Accuracy of Resting Energy Expenditure Estimation Equations in Polio Survivors.

OBJECTIVE: To evaluate the accuracy of 4 equations validated for the general population to determine resting energy expenditure (REE) in polio survivors. DESIGN: A descriptive, ambispective, single-center observational cohort study of minimal risk care. SETTING: Tertiary university care hospital. PARTICIPANTS: DATAPOL database of polio survivors followed up in a specialist department (N=298). INTERVENTIONS: None. MAIN OUTCOMES MEASURES: REE measurement by indirect calorimetry and estimated REE using 4 equations and comparing the values with indirect calorimetry. Analysis of correlations between measured REE and weight, height, and body mass index (BMI) and indicators of severity of polio sequelae. RESULTS: Of the 298 polio cases in the database between January 2014 and May 2017, 41 were included (19 men and 22 women). Mean±SD BMI was 26.0±5.6 kg/m2 (56.1% below 25). Measured REE correlated significantly and positively with weight and weaker with BMI. Correlations between measured and estimated REE were strong (between 0.49 and 0.59); correlations were strongest for the simplified World Health Organization and the Harris and Benedict equations. However, the equations systematically overestimated REE by more than 20%, especially in men. We calculated a correction factor for the World Health Organization scale: -340.3 kcal/d for women and -618.8 kcal/d for men. CONCLUSION: Analysis of REE is important for polio survivors; The use of estimation equations could lead to the prescription of a nonadapted diet. We determined a correction factor that should be validated in prospective studies.

International Recommendations to Manage Poststroke Equinovarus Foot Deformity Validated by a Panel of Experts Using Delphi.

OBJECTIVE: To establish international recommendations for the management of spastic equinovarus foot deformity. DESIGN: Delphi method. SETTING: International study. PARTICIPANTS: A total of 24 international experts (N=24) in neuro-orthopedic deformities, from different specialties (Physical and Rehabilitation Medicine physicians, neurologists, geriatricians, orthopedic surgeons, neurosurgeons, plastic surgeons). INTERVENTIONS: Experts answered 3 rounds of questions related to important aspects of diagnosis, assessment, and treatment of spastic equinovarus foot deformity. MAIN OUTCOME MEASURES: A consensus was established when at least 80% of experts agreed on a statement RESULTS: A total of 52 items reached consensus. Experts recommend assessing effect of the deformity on functional activities before treatment. Before treatment, it is crucial to differentiate spastic muscle overactivity from soft tissue contractures, identify which muscles are involved in the deformity, and evaluate the activity of antagonist muscles. Motor nerve blocks, 2-dimensional video analysis, and radiologic examinations are often required to complement a clinical examination. The treatment of equinovarus foot depends on the correctability of the deformity and the patient's ability to stand or walk. The preoperative assessment should include an interdisciplinary consultation that must finalize a formal agreement between physicians and the patient, which will define personalized attainable goals before surgery. CONCLUSION: The establishment of guidelines on managing equinovarus foot will help physicians and surgeons, specialists, and nonspecialists to diagnoses and assess the deformity and direct patients to a network of experts to optimize patient functional recovery and improve their autonomy.

Neuro-Orthopedic Surgery for Equinovarus Foot Deformity in Adults: A Narrative Review.

Neuro-orthopedic surgery is an alternative to the conservative treatment of spastic equinovarus foot (SEF) in adults. The objective of the present narrative review was to summarize current practice with regard to patient assessment, the choice of treatment, the various neuro-orthopedic procedures, and the latter's outcomes. We searched literature databases (MEDLINE, EMBASE, Cochrane) for original articles or opinion papers on surgical treatment of spastic equinovarus foot in adults. Neuro-orthopedic approaches require a careful analysis of the patient's and/or his/her caregiver needs and thus relevant treatment goals. Surgical planning requires detailed knowledge of impairments involved in the spastic equinovarus foot deformity based on a careful clinical examination and additional information from diagnostic nerve blocks and/or a quantitative gait analysis. Procedures mainly target nerves (neurotomy) and tendons (lengthening, transfer, tenotomy). These procedures reduce impairments (spasticity, range of motion, and foot position), improve gait and walking function, but their impact on participation and personalized treatment goals remains to be demonstrated. Neuro-orthopedic surgery is an effective treatment option for spastic equinovarus foot in adults. However, practice is still very heterogeneous and there is no consensus on the medical strategies to be applied before, during and after surgery (particularly the type of anesthesia, the need for immobilization, rehabilitation procedures).

When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification.

PURPOSE OF REVIEW: Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. RECENT FINDINGS: Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-ß1-mediated pathways. This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients.

Sciatic nerve compression by neurogenic heterotopic ossification: use of CT to determine surgical indications.

OBJECTIVE: To describe the characteristics of neurogenic heterotopic ossification (NHO) based on clinical tests, electroneuromyography (ENMG) and CT in a database of patients with lesions of the central nervous system who required sciatic nerve neurolysis along with posterior hip NHO resection, and to determine the respective roles of ENMG and CT in the management of posterior hip NHOs in patients who are unable to communicate or express pain. METHODS: The consistency of the ENMG results with clinical findings, CT results and macroscopic signs of lesions was retrospectively assessed after sciatic nerve neurolysis and ablation of 55 posterior hip NHOs. RESULTS: Sciatic nerve neurolysis was necessary in 55 cases (47.4%; 55 out of 116). CT showed contact of the NHO with the nerve in all cases: 5 in contact with no deflection, 3 in contact with deflection, 21 moulded into a gutter and 26 entrapped in the NHO. There were clinical signs of sciatic nerve lesion in 21.8% of cases (12 out of 55). ENMG showed signs of sciatic nerve lesions in only 55.6% (10 out of 18), only 4 of whom presented with clinical signs of a nerve lesion. No significant relationship was found between clinical symptoms and ENMG findings of sciatic nerve compression (n = 13, p = 0.77). CONCLUSION: Nerve compression by NHO is likely an underdiagnosed condition, particularly in patients who are unable to communicate. Diagnosis of sciatic compression by NHO should be based on regular clinical examinations and CT. ENMG is not sufficiently sensitive to be used alone for surgical decision-making.

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

PURPOSE: Neurogenic 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. METHOD: This 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. RESULTS: Twenty-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). CONCLUSION: MRI 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.

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-ß (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).

Heterotopic ossification and COVID 19: Imaging analysis of ten consecutive cases.

PURPOSE: Heterotopic ossification (HO) is defined by the formation of mature lamellar bone in periarticular soft tissue due to prolonged immobility. This study aimed to explore the imaging features of HOs in immobilized COVID-19 patients compared to other causes previously described in the literature. METHOD: This retrospective single centre study included patients with severe COVID-19 hospitalized in intensive care unit (ICU) with mechanical ventilation and affected by HOs between March 2020 and December 2021. Two radiologists reviewed imaging features of biphasic CT-scans using a standardized template including morphological findings and anatomical relationship of the HO with the joint, vessels and nerves. RESULTS: 10 COVID-19 patients with 19 analyzed HOs following ICU hospitalization were including. Biphasic CT imaging characteristics were analyzed. The hips were the most commonly affected joint (n = 14/19; 74%). The distribution was mainly posterior (n = 7/19; 38%). HOs were located away from main arteries. No case of severe demineralization was observed. Capsular disruption was observed for three HOs (n = 3/19; 16%). One patient presented concomitant venous thrombosis ipsilateral to the HO. CT-scan demonstrated neural involvement of the sciatic nerve in 3 patients with HO (n = 3/19; 16%). CONCLUSION: Severe COVID-19 patients with a biphasic CT imaging presented HO mainly located around the hips, with rare vessel and nerve invasion and no severe demineralization. Some features such as a lower level of local invasion differ from HOs related to other disorders as described in the literature whereas morphological aspects are similar.

Spinal cord injury reprograms muscle fibroadipogenic progenitors to form heterotopic bones within muscles.

The cells of origin of neurogenic heterotopic ossifications (NHOs), which develop frequently in the periarticular muscles following spinal cord injuries (SCIs) and traumatic brain injuries, remain unclear because skeletal muscle harbors two progenitor cell populations: satellite cells (SCs), which are myogenic, and fibroadipogenic progenitors (FAPs), which are mesenchymal. Lineage-tracing experiments using the Cre recombinase/LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in skeletal muscles under the control of the Pax7 or Prrx1 gene promoter, respectively. These experiments demonstrate that following muscle injury, SCI causes the upregulation of PDGFRα expression on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHOs. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury, suggesting that the cells of origin of NHOs are locally derived from the injured muscle. We validated these findings using human NHO biopsies. PDGFRα+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice, whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to undergo uncontrolled proliferation and differentiation into osteoblasts.

Interleukin-1 Is Overexpressed in Injured Muscles Following Spinal Cord Injury and Promotes Neurogenic Heterotopic Ossification.

Neurogenic heterotopic ossifications (NHOs) form in periarticular muscles after severe spinal cord (SCI) and traumatic brain injuries. The pathogenesis of NHO is poorly understood with no effective preventive treatment. The only curative treatment remains surgical resection of pathological NHOs. In a mouse model of SCI-induced NHO that involves a transection of the spinal cord combined with a muscle injury, a differential gene expression analysis revealed that genes involved in inflammation such as interleukin-1ß (IL-1ß) were overexpressed in muscles developing NHO. Using mice knocked-out for the gene encoding IL-1 receptor (IL1R1) and neutralizing antibodies for IL-1α and IL-1ß, we show that IL-1 signaling contributes to NHO development after SCI in mice. Interestingly, other proteins involved in inflammation that were also overexpressed in muscles developing NHO, such as colony-stimulating factor-1, tumor necrosis factor, or C-C chemokine ligand-2, did not promote NHO development. Finally, using NHO biopsies from SCI and TBI patients, we show that IL-1ß is expressed by CD68+ macrophages. IL-1α and IL-1ß produced by activated human monocytes promote calcium mineralization and RUNX2 expression in fibro-adipogenic progenitors isolated from muscles surrounding NHOs. Altogether, these data suggest that interleukin-1 promotes NHO development in both humans and mice. © 2021 American Society for Bone and Mineral Research (ASBMR).

A 6-Month Home-Based Functional Electrical Stimulation Program for Foot Drop in a Post-Stroke Patient: Considerations on a Time Course Analysis of Walking Performance.

Foot drop is a common disability in post-stroke patients and represents a challenge for the clinician. To date, ankle foot orthosis (AFO) combined with conventional rehabilitation is the gold standard of rehabilitation management. AFO has a palliative mechanical action without actively restoring the associated neural function. Functional electrical stimulation (FES), consisting of stimulation of the peroneal nerve pathway, represents an alternative approach. By providing an FES device (Bioness L-300, BIONESS, Valencia, CA, USA) for 6 months to a post-stroke 22-year-old woman with a foot drop, our goal was to quantify its potential benefit on walking capacity. The gait parameters and the temporal evolution of the speed were collected with a specific connected sole device (Feet Me®) during the 10-m walking, the time up and go, and the 6-minute walking tests with AFO, FES, or without any device (NO). As a result, the walking speed changes on 10-m were clinically significant with an increase from the baseline to 6 months in AFO (+0.14 m.s-1), FES (+0.36 m.s-1) and NO (+0.32 m.s-1) conditions. In addition, the speed decreased at about 4-min in the 6-minute walking test in NO and AFO conditions, while the speed increased in the FES conditions at baseline and after 1, 3, and 6 months. In addition to the walking performance improvement, monitoring the gait speed in an endurance test after an ecological rehabilitation training program helps to examine the walking performance in post-stroke patients and to propose a specific rehabilitation program.

Early diagnosis of heterotopic ossification among patients admitted to a neurological Post-Intensive Care Rehabilitation Unit.

BACKGROUND: Heterotopic ossification (HO) is defined as the formation of endochondral bone within soft tissue. Non-genetic forms, mainly corresponding to a consequence of bone, brain or spinal cord injury, are the most common. HO leads to important functional limitations and alteration of quality of life. To our knowledge, the time between brain, bone, or spinal cord injury and clinical suspicion of HO has never been studied. By admitting patients with severe neurological disorders, we hypothesized that the prevalence of HO in neurological post-intensive care rehabilitation units (PICRU) might be significant as these patients have recognized risk factors for HO. AIM: This study aimed to investigate HO among patients admitted to a neurological PICRU with two objectives: 1) to describe the prevalence of HO in PICRU; 2) to assess the time between neurological disorder, clinical suspicion of HO and radiological diagnosis. DESIGN: A monocentric retrospective cohort study. SETTING: PICRU in our public university teaching hospital. This inpatient referral department is specifically dedicated to the early discharge from Intensive Care Units (ICU) of patients with severe neurological impairment who need rehabilitation. POPULATION: We study all patients admitted between April 2016 and January 2019. One hundred twenty-five subjects were admitted for a rehabilitation program after neuro-trauma or stroke. We included all first-time stays in PICRU lasting 7 days or longer. METHODS: Retrospective data extraction using administrative data from an electronic patient management program was done to select eligible subjects. Included subjects were then identified by a retrospective review of electronic inpatient medical records after patient discharge. Data of interest were collected from these same medical records. RESULTS: Forty-four HO were diagnosed in 24 subjects (24/125; 19%), with a median number of 2 [1; 2] HO per subject. Neurological trauma was the main reason for admission to ICU (89/125; 71%) and half of patients had a traumatic brain injury (TBI) (67/125; 54%). The diagnosis of HO was made in PICRU in 75% of cases. Clinical suspicion of HO (autonomic dysfunction, local inflammatory signs, pain, or reduced joint range of motion) was made 6 [5; 7] weeks after admission to ICU. Radiological confirmation of clinical suspicion or fortuitous diagnosis by imaging (50% of the cases) occurred 8 [7; 12] weeks after admission to ICU. The median time of clinical suspicion or radiological diagnosis was 1 week after admission to PICRU. CONCLUSIONS: HO is a sub-acute complication which develops in patients admitted to ICU for severe central nervous system disorders as clinical suspicion or radiological confirmation of diagnosis was made within the first week after admission in neurological PICRU (i.e. 6 to 8 weeks after ICU admission). CLINICAL REHABILITATION IMPACT: As treatment for HO may at least partially improves rehabilitation and quality of life, we recommend a systematic screening in PICRU patients for HO by clinical examination supplemented by imaging in case of suspicion.

Comparison of magnetic resonance imaging and computed tomography for bone assessment of neurogenic heterotopic ossification of the hip: a preliminary study.

BACKGROUND: Neurogenic heterotopic ossification (NHO) is a frequent complication, often involving the hip. The functional impact may require surgical management and pre-surgical imaging assessment is necessary, usually by computed tomography (CT). We aimed to compare the performances of magnetic resonance imaging (MRI) and CT for bone assessment on pre-surgical imaging of the heterotopic ossifications and their features in NHO of the hip. METHODS: This single-center prospective preliminary study included all patients who underwent surgery for NHO with joint limitation from July 2019 to March 2020. All patients had a CT after biphasic iodinated solution injection and an MRI including T1-weighted, STIR and ZTE sequences. Standardized reports were completed for both exams for each patient, evaluating location, implantation and fragmentation of NHO, relation to the joint capsule and bone mineralization, then were compared. RESULTS: Seven patients from 32 to 70 years old (mean = 50.2 ± 17.2 years) were evaluated. NHO were bilateral in 2 patients, for a total of nine hips: six right hips and three left hips. Observed concordance rates between MRI and CT were, respectively, 94.4% for location, 100% for circumferential extension, 87.3% for implantation 88.9% for fragmentation, 77.8% for relation to the joint capsule and 66.7% for bone mineralization. It was 100% for femoral neck fracture and osteonecrosis of the femoral head. CONCLUSION: This preliminary study suggests that pre-surgical MRI imaging should be considered as effective as CT for bone assessment of NHO and their features. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03832556. Registered February 6, 2019, https://clinicaltrials.gov/ct2/show/NCT03832556 .

Neurogenic Heterotopic Ossifications Recapitulate Hematopoietic Stem Cell Niche Development Within an Adult Osteogenic Muscle Environment.

Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-ß in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO.

Effectiveness of radiotherapy to prevent recurrence of heterotopic ossification in patients with spinal cord injury and traumatic head injury: A retrospective case-controlled study.

OBJECTIVE: To evaluate recurrence and early postoperative complications (sepsis) following surgical excision combined with radiotherapy for troublesome hip heterotopic ossification in patients with spinal cord injury and traumatic brain injury. DESIGN: Retrospective case-control study. SETTING: Data relating to patients with spinal cord injury or traumatic brain injury who underwent surgical excision of hip heterotopic ossification were retrieved from the BANKHO database. Case patients underwent excision + radiotherapy and controls underwent excision only. Control patients were matched to case patients according to sex and age (± 4 years). PARTICIPANTS: Data from 19 case patients and 76 controls were analysed. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: The primary end-point was recurrence of heterotopic ossification. Secondary end-points were postoperative complications and, more specifically, sepsis that required surgical revision. RESULTS: There was no difference between the odds ratios (OR) for recurrence for each group (OR case group = 0.63, OR spinal cord injury subgroup = 0.45 and OR head injury subgroup = 1.04). The rate of sepsis requiring surgical revision was significantly higher in the case group (p < 0.05). CONCLUSION: Based on the results of this case-control study, we suggest that radiotherapy should not be combined with surgery in patients with troublesome hip heterotopic ossification undergoing excision. Radiotherapy does not appear to prevent recurrence and, moreover, it is associated with an increased risk of postoperative sepsis.

Neurogenic Heterotopic Ossifications Develop Independently of Granulocyte Colony-Stimulating Factor and Neutrophils.

Neurogenic heterotopic ossifications (NHOs) are incapacitating heterotopic bones in periarticular muscles that frequently develop following traumatic brain or spinal cord injuries (SCI). Using our unique model of SCI-induced NHO, we have previously established that mononucleated phagocytes infiltrating injured muscles are required to trigger NHO via the persistent release of the pro-inflammatory cytokine oncostatin M (OSM). Because neutrophils are also a major source of OSM, we investigated whether neutrophils also play a role in NHO development after SCI. We now show that surgery transiently increased granulocyte colony-stimulating factor (G-CSF) levels in blood of operated mice, and that G-CSF receptor mRNA is expressed in the hamstrings of mice developing NHO. However, mice defective for the G-CSF receptor gene Csf3r, which are neutropenic, have unaltered NHO development after SCI compared to C57BL/6 control mice. Because the administration of recombinant human G-CSF (rhG-CSF) has been trialed after SCI to increase neuroprotection and neuronal regeneration and has been shown to suppress osteoblast function at the endosteum of skeletal bones in human and mice, we investigated the impact of a 7-day rhG-CSF treatment on NHO development. rhG-CSF treatment significantly increased neutrophils in the blood, bone marrow, and injured muscles. However, there was no change in NHO development compared to saline-treated controls. Overall, our results establish that unlike monocytes/macrophages, neutrophils are dispensable for NHO development following SCI, and rhG-CSF treatment post-SCI does not impact NHO development. Therefore, G-CSF treatment to promote neuroregeneration is unlikely to adversely promote or affect NHO development in SCI patients. © 2020 American Society for Bone and Mineral Research.

Resection of heterotopic ossification around the hip after trauma.

Traumatic neurological lesions may lead to development of heterotopic ossification. These cases are classified as 'neurogenic heterotopic ossifications' (NHOs). The associated neurological lesions can be caused by cranial trauma or spinal cord injury and may sometimes include a local trauma.NHOs that form around the hip joints are of particular interest because they often cause the patient to avoid the sitting position or the resumption of walking.Whilst NHO can involve the knee, shoulder and elbow joints, hip-involving NHOs are more numerous, and sometimes develop in close contact with vascular or neurological structures.Multi-disciplinary clinical examination is fundamental to evaluate patients for surgical intervention and to define the objectives of the surgery. The best investigation to define an NHO mass is a computerized tomography (CT) scan.Resection is performed to liberate a fused joint to provide functionality, and this need not be exhaustive if it is not necessary to increase the range of motion.While recurrence does occur post-surgery, a partial resection does not pose a greater risk of recurrence and there are no adjuvant treatments available to reduce this risk.The greatest risks associated with NHO surgical resection are infection and haematoma; these risks are very high and must be considered when evaluating patients for surgery. Cite this article: EFORT Open Rev 2019;4 DOI: 10.1302/2058-5241.4.180098.

Inhibition of JAK1/2 Tyrosine Kinases Reduces Neurogenic Heterotopic Ossification After Spinal Cord Injury.

Neurogenic heterotopic ossifications (NHO) are very incapacitating complications of traumatic brain and spinal cord injuries (SCI) which manifest as abnormal formation of bone tissue in periarticular muscles. NHO are debilitating as they cause pain, partial or total joint ankylosis and vascular and nerve compression. NHO pathogenesis is unknown and the only effective treatment remains surgical resection, however once resected, NHO can re-occur. To further understand NHO pathogenesis, we developed the first animal model of NHO following SCI in genetically unmodified mice, which mimics most clinical features of NHO in patients. We have previously shown that the combination of (1) a central nervous system lesion (SCI) and (2) muscular damage (via an intramuscular injection of cardiotoxin) is required for NHO development. Furthermore, macrophages within the injured muscle play a critical role in driving NHO pathogenesis. More recently we demonstrated that macrophage-derived oncostatin M (OSM) is a key mediator of both human and mouse NHO. We now report that inflammatory monocytes infiltrate the injured muscles of SCI mice developing NHO at significantly higher levels compared to mice without SCI. Muscle infiltrating monocytes and neutrophils expressed OSM whereas mouse muscle satellite and interstitial cell expressed the OSM receptor (OSMR). In vitro recombinant mouse OSM induced tyrosine phosphorylation of the transcription factor STAT3, a downstream target of OSMR:gp130 signaling in muscle progenitor cells. As STAT3 is tyrosine phosphorylated by JAK1/2 tyrosine kinases downstream of OSMR:gp130, we demonstrated that the JAK1/2 tyrosine kinase inhibitor ruxolitinib blocked OSM driven STAT3 tyrosine phosphorylation in mouse muscle progenitor cells. We further demonstrated in vivo that STAT3 tyrosine phosphorylation was not only significantly higher but persisted for a longer duration in injured muscles of SCI mice developing NHO compared to mice with muscle injury without SCI. Finally, administration of ruxolitinib for 7 days post-surgery significantly reduced STAT3 phosphorylation in injured muscles in vivo as well as NHO volume at all analyzed time-points up to 3 weeks post-surgery. Our results identify the JAK/STAT3 signaling pathway as a potential therapeutic target to reduce NHO development following SCI.

Peripheral denervation participates in heterotopic ossification in a spinal cord injury model.

We previously reported the development of a new acquired neurogenic HO (NHO) mouse model, combining spinal cord transection (SCI) and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS) might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX) injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV) were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR) was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7), bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5) compared to contralateral sides (0.56 mm3 +/-0.4), p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6), bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI). Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro inflammatory mechanisms induced by central or peripheral nervous system injury plays a key role in triggering ectopic osteogenesis.