Takafumi Yayama

Cervical spondylotic myelopathy associated with kyphosis or sagittal sigmoid alignment: outcome after anterior or posterior decompression

OBJECT The effects of sagittal kyphotic deformities or mechanical stress on the development of cervical spondylotic myelopathy, or the reduction and fusion of kyphotic sagittal alignment have not been consistently documented. The aim in this study was to determine the effects of kyphotic sagittal alignment of the cervical spine in terms of neurological morbidity and outcome after 2 types of surgical intervention. METHODS The authors retrospectively reviewed the records of 476 patients who underwent cervical spine surgeries for spondylotic myelopathy between 1993 and 2006 at their university medical center. Among these were identified 43 patients-30 men and 13 women, with a mean age of 58.8 years-who had cervical kyphosis exceeding 10 degrees on preoperative sagittal lateral radiographs obtained in the neutral position, and their cases were analyzed in this study. Anterior decompression with interbody fusion was conducted in 28 patients, and en bloc open-door C3-7 laminoplasty in 15 patients. Both pre- and postoperative neurological, radiographic, and MR imaging findings were assessed in both surgical groups. RESULTS The mean preoperative kyphotic angle in all 43 patients was 15.9 +/- 5.9 degrees in the neutral position. Segmental instability was noted in 26 patients (61%) and reversed dynamic spinal canal stenosis at the level above the local kyphosis in 22 (51%). Preoperative T2-weighted MR images showed high-intensity signal within the cord at and around the level of maximal compression or segmental instability in 28 patients (65%). The mean kyphotic angle in both the neutral and flexion positions was significantly smaller at 4-6 weeks after surgery in the anterior spondylectomy group than in the laminoplasty group (p < 0.001). Furthermore, the angle in the neutral position was significantly smaller on follow-up in the anterior spondylectomy group than in the laminoplasty group (p = 0.034). The transverse area of the spinal cord was significantly larger in the anterior spondylectomy group than in the laminoplasty group on follow-up (p = 0.037). Preoperative neurological scores (assessed using the Japanese Orthopaedic Association scale) and improvement on follow-up > or = 2 years after treatment (average 3.3 years) were not significantly different between the 2 groups; however, there was a significant difference in Japanese Orthopaedic Association score at 4-6 weeks postoperatively (p = 0.047). CONCLUSIONS Kyphotic deformity and mechanical stress in the cervical spine may play an important role in neurological dysfunction. In a select group of patients with kyphotic deformity > or = 10 degrees , adequate correction of local sagittal alignment may help to maximize the chance of neurological improvement.

Tumor Necrosis Factor-α Antagonist Reduces Apoptosis of Neurons and Oligodendroglia in Rat Spinal Cord Injury

Study Design. To examine the effects of a tumor necrosis factor (TNF)-&agr; antagonist (etanercept) on rat spinal cord injury and identify a possible mechanism for its action. Objective. To elucidate the contribution of etanercept to the pathologic cascade in spinal cord injury and its possible suppression of neuronal and oligodendroglial apoptosis. Summary of Background Data. Etanercept has been recently used successfully for treatment of inflammatory disorders. However, only a few studies have examined its role in suppressing neuronal and oligodendroglial apoptosis in spinal cord injury. Methods. Etanercept or saline (control) was administered by intraperitoneal injection 1 hour after thoracic spinal cord injury in rats. The expressions and localizations of TNF-&agr;, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) were examined by immunoblot and immunohistochemical analyses. Spinal cord tissue damage between saline- and etanercept-treated groups was also compared after hematoxylin-eosin and luxol fast blue (LFB) staining. The Basso-Beattie-Bresnahan (BBB) scale was used to evaluate rat locomotor function after etanercept administration. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells were counted and the immunoreactivity to active caspase-3 and caspase-8 was examined after etanercept administration. Results. Immunoblot and double immunofluorescence staining revealed suppression of TNF-&agr;, TNFR1, and TNFR2 expression after administration of etanercept in the acute phase of spinal cord injury. LFB staining demonstrated potential myelination in the etanercept-treated group from 2 week after spinal cord injury, together with an increased BBB locomotor score. Double immunofluorescence staining showed a significant decrease in TUNEL-positive neurons and oligodendroglia from 12 hour to 1 week in the gray and white matters after etanercept administration. Immunoblot analysis demonstrated overexpression of activated caspase-3 and caspase-8 after spinal cord injury, which was markedly inhibited by etanercept. Conclusion. Our results indicated that etanercept reduces the associated tissue damage of spinal cord injury, improves hindlimb locomotor function, and facilitates myelin regeneration. This positive effect of etanercept on spinal cord injury is probably attributable to the suppression of TNF-&agr;, TNFR1, TNFR2, and activated caspase-3 and caspase-8 overexpressions, and the inhibition of neuronal and oligodendroglial apoptosis.

Thoracic ossification of the human ligamentum flavum: histopathological and immunohistochemical findings around the ossified lesion

OBJECT The object of this study was to histopathologically and immunohistochemically characterize ossification of the ligamentum flavum (OLF) in samples of the thoracic spine harvested en bloc during surgery and to enhance the understanding of the ossifying process, particularly calcification and ossification. METHODS Samples of OLF plaque were obtained en bloc from 43 patients who underwent posterior decompression. The histopathological findings were correlated with radiological subtypes using computed tomography. The expression of type I and type II collagens, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)beta, and bone morphogenetic protein (BMP)-2 was investigated. RESULTS Surgical decompression using the posterior floating and en bloc resection technique resulted in neurological improvement in 40 of 43 patients. Progression of the OLF lesion longitudinally and medially was associated with significant degeneration of elastic fibers, fiber bundle derangement, decrements in fiber diameter, and fragmentation. Calcification and ossification paralleled the degeneration of the elastic fibers, extended more medially, and fused in the central area. Expression of BMP-2, TGFbeta, and VEGF was significant in chondrocytes in the calcified cartilage and fibrocartilage layers, especially around the calcified front. CONCLUSIONS Histopathologically, the progress of calcification and ossification was closely associated with the degeneration of elastic fibers and with significant expression of BMP-2, TGFbeta, and VEGF in the ossification front.

Effects of Alendronate on Bone Metabolism in Glucocorticoid-Induced Osteoporosis Measured by 18F-Fluoride PET: A Prospective Study

Osteoporosis represents a significant side effect of glucocorticoid therapy, and alendronate has been reported to prevent this glucocorticoid-induced osteoporosis. Functional imaging with 18F-fluoride PET allows quantitative analysis of bone metabolism in specific skeletal regions. However, only a few studies have quantitatively determined bone turnover and metabolism in glucocorticoid-induced osteoporosis by radiologic imaging techniques including PET. The aim of this study was to examine changes in regional bone remodeling and turnover as measured by 18F-fluoride PET, the relationship between these measured changes and conventional bone metabolism parameters, and the effect of alendronate treatment. Methods: The study group consisted of 24 postmenopausal women (mean age, 59.7 y) who had various diseases, excluding rheumatoid arthritis, and had been treated with 10 mg or more of oral glucocorticoids (prednisolone equivalent) per day for more than 6 mo. Treatment with 5 mg of alendronate per day began at the time of study entry and continued for 12 mo. 18F-fluoride PET was performed at baseline, 3 mo, and 12 mo to determine localized bone turnover, and the results were compared with other bone metabolism parameters. Results: Lumbar spine standardized uptake values (SUVs) were significantly lower (P < 0.05) in the osteoporotic group (T-score ≤ −2.5) than in the group that was healthy or osteopenic (T-score > −2.5). Patients treated with alendronate for 12 mo exhibited significant decreases in serum bone-specific alkaline phosphate (P < 0.05), urinary N-telopeptide for type I collagen (P < 0.01), lumbar spine SUV (P < 0.01), and femoral neck SUV (P < 0.01) in association with a gradual increase in bone mineral density (BMD) of the lumbar spine relative to the baseline value (P < 0.05). Although there was a significant correlation between BMD and SUV in the lumbar spine at baseline (P < 0.05), there was no correlation between the 2 variables at 12 mo of treatment with alendronate. Conclusion: Alendronate treatment resulted in significant decreases in bone metabolism and turnover in the lumbar spine. It also led to an increase in BMD of the lumbar spine in patients with glucocorticoid-induced osteoporosis. Our findings suggest that antiresorptive therapy has a direct bone-metabolism effect on skeletal kinetics in glucocorticoid-induced osteoporosis at the clinically important site of the lumbar spine.

Targeted retrograde gene delivery of brain-derived neurotrophic factor suppresses apoptosis of neurons and oligodendroglia after spinal cord injury in rats.

Study Design. Histologic and immunohistochemical studies after targeted retrograde adenovirus (AdV)-mediated brain-derived neurotrophic factor (BDNF) gene delivery via intramuscular injection in rats with injured spinal cord. Objective. To investigate the neuroprotective effect of targeted retrograde AdV-BDNF gene transfection in the traumatically injured spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. Summary of Background Data. Several studies investigated the neuroprotective effects of neurotrophins including BDNF on spinal cord injury, with respect to prevention of neural cell apoptosis in injured spinal cord. However, no report has described the potential effect of targeted retrograde neurotrophic factor gene delivery in injured spinal cord on prevention of neural cell apoptosis. Methods. AdV-BDNF or AdV-LacZ was used for retrograde delivery via bilateral sternomastoid muscles to the spinal accessory motoneurons immediately after spinal cord injury in rats. Localization of β-galactosidase expression produced by LacZ gene or AdV-BDNF gene transfection was examined by immunofluorescence staining and double staining of cell markers (NeuN, RIP, GFAP, OX-42, and NG2) in the injured spinal cord. TUNEL-positive cells were counted and immunoreactivity to active caspase-3 and NG2 was examined after gene injection. Results. Retrograde delivery of LacZ marker gene was identified in cervical spinal neurons and glial cells including oligodendrocytes in the white matter. AdV-BDNF transfection resulted in a significant decrease in the number of TUNEL-positive apoptotic cells by downregulating the caspase apoptotic pathway, with significant promotion of NG2 expression in injured spinal cord, compared with AdV-LacZ injection. Conclusion. Our results suggest that targeted retrograde BDNF gene delivery suppresses apoptosis of neurons and oligodendrocytes in the injured rat spinal cord.

Effect of lumbar nerve root compression on primary sensory neurons and their central branches: changes in the nociceptive neuropeptides substance P and somatostatin.

Study Design. This study examined the effect of lumbar nerve root compression on nociceptive neuropeptides in the axonal flow using an in vivo model. Objectives. The aim was to investigate changes in axonal flow after nerve root compression by using immunohistochemical techniques to detect substance P (SP) and somatostatin (SOM), which is thought to be involved in temperature and pain sensation. Summary of Background Data. Disturbance of intraradicular blood flow and nerve fiber deformation caused by mechanical compression are thought to be involved in the pathophysiology of diseases characterized by radicular symptoms, such as lumbar disc herniation and lumbar canal stenosis. However, little research has been conducted into the changes of axonal flow associated with nerve root compression. Methods. In dogs, the lumbar nerve roots were compressed using four types of clips with different pressures. Changes of SP and SOM levels in the spinal dorsal horn, dorsal root, and dorsal root ganglions were examined immunohistochemically after compression for 24 hours or 1 week. Results. After compression for 24 hours, axonal flow in the dorsal root was impaired, accumulation of SP and SOM was observed distal to the site of compression, and there was a decrease in the number of dorsal root ganglion cells showing positively for these neurotransmitters. Compression for 1 week resulted in a decrease in the number of SP- and SOM-positive fibers in the spinal dorsal horn. Conclusion. Change of axonal flow resulting from direct nerve compression could affect the metabolism of neurotransmitters that flow inside the axons and may be a primary cause of the decline in nerve function.

Tumor necrosis factor-alpha and its receptors contribute to apoptosis of oligodendrocytes in the spinal cord of spinal hyperostotic mouse (twy/twy) sustaining chronic mechanical compression.

Study Design. To examine the distribution of apoptotic cells and expression of tumor necrosis factor (TNF)-α and its receptors in the spinal hyperostotic mouse (twy/twy) with chronic cord compression using immunohistochemical methods. Objective. To study the mechanisms of apoptosis, particularly in oligodendrocytes, which could contribute to degenerative change and demyelination in chronic mechanical cord compression. Summary of Background Data. TNF-α acts as an external signal initiating apoptosis in neurons and oligodendrocytes after spinal cord injury. Chronic spinal cord compression caused neuronal loss, myelin destruction, and axonal degeneration. However, the biologic mechanisms of apoptosis in chronically compressed spinal cord remain unclear. Methods. The cervical spinal cord of 34 twy mice aged 20 to 24 weeks and 11 control animals were examined. The apoptotic cells were detected by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) staining. The expression and the localization of TNF-α, TNF receptor 1 (TNFR1), and TNF receptor 2 (TNFR2) were examined using immunoblot and immnohistochemical analysis. Results. The number of TUNEL-positive cells in the white matter increased with the severity of compression, which was further increased bilaterally in the white matter of twy/twy mice. Double immunofluorescence staining showed that the number of cells positive for TUNEL and RIP, a marker of oligodendrocytes, increased in the white matter with increased severity of cord compression. Immunoblot analysis demonstrated overexpression of TNF-α, TNFR1, and TNFR2 in severe compression. The expression of TNF-α appeared in local cells including microglia while that of TNFR1 and TNFR2 was noted in apoptotic oligodendrocytes. Conclusion. Our results suggested that the proportion of apoptotic oligodendrocytes, causing spongy axonal degeneration and demyelination, correlated with the magnitude of cord compression and that overexpression of TNF-α, TNFR1, and TNFR2 seems to participate in apoptosis of such cells in the chronically compressed spinal cord.

High-mobility group box-1 and its receptors contribute to proinflammatory response in the acute phase of spinal cord injury in rats.

Study Design. To examine the localization and expression of high-mobility group box-1 (HMGB-1) protein and its receptors after rat spinal cord injury. Objective. To elucidate the contribution of HMGB-1 and its receptors as potential candidates in a specific upstream pathway to the proinflammatory response leading to a cascade of secondary tissue damage after spinal cord injury. Summary of Background Data. HMGB-1 was recently characterized as a key cytokine with a potential role in nucleosome formation and regulation of gene transcription. No studies have investigated the role of HMGB-1 in spinal cord injury. Methods. Injured thoracic spinal cord from 62 rats aged 8 to 12 weeks and spinal cord from 20 control rats were examined. HMGB-1 was localized by immunofluorescence staining, costaining with cell markers, and by immunoelectron microscopy. The expression of HMGB-1 and its receptors, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)2, and TLR4 were also examined by immunohistochemistry. Results. HMGB-1 expression appeared earlier than that of tumor necrosis factor-&agr;, interleukin (IL)-1&bgr;, and IL-6 in the spinal cord injury rats, with the HMGB-1 produced by both macrophages and neurons. HMGB-1 translocated from nucleus to cytoplasm in some neurons at an early stage after neural injury. Increased expression of HMGB-1, RAGE, and TLRs was observed after injury, and interaction of HMGB-1 with RAGE or TLRs, particularly in macrophage, was confirmed at 3 days after injury. Conclusion. Our results demonstrated an earlier onset in the expression of HMGB-1 than in tumor necrosis factor-&agr;, IL-1&bgr;, and IL-6 after spinal cord injury. The release of HMGB-1 from neurons and macrophages is mediated through the HMGB-1/RAGE or TLR pathways. HMGB-1 seems to play at least some roles in the proinflammatory cascade originating the secondary damage after the initial spinal cord injury.

Vertebroplasty-augmented short-segment posterior fixation of osteoporotic vertebral collapse with neurological deficit in the thoracolumbar spine: comparisons with posterior surgery without vertebroplasty and anterior surgery

OBJECT The surgical approach and treatment of thoracolumbar osteoporotic vertebral collapse with neurological deficit have not been documented in detail. Anterior surgery provides good decompression and solid fusion, but the surgery-related risk is relatively higher than that associated with the posterior approach. In posterior surgery, the major problem after posterior correction and instrumentation is failure to support the anterior spinal column, leading to loss of correction of kyphosis. The aim of this study was to evaluate the efficacy of reinforcing short-segment posterior fixation with vertebroplasty and to compare the outcome with those of posterior surgery without vertebroplasty and anterior surgery, retrospectively. METHODS The authors studied 83 patients who underwent surgical treatment for a single thoracolumbar osteoporotic vertebral collapse with neurological deficit. Twenty-eight patients treated by posterior surgery combined with vertebroplasty (Group A), 25 patients treated by posterior surgery without vertebroplasty (Group B), and 30 patients treated by anterior surgery (Group C) were followed up for a mean postoperative period of 4.4 years. Neurological outcome, visual analog scale pain score, and radiographic results were compared in the 3 groups. RESULTS Postoperative (4-6 weeks) and follow-up neurological outcome and visual analog scale scores were not significantly different among the 3 groups. Postoperative kyphotic angle was significantly reduced in Group B compared with Group C (p = 0.007), whereas the kyphotic angle was not significantly different among the 3 groups at follow-up. The mean ± SD loss of correction at follow-up was 4.6° ± 4.5°, 8.6° ± 6.2°, and 4.5° ± 5.9° in Groups A, B, and C, respectively. The correction loss at follow-up in Group B was significantly higher compared with Groups A and C (p = 0.0171 and p = 0.0180, respectively). CONCLUSIONS The results suggest that additional reinforcement with vertebroplasty reduces the kyphotic loss and instrumentation failure, compared with patients without the reinforcement of vertebroplasty. Vertebroplasty-augmented short-segment fixation seems to offer immediate spinal stability in patients with thoracolumbar osteoporotic vertebral collapse; the effect seems equivalent to that of anterior reconstruction.

Ultrastructural analysis on lumbar disc herniation using surgical specimens: role of neovascularization and macrophages in hernias.

Study Design. The mechanisms responsible for the spontaneous regression of lumbar disc herniation (LDH) were studied by examining herniated tissue collected at operation from patients with LDH. Objective. The aim of the present study was to investigate the role of neovascularization and macrophages in hernias when spontaneous regression of LDH occurred. Summary of Background Data. Spontaneous regression of LDHs has already been demonstrated by diagnostic imaging with tools such as magnetic resonance imaging. However, there have been few studies on the mechanisms of spontaneous regression based on pathologic examination of herniated tissue. In particular, there has been no detailed work on the role of macrophages, which are thought to be closely associated with spontaneous regression. Methods. The magnetic resonance imaging and operative findings of 73 patients who underwent surgery were investigated, and specimens collected during surgery were examined by light and transmission electron microscopy. Results. Capillaries that invade the hernia and macrophages derived from monocytes migrating out of these capillaries are considered to be important factors in the regression of the herniated disc. Macrophages contain lysosomes filled with collagen-degrading enzymes that break down substances after phagocytosis, whereas primary lysosomes are secreted by these cells and break down intercellular substances such as collagen. Both of these mechanisms are closely involved in the regression of herniation. Conclusion. The inflammatory response that occurs around hernia tissue in the epidural space is believed to play an important role in herniated disc resorption, although it may also have a harmful effect on the adjacent nerve root. Therefore, control of the inflammatory reac-tion is an important challenge when treating patients with disc herniation.