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Rujeedawa T, Mowforth OD, Davies BM, Yang C, Nouri A, Francis JJ, Aarabi B, Kwon BK, Harrop J, Wilson JR, Martin AR, Rahimi-Movaghar V, Guest JD, Fehlings MG, Kotter MR. Degenerative Thoracic Myelopathy: A Scoping Review of Epidemiology, Genetics, and Pathogenesis. Global Spine J 2024; 14:1664-1677. [PMID: 38146739 PMCID: PMC11394495 DOI: 10.1177/21925682231224768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2023] Open
Abstract
STUDY DESIGN Literature Review. OBJECTIVE Myelopathy affecting the thoracic spinal cord can arise secondary to several aetiologies which have similar presentation and management. Consequently, there are many uncertainties in this area, including optimal terminology and definitions. Recent collaborative cervical spinal research has led to the proposal and subsequent community adoption of the name degenerative cervical myelopathy(DCM), which has facilitated the establishment of internationally-agreed research priorities for DCM. We put forward the case for the introduction of the term degenerative thoracic myelopathy(DTM) and degenerative spinal myelopathy(DSM) as an umbrella term for both DCM and DTM. METHODS Following PRISMA guidelines, a systematic literature search was performed to identify degenerative thoracic myelopathy literature in Embase and MEDLINE. RESULTS Conditions encompassed within DTM include thoracic spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, calcification of ligaments, hypertrophy of ligaments, degenerative disc disease, thoracic osteoarthritis, intervertebral disc herniation, and posterior osteophytosis. The classic presentation includes girdle pain, gait disturbance, leg weakness, sensory disturbance, and bladder or bowel dysfunction, often with associated back pain. Surgical management is typically favoured with post-surgical outcomes dependent on many factors, including the causative pathology, and presence of additional stenosis. CONCLUSION The clinical entities encompassed by the term DTM are interrelated, can manifest concurrently, and present similarly. Building on the consensus adoption of DCM in the cervical spine and the recent proposal of degenerative cervical radiculopathy(DCR), extending this common nomenclature framework to the terms degenerative spinal myelopathy and degenerative thoracic myelopathy will help improve recognition and communication.
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Affiliation(s)
- Tanzil Rujeedawa
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Oliver D. Mowforth
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Benjamin M. Davies
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Cylene Yang
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Aria Nouri
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland
| | - Jibin J. Francis
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | | | - Brian K. Kwon
- Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - James Harrop
- Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | | | - Allan R. Martin
- Department of Neurosurgery, University of California Davis, Sacramento, CA, USA
| | - Vafa Rahimi-Movaghar
- Department of Neurosurgery, Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - James D. Guest
- Department of Neurosurgery and The Miami Project to Cure Paralysis, The Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Michael G. Fehlings
- Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Mark R. Kotter
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
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Liu F, Zhao Y, Pei Y, Lian F, Lin H. Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance. Cell Commun Signal 2024; 22:159. [PMID: 38439078 PMCID: PMC10910758 DOI: 10.1186/s12964-024-01533-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 02/13/2024] [Indexed: 03/06/2024] Open
Abstract
Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD-like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.
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Affiliation(s)
- Fangzhou Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yike Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yiran Pei
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Fengyu Lian
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Hui Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
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Kato H, Braddock DT, Ito N. Genetics of Diffuse Idiopathic Skeletal Hyperostosis and Ossification of the Spinal Ligaments. Curr Osteoporos Rep 2023; 21:552-566. [PMID: 37530996 PMCID: PMC10543536 DOI: 10.1007/s11914-023-00814-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2023] [Indexed: 08/03/2023]
Abstract
PURPOSE OF REVIEW The study aims to provide updated information on the genetic factors associated with the diagnoses 'Diffuse Idiopathic Skeletal Hyperostosis' (DISH), 'Ossification of the Posterior Longitudinal Ligament' (OPLL), and in patients with spinal ligament ossification. RECENT FINDINGS Recent studies have advanced our knowledge of genetic factors associated with DISH, OPLL, and other spinal ossification (ossification of the anterior longitudinal ligament [OALL] and the yellow ligament [OYL]). Several case studies of individuals afflicted with monogenic disorders, such as X-linked hypophosphatemia (XLH), demonstrate the strong association of fibroblast growth factor 23-related hypophosphatemia with OPLL, suggesting that pathogenic variants in PHEX, ENPP1, and DMP1 are associated with FGF23-phosphate wasting phenotype and strong genetic factors placing patients at risk for OPLL. Moreover, emerging evidence demonstrates that heterozygous and compound heterozygous ENPP1 pathogenic variants inducing 'Autosomal Recessive Hypophosphatemic Rickets Type 2' (ARHR2) also place patients at risk for DISH and OPLL, possibly due to the loss of inhibitory plasma pyrophosphate (PPi) which suppresses ectopic calcification and enthesis mineralization. Our findings emphasize the importance of genetic and plasma biomarker screening in the clinical evaluation of DISH and OPLL patients, with plasma PPi constituting an important new biomarker for the identification of DISH and OPLL patients whose disease course may be responsive to ENPP1 enzyme therapy, now in clinical trials for rare calcification disorders.
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Affiliation(s)
- Hajime Kato
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
- Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan
| | | | - Nobuaki Ito
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
- Osteoporosis Center, The University of Tokyo Hospital, Tokyo, Japan.
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Yoshizawa M, Nagai K, Asano S, Hori T, Takagawa K, Shimatsu A. Lumbar Spinal Canal Stenosis in Acromegaly: A Case Report and Literature Review. Intern Med 2022. [PMID: 36476548 PMCID: PMC10400399 DOI: 10.2169/internalmedicine.0763-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
A 60-year-old Japanese man diagnosed with acromegaly at 28 years old had difficulty walking due to worsening back pain. He had been treated with somatostatin analog since 57 years old, but his pain and numbness continued to worsen. Lumbar magnetic resonance imaging showed disc bulging at L3/4 and 4/5, and he was diagnosed with lumbar spinal canal stenosis due to hypertrophy of the yellow ligament. Patients with acromegaly may complain of osteoarthropathy, so we must pay attention to the symptoms of spinal canal stenosis in collaboration with orthopedic specialists.
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Affiliation(s)
- Miyako Yoshizawa
- Department of Endocrinology and Metabolism, Kurobe City Hospital, Japan
| | - Kosuke Nagai
- Department of Endocrinology and Metabolism, Kurobe City Hospital, Japan
| | - Shoko Asano
- Department of Endocrinology and Metabolism, Kurobe City Hospital, Japan
| | - Takeshi Hori
- Department of Orthopedics, Kurobe City Hospital, Japan
| | - Kiyoshi Takagawa
- Department of Pathological Diagnosis, Kurobe City Hospital, Japan
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Hoshino Y, Hidaka N, Kato H, Koga M, Taniguchi Y, Kobayashi H, Nangaku M, Makita N, Ito N. Incidence of ossification of the spinal ligaments in acromegaly patients. Bone Rep 2022; 17:101628. [PMID: 36299702 PMCID: PMC9589022 DOI: 10.1016/j.bonr.2022.101628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/10/2022] [Accepted: 10/15/2022] [Indexed: 11/05/2022] Open
Abstract
Some previous case reports have implied a relationship between acromegaly and ossification of the spinal ligaments. However, there have been no reports of a case series exploring the incidence of ossification of the spinal ligaments in patients with acromegaly. To this end, computed tomography (CT) of the spine in 10 consecutive patients with acromegaly was examined in this study. Five out of 10 patients had ossification of the spinal ligaments. Among them, two patients had ossification of the posterior longitudinal ligament (OPLL), which was noticeably higher than the prevalence of OPLL in the general adult population (1.9–4.3 %). Body mass index was significantly higher in the group with spinal ligament ossification (p = 0.03), but there were no significant differences in age, sex, serum phosphate, albumin-adjusted calcium, growth hormone (GH), standard deviation of insulin-like growth factor-1 (IGF-1), or the incidence of diabetes mellitus between the groups with or without ossification of the spinal ligaments. The ossification index (OS index) was used to determine the severity of spinal ligament ossification, and there were no significant correlations between the OS index and GH or IGF-1 (p = 0.51 and 0.75, respectively). This study was the first to report a high prevalence of spinal ossification in patients with acromegaly. In conclusion, this study suggested a possible association between acromegaly and ossification of the spinal ligaments, although the number of patients was insufficient to draw a conclusion. Acromegaly patients should be tested to confirm, or rule out, spinal ossification, and further studies to clarify the underlying mechanism of spinal ossification in acromegaly patients are warranted.
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Affiliation(s)
- Yoshitomo Hoshino
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Naoko Hidaka
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Hajime Kato
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Minae Koga
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Yuki Taniguchi
- Department of Orthopedic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Hiroshi Kobayashi
- Department of Orthopedic Surgery, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Noriko Makita
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Nobuaki Ito
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo 113-8655, Japan
- Corresponding author at: Division of Nephrology and Endocrinology, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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