Neurogenic Heterotopic Ossification Research Articles

Interleukin-6 Does Not Contribute to Neurogenic Heterotopic Ossification Pathogenesis

Interleukin-6 Does Not Contribute to Neurogenic Heterotopic Ossification Pathogenesis

A rare case of extensive neurogenic heterotopic ossification: a case report

IntroductionNeurogenic Heterotopic ossification (NHO) is a potential sequalae and a detrimental complication following neurological insult. It is characterized by formation of localized gradually progressive, peri-articular lamellar bone formation in extra-skeletal tissues. We would like to report a rare case of heterotopic ossification involving all 4 limbs, in which we tried to restore joint mobility to improve his functional status so that he could perform his daily tasks.Case presentationWe present a case of a 33-year-old bed ridden male, diagnosed with NHO involving all 4 limbs (bilateral hip, right knee, right shoulder, left elbow). The patient had a crippled posture, significant pain and impaired range of motion hampering movement of all four limbs which prevented him from lying down supine, sitting, walking and performing activities of daily living. After three surgeries, the patient achieved wheelchair mobilization and upright posture with the assistance of calipers.ConclusionThe management of NHO requires a multidisciplinary approach involving orthopaedic surgeons, neurologists & rehabilitation specialists. Prognosis of NHO depends on factors such as extent of ossification, underlying neurological condition & patients overall health.

Neurogenic heterotopic ossification of the hip: Magnetic resonance imaging versus computed tomography for pre-surgical assessment

PurposeNeurogenic heterotopic ossification (NHO) of the hip is a frequent complication of spinal cord injuries, often requiring surgical management. Pre-surgical imaging assessment is essential, usually with computed tomography (CT)-scan. We aimed to compare magnetic resonance imaging (MRI) and CT for pre-surgical imaging assessment of the NHO, particularly for their relationships with vessels and nerves. MethodThis prospective study included consecutive patients who underwent surgery for NHO from July 2019 to April 2022. All patients had CT angiography and MRI including Zero Echo Time and TRICKS sequences. Radiologists used standardized reports for CT and MRI to evaluate NHO and their features, bone mineralization, and relation to the arteries, veins and nerves. Agreement between pre-surgical CT and MRI was evaluated. ResultsTwenty-four patients (mean age: 53.5 ± 12.2 years) were included, among which 7 had bilateral NHO (31 hips). NHO were anterior in 15/31 hips (48 %), multifragmented in 25/31 hips (81 %). Mild and significant demineralization was most frequent. Gutter and tunnel were reported in 11.1 % of the arteries. Nerves were more often identified in MRI than in CT-scan. Agreement coefficients between CT and MRI were excellent for NHO location (0.95) and implantation (0.92), good for fragmentation (0.70), contact with joint capsule (0.66), bone mineralization (0.74), and relation to arteries (0.85), veins (0.76), sciatic nerve (0.7) and moderate for femoral nerve (0.47). ConclusionMRI exhibited a good agreement with CT for pre-surgical assessment of NHO of the hip, especially to evaluate their relationships with the arteries, veins and sciatic nerve. Femoral nerves were more often identified in MRI than in CT-scan.

The Role of Neuromodulation and Potential Mechanism in Regulating Heterotopic Ossification.

Heterotopic ossification (HO) is a pathological process characterized by the aberrant formation of bone in muscles and soft tissues. It is commonly triggered by traumatic brain injury, spinal cord injury, and burns. Despite a wide range of evidence underscoring the significance of neurogenic signals in proper bone remodeling, a clear understanding of HO induced by nerve injury remains rudimentary. Recent studies suggest that injury to the nervous system can activate various signaling pathways, such as TGF-β, leading to neurogenic HO through the release of neurotrophins. These pathophysiological changes lay a robust groundwork for the prevention and treatment of HO. In this review, we collected evidence to elucidate the mechanisms underlying the pathogenesis of HO related to nerve injury, aiming to enhance our understanding of how neurological repair processes can culminate in HO.

Neurogenic Heterotopic Ossification in the Non-paretic Limb: A Case Report

Heterotopic Ossification (HO) is a pathological condition characterized by the formation of bone outside the skeletal tissues, which is usually caused by either traumatic or neurogenic factors. Neurogenic HO is a rare complication that can occur after a cerebral or spinal injury. The condition can manifest with a range of symptoms and is often challenging to diagnose clinically. Although various imaging techniques have been employed to diagnose HO, clinicians and radiologists may occasionally encounter radiological features of HO that can resemble other disease conditions. In this report, we present a unique case of neurogenic HO that developed in the nonparetic limb of a patient with Traumatic Brain Injury (TBI).

Interorgan communication in neurogenic heterotopic ossification: the role of brain-derived extracellular vesicles

Brain-derived extracellular vesicles participate in interorgan communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome-related proteins encapsulated in brain-derived extracellular vesicles can cross the blood‒brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction, such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification induced by combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon revealed the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlights the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offers a potential strategy for preventing neurogenic heterotopic ossification after traumatic brain injury.Brain-derived extracellular vesicles (BEVs) are released after traumatic brain injury. These BEVs contain pathogens and participate in interorgan communication to initiate secondary injury in distal tissues. After achillotenotomy, the phagocytosis of BEVs by fibroblasts induces pyroptosis, which is a highly inflammatory form of lytic programmed cell death, in the injured tendon. Fibroblast pyroptosis leads to an increase in calcium and phosphorus concentrations and creates a microenvironment that promotes osteogenesis. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk suppressed fibroblast pyroptosis and effectively prevented the onset of heterotopic ossification after neuronal injury. The use of a pyroptosis inhibitor represents a potential strategy for the treatment of neurogenic heterotopic ossification.

Medical comorbidities in patients with prolonged disorder of consciousness: A narrative review.

A few studies specifically addressed medical comorbidities (MCs) in patients with severe acquired traumatic or non-traumatic brain injury and prolonged disorders of consciousness (pDoC; i.e., patients in vegetative state/unresponsive wakefulness syndrome, VS/UWS, or in minimally conscious state, MCS). To provide an overview on incidence of MCs in patients with pDoC. Narrative review on most impacting MCs in patients with pDoC, both those directly related to brain damage (epilepsy, neurosurgical complications, spasticity, paroxysmal sympathetic hyperactivity, PSH), and those related to severe disability and prolonged immobility (respiratory comorbidities, endocrine disorders, metabolic abnormalities, heterotopic ossifications). Patients with pDoC are at high risk to develop at least one MC. Moderate or severe respiratory and musculoskeletal comorbidities are the most common MCs. Epilepsy and PSH seem to be more frequent in patients in VS/UWS compared to patients in MCS, likely because of higher severity in the brain damage in VS. Endocrine metabolic, PSH and respiratory complications are less frequent in traumatic etiology, whereas neurogenic heterotopic ossifications are more frequent in traumatic etiology. Spasticity did not significantly differ between VS/UWS and MCS and in the three etiologies. MCs are associated with higher mortality rates, worse clinical improvement and can impact accuracy in the clinical diagnosis. The frequent occurrence of several MCs requires a specialized rehabilitative setting with high level of multidisciplinary medical expertise to prevent, appropriately recognize and treat them. Comprehensive rehabilitation could avoid possible progression to more serious complications that can negatively impact clinical outcomes.

Neurogenic heterotopic ossification: A review. Part 2

BACKGROUND: Neurogenic heterotopic ossification is characterized by the formation of bone tissue in the soft tissues of the body caused by severe brain or spinal cord injury of various etiologies. In neurogenic heterotopic ossification, the hip joints are most often affected.
 AIM: To analyze publications on the instrumental diagnosis, surgical and nonsurgical methods of treatment, and prevention of neurogenic heterotopic ossification of the hip joints.
 MATERIALS AND METHODS: In the second part of our review, we analyzed the literature on modern diagnostics, surgical and conservative methods of treatment, prevention of the formation and recurrence of neurogenic heterotopic ossification of the hip joints. Data were searched in scientific literature databases, namely, PubMed, Google Scholar, Cochrane Library, CrossRef, and eLibrary, without language restrictions.
 RESULTS: Modern diagnostic methods allow the screening of hip neurogenic heterotopic ossification in patients at high risk of their formation, with further verification of the diagnosis by computed tomography or magnetic resonance imaging. Despite the lack of consensus on the timing of hip neurogenic heterotopic ossification removal at present, surgical treatment is the most effective method, which allows the removal or reduction of the volume of neurogenic heterotopic ossification. Most cases require controlling the pain syndrome and improving the quality of life of the patients. Despite the common etiologic factor (damage to the central nervous system), nonsurgical methods of the prevention and treatment of patients with neurogenic heterotopic ossification of the hip joints have different effectiveness because of spinal cord injury, cerebral trauma, and cerebral palsy.
 CONCLUSIONS: Randomized controlled trials will help to establish the efficacy of conservative treatment methods to prevent the formation and recurrence of hip joint neurogenic heterotopic ossification, taking into account the cause of central nervous system lesions.

Surgical Resection of Neurogenic Heterotopic Ossification around Hip Joint in Stroke Patients: A Safety and Outcome Report.

Resection remains the most reliable treatment for established heterotopic ossification, despite questions regarding its effectiveness due to the potential for complications. This study evaluated the clinical outcomes and complications of neurogenic heterotopic ossification (NHO) resection in stroke patients' ankylosed hips. We retrospectively analyzed nine hip NHO resections performed on seven patients from 2010 to 2018. The pre- and postoperative range of motion of the operated hip were compared. Analysis of postoperative complications, including infection, recurrence, iatrogenic fracture, and neurovascular injury was performed. The mean operative time was 132.78±21.08 minutes, with a mean hemoglobin drop of 3.06±0.82 g/dL within the first postoperative week. The mean duration of postoperative follow-up was 52.08±28.72 months for all patients. Postoperative range of motion showed improvement from preoperative. Flexion and external rotation (mean, 58.89±30.60° and 16.67±18.03°, respectively) showed the greatest gain of motion of the operated hip joint. Postoperative infections resolved in two cases through surgical debridement, and one case required conversion to total hip arthroplasty due to instability. There were no recurrences, iatrogenic fractures, or neurovascular injuries. Resection is a beneficial intervention for restoring the functional range of motion of the hip in order to improve the quality of life for patients with NHO and neurological disorders. We recommend performance of a minimal resection to achieve a targeted functional arc of motion in order to minimize the risk of postoperative complications.

Bacterial Lipopolysaccharides Exacerbate Neurogenic Heterotopic Ossification Development.

Neurogenic heterotopic ossifications (NHO) are heterotopic bones that develop in periarticular muscles after severe central nervous system (CNS) injuries. Several retrospective studies have shown that NHO prevalence is higher in patients who suffer concomitant infections. However, it is unclear whether these infections directly contribute to NHO development or reflect the immunodepression observed in patients with CNS injury. Using our mouse model of NHO induced by spinal cord injury (SCI) between vertebrae T11 to T13 , we demonstrate that lipopolysaccharides (LPS) from gram-negative bacteria exacerbate NHO development in a toll-like receptor-4 (TLR4)-dependent manner, signaling through the TIR-domain-containing adapter-inducing interferon-β (TRIF/TICAM1) adaptor rather than the myeloid differentiation primary response-88 (MYD88) adaptor. We find that T11 to T13 SCI did not significantly alter intestinal integrity nor cause intestinal bacteria translocation or endotoxemia, suggesting that NHO development is not driven by endotoxins from the gut in this model of SCI-induced NHO. Relevant to the human pathology, LPS increased expression of osteoblast markers in cultures of human fibro-adipogenic progenitors isolated from muscles surrounding NHO biopsies. In a case-control retrospective study in patients with traumatic brain injuries, infections with gram-negative Pseudomonas species were significantly associated with NHO development. Together these data suggest a functional association between gram-negative bacterial infections and NHO development and highlights infection management as a key consideration to avoid NHO development in patients. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Neurogenic heterotopic ossification: A review. Part 1

BACKGROUND: Heterotopic ossification is the formation of bone tissues in the soft tissues of the body. A distinct form of heterotopic ossification is neurogenic, that is, resulting from severe injury to the brain or spinal cord of different genesis. Neurogenic heterotopic ossification is a complex multifactorial process of differentiated bone formation in the paraarticular soft tissues of large joints. Heterotopic ossification leads to the formation of persistent contractures and ankylosis, which cause severe disability and complicate rehabilitation.
 AIM: To analyze publications dealing with various aspects of neurogenic heterotopic ossification.
 MATERIALS AND METHODS: In the first part of our review, we present the results of the literature analysis on the epidemiology, risk factors, pathogenesis, and clinic and laboratory diagnosis of neurogenic heterotopic ossification. Scientific literature databases PubMed, Google Scholar, Cochrane Library, Crossref, and eLibrary were searched for without language limitations.
 RESULTS: Current literature data on heterotopic ossification in patients with central nervous system pathologies are presented. Topical questions of etiology, risk factors, pathogenesis, and clinic and laboratory diagnostics of this pathological process are highlighted.
 CONCLUSIONS: Understanding the risk factors of heterotopic ossification development and their prevention in the context of the modern knowledge of heterotopic ossification pathogenesis may help reduce the incidence of heterotopic ossification in patients with severe central nervous system injury.

Spinal cord injury dysregulates fibro-adipogenic progenitors miRNAs signaling to promote neurogenic heterotopic ossifications

Neurogenic heterotopic ossifications are intramuscular bone formations developing following central nervous system injury. The pathophysiology is poorly understood and current treatments for this debilitating condition remain unsatisfying. Here we explored the role of miRNAs in a clinically relevant mouse model that combines muscle and spinal cord injury, and in patients’ cells. We found an osteo-suppressive miRNAs response in injured muscle that was hindered when the spinal cord injury was associated. In isolated fibro-adipogenic progenitors from damaged muscle (cells at the origin of ossification), spinal cord injury induced a downregulation of osteo-suppressive miRNAs while osteogenic markers were overexpressed. The overexpression of selected miRNAs in patient’s fibro-adipogenic progenitors inhibited mineralization and osteo-chondrogenic markers in vitro. Altogether, we highlighted an osteo-suppressive mechanism involving multiple miRNAs in response to muscle injury that prevents osteogenic commitment which is ablated by the neurologic lesion in heterotopic ossification pathogenesis. This provides new research hypotheses for preventive treatments.

Treating Neurogenic Heterotopic Ossification around a Femur Following Paraplegia after an Open Surgery for Thoracoabdominal Aortic Aneurysm

症例は生来著患のない59歳男性．検診で高血圧症を指摘され近医を受診した．精査のCT検査でCrawford II型相当の胸腹部大動脈瘤が指摘され，精査加療目的に当科紹介となった．手術侵襲を低減させる目的で，一期目に全弓部置換術，二期目に胸部ステントグラフト内挿術，三期目にIII型相当の胸腹部置換術を行う計画的分割手術を施行した．三期目の胸腹部置換術後に対麻痺を認め種々の支持療法にても改善を得られず，下肢麻痺および膀胱直腸障害が残存した．リハビリ施行ののち術後67日目に回復期病院に転院となった．転院後褥瘡形成や反復する尿路感染を認め抗生剤加療が開始されていたが改善に乏しく，またCT上両側大腿骨周囲に血腫形成と異所性骨化を認め，集学的治療が必要と判断され転院後約4カ月で当院へ再入院となった．臨床経過および画像所見から術後対麻痺に合併したNeurogenic heterotopic ossificationと診断した．褥瘡および尿路感染に対する抗生剤加療を継続すると同時に，強度に留意しながらリハビリを継続することで異所性骨化の増悪を認めず経過した．入院後44日目に皮弁を施行し，79日目に再転院となった．Neurogenic heterotopic ossification自体の病態生理は不明な点が多く治療法も定まったものはないが，術後対麻痺を合併した症例においてはNeurogenic heterotopic ossificationが生じるリスクにより術後のリハビリ自体が制限され，手術侵襲からの回復やADL維持を困難にさせる可能性が考えられた．リスク因子に対する適切な予防マネージメントを講じ，早期発見に務めることが重要と考えられた．

Interesting Findings in 68 Ga-FAPI-46 PET/CT Imaging in a Patient With Glioblastoma Multiforme.

A 55-year-old disabled man with glioblastoma multiforme was referred to us for fibroblast activation protein inhibitor (FAPI) PET/CT imaging. 68 Ga-DOTA-FAPI-46 scan revealed uptake in the primary tumor and unexpected uptakes in soft tissue, especially in periarticular regions. These latter foci were compatible with calcifications on the CT. One in the breast was compatible with fibrotic tissue, but 2 other foci, in the rectus abdominis and gallbladder wall, could not be correlated with the CT findings. In Neurogenic heterotopic ossification, hypoxia-associated oxidative stress results in the metaplastic transformation of fibroblasts. Abnormal differentiation of fibroblasts in neurogenic heterotopic ossification before ossification could explain radiolabeled FAPI avidity in the mentioned areas.

A rare femoral heterotopic bone formation in a 14th-19th century female skeleton from Constância (Portugal)

ObjectiveThis paper aims to: (1) document a rare femoral heterotopic ossification (HO), and (2) discuss its aetiology and impact on the individual's locomotion and daily living activities. MaterialsAdult female skeleton (SG.14-SK.7) from the village of Constância (Portugal), and dated from the 14th-19th centuries CE. MethodsThe biological profile and the macroscopic analysis of the bone changes were assessed using standardized methods. ResultsThe macroscopic analysis revealed a large bony mass (8 cm length) located immediately inferior to the small trochanter of the right femur. The lesion exhibited a compact, tubular appearance located at the site of attachment of the pectineus muscle. No signs of bone fracture were observed. ConclusionsThe morphology of the SG.14-SK.7 femoral lesion is compatible with a probable case of myositis ossificans traumatica (MOT), secondary to acute trauma of the pectineus muscle. The underlying trauma episode, such as random accidental and/or occupation-related injury, is unknown. However, it is highly possible that this self-limiting condition significantly impaired the individual's daily life and mobility. SignificanceEvidence of severe acute muscle trauma is a rare finding compared with HO secondary to bone trauma and other minor muscle injuries. Moreover, no cases of MOT affecting the pectineus muscle have been reported in the paleopathological literature to date. LimitationsAlthough unlikely, a case of neurogenic or burn-related HO cannot be completely disregarded. It was not possible to undertake radiography as part of this study. Suggestions for further researchThe use of imaging techniques to complement the paleopathological description is advised.

Preoperative Arterial Embolization for Heterotopic Ossification of the Hip

PurposeTo investigate the efficacy and safety of preoperative arterial embolization for neurogenic heterotopic ossification (NHO) of the hip. Materials and MethodsThis single-center retrospective study reviewed outcomes in 16 consecutive patients who had surgical resection of NHO of the hip: 8 of whom underwent preoperative arterial embolization and 8 of whom did not. Both patient cohorts had similar baseline characteristics. A mean of 2.62 ± 1.9 arteries per patient, including the gluteal, lateral circumflex femoral, and deep circumflex iliac branches, were embolized using an n-butyl cyanoacrylate (NBCA)–ethiodized oil mixture. Data from both cohorts regarding intraoperative blood loss, volume of blood transfused, complications, and duration of hospitalization were compared. ResultsA mean of 2.6 ± 1.9 arteries were embolized with NBCA–ethiodized oil, mainly the gluteal arteries, lateral circumflex femoral artery, and deep circumflex iliac artery. In the embolization group, mean intraoperative blood loss was 875 mL ± 320, mean number of units of blood used was 0.5 ± 0.7, and mean number of days of hospitalization was 6.4 days ± 1.6. In the control group, mean intraoperative blood loss was 1,350 mL ± 120, mean number of units of blood used was 2 ± 1.1, and average number of days of hospitalization was 11.5 days ± 1.4. The embolization group had a mean reduction in blood loss of 40.7% (P = 0.035), reduction in units of blood administered of 75% (P = 0.021), and reduction in days of hospitalization of 44.7% (P = 0.014). No procedural complications were recorded. ConclusionsPreoperative arterial embolization is effective and safe in reducing intraoperative blood loss, number of hospitalization days, and need for blood transfusions in surgical resection of NHO of the hip.

Effectiveness of Prophylactic Interventions in Neurogenic Heterotopic Ossification (NHO): A Systematic Review.

Neurogenic heterotopic ossification (NHO) is the formation of mature lamellar bone in peri-articular tissues following a neurological insult, most commonly traumatic brain injury (TBI) or spinal cord injury (SCI). NHO is a debilitating condition associated with significant morbidity and reduced quality of life. However, its pathophysiology remains poorly understood. While surgery is the mainstay of treatment once NHO has been diagnosed, prophylactic options are limited and not well studied. This review aimed to determine the efficacy of various interventions used in the primary prevention of NHO. We conducted an electronic literature search using five databases (PubMed, Embase, ScienceDirect, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL)) for records published until April 10, 2022. We identified 2,610 potentially eligible records across all databases. Nine reports met our eligibility criteria and were included in this review. Four were clinical trials (three randomized control trials, one nonrandomized trial), four were observational studies, and one was a systematic review/meta-analysis. The medications/interventions used included: warfarin, pulse low-intensity electromagnetic field therapy (PLIMF), bisphosphonates, and nonsteroidal anti-inflammatory drugs (NSAIDs). We did not find conclusive evidence to recommend the use of bisphosphonates and warfarin in the prevention of NHO. On the contrary, we found NSAIDs and PLIMF as effective prophylactic options based on the results of high-quality randomized control trials. Further prospective randomized studies with prolonged follow-ups are needed to confirm the long-term efficacy of these preventive interventions.

Neurogenic Heterotopic Ossification of the Hip: A Surgical Management

Neurogenic Heterotopic Ossification of the Hip: A Surgical Management

Metabolic Activity of Neurogenic Heterotopic Ossification on 18F-FDG PET/CT Matching with Ongoing Osteoblastic Activity on Bone Scan.

A 54-year-old man, with previous history of neurogenic heterotopic ossification (HO) in muscles around the left hip following a spinal cord injury ten months earlier, was referred to our nuclear medicine center for an 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) to rule out a spondylodiscitis. No sign of spondylodiscitis was found on 18F-FDG PET/CT, but images revealed an increased 18F-FDG uptake in HO areas, matching with ongoing osteoblastic activity on a following bone scan.

Role of Kinesiotherapy in the Prevention of Heterotopic Ossification: A Systematic Review.

The role of kinesiotherapy in heterotopic ossification remains unclear. The goal of this study was to revisit the literature on the preventive role of kinesiotherapy against heterotopic ossification formation and maturation. A systematic review was performed in MEDLINE, OVID, Scopus, and Cochrane databases. A high-quality clinical trial is missing from the literature. Of 9617 studies primarily identified, nine studies offered the proper data and were included. They infer that satisfactory results on neurogenic heterotopic ossification prevention were achieved with passive exercises, including continuous passive motion, that were initiated early and at a painless range of motion. On the contrary, for elbow posttraumatic heterotopic ossification and major joints burn-associated heterotopic ossification, active range of motion is indicated as early as possible. Because of the very low quality of the studies included in this review, firm conclusions cannot be drawn about the effectiveness of kinesiotherapy. Nevertheless, it is recommended that controlled passive range of motion exercises (especially continuous passive motion) be applied early and pain-free especially in the neurogenic heterotopic ossification patients while active range of motion in painless limits is beneficial in the heterotopic ossification prevention of traumatic elbows or burn joints.