Masazumi Murakami

Vertebral bone-marrow changes in degenerative lumbar disc disease. An MRI study of 74 patients with low back pain

We carried out MRI studies of 74 patients with end-plate and vertebral bone-marrow changes associated with degenerative lumbar disc disease. Abnormalities were classified into type A, with decreased signal intensities, and type B, with increased signal intensities on T1-weighted spin-echo images. Twenty-seven (73%) of the 37 patients with type-A changes had low back pain, in contrast to only four (11%) of the 37 patients with type-B changes. Lateral flexion-extension radiographs showed hypermobility in 26 patients (70%) with type-A changes, and in only six (16%) with type-B changes. Type-A changes correlated with segmental hypermobility and low back pain, while type-B changes were more common in patients with stable degenerative disc disease.

Long-term results of anterior interbody fusion for treatment of degenerative spondylolisthesis

Thirty-nine patients, 34 women and five men, underwent anterior decompression and interbody fusion for degenerative spondylolisthesis between February 1958 and August 1988. Their average age at surgery was 51 years (range, 34-74 years), and their average follow-up period was 12 years 7 months (range, 6 months to 30 years). Clinical evaluation was done by the score rating system of the Japanese Orthopaedic Association (JOA Score). Patients with JOA scores of 25 points or more were rated as “satisfactory.” Survivorship was analyzed by the method of Kaplan and Meier to determine the cumulative percentage of patients with satisfactory results. The following results were obtained: Seventy-six percent of the patients had satisfactory results for 10 years after the anterior interbody fusion, 60% for 20 years, and 52% for 30 years. Irrespective of their age at surgery, the patients generally maintained satisfactory results up to 65 years of age.

Brain-Derived Neurotrophic Factor Suppresses Delayed Apoptosis of Oligodendrocytes after Spinal Cord Injury in Rats

We evaluated the effect of brain-derived neurotrophic factor (BDNF) on cell death after spinal cord injury. A rat spinal cord injury model was produced by static load, and continuous intrathecal BDNF or vehicle infusion was carried out either immediately or 3 days after the injury. Cell death was examined by nuclear staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). After injury, typical apoptotic cells were observed. Double staining with TUNEL and specific cell markers revealed that, soon after the injury, the apoptotic or necrotic cells at the injury site were neurons and microglia. One week after the injury, apoptotic oligodendrocytes, but not apoptotic astrocytes, were observed in the white matter rostral and caudal to the injury site, whereas few apoptotic cells were found in the gray matter. The immediate BDNF treatment significantly reduced the number of TUNEL-positive cells in the adjacent rostral site 1 and 2 weeks after the injury, and in the adjacent caudal site 3 days and 1 week after the injury, even though there was no significant difference between BDNF-treated and control rats at the injury site itself. In addition, similar antiapoptotic effects were observed in these regions 1 week after injury in rats that received BDNF treatment from the third day after injury. These findings suggest that BDNF suppresses delayed apoptosis of oligodendrocytes after spinal cord injury, for which even delayed injections are effective. BDNF administration may therefore be useful for the clinical treatment of spinal cord injury through the suppression of secondary events.

Adenovirus Vector-Mediated In Vivo Gene Transfer of Brain-Derived Neurotrophic Factor (BDNF) Promotes Rubrospinal Axonal Regeneration and Functional Recovery after Complete Transection of the Adult Rat Spinal Cord

Neurotrophins have been shown to promote axonal regeneration, but the techniques available for delivering neurotrophins have limited effectiveness. The aim of this study was to evaluate the effect of adenovirus vector mediated gene transfer of brain-derived neurotrophic factor (BDNF) on axonal regeneration after spinal cord injury. We prepared adenovirus vectors encoding either beta-galactosidase (AxCALacZ) or BDNF (AxCABDNF). AxCALacZ was used to assess infection levels of the adenovirus BDNF produced by AxCABDNF was detected by Western blotting and its bioactivity was confirmed by bioassay. As a model of spinal cord injury, the rat spinal cord was completely transected at the T8 level. Immediately after transection, the vectors were injected into both stumps of the spinal cord. Axonal regeneration after transection was assessed by retrograde and anterograde tracing. In AxCALacZ-injected rats, adenovirus-infected cells were observed not only at the injected site but also in brainstem nuclei, as shown by LacZ expression. After the injection of the retrograde tracer fluorogold (FG) distal portion to the transection, AxCABDNF-injected rats showed FG-labeled neurons in the red nucleus. The anterograde tracer biotinylated dextran amine (BDA) injected into the red nucleus was also found in regenerating rubrospinal fibers distal to the transection. These tracing experiments demonstrated the regeneration of descending axons. In addition, rats of the AxCABDNF group showed significant locomotor recovery of hindlimb function, which was completely abolished by re-transection. These results indicate that the recovery was caused by regeneration of rubrospinal axons, not by simple enhancement of the central pattern generator.

Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor to bone marrow stromal cells promotes axonal regeneration after transplantation in completely transected adult rat spinal cord.

The aim of this study was to evaluate the efficacy in adult rat completely transected spinal cord of adenovirus vector-mediated brain-derived neurotrophic factor (BDNF) ex vivo gene transfer to bone marrow stromal cells (BMSC). BMSC were infected with adenovirus vectors carrying β-galactosidase (AxCALacZ) or BDNF (AxCABDNF) genes. The T8 segment of spinal cord was removed and replaced by graft containing Matrigel alone (MG group) or Matrigel and BMSC infected by AxCALacZ (BMSC-LacZ group) or AxCABDNF (BMSC-BDNF group). Axons in the graft were evaluated by immunohistochemistry and functional recovery was assessed with BBB locomotor scale. In the BMSC-BDNF group, the number of fibers positive for growth associated protein-43, tyrosine hydroxylase, and calcitonin gene-related peptide was significantly larger than numbers found for the MG and BMSC-LacZ groups. Rats from BMSC-BDNF and BMSC-LacZ groups showed significant recovery of hind limb function compared with MG rats; however, there was no significant difference between groups in degree of functional recovery. These findings demonstrate that adenovirus vector-mediated ex vivo gene transfer of BDNF enhances the capacity of BMSC to promote axonal regeneration in this completely transected spinal cord model; however, BDNF failed to enhance hind limb functional recovery. Further investigation is needed to establish an optimal combination of cell therapy and neurotrophin gene transfer for cases of spinal cord injury.

Visualisation of symptomatic nerve roots. Prospective study of contrast-enhanced MRI in patients with lumbar disc herniation

We studied the use of gadolinium diethylenetriaminepentaacetic acid-enhanced MRI in the detection of pathological changes in the nerve roots of 25 patients with unilateral sciatica due to lumbar disc herniation. Enhancement was observed in the affected nerve roots within the root sleeve at the caudal edge of the herniation and was classified into three categories: grade 0, none; grade 1, enhancement restricted to a focal region within the sleeve; and grade 2, diffuse and homogeneous. The grade of enhancement correlated well with the severity of the sciatica, and was considered to be due to a disruption of the blood-nerve barrier, leading to oedema.

Juvenile amyotrophy of the distal upper extremity : Pathologic findings of the dura mater and surgical management

Study Design. Five cases of juvenile amyotrophy of the distal upper extremity were reviewed retrospectively to elucidate the pathophysiology of spinal cord dysfunction and the results of surgical management. Objectives. To clarify the pathogenesis of juvenile amyotrophy of the distal upper extremity and to present the results of a new surgical treatment. Summary of Background Data. Hirayama first reported this disorder in 1959. It is characterized by juvenile onset, slow progression, and involvement of the unilateral distal upper extremity. Recently, compression of the cervical spinal cord during neck flexion was implicated as a possible etiology of the disorder, but the exact etiology is still unknown. The value of surgical treatment for patients with juvenile amyotrophy of the distal upper extremity has not been established. Methods. The clinical and radiographic characteristics of five patients with juvenile amyotrophy of the distal upper extremity were examined. All five patients were treated surgically with duraplasty in combination with posterior spinal fusion. Dynamic and computed tomographic myelography were performed before and after surgery. Intraoperative ultrasonography and conductive spinal cord evoked potentials were recorded before and after duraplasty. The surgical results and the histology of the resected dura were studied. Results. Myelograms taken with the neck in a neutral position showed that the spinal cord was flattened in all five patients. When the neck was flexed, the dura and the spinal cord were compressed further. Intraoperative ultrasonography during neck flexion revealed an anterior shift of the spinal cord and decreased spinal cord pulsation. Amplitude of the conductive spinal cord evoked potentials decreased with neck flexion but in creased after dural incision. Histologically, the dura appeared abnormal in that it contained few elastic fibers without the normal wavy structure. Conclusions. Juvenile amyotrophy of the distal upper extremity was characterized by inelastic dura that constricts and compresses the cervical spinal cord when the neck is in either a neutral or a flexed position. Abnormal dura appeared to be the cause of juvenile amyotrophy of the distal upper extremity. Duraplasty with spinal fusion are proposed as treatments.

Upregulation of Osteopontin Expression in Rat Spinal Cord Microglia after Traumatic Injury

Osteopontin is a noncollagenous extracellular matrix protein that is expressed in various tissues. Recent studies have shown the upregulation of osteopontin expression in the ischemic cortex after cerebral infarction. We demonstrate here the upregulation of osteopontin expression in the spinal cord after compression injury. Laboratory rats were used in a compression model of spinal cord injury (30-g load for 5 min). Northern blot analysis showed that osteopontin mRNA expression levels reached a peak 3 days after injury (sevenfold; p < 0.05). In situ hybridization demonstrated osteopontin mRNA expression in necrotic areas from 24 h, peaking 3 days after injury. Immunohistochemistry detected osteopontin protein immunoreactivity from 12 h, peaking at 3 days. The peak time and distribution of osteopontin protein expression were coincident with those of osteopontin mRNA expression. Osteopontin expression in our model preceded that shown in the previously reported cerebral infarction models. Osteopontin protein was found in the cytoplasm at 3 days and secreted into the extracellular matrix at 7 days. Triple immunolabeling showed that osteopontin was localized in activated microglia surrounded by astrocytes.

Effects of intravenous lipoprostaglandin E1 on neurogenic intermittent claudication.

Circulation disturbances in the cauda equina and nerve roots have been implicated in the genesis of neurogenic intermittent claudication (NIC) in patients with lumbar spinal stenosis (LSS). We report the clinical results of lipoprostaglandin E1 (lipo-PGE1) treatments in patients with NIC. Lipo-PGE1 was administered intravenously for 10 consecutive days to 40 patients, 31 of whom showed a response to the treatment. Of the clinical symptoms examined, walking ability and leg numbness were significantly improved with an average effective period of 2.5 months. However, patients with radicular pain and severely affected patients did not respond well. Nerve root circulation in eight patients who subsequently underwent surgery was measured with a laser Doppler flowmeter. We observed increased blood flow in seven of these eight patients, after the intraoperative administration of lipo-PGE1. Lipo-PGE1 produced symptomatic improvement for a limited period in the treatment of NIC associated with LSS. The drug appeared to exert its effects through an increase in the circulation of blood in the nerve roots and the cauda equina.

Behavioral and morphologic studies of the chronically compressed cauda equina. Experimental model of lumbar spinal stenosis in the rat.

STUDY DESIGN An experimental model in rats of chronically compressed cauda equina was produced, and behavioral and morphologic changes were examined. OBJECTIVES To provide a useful model for analyzing the pathophysiologic changes of the cauda equina by chronic compression and to examine behavioral and morphologic changes in this model. SUMMARY OF BACKGROUND DATA Several animal models have been reported in which various materials were used to compress the cauda equina. However, the pathophysiology of the cauda equina by chronic compression is not yet well understood. Studies in which rats were used are scarce. METHODS A silicone sheet was applied to the spinal canal at L4 in the rat. Walking durations on treadmill tests and paw-withdrawal latencies to thermal stimuli were measured before and after the operation for 24 weeks. Histologic changes also were examined. RESULTS Walking durations decreased after chronic compression. However, paw-withdrawal latencies were not significantly changed. Histologically, the number of large-diameter myelinated axons decreased after compression, whereas the number of small-diameter myelinated axons increased. Electron microscopic observation indicated that the continuous degeneration and regeneration of axons occurred throughout the chronic compression experiment. CONCLUSIONS The current model and behavioral assessments may be useful in analyzing the pathophysiology of chronically compressed cauda equina.