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.

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.

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.

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.

Dropped head syndrome after cervical laminoplasty: A case control study.

Dropped head syndrome (DHS) is characterized by apparent neck extensor muscle weakness and difficulty extending the neck to raise the head against gravity. The aim of the present study was to elucidate possible risk factors for DHS after cervical laminoplasty. Five patients who developed DHS after cervical laminoplasty (DHS group) and twenty age-matched patients who underwent laminoplasty without DHS after surgery (control group) were compared. The surgical procedure was single-door laminoplasty with strut grafting using resected spinous processes or hydroxyapatite spacers from C3 to C6 or C7. Analyses of preoperative images including the C2-C7 angle, C7-T1 kyphosis, T1 tilt, center of gravity line from the head-C7 sagittal vertical axis (CGH-C7 SVA) were performed on lateral plain cervical spine radiographs. Preoperative T2-weighted MRI at the C5 vertebral level was used to measure the cross-sectional area of the deep extensor muscles. Widths of the lateral gutters were assessed postoperatively using CT scans of the C5 vertebral body. The average preoperative C2-C7 angle was significantly smaller in the DHS group compared with the control group. The average preoperative C7-T1 angle was significantly larger in the DHS group compared with the control group. The average preoperative CGH-C7 SVA was significantly larger in the DHS group compared with the control group. In conclusion, patients with more pronounced preoperative C2-C7 kyphosis, C7-T1 kyphosis, and CGH-C7 SVA are more likely to develop DHS following laminoplasty.

Addition of instrumented fusion after posterior decompression surgery suppresses thickening of ossification of the posterior longitudinal ligament of the cervical spine.

Laminoplasty (LMP) is a widely accepted surgical procedure for ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. Progression of OPLL can occur in the long term after LMP. The aim of the present study was to determine whether addition of the instrumented fusion, (posterior decompression with instrumented fusion [PDF]), can suppress progression of OPLL or not. The present study included 50 patients who underwent LMP (n=23) or PDF (n=27) for OPLL of the cervical spine. We performed open door laminoplasty. PDF surgery was performed by double-door laminoplasty followed by instrumented fusion. We observed the non-ossified segment of the OPLL and measured the thickness of the OPLL at the thickest segment with pre- and postoperative sagittal CT multi-planar reconstruction images. Postoperative CT scan revealed fusion of the non-ossified segment of the OPLL was obtained in 4/23 patients (17%) in the LPM group and in 23/27 patients (85%) in the PDF group, showing a significant difference between both groups (p=0.003). Progression of the thickness of the OPLL in the PDF group (-0.1±0.4mm) was significantly smaller than in the LMP group (0.6±0.7mm, p=0.0002). The proportion of patients showing the decrease in thickness of OPLL was significantly larger in the PDF group (6/27 patients; 22%) than in the LMP group (0/23 patients; 0%, p=0.05). In conclusion, PDF surgery can suppress the thickening of OPLL.