Mikito Tsushima

Zonisamide Enhances Neurite Elongation of Primary Motor Neurons and Facilitates Peripheral Nerve Regeneration In Vitro and in a Mouse Model.

No clinically applicable drug is currently available to enhance neurite elongation after nerve injury. To identify a clinically applicable drug, we screened pre-approved drugs for neurite elongation in the motor neuron-like NSC34 cells. We found that zonisamide, an anti-epileptic and anti-Parkinson’s disease drug, promoted neurite elongation in cultured primary motor neurons and NSC34 cells in a concentration-dependent manner. The neurite-scratch assay revealed that zonisamide enhanced neurite regeneration. Zonisamide was also protective against oxidative stress-induced cell death of primary motor neurons. Zonisamide induced mRNA expression of nerve growth factors (BDNF, NGF, and neurotrophin-4/5), and their receptors (tropomyosin receptor kinase A and B). In a mouse model of sciatic nerve autograft, intragastric administration of zonisamide for 1 week increased the size of axons distal to the transected site 3.9-fold. Zonisamide also improved the sciatic function index, a marker for motor function of hindlimbs after sciatic nerve autograft, from 6 weeks after surgery. At 8 weeks after surgery, zonisamide was protective against denervation-induced muscle degeneration in tibialis anterior, and increased gene expression of Chrne, Colq, and Rapsn, which are specifically expressed at the neuromuscular junction. We propose that zonisamide is a potential therapeutic agent for peripheral nerve injuries as well as for neuropathies due to other etiologies.

Staged decrease of physical ability on the locomotive syndrome risk test is related to neuropathic pain, nociceptive pain, shoulder complaints, and quality of life in middle-aged and elderly people – The utility of the locomotive syndrome risk test

Abstract Objectives: A locomotive syndrome (LS) risk test for evaluation of physical ability is recently proposed. The objective of this study is to evaluate the utility of this test by examining physical ability, neuropathic pain, nociceptive pain, shoulder complaints, and quality of life (QOL). Methods: A prospective cohort study was conducted in 523 subjects (240 males, 283 females; mean age: 63.3 years) at a health checkup. Data collected using visual analog scales (VAS) for shoulder pain, low back pain, sciatica, and knee pain, neuropathic pain, shoulder complaint, body mass index (BMI), osteoporosis, and SF-36 were compared among three LS risk stages. Results: Subjects in LS risk stage 1 (24%) had significantly more osteoporosis, slower gait speed, weaker muscle strength and higher VAS, with no difference in age and BMI compared to those with no LS risk (50%). Subjects in stage 2 (26%) had significantly poorer results for all items. Shoulder complaint, neuropathic pain and QOL differed significantly among all three groups and worsened with decline in mobility on the LS risk test. Conclusions: LS risk test is easy and useful screening tool for evaluation of mobility and for screening for pain and complaint associated with activity of daily living and QOL.

Transcranial motor evoked potential waveform changes in corrective fusion for adolescent idiopathic scoliosis

OBJECTIVE Corrective surgery for spinal deformities can lead to neurological complications. Several reports have described spinal cord monitoring in surgery for spinal deformity, but only a few have included patients younger than 20 years with adolescent idiopathic scoliosis (AIS). The goal of this study was to evaluate the characteristics of cases with intraoperative transcranial motor evoked potential (Tc-MEP) waveform deterioration during posterior corrective fusion for AIS. METHODS A prospective database was reviewed, comprising 68 patients with AIS who were treated with posterior corrective fusion in a prospective database. A total of 864 muscles in the lower extremities were chosen for monitoring, and acceptable baseline responses were obtained from 819 muscles (95%). Intraoperative Tc-MEP waveform deterioration was defined as a decrease in intraoperative amplitude of ≥ 70% of the control waveform. Age, Cobb angle, flexibility, operative time, estimated blood loss (EBL), intraoperative body temperature, blood pressure, number of levels fused, and correction rate were examined in patients with and without waveform deterioration. RESULTS The patients (3 males and 65 females) had an average age of 14.4 years (range 11-19 years). The mean Cobb angles before and after surgery were 52.9° and 11.9°, respectively, giving a correction rate of 77.4%. Fourteen patients (20%) exhibited an intraoperative waveform change, and these occurred during incision (14%), after screw fixation (7%), during the rotation maneuver (64%), during placement of the second rod after the rotation maneuver (7%), and after intervertebral compression (7%). Most waveform changes recovered after decreased correction or rest. No patient had a motor deficit postoperatively. In multivariate analysis, EBL (OR 1.001, p = 0.085) and number of levels fused (OR 1.535, p = 0.045) were associated with waveform deterioration. CONCLUSIONS Waveform deterioration commonly occurred during rotation maneuvers and more frequently in patients with a larger preoperative Cobb angle. The significant relationships of EBL and number of levels fused with waveform deterioration suggest that these surgical invasions may be involved in waveform deterioration.

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5

At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering. Rspo2 requires Wnt ligands, but not agrin, for promoting AChR clustering in cultured myotubes. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), an Rspo2 receptor, is also accumulated at the NMJ, and is associated with MuSK via LRP4. Lgr5 is required for Rspo2-mediated AChR clustering in myotubes. In Rspo2-knockout mice, the number and density of AChRs at the NMJ are reduced. The Rspo2-knockout diaphragm has an altered ultrastructure with widened synaptic clefts and sparse synaptic vesicles. Frequency of miniature endplate currents is markedly reduced in Rspo2-knockout mice. To conclude, we demonstrate that Rspo2 and its receptor Lgr5 are Wnt-dependent and agrin-independent regulators of AChR clustering at the NMJ.

Resection of Beak-Type Thoracic Ossification of the Posterior Longitudinal Ligament from a Posterior Approach under Intraoperative Neurophysiological Monitoring for Paralysis after Posterior Decompression and Fusion Surgery

Study Design Prospective clinical study. Objective Posterior decompression and fusion surgery for beak-type thoracic ossification of the posterior longitudinal ligament (T-OPLL) generally has a favorable outcome. However, some patients require additional surgery for postoperative severe paralysis, a condition that is inadequately discussed in the literature. The objective of this study was to describe the efficacy of a procedure we refer to as “resection at an anterior site of the spinal cord from a posterior approach” (RASPA) for severely paralyzed patients after posterior decompression and fusion surgery for beak-type T-OPLL. Methods Among 58 consecutive patients who underwent posterior decompression and fusion surgery for beak-type T-OPLL since 1999, 3 with postoperative paralysis (5%) underwent RASPA in our institute. Clinical records, the Japanese Orthopaedic Association score, gait status, intraoperative neurophysiological monitoring (IONM) findings, and complications were evaluated in these cases. Results All three patients experienced a postoperative decline in Manual Muscle Test (MMT) scores of 0 to 2 after the first surgery. RASPA was performed 3 weeks after the first surgery. All patients showed gradual improvements in MMT scores for the lower extremity and in ambulatory status; all could walk with a cane at an average of 4 months following RASPA surgery. There were no postoperative complications. Conclusions RASPA surgery for beak-type T-OPLL after posterior decompression and fusion surgery resulted in good functional outcomes as a salvage surgery for patients with severe paralysis. Advantages of RASPA include a wide working space, no spinal cord retraction, and additional decompression at levels without T-OPLL resection and spinal cord shortening after additional dekyphosis and compression maneuvers. When used with IONM, this procedure may help avoid permanent postoperative paralysis.

Rapid Worsening of Symptoms and High Cell Proliferative Activity in Intra- and Extramedullary Spinal Hemangioblastoma: A Need for Earlier Surgery

Study Design A retrospective analysis of a prospective database. Objective To compare preoperative symptoms, ambulatory ability, intraoperative spinal cord monitoring, and pathologic cell proliferation activity between intramedullary only and intramedullary plus extramedullary hemangioblastomas, with the goal of determining the optimal timing for surgery. Methods The subjects were 28 patients (intramedullary only in 23 cases [group I] and intramedullary plus extramedullary in 5 cases [group IE]) who underwent surgery for spinal hemangioblastoma. Preoperative symptoms, ambulatory ability on the McCormick scale, intraoperative spinal cord monitoring, and pathologic findings using Ki67 were compared between the groups. Results In group IE, preoperative motor paralysis was significantly higher (100 versus 26%, p < 0.005), the mean period from initial symptoms to motor paralysis was significantly shorter (3.5 versus 11.9 months, p < 0.05), and intraoperative spinal cord monitoring aggravation was higher (65 versus 6%, p < 0.05). All 5 patients without total resection in group I underwent reoperation. Ki67 activity was higher in group IE (15% versus 1%, p < 0.05). Preoperative ambulatory ability was significantly poorer in group IE (p < 0.05), but all cases in this group improved after surgery, and postoperative ambulatory ability did not differ significantly between the two groups. Conclusions Intramedullary plus extramedullary spinal hemangioblastoma is characterized by rapid preoperative progression of symptoms over a short period, severe spinal cord damage including preoperative motor paralysis, and poor gait ability compared with an intramedullary tumor only. Earlier surgery with intraoperative spinal cord monitoring is recommended for total resection and good surgical outcome especially for an IE tumor compared with an intramedullary tumor.

How do spinal schwannomas progress? The natural progression of spinal schwannomas on MRI

OBJECTIVE Little is known about the progression of spinal schwannomas. The aim of this study was to determine the natural progression of spinal schwannomas and establish the risk of tumor growth. METHODS This study retrospectively analyzed data from 23 patients (12 men and 11 women, 40-89 years old) with schwannomas detected by MRI. The mean follow-up period was 5 years (range 2-10 years). The absolute and relative growth rates of the tumors were calculated. RESULTS The average tumor size was 1495 mm(3) at the initial visit and 2224 mm(3) at the final follow-up. The average absolute growth rate was 139 mm(3) per year, and the average relative growth rate was 5.3% per year. Tumors were classified into 3 groups based on enhancement patterns: isointense/hyperintense (iso/high; 11 cases), rim enhancement when enhancement was peripheral (high/rim; 5 cases), and heterogeneous/heterogeneous (hetero/hetero; 7 cases) based on Gd-enhanced T2-weighted MRI. The average absolute growth rates of the 3 lesion groups were 588 mm(3), 957 mm(3), and 3379 mm(3), respectively (p < 0.01). CONCLUSIONS Although the tumors classified as iso/high and high/rim on T2-weighted Gd-enhanced MR images were small and grew very little, most tumors with hetero/hetero classification increased in size. Hetero/hetero-type tumors should be followed closely and may require surgery.

Mri Signal Intensity Classification in Cervical Ossification of the Posterior Longitudinal Ligament: Predictor of Surgical Outcomes

Study Design. Prospective cohort study. Objective. To investigate whether classification of increased signal intensity (ISI) on magnetic resonance imaging (MRI) of spinal cord in patients with cervical ossification of the posterior longitudinal ligament (C-OPLL) reflects severity of myelopathy and surgical outcome. Summary of Background Data. The relationship between classification of ISI on C-OPLL and severity is unknown. Methods. The 119 consecutive patients (91 men, 28 women) with C-OPLL who underwent surgery were enrolled. T2-weighted MRI was performed before surgery and ISI was classified into three groups as follows, Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). The severity of myelopathy and surgical outcome were evaluated by the Japanese Orthopedic Association score. To determine factors that influence ISI, the change of the spinal cord cross-sectional area (SCA) during flexion and extension was calculated by computed tomography after myelography. Results. The preoperative MRI showed 55 patients in Grade 0, 46 patients in Grade 1, and 18 patients in Grade 2. The preoperative Japanese Orthopedic Association score (Grade 0, 11.2; Grade 1, 10.3; Grade 2, 9.6 points) and surgical outcome got worsened with increasing ISI grade. The patients in Grade 2 had a longer duration of disease, while those in Grade 1 and Grade 2 had a larger change of SCA during flexion and extension (Grade 0, 4.8 mm2; Grade 1, 7.3 mm2; Grade 2, 7.8 mm2). However age, alignment of the cervical spine, range of motion, and occupying ratio of the ossification were not different in the three grades. Conclusion. Grade of ISI correlated with preoperative severity of myelopathy and surgical outcome in patients with C-OPLL. Increased signal intensity of the spinal cord on MRI was associated with a larger change in SCA and longer duration of disease. Level of Evidence: 3

The Image Diagnostic Classification of Mr T2 Increased Signal Intensity in Cervical Spondylotic Myelopathy: Clinical Evaluation Using Quantitative and Objective Assessment

Study Design. A prospective imaging study. Objective. The study investigated whether the classification of increased signal intensity (ISI) using magnetic resonance imaging (MRI) reflects the severity of symptoms in patients with cervical spondylotic myelopathy (CSM). Summary of Background Data. Although the ISI on MRI in patients with CSM is observed, the degree of ISI has not been examined. The association between ISI and the surgical outcomes in cervical myelopathy remains controversial. Methods. A total of 505 consecutive patients with CSM (311 males; 194 females) were enrolled. The mean age was 66.6 years (range, 41–91 yrs), with an average postoperative follow-up period of 26.5 ± 12.5 months. The ISI was classified into three groups based on sagittal T2-weighted MRI as follows: Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). Pre- and postoperative neurological status was evaluated using the Japanese Orthopedic Association scoring system for cervical myelopathy (JOA score) and quantifiable tests, including the 10-s grip and release test (10-s G&R test) and the 10-s step test. Results. The preoperative MRI showed 168 patients in Grade 0, 169 patients in Grade 1, and 168 in Grade 2, with no age differences among three groups. Grade 2 patients had a longer duration of symptom compared with the other grades. Grade 0 patients had a better postoperative JOA score and recovery rate compared with the other grades. The preoperative and postoperative scores in the G&R test and steps were better in the Grade 0 patients compared with the other grades. Grade 1 and 2 patients had similar outcomes and recovery rates. Conclusion. ISI on MRI in patients with CSM was prospectively classified into three grades. The ISI grading was not associated with the preoperative severity of myelopathy and outcomes. Level of Evidence: 2

Optimal Timing of Surgery for Intramedullary Cavernous Hemangioma of the Spinal Cord in Relation to Preoperative Motor Paresis, Disease Duration, and Tumor Volume and Location

Study Design: Prospective study. Objective: Investigate factors associated with preoperative motor paresis, recovery, ambulatory status, and intraoperative neurophysiological monitoring (IONM) among patients with no preoperative paresis (N group), complete preoperative motor recovery (CR group), and no complete recovery (NCR group) in patients with intramedullary spinal cavernous hemangioma to determine the optimal timing of surgery. Methods: The study evaluated 41 surgical cases in our institute. Disease duration, tumor lesion, manual muscle testing (MMT), and gait at onset, just before surgery, and final follow-up (FU), tumor and lesion volume, IONM, extent of tumor resection, and tumor recurrence were evaluated among N, CR, and NCR groups. Results: Motor paresis at onset was found in 26 patients (63%), with 42% of those in CR group. Disease duration from onset negatively affected stable gait just before surgery and FU as well as lower preoperative MMT (P < .05). Thoracic tumors were associated with patients with unstable gait before surgery (P < .05). Tumor volume was larger in NCR group (P < .05). IONM significantly decreased in NCR and CR groups than in N group (P < .05). The NCR group had residual mild motor paresis at FU (P < .05). Stable gait at FU was similar in N group and CR group, though lower in NCR group (P < .05). Conclusions: Early surgery is generally recommended for thoracic tumors and large tumors during stable gait without motor paresis before long disease duration. Surgery may be postponed until patients recover from preoperative motor paresis to allow optimal surgical outcome. IONM should be carefully monitored in patients with a history of preoperative paresis even with preoperative complete motor recovery.