Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

A refined method of en bloc open-door laminoplasty for resection of intradural spinal tumors in the thoracic and lumbar spine.

BACKGROUND: The open-door laminoplasty has been used to treat cervical spondylotic myelopathy. This technique has been applied to the surgical treatment of thoracic and lumbar spinal canal tumors instead of simple laminectomy or hemilaminectomy. However, previously reported laminoplasty methods did not keep posterior supporting elements intact such as the laminae and the spinous processes with supraspinous and interspinous ligaments, and almost all of them needed instruments for the fixation of reconstructed laminae. The purpose of this paper is to introduce our open-door laminoplasty method, which keep all posterior supporting elements intact and reconstruct the laminae without instrument. METHODS: Eight patients (mean age 61 years) underwent en bloc open-door laminoplasty in the thoracic and lumbar spine for resection of intradural spinal tumors. Two grooves are made bilaterally on the laminae just medial side of the facet joints. One-half of each spinous process of the adjacent vertebrae above and below the laminoplasty is cracked diagonally to create a green stick fracture and bent to the hinged side for sufficient elevation of the laminar flap. After tumor resection, the laminar flap is restored to its original site, resulting in the complete preservation of the posterior supporting elements. RESULTS: Operative exposure was good and permitted complete resection. No complications such as postoperative spinal canal stenosis or kyphosis were observed. Computed tomography(CT) indicated that bony fusion occurred in all cases. CONCLUSION: The supraspinous and interspinous ligaments above and below laminoplasty were kept intact during surgery in our method. Therefore, the continuity of posterior supporting elements (laminae and spinous processes connected by supraspinous and interspinous ligaments) were completely preserved.

Evaluation of low back pain using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire for lumbar spinal disease in a multicenter study: differences in scores based on age, sex, and type of disease.

BACKGROUND: The Japanese Orthopaedic Association (JOA) has investigated the JOA Back Pain Evaluation Questionnaire (JOABPEQ) to evaluate several aspects of low back pain in patients. The score includes five categories (25 items) selected from the Roland Morris Disability Questionnaire and Short Form 36, and a visual analogue scale. Japanese physicians have recently used these scores to evaluate back pain; however, the efficacy has not been fully explored in large-scale studies. In the current study, we used the JOABPEQ to evaluate lumbar spinal disease in 555 patients (with lumbar disc herniation, lumbar spinal stenosis, and lumbar disc degeneration/spondylosis) in multiple spine centers and compared the results based on age, sex, and type of disease. METHODS: A total of 555 patients who had low back or leg pain were selected in 22 hospitals in Chiba Prefecture. Spine surgeons diagnosed their disease type based on symptoms, physical examination, radiography images, and magnetic resonance imaging. In all, 486 patients were diagnosed with spinal stenosis (239 patients), disc degeneration/spondylosis (143 patients), or disc herniation (104 patients). The other 69 patients were diagnosed with spondylolysis (16 patients) or other diseases (53 patients). The pain score in all patients was evaluated using the JOABPEQ (from 0 to 100, with 0 indicating the worst pain). RESULTS: The age of the patients was 56.1 +/- 13.3 years (mean +/- SD); the age of patients in the disc herniation and disc degeneration/spondylosis group was significantly lower than that in the spinal stenosis group. The average JOABPEQ scores in all patients were, for low back pain, 47.1; lumbar function, 53.6; walking ability, 54.8; social life function, 48.7; and mental health, 48.3. The low back pain score in men was significantly worse than that in women. In contrast, the mental health score in women was significantly higher than that in men. The low back pain score in patients <40 years old and the walking ability score in patients >65 years old were significantly lower than those scores in other patients. Based on the disease type, low back pain, lumbar function, social life function, and mental health scores for patients with disc herniation were significantly worse than for those with spinal stenosis. CONCLUSION: JOABPEQ scores were evaluated for several lumbar diseases. The average of five categories of JOABPEQ scores in all patients was similarly distributed. However, the average scores in the five categories were significantly different depending on age, sex, and type of disease. Compared with prior mass data (baseline data on the observational cohort of the Spine Patient Outcomes Research Trial in the United States), many data were similar based on the type of disease in the current study. Furthermore, the JOABPEQ is easy to use compared with the SF-36. Hence, we concluded that the JOABPEQ could be used worldwide as a tool for evaluating low back pain.

Study protocol for the G-SPIRIT trial: a randomised, placebo-controlled, double-blinded phase III trial of granulocyte colony-stimulating factor-mediated neuroprotection for acute spinal cord injury.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial. METHODS AND ANALYSIS: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m2/day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients). ETHICS AND DISSEMINATION: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper. TRIAL REGISTRATION NUMBER: UMIN000018752.

Organization of cutaneous ventrodorsal and rostrocaudal axial lines in the rat hindlimb and trunk in the dorsal horn of the spinal cord.

The somatotopic organization of cutaneous primary afferents projecting to the dorsal horn of the rat spinal cord was investigated. The fluorescent neurotracer, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) was applied to cutaneous incisions made along ventrodorsal axial lines (VDALs) or rostrocaudal axial lines (RCALs) of the trunk and hindlimb. DiI-induced fluorescent zones appeared in laminae I-III of the dorsal horn in the transverse section. Several fluorescent zones appeared at different mediolateral portions after tracer application to VDALs. After tracer was applied to RCALs, a single zone of fluorescence was observed. Serial transverse sections were used to reconstruct fluorescent zones in lamina II and to illustrate the rostrocaudally elongated band-like projection fields in a horizontal plane. In the horizontal plane, the fluorescent zones of VDALs were reconstructed to band-like projection fields. These fields were arranged mediolaterally and extended rostrocaudally for approximately the length of one spinal cord segment or less. The fluorescent zones of RCALs were reconstructed to one band-like projection field. This field extended rostrocaudally over several spinal cord segments. Cutaneous afferents from the ventral median line of the trunk, tail, hindlimb, sole, and ventral side of the digits projected to the medial margin of the dorsal horn. Cutaneous afferents from the dorsal median lines projected to the lateral margin of the dorsal horn. By analyzing the pattern of the body surface regions and the VDALs and RCALs, the central projection fields of body surface regions could be hypothesized, based on the central projection fields of the individual VDAL and RCAL afferents. Thus, we established a detailed dorsal view map of the central projection fields of cutaneous primary afferents.

Injury to the lateral femoral cutaneous nerve during harvest of iliac bone graft, with reference to the size of the graft.

In patients who underwent autogenous iliac bone grafting we studied prospectively injury to the lateral femoral cutaneous nerve (LFCN) in relation to the size (length, depth, width) of the graft. We also examined the neurological deficit, by questioning them about numbness and/or pain in the lateral thigh. The risk of injury was significantly higher in those in whom the depth of the graft was more than 30 mm. With regard to the length of the graft the incidence of nerve injury was 20% when the graft was 45 mm long or more, 16% when it was between 30 mm and 45 mm long, and 8% when it was less than 30 mm long. We should inform patients of the possibility of such injury, and take size into consideration when harvesting grafts from the ilium.

Up-regulation of substance P and NMDA receptor mRNA in dorsal horn and preganglionic sympathetic neurons during adjuvant-induced noxious stimulation in rats.

Substance P (SP) and glutamate-containing terminals are found in the dorsal horn and preganglionic sympathetic neurons (PSNs) in the intermedio-lateral nucleus of the spinal cord. SP receptor (SPR) and N-methyl-D-aspartate type glutamate receptor (NMDAR) were also recognized in portions of the dorsal horn and PSNs. Primary sensory nerve fibers containing SP and glutamate terminated around PSNs, or partly on PSNs directly as well as on dorsal horn neurons (DHNs). The present study was performed to investigate the changes in SPR and NMDAR mRNA expressions during nociception in rats. Upon the injection of complete Freund's adjuvant (CFA) into the front paw, edema and hyperalgesia occurred immediately, with the difference in latency score between injected and non-injected paws continuing to day 10. The up-regulation of SPR and NMDAR mRNAs in DHNs and PSNs was recognized using in situ hybridization and northern blot techniques. CFA injection increased SPR mRNA expression in PSNs at days 1 and 4, and NMDAR mRNA expression at days 1, 4 and 7. At day 14, the mRNA expression of both receptors decreased to the control level. These changes in the amount of receptor mRNAs in DHNs and PSNs may cause hyperalgesia and sympathetically mediated pain.

Substance P and calcitonin gene-related peptide immunoreactive sensory DRG neurons innervating the lumbar intervertebral discs in rats.

The rat L5/6 disc is innervated from T13 to L6 dorsal root ganglia (DRGs) multisegmentally. Sensory fibers from T13, L1 and L2 DRGs have been reported to innervate through the paravertebral sympathetic trunks, whereas those from L3 to L6 DRGs innervate directly through sinuvertebral nerves on the posterior longitudinal ligament (PLL). The presence of substance P (SP)- and calcitonin gene-related peptide (CGRP)-immunoreactive (ir) nerve fibers has been demonstrated in the lumbar intervertebral discs, but their percentages in DRG neurons have not been studied. Fluoro-gold (F-G) labeled neurons innervating the L5/6 disc were distributed throughout DRGs from T13 to L6 levels. Of F-G labeled neurons innervating the L5/6 disc, the percentage of SP-ir T13 to L6 DRG neurons was 30%, and that of CGRP-ir neurons was 47%. The mean cross-sectional area of the cell of SP-ir neurons was 696+/-66 microm2 (mean +/- S. E.), and that of CGRP-ir neurons was 695+/-72 microm2 (mean +/- S. E.). SP- and CGRP-ir were mainly observed in small neurons. The percentages of SP- or CGRP-ir neurons in L1 and L2 DRGs innervating the L5/6 disc were not different from those in L3, L4 or L5 DRGs. In the physiological condition in rats, DRG neurons at all levels may have the same significant role in pain sensation of the disc.

Simultaneous anterior and posterior screw fixations confined to the axis for stabilization of a 3-part fracture of the axis (odontoid, dens, and hangman fractures): report of 2 cases.

Fractures of the axis are considered to be one of the most common injuries to the cervical spine, accounting for more than 20% of all cervical spine fractures. Multiple fractures of the axis are much rarer, accounting for 1% of all cervical fractures. Management of such complex fractures is still challenging, and there is no strong consensus for the treatment. The authors describe the cases of 2 patients who presented with 3-part fractures of the axis consisting of an odontoid Type II fracture and a Levine-Edwards Type IA fracture, which were treated with concurrent insertion of an anterior odontoid screw and bilateral posterior pedicle screws. The cases presented were characterized by 1) a Type II odontoid fracture; 2) a Type IA traumatic spondylolisthesis with no or a little translation and angulation of C-2 on C-3 in a ring fracture of the axis; and 3) no disorders at the C2-3 disc on MR images. Therefore, the authors performed surgery confined to the axis by concurrently inserting an anterior odontoid screw and posterior bilateral pedicle screws without arthrodesis of C2-3. This was followed with cervical soft collar fixation for only 1-2 weeks. The outcomes were favorable, including good osteosynthesis, high primary stability, early patient mobilization, and preserved range of motion of the cervical spine at C2-3 as well as at C1-2.

Incidence of nocturnal leg cramps in patients with lumbar spinal stenosis before and after conservative and surgical treatment.

PURPOSE: To examine the effects of conservative and surgical treatments for nocturnal leg cramps in patients with lumbar spinal stenosis (LSS). Nocturnal leg cramps is frequently observed in patients with peripheral neuropathy. However, there have been few reports on the relationship between nocturnal leg cramps and LSS, and it remains unknown whether conservative or surgical intervention has an impact on leg cramps in patients with LSS. MATERIALS AND METHODS: The subjects were 130 LSS patients with low back and leg pain. Conservative treatment such as exercise, medication, and epidural block was used in 66 patients and surgical treatment such as decompression or decompression and fusion was performed in 64 patients. Pain scores and frequency of nocturnal leg cramps were evaluated based on self-reported questionnaires completed before and 3 months after treatment. RESULTS: The severity of low back and leg pain was higher and the incidence of nocturnal leg cramps was significantly higher before treatment in the surgically treated group compared with the conservatively treated group. Pain scores improved in both groups after the intervention. The incidence of nocturnal leg cramps was significantly improved by surgical treatment (p=0.027), but not by conservative treatment (p=0.122). CONCLUSION: The findings of this prospective study indicate that the prevalence of nocturnal leg cramps is associated with LSS and severity of symptoms. Pain symptoms were improved by conservative or surgical treatment, but only surgery improved nocturnal leg cramps in patients with LSS. Thus, these results indicate that the prevalence of nocturnal leg cramps is associated with spinal nerve compression by LSS.

Conservative and surgical treatment improves pain and ankle-brachial index in patients with lumbar spinal stenosis.

PURPOSE: The pathological mechanism of lumbar spinal stenosis is reduced blood flow in nerve roots and degeneration of nerve roots. Exercise and prostaglandin E1 is used for patients with peripheral arterial disease to increase capillary flow around the main artery and improve symptoms; however, the ankle-brachial index (ABI), an estimation of blood flow in the main artery in the leg, does not change after treatment. Lumbar spinal nerve roots contain somatosensory, somatomotor, and unmyelinated autonomic nerves. Improved blood flow by medication with prostaglandin E1 and decompression surgery in these spinal nerve roots may improve the function of nerve fibers innervating muscle, capillary, and main vessels in the lower leg, resulting in an increased ABI. The purpose of the study was to examine whether these treatments can improve ABI. MATERIALS AND METHODS: One hundred and seven patients who received conservative treatment such as exercise and medication (n=56) or surgical treatment (n=51) were included. Low back pain and leg pain scores, walking distance, and ABI were measured before treatment and after 3 months of conservative treatment alone or surgical treatment followed by conservative treatment. RESULTS: Low back pain, leg pain, and walking distance significantly improved after both treatments (p<0.05). ABI significantly increased in each group (p<0.05). CONCLUSION: This is the first investigation of changes in ABI after treatment in patients with lumbar spinal stenosis. Improvement of the spinal nerve roots by medication and decompression surgery may improve the supply of blood flow to the lower leg in patients with lumbar spinal stenosis.

Osteochondroma in the lumbar spinal canal causing sciatic pain: report of two cases.

A search of the English-language medical literature found only two cases in which expansion of an osteochondroma into the lumbar spinal canal caused sciatica. We report another two cases of spinal nerve root compression by solitary lumbar spinal canal osteochondromas: in a 56-year-old man and a 55-year-old woman with no history of hereditary multiple exostoses. Osteochondromas compressing the spinal nerve root were seen at the inferior articular processes of the lumbar vertebrae by computed tomography (CT), three-dimensional reconstruction of CT scans, myelography, and magnetic resonance imaging. The symptoms disappeared after surgical removal of the lesions. Histopathologic examination confirmed the diagnosis of benign osteochondroma.

Calcitonin gene-related peptide immunoreactive neurons with dichotomizing axons projecting to the lumbar muscle and knee in rats.

Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. However, these neurons, which have dichotomizing axons to the lumbar muscles and to the knee, have not been investigated. Clinically, pain from the lumbar muscles is sometimes referred to the lower extremities. Two kinds of neurotracers [1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) and fluoro-gold (FG)] were used in the present double-labelling study. DiI crystals were placed in the left lower back muscle, and FG was applied to the medial side of the knee. Bilateral DRGs from L1 through L6 were immunoreacted with calcitonin gene-related peptide (CGRP) antibodies and observed under a fluorescence microscope. DRG neurons double-labelled with DiI and FG were recognized only in the ipsilateral DRGs from levels L1 to L6. Approximately 1% of DRG neurons innervating the low back muscles had other axons to the medial side of the knee. In double-labelled neurons, the ratio of CGRP-immunoreactive DRG neurons was 60%. This finding provides a possible neuroanatomical explanation for referred knee pain from the lower back since CGRP is a marker of sensory neurons typically involved with pain perception. However, these neurons are rare, and mechanisms of referred pain may be explained by the convergence-projection hypothesis.