Akihiko Okawa

An analysis of factors causing poor surgical outcome in patients with cervical myelopathy due to ossification of the posterior longitudinal ligament: anterior decompression with spinal fusion versus laminoplasty.

Objective We compared the surgical outcome of anterior decompression with spinal fusion (ASF) with the surgical outcome of laminoplasty for patients with cervical myelopathy due to ossification of the posterior longitudinal ligament. Methods The study group comprised 19 ASF patients (A-group) and 40 laminoplasty patients (P-group) treated from 1993 to 2002 with 1 year or longer follow-up. The Japanese Orthopedic Association scoring system was used to evaluate cervical myelopathy, and the recovery rate calculated 1 year after surgery. Results The mean recovery rate was 68.4% in the A-group and 52.5% in the P-group (P<0.05). Fifteen patients had a recovery rate less than 40%: 2 in the A-group and 13 in the P-group. One P-group patient and none of the A-group patients developed postoperative aggravation of their neurologic status. The P-group was divided into 2 subgroups: a good outcome group comprising patients whose recovery rate was 40% or higher (n=27) and a poor outcome group comprising patients whose recovery rate was less than 40% (n=13). The mean age at surgery was 59.9 years in the good outcome group and 68.0 years in the poor outcome group (P<0.05). The mean range of intervertebral mobility at maximum cord compression level before surgery was 6.9 degrees in the good outcome group and 10 degrees in the poor outcome group (P<0.05). Conclusions These results demonstrated that the surgical outcome of ASF was superior to the surgical outcome of laminoplasty. Elderly patients treated with laminoplasty showed an especially poor surgical outcome. We suggest that hypermobility of vertebrae at the cord compression level is a risk factor for poor surgical outcome after laminoplasty. Based on these results, we recommend that ASF should be the first choice of treatment for patients with significant ossification of the posterior longitudinal ligament and a hypermobile cervical spine. When laminoplasty is used for such cases, the addition of posterior instrumented fusion would be desirable for stabilizing the spine and decreasing damage to the spinal cord.

Granulocyte colony-stimulating factor (G-CSF) mobilizes bone marrow-derived cells into injured spinal cord and promotes functional recovery after compression-induced spinal cord injury in mice

The aim of the present study was to elucidate the effects of granulocyte colony-stimulating factor (G-CSF)-mediated mobilization of bone marrow-derived stem cells on the injured spinal cord. Bone marrow cells of green fluorescent protein (GFP) transgenic mice were transplanted into lethally irradiated C57BL/6 mice. Four weeks after bone marrow transplantation, spinal cord injury was produced by a static load (20 g, 5 min) at T8 level. G-CSF (200 microg/kg/day) was injected subcutaneously for 5 days. Immunohistochemistry for GFP and cell lineage markers was performed to evaluate G-CSF-mediated mobilization of bone marrow-derived cells into injured spinal cord. Hind limb locomotor recovery was assessed for 6 weeks. Immunohistochemistry revealed that G-CSF increased the number of GFP-positive cells in injured spinal cord, indicating that bone marrow-derived cells were mobilized and migrated into injured spinal cord. The numbers of double positive cells for GFP and glial markers were larger in the G-CSF treated mice than in the control mice. Luxol Fast Blue staining revealed that G-CSF promoted white matter sparing. G-CSF treated mice showed significant recovery of hind limb function compared to that of the control mice. In conclusion, G-CSF showed efficacy for spinal cord injury treatment through mobilization of bone marrow-derived cells.

A new concept for making decisions regarding the surgical approach for cervical ossification of the posterior longitudinal ligament: the K-line.

Study Design. To report a new index, the K-line, for deciding the surgical approach for cervical ossification of the posterior longitudinal ligament (OPLL). Objective. To analyze the correlation between the K–line-based classification of cervical OPLL patients and their surgical outcome. Summary of Background Data. Previous studies showed that kyphotic alignment of the cervical spine and a large OPLL are major factors causing poor surgical outcome after laminoplasty for cervical OPLL patients. However, no report has evaluated these 2 factors in 1 parameter. Methods. The K-line was defined as a line that connects the midpoints of the spinal canal at C2 and C7. Twenty-seven patients who had cervical OPLL and underwent posterior decompression surgery were classified into 2 groups according to their K-line classification. OPLL did not exceed the K-line in the K-line (+) group and did exceed it in the K-line (−) group. By intraoperative ultrasonography, we evaluated the posterior shift of the spinal cord after the posterior decompression procedure. The Japanese Orthopedic Association scores before surgery and 1 year after surgery were evaluated, and the recovery rate was calculated. Results. Eight patients were classified as K-line (−), and 19 patients were classified as K-line (+). The mean recovery rate was 13.9% in the K-line (−) group and 66.0% in the K-line (+) group (P < 0.01). Ultrasonography showed that the posterior shift of the spinal cord was insufficient in the K-line (−) group. Conclusion. The present results demonstrate that a sufficient posterior shift of the spinal cord and neurologic improvement will not be obtained after posterior decompression surgery in the K-line (−) group. Our new index, the K-line, is a simple and practical tool for making decisions regarding the surgical approach for cervical OPLL patients.

FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion

The spontaneous dominant mouse mutant, Elbow knee synostosis (Eks), shows elbow and knee joint synosotsis, and premature fusion of cranial sutures. Here we identify a missense mutation in the Fgf9 gene that is responsible for the Eks mutation. Through investigation of the pathogenic mechanisms of joint and suture synostosis in Eks mice, we identify a key molecular mechanism that regulates FGF9 signaling in developing tissues. We show that the Eks mutation prevents homodimerization of the FGF9 protein and that monomeric FGF9 binds to heparin with a lower affinity than dimeric FGF9. These biochemical defects result in increased diffusion of the altered FGF9 protein (FGF9Eks) through developing tissues, leading to ectopic FGF9 signaling and repression of joint and suture development. We propose a mechanism in which the range of FGF9 signaling in developing tissues is limited by its ability to homodimerize and its affinity for extracellular matrix heparan sulfate proteoglycans.

Granulocyte colony-stimulating factor attenuates neuronal death and promotes functional recovery after spinal cord injury in mice

Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of granulocytic lineage cells. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction. The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for spinal cord injury (SCI) in mice. We found that G-CSF is neuroprotective against glutamate-induced cell death of cerebellar granule neurons in vitro. Moreover, we used a mouse model of compressive SCI to examine the neuroprotective potential of G-CSF in vivo. Histologic assessment with cresyl violet staining revealed that the number of surviving neurons in the injured spinal cord was significantly increased in G-CSF-treated mice. Immunohistochemistry for neuronal apoptosis revealed that G-CSF suppressed neuronal apoptosis after SCI. Moreover, administration of G-CSF promoted hindlimb functional recovery. Examination of signaling pathways downstream of the G-CSF receptor suggests that G-CSF might promote functional recovery by inhibiting neuronal apoptosis after SCI. G-CSF is currently used in the clinic for hematopoietic stimulation, and its ongoing clinical trial for brain infarction makes it an appealing molecule that could be rapidly placed into trials for patients with acute SCI.

Clinical results of surgery for thoracic myelopathy caused by ossification of the posterior longitudinal ligament: operative indication of posterior decompression with instrumented fusion.

Study Design. This retrospective study was conducted to investigate the clinical outcomes of several surgical procedures for thoracic myelopathy caused by ossification of the posterior longitudinal ligament (OPLL). Objective. To evaluate the effect of myelopathy treatment and safety of posterior decompression with instrumented fusion. Summary of Background Data. Many different surgical procedures have been used for the treatment of thoracic OPLL. However, the possibility of postoperative paraplegia remains a major risk, and consistent protocols and procedures for surgical treatment of thoracic OPLL have also not been established. Methods. A total of 51 patients who underwent surgery for thoracic OPLL were classified into 3 groups: (1) posterior decompression group (18 patients), which included 12 who underwent laminectomy and 6 who underwent cervicothoracic laminoplasty; (2) OPLL extirpation group (16 patients), which included 4 who underwent anterior decompression through thoracotomy and 12 who underwent anterior decompression through the posterior approach; and (3) posterior decompression and fusion group (17 patients), all of whom underwent laminectomy with posterior instrumented fusion. In each group, the Japanese Orthopedic Association score was used to evaluate thoracic myelopathy, and the recovery rate calculated 1 year after surgery and at final examination. Results. Mean recovery rate at final follow-up was 41.9% in the posterior decompression group, 62.1% in the OPLL extirpation group, and 59.3% in the posterior decompression and fusion group. Postoperative paralysis occurred in 3 patients in the posterior decompression group and in 3 in the OPLL extirpation group. In the OPLL extirpation group, leakage of cerebrospinal fluid occurred in 8 patients and hydrothorax in 2. Late neurologic deterioration occurred in 7 patients in the posterior decompression group. There were no cases of postoperative paralysis or late neurologic deterioration in the posterior decompression and fusion group. Conclusions. A considerable degree of neurologic recovery was obtained by posterior decompression with instrumented fusion, despite the anterior impingement of the spinal cord by OPLL remaining. In addition, the rate of postoperative complications was extremely low with this procedure. We recommend that 1-stage posterior decompression and instrumented fusion be selected for patients in whom the spinal cord is severely damaged before surgery and/or when extirpation of OPLL is associated with increased risk.

Anomalous vertebral artery at the extraosseous and intraosseous regions of the craniovertebral junction: analysis by three-dimensional computed tomography angiography.

Study Design. This study examined the extraosseous and intraosseous anomalies of vertebral arteries in patients who underwent surgery of the craniovertebral junction. Objectives. To describe the usefulness of three-dimensional computed tomography angiography for evaluating vertebral artery anomalies before surgery. Summary of Background Data. Previous studies using catheter angiograms have identified anomalous courses of the vertebral artery at the craniovertebral junction. Studies using computed tomography reconstruction also showed deviation of the vertebral artery groove at the C2 isthmus, demonstrating a risk of vertebral artery injury for C1–C2 transarticular screw placement. These analyses provided us with useful information for identifying anomalies of the vertebral artery, but they could not visualize the artery and its circumferential osseous tissue simultaneously, nor could they analyze the reciprocal anatomy of both tissues. Methods. Thirty-one consecutive patients who submitted to surgery at the craniovertebral junction were evaluated before surgery by three-dimensional computed tomography angiography. Eleven of the patients had congenital osseous anomalies at the craniovertebral junction including os odontoideum and ossiculum terminale. Anomalous vertebral arteries at the extraosseous region were visualized by three-dimensional reconstruction images, and the intraosseous deviation of the vertebral artery at the C2 isthmus was evaluated by multiplanar reconstruction images. Results. Extraosseous and/or intraosseous vertebral artery anomalies were detected in 9 cases. Eight of the 9 cases had osseous anomalies at the craniovertebral junction. Abnormal courses of the vertebral artery at the extraosseous region were detected in 4 cases: 2 had fenestration and 2 had persistent first intersegmental artery. Asymmetry of bilateral vertebral arteries was found in 5 cases: the right was dominant in 3 cases and the left in 2 cases. A high-riding vertebral artery at the C2 isthmus was detected in 5 cases. Based on these findings, we modified our surgical approach and the screw placement; consequently, no vertebral artery injury occurred. Conclusions. In patients having osseous anomalies at the craniovertebral junction, the frequency of vertebral artery anomalies at the extraosseous and intraosseous regions is increased. With preoperative three-dimensional computed tomography angiography, we can precisely identify the anomalous vertebral artery and reduce the risk of intraoperative injury to the vertebral artery, in advance.

Anomalous vertebral arteries in the extra- and intraosseous regions of the craniovertebral junction visualized by 3-dimensional computed tomographic angiography: analysis of 100 consecutive surgical cases and review of the literature.

Study Design. Consecutive case series and literature review. Objective. To describe the utility of 3-dimensional computed tomographic angiography (3D CTA) for evaluating vertebral artery (VA) anomalies before surgery. Summary of Background Data. Recent advances in instrumentation surgery at the craniovertebral junction (CVJ) enable us to perform rigid internal fixation. However, the risk of VA injury as a complication of the surgery has become a major problem. Thus, the importance of preoperative evaluation of the VA course has been emphasized. Methods. Cases of 100 consecutive patients who underwent CVJ instrumentation surgery since July 1998 were analyzed. Occipitocervical/thoracic or C1–C2 posterior fusion was performed for atlantoaxial subluxation (AAS) in 59 patients and cervical fixation including C2 was required for middle-to-lower cervical lesions in 41 patients. Twenty-seven patients with AAS had a congenital skeletal anomaly (CSA) at the CVJ including os odontoideum and occipitalization of C1 (AAS-CSA[+] group). Anomalous VAs at the extra- and intraosseous regions were evaluated by 3D CTA. Results. No neurovascular injury occurred during surgery. Abnormal courses of the VA at the extraosseous region were detected in 10 cases: 2 had fenestration and 8 had a persistent first intersegmental artery. All 10 cases were in the AAS-CSA(+) group. A high-riding VA was detected in 31 cases. Fourteen out of the 31 cases were in the AAS-CSA(+) group, indicating 51.9% of the AAS-CSA(+) group had high-riding VA. In the AAS-CSA(+) group, a C1–C2 transarticular screw and C2 pedicle screw were actually inserted in 58% and 31% of the planned insertions, respectively. Conclusion. The present findings suggest that the frequency of an abnormal VA at the extra- and intraosseous regions is increased when patients have AAS and CSA at the CVJ. Using preoperative 3D CTA, we can precisely identify anomalous VAs and thereby reduce the risk of their intraoperative injury.

C5 palsy following anterior decompression and spinal fusion for cervical degenerative diseases

Postoperative C5 palsy is a common complication after cervical spine decompression surgery. However, the incidence, prognosis, and etiology of C5 palsy after anterior decompression with spinal fusion (ASF) have not yet been fully established. In the present study, we analyzed the clinical and radiological characteristics of patients who developed C5 palsy after ASF for cervical degenerative diseases. The cases of 199 consecutive patients who underwent ASF were analyzed to clarify the incidence of postoperative C5 palsy. We also evaluated the onset and prognosis of C5 palsy. The presence of high signal changes (HSCs) in the spinal cord was analyzed using T2-weighted magnetic resonance images. C5 palsy occurred in 17 patients (8.5%), and in 15 of them, the palsy developed after ASF of 3 or more levels. Among ten patients who had a manual muscle test (MMT) grade ≤2 at the onset, five patients showed incomplete or no recovery. Sixteen of the 17 C5 palsy patients presented neck and shoulder pain prior to the onset of muscle weakness. In the ten patients with a MMT grade ≤2 at the onset, nine patients showed HSCs at the C3–C4 and C4–C5 levels. The present findings demonstrate that, in most patients with severe C5 palsy after ASF, pre-existing asymptomatic damage of the anterior horn cells at C3–C4 and C4–C5 levels may participate in the development of motor weakness in combination with the nerve root lesions that occur subsequent to ASF. Thus, when patients with spinal cord lesions at C3–C4 and C4–C5 levels undergo multilevel ASF, we should be alert to the possible occurrence of postoperative C5 palsy.

Transplantation of human bone marrow stromal cell-derived Schwann cells reduces cystic cavity and promotes functional recovery after contusion injury of adult rat spinal cord

The aim of this study was to evaluate whether transplantation of human bone marrow stromal cell‐derived Schwann cells (hBMSC‐SC) promotes functional recovery after contusive spinal cord injury of adult rats. Human bone marrow stromal cells (hBMSC) were cultured from bone marrow of adult human patients and induced into Schwann cells (hBMSC‐SC) in vitro. Schwann cell phenotype was confirmed by immunocytochemistry. Growth factors secreted from hBMSC‐SC were detected using cytokine antibody array. Immunosppressed rats were laminectomized and their spinal cords were contused using NYU impactor (10 g, 25 mm). Nine days after injury, a mixture of Matrigel and hBMSC‐SC (hBMSC‐SC group) was injected into the lesioned site. Five weeks after transplantation, cresyl‐violet staining revealed that the area of cystic cavity was smaller in the hBMSC‐SC group than that in the control group. Immunohistochemstry revealed that the number of anti‐growth‐associated protein‐43‐positive nerve fibers was significantly larger in the hBMSC‐SC group than that in the control group. At the same time, the number of tyrosine hydroxylase‐ or serotonin‐positive fibers was significantly larger at the lesion epicenter and caudal level in the hBMSC‐SC group than that in the control group. In electron microscopy, formation of peripheral‐type myelin was recognized near the lesion epicenter in the hBMSC‐SC group. Hind limb function recovered significantly in the hBMSC‐SC group compared with the control group. In conclusion, the functions of hBMSC‐SC are comparable to original Schwann cells in rat spinal cord injury models, and are thus potentially useful treatments for patients with spinal cord injury.