Syndrome: A Common Cause of Carpal Tunnel Syndrome in the Elderly. Human Pathology, 42, 1785-1791. https://doi.org/10.1016/j.humpath.2011.03.004
[20]
Uchiyama, S., Sekijima, Y., Tojo, K., Sano, K., Imaeda, T., Moriizumi, T., et al. (2014) Effect of Synovial Transthyretin Amyloid Deposition on Preoperative Symptoms and Postoperative Recovery of Median Nerve Function among Patients with Idiopathic Carpal Tunnel Syndrome. Journal of Orthopaedic Science, 19, 913-919. https://doi.org/10.1007/s00776-014-0635-y
[21]
Nakagawa, M., Sekijima, Y., Yazaki, M., Tojo, K., Yoshinaga, T., Doden, T., et al. (2016) Carpal Tunnel Syndrome: A Common Initial Symptom of Systemic Wild-Type ATTR (attrwt) Amyloidosis. Amyloid, 23, 58-63. https://doi.org/10.3109/13506129.2015.1135792
[22]
Sperry, B.W., Reyes, B.A., Ikram, A., Donnelly, J.P., Phelan, D., Jaber, W.A., et al. (2018) Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. Journal of the American College of Cardiology, 72, 2040-2050. https://doi.org/10.1016/j.jacc.2018.07.092
[23]
Scott, K.L., Conley, C.R. and Renfree, K.J. (2019) Histopathologic Evaluation of Flexor Tenosynovium in Recurrent Carpal Tunnel Syndrome. Plastic & Reconstructive Surgery, 143, 169-175. https://doi.org/10.1097/prs.0000000000005090
[24]
Milandri, A., Farioli, A., Gagliardi, C., Longhi, S., Salvi, F., Curti, S., et al. (2020) Carpal Tunnel Syndrome in Cardiac Amyloidosis: Implications for Early Diagnosis and Prognostic Role across the Spectrum of Aetiologies. European Journal of Heart Failure, 22, 507-515. https://doi.org/10.1002/ejhf.1742
[25]
Bäcker, H.C., Galle, S.E., Lentzsch, S., Freibott, C.E., Shoap, S., Strauch, R.J., et al. (2021) Flexor Tenosynovectomy in Carpal Tunnel Syndrome as a Screening Tool for Early Diagnosis of Amyloidosis. Irish Journal of Medical Science (1971-), 191, 2427-2430. https://doi.org/10.1007/s11845-021-02832-8
[26]
Vidal-Perez, R., Vázquez-García, R., Barge-Caballero, G., Bouzas-Mosquera, A., Soler-Fernandez, R., Larrañaga-Moreira, J.M., et al. (2020) Diagnostic and Prognostic Value of Cardiac Imaging in Amyloidosis. World Journal of Cardiology, 12, 599-614. https://doi.org/10.4330/wjc.v12.i12.599
[27]
Fosbøl, E.L., Rørth, R., Leicht, B.P., Schou, M., Maurer, M.S., Kristensen, S.L., et al. (2019) Association of Carpal Tunnel Syndrome with Amyloidosis, Heart Failure, and Adverse Cardiovascular Outcomes. Journal of the American College of Cardiology, 74, 15-23. https://doi.org/10.1016/j.jacc.2019.04.054
[28]
Boyle, R., Sharan, J., Schwartz, G. (2021) Carpal Tunnel Syndrome in Transthyretin Amyloidosis: Implications and Protocols for Diagnosis and Treatment. Cureus, 13, e14546.
[29]
Sperry, B.W., Jones, B.M., Vranian, M.N., Hanna, M. and Jaber, W.A. (2016) Recognizing Transthyretin Cardiac Amyloidosis in Patients with Aortic Stenosis: Impact on Prognosis. JACC: Cardiovascular Imaging, 9, 904-906. https://doi.org/10.1016/j.jcmg.2015.10.023
[30]
Zegri-Reiriz, I., de Haro-del Moral, F.J., Dominguez, F., Salas, C., de la Cuadra, P., Plaza, A., et al. (2019) Prevalence of Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome. Journal of Cardiovascular Translational Research, 12, 507-513. https://doi.org/10.1007/s12265-019-09895-0
[31]
Kleefeld, F., Scherret, E., Knebel, F., Messroghli, D., Heidecker, B., Wetz, C., et al. (2022) Same Same, but Different? The Neurological Presentation of Wildtype Transthyretin (attrwt) Amyloidosis. Amyloid, 29, 92-101. https://doi.org/10.1080/13506129.2021.2014448
[32]
Adams, D., Sekijima, Y., Conceição, I., Waddington-Cruz, M., Polydefkis, M., Echaniz-Laguna, A., et al. (2023) Hereditary Transthyretin Amyloid Neuropathies: Advances in Pathophysiology, Biomarkers, and Treatment. The Lancet Neurology, 22, 1061-1074. https://doi.org/10.1016/s1474-4422(23)00334-4
[33]
Gillmore, J.D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M.L., et al. (2021) Crispr-cas9 in Vivo Gene Editing for Transthyretin Amyloidosis. New England Journal of Medicine, 385, 493-502. https://doi.org/10.1056/nejmoa2107454
[34]
Coelho, T., Maia, L.F., Martins da Silva, A., Waddington Cruz, M., Planté-Bordeneuve, V., Lozeron, P., et al. (2012) Tafamidis for Transthyretin Familial Amyloid Polyneuropathy: A Randomized, Controlled Trial. Neurology, 79, 785-792. https://doi.org/10.1212/wnl.0b013e3182661eb1
[35]
Maurer, M.S., Schwartz, J.H., Gundapaneni, B., Elliott, P.M., Merlini, G., Waddington-Cruz, M., et al. (2018) Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. New England Journal of Medicine, 379, 1007-1016. https://doi.org/10.1056/nejmoa1805689