Published papers

Background Although microendoscopic discectomy (MED) is a minimally invasive surgical method for lumbar disc herniation (LDH), early postoperative recurrence may outweigh that advantage. The purpose of the present study was to retrospectively investigate the recurrence rate after MED for LDH and to determine the risk factors for recurrence in patients treated by a single surgeon. Materials and Methods The study included 344 patients who underwent MED (213 males and 131 females; mean age, 39.3 years; age range, 11-82 years; mean follow-up, 3.6 years; follow-up range, 2.0-6.5 years). The clinical outcomes were evaluated using the Japanese Orthopedic Association Score for Low Back Pain (JOA score). Recurrence factors investigated by logistic regression analysis included age; sex; level, laterality, and classified type of LDH; occupation; sports activity; and learning curve of the surgeon. Results LDH recurrence was observed in 37 patients (10.8%). It was observed at the same level in the ipsilateral side as the original LDH in 30 patients, in the contralateral side in three patients, and at a level adjacent to the original level in four patients. The mean time interval between MED and the recurrence was 16.6 months (range, 0.5-52 months). Twenty patients (54.1%) developed recurrence within 1 year after MED. Twenty-two patients (59.5%) were treated by revision surgery (MED in 20 patients and microdiscectomy in two patients), and 15 patients (40.5%) were treated conservatively. The mean JOA score of all the patients was 14.7 ± 3.5 before surgery and 26.5 ± 2.2 at the final follow-up, yielding an average recovery rate of 82.3 ± 15.7%. The recovery rate was 83.1 ± 14.8% in patients without recurrence and 75.7 ± 20.4% in patients with recurrence (p = 0.006). By logistic regression analysis, we identified migration of LDH as a significant factor related to recurrence. The patients with caudal migration of LDH had recurrence more frequently (19.0%) than those with rostral migration (12.5%) or without migration (10.2%) (p = 0.04; odds ratio, 2.0; 95% confidence interval, 1.0-3.8). Conclusion The recurrence rate and reoperation rate for LDH after MED were comparable to those of conventional discectomy. More than half of the cases of recurrence occurred at an early postoperative phase, and patients with caudally migrated LDH experienced recurrence significantly more often than those with rostrally migrated or nonmigrated LDH. ©2013 Georg Thieme Verlag KG Stuttgart, New York.

Objectives: The precise causes of Complex Regional Pain Syndrome (CRPS) are as yet not well known. Some consider CRPS type 1 without apparent nerve injury to arise due to a prolonged inflammatory state after initial trauma and its underlying pathophysiology indicates Nociceptive/Inflammatory Pain (NocP) components. Yet others have shown clear direct evidence of nerve injury in CRPS type 1-affected limbs, and they consider CRPS type 1to be Neuropathic Pain (NeP). The McGill Pain Questionnaire (MPQ) has the potential to diagnose pain disorders as well as suggest the underlying pathophysiology. Methods: We investigated pain characteristics of 165 NeP and 66 NocP patients, by using the 78 words of the MPQ, and thereby developed a discriminant function which efficiently discriminates NocP from NeP. We then applied this function to 36 CRPS type 1 patients' complaints and classified their pain into either NocP or NeP. Results: The discriminant probability of the function was 81.0% (chi-square, p=0.24) and this function revealed 47.2% of CRPS type 1 patients' complaints were classified as NocP and 52.8% as NeP. These subgroups showed almost comparable demographic data. Considerations: Our results indicate that CRPS type 1 cannot be classified as NeP or NocP dichotomously according to pain descriptions. This raises the possibility that CRPS type 1 represents a "mixed" pain mechanism comprised of both NeP and NocP. © 2013 Sumitani M, et al.

Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the iPS cells and reprogramming technologies in medical science. While iPS cells are expected to open new era providing enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this symposium, the pre-clinical investigations of cell therapy for SCI using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo are outlined.

Purpose: Although the occurrence and progression of AIS has been linked to low bone mineral density (BMD), the relationships between spinal curvature and bilateral differences in proximal femur BMD are controversial. Few correlation studies have stratified patients by curve type. The purpose of this study was to evaluate the relationships between spinal coronal profile and bilateral differences in proximal femur BMD in patients with adolescent idiopathic scoliosis (AIS). Methods: This study included 67 patients with AIS who underwent posterior correction and fusion surgery between January 2009 and October 2011. The mean age at the time of surgery was 17.4 ± 4.1 years. Bilateral proximal femur BMD was measured before surgery by dual-energy X-ray absorptiometry. We compared the proximal femur BMDs by determining the bilateral BMD ratio (left proximal femur BMD divided by that of the right). We evaluated correlations between coronal parameters, obtained from preoperative radiographs, and the BMD ratio using Pearson's correlation analysis. Results: Patients with Lenke type 1 curve (48; all with a right convex curve) had a mean bilateral proximal femur BMD ratio of 1.00 ± 0.04. Patients with Lenke type 5 curve (19; all with a left convex curve) had a mean bilateral proximal femur BMD ratio of 0.94 ± 0.04, indicating that the BMD in the proximal femur on the right side (concave) was greater than that in the left (convex). Coronal balance was significantly correlated with the BMD ratio in both the Lenke type 1 and type 5 groups, with a correlation coefficient of 0.46 and 0.50, respectively. Conclusions: The bilateral proximal femur BMD ratio was significantly correlated with the coronal balance in AIS patients. When the C7 plumb line was shifted toward one side, the BMD was greater in the contralateral proximal femur. © 2013 Springer-Verlag Berlin Heidelberg.

Spinal extradural arachnoid cyst (SEDAC) is a cyst in the spinal canal that protrudes into the epidural space from a defect in the dura mater. Most cases are sporadic; however, three familial SEDAC cases have been reported, suggesting genetic etiological factors. All familial cases are associated with lymphedema-distichiasis syndrome (LDS), whose causal gene is FOXC2. However, FOXC2 mutation analysis has been performed in only 1 family, and no mutation analysis has been performed on sporadic (non-familial) SEDACs. We recruited 17 SEDAC subjects consisting of 2 familial and 7 sporadic cases and examined FOXC2 mutations by Sanger sequencing and structural abnormalities by TaqMan copy number assay. We identified 2 novel FOXC2 mutations in 2 familial cases. Incomplete LDS penetrance was noted in both families. Four subjects presented with SEDACs only. Thus, SEDAC caused by the heterozygous FOXC2 loss-of-function mutation should be considered a feature of LDS, although it often manifests as the sole symptom. Seven sporadic SEDAC subjects had no FOXC2 mutations, no symptoms of LDS, and showed differing clinical characteristics from those who had FOXC2 mutations, suggesting that other gene(s) besides FOXC2 are likely to be involved in SEDAC. © 2013 Ogura et al.

In ossification of the posterior longitudinal ligaments (OPLL), axonal disruption results in motor and sensory function impairment. Twy (tiptoe-walking Yoshimura) mice develop spontaneous calcification in the cervical ligaments, thereby causing chronic compression of the spinal cords. To determine whether in vivo diffusion tensor tractography (DTT) can evaluate the axonal disruption of the chronic compressive spinal cords in twy mice, 6-, 15-, and 20-week-old twy mice were chronologically subjected to DTT. MRI was performed using a 7.0-Tesla magnet with a surface coil (CryoProbe). Diffusion tensor images were analyzed using TrackVis (Massachusetts General Hospital, MA, USA). We succeeded in depicting in vivo high-resolution DTT of the twy mice. The progress of the ligamentous calcification was observed at C2-3 level in each twy mouse, and the number of RT-97 or SMI31 positive fibers was decreased depending on the severity of the compression of the spinal cord. Quantitative analysis of sequential DTT enabled to detect subtle damage of the compressed spinal cord prior to the deterioration of neurological function in twy mice. Thus, in a clinical setting, DTT could be a new effective imaging modality in patients with cervical OPLL.

In recent years, a variety of studies have been conducted towards the goal of achieving regeneration of the central nervous system using neural stem cells. However, various complex factors are involved in the regulation of neural stem cell differentiation, and many unresolved questions remain. It has been reported that after spinal cord injury, the intrinsic neural stem cells do not differentiate into neurons but into astrocytes, resulting in the formation of glial scars. Based on reports that the expression of IL-6 and the IL-6 receptor is sharply increased in the acute stages after spinal cord injury and that IL-6 may serve as a factor strongly inducing the differentiation of neural stem cells into astrocytes, we examined the effects of an antibody to the IL-6 receptor in cases of spinal cord injury and found that the antibody indeed suppressed secondary injury (caused by inflammatory reactions) and glial scar formation, facilitating functional recovery. In this paper, we present the data from this investigation and discuss the relationship between IL-6 signals and spinal cord injury.

The spinal cord has remarkable ability to resist chronic compression; however, delayed paralysis is sometimes seen following the development of spinal kyphosis. In the past, no animal model to clarify the mechanism of spinal cord damage due to spinal kyphotic deformity has been available. We developed a new experimental model of chronic spinal cord compression using a bird, to evaluate the effects of chronic compression associated with kyphotic deformity of the cervical spine on the spinal cord. As kyphosis progressed, the spinal cord flattening became more marked, causing histopathological changes, including demyelination and neuronal loss. Demyelination of the axons progressed in the order of the anterior, lateral, and then posterior funiculus. Furthermore, microangiography suggested that vascular disturbance in addition to mechanical compression may have contributed to the development of histological changes. In conclusion, progressive kyphosis of the cervical spine resulted in demyelination of nerve fibers in the funiculi and neuronal loss in the anterior horn due to chronic compression of the spinal cord. These histological changes seem to be associated with both continuous mechanical compression and vascular changes in the spinal cord.

The objective of this study was to clarify the effects of a temporal blockade of IL-6/IL-6 receptor (IL-6R) engagement, using an anti-mouse IL-6R monoclonal antibody (MR16-1), on macrophage activation and the inflammatory response in the acute phase after spinal cord injury (SCI) in mice. MR16-1 antibodies versus isotype control antibodies or saline alone was administered immediately after thoracic SCI in mice. MR16-1-treated group samples showed increased neuronal regeneration and locomotor recovery compared with controls. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. MR16-1 treatment promoted arginase-1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site and enhanced positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior. The results suggest that temporal blockade of IL-6 signaling after SCI abrogates damaging inflammatory activity and promotes functional recovery by promoting the formation of alternatively activated M2 macrophages.

Neuroprotection and Regeneration of the Spinal Cord comprehensively covers the most recent research in the field of spinal cord injury. The first part of this book focuses on the latest animal models and clinically oriented work, providing extensive information on morphological factors and, biomechanical analysis, in addition to the mechanism of functional recovery. The book goes on to provide information on clinical relevance introducing analysis of spinal cord injuries using MRI and PET. Edited by renowned experts in the field, this book will provide clinical physicians, basic researchers, and postgraduate students with valuable insight into the cutting-edge research and progress in the field of spinal cord injury, treatment, and repair.

In spinal cord injury (SCI), the evaluation of axonal fibers is important to assess the severity of injury and efficacy of any treatment protocol, but conventional methods such as tracer injection in the brain parenchyma are highly invasive and require histological evaluation, precluding clinical applications. Magnetic resonance imaging (MRI) is essential for predicting prognosis and planning treatment of patients with SCI noninvasively. However, the information provided by conventional T1- and T2-weighted MRI of the spinal cord is essentially limited to the differentiation of the white matter from the gray matter. By contrast, diffusion-weighted magnetic resonance imaging (DWI) provides much information about biological structures. In particular, diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) are powerful tools for evaluating white matter fibers in the central nervous system. We previously established a reproducible SCI model in adult common marmosets and demonstrated that DTT could be used to trace the neural tracts in the intact and injured spinal cord of these animals in vivo. Recently, many reports using DTT to analyze the spinal cord area have been published. Based on the findings from our experimental studies, we are now routinely performing DTT of the human spinal cord clinically. In this chapter, we outline the basic principles of DTT and describe the characteristics, limitations, and clinical application of DTT in the spinal cord.

Hepatocyte growth factor (HGF), which is a potent mitogen for mature hepatocytes and a mediator of the inflammatory responses to tissue injury, was recently highlighted as a potent neurotrophic factor in the central nervous system. We revealed that introducing exogenous HGF into the injured rat spinal cord using a herpes simplex virus-1 vector significantly reduces the area of damaged tissue and promotes functional recovery. However, this rat study did not examine the therapeutic effects of administering HGF after injury, which is the most critical issue for clinical application. To translate this strategy to human treatment, we induced a contusive cervical SCI in the common marmoset, a primate, and then administered recombinant human HGF (rhHGF) intrathecally. Motor function was assessed using an original open-field scoring system focusing on manual function, including reach-and-grasp performance and hand placement in walking. The intrathecal rhHGF preserved the corticospinal fibers and myelinated areas, thereby promoting functional recovery. This study demonstrates the therapeutic effects, safety, and clinical efficacy of intrathecal rhHGF treatment for SCI in adult nonhuman primates and the possibility that this novel therapy may be suitable for clinical application.

Reports of functional recovery from spinal cord injury (SCI) after the transplantation of rat-fetus-derived neural stem/precursor cells (NS/PCs) and murine embryonic stem cells (ES cells) have raised great expectations for the successful clinical trial of stem cell transplantation therapy. However, the ethical issues concerning about destroying human embryos or fertilized oocytes to obtain such stem cells have been a major impediment to developing clinically useful stem cell sources and to use them in clinical applications. Recently, induced pluripotent stem cells (iPS cells), which can serve as a source of autologous cell transplantation, have been attracting a lot of attention as a clinically practical alternative to stem cells obtained directly from tissues. In this chapter, we outline the neural induction of murine and human iPS cells, their therapeutic efficacy in mouse and primate SCI models, and their safety in vivo.

Study Design: A retrospective case series. Objective: To evaluate the long-term effectiveness and problems of total en bloc spondylectomy (TES) for treating metastatic thyroid cancer of the spine. Summary of Background Data: Although TES is indicated for low-grade malignant spinal tumors, its efficacy in treating thyroid cancer metastases in the spine is uncertain. Methods: This study followed 8 patients who underwent TES for spinal metastasis of thyroid cancer (5 males, 3 females; mean age, 55.3 y; mean follow-up period, 6.4 y), 6 with follicular carcinomas and 2 with papillary carcinomas. In 6 patients without a marked paravertebral tumor extension, TES was performed using a posterior approach. Two patients had prominent anterior or anterolateral tumor extension into the thoracic and retroperitoneal cavities, and a combined anterior and posterior approach was used. We evaluated the patients' clinical symptoms, operative procedures, complications, and prognoses. Results: Before surgery, the patients' neurological status was evaluated by the Frankel classification (grade C, 4 patients; grade D, 1 patient; grade E, 3 patients) and Tokuhashi scores (9, 1 patient; 11, 2 patients; 13 and 14, 1 patient each; 15, 3 patients). One year after surgery, all the patients had improved by at least a Frankel grade, and 4 patients classified as grade C before surgery had become ambulatory. At the final follow-up (average of 6.4 y), 5 patients had a grade E Frankel classification and 1 had grade D, but 2 patients had suffered neurological deterioration, because of tumor recurrence, at the same level as the TES in one patient and at an adjacent level in the other. At follow-up, all patients were alive; 5 showed no evidence of disease. Two patients experienced rod breakage, at 2.8 and at 3.3 years after TES, and 1 patient suffered an endplate fracture 6 months after TES; this patient developed a late infection, 7 years after TES. Conclusions: TES was effective in controlling spinal thyroid cancer metastasis locally and in preserving the ability to walk. However, instrumentation failure and other late complications arose during the patients' long survival times after TES. Copyright © 2012 by Lippincott Williams & Wilkins.

Diffusion-weighted magnetic resonance imaging provides detailed information about biological structures. In particular, diffusion tensor imaging and diffusion tensor tractography (DTT) are powerful tools for evaluating white matter fibers in the central nervous system. We previously established a reproducible spinal cord injury model in adult common marmosets and showed that DTT could be used to trace the neural tracts in the intact and injured spinal cord of these animals in vivo. Recently, many reports using DTT to analyze the spinal cord area have been published. Based on the findings from our experimental studies, we are now routinely performing DTT of the human spinal cord in the clinic. In this review we outline the basic principles of DTT, and describe the characteristics, limitations, and future uses of DTT to examine the spinal cord. © 2012.

We conducted a survey of adults in Kotohira, a town of about 10,000 people located in the Nakatado District of Kagawa Prefecture, Japan. The survey was distributed to 8184 individuals, and effective responses were received from 3863 persons (response rate, 47.2%) during the survey period. Results regarding numbness and pain showed numbness alone in 7.7%, pain alone in 7.2%, both numbness and pain in 6.0%, and neither numbness nor pain in 79.6%. Spine and spinal cord damage was reported present by 5.4%, and absent by 94.6%. Analysis using the Short-Form Health Survey questionnaire, with comparison between subjects reporting both numbness and pain in the extremities and subjects with either numbness or pain alone, showed lower scores for in Short-Form Health Survey subscales (physical functioning, role [physical, emotional], bodily pain, vitality, and mental health). Subjects with numbness alone generally reported no disability in daily life. In a secondary survey, analysis of neurological findings by specialists identified 6 cases of "pain following spinal cord damage" in which spinal cord-related pain developed in the hands or feet. This represented 0.15% of the survey population starting from the primary survey. © 2013 Inoue et al.

Objective: Complex regional pain syndrome (CRPS) describes a broad spectrum of symptoms that predominantly localize to the extremities. Although limb fracture is one of the most frequently reported triggering events, few large-scale studies have shown the occurrence of and factors associated with CRPS following limb fracture. This study aimed to show the occurrence and identify of those factors. Methods: Using the Japanese Diagnosis Procedure Combination database, we identified 39 patients diagnosed with CRPS immediately after open reduction and internal fixation (ORIF) for limb fracture from a cohort of 185 378 inpatients treated with ORIF between 1 July and 31 December of each year between 2007 and 2010. Patient and clinical characteristics such as age, gender, fracture site, duration of anaesthesia and use of regional anaesthesia were investigated by logistic regression analyses to examine associations between these factors and the in-hospital occurrence of CRPS after ORIF. Results: The occurrence of CRPS was relatively high in fractures of the distal forearm, but low in fractures of the lower limb and in patients with multiple fractures. Generally females are considered to be at high risk of CRPS; however, we found a comparable number of male and female patients suffering from CRPS after ORIF for limb fracture. In terms of perioperative factors, a longer duration of anaesthesia, but not regional anaesthesia, was significantly associated with a higher incidence of CRPS. Conclusion: Although a limited number of CRPS patients were analysed in this study, reduced operative time might help to prevent the development of acute CRPS following limb fracture. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.