Kyohei Sakaki

Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Hybrid grafting using bone marrow aspirate combined with porous β-tricalcium phosphate and trephine bone for lumbar posterolateral spinal fusion: a prospective, comparative study versus local bone grafting.

Study Design. A prospective, comparative study. Objective. We developed a hybrid graft (HBG) of porous &bgr;-tricalcium phosphate ceramics/percutaneously harvested bone sticks/autologous bone marrow aspirate for lumbar posterolateral fusion (PLF). The aim of this study was to investigate the efficacy of the HBG as a substitute for conventional corticocancellous iliac autografts. Summary of Background Data. Iliac crest bone graft (ICBG) has been traditionally used as the golden standard for lumbar spinal fusion. The significant complication rate associated with harvesting corticocancellous ICBG, however, has encouraged development of alternative graft substitutes. Methods. From September 2005, 61 consecutive patients underwent decompressive laminotomy and 1-level instrumented PLF. Each patient in this study had the constructs of the HBG placed on 1 side of the intertransverse process gutter. An autologous local bone graft (LBG) harvested during decompressive laminotomy was placed on the other side as a control. Radiographic evaluation was performed at 6 months, 1 year after surgery, and subsequently on an annual basis. The fusion statuses on either side of vertebra were compared. Results. The flexion-extension motion in the dynamic x-rays at the target level decreased over time. Only 1 case exhibited over 5° of angular motion 2 years after surgery. In the evaluation of fusion status, the fusion rate for the HBG side (68.9% at 6 months, 83.6% at 1 year, 93.5% at 2 years) was higher than that for the LBG side (49.2% at 6 months, 75.4% at 1 year, 89.1% at 2 years) with a significant difference at 6 months after surgery. No significant complications at the donor site were found postoperatively. Conclusion. The HBG promoted posterolateral spinal fusion without significant donor site morbidity. Because of its efficacy and safety, this hybrid construct seems promising as an alternative to conventional iliac bone grafts for lumbar spinal fusion.

Dural closure for the treatment of superficial siderosis.

Superficial siderosis (SS) of the CNS is a rare disease caused by repeated hemorrhages in the subarachnoid space. The subsequent deposition of hemosiderin in the brain and spinal cord leads to the progression of neurological deficits. The causes of bleeding include prior intradural surgery, carcinoma, arteriovenous malformation, nerve root avulsion, and dural abnormality. Recently, surgical treatment of SS associated with dural defect has been reported. The authors of the present report describe 2 surgically treated SS cases and review the literature on surgically treated SS. The patients had dural defects with fluid-filled collections in the spinal canal. In both cases, the dural defects were successfully closed, and the fluid collection was resolved postoperatively. In one case, the neurological symptoms did not progress postoperatively. In the other case, the patient had long history of SS, and the clinical manifestations partially deteriorated after surgery, despite the successful dural closure. In previously reported surgically treated cases, the dural defects were closed by sutures, patches, fibrin glue, or muscle/fat grafting. Regardless of the closing method, dural defect closure has been shown to stop CSF leakage and subarachnoid hemorrhaging. Successfully repairing the defect can halt the disease progression in most cases and may improve the symptoms that are associated with CSF hypovolemia. However, the effect of the dural closure may be limited in patients with long histories of SS because of the irreversibility of the neural tissue damage caused by hemosiderin deposition. In patients with SS, it is important to diagnose and repair the dural defect early to minimize the neurological impairments that are associated with dural defects.

Presence of Anterior Compression of the Spinal Cord After Laminoplasty Inhibits Upper Extremity Motor Recovery in Patients With Cervical Spondylotic Myelopathy

Study Design. A retrospective single-center study. Objective. To investigate how functional recovery is influenced by anterior compression of the spinal cord (ACS) and instability at the level of ACS after laminoplasty in patients with cervical spondylotic myelopathy. Summary of Background Data. There have been many reports that patients whose spinal cord cannot be decompressed sufficiently after laminoplasty are likely to show unsatisfactory neurologic outcomes. Notably, postoperative ACS is well known to cause problems. Clinically, however, it remains unknown how functional recovery is inhibited by postoperative ACS. Methods. Sixty-four consecutive patients who underwent expansive laminoplasty for the treatment of myelopathy at our hospital between 1998 and 2005 were reviewed. All 64 patients were available for follow-up. The average follow-up period was 97 months (60–156 months). Patients were divided into 2 groups: the ACS(+) group comprised 16 patients who had ACS 3 years postoperatively, and the ACS(−) group comprised 48 patients with no ACS. Clinical outcome was compared in terms of the Japanese Orthopaedic Association score (mean total score, mean score of each item, and recovery rates). Results. Demographics were similar between the 2 groups. Mean Japanese Orthopaedic Association score at final follow-up was 12.1 points (recovery rate 34.0%) in the ACS(+) group and 13.8 points (recovery rate 56.6%) in the ACS(−) group, and there was a significant difference in recovery rate between the groups (P < 0.05). Notably, a significant difference was found between the 2 groups in improvement of upper extremity motor function (P < 0.05). In addition, we found that not only the presence of ACS but also postoperative hypermobility of the intervertebral segment with ACS influenced clinical outcome negatively. Conclusion. These results demonstrate that ACS after laminoplasty could be a risk factor for clinical outcome and might prevent improvement in upper extremity motor function in patients with myelopathy.

Warning thresholds on the basis of origin of amplitude changes in transcranial electrical motor-evoked potential monitoring for cervical compression myelopathy

Study Design. A retrospective analysis of prospectively collected data from consecutive patients undergoing transcranial electrical motor-evoked potential (TCE-MEP: compound muscle action potentials) monitoring during cervical spine surgery. Objective. To divide the warning threshold of TCE-MEP amplitude changes on the basis of origin into the spinal tract and spinal segments and decide warning thresholds for each. Summary of Background Data. The parameter commonly used for the warning threshold in TCE-MEP monitoring is wave amplitude, but amplitude changes have not been examined by anatomical origin. Methods. Intraoperative TCE-MEP amplitude changes were reviewed for 357 patients with cervical myelopathy. Most of the patients were monitored by transcranial electrical stimulated spinal-evoked potential combined with TCE-MEP. The warning threshold of TCE-MEP was taken as waveform disappearance. For each patient, amplitude changes were separated, according to origin, into the spinal tract and spinal segments and compared with clinical outcome. Results. Assessable TCE-MEP waves were obtained in 350 cases. Disappearance of TCE-MEP waves, which were innervated by the spinal levels exposed to the surgical invasion, was seen in 11 cases. Disappearance of TCE-MEPs, which were innervated by the spinal levels inferior to them, was seen in 43 cases. There was no postoperative motor deficit in those cases. However, such deficits caused by spinal segment injury were seen in 2 cases, which showed that intraoperative amplitude decreased to 4.5% and 27%. Conclusion. If we had established the warning threshold as 30% of the control amplitude, we would likely have prevented both cases of postoperative motor deficits, but 106 (30.3%) cases would have become positive cases. If we had established the warning threshold separately as wave disappearance for the spinal tract and 30% of the control amplitude for the spinal segments, sensitivity and specificity would have been 100% and 83.7%, respectively. Dividing the warning threshold on the basis of origin of amplitude changes could reduce false-positive cases and prevent intraoperative injuries.

Increase in paravertebral muscle activity in lumbar kyphosis patients by surface electromyography compared with lumbar spinal canal stenosis patients and healthy volunteers.

Study Design: Paravertebral muscle activity measurement by surface electromyography (EMG) in lumbar degenerative patients and healthy volunteers. Objective: Muscle activity was tested in the standing position, and the influence of low back pain and alignment of the lumbar spine was assessed in the patients with lumbar kyphosis (LDK) or canal stenosis. Summary of Background Data: The number of kyphosis patients has increased as the population has grown older. Advanced kyphosis can cause difficulties in maintaining a standing position and affect daily living activities. The most direct cause is the atrophy of erector spinae muscles. The activity of these muscles has not yet been sufficiently evaluated and needs to be assessed objectively for the purpose of diagnosis and treatment. Methods: The subjects were kyphosis patients who were 60 years of age or older, age‐matched lumbar spinal canal stenosis patients, and healthy volunteers. Muscular activity at the L1–L2 and the L4–L5 intervertebral areas was recorded by surface EMG in the resting standing position and also with a weight load held in the standing position. Muscle activity and muscle fatigue, and the association between the Visual Analogue Scale, the Japanese Orthopaedic Association score for low back pain, and muscle activity, were analyzed. Results: Kyphosis patients had a greater muscle activity in the lower back in the resting standing position and more severe muscle fatigue at the upper lumbar spine in comparison with patients with lumbar spinal canal stenosis. There was no association between muscle activity and clinical findings in patients with LDK although. Conclusions: Our study revealed the constant activity of paravertebral muscles and the susceptibility to muscle fatigue in patients with LDK. The quantification of muscle activity by surface EMG may show the pathology of LDK, and the decrease in muscle activity in the standing position may be a potentially useful index for guiding treatment.

Hemolysate pretreatment ameliorates ischemic acute renal injury in rats.

Heme oxygenase-1 (HO-1) is an antioxidant enzyme and is believed to protect against oxidative stress-induced tissue injury. Renal ischemia-reperfusion (IR) injury seems at least in part to be caused by the oxidative stress. The aim of this study was to improve the renal IR injury by clinically available means. When littermate hemolysate was intravenously administered into rats, HO-1 was markedly induced in the kidneys. To investigate whether prior induction of HO-1 by the hemolysate injection ameliorates the subsequent renal IR injury, we assessed the levels of blood urea nitrogen (BUN) and serum creatinine (SCr), markers for renal injury, in rats with 45 min of ischemia followed by 18 h of reperfusion. To avoid the nephrotoxicity induced by hemolysate, small but effective amounts of hemolysate was injected into rats at 48 h prior to the ischemia. The levels of BUN and SCr values were significantly improved as compared to the rats with renal IR injury alone. Administration of HO inhibitor abolished the efficacy of hemolysate pretreatment. Our findings indicated that the prior induction of HO-1 by treatment of littermate hemolysate ameliorated the subsequent renal IR injury. Prior injection of self-hemolysate would be clinically useful for the protection against the renal IR injury induced by kidney transplantation and kidney surgery without immunological and infectious problems.

Porous/dense Composite Hydroxyapatite for Anterior Cervical Discectomy and Fusion

Study Design. A prospective analysis Objective. Our aim was to investigate the efficacy of new synthetic porous/dense composite hydroxyapatite (HA) for use in anterior cervical discectomy and fusion (ACDF). Summary of Background Data. Iliac crest bone graft (ICBG) has been traditionally used as the “gold standard” for ACDF. The significant complication rate associated with harvesting tricortical ICBG, however, has encouraged development of alternative graft substitutes. Methods. The morphology of the porous/dense HA was observed by scanning electron microscopy (SEM), and the in vitro compressive strength of the composite HA was measured. From April 2005, 51 consecutive patients underwent 81 levels of ACDF using the composite HA with percutaneously harvested trephine bone chips. Clinical and radiological evaluation was performed during the postoperative hospital stay and at follow-up. Furthermore, the outcomes in ACDF using the composite HA were compared with those using tricortical ICBG. Results. The SEM images demonstrated 100- to 300-&mgr;m pores (approximately 40% of porosity) in the porous layers of the HA. The compressive strength of the composite HA was 203.1 ± 4.1 MPa. In the clinical study, the demographic data of the patients were similar in HA and ICBG groups. The fusion rates in HA group were comparable with those in ICBG group. The cervical lordosis was enhanced postoperatively in both groups and well preserved at 2-year follow-up without significant differences between the groups. The intraoperative blood loss in HA group was significantly lesser than that in ICBG group. Donor site complications were found in 29.2% of the patients in ICBG group, whereas no donor site morbidity was found in HA group. No major collapse or fragmentation of the composite HA was found. Conclusion. The hybrid graft of composite HA and percutaneously harvested trephine chips seemed promising as a graft substitute for ACDF. Level of Evidence: 4

Adhesive arachnoiditis with extensive syringomyelia and giant arachnoid cyst after spinal and epidural anesthesia: a case report.

Study Design. A case report of a patient with adhesive arachnoiditis after combined spinal and epidural anesthesia. Objective. To report an extremely rare case of paraplegia due to adhesive arachnoiditis with extensive syringomyelia (ES) and a giant anterior arachnoid spinal cyst (AASC) after spinal and epidural anesthesia for obstetric surgery. Summary of Background Data. Progressive inflammation of the arachnoid mater due to trauma, infection, or hydrocortisone was reported as early as the 1970s. However, coexistence of ES and a giant AASC after spinal and epidural anesthesia is extremely rare. Methods. A 29-year-old woman suffered from sudden anuresis 5 months after spinal and epidural anesthesia for a cesarean section and subsequently experienced paraplegia and numbness below the chest. Magnetic resonance imaging showed an AASC compressing the spinal cord at T1–T6 and an adhesive lesion at T7. Posterior laminectomy at T6–T7 and adhesiolysis for arachnoid adhesion at T7 were performed. Although there was slight recovery of locomotive function postoperatively, it gradually worsened until 3 years after surgery. Magnetic resonance imaging at that time demonstrated a giant AASC and ES at the lower-thoracic cord. The cord compressed by the AASC became thinner sagittally. Secondary surgery involving posterior laminectomy at T5–T6 and insertion of a cyst-peritoneal shunt into the AASC was performed. Results. The patient could walk without a cane 3 years after the shunt operation, although numbness and motor weakness of the lower extremities remained. Magnetic resonance imaging 3 years after the shunt operation showed a reduction of the AASC and decompression of the cord despite no improvement in ES. Conclusion. This is the first report of a patient with a giant AASC and ES caused by spinal and epidural anesthesia. Although the optimal surgical treatment for these conditions remains unclear, shunting of the cyst effectively prevented the progression of symptoms.

Efficacy of biphasic transcranial electric stimulation in intraoperative motor evoked potential monitoring for cervical compression myelopathy.

Study Design. Retrospective analysis of prospectively collected data from consecutive patients undergoing 2 methods of transcranial electrical motor evoked potential (TCE-MEP) monitoring during cervical spine surgery. Objective. To investigate the efficacy of biphasic transcranial electric stimulation, the deviation rate, amplitude of TCE-MEPs, complications, and sensitivity and specificity of TCE-MEP monitoring were compared between the biphasic and conventional monophasic stimulation methods. Summary of Background Data. With biphasic stimulation, unlike monophasic stimulation, measurement time can be reduced considerably because a single stimulation elicits bilateral responses almost simultaneously. However, no study has yet reported a detailed comparison of the 2 methods. Methods. Examination 1: Amplitude and derivation rate of TCE-MEPs was compared for monophasic and biphasic stimulation in the same 31 patients with cervical compression myelopathy. Examination 2: Sensitivity, specificity, and complications of TCE-MEP monitoring were compared in 200 patients with cervical compression myelopathy who received monophasic or biphasic stimulation (100 patients each) during intraoperative monitoring. Results. Examination 1: Derivation rates of biphasic stimulation in the deltoid, biceps brachii, abductor digiti minimi, and flexor hallucis brevis muscles were the same or higher than for monophasic stimulation. TCE-MEP amplitudes elicited by biphasic stimulation compared with monophasic stimulation were significantly larger in the biceps (paired t, P < 0.0001), but similar in the other 3 muscles. Examination 2: In the biphasic and monophasic stimulation groups, warnings were issued to surgeons in 10 and 11 cases, for a sensitivity of 100% for both groups and specificity of 97.8% and 96.7%, respectively. No complications related to stimulation were observed in any of the 200 patients. Conclusion. Biphasic stimulation had similar or higher derivation rates and equivalent sensitivity and specificity than monophasic stimulation. No complications were observed for either stimulation method. Biphasic stimulation is an effective TCE-MEP monitoring method for cervical spine surgery that may also reduce measurement time. Level of Evidence: 4