Hirofumi Sasaki

Expansive laminoplasty for cervical myelopathy with interconnected porous calcium hydroxyapatite ceramic spacers: comparison with autogenous bone spacers.

Study Design Expansive cervical laminoplasties with interconnected porous calcium hydroxyapatite ceramic (IP-CHA) spacers were performed in cervical myelopathy patients. Objectives To evaluate the usefulness and osteoconductive capability of IP-CHA spacers in expansive laminoplasty. Summary of Background Data Expansive laminoplasty for cervical myelopathy is designed to preserve the posterior structures, so as to prevent postoperative development of instability and cervical kyphosis. The technique requires successful reconstruction of the laminae of vertebral arches, as sinking or nonunion of the expanded laminae may induce neurologic regression, segmental motor paralysis, and postoperative axial pain. A novel IP-CHA with sufficient biocompatibility and mechanical strength was developed as an artificial bone substitute. Methods Expansive open-door laminoplasties were performed in 88 cervical myelopathy patients, and both autogenous bone spacers harvested from the spinous processes and IP-CHA spacers in combination with bone marrow were alternately grafted into the opened side of each lamina. All patients were followed up with computerized tomography scans, and bonding rates for both the IP-CHA and autogenous spacers, bone fusion rates of the hinges of the laminae, and complications associated with the implants were examined. Results Clinical symptoms significantly improved in all patients without major complications related to the procedure. The IP-CHA spacers demonstrated comparable bone bonding to the autogenous spacers on postoperative computerized tomography scans. The expanded laminae withstood expanded positions without sinking or floating throughout the followups, and the hinges completely fused in more than 95% of patients in both groups within 1 year. Conclusions The IP-CHA spacer contributed to high bone fusion rates of the spacers and hinges of the laminae, and there were no complications associated with their use. Cervical laminoplasty with the IP-CHA spacers is a safe and simple method that yields sufficient fixation strength and provides sufficient bone bonding within a short period of time after operation.

Administration of human peripheral blood-derived CD133+ cells accelerates functional recovery in a rat spinal cord injury model

Study Design. Magnetically isolated, peripheral blood-derived CD133+ cells were used as the therapeutic agent of spinal cord injury (SCI). A rat model was used to investigate the hypothesis that the cell therapy using this clinically accessible cell fraction could be an attractive option for injured spinal cord. Objective. Given the capacity for the peripheral blood-derived CD133+ cells in vivo to produce neurogenesis via vasculogenesis as the feasible candidate for SCI in the clinical setting, the focus of the experiment was to investigate whether the cells could contribute to histologic and functional recovery of SCI after transplantation. Summary of Background Data. No evidence for peripheral blood-derived CD133+ cells application to SCI and no experimental studies showed functional recovery from SCI using this cell fraction have been published. Methods. Contusion SCI was induced by placing a 25-g rod onto the spinal cord for 90 seconds in athymic nude rats. CD133+ cells or phosphate-buffered saline was administered intravenously immediately after SCI. The animals were analyzed at specific times after transplantation by several methods to examine histologic vasculogenesis and neurogenesis and to confirm functional recovery from SCI. Results. After cell transplantation, intrinsic angiogenesis and axonal regeneration were enhanced, and cavity formation was reduced in injured spinal cord, histologically, with significant functional recovery. Gene expression of vascular endothelial growth factor increased in the cell-administrated group. Conclusion. The administration of CD133+ cells has a therapeutic potential to a rat spinal cord injury model and could be an optional treatment for spinal cord injury in the clinical settings.

Therapeutic effects with magnetic targeting of bone marrow stromal cells in a rat spinal cord injury model.

Study Design. Experimental rat animal study using a new cell delivery system. Objective. To investigate the therapeutic effects with magnetic targeting of bone marrow stromal cells (BMSCs) in a rat spinal cord injury (SCI) model. Summary of Background Data. Several methods to deliver therapeutic agents have been used for the treatment of SCI in animal studies. However, the most appropriate administration method for clinical application has not been established. Previously, we reported the development of a new cell delivery system using magnetic targeting. This system has potential as a clinical application for a minimally invasive and efficient transplant method in SCI. Methods. Contusion SCI was induced by placing a 25 g rod onto the spinal cord for 90 seconds in adult SD rats. A neodymium magnet was placed in the paravertebral muscles at the T7 level in the magnet group, whereas a nonmagnet metal was placed at the same spinal cord level in the nonmagnet group. Magnetically labeled BMSCs were injected into the subarachnoid space in both the magnet and nonmagnet group. Results. Aggregations of the BMSCs were detected on the surface of the injured spinal cord in the magnet group, whereas few BMSCs were observed in the nonmagnet group. Hindlimb motor function of the magnet group demonstrated significant improvement compared with that of the nonmagnet group. Conclusion. This cell delivery system may be a useful method for future clinical application in the treatment of SCI.

Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures

Study design:Organotypic coculture model using brain cortex and spinal cord of neonatal rats was used to test the effect of chondroitinase ABC (ChABC) on corticospinal axon growth.Objective:Chondroitin sulfate proteoglycan (CSPG) is neurite outgrowth inhibitory factor that combines with reactive astrocyte at the lesion site to form a dense scar that acts as a barrier to regenerating axons. ChABC is a bacteria enzyme that digests the glycosaminoglycan side chain of CSPG. We investigated the effect of ChABC on corticospinal axon growth quantitatively using the organotypic cocultures of brain cortex and spinal cord.Setting:Department of Orthopaedic Surgery, Graduate School of Biomedical Sciences, Hiroshima University.Method:We used organotypic cocultures with neonatal brain cortex and spinal cord as an in vitro assay system for assessing axon growth. After administering ChABC, we counted the number of axons passing through a reference line running parallel to the junction between the brain cortex and spinal cord 500 and 1000 μm from the junction. The immunoreactivity of CSPG was assessed.Result:The average number of axons after ChABC administration was significantly greater than in the control group. Administration of ChABC decreased CSPG expression in this coculture system.Conclusion:ChABC induces axonal regeneration by degrading CSPG after central nerve system injury. ChABC has great potential for future therapeutic use in spinal cord-injured patients.

Quantitative assessment of myelopathy patients using motor evoked potentials produced by transcranial magnetic stimulation

Motor evoked potentials (MEPs) study using transcranial magnetic stimulation (TMS) may give a functional assessment of corticospinal conduction. But there are no large studies on MEPs using TMS in myelopathy patients. The purpose of this study is to confirm the usefulness of MEPs for the assessment of the myelopathy and to investigate the use of MEPs using TMS as a screening tool for myelopathy. We measured the MEPs of 831 patients with symptoms and signs suggestive of myelopathy using TMS. The MEPs from the abductor digiti minimi (ADM) and abductor hallucis (AH) muscles were evoked by transcranial magnetic brain stimulation. Central motor conduction time (CMCT) is calculated by subtracting the peripheral conduction time from the MEP latency. Later, 349 patients had surgery for myelopathy (operative group) and 482 patients were treated conservatively (nonoperative group). CMCTs in the operative group and nonoperative group were assessed. MEPs were prolonged in 711 patients (86%) and CMCTs were prolonged in 493 patients (59%) compared with the control patients. CMCTs from the ADM and AH in the operative group were significantly more prolonged than that in the nonoperative group. All patients in the operative group showed prolongation of MEPs or CMCTs or multiphase of the MEP wave. MEP abnormalities are useful for an electrophysiological evaluation of myelopathy patients. Moreover, MEPs may be effective parameters in spinal pathology for deciding the operative treatment.

CD133+ cells from human peripheral blood promote corticospinal axon regeneration.

To assess the effect of endothelial progenitor cells on the axon growth of cortex neurons, we transplanted CD133+ cells derived from human peripheral blood to an organotypic coculture system consisting of spinal cord and cortex from neonatal rats. The axon growth from cortex to spinal cord was significantly promoted in cultures after CD133+ cells transplantation compared with that of the control cultures. In addition, real-time reverse transcription-PCR showed a significant upregulation of vascular endothelial growth factor mRNA in the spinal cord of the cultures containing CD133+ cells. In contrast, the transplanted cells did not differentiate into endothelial cells. These data suggest that CD133+ cells may promote axonal regeneration by upregulating vascular endothelial growth factor mRNA in spinal cord tissues.

Assessment of central motor conduction time in the diagnosis of compressive thoracic myelopathy.

Study Design. Prospective clinical study. Objective. The objective of this study was to investigate central motor conduction time (CMCT) values in patients with compressive thoracic myelopathy (CTM) and analyze its power to diagnose this condition. Summary of Background Data. CTM is rare and its diagnosis is often difficult, when other spinal disorders such as cervical or lumbar degenerative spondylosis supervene. Measurement of CMCT following transcranial magnetic stimulation is a useful means to evaluate the electrophysiological functions of the corticospinal tract; however, there are few reports describing CMCT values among patients with CTM. Methods. Motor-evoked potentials following transcranial magnetic stimulation, and compound muscle action potentials and F-waves following electrical stimulation in the ulnar and tibial nerves were measured from the abductor digiti minimi (ADM) and abductor hallucis (AH) muscles in 20 patients with CTM, 92 patients with compressive cervical myelopathy (CCM), and 18 control subjects. The CMCT detected from the ADM (CMCT-ADM), the AH (CMCT-AH), and the CMCT-ADM/AH ratio (CMCT-ADM/CMCT-AH) were calculated. Results. The CMCT-AHs in patients with CTM were significantly longer than in control subjects, although there were no significant differences in the CMCT-ADMs. In contrast, both the CMCT-ADMs and CMCT-AHs in the CCM group were significantly longer than those of the control group. The CMCT-ADM/AH ratios in the CTM group were significantly lower than those of the other groups. Among the CTM and CCM groups, when the cutoff point of the CMCT-ADM/AH ratio was set at equal to or lower than 0.52, i.e., the mean CMCT-ADM/AH ratio in the control group, the odds ratio for CTM was 68.4 (95% confidence interval: 8.62–543; P < 0.001). Conclusion. Our data showed a significant pattern of CMCT parameters and low CMCT-ADM/AH ratios in patients with CTM. The measurement of CMCT is valuable as a noninvasive technique for screening patients with CTM or CCM before magnetic resonance imaging.

The effects of combining chondroitinase ABC and NEP1-40 on the corticospinal axon growth in organotypic co-cultures

The area surrounding the injured spinal cord is a non-permissive milieu for axonal growth due to the inhibitory factors, especially chondroitin sulfate proteoglycan (CSPG) and Nogo. Recent studies have reported that chondroitinase ABC (ChABC) or Nogo-66(1-40) antagonist peptide (NEP1-40) promote axonal growth after spinal cord injury. But no study has addressed the effects on spinal cord injury of combining ChABC and NEP1-40. Previously, we described an organotypic co-culture system using the brain cortex and spinal cord from neonatal rats. In this study, we examined whether the combination of ChABC and NEP1-40 creates an action that promotes corticospinal axon growth in organotypic co-cultures. Organotypic co-cultures of brain and spinal cord were prepared from rats, and ChABC or NEP1-40 was delivered to them. To examine the effects of this combination these two drugs were applied together. We counted the number of labeled axons with DiI and assessed the immunoreactivity of CSPG and Nogo. Axonal growth was enhanced by infusing ChABC or NEP1-40 compared with that in the control group, whereas synergistic effects of combined administration of ChABC and NEP1-40 on axonal growth were not observed. There is a possibility that ChABC and NEP1-40 affect the same intracellular pathways and have no synergistic influence on axonal growth.

Clinical results of cervical myelopathy in patients older than 80 years of age: evaluation of spinal function with motor evoked potentials.

OBJECT In this prospective analysis the authors describe the clinical results of surgical treatment in patients > 80 years of age in whom spinal function was evaluated with motor evoked potential (MEPs) monitoring. METHODS The authors included 57 patients > 80 years of age who were suspected of having cervical myelopathy. The mean age of the patients was 83.0 years (range 80-90 years). The central motor conduction time (CMCT) was calculated from the latencies of the MEPs following transcranial magnetic stimulation and from M and F waves following peripheral nerve stimulation. RESULTS Preoperative electrophysiological evaluation demonstrated significant elongation of CMCT or abnormalities in MEP waveforms in 37 patients (65%), and 35 patients of these underwent laminoplasty. In 30 patients cervical spondylotic myelopathy was diagnosed and 5 patients ossification of the posterior longitudinal ligament was diagnosed. The preoperative mean Japanese Orthopaedic Association Scale score was 8.6 (range 3-12.5) and the mean postoperative score was 12.6 (range 6-14.5) with an average recovery rate of 45% (range -21 to 100%). There were no major complications in any of the patients during the operative period and there were no cases of death resulting from operative intervention. CONCLUSIONS Sufficient clinical results are expected even in patients with myelopathy who are older than 80 years of age, provided the patients are correctly selected by electrophysiological evaluation with MEPs and CMCT.