Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Assessment of locomotive syndrome in patients with visceral cancer, the comparison with non-cancer patients using propensity score matching.

BACKGROUND: When treating cancer patients, the progression of symptoms is accompanied by the deterioration of systemic conditions and motor function. From a risk-benefit perspective, a certain level of physical function must be maintained to continue cancer treatment. Recently, outpatient cancer treatment has become more common. Motor function is important to determine the feasibility of continuing cancer treatment. The study aimed to evaluate the motor function of patients with visceral cancer using locomo tests established by Japanese Orthopaedic Association. METHODS: Locomo tests were performed, and the results were compared with data from non-cancer individuals. Background data were matched by propensity score matching. Data from 53 cancer patients (group C) were compared with that of 75 non-cancer patients (group N). RESULTS: The average score in the two-step test of group C was lower than that of group N (1.27: 1.37, p = 0.004). The average function in the stand-up test of group C was worse than that of group N (p = 0.001). The average score in the 25-question geriatric locomotive function scale (GLFS) of group C was significantly higher than that of group N (19.92: 5.29, SE 2.21, p < 0.001). Higher 25-question GLFS scores indicate reduced mobility. The proportion of the locomo stage 2 in group C was significantly higher than in group N (51%: 13%, p < 0.001). The results of the two field tests revealed a clinically minimal difference between the two groups, but a statistically significant difference. Locomo tests may be detect potential motor dysfunction in outpatient cancer patients with apparently maintained motor function. CONCLUSIONS: Even in cancer patients who attend outpatient clinics, their motor functions could be potentially impaired. Therapeutic interventions to maintain and enhance motor function for cancer patients could be useful for continuing cancer treatment, and furthermore, improving prognosis.

Minimally displaced unilateral facet fracture of cervical spine can lead to spinal cord injury: a report of two cases.

BACKGROUND: According to most of the commonly used classification systems for subaxial spine injuries, unilateral and minimally displaced facet fractures without any sign of a spinal cord injury would be directed to non-operative management. However, the failure rate of non-operative treatment varies from 20 to 80%, and no consensus exists with regard to predictors of failure after non-operative management. CASE PRESENTATION: Case 1 is a patient with a unilateral facet fracture. The patient had only numbness in the right C6 dermatome but failed non-operative treatment, which resulted in severe spinal cord injury. Case 2 is a patient who had a similar injury pattern as case 1 but presented with immediate instability and underwent fusion surgery. Both patients had a minimally displaced unilateral facet fracture accompanied by disc injury and blunt vertebral artery injury, which are possible signs indicating significant instability. CONCLUSIONS: This is the first report of an isolated unilateral facet fracture that resulted in catastrophic spinal cord injury. These two cases illustrate that an isolated minimally displaced unilateral facet fracture with disc injury and vertebral artery injury were associated with significant instability that can lead to spinal cord injury.

Postoperative K-line conversion from negative to positive is independently associated with a better surgical outcome after posterior decompression with instrumented fusion for K-line negative cervical ossification of the posterior ligament.

PURPOSE: Addition of posterior instrumented fusion to laminoplasty (posterior decompression with instrumented fusion: PDF) can improve the surgical outcome of patients with K-line (-) cervical ossification of the longitudinal ligament (OPLL) compared with laminoplasty alone. We sought to elucidate the factors that are significantly associated with a better outcome after PDF for K-line (-) OPLL. METHODS: The present study included 38 patients who underwent PDF for K-line (-) OPLL and were followed up for at least 1 year after surgery. Clinical outcome was assessed using Japanese Orthopedic Association (JOA) scores for cervical myelopathy and the recovery rate was calculated. Patients who belonged to the upper quartile of all the patients according to rank order of the JOA score recovery rate were considered to have a good outcome. The correlations between good outcome, patient factors and imaging assessments were analyzed statistically. RESULTS: Univariate analyses showed that postoperative conversion of K-line from (-) to (+) (p = 0.004), no increase in the sagittal vertical axis from the center of gravity of the head to C7 (p = 0.07), and a lower grade of preoperative intramedullary T2-signal intensity (p = 0.03) were candidates for the association. Stepwise logistic regression analysis revealed that postoperative K-line conversion from (-) to (+) is an independent factor that is significantly associated with a better surgical outcome (p = 0.04). CONCLUSION: Postoperative K-line conversion from (-) to (+) is a factor independently associated with a better surgical outcome. These slides can be retrieved under Electronic Supplementary material.

Drop finger caused by 8th cervical nerve root impairment: a clinical case series.

PURPOSE: Recently, it has been reported that impairment by an 8th cervical nerve root lesion can cause drop finger, namely C8 drop finger. Here, we report a clinical case series of C8 drop finger to reveal the clinical outcome of surgical treatments to allow for a better choice of treatment. METHODS: The present study included 17 consecutive patients who were diagnosed as having C8 drop finger, in which muscle strength of the extensor digitorum communis (EDC) showed a manual muscle testing (MMT) grade of 3 or less. We retrospectively investigated the clinical characteristics of C8 drop finger and recovery of muscle power was measured by subtraction of preoperative MMT of the EDC from the final follow-up values. RESULTS: Nine cases showed recovery of muscle power of EDC, whereas the remaining eight cases did not show any recovery including two cases of deterioration. None of the conservatively treated patients showed any recovery. Surgically treated cases included two cases of deterioration. In the cases showing recovery, recovery began 9.9 months after surgery on average and recovery took 13.8 months after surgery on average. There was a significant difference in the recovery of MMT grade between the groups treated conservatively and surgically (p = 0.049). Preoperative MMT grade of EDC showed a moderate correlation with postoperative recovery (r 2 = 0.45, p = 0.003). In other words, the severity of preoperative muscular weakness correlated negatively with postoperative recovery. CONCLUSIONS: C8 drop finger is better treated by surgery than conservative therapy.

Diffusion tensor imaging can predict surgical outcomes of patients with cervical compression myelopathy.

PURPOSE: The aim of this study was to assess the potential role of diffusion tensor imaging (DTI) as a predictor of surgical outcomes in patients with cervical compressive myelopathy (CCM). Surgical decompression is often recommended for symptomatic CCM. It is important to know the prognosis of surgical outcomes and to recommend appropriate timing for surgery. METHODS: We enrolled 26 patients with CCM who underwent surgery. The Japanese Orthopaedic Association (JOA) score for cervical myelopathy was evaluated before and 6 months after surgery. Surgical outcomes were regarded as good if there was a change in JOA score of three points or more, or the recovery rate of JOA score was 50% or more. The patients were examined using a 3.0 T magnetic resonance system before surgery. Measured diffusion parameters were fractional anisotropy (FA) and mean diffusivity (MD). The correlations between DTI parameters and surgical outcomes were analyzed. RESULTS: Both change and recovery rate of JOA score moderately correlated with FA. Furthermore, the area under the receiver-operator characteristic curve based on FA for prognostic precision of surgical outcomes indicates that FA is a good predictive factor. The cut-off values of FA for predicting good surgical outcomes evaluated by change and recovery rate of JOA score were 0.65 and 0.57, respectively. Neither change nor recovery rate of JOA score correlated with MD. CONCLUSIONS: FA in spinal cord DTI can moderately predict surgical outcomes. DTI can serve as a supplementary tool for decision-making to guide surgical intervention in patients with CCM.

Determining the short-term neurological prognosis for acute cervical spinal cord injury using machine learning.

It is challenging to predict neurological outcomes of acute spinal cord injury (SCI) considering issues such as spinal shock and injury heterogeneity. Deep learning-based radiomics (DLR) were developed to quantify the radiographic characteristics automatically using a convolutional neural network (CNN), and to potentially allow the prognostic stratification of patients. We aimed to determine the functional prognosis of patients with cervical SCI using machine learning approach based on MRI and to assess the ability to predict the neurological outcomes. We retrospectively analyzed the medical records of SCI patients (n=215) who had undergone MRI and had an American Spinal cord Injury Association Impairment Scale (AIS) assessment at 1 month after injury, enrolled with a total of 294 MR images. Sagittal T2-weighted MR images were used for the CNN training and validation. The deep learning framework TensorFlow was used to construct the CNN architecture. After we calculated the probability of the AIS grade using the DLR, we built the identification model based upon the random forest using 3 features: the probability of each AIS grade obtained by the DLR method, age, and the initial AIS grade at admission. We performed a statistical evaluation between the actual and predicted AIS. The accuracy, precision, recall and f1 score of the ensemble model based on the DLR and RF were 0.714, 0.590, 0.565 and 0.567, respectively. The present study demonstrates that prediction of the short-term neurological outcomes for acute cervical spinal cord injury based on MRI using machine learning is feasible.

Longitudinal diffusion tensor imaging of patients with degenerative cervical myelopathy following decompression surgery.

Previous studies have reported the utility of diffusion tensor imaging (DTI) as an imaging biomarker for the severity of myelopathy and subsequent surgical outcome in patients with degenerative cervical myelopathy (DCM). We hypothesized that DTI may reflect neurological recovery following surgery. The purpose of this study was to evaluate the ability of DTI to assess the post-operative alteration of neural status in patients with DCM as well as to predict post-operative recovery. We enrolled 15 patients with DCM who underwent decompression surgery. The Japanese Orthopaedic Association (JOA) score was evaluated before and 1 year after surgery. The participants were examined using DTI on a 3.0 T magnetic resonance scanner before, and 1 year after surgery. Fractional anisotropy (FA) and mean diffusivity (MD) were assessed for both time points. The correlations between the pre- and post-operative FA and MD values and the pre- and post-operative JOA scores were analyzed. Although the JOA score improved significantly after surgery from 8.9 to 12.3, there was no significant change between the pre- and post-operative FA and MD values. The post-operative outcomes after 1 year moderately correlated with the pre-operative FA values (Spearman's ρ = 0.55, p = 0.03 and Spearman's ρ = 0.56, p = 0.03 for change and recovery rate of the JOA score, respectively). However, there was no correlation between the post-operative FA and post-operative JOA scores nor between MD and clinical outcomes. DTI cannot be utilized as a biomarker for post-operative alterations of neural status of the spinal cord; however, pre-operative DTI may be useful as a predictor of surgical outcomes.

Segmental motion at the peak of the ossification foci is independent risk factor except for mal-alignment and thick ossification foci for poor outcome after laminoplasty for cervical ossification of the posterior longitudinal ligament: analyses in patients with positive K-line, lordotic alignment, and lower canal occupying ratio.

PURPOSE: To elucidate the independent preoperative factors that have a significant impact on poor surgical outcome after laminoplasty for K-line (+) ossification of the posterior longitudinal ligament (OPLL). Analyses in K-line (+) patient population can exclude the influence by mal-alignment and thick OPLL, both of which are well known two major factors that have significant impact on clinical outcome. METHODS: The present study included 72 patients (50 male and 22 female) who underwent laminoplasty for K-line (+) cervical OPLL and were followed-up for at least 1 year. Recovery of Japanese Orthopedic Association score (JOA score) for cervical myelopathy was used as the measure of clinical outcome. For radiographic assessment, the type of OPLL, the maximum OPLL occupation ratio, the C2-C7 angle, and the segmental range of motion at the peak of OPLL (segmental ROM) were assessed. To elucidate the factors that are significantly associated with a poor clinical outcome after laminoplasty for K-line (+) OPLL, statistical analyses were conducted. RESULTS: The mean preoperative JOA score was 8.9 points and improved to 12.8 points after surgery. The recovery of JOA score was 47 ± 35%. Stepwise logistic regression following univariate analyses revealed that preoperative segmental ROM at the peak of OPLL is an independent factor associated with a poor outcome (p = 0.04, odds ratio = 1.15). CONCLUSIONS: Large preoperative segmental ROM at the peak of the OPLL is an independent factor that has significant impact on poor surgical outcome after laminoplasty for K-line (+) OPLL.

The K-line in the cervical ossification of the posterior longitudinal ligament is different on plain radiographs and CT images.

BACKGROUND: The K-line, which is a virtual line between the midpoints of the antero-posterior canal diameter at C2 and C7, can be useful for determination of surgical procedures for cervical ossification of the posterior longitudinal ligament (OPLL). Although K-line is originally measured with plain radiogram, computed tomography multiplanar reconstruction (CT-MPR) is applied for K-line measurement by several surgeons. The purpose of the present study was to analyze whether there is a difference in K-lines obtained from radiographs of standing patients and those obtained from CT-MPR images of supine patients. METHODS: The present study included 65 patients with cervical OPLL underwent surgical treatment. We investigated the K-line (+ or -) before surgery, measured from lateral cervical spine radiographs taken in standing patients in a neutral position (X-P-based K-line) and CT-MPR mid-sagittal images obtained in supine patients (CT-based K-line). The X-P-based and CT-based K-lines were compared and differences between them were assessed. RESULTS: The-X-P-based K-line was found to be (+) in 35 patients and (-) in 30 patients. Four of 35 patients with an X-P-based K-line (11%) showed a change from K-line (+) to (-) in CT-based K-line measurements. One of 30 patients with an X-P-based K-line (3%) showed a change from (-) to (+) in CT-based measurements. CONCLUSIONS: The K-line should be measured with plain radiogram of standing patients because X-P-based K-line and CT-based K-line can be different.

Huge Pseudoaneurysm of the Femoral Artery after Internal Fixation of Femoral Trochanteric Fracture.

Pseudoaneurysm is one of the most serious complications of femoral trochanteric fracture surgery. Since the rupture of pseudoaneurysm may lead to death, early detection is important. We report the case of an 80-year-old male who developed pain in the proximal thigh and severe swelling after internal fixation of a femoral trochanteric fracture with a hip nail. Angiography revealed a pseudoaneurysm of a branch of the deep femoral artery near the interlocking screw. The vascular lesion was immediately treated by transcatheter embolization, and the vascular leakage was completely resolved with catheter embolization. After embolization, the patient's clinical state improved rapidly, and the laboratory values improved to normal after several weeks. The current case study reminds us that pseudoaneurysm can occur after intramedullary nail placement to treat a femoral trochanteric fracture.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. METHODS AND ANALYSIS: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). ETHICS AND DISSEMINATION: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. TRIAL REGISTRATION NUMBER: UMIN000018752.

Experimental rat model for cervical compressive myelopathy.

Previously, a rat model of chronic compressive myelopathy that uses a water-absorbing polymer inserted under a spinal lamina was reported. However, the best size and coefficient of expansion of the polymer sheet have not yet been established. The aim of the present study was to optimize these properties in an ideal rat model of cervical compressive myelopathy. Thirty rats were used in this study. A sheet of water-absorbing polymer was inserted under the cervical laminae. Rats were divided randomly into five experimental groups by the expansion rate (350 or 200%) and thickness (0.5 or 0.7 mm) and the control. After the surgery, the severity of paralysis was evaluated for 12 weeks. At 12 weeks after the surgery, cresyl violet staining was performed to assess the number of motor neurons in the anterior horn at the C4/C5 segment and Luxol Fast Blue staining was performed to assess demyelination in the corticospinal tract at the C7 segment. 'Slow-progressive' paralysis appeared at 4-8 weeks postoperatively in rat models using sheets with 200% expansion. By contrast, only temporary paralysis was observed in rat models using sheets with 350% expansion. A loss of motor neurons in the anterior horn was observed in all groups, except for the control. Demyelination in the corticospinal tract was observed in rat models using sheets with 200% expansion, but not rat models using sheets with 350% expansion. A polymer sheet that expands its volume by 200% is an ideal material for rat models of cervical compressive myelopathy.

Exploration of Spinal Cord Aging-Related Proteins Using a Proteomics Approach.

How aging affects the spinal cord at a molecular level is unclear. The aim of this study was to explore spinal cord aging-related proteins that may be involved in pathological mechanisms of age-related changes in the spinal cord. Spinal cords of 2-year-old and 8-week-old female Sprague-Dawley rats were dissected from the animals. Protein samples were subjected to 2-dimentional polyacrylamide gel electrophoresis followed by mass spectrometry. Screened proteins were further investigated with immunohistochemistry and Western blotting. Among the screened proteins, we selected α-crystallin B-subunit (αB-crystallin) and peripherin for further investigation because these proteins were previously reported to be related to central nervous system pathologies. Immunohistochemistry and Western blotting revealed significant upregulation of αB-crystallin and peripherin expression in aged rat spinal cord. Further exploration is needed to elucidate the precise mechanism and potential role of these upregulated proteins in spinal cord aging processes.

A case of symptomatic extra-foraminal lumbosacral stenosis ("far-out syndrome") diagnosed by diffusion tensor imaging.

STUDY DESIGN: Case report. OBJECTIVE: Diagnosis of symptomatic extra-foraminal lumbosacral stenosis using diffusion tensor imaging (DTI). SUMMARY OF BACKGROUND DATA: Conventional magnetic resonance imaging (MRI) has sometimes proved inadequate for evaluating symptomatic spinal nerve lesions. DTI has been developed to visualize anisotropy of nerve-fiber tracts to evaluate nerve degeneration. We report a case of nerve compression causing a far-out lesion diagnosed using DTI. METHODS: A 68-year-old patient presented with an 8-month history of severe right-sided sciatica. Computed tomography and MRI showed right L5-S1 foraminal stenosis and contact of the L5 transverse process and S1 ala without canal stenosis at the L4-L5 level. We evaluated the fractional anisotropy (FA) of the right L5 spinal nerve and compared it with bilateral L3-S1 spinal nerves to determine the L5 spinal nerve compression site. RESULTS: DTI revealed narrowing of the right L5 spinal nerve between the L5 transverse process and S1 ala. FA was significantly decreased in the right L5 spinal nerve between the L5 transverse process and S1 ala. There was no significant difference in the FA of spinal nerves between the right and left sides at L3, L4, or S1. The right L5 spinal nerve from the central spinal canal to the extra-foraminal lumbosacral lesion was exposed during surgery and found to be severely compressed by the L5 transverse process and S1 ala. Postoperatively, the patient's symptoms disappeared immediately. CONCLUSION: We used DTI to diagnose a symptomatic lesion as an extra-foraminal lumbosacral lesion caused by compression of the L5 spinal nerve at the foramina. Because DTI can quantitatively measure damage to nerve fibers, it may be advantageous for the diagnosis of far-out syndrome.