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Background/Objectives: An important aspect of the pathophysiology of frailty seems to be the dysregulation of inflammatory pathways and the coagulation system. However, an objective assessment of the impact of frailty on the recovery from surgery is not fully studied. This study sought to assess how frailty affects the recovery of adult spinal deformity (ASD) surgery using blood biomarkers. Methods: 153 consecutive ASD patients (age 64 ± 10 yr, 93% female) who had corrective spine surgery in a single institution and reached 2y f/u were included. The subjects were stratified by frailty using the modified frailty index-11 (robust [R] group or prefrail and frail [F] group). Results of commonly employed laboratory tests at baseline, 1, 3, 7, and 14 post-operative days (POD) were compared. Further comparison was performed in propensity-score matched-39 paired patients between the groups by age, curve type, and baseline alignment. A correlation between HRQOLs, major complications, and biomarkers was performed. Results: Among the propensity-score matched groups, CRP was significantly elevated in the F group at POD1,3(POD1; 5.3 ± 3.1 vs. 7.9 ± 4.7 p = 0.02, POD3; 6.6 ± 4.6 vs. 8.9 ± 5.2 p = 0.02). Transaminase was also elevated in the F group at POD3(ASD: 36 ± 15 vs. 51 ± 58 U/L, p = 0.03, ALT: 32 ± 16 vs. 47 ± 55 U/L, p = 0.04). Interestingly, moderate correlation was observed between transaminase at POD1 and 2 y SRS22 (AST; function r = −0.37, mental health r = −0.39, satisfaction −0.28, total r = −0.40, ALT; function r = −0.37, satisfaction −0.34, total r = −0.39). Conclusions: Frailty affected the serum CRP and transaminase differently following ASD surgery. Transaminase at early POD was correlated with 2 y HRQOLs. These findings support the hypothesis that there is a specific physiological basis to the frailty that is characterized in part by increased inflammation and that these physiological differences persist. [ABSTRACT FROM AUTHOR]

There is no choice other than rehabilitation as a practical medical treatment to restore impairments or improve activities after acute treatment in people with spinal cord injury (SCI); however, the effect is unremarkable. Therefore, researchers have been seeking effective pharmacological treatments. These will, hopefully, exert a greater effect when combined with rehabilitation. However, no review has specifically summarized the combinatorial effects of rehabilitation with various medical agents. In the current review, which included 43 articles, we summarized the combinatorial effects according to the properties of the medical agents, namely neuromodulation, neurotrophic factors, counteraction to inhibitory factors, and others. The recovery processes promoted by rehabilitation include the regeneration of tracts, neuroprotection, scar tissue reorganization, plasticity of spinal circuits, microenvironmental change in the spinal cord, and enforcement of the musculoskeletal system, which are additive, complementary, or even synergistic with medication in many cases. However, there are some cases that lack interaction or even demonstrate competition between medication and rehabilitation. A large fraction of the combinatorial mechanisms remains to be elucidated, and very few studies have investigated complex combinations of these agents or targeted chronically injured spinal cords. [ABSTRACT FROM AUTHOR]

Cell transplantation therapy using human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) has attracted attention as a regenerative therapy for spinal cord injury (SCI), and its efficacy in treating the subacute phase of SCI has been reported in numerous studies. However, few studies have focused on treatment in the chronic phase, which accounts for many patients, suggesting that there are factors that are difficult to overcome in the treatment of chronic SCI. The search for therapeutic strategies that focus on chronic SCI is fraught with challenges, and the combination of different therapies is thought to be the key to a solution. In addition, many issues remain to be addressed, including the investigation of therapeutic approaches for more severe injury models of chronic SCI and the acquisition of practical motor function. This review summarizes the current progress in regenerative therapy for SCI and discusses the prospects for regenerative medicine, particularly in animal models of chronic SCI. [ABSTRACT FROM AUTHOR]

The features of non-neoplastic lesions are often similar to those of intramedullary tumors, and a differential diagnosis is challenging to obtain in some cases. A surgical biopsy, which is performed on highly invasive tumors, should be avoided in cases of non-neoplastic lesions. Therefore, an accurate diagnosis is important prior to treatment. We evaluated 43 patients suspected of having spinal cord tumors and, finally, were diagnosed with non-neoplastic intramedullary lesions via magnetic resonance imaging. The patients commonly presented with myelitis. The patients with non-neoplastic neurological diseases had a significantly shorter symptom duration than those with intramedullary astrocytomas. The proportion of patients with non-neoplastic neurological diseases who presented with lesions at the cervical spinal level and focal lesions on axial imaging but without a spinal cord enlargement was significantly higher than that of patients with intramedullary astrocytomas. The current study aimed to distinguish spinal cord tumors from non-neoplastic intramedullary lesions based on their distinct features. [ABSTRACT FROM AUTHOR]

The ideal surgical strategy for cervical ossification of the posterior longitudinal ligament (OPLL) remains controversial due to the lack of high-quality evidence. Herein, we prospectively investigated the surgical outcomes of anterior cervical decompression with fusion (ADF) and laminoplasty (LAMP) with cervical OPLL. Three hundred patients were included in this study (ADF: n = 89; LAMP: n = 211 patients), and propensity score matching yielded 67 pairs of patients with ADF and LAMP, in which clinical outcomes were compared. Crude analysis revealed that the ADF group showed greater neurological recovery in cervical Japanese Orthopedic Association scores at two years, compared with that in the LAMP group (53.1% vs. 44.3%, p = 0.037). The ratio of minimum clinically important difference (MCID) success was significantly greater in the ADF group (59.6% vs. 43.6%, p = 0.016). Multivariate analysis showed that the factors affecting MCID success were age, body mass index, duration of symptoms, and choice of ADF. In the 1:1 matched analysis, neurological improvement was more favorable in the ADF group (57.2%) compared to the LAMP group (46.8%) at two years (p = 0.049). However, perioperative complications, such as dysphagia and graft-related complications, were more common in the ADF group. [ABSTRACT FROM AUTHOR]

The development of tissue clearing technologies allows 3D imaging of whole tissues and organs, especially in studies of the central nervous system innervated throughout the body. Although the three-dimensional imaging of solvent-cleared organs (3DISCO) method provides a powerful clearing capacity and high transparency, the rapid quenching of endogenous fluorescence and peroxide removal process decreases its practicability. This study provides a modified method named tDISCO to solve these limitations. The tDISCO protocol can preserve AAV-transduced endogenous EGFP fluorescence for months and achieve high transparency in a fast and simple clearing process. In addition to the brain, tDISCO was applied to other organs and even hard bone tissue. tDISCO also enabled us to visualize the long projection neurons and axons with high resolution. This method provides a fast and simple clearing protocol for 3D visualization of the AAV- transduced long projection neurons throughout the brain and spinal cord. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to clarify the clinical features of ossification of the posterior longitudinal ligament (OPLL) and extreme ossification at multiple sites. Methods: This prospective study involved patients with a diagnosis of cervical OPLL at 16 institutions in Japan. Patient-reported outcome measures, including responses on the Japanese Orthopaedic Association (JOA) Cervical Myelopathy Evaluation Questionnaire (JOA-CMEQ), JOA Back Pain Evaluation Questionnaire (JOA-BPEQ), and visual analog scale pain score, were collected to investigate clinical status. In each patient, the sum of the levels at which OPLL was located (OP index) was evaluated on whole-spine computed tomography, along with ossification of other spinal ligaments including the anterior longitudinal ligament (OALL), ligament flavum (OLF), supra- and intraspinous ligaments (SSL), and diffuse idiopathic skeletal hyperostosis (DISH). The distribution of OP index values in the study population was investigated, and the clinical and radiologic characteristics of patients in the top 10% were assessed. Results: In total, 236 patients (163 male, 73 female; mean age 63.5 years) were enrolled. Twenty-five patients with OP index ≥ 17 were categorized into a high OP index group and the remainder into a moderate/low OP index group. There were significantly more women in the high OP index group. Patients in the high OP index group also had significantly poorer scores for lower extremity function and quality of life on the JOA-CMEQ and in each domain but not for body pain on the JOA-BPEQ compared with those in the moderate/low OP index group. Patients in the high OP index group had more OALL in the cervical spine and more OLF and SSL in the thoracic spine. The prevalence of DISH was also significantly higher in the high OP index group. In the high OP index group, interestingly, OPLL was likely to be present adjacent to DISH in the cervicothoracic and thoracolumbar spine, especially in men, and often coexisted with DISH in the thoracic spine in women. Conclusion: This prospective cohort registry study is the first to demonstrate the clinical and radiologic features of patients with OPLL and a high OP index. In this study, patients with a high OP index had poorer physical function in the lumbar spine and lower extremities and were also predisposed to extreme ossification of spinal ligaments other than the OPLL. [ABSTRACT FROM AUTHOR]

We aimed to investigate the risk factors of spontaneous osseous fusion (SOF) of the atlantoaxial joint after closed reduction under general anesthesia followed by halo fixation (remodeling therapy) for chronic atlantoaxial rotatory fixation, and to elucidate the recovery mechanism of the rotatory range of motion (ROM) after halo removal. Twelve patients who underwent remodeling therapy were retrospectively reviewed. Five patients with SOF were categorized as the fusion group and seven patients without SOF as the non-fusion group. Three dimensional CT was used to detect direct osseous contact (DOC) of facet joints before and during halo fixation, while dynamic CT at neutral and maximally rotated head positions was performed to measure rotatory ROM after halo removal. The duration from onset to initial visit was significantly longer (3.2 vs. 5.7 months, p = 0.04), incidence of DOC during halo fixation was higher (0/7 [0%] vs. 4/5 [80%], p = 0.004), and segmental rotatory ROM of Occiput/C1 (Oc/C1) at final follow-up was larger (9.8 vs. 20.1 degrees, p = 0.003) in the fusion group. Long duration from the onset to the initial visit might induce irreversible damage to the articular surface of the affected facet, which was confirmed as DOC during halo fixation and resulted in SOF. Long duration from the onset to the initial visit and DOC during halo fixation could be used to suggest the risk for SOF. Nonetheless, rotatory ROM of Oc/C1 increased to compensate for SOF. [ABSTRACT FROM AUTHOR]

Postoperative neck pain has been reported as an unsolved postoperative complication of surgery for cervical ossification of the posterior longitudinal ligament (OPLL). The aim of the present study was to elucidate factors having a significant association with postoperative deterioration of neck pain in cervical OPLL patients. We studied a cohort of patients in a prospective registry of 478 patients who had undergone cervical spine surgery for cervical OPLL. We excluded those without evaluation of preoperative neck pain. Therefore, 438 patients were included in the present study. Neck pain was evaluated with the visual analogue scale (VAS, 0–100 mm). Postoperative neck pain deterioration was defined as a ≥20 mm increase of VAS neck pain. Patient factors, neurological status, imaging factors and surgical factors were assessed. Univariate analyses followed by multivariate analysis using stepwise logistic regression was performed. Six months after surgery, 50 (11.6%) patients showed postoperative neck pain deterioration and 76 (17.4%) patients showed postoperative neck pain deterioration 2 years after surgery. Six months after surgery, the rate of neck pain deterioration was significantly higher in patients who had undergone posterior surgery. Two years after surgery, the number of levels fused was significantly correlated with neck pain deterioration. [ABSTRACT FROM AUTHOR]

Background: Although diffuse idiopathic skeletal hyperostosis (DISH) is known to coexist with the ossification of spinal ligaments (OSLs), details of the radiographic relationship remain unclear. Methods: We prospectively collected data of 239 patients with symptomatic cervical ossification of the posterior longitudinal ligament (OPLL) and analyzed the DISH severity on whole-spine computed tomography images, using the following grades: grade 0, no DISH; grade 1, DISH at T3–T10; grade 2, DISH at both T3–T10 and C6–T2 and/or T11–L2; and grade 3, DISH beyond C5 and/or L3. Ossification indices were calculated as the sum of vertebral and intervertebral levels with OSL for each patient. Results: DISH was found in 107 patients (44.8%), 65 (60.7%) of whom had grade 2 DISH. We found significant associations of DISH grade with the indices for cervical OPLL (r = 0.45, p < 0.0001), thoracic ossification of the ligamentum flavum (OLF; r = 0.41, p < 0.0001) and thoracic ossification of the supra/interspinous ligaments (OSIL; r = 0.53, p < 0.0001). DISH grade was also correlated with the index for each OSL in the whole spine (OPLL: r = 0.29, p < 0.0001; OLF: r = 0.40, p < 0.0001; OSIL: r = 0.50, p < 0.0001). Conclusion: The DISH grade correlated with the indices of OSL at each high-prevalence level as well as the whole spine. [ABSTRACT FROM AUTHOR]

Every year, 0.93 million people worldwide suffer from spinal cord injury (SCI) with irretrievable sequelae. Rehabilitation, currently the only available treatment, does not restore damaged tissues; therefore, the functional recovery of patients remains limited. The pathophysiology of spinal cord injuries is heterogeneous, implying that potential therapeutic targets differ depending on the time of injury onset, the degree of injury, or the spinal level of injury. In recent years, despite a significant number of clinical trials based on various types of stem cells, these aspects of injury have not been effectively considered, resulting in difficult outcomes of trials. In a specialty such as cancerology, precision medicine based on a patient's characteristics has brought indisputable therapeutic advances. The objective of the present review is to promote the development of precision medicine in the field of SCI. Here, we first describe the multifaceted pathophysiology of SCI, with the temporal changes after injury, the characteristics of the chronic phase, and the subtypes of complete injury. We then detail the appropriate targets and related mechanisms of the different types of stem cell therapy for each pathological condition. Finally, we highlight the great potential of stem cell therapy in cervical SCI. [ABSTRACT FROM AUTHOR]

Background: This study investigated how diffuse idiopathic skeletal hyperostosis (DISH) influences clinical characteristics in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Although DISH is considered unlikely to promote neurologic dysfunction, this relationship remains unclear. Methods: Patient data were prospectively collected from 16 Japanese institutions. In total, 239 patients with cervical OPLL were enrolled who had whole-spine computed tomography images available. The primary outcomes were visual analog scale pain scores and the results of other self-reported clinical questionnaires. Correlations were sought between clinical symptoms and DISH using the following grading system: 1, DISH at T3-T10; 2, DISH at both T3–10 and C6–T2 and/or T11–L2; and 3, DISH beyond the C5 and/or L3 levels. Results: DISH was absent in 132 cases, grade 1 in 23, grade 2 in 65, and grade 3 in 19. There were no significant correlations between DISH grade and clinical scores. However, there was a significant difference in the prevalence of neck pain (but not in back pain or low back pain) among the three grades. Interestingly, DISH localized in the thoracic spine (grade 1) may create overload at the cervical spine and lead to neck pain in patients with cervical OPLL. Conclusion: This study is the first prospective multicenter cross-sectional comparison of subjective outcomes in patients with cervical OPLL according to the presence or absence of DISH. The severity of DISH was partially associated with the prevalence of neck pain. [ABSTRACT FROM AUTHOR]

Ossification of the posterior longitudinal ligament (OPLL) is commonly associated with diabetes mellitus (DM); however, the impact of DM on cervical spine surgery for OPLL remains unclear. This study was performed to evaluate the influence of diabetes DM on the outcomes following cervical spine surgery for OPLL. In total, 478 patients with cervical OPLL who underwent surgical treatment were prospectively recruited from April 2015 to July 2017. Functional measurements were conducted at baseline and at 6 months, 1 year, and 2 years after surgery using JOA and JOACMEQ scores. The incidence of postoperative complications was categorized into early (≤30 days) and late (>30 days), depending on the time from surgery. From the initial group of 478 patients, 402 completed the 2-year follow-up and were included in the analysis. Of the 402 patients, 127 (32%) had DM as a comorbid disease. The overall incidence of postoperative complications was significantly higher in patients with DM than in patients without DM in both the early and late postoperative periods. The patients with DM had a significantly lower JOA score and JOACMEQ scores in the domains of lower extremity function and quality of life than those without DM at the 2-year follow-up. [ABSTRACT FROM AUTHOR]

This study aimed to clarify whether ossification predisposition influences clinical symptoms including pain, restriction of activities of daily living, and quality of life in patients with cervical ossification of the posterior longitudinal ligament (OPLL). Cervical ossification predisposition potentially causes neurologic dysfunction, but the relationship between clinical symptoms and radiologic severity of OPLL has not yet been investigated. Data were prospectively collected from 16 institutions across Japan. We enrolled 239 patients with cervical OPLL. The primary outcomes were patient-reported outcomes, including visual analog scale (VAS) pain scores and other questionnaires. Whole-spine computed tomography images were obtained, and correlations were investigated between clinical symptoms and radiologic findings, including the distribution of OPLL, the sum of the levels where OPLL was present (OP-index), and the canal narrowing ratio (CNR) grade. The cervical OP-index was Grade 1 in 113 patients, Grade 2 in 90, and Grade 3 in 36. No significant correlations were found between radiologic outcomes and VAS pain scores. The cervical OP-index was associated with lower extremity function, social dysfunction, and locomotive function. The CNR grade was not correlated with clinical symptoms, but Grade 4 was associated with lower extremity dysfunction. Thickness and extension of ossified lesions may be associated with lower extremity dysfunction in cervical OPLL. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) was first identified as a potent mitogen for mature hepatocytes, and has also gained attention as a strong neurotrophic factor in the central nervous system. We found that during the acute phase of spinal cord injury (SCI) in rats, c-Met, the specific receptor for HGF, increases sharply, while the endogenous HGF up-regulation is relatively weak. Introducing exogenous HGF into the spinal cord by injecting an HGF-expressing viral vector significantly increased the neuron and oligodendrocyte survival, angiogenesis, and axonal regeneration, to reduce the area of damage and to promote functional recovery in rats after SCI. Other recent studies in rodents have shown that exogenously administered HGF during the acute phase of SCI reduces astrocyte activation to decrease glial scar formation, and exerts anti-inflammatory effects to reduce leukocyte infiltration. We also reported that the intrathecal infusion of recombinant human HGF (intrathecal rhHGF) improves neurological hand function after cervical contusive SCI in the common marmoset, a non-human primate. Based on these collective results, we conducted a phase I/II clinical trial of intrathecal rhHGF for patients with acute cervical SCI who showed a modified Frankel grade of A/B1/B2 72 h after injury onset, from June 2014 to May 2018. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI.