Published papers

OBJECT: Although neurological examination is the key step to reaching a correct diagnosis of cervical compressive myelopathy (CCM), the accuracy of diagnosis of the affected spinal level for CCM has not yet been tested. METHODS: The authors conducted a prospective study to elucidate how accurately the affected intervertebral level can be determined and decompressed based on neurological examination. Fifty patients who underwent successful decompressive surgery for cervical myelopathy caused by single-level disc herniation or spondylosis were included in this study (38 men and 12 women, mean age 60 years). Three board-certified spine surgeons participated in establishing the neurological diagnoses. One of the three surgeons made a diagnosis of CCM, and the other two conducted the neurological examination including deep tendon reflex, pinprick response, muscle weakness, and numbness in the hand only, knowing that the patient had CCM, and established the neurological-level diagnosis. A single intervertebral level responsible for patient's symptoms was determined concordantly based on magnetic resonance imaging and myelography findings by two spine surgeons, and this served as the standard. Agreement between neurological and neuroimaging/radiological level diagnoses was determined. The rate of agreement between neurological and neuroimaging diagnosis was 66%. Among the neurological tests, patient-perceived location of numbness in the hands was the most useful for establishing the affected level. For the other three tests the agreement rate was lower than 50% and thus each individual test may not be reliable for diagnosing the affected level. CONCLUSIONS: The results of this study suggested that neurological examination in patients with CCM is moderately accurate and reliable for determining the neurological level of disease.

Recent studies have shown that delayed transplantation of neural stem/progenitor cells (NSPCs) into the injured spinal cord can promote functional recovery in adult rats. Preclinical studies using nonhuman primates, however, are necessary before NSPCs can be used in clinical trials to treat human patients with spinal cord injury (SCI). Cervical contusion SCIs were induced in 10 adult common marmosets using a stereotaxic device. Nine days after injury, in vitro-expanded human NSPCs were transplanted into the spinal cord of five randomly selected animals, and the other sham-operated control animals received culture medium alone. Motor functions were evaluated through measurements of bar grip power and spontaneous motor activity, and temporal changes in the intramedullary signals were monitored by magnetic resonance imaging. Eight weeks after transplantation, all animals were sacrificed. Histologic analysis revealed that the grafted human NSPCs survived and differentiated into neurons, astrocytes, and oligodendrocytes, and that the cavities were smaller than those in sham-operated control animals. The bar grip power and the spontaneous motor activity of the transplanted animals were significantly higher than those of sham-operated control animals. These findings show that NSPC transplantation was effective for SCI in primates and suggest that human NSPC transplantation could be a feasible treatment for human SCI. © 2005 Wiley-Liss, Inc.

Most previous studies on spinal cord injury (SCI) have used rodent models. Direct extrapolation of the results obtained in rodents to clinical cases is difficult, however, because of neurofunctional and anatomic differences between rodents and primates. In the present study, the development of histopathologic changes and functional deficits were assessed quantitatively after mild, moderate, and severe spinal cord contusive injuries in common marmosets. Contusive SCI was induced by dropping one of three different weights (15, 17, or 20 g) at the C5 level from a height of 50 mm. Serial magnetic resonance images showed significant differences in the intramedullary T1 low signal and T2 high signal areas among the three groups. Quantitative histologic analyses revealed that the number of motor neurons, the myelinated areas, and the amounts of corticospinal tract fibers decreased significantly as the injury increased in severity. Motor functions were evaluated using the following tests: original behavioral scoring scale, measurements of spontaneous motor activity, bar grip test, and cage-climbing test. Significant differences in all test results were observed among the three groups. Spontaneous motor activities at 10 weeks after injury were closely correlated with the residual myelinated area at the lesion epicenter. The establishment of a reliable nonhuman primate model for SCI with objective functional evaluation methods should become an essential tool for future SCI treatment studies. Quantitative behavioral and histopathologic analyses enabled three distinct grades of injury severity (15-g, 17-g, and 20-g groups) to be characterized with heavier weights producing more serious injuries, and relatively constant behavioral and histopathologic outcomes. © 2005 Wiley-Liss, Inc.

Advances in the stem cell biology of the central nervous system (CNS) and other studies enhance the possibility of regeneration of the damaged CNS, which has previously been considered to be almost impossible. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are vital factors for improving the functional recovery of the damaged CNS. Because the immediate post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it does not favor the survival and differentiation of the transplants. Furthermore, in the chronic disease stage after injury, glial scars that inhibit the regeneration of neuronal axons form in the injured site. Thus, we consider that the optimal period of transplantation is 1-2 weeks after injury.

OBJECT: Structural interlaminar graft materials were used for atlantoaxial transarticular screw fixation (TSF), and its impact on the fusion status was investigated. METHODS: Forty-two patients (10 men, 32 women, mean age 51 years, mean follow-up period 45 months; 30 with rheumatoid arthritis, and 12 with os odontoideum) underwent TSF and modified Brooks posterior wiring involving titanium cables. As interlaminar graft materials, autologous bone from posterior iliac crest alone was used in 20 patients (Group A), and a structural spacer (13 ceramic spacers, nine titanium mesh cages) in 22 (Group B). Lateral radiographs were evaluated to determine bone fusion, alignment of the cervical spine, and wire loosening. Solid osseous fusion was obtained in 95% of Group A and 96% of Group B patients. The mean atlantoaxial angle was 19.1+/-9.7 degrees and 16.7+/-10.4 degrees before surgery (p = 0.45), and 27.4+/-7.8 degrees and 22.1+/-5.5 degrees after surgery (p = 0.02) in Groups A and B, respectively. Atlantoaxial hyperlordosis (atlantoaxial angle > or = 30 degrees) was observed in 32% of Group A and 18% of Group B patients (p = 0.26). Postoperative kyphosis occurred in 40% of Group A and 23% of Group B patients (p = 0.28). Loosening of the cable was demonstrated in 50% of Group A and 36% of Group B patients(p = 0.37). In Group B patients maintenance of cervical lordosis was more likely than in those in Group A, although the differences did not reach statistical significance. CONCLUSIONS: These results indicate that structural interlaminar spacers can maintain proper cervical alignment without a decease in the fusion rate; the authors recommend their use in conjunction with TSF.

Recently, we have shown that the transplantation of spinal-cord-derived neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cords in adult rats, which may correspond to a behavioral recovery. To apply these results to clinical practice, a system for supplying human NSPCs on a large scale must be established. However, human spinal-cord-derived NSPCs are known to have a low proliferation rate, compared with forebrain-derived NSPCs. This low proliferative potency limits the feasibility of large-scale spinal cord-derived NSPC use. Thus, forebrain-derived NSPCs should be examined as an alternative to spinal-cord-derived NSPCs for the treatment of spinal cord injuries. In this study, we compared spinal-cord- and forebrain-derived NSPCs transplanted into injured spinal cords with respect to their fates in vivo as well as the animals' functional recovery. Both spinal-cord- and forebrain-derived NSPCs promoted functional recovery in rats with spinal cord injuries. While both spinal-cord- and fore-brain-derived NSPCs survived, migrated and differentiated into neurons, astrocytes and oligodendrocytes in response to the microenvironment within the injured spinal cord after transplantation, forebrain-derived NSPCs differentiated into more neurons and fewer oligodendrocytes, compared to spinal-cord-derived NSPCs. Neurons that had differentiated from the transplanted forebrain-derived NSPCs were shown to be positive for neurotransmitters like GABA, glutamate and glycine, although authentic glycinergic neurons are not normally present within the forebrain. Thus, at least a subpopulation of the transplanted forebrain-derived NSPCs differentiated into spinal-cord-type neurons. In conclusion, forebrain-derived NSPCs could be used as an alternative to spinal-cord-derived NSPCs as a potential therapeutic agent for spinal cord injuries. Copyright © 2004 S. Karger AG.

OBJECT: Numerous surgical procedures have been developed for treatment of ossification of the posterior longitudinal ligament (OPLL) of the cervical spine, and these can be performed via three approaches: anterior, posterior, or combined anterior-posterior. The optimal approach in cases involving OPLL-induced cervical myelopathy, however, remains controversial. To address this issue, the authors assessed the benefits and limitations of expansive open-door laminoplasty for OPLL-related myelopathy by evaluating mid- and long-term clinical results. METHODS: Clinical results obtained in 72 patients who underwent expansive open-door laminoplasty between 1983 and 1997 and who were followed for at least 5 years were assessed using the Japanese Orthopaedic Association (JOA) scoring system. The mean preoperative JOA score was 9.2 +/- 0.4; at 3 years postoperatively, the JOA score was 14.2 +/- 0.3 and the recovery rate (calculated using the Hirabayashi method) was 63.1 +/- 4.5%, both having reached their highest level. These favorable results were maintained up to 5 years after surgery. An increase in cervical myelopathy due to progression of the ossified ligament was observed in only two of 30 patients who could be followed for more than 10 years. Severe surgery-related complications were not observed. Preoperative JOA score, age at the time of surgery, and duration between onset of initial symptoms and surgery affected clinical results. CONCLUSIONS: Mid-term and long-term results of expansive open-door laminoplasty were satisfactory. Considering factors that affected surgical results, early surgery is recommended for OPLL of the cervical spine.

Objective: We sought to determine factors likely to influence postoperative changes in cervical spinal curvature and range of motion (ROM) in patients with cervical spinal cord tumors. Methods: Fifty-one patients who underwent tumor excision via a single posterior approach were examined. Surgical methods were classified as follows: group A, expansive open-door laminoplasty (ELAP); group B, conventional laminectomy; and group C, hemilaminectomy (HL). Pre- and postoperative cervical spinal curvature, cervical curvature type, and ROM were evaluated using lateral radiographs. Results: Worsening of cervical curvature type was statistically less frequent in group C than in group A or B (P < 0.05), although no significant difference was evident overall between pre- and postoperative cervical curvature indexes or ROM in any group. Cases of C2 surgery showed more frequent curvature worsening (80%) in group A than in other groups (P < 0.05). Postoperative changes of the cervical curvature in patients with cervical spinal cord tumors were greatly influenced by the surgical method; the cervical curvature was particularly unfavorable when patients had C2 decompression. Conclusions: Careful attention to postoperative changes in the spinal curvature is needed when ELAP is performed, especially if surgery involves C2. HL is the best posterior approach for resection of cervical spinal cord tumors from the viewpoint of postoperative spinal curvature and ROM.

We report a treatment for spinal cord injury involving implantation of dendritic cells (DCs), which act as antigen-presenting cells in the immune system. The novel mechanisms underlying this treatment produce functional recovery. Among the immune cells tested, DCs showed the strongest activity inducing proliferation and survival of neural stem/progenitor cells (NSPCs) in vitro. Furthermore, in DC-implanted adult mice, endogenous NSPCs in the injured spinal cord were activated for mitotic de novo neurogenesis. These DCs produced neurotrophin-3 and activated endogenous microglia in the injured spinal cord. Behavioral analysis revealed the locomotor functions of DC-implanted mice to have recovered significantly as compared to those of control mice. Our results suggest that DC-implantation exerts trophic effects, including activation of endogenous NSPCs, leading to repair of the injured adult spinal cord. © 2004 Wiley-Liss, Inc.

Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin-6 (IL-6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti-mouse IL-6 receptor monoclonal antibody (MR16-1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16-1 (100 μg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16-1 not only suppressed the astrocytic diffentiation-promoting effect of IL-6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16-1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16-1 compared with control mice. These findings suggest that neutralization of IL-6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI. © 2004 Wiley-Liss, Inc.

Object. Pain is one of the major symptoms in patients with syringomyelia; however, its origin is not fully understood, and postoperative improvement of pain is difficult to predict. The objectives of this study were to assess the surgery-related results obtained in patients who underwent treatment for syringomyelia associated with Chiari I malformation, particularly related to pain status, and to identify factors that may influence improvement in postoperative pain by comparing pre- and postoperative magnetic resonance (MR) imaging findings. Methods. The correlation between pre- and postoperative changes in the size and the location of the syrinx and pain improvement was investigated in 25 patients. The shapes of the syringes were classified into three types: central, enlarged, and deviated. In most cases in which the syrinx deviated toward the posterolateral aspect of the spinal cord at the level corresponding to dermatomal distribution of preoperative pain, the lesion remained at the same position postoperatively, and improvement in pain was poor. On the other hand, enlarged-type syringes were the most frequently observed prior to surgery, exhibited diverse changes postoperatively, and improvement in pain status was difficult to predict. When postoperative MR imaging revealed a transformation to the deviated type, poor pain improvement was noted. Conclusions. Neurons in the dorsal horn were thought to be involved in the development of pain as a result of the deafferentiation mechanism in cases of syringomyelia.

Recovery from central nervous system damage in adult mammals is hindered by their limited ability to replace lost cells and damaged myelin, and reestablish functional neural connections. However, recent progresses in stem cell biology are making it feasible to induce the regeneration of injured axons after spinal cord injury. Transplantation of in vitro expanded neural stem cells into rat spinal cord 9 days after contusion injury induced their differentiation into neurons and oligodendrocytes, and the functional recovery of skilled forelimb movement. It was partly because the microenvironment within the injured spinal cord at 9 days after injury was more favorable for grafted neural stem cells in terms of their survival and differentiation.

We analyzed dynamic processes of neural excitation propagation in the experimentally compressed spinal cord using a high-speed optical recording system. Transverse slices of the juvenile rat cervical spinal cord were stained with a voltage-sensitive dye (di-4-ANEPPS). Two components were identified in the depolarizing optical responses to dorsal root electrical stimulation: a fast component of short duration corresponding to pre-synaptic excitation and a slow component of long duration corresponding to post-synaptic excitation. In the directly compressed dorsal horn, the slow component was attenuated more (attenuated to 37.4 ± 9.1% of the control) than the fast component (to 70.5 ± 14.9%) (p < 0.01) at 400 msec after stimulation. Depolarizing optical responses to compression and to chemical synaptic blockade were similar. There was a regional difference between white matter (attenuated to 86.2 ± 10.5%) and gray matter (to 72.6 ± 10.4%) (p < 0.03) in compression-induced changes of the fast components; neural activity in the white matter was resistant to compression, especially in the dorsal root entry zone. Depolarizing optical signals in the region adjacent to the directly compressed site were also attenuated; the fast component was attenuated to 77.6 ± 10.4% and the slow component to 31.8 ± 11.3% of the control signals (p < 0.01). Spinal cord dysfunction induced by purely mechanical compression without tissue destruction was virtually restored with early decompression. We suggest that a disturbance of synaptic transmission plays an important role in the pathophysiological mechanisms of spinal cord compression, at least under in vitro experimental conditions of juvenile rats.

It is likely that the environment within the injured spinal cord influences the capacity of fetal spinal cord transplants to support axonal growth. We have recently demonstrated that fetal spinal cord transplants and neurotrophin administration support axonal regeneration after spinal cord transection, and that the distance and amount of axonal growth is greater when these treatments are delayed by several weeks after injury (Coumans et al., 2001). In this study, we sought to determine whether differences in inflammatory mediators exist between the acutely injured spinal cord and the spinal cord after a second injury and re-section, which could provide a more favorable environment for the axonal re-growth. The results of this study show a more rapid induction of transforming growth factor (TGF) β1 mRNA expression in the re-injured spinal cord than the acutely injured spinal cord and an attenuation of proinflammatory cytokine mRNA expression. Furthermore, there was a rapid recruitment of activated microglia/macrophages in the degenerating white matter rostral and caudal to the injury but fewer within the lesion site itself. These findings suggest that the augmentation of TGFβ-1 gene expression and the attenuation of pro-inflammatory cytokine gene expression combined with an altered distribution of activated microglia/macrophages in the re-injured spinal cord might create a more favorable milieu for transplants and axonal regrowth as compared to the acutely injured spinal cord. © 2003 Elsevier Inc. All rights reserved.

Object. The aim of this study was to establish standard values for the normal alignment of the upper cervical spine and to clarify its relationship with the lower cervical spine in terms of alignment. Methods. Three hundred thirteen asymptomatic volunteers (155 men and 158 women) participated in this study. Lateral radiographs were obtained with the neck in neutral position, and the angles formed by the occiput (Oc) and the axis, the atlas and the axis, and C-2 to C-7 were measured. The mean Oc-C2 angle was 14.5 ± 8° in men and 16 ± 8.5° in women; the mean C1-2 angle was 26.5 ± 7° and 28.9 ± 6.7°, respectively; and the mean C2-7 angle was 16.2 ± 12.9° and 10.5 ± 10.3°, respectively. Although weak, statistically significant negative correlation was observed between Oc-C2 and C2-7 angles (r = -0.31 in men and -0.37 in women), and between C1-2 and C2-7 angles (r = -0.22 in men and -0.22 in women). The correlation coefficient between the Oc-C2 and C2-7 angles was greater than that between the C1-2 and C2-7 angles. Conclusions. Such relationships between alignment of the upper and lower cervical spines should be taken into consideration when performing occipitocervical fusion.

Thanks to advances in the stem cell biology of the central nervous system (CNS), the previously inconceivable regeneration of the damaged CNS is approaching reality. The availability of signals to induce the appropriate differentiation of the transplanted and/or endogenous neural stem cells (NSCs) as well as the timing of the transplantation are important for successful functional recovery of the damaged CNS. Because the immediately post-traumatic microenvironment of the spinal cord is in an acute inflammatory stage, it is not favorable for the survival and differentiation of NSC transplants. On the other hand, in the chronic stage after injury, glial scars form in the injured site that inhibit the regeneration of neuronal axons. Thus, we believe that the optimal timing of transplantation is 1-2 weeks after injury. © 2003 Elsevier Science Ltd. All rights reserved.