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Background The bicortical or tricortical fixation technique with purchase into the anterior sacral wall or promontory has been recommended to achieve rigid sacral pedicle screw fixation, which carries the potential risk of neurovascular injuries. The penetrating endplate screw (PES) technique was proposed as an alternative screw trajectory to facilitate both strong fixation and safety. However, there has been no report on the practical significance of using the PES technique. The aim of the present study was to investigate radiological outcomes using the PES technique for lumbosacral fusion by comparing it with the anterior bicortical technique. Methods The subjects consisted of 44 patients with L5 isthmic spondylolisthesis who underwent single-level posterior lumbar interbody fusion at L5-S using the PES technique (20 patients) or the anterior bicortical technique (24 patients) and were followed up for > 2 years (mean follow-up: 36.6 months). Screw loosening and bone fusion were radiologically assessed and compared between the two groups. Factors contributing to bone fusion were investigated using the following factors: (1) age, (2) sex, (3) body mass index, (4) bone mineral density, (5) screw diameter, (6) screw length, (7) pelvic incidence, (8) crosslink connector, (9) cage material, and (10) sacral screw insertion technique. Results Respective screw loosening and bone fusion rates were 10.0 and 90.0% using the PES technique and 29.2 and 79.2% using the anterior bicortical technique, with no significant differences between the two techniques. Multivariate logistic regression analysis revealed that the age (odds ratio = 0.87, p = 0.02) and PES technique (odds ratio = 22.39, p = 0.02) were significant independent factors contributing to bone fusion. Conclusions This is the first study to demonstrate the significance of using the PES technique to improve radiological outcomes. The PES technique could be a valid option for lumbosacral fixation for L5 isthmic spondylolisthesis in terms of improved bone fusion.

Reoperation is usually associated with poor results and increased morbidity and hospital costs. However, the rates, causes, and risk factors for reoperation in patients undergoing lumbar spinal fusion surgery remain controversial. This study aimed to identify the risk factors for early reoperation after posterior lumbar interbody fusion surgery and to compare the clinical outcomes between patients who underwent reoperation and those who did not.We investigated a multicenter medical record database of 1263 patients who underwent posterior lumbar interbody fusion surgery between 2012 and 2015. A total of 72 (5.7%) reoperations within two years after surgery were identified and were propensity-matched for age, sex, number of fusion segments, and surgeon's experience.We analyzed a total of 114 patients (57 who underwent reoperation (R group) and 57 who did not (C group)). The mean age was 62.6 ± 13.4 years, with 78 men and 36 women. The mean number of fused segments was 1.2 ± 0.5. Surgical site infection was the most common cause of reoperation. There were significant differences in the incidence of diabetes mellitus (p = 0.024), preoperative ambulation status (p = 0.046), and ASA grade (p 0.001) between the C and R groups. The recovery rate of the Japanese Orthopaedic Association score was significantly lower in the R group compared to the C group (R: 50.5 ± 28.8%, C: 63.9 ± 33.7%, p = 0.024). There were significant differences in the bone fusion rate (R: 63.2%, C: 96.5%, p 0.001) and incidence of screw loosening (R: 31.6%; C: 10.5%; p = 0.006).Diabetes mellitus, preoperative ambulation status, and ASA grade were significant risk factors for early reoperation following posterior lumbar interbody fusion surgery. The patients who underwent early reoperation had worse clinical outcomes than those who did not.

Study design A retrospective, single-center clinical study with follow-up of more than 24 months. Purpose To evaluate the union rates and relevant risk factors for non-union after posterior lumbar interbody fusion (PLIF) using porous-coated closed-box titanium spacers. Overview of literature Although the use of a closed-box interbody spacer for PLIF could avoid potential complications associated with the harvesting of autologous bone, few studies have reported detailed follow-up of fusion progression and risk factors for non-union in the early postoperative period. Methods PLIF using closed-box spacers without filling the autologous bone was performed in 78 (88 levels) consecutive patients. Surgical procedures included PLIF using traditional pedicle screw fixation (PLIF, n=37), PLIF using cortical bone trajectory screw fixation (CBT-PLIF, n=30), and transforaminal lumbar interbody fusion with traditional pedicle screw fixation (TLIF, n=11). Lateral dynamic radiography and computed tomography findings were investigated, and the relationship between the union status and variables that may be related to the risk of non-union was tested statistically. Results The overall bone union rates at 12 and 24 months were 68.0% and 88.5%, respectively. Incidences of bone cyst formation, subsidence, and retropulsion of spacers were 33.3%, 47.4%, and 14.1%, respectively. Union rates at 24 months were 94.6% in PLIF, 80.0% in CBT-PLIF, and 90.9% in TLIF. Multivariate logistic regression analyses showed that at 12 months postoperatively, the risk factor for non-union was age >75 years (p =0.02). In contrast, no significant risk factor was observed at 24 months. Conclusions These findings demonstrated the efficacy of interbody closed-box spacers for PLIF without the need to fill the spacer with autologous bone. However, the risk of non-union should be considered in elderly patients, especially intra-operatively and during the early postoperative stage.

BACKGROUND Iatrogenic pseudomeningocele incidence after lumbar surgery is 0.068%–2%, and most lumbar pseudomeningoceles are smaller than 5 cm; however, in rare cases, “giant” pseudomeningoceles greater than 8 cm in size may develop. Normal pressure hydrocephalus (NPH) is another rare condition in which the ventricles expand despite the presence of normal intracranial pressure. To date, pseudomeningocele associated with NPH has not been reported. OBSERVATIONS An 80-year-old woman underwent L3–5 laminectomy and posterior lumbar interbody fusion, and her symptoms improved after surgery. However, dementia appeared 1 month after surgery. Repeated brain computed tomography showed ventricular enlargement, and lumbar magnetic resonance imaging showed a long pseudomeningocele in the subcutaneous tissues at the L4 level. Here, the authors report a rare case of an iatrogenic giant pseudomeningocele accompanied by NPH after lumbar surgery. The symptoms of NPH in the present case occurred after spinal surgery and recovered after dural repair surgery, indicating that the changes in cerebrospinal fluid circulation and/or pressure due to pseudomeningoceles may cause NPH. LESSONS The prevention of dural tears through precise surgical technique and primary repair of dural tears are the best approaches to prevent pseudomeningocele incidence and subsequent events.

Cross-sectional study. Patients who undergo intramedullary spinal surgery occasionally experience post-surgical chronic pain; however, the underlying mechanisms are not yet completely understood. Therefore, this study aimed to identify the cerebral structural changes in patients with post-surgical chronic myelopathic pain using voxel-based morphometry. Single university hospital in Tokyo, Japan. Forty-nine patients who had undergone intramedullary spinal surgery between January 2002 and April 2014 participated in this study. Participants were classified into two groups based on their post-surgical chronic pain intensity: control (numeric rating scale score of

Progress in regenerative medicine is realizing the possibility of neural regeneration and functional recovery in spinal cord injury (SCI). Recently, rehabilitation has attracted much attention with respect to the synergistic promotion of functional recovery in combination with neural stem/progenitor cell (NS/PC) transplantation, even in the chronic refractory phase of SCI. Nevertheless, sensory disturbance is one of the most prominent sequelae, even though the effects of combination or single therapies have been investigated mostly in the context of motor recovery. To determine how combination therapy with treadmill training (TMT) and NS/PC transplantation affects the manifestation of thermal allodynia and tactile hyperalgesia in chronic phase SCI, four groups of SCI mice were used to assess pain-related behavior and histological changes: combined transplantation and TMT therapy, transplantation only, TMT only, and control groups. Thermal allodynia and coarse touch-pressure hyperalgesia exhibited significant recovery in the combined therapy group in comparison with controls, whereas there were no significant differences with fine touch-pressure hyperalgesia and motor function. Further investigation revealed fewer fibers remaining in the posterior funiculus, which contained the tracts associated with the two modalities showing less recovery; that is, touch-pressure hyperalgesia and motor function. A significant correlation was only observed between these two modalities. Although no remarkable histological recovery was found within the lesion epicenter, changes indicating amelioration of pain were observed in the lumbar enlargement of the combination therapy group. Our results suggest that amelioration of thermal allodynia and tactile hyperalgesia can be brought about by the additive effect of NS/PC transplantation and TMT. The degree of recovery seems dependent on the distribution of damage.

Study design Retrospective chart audit. Objectives This study aimed to identify conventional routine blood testing biomarkers associated with the progression of intramedullary injured area in patients with spinal cord injury (SCI). Setting A spinal cord injury center in Hokkaido, Japan. Methods We retrospectively reviewed 71 consecutive adults with acute SCI who were admitted within 24 h after injury and diagnosed as American Spinal Injury Association Impairment Scale Grade A or B at admission. Participants were divided into the progression (P group) and no progression group (NP group) based on the change of the hyperintense signal abnormality in the spinal cord on magnetic resonance imaging from the time of admission to 4 weeks after injury. Individual characteristics and blood testing data obtained in the first 4 weeks after injury were compared between groups. Results The P and NP groups were comprised of 16 and 55 participants, respectively. In univariate analyses, white blood cell (WBC) count on day 3 was significantly higher in group P than group NP (P = 0.021), as was serum C-reactive protein (CRP) level on day 3 (P = 0.015) and day 7 (P = 0.047). Multivariable analysis identified serum CRP level on day 3 as a significant independent prognostic factor for the progression of secondary SCI (OR, 1.138; 95% confidence interval, 1.01-1.28; P = 0.034). Conclusions Serum CRP level on day 3 after injury was a good predictor for the progression of intramedullary signal intensity change on MRI from acute to subacute stage in patients with SCI.

Retrospective cohort study. The purpose of the current study was to examine the effectiveness of late decompression surgery for traumatic cervical spinal cord injury (CSCI) with pre-existing cord compression. Murayama Medical Center, National Hospital Organization, Tokyo, Japan. In total 78 patients with traumatic CSCI without bone injury hospitalized in 2012–2015 in our institute for rehabilitation after initial emergency care were divided into four groups according to the compression rate (CR) of the injured level and whether or not decompression surgery was performed. Neurological status was evaluated by American Spinal Injury Association impairment scale (AIS), Barthel index, and Spinal Cord Independence Measure (SCIM). In the severe compression group (CR ≥ 40%), >2 grade improvement in the AIS was observed in 30% of patients with surgical treatment, although it was not observed in any patient without surgery. The SCIM improvement rate at discharge was 60% in the surgical treatment group and 20% in the non-surgical treatment group. In the minor compression group (CR 2 grade improvement in the AIS was observed in 18% of patients with surgical treatment and in 11% without surgery. The SCIM improvement rate at discharge was 52% in the surgical treatment group and 43% in the non-surgical treatment group. These results indicate that surgical treatment has an advantage for patients following traumatic CSCI with severe cord compression. In contrast, surgical efficacy is not proved for CSCI patients without severe cord compression.

Study design A retrospective observational study. Objectives To elucidate predictive clinical factors associated with irreversible complete motor paralysis following traumatic cervical spinal cord injury (CSCI). Setting Hokkaido Spinal Cord Injury Center, Japan. Methods A consecutive series of 447 traumatic CSCI persons were eligible for this study. Individuals with complete motor paralysis at admission were selected and divided into two groups according to the motor functional outcomes at discharge. Initial findings in magnetic resonance imaging (MRI) and other clinical factors that could affect functional outcomes were compared between two groups of participants: those with and those without motor recovery below the level of injury at the time of discharge. Results Of the 73 consecutive participants with total motor paralysis at initial examination, 28 showed some recovery of motor function, whereas 45 remained complete motor paralysis at discharge, respectively. Multivariate logistic regression analysis showed that the presence of intramedullary hemorrhage manifested as a confined low intensity changes in diffuse high-intensity area and more than 50% of cord compression on MRI were significant predictors of irreversible complete motor paralysis (odds ratio [OR]: 8.4; 95% confidence interval [CI]: 1.2-58.2 and OR: 14.4; 95% CI: 2.5-82.8, respectively). Conclusion The presence of intramedullary hemorrhage and/or severe cord compression on initial MRI were closely associated with irreversible paralysis in persons with motor complete paralysis following CSCI. Conversely, subjects with a negligible potential for recovery could be identified by referring to these negative findings.

INTRODUCTION: There are considerable risks for vertebral artery (VA) injury in case of corrective surgery for a severe and rigid cervical kyphotic deformity. This case report describes a rare case of surgical management for pre-existing traumatic rigid cervical kyphosis associated with unilateral VA occlusion. CASE PRESENTATION: A 73-year-old male fell down and injured his neck. He was referred to our hospital 10 months after injury because his degree of head drop progressed gradually to a chin-on-chest position such that he could not look straight forward. On plain X-ray, the C2–7 angles in the neutral, flexion, and extension positions were 61°, 71°, and 50°, respectively. CT revealed a collapse of the C5 vertebral body and bone fusion between C4 and C5 in the anterior vertebrae, and unilateral VA occlusion was confirmed by angiography. Two-stage surgery was planned to correct the kyphosis. In the first stage, anterior release of the C4/5 bone-spur fusion and dissection of the intervertebral disk were performed. After release, angiography confirmed neither occlusion nor rupture of the VA. In the second stage, anterior and posterior fixation was performed at correcting position while maintaining slight kyphosis in order to avoid excessive distortion of the VA. The postoperative C2–7 kyphosis angle improved to 16° without any VA injury, and the patient could look forward easily. DISCUSSION: The degree of correction as well as risk management of VAs should be considered carefully during corrective surgery for severe and rigid cervical kyphosis, especially with unilateral VA occlusion.

INTRODUCTION: We present an unusual case of traumatic occult lateral mass fracture of the cervical spine with unilateral occlusion of the vertebral artery (VA), that was missed by plain X-ray and magnetic resonance imaging (MRI), but identified by computed tomography (CT) after suspecting high-energy trauma as the underlying cause. CASE PRESENTATION: A 67-year-old male was injured in a car accident and came to our institute on foot 4 days after injury with complaints of neck pain and numbness in the right hand. Although, no specific bone injury was visible on plain X-ray, the absence of flow voids in the right VA was confirmed on axial T2-weighted MRI. We suspected high-energy trauma of the cervical spine at that point and performed CT for a more detailed assessment. Consequently, a fracture was detected in the right lateral mass of C6 and we speculated that spontaneous reduction of the fracture-dislocation had occurred. One-stage surgery with posterior fixation was subsequently performed for instability. The patient’s preoperative symptoms were improved and neither recanalization of the occlusion nor another VA occlusion was observed after surgery. DISCUSSION: VA injury occurs frequently as a complication of blunt cervical spine trauma. In the present case, however, the lateral mass fracture was not seen on MRI and missed until the unilateral VA injury was detected. When high-energy trauma of the cervical spine is suspected, it is important to evaluate damage to the spinal cord, bone, soft-tissue, and VA by MRI and CT.

Secondary degeneration after spinal cord injury (SCI) is caused by increased vascular permeability, infiltration of inflammatory cells, and subsequent focal edema. Therapeutic interventions using neurotrophic factors have focused on the prevention of such reactions to reduce cell death and promote tissue regeneration. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. However, the effect of VEGF on SCI remains controversial. VEGF signaling is primarily regulated through two primary receptors, VEGF receptor 1 (VEGF-R1) and VEGF receptor 2 (VEGF-R2). The purpose of this study was to examine the effects of intraperitoneal administration of VEGF-R1- and VEGF-R2-neutralizing antibodies on a mouse model of SCI. VEGF-R1 blockade, but not VEGF-R2 blockade, decreased the permeability and infiltration of inflammatory cells, and VEGF-R2 blockade caused a significant increase in neuronal apoptosis in the acute phase of SCI. VEGF-R2 blockade decreased the residual tissue area and the number of neural fibers in the chronic phase of SCI. VEGF-R2 blockade worsened the functional recovery and prolonged the latency of motor evoked potentials. These data suggest that endogenous VEGF-R2 plays a crucial role in neuronal protection after SCI.

Allodynia, a form of neuropathic pain, is defined as pain in response to a non-nociceptive stimulus. The brain regions responsible for pain, which are not normally activated, can be activated in allodynic mice by providing a suitable stimulus to Aβ-fibers, which transmit signals from tactile sensory fibers. Functional MRI (fMRI) can be used to objectively observe abnormal brain activation. In the present study, fMRI was conducted to investigate allodynia in mice; allodynia was generated by surgical injury at the L4 spinal nerve root, thus selectively stimulating sensory nerve fibers. In intact mice, only the primary somatosensory cortex (S1) was activated by stimulation of Aβ-fibers. Meanwhile, allodynic mice showed significantly higher BOLD signals in the anterior cingulate area (ACA) and thalamus. Using resting state fMRI, both degree and eigenvector centrality were significantly decreased in the contralateral S1, clustering coefficient and local efficiency were significantly increased in the ACA, and betweenness centrality was significantly higher in the ventral posterolateral nucleus of the thalamus. These results suggest that the observed abnormal BOLD activation is associated with defects in Aβ-fibers when Aβ-fibers in allodynic mice are selectively stimulated. The objective approach enabled by fMRI can improve our understanding of pathophysiological mechanisms and therapeutic efficacy.

White matter abnormalities in the CNS have been reported recently in various neurological and psychiatric disorders. Quantitation of non-Gaussianity for water diffusion byq-space diffusional MRI (QSI) renders biological diffusion barriers such as myelin sheaths; however, the time-consuming nature of this method hinders its clinical application. In the current study, we aimed to refine QSI protocols to enable their clinical application and to visualize myelin signals in a clinical setting. For this purpose, animal studies were first performed to optimize the acquisition protocol of a non-Gaussian QSI metric. The heat map of standardized kurtosis values derived from optimal QSI (myelin map) was then created. Histological validation of the myelin map was performed in myelin-deficient mice and in a nonhuman primate by monitoring its variation during demyelination and remyelination after chemical spinal cord injury. The results demonstrated that it was sensitive enough to depict dysmyelination, demyelination, and remyelination in animal models. Finally, its utility in clinical practice was assessed by a pilot clinical study in a selected group of patients with multiple sclerosis (MS). The human myelin map could be obtained within 10 min with a 3 T MR scanner. Use of the myelin map was practical for visualizing white matter and it sensitively detected reappearance of myelin signals after demyelination, possibly reflecting remyelination in MS patients. Our results together suggest that the myelin map, a kurtosis-related heat map obtainable with time-saving QSI, may be a novel and clinically useful means of visualizing myelin in the human CNS.SIGNIFICANCE STATEMENTMyelin abnormalities in the CNS have been gaining increasing attention in various neurological and psychiatric diseases. However, appropriate methods with which to monitor CNS myelin in daily clinical practice have been lacking. In the current study, we introduced a novel MRI modality that produces the “myelin map.” The myelin map accurately depicted myelin status in mice and nonhuman primates and in a pilot clinical study of multiple sclerosis patients, suggesting that it is useful in detecting possibly remyelinated lesions. A myelin map of the human brain could be obtained in

The paranodal junction is a specialized axon-glia contact zone that is important for normal neuronal activity and behavioral locomotor function in the central nervous system (CNS). Histological examination has been the only method for detecting pathological paranodal junction conditions. Recently, diffusion tensor MRI (DTI) has been used to detect microstructural changes in various CNS diseases. This study was conducted to determine whether MRI and DTI could detect structural changes in the paranodal junctions of the spinal cord in cerebroside sulfotransferase knock-out (CST-KO) mice. Here, we showed that high-resolution MRI and DTI characteristics can reflect paranodal junction failure in CST-KO mice. We found significantly lower T1 times and significantly higher T2 times in the spinal cord MRIs of CST-KO mice as compared to wild-type (WT) mice. Spinal cord DTI showed significantly lower axial diffusivity and significantly higher radial diffusivity in CST-KO mice as compared to WT mice. In contrast, the histological differences in the paranodal junctions of WT and CST-KO mice were so subtle that electron microscopy or immunohistological analyses were necessary to detect them. We also measured gait disturbance in the CST-KO mice, and determined the conduction latency by electrophysiology. These findings demonstrate the potential of using MRI and DTI to evaluate white matter disorders that involve paranodal junction failure.

Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated “safe” hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.

Conventional magnetic resonance imaging (MRI) can detect hemorrhage, edema, syrinx, and spinal cord atrophy, but not axonal disruption after spinal cord injury (SCI). We previously demonstrated that diffusion tensor tractography (DTT) could depict axonal disruption after hemisection SCI in common marmosets. In the present study, to determine the relationship between DTT results and functional recovery after contusive SCI, we performed longitudinal DTT, behavioral, and histological analyses before and after contusive SCI in common marmosets. By comparing the tract fiber estimate depicted by DTT with neuronal fibers labeled with RT97 and SMI-31, anti-neurofilament antibodies, we determined the optimal fractional anisotropy (FA) threshold for fiber tracking to be 0.40. The ratio of the number of tract fiber estimates at the lesion site to the number before SCI, determined by DTT, was significantly correlated with the functional recovery after SCI. Moreover, comparison of the longitudinal pre- and post-SCI FA and axial diffusivity (λ(‖)) values revealed that they decreased after injury at the sites caudal to the lesion epicenter in the corticospinal tract and rostral to the lesion epicenter in the dorsal column. The FA values, then, showed partial recovery in the dorsal column. FA-value-oriented color DTT was used to represent axonal sparing or regeneration of the different tracts. These findings indicated that DTT analysis might be a versatile non-invasive tool for evaluating the axonal disruption after SCI.