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A basic study using a rodent model of sarcopenia.To elucidate the contribution of oxidative stress to muscle degeneration and the efficacy of antioxidant treatment for sarcopenia using an animal model of neurogenic sarcopenia.Oxidative stress has been reported to be involved in a number of pathologies, including musculoskeletal disorders. Its relationship with sarcopenia, one of the potential origins of lower back pain, however, is not yet fully understood.Myoblast cell lines (C2C12) were treated with H2O2, an oxidative stress inducer, and N-acetyl-L-cysteine (NAC), an antioxidant. Apoptotic effects induced by oxidative stress and the antioxidant effects of NAC were assessed by western blotting, immunocytochemistry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assays. An animal model of sarcopenia was produced via axotomy of the sciatic nerves to induce muscle atrophy. Twenty-four male Sprague-Dawley rats were divided into sham, sham+NAC, axotomy, and axotomy+NAC groups. Rats were provided water only or water containing NAC (1 g/L) for 4 weeks. The gastrocnemius muscle was isolated and stained with hematoxylin and eosin (HE) 2 weeks after axotomy, from which muscle cells were harvested and protein extracted for evaluation.Mitogen-activated protein kinases (MAPKs) were significantly activated by H2O2 treatment in C2C12 cells, which was ameliorated by NAC pretreatment. Furthermore, H2O2 induced apoptosis and death of C2C12 cells, which was prevented by NAC pretreatment. The weight of the gastrocnemius muscle was reduced in the axotomy group, which was prevented by NAC administration. Lastly, although muscle specimens from the axotomy group showed greater reductions in muscle fiber, the oral administration of NAC significantly inhibited amyotrophy via antioxidant effects.The current in vitro and in vivo study demonstrated the possible involvement of oxidative stress in sarcopenic pathology. NAC represents a potential anti-sarcopenic drug candidate, preventing amyotrophy and fatty degeneration.4.

Study design A case-control study. Objective The aim of this study was to investigate the long-term prevalence of the Modic changes and disc degeneration in the nonfused segments of the surgically treated adolescent idiopathic scoliosis (AIS) patients and compare with age- and sex-matched healthy controls. Summary of background data No studies have looked at the association between Modic changes and low back pain in patients who underwent AIS surgery many years ago. Methods Study subjects consisted of 194 patients with AIS who underwent spinal fusion with Harrington instrumentation between 1968 and 1987. Twenty-six patients (AIS group) underwent lumbar magnetic resonance imaging (MRI), whole spine X-ray, and patient-reported outcomes evaluations [Scoliosis Research Society-22 Patient Questionnaire (SRS-22), Oswestry Disability Index (ODI)]. The mean duration of follow-up observation was 36.1 years. The lowest fusion vertebra was used as follows: T12: 2 patients, L1: 4, L2: 11, L3: 6, L4: 2, L5: 1. Twenty-nine healthy age- and sex-matched individuals were selected as a control (CTR) group. Results On the basis of MRI findings, a significantly higher percentage of subjects showed Modic changes in the AIS group (AIS group: 57.7%, CTR group: 13.8%). There were no significant differences in the percentage of subjects with disc degeneration rated Pfirrmann grade 4 or higher (AIS group: 61.5%, CTR group: 65.5%). SRS-22 scores for function and self-image were significantly lower in the AIS group. ODI was significantly worse in the AIS group. Modic changes in AIS group were found in the concave side of the curve in 61.9%. The magnitude of lumbar coronal curve was found to be a significant risk factor of Modic changes. Conclusion Modic changes were observed in 57.7% of AIS patients 27 years or more after spinal fusion with Harrington instrumentation. The magnitude of lumbar coronal curve was found to be a significant risk factor of Modic changes. Modic change occurred at a higher frequency in AIS patients than CTR individuals, with lower function and worse ODI scores. Level of evidence 4.

STUDY DESIGN Delphi. OBJECTIVE The aim of this study was to obtain an expert consensus on which history factors are most important in the clinical diagnosis of lumbar spinal stenosis (LSS). SUMMARY OF BACKGROUND DATA LSS is a poorly defined clinical syndrome. Criteria for defining LSS are needed and should be informed by the experience of expert clinicians. METHODS Phase 1 (Delphi Items): 20 members of the International Taskforce on the Diagnosis and Management of LSS confirmed a list of 14 history items. An online survey was developed that permits specialists to express the logical order in which they consider the items, and the level of certainty ascertained from the questions. Phase 2 (Delphi Study) Round 1: Survey distributed to members of the International Society for the Study of the Lumbar Spine. Round 2: Meeting of 9 members of Taskforce where consensus was reached on a final list of 10 items. Round 3: Final survey was distributed internationally. Phase 3: Final Taskforce consensus meeting. RESULTS A total of 279 clinicians from 29 different countries, with a mean of 19 (±SD: 12) years in practice participated. The six top items were "leg or buttock pain while walking," "flex forward to relieve symptoms," "feel relief when using a shopping cart or bicycle," "motor or sensory disturbance while walking," "normal and symmetric foot pulses," "lower extremity weakness," and "low back pain." Significant change in certainty ceased after six questions at 80% (P

STUDY DESIGN A cross-sectional study of 1804 consecutive patients. OBJECTIVE The aim of this study was to investigate the prevalence of pathological pain and its distribution features in patients with chronic lumbar spinal disorders. SUMMARY OF BACKGROUND DATA Clinical spinal disorders can involve pathological neuropathic pain (NeP) as well as physiological nociceptive pain (NocP), as they have varied pathology, including spinal cord injury, stenosis, and compression. A study conducted by the Japanese Society for Spine Surgery and Related Research (JSSR) has determined a prevalence of 29.4% for NeP in patients with lumbar spinal disorder. However, the data did not include information on pain location. METHODS Patients aged 20 to 79 years with chronic lower back pain (≥3 months, visual analog scale score ≥30) were recruited from 137 JSSR-related institutions. Patient data included an NeP screening questionnaire score and pain location (lower back, buttock, and legs). The association between the pain pathology and its location was analyzed statistically using the unpaired t test and Chi-square test followed by Fisher test. P

STUDY DESIGN A retrospective study. OBJECTIVE The aim of this study was to determine the publication rate and impact factors (IFs) among all abstracts presented at the 2010 and 2012 meetings of the International Society for the Study of Lumbar Spine (ISSLS). SUMMARY OF BACKGROUND DATA The publication rate of abstracts presented at overseas meetings was reported to be around 50%. However, the publication rate and IFs of oral and poster presentations made at ISSLS meetings were unclear. Moreover, whether the publication rates and IFs differed for papers associated with oral or poster presentations at ISSLS meetings was unknown. METHODS We investigated all 1126 abstracts (oral, special posters, general posters) presented at ISSLS meetings held between 2010 and 2012. PubMed was searched to identify publications and IFs were determined using journal citation reports. We also compared the publication rates and IFs between oral and poster presentations. RESULTS The overall publication rate was 50.1% for three ISSLS meetings (564 publications/1126 abstracts). The overall publication rate for oral presentations, special posters, and general posters given in the 2010 to 2012 meetings was 62.0%, 48.3, and 46.6%, respectively. Overall, papers related to oral presentations had significantly higher publication rates than those of special and general posters (P = 0.0002). The average IFs of publications associated with abstracts presented at three ISSLS meetings was 2.802 for oral presentations, 2.593 for special posters, and 2.589 for general posters. There were no significant differences in average IFs between oral and poster presentations (P > 0.05). CONCLUSION The publication rate for abstracts presented at ISSLS meetings was high and similar to publication rates for abstracts presented at other meetings concerning orthopedic and spine research. However, there was no significant difference in IFs between oral and poster presentations, suggesting that abstract evaluations cannot predict IFs of the eventual publication. LEVEL OF EVIDENCE 4.

Study Design. Immunohistochemical and behavioral study using the SPARC (secreted protein, acidic, rich in cysteine)-null mouse model of low back pain (LBP) associated with accelerated intervertebral disc (IVD) degeneration. Objective. To determine if behavioral signs of LBP in SPARC-null mice are accompanied by sensory nervous system plasticity. Summary of Background Data. IVD pathology is a significant contributor to chronic LBP. In humans and rodents, decreased expression of SPARC is associated with IVD degeneration. We previously reported that SPARC-null mice exhibit age-dependent behavioral signs of chronic axial LBP and radiating leg pain. Methods. SPARC-null and age-matched control young, middle-aged, and old mice (1.5, 6, and 24 mo of age, respectively) were evaluated. Cutaneous hind paw sensitivity to cold, heat, and mechanical stimuli were evaluated as measures of radiating pain. The grip force and tail suspension assays were performed to evaluate axial LBP. Motor impairment was assessed using an accelerating rotarod. IVD innervation was identified by immunohistochemistry targeting the nerve fiber marker PGP9.5 and the sensory neuropeptide calcitonin gene-related peptide (CGRP). Sensory nervous system plasticity was evaluated by quantification of CGRP- and neuropeptide-Y-immunoreactivity (-ir) in dorsal root ganglia neurons and CGRP-ir, GFAP-ir (astrocyte marker), and Iba-1-ir (microglia marker) in the spinal cord. Results. SPARC-null mice developed hypersensitivity to cold, axial discomfort, age-dependent motor impairment, age-dependent increases in sensory innervation in and around the IVDs, age-dependent upregulation of CGRP and neuropeptide-Y in dorsal root ganglia, and age-dependent upregulation of CGRP, microglia, and astrocytes in the spinal cord dorsal horn. Conclusion. Increased innervation of degenerating IVDs by sensory nerve fibers and the neuroplasticity in sensory neurons and spinal cord could contribute to the underlying pathobiology of chronic discogenic LBP. Conclusion. Level of Evidence: N/A

Study design Animal study. Objective To evaluate pain behavior and neuropeptide changes in the spinal dorsal horn after sciatic nerve compression and application of nucleus pulposus (NP) in rats. Summary of background data The pathomechanisms of lumbar disc herniation pain have not been fully elucidated. Pain-associated neuropeptides, including substance P and calcitonin gene-related peptide (CGRP), are produced in dorsal root ganglion neurons and transported to spinal dorsal horn nerve terminals where they function in pain transmission. However, changes in CGRP-immunoreactive (IR) sensory nerve terminals have not been reported in models of disc herniation. This study evaluated pain-related behavior and changes in CGRP-IR terminals in the spinal dorsal horn after combined sciatic nerve compression and NP application. Methods Five groups of rats underwent either sciatic nerve compression with NP (n = 20), application of NP only (n = 20), nerve compression only (n = 20), and sham operation with neither compression nor NP (n = 20) or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for 3 weeks. CGRP-IR terminals in each spinal dorsal horn lamina were examined 7 and 14 days postsurgery. Pain behavior and CGRP immunoreactivity were compared among the 5 groups. Results Mechanical hyperalgesia was found in the NP only, nerve compression only, and the NP with nerve compression groups (P ≤ 0.05). CGRP-IR nerve terminals in the superficial laminae (I and II) and the deep laminae (III-VI) significantly increased in the NP only, nerve compression only, and NP with nerve compression groups compared with control and sham groups (P ≤ 0.05). Significant mechanical hyperalgesia and increased CGRP-IR nerve terminals were found in the NP with nerve compression group compared with the NP only and nerve compression only groups (P ≤ 0.05). Conclusion Our results indicate that nerve compression plus NP application produces the most pain-related behavior. CGRP-IR nerve terminals increased in laminae I and II that transmit pain and in laminae III to VI that transmit proprioception. Findings suggest that nerve compression plus NP application induces changes in CGRP expression in the superficial and deep laminae, and these changes are partly responsible for disc herniation pain.

Study design An open-labeled multicenter prospective nonrandomized controlled clinical trial. Objective To confirm the feasibility of using granulocyte colony-stimulating factor (G-CSF) for treatment of acute spinal cord injury (SCI). Summary of background data We previously reported that G-CSF promotes functional recovery after compression-induced SCI in mice. On the basis of these findings, we conducted a multicenter prospective controlled clinical trial to assess the feasibility of G-CSF therapy for patients with acute SCI. Methods The trial ran from August 2009 to March 2011, and included 41 patients with SCI treated within 48 hours of onset. Informed consent was obtained from all patients. After providing consent, patients were divided into 2 groups. In the G-CSF group (17 patients), G-CSF (10 μg/kg/d) was intravenously administered for 5 consecutive days, and in the control group (24 patients), patients were similarly treated except for the G-CSF administration. We evaluated motor and sensory functions using the American Spinal Cord Injury Association score and American Spinal Cord Injury Association impairment scale at 1 week, 3 months, 6 months, and 1 year after onset. Results Only 2 patients did not experience American Spinal Cord Injury Association impairment scale improvement in the G-CSF group. In contrast, 15 patients in the control group did not experience American Spinal Cord Injury Association impairment scale improvement. In the analysis of increased American Spinal Cord Injury Association motor score, a significant increase in G-CSF group was detected from 1 week after the administration compared with the control group. After that, some spontaneous increase of motor score was detected in control group, but the significant increase in G-CSF group was maintained until 1 year of follow-up. Conclusion Despite the limitation that patient selection was not randomized, the present results suggest the possibility that G-CSF administration has beneficial effects on neurological recovery in patients with acute SCI. Level of evidence 3.

STUDY DESIGN Animal study. OBJECTIVE To determine the existence of dichotomizing sensory nerve fibers innervating both the lumbar vertebral body and the area surrounding the iliac crest (ASIC). SUMMARY OF BACKGROUND DATA Elderly patients with osteoporosis sometimes experience lumbar vertebral fracture and may feel diffuse nonlocalized pain in the back, the lateral portion of the trunk, and the ASIC. The pattern of sensory innervation of vertebral bodies remains unclear. DRG neurons with dichotomizing axons have been reported and are thought to be related to referred pain. The purpose of this study was to investigate the existence of dichotomizing axons to the lumbar vertebral bodies and the ASIC in rats. METHODS Two kinds of neurotracers (1,1´-dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate [DiI] and Fluoro-Gold [FG]) were used. DiI crystals were placed in the left ASIC, and FG was applied into the L2 vertebral body in 10 rats. Four weeks later, left DRGs from L1 to L6 were resected, sectioned, and observed under a fluorescence microscope. RESULTS DiI-labeled DRG neurons innervating the ASIC and FG-labeled DRG neurons innervating the vertebral L2 body were distributed from L1 to L6. The ratio of total double-labeled per total DiI-labeled DRG neurons was 10.2%, and that of total double-labeled per total FG-labeled DRG neurons was 14.7%. These double-labeled DRG neurons innervating the L2 vertebral body had other axons that extended to the ASIC. CONCLUSION This finding provides a possible neuroanatomical explanation for referred pain in the ASIC from vertebral bodies.

STUDY DESIGN Assessment of pain-related behavior and immunohistology of the dorsal root ganglion in a rat model. OBJECTIVE To investigate pain-related behavior in a rat model of nerve crush plus inflammation using the CatWalk system. SUMMARY OF BACKGROUND DATA A definitive method for evaluating animal models of lumbar disease has not been established. Von Frey testing has often been used in this type of study, but the reliability remains in question. The CatWalk system is a computer-assisted apparatus for analyzing gait that provides an automated way to assess gait function during pain. However, there have been few reports using this system for models of lumbar disease. METHODS Fourteen rats were divided into 2 groups: a treatment group and a sham group. For the treatment group, nucleus pulposus was applied to the sciatic nerve and the sciatic nerve was pinched. Two different methods for assessment of pain-related behavior, von Frey testing and CatWalk analysis, were used before surgery and at 4 and 7 days after surgery. Immunohistochemistry was used to examine calcitonin gene-related peptide expression in L4 to L6 dorsal root ganglia. RESULTS No significant differences were found between the treatment and sham control groups using von Frey testing. However, significant differences in 4 parameters were found between the 2 groups using the CatWalk system (P < 0.05). The proportion of calcitonin gene-related peptide-immunoreactive neurons was higher in the treatment group than in the control group (P < 0.05). CONCLUSION Our results demonstrate that the CatWalk system is useful for the measurement of pain-related behavioral change in our rat model in which nociception was indicated at a cellular level. Although further studies are needed, we think that this system is a valid alternative method for the evaluation of models of lumbar disease in rodents.

Prospective study.To examine the efficacy of teriparatide or bisphosphonate treatment to reduce pedicle screw (PS) loosening after instrumented lumbar posterolateral fusion in postmenopausal women with osteoporosis.Failure of fixation caused by loosening of PSs in osteoporosis is a problem in spinal surgery. Oral administration of bisphosphonate or intermittent injection of parathyroid hormone treatment increases bone mass and reduces the risk of osteoporotic vertebral fractures. Although these treatments may be factor in improving bone quality, a clinical study of the efficacy of bisphosphonate or parathyroid hormone for reducing PS loosening that addresses the quality of the bone marrow and pedicle cortex has not yet been reported.Sixty-two women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 3 groups: a teriparatide group (daily subcutaneous injection of 20 μg of teriparatide, n = 20), a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and a control group (without medication for osteoporosis, n = 22). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Loosening of PSs and surgical outcome were evaluated radiographically, clinically, and by computed tomography 12 months after surgery.At 12-month follow-up, the incidence of PS loosening was 7% to 13% in the teriparatide group, 13% to 26% in the risedronate group, and 15% to 25% in the control group. The incidence of PS loosening in the teriparatide group was significantly lower than that in the risedronate or the control group (P0.05). In contrast, the extent of PS loosening in the risedronate group was not significantly different from that in the control group (P0.05).Our findings suggest that administration of teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex.

Study design We measured the response of the behavior and spinal glial activation to anti-nerve growth factor receptor (p75 neurotrophin receptor [p75NTR]) antibodies in the rat brachial plexus avulsion (BPA) model. Objective The aim of this study was to investigate the effect of anti-p75NTR antibodies on nociceptive behavior and activation of spinal microglia in the rat BPA model. Summary of background data Tanezumab (anti-nerve growth factor antibody) treatment is associated with pain reduction and improvement in function, but with several complications. Methods Thirty male Wistar rats were used. In the BPA group, the C8-T1 roots were avulsed from the spinal cord with forceps at the lower trunk level and 10 μL of saline was applied locally (n = 10). In the anti-p75NTR group, the C8-T1 roots were avulsed and 10 μL of anti-p75NTR antibody was applied locally (n = 10). In a sham-operated group, the lower trunk was simply exposed (n = 10). Mechanical hyperalgesia and pain-induced walking patterns were measured using von Frey filaments (Stoelting, Wood Dale, IL) and the CatWalk gait analysis (Noldus Information Technology, the Netherlands) system every third day for 3 weeks. Activation of astrocytes and microglia was immunohistochemically examined in the spinal cord using anti-glial fibrillary acidic protein (GFAP) and anti-Iba1 antibodies both 7 and 21 days after surgery. Results Animals in the BPA group displayed significant mechanical hyperalgesia that continued through day 21 compared with animals in the sham-operated group, and mechanical hyperalgesia in the anti-p75NTR group was significantly improved 6 days after the operation. Regarding pain-induced gait analysis via CatWalk, animals in the BPA group displayed a significantly greater pain-like gait pattern than the p75 group for up to 3 weeks. Levels of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia in the anti-p75NTR group were significantly reduced compared with the BPA group. Conclusion Our results suggest that p75NTR contributes to neuropathic pain associated with BPA, and that inhibition of p75NTR reduces neuropathic pain. Level of evidence N/A.

STUDY DESIGN Immunohistological analysis of spinal glial cells and analysis of pain behavior in the rat neuropathic pain model were investigated to clarify the function of tumor necrosis factor (TNF)-α receptors p55 type 1 and p75 type 2. OBJECTIVE Our objective was to investigate changes in hyperalgesia and glial cell activation after injection of antibodies to each TNF receptor in a rat sciatic nerve injury model. SUMMARY OF BACKGROUND DATA Recent research has revealed that activation of spinal glia plays an important role in radicular and neuropathic pain. TNF-α is reportedly a modulator for glial cell activation; however, the precise relationship between TNF-α and its 2 receptors on glial cells has not been fully delineated. METHODS Chronic constriction sciatic nerve injury and sham-operated rats were used. Antibodies to p55 or p75 or saline were intrathecally injected at the L5 level into rats with chronic constriction injury. Mechanical allodynia was examined for 2 weeks. Spinal cords were removed for immunohistochemical studies of ionized calcium-binding adaptor molecule 1 or glial fibrillary acidic protein. RESULTS Saline rats showed significantly more mechanical allodynia and the number of ionized calcium-binding adaptor molecule 1--immunoreactive microglia and glial fibrillary acidic protein--immunoreactive astrocytes were significantly increased in the saline rats compared with sham-operated rats during the 2 weeks. Injection of both antibodies significantly reduced pain behavior and anti-p55 caused significantly greater reduction compared with anti-p75. The numbers of microglia in both the antibodies groups were significantly decreased when compared with the saline group. In addition, the anti-p55 antibody suppressed microglial activation more than the anti-p75 antibody. CONCLUSION These results indicate that the microglial TNF-α p55 pathway played a more important role than the TNF-α p75 pathway in the pathogenesis of peripheral nerve injury pain. This suggests that future studies seeking to clarify neuropathic pain should target TNF-α and p55 receptors in microglia.

Study design Case series. Objective To present the difficulty of diagnosing the origin of lower leg pain in patients with lumbar spinal stenosis and hip joint arthritis. Summary of background data Pain arising from a degenerated hip joint is sometimes localized to the lower leg. Patients with lumbar spinal disease may also show radicular pain corresponding to the lower leg area. If patients present with both conditions and only pain at the lower leg, it is difficult to determine the origin of the pain. Methods We reviewed 420 patients who had leg pain with lumbar spinal stenosis diagnosed by myelography, computed tomography after myelography, or magnetic resonance imaging. Pain only at the ipsilateral lateral aspect of the lower leg but slight low back pain or pain around the hip joint was shown in 4 patients who had lumbar spinal stenosis and hip osteoarthritis. The symptoms resolved after L5 spinal nerve block, but remained after lidocaine infiltration into the hip joint. We performed decompression and posterolateral fusion surgery for these 4 patients. Results Leg pain did not resolve after lumbar surgery in all patients. Conservative treatment was not effective from 6 to 12 months, so ultimately we performed ipsilateral total hip replacement for all patients and they became symptom-free. Conclusion It is difficult to determine the origin of lower leg pain by spinal nerve block and hip joint block in patients with lumbar spinal stenosis and hip osteoarthritis. We take this into consideration before surgery.

Study design Prospective trial. Objective To examine the clinical efficacy of teriparatide for bone union after instrumented lumbar posterolateral fusion using local bone grafting in women with postmenopausal osteoporosis. Summary of background data Intermittent parathyroid hormone (PTH) treatment increases bone mass and reduces the risk for osteoporotic vertebral fractures. Recombinant human PTH (1-34) has already been approved as a treatment for severe osteoporosis. Preclinical data support the efficacy of PTH for lumbar spinal fusion. However, clinical results of PTH for spinal fusion have not yet been reported. Methods Fifty-seven women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 2 treatment groups, a teriparatide group (n = 29; daily subcutaneous injection of 20 μg of teriparatide) and a bisphosphonate group (n = 28; weekly oral administration of 17.5 mg of risedronate). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Fusion rate, duration of bone union, and pain scores were evaluated 1 year after surgery. Results Pain scores improved after surgery; however, no significant difference was noted between the groups after surgery. The rate of bone union was 82% in the teriparatide group and 68% in the bisphosphonate group. Average duration of bone union was 8 months in the teriparatide group and 10 months in the bisphosphonate group. The rate of bone union and average of duration of bone union in the teriparatide group patients were significantly superior to those in the bisphosphonate group. Conclusion Daily subcutaneous injection of teriparatide for bone union using local bone grafting after instrumented lumbar posterolateral fusion in women with postmenopausal osteoporosis was more effective than oral administration of bisphosphonate.

Study design A case report. Objective An elderly patient presented with an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. Summary of background data Although gout and pseudogout are common diseases causing inflammatory arthropathy in peripheral joints, involvement of the spine is uncommon. Here, we report a patient experiencing an acute lumbar spinal pseudogout attack after lumbar instrumented surgery. Methods The patient was treated for lumbar spondylolisthesis at L4 and L5 level and afterward complained of lower back and bilateral leg pain. Conservative treatment was not effective for the patient; therefore, we preformed posterior transforaminal lumbar interbody fusion surgery. Results The postoperative course was uneventful; however, he experienced lower back pain 4 weeks after surgery. Magnetic resonance image showed changes in signal intensities of vertebra and fluid accumulation in posterior back muscles. A biopsy was performed, but the culture was negative for infection. Calcium pyrophosphate dehydrate was detected in the fluid. Thus, conservative therapy without antibiotics was performed, and the patient's symptoms disappeared within 2 weeks. Conclusion Here, we reported the first case of acute lumbar spinal pseudogout attack after lumbar instrumented surgery. We recommend considering pseudogout before and after surgery.

Study Design. A prospectively study. Objective. Our objective was to clarify the safety and efficacy of asymmetrical pedicle subtraction osteotomy (PSO) in the treatment of severe adult lumbar deformities prospectively. Summary of Background Data. Vertebral wedge osteotomy provides good correction of kyphosis but has rarely been applied to degenerative lumbar kyphoscoliosis. Methods. A total of 14 patients who had undergone corrective osteotomy were enrolled. The average age at PSO was 67 years (range, 45–76 yr). The minimum follow-up was 2 years. Patient questionnaires were administered prospectively. Radiographical parameters including sagittal and coronal balance were analyzed. Results. Average operative time was 310 minutes (range, 254–375 min). Average blood loss was 1090 mL (range, 700–2900 mL). Results. Mean preoperative lumbar lordosis improved from −3° to 42° at the final follow-up, and sagittal balance improved from 12 to 3 cm, respectively. Mean lumbar scoliosis improved from 40° to 12°, and coronal offset improved from 3 to 1 cm, respectively. There was also statistically significant improvement from preoperative to final evaluation in all clinical domains. There were 4 complications: 1 dural tear, 2 hook dislodgements at the cephalad side requiring revision instrumentation, and 1 rod breakage not requiring surgical intervention. Overall, all 14 patients were satisfied with their surgical management and would choose to repeat the procedure. Conclusion. Our data suggest that the surgical procedure of asymmetrical PSO is to correct the scoliosis, to restore the lumbar lordosis by way of convex-sided posterolateral wedge osteotomy, and may go a long way toward solving the problems of rigid lumbar degenerative kyphoscoliosis.

Study design Animal model of intravertebral disc (IVD) degeneration. Objective To examine production of inflammatory mediators in IVDs and neuropeptides in dorsal root ganglia (DRGs) in rat models of IVD compression and injury. Summary of background data Sensory nerve fibers in IVDs and inflammatory mediator responses have been verified in animal models of IVD injury. However, the IVD injury in animals incompletely models degenerated human IVDs causing discogenic low back pain, because human IVDs are also subject to compression. Methods Experimental groups (controls, IVD injury, IVD compression, and their combination) of Sprague Dawley rats were prepared. Fluoro-Gold (FG; Fluorochrome, Denver, CO) was applied into coccygeal IVDs. Inflammatory mediators in IVDs, including nerve growth factor, tumor necrosis factor α, interleukin 1β, and interleukin 6, were quantified using enzyme-linked immunosorbent assays. DRGs were immunostained for calcitonin gene-related peptide, activating transcription factor 3, and growth-associated phosphoprotein 43. Results The upregulation of inflammatory mediators was transient in the IVD injury group but delayed and long-lasting in the IVD compression group. When the IVD injury and compression were combined, the upregulation of inflammatory mediators was long-lasting through 8 weeks. The proportion of calcitonin gene-related peptide-immunoreactive neurons among Fluoro-Gold-labeled neurons remained significantly higher in the IVD injury, compression, and combination groups than in the controls. In contrast, increases in the proportions of activating transcription factor 3-immunoreactive or growth-associated phosphoprotein 43-immunoreactive neurons in the IVD injury group animals were transient but long-lasting in the compression and combination groups compared with controls. Conclusion Disc injury in rats produces persistent increases in neuropeptides in DRGs but only transient increases in inflammatory mediators in IVDs. On the contrary, disc compression in rats produces a long-lasting increase in inflammatory mediators in IVDs and neuropeptides in DRGs. Moreover, disc compression induces persistent nerve injury and regeneration of the afferent fibers innervating IVDs.

A retrospective radiological study on vascular anatomy.The aim of this study was to evaluate the anatomical and radiological features of lumbar segmental arteries with respect to the surgical field of the oblique lateral interbody fusion (OLIF) approach by using magnetic resonance imaging (MRI).OLIF surgery restores disc height and enables indirect decompression of narrowed spinal canals through an oblique lateral approach to the spine, by using a specially designed retractor. In a minimal surgical field, injuring segmental arteries can cause massive hemorrhage.We reviewed 272 lumbar MRIs. In the sagittal images, the intersection of one-third of the anterior and median lines of the intervertebral disc (IVD) was considered the center of the virtually installed OLIF retractor. The cephalad/caudal distances from the center and branch angles of segmental arteries to the longitudinal axes of the aorta were measured to determine whether the segmental arteries run into the surgical area. Statistical significance was set at P 0.05.The branch angles of segmental arteries were significantly acute (≤90°) in L1-L3 arteries and significantly blunt (90°) in L4 and L5 arteries. The average distance to the center of the caudal adjacent IVD was significantly larger, and there were generally low possibilities for the existence of segmental arteries below half of the vertebral height, where the surgeons can install fixation pins with ease and safety. Among the lumbar segmental arteries, L5 showed specific characteristics with significant deviation, a four times (4.1% vs. L1-L3 segmental arteries) higher adjacency rate, and a two-fifth (38.6% vs. 100%) lower existence rate.Segmental arteries can be involved in the surgical field of OLIF especially in the lower lumbar spine level of L4 and L5 arteries, which can directly run across IVDs. L5 segmental arteries can also be iliolumbar arteries that have an abnormal trajectory by nature.4.

Study design A retrospective multicenter survey. Objective To investigate the perioperative complications of oblique lateral interbody fusion (OLIF) surgery. Summary of background data OLIF has been widely performed to achieve minimally invasive, rigid lumbar lateral interbody fusion. The associated perioperative complications are not yet well described. Methods The participants were patients who underwent OLIF surgery under the diagnosis of degenerative lumbar diseases between April 2013 and May 2015 at 11 affiliated medical institutions. The collected data were classified into intraoperative and early-stage postoperative (≤1 mo) complications. The intraoperative complications were then subcategorized into organ damage (neural, vertebral, vascular, and others) and other complications, mainly related to instrumental failure. The collected data were also divided and analyzed based on whether the surgeon was certified to perform the surgery and the incidence of complications in the early (April 2013-March 2014) and late stages (April 2014-May 2015) of OLIF introduction. Results In the 155 included patients, 75 complications were reported (incidence rate, 48.3%). The most common complication was endplate fracture/subsidence (18.7%), followed by transient psoas weakness and thigh numbness (13.5%) and segmental artery injury (2.6%). Almost all these complications were transient, except for three patients who had permanent damage: one had ureteral injury and two had neurological injury. Postoperative complications included surgical site infection (1.9%) and reoperation (1.9%). Whether the primary operator was experienced did not affect the incidence of complications. Regarding the introductory stage, the incidence of complications was 50% in the early stage and 38% in the late stage. Conclusion The overall incidence of perioperative complications of OLIF surgery reached 48.3%, of which only 1.9% resulted in permanent damage. Our analysis based on surgeon experience indicated that the OLIF procedure could be performed without increasing incidence of complications, under the guidance of experienced supervisors. Level of evidence 3.

Study design A prospective interventional trial, using a rat model of lumbar interbody fusion. Objective To examine the potential efficacy of platelet-rich plasma (PRP) for lumbar interbody fusion, using hydroxyapatite (HA). Summary of background data PRP is an autologous product containing a high concentration of platelets in a small volume of plasma and has osteoinductive effects. HA has osteoconductive ability and has been used in combination with autogenous bone for spine fusion. However, reports using PRP with HA for spine fusion are very few. The purpose of this study was to examine the efficacy of PRP with HA for spinal interbody fusion and at the same time to estimate the change in immunoreactivity of the inflammatory neuropeptide, calcitonin gene-related peptide (CGRP), in dorsal root ganglion (DRG) neurons innervating spinal discs. Methods A total of 35 Sprague-Dawley rats were used in this study. Twenty-one rats were used for conducting interbody fusion experiments, 7 rats were used as immunostaining controls, and 7 other rats were used as blood donors for making PRP. L5-L6 interbody fusion was performed on 21 rats using HA + PRP (n = 7), HA + platelet-poor plasma (n = 7), or HA + saline (n = 7). Simultaneously, Fluoro-Gold neurotracer was applied to the intervertebral space to detect DRG neurons innervating the discs. L5-L6 lumbar radiographs were obtained and lumbar DRGs were immunostained for CGRP. The rate of bone union and the change in CGRP immunoreactive DRG neurons innervating the discs were evaluated and compared among groups. Results All L5-L6 lumbar discs were fused in the PRP + HA group (fused 7/total 7), whereas only 1 case was fused in the platelet-poor plasma group (1 of 7) and no cases in the HA-only group (0 of 7), which was a significant difference. Upon immunohistochemical analysis, CGRP-positive neurons innervated L5-L6 intervertebral discs in nonunion cases, and these were significantly increased compared with those in union cases. Conclusion Our study suggests that using PRP with HA was beneficial for spine fusion. This combination may promote bone union and also decrease inflammatory neuropeptide in sensory neurons innervating the discs.

STUDY DESIGN: An immunohistological analysis of the cervical intervertebral disc (IVD). OBJECTIVE: To investigate sensory and autonomic innervation of the rat cervical IVD. SUMMARY OF BACKGROUND DATA: Many clinicians are challenged with treating wide-ranging chronic neck pain. Several authors have reported that sympathetic nerves participate in chronic pain, and various sympathectomy procedures can effectively treat chronic pain. METHODS: The neuro-tracer Fluoro-gold (FG) was applied to the anterior surfaces of C5-C6 IVDs from 10 Sprague-Dawley rats to label the neurons of the innervating dorsal root ganglion (DRG), stellate ganglion (SG; sympathetic ganglion), and nodose ganglion (NG; parasympathetic ganglion). Seven days postsurgery, DRGs from level C1-C8, SG, and NG neurons were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP; a marker for peptide-containing neurons) and isolectin B4 (IB4; a marker for nonpeptide-containing neurons). The proportion of FG-labeled DRG neurons that were CGRP-immunoreactive (CGRP-IR), IB4-binding, and non-CGRP-IR and IB4-binding, and the proportion of FG-labeled SG neurons and NG neurons were calculated. RESULTS: FG-labeled neurons innervating the C5-C6 IVD were distributed throughout the C2-C8 DRGs. The proportions of FG-labeled DRG neurons that were CGRP-IR, IB4-binding, non-CGRP-IR and IB4-binding, as well as SG neurons, and NG neurons were 20.6%, 3.3%, 55.7%, 8.9%, and 11.5%, respectively. The proportion of CGRP-IR FG-labeled DRG neurons was significantly higher than the proportion of IB4-binding FG-labeled DRG neurons at each level (P < 0.05). CONCLUSION: The C5-C6 IVD was innervated multisegmentally from neurons of the C2-C8 DRG, SG, and NG. Overall, 79.6% of the nerve fibers innervating the IVD were sensory nerves and 20.4% were autonomic nerves. Furthermore, 23.9% of the nerve fibers innervating the IVD were afferent sensory pain-related nerves, 8.9% were efferent sympathetic nerves, and 11.5% were efferent parasympathetic nerves. These findings may explain the wide-ranging and chronic discogenic pain that occurs via the somatosensory and autonomic nervous system.

Study design Case report. Objective Diagnosis of symptomatic extra-foraminal lumbosacral stenosis using diffusion tensor imaging (DTI). Summary of background data Conventional magnetic resonance imaging (MRI) has sometimes proved inadequate for evaluating symptomatic spinal nerve lesions. DTI has been developed to visualize anisotropy of nerve-fiber tracts to evaluate nerve degeneration. We report a case of nerve compression causing a far-out lesion diagnosed using DTI. Methods A 68-year-old patient presented with an 8-month history of severe right-sided sciatica. Computed tomography and MRI showed right L5-S1 foraminal stenosis and contact of the L5 transverse process and S1 ala without canal stenosis at the L4-L5 level. We evaluated the fractional anisotropy (FA) of the right L5 spinal nerve and compared it with bilateral L3-S1 spinal nerves to determine the L5 spinal nerve compression site. Results DTI revealed narrowing of the right L5 spinal nerve between the L5 transverse process and S1 ala. FA was significantly decreased in the right L5 spinal nerve between the L5 transverse process and S1 ala. There was no significant difference in the FA of spinal nerves between the right and left sides at L3, L4, or S1. The right L5 spinal nerve from the central spinal canal to the extra-foraminal lumbosacral lesion was exposed during surgery and found to be severely compressed by the L5 transverse process and S1 ala. Postoperatively, the patient's symptoms disappeared immediately. Conclusion We used DTI to diagnose a symptomatic lesion as an extra-foraminal lumbosacral lesion caused by compression of the L5 spinal nerve at the foramina. Because DTI can quantitatively measure damage to nerve fibers, it may be advantageous for the diagnosis of far-out syndrome.

STUDY DESIGN Immunohistological analysis of dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and intervertebral disc (IVD), facet joint (FJ), or sacroiliac joint (SIJ) in rats. OBJECTIVE To elucidate dichotomizing sensory nerve fibers projecting to the lumbar multifidus muscles and to IVDs, FJs, or SIJs. SUMMARY OF BACKGROUND DATA Clinically, the origin of low back pain remains unknown. Multiple studies have identified lumbar muscles, IVDs, FJs, and SIJs as sources of low back pain. Pain may originate directly from lumbar muscles or be referred from the spine, or both. Dorsal root ganglion (DRG) neurons with dichotomizing axons have been reported in several species and are thought to be related to referred pain. METHODS We used 2 neurotracers, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) and fluorogold (FG), in this double-labeling study involving 30 Sprague Dawley rats. DiI was applied to lumbar multifidus muscles in all rats. Simultaneously, FG was applied to the anterior left portion of L5-L6 IVDs in the IVD group (n = 10), to the left L5-L6 FJs in the FJ group (n = 10), and to the left SIJs in the SIJ group (n = 10). Fourteen days after surgery, left DRGs from L1 to L6 were harvested, sectioned, and observed under a fluorescence microscope. RESULTS We verified the existence of double-labeled DRG neurons (i.e., dichotomizing sensory nerve fibers) projecting to lumbar multifidus muscles and to IVDs, FJs, or SIJs, depending on the group. The proportion of double-labeled cells in all DiI-labeled DRG neurons was higher in the FJ group (6.8%) and SIJ group (7.1%) than in the IVD group (3.1%) (P < 0.05). CONCLUSION Our results document the presence of dichotomizing sensory nerve fibers projecting to lumbar multifidus muscles and to IVDs, FJs, and SIJs. Referred low back muscle pain may reflect disorders of lumbar posterior structures, such as FJs and SIJs, rather than disorders of lumbar anterior structures, such as IVDs.

STUDY DESIGN Prospective randomized trial. OBJECTIVE To examine the effect of the tumor necrosis factor alpha (TNF-α) inhibitor, etanercept, on radicular pain by its epidural administration onto spinal nerves in patients with lumbar spinal stenosis. SUMMARY OF BACKGROUND DATA TNF-α is thought to play a crucial role in the radicular pain caused by lumbar disc herniation and spinal stenosis. Intravenous infusion of infliximab for sciatica has been examined in 2 studies; however, the results were equivocal. METHODS Eighty patients with low back and radicular leg pain were investigated. We diagnosed the patients by physical examination, and X-ray and magnetic resonance imaging. In 40 patients, we epidurally administered 2.0 mL of lidocaine and 10 mg of etanercept onto the affected spinal nerve, and 2.0 mL of lidocaine and 3.3 mg of dexamethasone was used in 40 patients. Low back pain, leg pain, and leg numbness were evaluated using a visual analogue scale (VAS) and Oswestry Disability Index (ODI) score before and for 1 month after epidural administration. RESULTS Low back pain, leg pain, and leg numbness in the 2 groups were not significantly different before epidural administration. Epidural administration of etanercept was more effective than dexamethasone for leg pain (3 days, and 1, 2, and 4 weeks: P < 0.05), low back pain (3 days, and 1 and 2 weeks: P < 0.05), and leg numbness (3 days, and 1 and 2 weeks: P < 0.05). No adverse event was observed in either group. CONCLUSION Our results indicate that epidural administration of a TNF-α inhibitor onto the spinal nerve produced pain relief, but no adverse event. TNF-α inhibitors may be useful tools for the treatment of radicular pain caused by spinal stenosis.

STUDY DESIGN Immunohistochemical study. OBJECTIVE To evaluate invasive surgical approaches by analyzing the number of sensory nerve fibers at 2 back muscle sites in rats and humans and the number of injured nerve fibers innervating these 2 sites after muscle injury in rats. SUMMARY OF BACKGROUND DATA.: Several minimally invasive approaches have recently become popular in the treatment of lumbar spine disorders. Minimally invasive surgery (MIS) is not invasive to back muscle and is thought to reduce low back pain. Muscle damage has been generally evaluated by magnetic resonance imaging (MRI); however, damage to sensory nerve fibers in and around back muscle that is directly related to pain has apparently not been explored. METHODS Human muscle at L4-L5 was obtained from the paraspinous process (during a midline approach) and from paraspinal back muscle (during a Wiltse paraspinal approach) (n = 10 each). The muscle was sectioned and immunostained for calcitonin gene-related peptide (CGRP). To detect dorsal root ganglion (DRG) neurons innervating back muscle in rats, Fluoro-Gold (FG) was applied to the same 2 sites on the lower back muscle at L4-L5 (only application, n = 12; application of FG + muscle injury, n = 12). DRGs were harvested and immunostained for CGRP and activating transcription factor-3 (ATF-3: marker for nerve injury). The numbers of FG-labeled CGRP-immunoreactive or FG-labeled ATF-3-immunoreactive DRG neurons innervating the 2 sites were counted and compared. RESULTS CGRP-immunoreactive sensory nerve fibers were found at the 2 sites. The average number of CGRP-immunoreactive sensory nerve fibers in muscle obtained in a midline approach was significantly higher than that in muscle obtained in a Wiltse paraspinal approach (P < 0.01). The numbers of FG-labeled CGRP- and ATF-3-immunoreactive DRG neurons innervating paraspinous process muscle were significantly greater than those innervating paraspinal back muscle in rats (P < 0.01). CONCLUSION There are more CGRP-immunoreactive sensory nerve fibers and DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area in humans and rats. There are more ATF-3-immunoreactive DRG neurons innervating muscle in the midline approach area than in the Wiltse paraspinal approach area after muscle injury in rats. This result may show the differences in sensory nerve injury during the 2 surgical approaches.

STUDY DESIGN Retrograde neurotracing and immunohistochemical investigation of brain-derived neurotrophic factor (BDNF)-related sensory innervation of punctured lumbar intervertebral discs (IVDs) in rat dorsal root ganglia (DRG). OBJECTIVE To investigate the association between BDNF and sensory innervation of multiple-punctured lumbar IVD in rats. SUMMARY OF BACKGROUND DATA BDNF--a neurotrophin in DRG neurons--is anterogradely transported to the spinal cord and transmits pain signals. Its presence in the peripheral sites of degenerative IVDs has been recently reported, although its association with discogenic pain remains unclear. METHODS Forty female Sprague-Dawley rats were equally divided into four groups: naive, sham, and two agent-treated groups (vehicle [saline-treated] group and anti-BDNF [anti-BDNF antibody] group). L5-L6 IVDs of the agent-treated rats were exposed and injured by repeated punctures. The retrograde neurotracer Fluoro-Gold (FG) and treatment agents were intradiscally applied. In the sham group, FG alone was applied onto uninjured IVD. One week later, L1-L3 DRGs were harvested and immunolabeled for the inflammatory pain-related calcitonin gene-related peptide (CGRP), that is, the pain marker. The proportions of FG-labeled CGRP-immunoreactive (-ir) DRG neurons were assessed. Each L5-L6 IVD was resected for measuring the BDNF concentration using enzyme-linked immunosorbent assay. RESULTS FG-labeled DRG neurons were almost equally prevalent at each DRG level. The proportions of FG-labeled CGRP-ir DRG neurons in the two agent-treated groups were significantly elevated (average 37.9% ± 7.2% and 25.4% ± 9.1%; vehicle and anti-BDNF groups, respectively; P < 0.05) in comparison with the naive and sham groups (19.6% ± 1.3% and 19.2% ± 3.6%, respectively) and were significantly decreased in the anti-BDNF group in comparison with the vehicle group (P < 0.05). BDNF concentrations were elevated maximally in the vehicle group (18.5 ± 5.2 pg/g) but suppressed in the anti-BDNF group (14.0 ± 3.0 pg/g). CONCLUSION Direct intradiscal application of the anti-BDNF antibody significantly suppressed both CGRP production and the local concentration of BDNF. Our results indicate a possible association between the local production of BDNF and the pathophysiology of discogenic pain.

STUDY DESIGN Prospective trial. OBJECTIVE To examine the difference in bone union and clinical results after one-, two-, and three-level instrumented posterolateral fusion surgery using a local bone graft. SUMMARY OF BACKGROUND DATA The iliac crest bone graft technique for lumbar posterolateral fusion surgery is widely used; however, donor site problems such as pain and sensory disturbance have been reported. Local bone has been used for fusion surgery; however, its reliability as a graft for multiple segments has not been fully reported. METHODS One hundred twenty-two patients diagnosed with degenerated spondylolisthesis were divided into three groups [spondylolisthesis at 1 level (n = 42), at 2 levels (n = 40), and at 3 levels (n = 40)]. All patients underwent decompression and instrumented posterolateral fusion with a local bone graft. The amount of bone graft, proportion of patients with (rate) and duration of bone union, Visual Analog Scale (VAS) score, Japanese Orthopedic Association Score (JOAS), and Oswestry Disability Index (ODI) were evaluated before and 2 years after therapy. RESULTS VAS score, JOA score, and ODI were not significantly different among the three groups before and after surgery (P > 0.05). Average amount of local bone graft used for one segment significantly decreased in proportion to the number of fusion levels (P < 0.05). The rate of bone union was 88% in the one-level group, 85% in the two-level group, and 62.5% in the three-level group, which was significantly lower than that in the one- and two-level groups (P < 0.05). CONCLUSION If one- and two-level posterolateral fusion were performed, the local bone graft technique provides a good and uniform bone union rate; however, for three-level fusion poor results were obtained because of an insufficient amount of local bone.

Study design A retrospective observational study of healthy volunteers and patients with degenerative and infectious endplate abnormalities in the lumbar spine. Objectives Our purpose was to evaluate the usefulness of diffusion-weighted imaging (DWI) for the differentiation of degenerative and infectious endplate abnormalities using 1.5-T magnetic resonance imaging (MRI). Summary of background data DWI can provide valuable structural information about tissues that may be useful for clinical applications in differentiation between degenerative and infectious endplate abnormalities. Methods Sixteen consecutive patients with endplate abnormalities that was detected by MRI of the lumbar spine, and 15 healthy volunteers were studied. DWI was performed using whole-body imaging with background body signal suppression with a b value of 1000 s/mm2. Apparent diffusion coefficient values of normal and abnormal vertebral bone marrow were calculated. Results Twenty-nine vertebral abnormalities were found in 16 patients. Nine vertebral abnormalities in 5 patients were because of infections and 20 vertebral abnormalities in 11 patients were because of degenerative changes; 7 levels were classified as Modic type 1, 7 levels as type 2, and 6 levels as type 3. DWI showed hyperintensity in all patients with infection, similar to that used in positron emission tomography, but not in the intervertebral spaces of any patients with degenerative disease. Apparent diffusion coefficient values of infectious bone marrow were significantly higher than normal and degenerative bone marrow. Conclusion DWI is useful for differentiation of degenerative and infectious endplate abnormalities. Moreover, MRI is widely used clinically because of the lack of ionizing radiation, low cost, and fast imaging time as compared with positron emission tomography. Therefore, DWI has the potential to be used as a screening tool.

Study design retrograde neurotracing and immunohistochemistry were used to investigate the effect of the tumor necrosis factor (TNF)-α inhibitor, etanercept, on calcitonin gene-related peptide (CGRP) expression in dorsal root ganglion (DRG) neurons innervating intervertebral discs in rats. Objective to clarify the action of a TNF-α inhibitor on a sensory neuropeptide in DRG neurons innervating intervertebral discs. Summary of background data degeneration of lumbar intervertebral discs is a cause of low back pain. TNF-α in the intervertebral disc is a major contributor to discogenie pain. Effects of TNF-α inhibition on CGRP expression in DRG neurons were evaluated. Methods the neurotracer FluoroGold was applied to the surfaces of L4/5 discs to label their innervating DRG neurons (n = 30). Of 30 rats, 10 were in a nonpunctured disc sham surgery control group, whereas the other 20 were in experimental groups in which intervertebral discs were punctured with a 23-gauge needle. Etanercept or saline was applied into the punctured discs (n = 10 each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP. The proportion of FluoroGold-labeled CGRP-immunoreactive DRG neurons was evaluated in all groups. Results FluoroGold-labeled neurons innervating the L4/5 disc were distributed throughout L1-L6 DRGs in all groups. Of the FluoroGold-labeled neurons, the proportion of CGRP-immunoreactive neurons was 21% ± 4% in the sham surgery control group, 32% ± 7% in the puncture + saline group, and 23% ± 4% in the puncture + etanercept group. The proportion of CGRP-immunoreactive neurons was significantly greater in the puncture + saline group compared with the sham control and puncture + etanercept groups (P Conclusion in this model, CGRP was upregulated in DRG neurons innervating damaged discs. However, direct intradiscal application of etanercept immediately after disc puncture suppressed CGRP expression in DRG neurons innervating injured discs. This finding may further elucidate the mechanism for the effectiveness of etanercept in upregulation of neuropeptide in DRG neurons innervating intervertebral discs.

STUDY DESIGN We examined the sensory innervation of the coccygeal (Co) 5/6 intervertebral disc in rats using a retrograde neurotracing method and immunohistochemistry. OBJECTIVE To investigate the properties of the sensory innervation of the rat coccygeal disc. SUMMARY OF BACKGROUND DATA Developing a rat disease model for degenerative intervertebral disc compression using lumbar discs is technically impractical because of their location. Coccygeal intervertebral discs are more readily accessible and several reports of morphologic evaluation of degenerative coccygeal intervertebral discs using compression devices exist. However, their sensory innervation and properties have not yet been characterized. METHODS FluoroGold neurotracer was applied to the Co5/6 intervertebral discs of intraperitoneally anesthetized Sprague Dawley rats (n = 10). Subsequently, the discs and the L1-S4 dorsal root ganglions (DRGs) were resected and sectioned. The discs were double-stained for immunoreactivity to the neuronal marker beta-tubulin (Tuj-1) and biotin-labeled isolectinB4 (IB4), a neuropathic pain marker, or Tuj-1 and calcitonin gene-related peptide (CGRP), an inflammatory pain marker. The DRGs were double-stained for IB4-binding and CGRP immunoreactivity (IR). The proportions of IB4-binding or CGRP-IR DRG neurons were assessed by cell counting and compared. RESULTS The disc immunohistochemistry showed evidence of sensory nerve fibers lying in the outermost layer of the anulus fibrosus. FluoroGold labeled DRG neurons mainly derived from S1 to S3 DRGs, especially S2 and S3. No labeled neurons were observed in the S4 DRG. The histochemistry of the DRGs showed a predominance of CGRP-IR DRG neurons (3.5 +/- 1.7% IB4-binding and 15.4 +/- 5.6% CGRP-IR on average). CONCLUSION This study showed evidence for nerve fibers in the discs and predominant innervation by CGRP-IR DRG neurons. The neurons innervating the discs mostly derived from S1 to S3 DRGs, especially S2 and S3. These findings may be useful in developing rat models of disease involving degenerative intervertebral disc compression.

Study design Prospective cohort study. Objective To examine the relationship between low back pain after discectomy for disc herniation and Modic type 1 change. Summary of background data Lumbar vertebral bone marrow change is divided into Modic types. Some reports indicate that Modic type 1 is related to low back pain, but the reliability of this assertion is unclear. The current study examines changes in low back pain in patients with lumbar disc herniation and Modic type 1 change after lumbar discectomy without fusion surgery. Methods Forty-five patients with lumbar disc herniation showing normal or Modic type 1 signals in their bone marrow were selected (mean age 35 years). All patients suffered low back and leg pain because of lumbar disc herniation, and underwent a discectomy without fusion. We evaluated change in low back pain [Visual analogue scale (VAS) score, Japanese Orthopedic Association score (JOAS), and Oswestry Disability Index (ODI)] before, 12 and 24 months after surgery. Results Twenty-three patients showed Modic type 1 signals and 22 patients showed normal intensity before surgery. VAS score, JOAS, and ODI were not significantly different between the normal and Modic type 1 groups. VAS score, JOAS, and ODI improved after surgery in both groups (P>0.05). Low back pain after surgery evaluated from the 3 scores was not significantly different in the 2 groups 12 or 24 months after surgery (P>0.05). Conclusion Discectomy improved low back pain in patients suffering from lumbar disc herniation. Patients with or without Modic type 1 change showed a similar improvement of low back pain score. Low back pain in patients with disc herniation appears to mainly originate from disc or nerve root compression, and decompression surgery without fusion is an option for these patients, even those with Modic type 1 changes.

Study design Prospective cohort study. Objective To examine the change of Modic Type 1 to Type 2 after posterolateral fusion surgery. Summary of background data Lumbar vertebral bone marrow change is divided into Modic types. Magnetic resonance imaging reveals Modic Type 1 and 2 signals. Some reports indicate that with time, Type 1 signals (intervertebral instability) change to Type 2 (restabilization), but the reliability of this assertion is unclear. The current study examines the change of Modic Type 1 signals to Type 2 after posterolateral fusion surgery. Methods Patients with Modic Type 1 and 2 signals were selected (mean age, 65 years). All patients suffered low back pain and leg pain due to lumbar spinal canal stenosis, and underwent decompression and posterolateral fusion surgery. We evaluated change in Modic signal and severity of low back pain (Visual analogue scale score, Japanese Orthopedic Association score, and Oswestry Disability Index before and 24 months after surgery. Results Of 21 patients with Modic Type 1 signals before surgery, 2 cases changed to normal bone marrow, 9 to Type 2, and 12 remained Type 1. Of 12 patients with Type 2 signals, none changed to Type 1, 2 changed to normal bone marrow, and 10 remained Type 2. Visual analogue scale score, Japanese Orthopedic Association score, and Oswestry Disability Index improved after surgery; however, low back pain was not significantly associated with signal change after surgery (P > 0.05). Conclusion In the current study, Modic Type 1 signals changed to Type 2; however, Type 2 did not change to Type 1, suggesting that Type 2 signals indicate a stabilized stage. For Modic Type 1 and 2 signals, there were changes to normal bone marrow signals in 4 cases. Therefore, degenerated bone marrow may be able to regenerate after surgical stabilization. We did not show a significant difference between low back pain and signal type.

STUDY DESIGN.: Immunohistological analysis of punctured disc after application of a p38 MAP kinase inhibitor. OBJECTIVE.: To examine effect of direct application on dorsal root ganglion (DRG) neurons innervating damaged rat discs. SUMMARY OF BACKGROUND DATA.: Degeneration of lumbar discs is one cause of low back pain. Pathogenesis may involve sensory nerve ingrowth into disc inner layers; tumor necrosis factor-alpha (TNF-alpha) is thought to be a major inducer of ingrowth. Because p38 mitogen-activated protein kinase (p38) upregulates TNF-alpha expression and may play a crucial role in pain sensation, we investigated the effect of one injection of inhibitor on expression of the pain-related neuropeptide calcitonin gene-related peptide (CGRP). METHODS.: The neuro-tracer fluoro-gold was applied to the surfaces of L4/5 discs to label the innervating DRG neurons (n = 30). Of 30 rats, 10 were controls, whereas the other 20 were the experimental model (i.e., discs were punctured with 23-gauge needle). P38 specific inhibitor or saline was applied simultaneously (n = 10 each, Puncture + inhibitor and puncture + saline groups). Fourteen days postsurgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for CGRP. Proportion of CGRP-immunoreactive DRG neurons was evaluated in all groups. RESULTS.: Fluoro-gold-labeled neurons innervating the L4/5 disc were distributed throughout L1 to L6 DRGs in all groups. Proportions of labeled neurons positive for CGRP were 15.2% +/- 8% (controls), 27.2% +/- 10% (puncture + saline), and 25.2% +/- 8% (puncture + inhibitor). Proportion of immunoreactive neurons was significantly increased in the puncture groups compared with controls. However, there was no significant difference between the 2 puncture groups (P > 0.1). CONCLUSION.: In this model, CGRP was upregulated in DRG neurons innervating the damaged disc. However, a direct single application of p38 inhibitor did not suppress CGRP expression in innervating DRG neurons. Future research with p38 inhibitor in this model should evaluate multiple or systemic administration of inhibitor.

STUDY DESIGN The effect of proopiomelanocortin (POMC) gene transfer with radial shock waves (RSW) was investigated in vitro and in vivo rat pain models. OBJECTIVE To examine the efficacy of POMC gene transfer with RSW, efficiency of beta-endorphin production in transfected cells, and its effects and side effects in pain models. SUMMARY OF BACKGROUND DATA Opioids have been used to treat chronic pain originating from knee osteoarthritis and the lower back; however, several side effects have been reported. Endogenous opioids are safe, but they are not used for clinical treatment because their metabolism is very fast. METHODS POMC plasmid was produced from pretransformed rat brain cDNA. POMC gene was added to the muscle of rat in vitro and in vivo with RSWs. We assessed beta-endorphin activity using immunohistochemistry. For assessment of pain behavior, we evaluated change in pain score and the level of the inflammatory neuropeptide, calcitonin gene-related peptide (CGRP), after transfection of the POMC gene in an adjuvant induced pain model for 28 days after treatment. RESULTS POMC transfected using RSW expressed beta-endorphin at a significantly increased level in muscle cells compared with non-RSW transfection and controls in vitro and in vivo (P < 0.05).Animals showed significant pain sensitivity and increased CGRP expression in dorsal root ganglia neurons in this model; however, these findings decreased for 14 days after transfection of POMC into muscle. There was no significant difference in side effects, such as a change in the level of food pellet intake or constipation, between POMC-treated animals and untreated animals. CONCLUSION POMC transfection with RSW increased beta-endorphin expression in muscle for 14 days, and suppressed pain behavior and CGRP expression in dorsal root ganglia neurons without side effects. This suggested that transfer of POMC by RSW is an effective treatment for inflammatory pain.

Study Design. Randomized, controlled study. Objective. To evaluate the diagnosis of discogenic low back pain (LBP) with discography and discoblock. Summary of Background Data. Discogenic LBP is usually diagnosed by magnetic resonance imaging and discography. However, the reliability of discography is controversial. Previously, we reported the usefulness of discoblock with bupivacaine for diagnosis, and discoblock improved the results of anterior interbody fusion surgery. However, that study was not a randomized, controlled study. Therefore, the purpose of the current study was to compare the results of surgery after diagnosis of LBP by discography and discoblock. Methods. Patients (n = 42) with severe LBP showing L4-L5 or L5-S1 disc degeneration on magnetic resonance imaging were evaluated by discography (1.5 mL of contrast medium) or discoblock (intradisc injection of 0.75 mL of 0.5% bupivacaine). We randomized the patients in turn. Anterior discectomy and interbody fusion were performed in patients who responded to the diagnostic procedures. The visual analogue scale score (0, no pain; 100, worst pain), Japanese Orthopedic Association Score (0, worst pain; 3, no pain), Oswestry Disability Index, and patient satisfaction before and 3 years after surgery were recorded and compared between groups. Results. Twelve patients did not show pain provocation by discography or pain relief by discoblock and were excluded. Fifteen patients who showed pain provocation by discography and 15 patients who experienced pain relief with discoblock were evaluated. Rates of improvement in the visual analogue scale score, Japanese Orthopedic Association Score, and Oswestry Disability Index score in the discoblock group were significantly higher than those in the discography group (P < 0.05) from baseline to 3 years after surgery. Three patients were dissatisfied with surgery after discography compared with one patient after discoblock. Conclusion. Pain relief after injection of a small amount of bupivacaine into the painful disc was a useful tool for the diagnosis of discogenic LBP compared with discography.

Study design A case report of 3 patients with posterior migration of bullet-shaped fusion cages after transforaminal lumbar interbody fusion (TLIF). One patient required emergency revision surgery; the other 2 patients are being observed during conservative treatment. Objective To review cases of posterior migration of fusion cages and report ensuing clinical courses. Summary of background data TLIF is a commonly used procedure; however, there are few reports describing cage migration after the procedure. In most cases, when posterior cage migration follows posterior lumbar interbody fusion, emergency revision surgery is required. One recent study reported a case of posterior cage migration after TLIF, which was treated conservatively. Methods Posterior migration of the bullet-shaped fusion cages occurred 1 to 2 months after TLIF in 3 patients. One of the 3 patients had isthmic spondylolisthesis treated by TLIF with bilateral pedicle screw fixation. The other 2 patients had degenerative scoliosis and were treated by TLIF with unilateral pedicle screw fixation. Results The patient with isthmic spondylolisthesis required revision surgery because the migrated cage caused nerve root irritation. The migrated cage was removed and a large-sized cage was employed to achieve stability. The other 2 patients had no pathologic symptoms after the posterior migration of the cage and were treated conservatively and observed. Conclusion Revision surgery after TLIF appears relatively safe because the migrated cage tends to locate more laterally than in patients with cage migration after posterior lumbar interbody fusion. Cage migration subsequent to TLIF may not cause compression of neural tissues, so conservative treatment may suffice for these patients. Unilateral pedicle screw fixation may not provide sufficient stability to prevent cage migration in patients with degenerative scoliosis. Further study is needed to clarify surgical indications for unilateral pedicle screw fixation in TLIF.

STUDY DESIGN Changes in behavior and the immunohistochemistry of dorsal root ganglion (DRG) neurons were examined using a mouse model of radicular pain. OBJECTIVE To examine the effects of TNF-alpha in the nucleus pulposus (NP) on nerve roots. SUMMARY OF BACKGROUND DATA Radicular pain is induced by mechanical compression and inflammation of nerve roots. Many authors have reported that following disc herniation, producing TNF-alpha plays a major role in neuropathic pain. Their findings suggest that TNF-alpha contained in the NP is significant in the development of pain and nerve root degeneration, but it has not been clearly demonstrated. METHODS Wild-type NPs or TNF-KO NPs, which were harvested from C57BL/6 mice (wild-type NP) or TNF-knock-out mice (TNF-KO NP), were applied to the left sciatic nerves of 30 wild-type mice, and the nerves were pinched. Production of hind paw mechanical allodynia, activating transcription factor 3, and calcitonin gene- related peptide (CGRP) were assessed. RESULTS Animals receiving a NP application demonstrated significant mechanical allodynia compared to the pinch-only and the control groups. The degree of mechanical allodynia was greater in the wild-type than in the TNF-KO group. The number of activating transcription factor 3 immunoreactive neurons was significantly higher in the wild-type than in the TNF-KO group. The number of CGRP-immunoreactive neurons was higher in the wild-type and TNF-KO than in the control groups. However, no significant difference in activity was observed between both CGRP positive groups. CONCLUSION In this study TNF-alpha contained in the NP was important for the production of radicular pain accompanied by long-lasting degeneration of DRG neurons. However, other cytokines in the NP and nerve compression may also play important roles in pain transmission. In this model system, TNF-alpha in the NP appears to mediate pain, but not cause an increase in CGRP in the DRG neurons.

The mechanisms of apoptosis underlying a characteristic tissue reaction at the surface of the dorsal root ganglion (DRG) exposed to nucleus pulposus were studied in rats with special reference to the role of tumor necrosis factor-alpha (TNF).To study the characteristic tissue reaction at the surface of the DRG exposed to nucleus pulposus with special reference to the role of TNF.Nucleus pulposus cells are capable of producing TNF. Recently, local application of nucleus pulposus was shown to induce a characteristic tissue reaction at the DRG surface due to apoptosis.Recombinant TNF was applied to the DRG to mimic L4-L5 disc herniation in rats. The DRGs were resected 24 hours after surgery. Sections of the specimens were processed for immunohistochemistry using antisera to single-stranded DNA, Caspase 3, and TNF, and observed by light and electron microscopy.Typical apoptotic changes of the cell nuclei were observed in the DRG after application of TNF. The presence of single-stranded DNA, Caspase 3, and TNF further confirmed the occurrence of DRG cell apoptosis.TNF seemed to play a key role in induction of apoptosis of DRG cells, which resembled that induced by application of nucleus pulposus.

Study Design. Immunohistochemical and behavioral study using a rat cauda equina compression model. Objective. To investigate, after cauda equina compression by spinal canal stenosis (SCS), Rho activation in the spinal cord and cauda equina, and the effect of intrathecal administration of a Rho kinase inhibitor on hypoalgesia and motor dysfunction. Summary of Background Data. Compression of the cauda equina caused by SCS is a common clinical disorder associated with sensory disturbance and intermittent claudication. Cauda equina compression is thought to reduce blood flow and result in nerve degeneration caused by various cytokines. Rho, a member of the small GTPases, is a signal transmitter. It promotes Wallerian degeneration, decreases blood flow in the spinal cord and brain, and increases expression of several cytokines. Currently, Rho kinase inhibitor is used clinically to treat progressive nerve damage due to cerebrovascular disorders. However, its effect for SCS has not been evaluated. Methods. Forty-two 6-week-old male Sprague-Dawley rats (200–250 g) were used. For the SCS model (n = 27), a small piece of silicon was placed under the lamina of the fourth lumbar vertebra. In the sham-operated group, laminectomies were performed at L5 only (n = 15). We examined mechanical sensitivity and motor function using von Frey hairs and a treadmill, and immunohistochemically localized Rho in the spinal ventral neurons, axons, and Schwann cells in the cauda equina. We also examined the effects of intrathecally administered Rho kinase inhibitor for hypoalgesia or motor dysfunction caused by SCS. Results. We observed motor dysfunction and hypoalgesia and activated Rho-immunoreactive cells in spinal ventral neuroreported to induce neurite and axonal outgrowth in the spinal cord and brain after nervous system injury.10,11 In addition, 1 report showed that Rho kinase was involved in Wallerian degeneration that was rescued by Rho kinase inhibitor.16 Furthermore, it is thought that Rho is involved in TNF-α and interleukin (IL) production in the central nervous system, and the production was inhibited by administering Rho kinase inhibitor in the central nervous system.17 Regardns, axons, and Schwann cells in the cauda equina. Intrathecal administration of Rho kinase inhibitor improved mechanical hypoalgesia and motor dysfunction caused by SCS. Conclusion. Activated Rho may play an important role in nerve damage in the cauda equina in SCS. Rho kinase inhibitor may be a useful tool in determining the pathomechanism of cauda equina syndrome caused by SCS.

Study design Using a retrograde neurotracing method with Fluoro-Gold (FG), the level at which dorsal root ganglions (DRGs) innervate the L2 and L5 vertebral bodies and the innervation pathways were investigated in rats. Objective To clarify the levels at which DRGs innervate the lumbar vertebral bodies and to determine the pathways from the L2 and L5 vertebral bodies to DRGs. Summary of background data Elderly patients with osteoporosis sometimes experience lumbar vertebral fracture and may also feel diffuse nonlocalized pain in the back, lateral portion of the trunk, and area surrounding the iliac crest. However, the pattern of sensory innervation of vertebral bodies remains unclear. Methods Forty female Sprague-Dawley rats were used. FG crystals were applied to the L2 (L2 vertebra group) or L5 (L5 vertebra group) vertebral bodies via an anterior approach, and numbers of labeled neurons in DRGs from T10 to L6 were counted. To determine sensory pathways, bilateral sympathectomy was performed. Results In nonsympathectomy animals, FG-labeled neurons were present in DRGs from T11 through L3 in the L2 vertebra group and from T13 through L6 in the L5 vertebra group. The number of labeled neurons following sympathectomy was not significantly different in L1, L2, and L3 DRGs in the L2 vertebra group or in L3, L4, L5, and L6 DRGs in the L5 vertebra group from those in nonsympathectomy animals. In contrast, fewer labeled DRG neurons were present in sympathectomy animals at T11, T12, and T13 in the L2 vertebra group, and at T13, L1, and L2 in the L5 vertebra group than in nonsympathectomy animals (P Conclusion Sensory nerve fibers in the L2 and L5 vertebral bodies are derived from the T11-L3 and T13-L6 DRGs, respectively. Some sensory nerves from the L2 and L5 vertebral bodies enter the paravertebral sympathetic trunks and reach the DRGs at multisegmental levels. The present findings regarding multisegmental innervation to vertebral bodies may explain the diffuse pain that originates within osteoporotic vertebral fractures in elderly patients.

Study design The axonal growth potential of dorsal root ganglion (DRG) neurons in an organ culture system was investigated. Objective To examine the effects of neuronal injury and tumor necrosis factor-alpha (TNF-alpha) on the axonal growth potential of 2 types of nociceptive DRG neurons: nerve growth factor (NGF)-sensitive and glial cell line-derived neurotrophic factor (GDNF)-sensitive neurons. Summary of background data Nerve ingrowth into the disc is recognized to be one of the causes of discogenic pain. Almost all of these disc-innervating neurons are NGF-sensitive. The axonal growth potential of NGF-sensitive neurons has not been investigated. Methods Adult Sprague-Dawley rats were used for immunohistochemistry (n = 7) and cell viability studies (n = 6). Bilateral L3-L5 DRGs, which were successfully removed without damage, were noncultured or cultured in serum-free medium containing TNF-alpha at 0, 0.01, 0.1, and 1 ng/mL for 48 hours (n = 5, each treatment). The DRGs were then immunostained for activating transcription factor 3 (ATF3, a marker for injured neurons) or double-stained for growth-associated protein 43 (GAP-43, a marker for axonal growth) with calcitonin gene-related peptide (CGRP, a marker for NGF-sensitive neurons) or isolectin B4 (IB4, a marker for GDNF-sensitive neurons). Cell viability was assessed by a lactate dehydrogenase (LDH) assay and an MTS assay (n = 6, each treatment). Results Immunoreactive evidence of injured neurons (ATF3 positive) was frequently observed in cultured DRGs, but never in noncultured DRGs. The percentage of neurons exhibiting axonal growth potential (GAP-43 immunoreactive) was significantly higher for NGF-sensitive neurons than for GDNF-sensitive neurons at any concentration of TNF-alpha. More than 95% of the cultured neurons were viable. Conclusions The results suggest that the cultured DRG neurons exhibit pathologic changes similar to those found in injured neurons. NGF-sensitive neurons, which include disc-innervating neurons, may have a greater potential to extend their axons in response to neuronal injury under pathologic conditions in the presence of TNF-alpha than GDNF-sensitive neurons.

Study design A cross-sectional study. Objective The aim of this study was to quantify spinal cord dysfunction at the tract level in patients with cervical compressive myelopathy (CCM) using reduced field-of-view (rFOV) diffusion tensor imaging (DTI). Summary of background data Although magnetic resonance imaging (MRI) is the standard used for radiological evaluation of CCM, information acquired by MRI does not necessarily reflect the severity of spinal cord disorder. There is a growing interest in developing imaging methods to quantify spinal cord dysfunction. To acquire high-resolution DTI, a new scheme using rFOV has been proposed. Methods We enrolled 10 healthy volunteers and 20 patients with CCM in this study. The participants were studied using a 3.0-T MRI system. For DTI acquisitions, diffusion-weighted spin-echo rFOV single-shot echo-planar imaging was used. Regions-of-interest (ROI) for the lateral column (LC) and posterior column (PC) tracts were determined on the basis of a map of fractional anisotropy (FA) of the spinal cord and FA values were measured. The FA of patients with CCM was compared with that of healthy controls and correlated with Japanese Orthopaedic Association (JOA) score. Results In LC and PC tracts, FA values in patients with CCM were significantly lower than in healthy volunteers. Total JOA scores correlated moderately with FA in LC and PC tracts. JOA subscores for motor dysfunction of the lower extremities correlated strongly with FA in LC and PC tracts. Conclusion It is feasible to evaluate the cervical spinal cord at the tract level using rFOV DTI. Although FA values at the maximum compression level were not well correlated with total JOA scores, they were strongly correlated with JOA subscores for motor dysfunction of the lower extremities. Our findings suggest that FA reflects white matter dysfunction below the maximum compression level and FA can be used as an imaging biomarker of spinal cord dysfunction. Level of evidence 4.

Study design Prospective consecutive series. Objective The objective of this 10-year follow-up study was to assess the efficacy of concave PLIF for lumbosacral hemicurve in treating patients with adult scoliosis. Summary of background data Long-term results and clinical significance of PLIF for allowing L3 vertebra to become horizontal in adult scoliosis have not yet been reported. Methods Fourteen patients (53-72 yr) were operatively treated and prospectively studied. The surgical procedure was, after decompression of the affected nerve root, to correct the wedged disc below the caudal end vertebra, L3 or L4, which allowed for the end vertebra to become horizontal by way of concave PLIF. The follow-up period was 10 years. Results Mean visual analogue scale (100 mm) score was 78 before surgery, 20 at 2 years after surgery, and 17 at the final follow-up in leg pain, 67, 25, and 28, respectively, in low back pain, and 13, 7, and 7, respectively, in the disability score (Rolland-Morris). The mean Cobb angles were 24°, 16°, and 17°, respectively, in scoliosis, 17°, 9°, and 10°, respectively, in L3 vertebral tilt, and 21°, 28°, and 26°, respectively, in lumbar lordosis. In 7 patients with postoperative L3 vertebral tilt of less than 5°, the Cobb angle of the unfused main curve improved over time. Conclusion The results of this study suggest that horizontal fixation of the L3 vertebra can prevent the long-term development of unfused adult scoliosis. Level of evidence 4.

Study Design. To examine changes in substance P receptors on dorsal root ganglion cells innervating the rat lumbar intervertebral discs using immunohistochemistry and a retrograde neurotracing method. Objective. We evaluated the effects of intradiscal administration of substance P-saporin, a toxin selective for cells expressing substance P receptors. Summary of Background Data. The rat L5/6 intervertebral disc is multi-segmentally innervated from the L1–L6 dorsal root ganglions. Substance P and the neurokinin-1 receptor contribute to inflammatory pain transmission. Substance P immunoreactive-sensory nerve fibers in human intervertebral discs and immunoreactive-dorsal root ganglion neurons innervating rat intervertebral discs have been reported to be important in the transmission of discogenic low back pain. In the current study, we evaluated the effects of intradiscal administration of substance P-saporin, a toxin selective for cells expressing substance P receptor. Methods. Sixteen rats were used (control group, n = 8; substance P-saporin group, n = 8). To detect dorsal root ganglion neurons innervating the L5/6 intervertebral disc, neurotracer (fluoro-gold crystals) was placed into the intervertebral disc. Seven days after fluoro-gold application, the L5/6 intervertebral disc was exposed and injected with 175 ng of sterile substance P-saporin (substance P-saporin group, n = 8). Fourteen days after the first operation, each dorsal root ganglion was harvested, sectioned, and processed for neurokinin-1 immunohistochemistry using rabbit antibody to neurokinin-1. The numbers of fluoro-gold labeled neurons, and fluoro-gold labeled and neurokinin-1 immunoreactive neurons were counted in both groups. Results. Neurons innervating the L5/6 intervertebral discs, retrogradely labeled with fluoro-gold, were distributed throughout dorsal root ganglions from L1 to L6 in both groups. Of fluoro-gold labeled neurons, the proportion of neurokinin-1 immunoreactive neurons was 35% in the control group. However, the proportion of neurokinin-1 immunoreactive neurons was 8% after administration of substance P-saporin into the intervertebral discs (substance P-saporin group). Substance P-saporin significantly decreased the ratio of neurokinin-1 immunoreactive neurons. Conclusion. Substance P-saporin decreased the ratio of neurokinin-1 immunoreactive neurons innervating the disc related to discogenic low back pain. Substance P-saporin may be a useful tool to investigate the mechanism of discogenic low back pain.

STUDY DESIGN In vivo histologic study of nerve ingrowth in the rabbit anular-puncture disc degeneration model. OBJECTIVE To examine innervation of intervertebral discs and surrounding tissues in the rabbit anular-puncture model with various magnitudes of injury. SUMMARY OF BACKGROUND DATA A rabbit anular-puncture model of disc degeneration was recently established. However, to our knowledge, the neuropathologic changes in the degenerated disc and surrounding tissues in this model have not been examined. METHODS Anular punctures with an 18-gauge needle at depths of 1 and 5 mm were randomly performed at the L2-L3 or L4-L5 discs in New Zealand white rabbits (n = 16; 3.0-3.5 kg). The degree of disc degeneration was followed radiographically, and was further evaluated by magnetic resonance imaging and histology at sacrifice 4 or 12 weeks after the puncture. To identify nerve ingrowth into the discs, the L2-L3 to L4-L5 discs were immunostained with an antibody against protein gene product 9.5, a general marker for nerve fibers. RESULTS Significant decreases in disc height and signal intensity in magnetic resonance imaging were observed only in the 5 mm punctured discs (P < 0.05). In all the discs, including nonpunctured control discs, protein gene product 9.5-immunoreactive fibers were only occasionally observed in the outermost part of the anulus fibrosus. In the 5 mm punctured discs, nucleus pulposus tissues were extruded, and scar tissues formed outside the discs. No nerve ingrowth into the needle track lesion at the anular puncture site was observed. However, protein gene product 9.5-immunoreactive fibers were observed in scar tissues on the surface of the puncture site. This finding was more evident in the 5 mm than in the 1 mm punctured discs (P < 0.05). CONCLUSIONS This study indicates that in the rabbit anular-puncture disc degeneration model, disc degeneration associated with a higher nerve growth into the scar tissue was more evident when induced by a 5 mm than a 1 mm puncture. Although nerve ingrowth was observed in the extruded disc tissue, nerve ingrowth into the outer anulus, which has been reported in patients with discogenic pain, was not observed during the short observation period in this disc degeneration model. The limitation in assessing pain by behavior analysis or histologic evaluation of nerve ingrowth should be considered. Further studies to identify a surrogate marker of pain should be encouraged.

Study design Immunohistochemical study of the sensory innervation of the human lumbar intervertebral disc. Objective To determine the type of sensory fibers innervating human degenerated lumbar intervertebral discs. Summary of background data Sensory neurons involved in pain perception related to inflammation in rats are typically small, peptide-containing neurons immunoreactive for calcitonin gene-related peptide (CGRP). Small non-peptide-containing neurons binding to isolectin B4 (IB4) may also be involved in pain states, such as nerve injury pain. The character of such sensory neurons in humans has not been clarified. Methods A degenerated, painful lumbar intervertebral disc was harvested from each of 8 patients during surgery. Sections were immunostained for protein gene product 9.5 (PGP 9.5, a general neuronal marker), CGRP, and IB4. The numbers of PGP 9.5- and CGRP-immunoreactive, and IB4-binding nerve fibers in the discs were counted. Results PGP 9.5-immunoreactive fibers were observed in all discs. Nerve fibers immunoreactive for CGRP were also observed in 6 of 8 cases. IB4-binding nerve fibers were not found in any case. Conclusions Almost all of the nociceptive nerve fibers in the human intervertebral disc are peptide-containing nerve fibers, similar to the rat disc, suggesting that nerve fibers related to inflammation may transmit pain originating from human degenerated intervertebral discs.

Immunohistochemistry for tumor necrosis factor (TNF) and protein gene product (PGP) 9.5 in vertebral endplates of patients with discogenic low back pain and Modic Type 1 or Type 2 endplate changes on MRI.To examine whether inflammatory cytokines and nerve in-growth into the vertebral endplate are associated with discogenic low back pain.Degenerated discs and endplate abnormalities can be a cause of discogenic low back pain. However, the presence of TNF-immunoreactive cells and PGP 9.5-immunoreactive nerve fibers has not been studied in patients with discogenic low back pain and endplate changes on MRI.Eighteen endplates showing either normal intensity signals on MRI (endplate change -), Modic Type 1 signals (low intensity on T1-weighted spin-echo images), or Modic Type 2 signals (high intensity) from patients with discogenic low back pain (n = 14) or controls requiring surgery for other back problems (n = 4; scoliosis and traumatic injury of vertebra) were harvested during surgery. Endplates were immunostained using antibodies to TNF and PGP 9.5 and immunostained cells and nerve fibers in the endplates were counted.Vertebral endplates from patients with Modic Type 1 or Type 2 endplate changes on MRI had significantly more PGP 9.5-immunoreactive nerve fibers and TNF-immunoreactive cells in comparison with patients with normal endplates on MRI (P0.01). The number of TNF-immunoreactive cells in endplates exhibiting Modic Type 1 changes was significantly higher than in endplates exhibiting Modic Type 2 changes (P0.05).The results suggest that endplate abnormalities are related to inflammation and axon growth induced by TNF. TNF expression and PGP 9.5-positive nerve in-growth in abnormal endplates may be a cause of low back pain.

Study design Histologic changes in the dorsal root ganglion (DRG) and the nociceptive stimulation thresholds were studied in rats. Objective To examine the effects of tumor necrosis factor-alpha (TNF) with special reference to pain behavior and histology of the DRG. Summary of background data Recently, it was reported that local application of nucleus pulposus induces a characteristic tissue reaction at the surface of the DRG. However, to our knowledge, there have been no previous reports about the relationship between the histologic changes and pain behavior caused by cytokines. Methods Recombinant TNF was applied to the L4 DRG. Mechanical and thermal nociceptive thresholds were tested. The L4 DRG was sectioned and observed by light microscopy. Results After the application of 5 ng/microL TNF, significant differences were observed in mechanical and thermal stimulation thresholds. At the site of application of TNF, a characteristic a semilunar-shaped enlargement was observed. The average width of the part was significantly larger in the 5 ng/microL TNF application, as compared to the 0.5-ng/microL TNF application. Conclusions The higher concentration of TNF used induced allodynia and hyperalgesia responses. Because the region showing the histologic changes was significantly larger after application of the higher concentration of TNF, the reaction of the DRG may be related to pain.

STUDY DESIGN Retrospective comparative cohort study. OBJECTIVE To elucidate the characteristics of low back pain (LBP) in adolescent patients with early-stage spondylolysis (ESS). SUMMARY OF BACKGROUND DATA ESS is a common cause of acute LBP in adolescents. When treating patients with ESS, early diagnosis is important; however, early diagnosis is difficult without magnetic resonance imaging. METHODS Adolescent patients (n = 77) with acute LBP showing no pathological findings on plain radiography were included (