Symptom-based characteristics and treatment efficacy of neuropathic pain related to spinal disorders.

BACKGROUND: Symptom-based therapeutic management is required for neuropathic pain (NeP) to achieve higher treatment efficacy. In spinal disorders, which have a high prevalence of NeP, neurological symptoms are classified into myelopathy, radiculopathy, and cauda equina syndrome. The characteristics of pain and the treatment efficacy for each of these symptoms require clarification. METHODS: A retrospective patient-based outcome study was conducted in 265 outpatients with chronic NeP (≥3 months) related to spinal disorders. The patients were classified into three groups according to their neurological symptoms: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using the Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP), and from clinical information. RESULTS: Most of the patients with NeP had a NPSI score >10 (moderate to severe pain) and 40% had psychiatric problems. The common subtype of NeP was spontaneous pain and paresthesia/dysesthesia in patients with radicular pain and cauda equina syndrome, whereas more severe paresthesia/dysesthesia was particularly prominent in patients with spinal cord-related pain. The pain reduction rate was significantly lower in these latter patients, especially in association with residual paresthesia/dysesthesia. CONCLUSIONS: The characteristics and treatment efficacy of NeP in patients with spinal disorders varied according to neurological symptoms. Effective treatment was difficult, especially for paresthesia/dysesthesia in patients with spinal cord-related pain. These findings enhance the understanding of the underlying mechanisms of pain and could help in design of symptom-based therapeutic management.

Differences in clinical and radiological features of thoracic disc herniation presenting with acute progressive myelopathy.

PURPOSE: Symptomatic thoracic disc herniation (TDH) is relatively rare, but patients with progressive myelopathy require surgical treatment without delay in diagnosis. The aim of this study was to review clinical and radiological features in patients with TDH presenting with myelopathy. METHODS: A total of 28 consecutive patients with thoracic myelopathy (Frankel grade C or worse) due to TDH who underwent surgery were divided into 3 groups based on the time for development of myelopathy (acute (< 72 h), subacute (within a few weeks), and chronic [gradually over > 1 month)] and their data were analyzed. RESULTS: The patients in the acute group were significantly younger and had a higher body mass index (BMI) compared to those in the subacute and chronic groups. Most cases of acute myelopathy were affected in the upper thoracic level, whereas all patients with subacute and chronic myelopathy had lesions in the lower thoracic level below T8-9. Interestingly, the affected thoracic level in patients with acute myelopathy matched the upper line of the sternum. The rate of acquired walking ability without assistance was only 50.0% in the acute group. CONCLUSIONS: This study suggests that TDH presenting with acute myelopathy may have different clinical and radiological features compared to those of TDH with subacute and chronic myelopathy. Upper TDH should be suspected in cases of acute myelopathy that develops with sudden-onset back pain after certain triggers in younger and higher BMI people. These affected thoracic level matched with the upper line of the sternum in each case.

The diagnostic utility of retroperitoneoscopic tissue biopsy for unresectable retroperitoneal lesions excluding urogenital cancers.

BACKGROUND: Retroperitoneal tumors are an uncommon disease known to consist of a diverse group of benign and malignant neoplasms. Treatment of unresectable retroperitoneal lesions requires pathological diagnosis. Here, we report the utility and safety of retroperitoneoscopic biopsy for unresectable retroperitoneal lesions excluding urogenital cancers. METHODS: We analyzed 47 patients consisting of 23 (49%) and 24 (51%) cases that underwent retroperitoneoscopic tissue biopsy and open biopsy, respectively. The clinicopathological features, including postoperative complications, were compared between the two groups. RESULTS: Tumor pathology was diagnosed successfully with a single operation in all patients. Malignant pathology (68%) was more common than benign pathology (32%). The most common pathology was malignant lymphoma, which accounted for about 50% of all cases. There was no significant difference with respect to the age, sex, tumor size, presence of tumor-related symptom, histopathology, operative time, and complications. Three (13%) of 23 patients in the retroperitoneoscopic biopsy group received percutaneous needle biopsy before laparoscopic excisional biopsy because the evaluation of needle cores failed to confirm subclasses of diagnosed pathologies. One patient was converted to open surgery just after the initiation of operation due to severe adhesion of adjacent structures. We had two cases with iatrogenic urinoma due to ureteral injury after retroperitoneoscopic biopsy. CONCLUSIONS: We conclude that retroperitoneoscopic biopsy is a safe and useful tool for benign and malignant retroperitoneal lesions, in comparison to open biopsy. It is critical to carefully examine the preoperative imaging for the location of tumors, especially those close to the renal pelvis and ureter.

Intraarticular injection of processed lipoaspirate cells has anti-inflammatory and analgesic effects but does not improve degenerative changes in murine monoiodoacetate-induced osteoarthritis.

BACKGROUND: Previous basic research and clinical studies examined the effects of mesenchymal stem cells (MSCs) on regeneration and maintenance of articular cartilage. However, our pilot study suggested that MSCs are more effective at suppressing inflammation and pain rather than promoting cartilage regeneration in osteoarthritis. Adipose tissue is considered a useful source of MSCs; it can be harvested easily in larger quantities compared with the bone marrow. The present study was designed to evaluate the anti-inflammatory, analgesic, and regenerative effects of intra-articularly injected processed lipoaspirate (PLA) cells (containing adipose-derived MSCs) on degenerative cartilage in a rat osteoarthritis model. METHODS: PLA cells were isolated from subcutaneous adipose tissue of 12-week-old female Sprague-Dawley rats. Osteoarthritis was induced by injection of monoiodoacetate (MIA). Each rat received 1 × 106 MSCs into the joint at day 7 (early injection group) and day 14 (late injection group) post-MIA injection. At 7, 14, 21 days after MIA administration, pain was assessed by immunostaining and western blotting of dorsal root ganglion (DRG). Cartilage quality was assessed macroscopically and by safranin-O and H&E staining, and joint inflammation was assessed by western blotting of the synovium. RESULTS: The early injection group showed less cartilage degradation, whereas the late injection group showed cartilage damage similar to untreated OA group. The relative expression level of CGRP protein in DRG neurons was significantly lower in the two treatment groups, compared with the untreated group. CONCLUSIONS: Intra-articular injection of PLA cells prevented degenerative changes in the early injection group, but had little effect in promoting cartilage repair in the late injection group. Interestingly, intra-articular injection of PLA cells resulted in suppression of inflammation and pain in both OA groups. Further studies are needed to determine the long-term effects of intra-articular injection of PLA cells in osteoarthritis.

Prognostic factors and optimal management for patients with cervical spinal cord injury without major bone injury.

BACKGROUND: Even though the number of patients with cervical spinal cord injury (CSCI) without major bone injury is increased, the treatment with either surgery or conservative measures remains controversial. The aim of this study was to assess its prognostic value in the prediction of useful motor recovery and to clarify whether the patients should be treated surgically are present. METHODS: We reviewed 63 patients (conservative, n = 36; surgery, n = 27) with CSCI without major bone injury (Frankel A-C). Neurological examination using modified Frankel grade at admission and 6 months after injury and International Stoke Mandeville Games (ISMG) classification at subacute phase after injury, MRI findings including rate of spinal cord compression, extent of cord damage and type of signal intensity change were assessed. RESULTS: Thirty-five of 63 patients were improved to walk at 6 months after injury. In multivariate analysis, rate of spinal cord compression, extent of cord damage and improvement of ISMG grade were associated with useful motor recovery. There was no difference in the neurological improvement between conservative and surgical groups. However, patients with spinal cord compression of ≥33.2% showed better motor recovery at 6 months post-injury after surgery than those treated conservatively. There was a positive correlation between the improvement of ISMG grade at subacute phase and Frankel grade at 6 months post-injury. It is difficult to obtain satisfactory surgical outcome for patients with Frankel A or B1 on admission and/or extensive spinal cord damage on T2-weighted image. CONCLUSIONS: Conservative treatment is recommended for patients with CSCI without major bone injury. However, we also recommend surgical treatment to acquire walking ability for patients with spinal cord compression of ≥33.2% and low ISMG grade at subacute phase. Among such patients, careful consideration should be given to patients with Frankel A or B1 and/or extensive spinal cord damage on MRI.

Early transplantation of mesenchymal stem cells after spinal cord injury relieves pain hypersensitivity through suppression of pain-related signaling cascades and reduced inflammatory cell recruitment.

Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C-γ and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double-positive hematogenous macrophages without decreasing the CD11b-positive and GFP-negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-α, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages.

Risk factors for early-onset adjacent segment degeneration after one-segment posterior lumbar interbody fusion.

Adjacent segment degeneration (ASD) is a major postoperative complication associated with posterior lumbar interbody fusion (PLIF). Early-onset ASD may differ pathologically from late-onset ASD. The aim of this study was to identify risk factors for early-onset ASD at the cranial segment occurring within 2 years after surgery. A retrospective study was performed for 170 patients with L4 degenerative spondylolisthesis who underwent one-segment PLIF. Of these patients, 20.6% had early-onset ASD at L3-4. In multivariate logistic regression analysis, preoperative larger % slip, vertebral bone marrow edema at the cranial segment on preoperative MRI (odds ratio 16.8), and surgical disc space distraction (cut-off 4.0 mm) were significant independent risk factors for early-onset ASD. Patients with preoperative imaging findings of bone marrow edema at the cranial segment had a 57.1% rate of early-onset ASD. A vacuum phenomenon and/or concomitant decompression at the cranial segment, the degree of surgical reduction of slippage, and lumbosacral spinal alignment were not risk factors for early-onset ASD. The need for fusion surgery requires careful consideration if vertebral bone marrow edema at the cranial segment adjacent to the fusion segment is detected on preoperative MRI, due to the negative impact of this edema on the incidence of early-onset ASD.

Prospective Registration Study for Establishing Minimal Clinically Important Differences in Patients Undergoing Surgery for Spinal Metastases.

STUDY DESIGN: Multicenter, prospective registry study. OBJECTIVE: To clarify minimal clinically important differences (MCIDs) for surgical interventions for spinal metastases, thereby enhancing patient care by integrating quality of life (QoL) assessments with clinical outcomes. SUMMARY OF BACKGROUND DATA: Despite its proven usefulness in degenerative spinal diseases and deformities, the MCID remains unexplored regarding surgery for spinal metastases. METHODS: This study included 171 (out of 413) patients from the multicenter "Prospective Registration Study on Surgery for Metastatic Spinal Tumors" by the Japan Association of Spine Surgeons. These were evaluated preoperatively and at 6 months postoperatively using the Face scale, EuroQol-5 Dimensions-5 Levels (EQ-5D-5L), including the visual analog scale (VAS), and performance status. The MCIDs were calculated using an anchor-based method, classifying participants into the improved, unchanged, and deteriorated groups based on the Face scale scores. Focusing on the improved and unchanged groups, the change in the EQ-5D-5L values from before to after treatment was analyzed, and the cutoff value with the highest sensitivity and specificity was determined as the MCID through receiver operating characteristic curve analysis. The validity of the MCIDs was evaluated using a distribution-based calculation method for patient-reported outcomes. RESULTS: The improved, unchanged, and deteriorated groups comprised 121, 28, and 22 participants, respectively. The anchor-based MCIDs for the EQ-5D-5L index, EQ-VAS, and domains of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were 0.21, 15.50, 1.50, 0.50, 0.50, 0.50, and 0.50, respectively; the corresponding distribution-based MCIDs were 0.17, 15,99, 0.77, 0.80, 0.78, 0.60, and 0.70, respectively. CONCLUSION: We identified MCIDs for surgical treatment of spinal metastases, providing benchmarks for future clinical research. By retrospectively examining whether the MCIDs are achieved, factors favoring their achievement and risks affecting them can be explored. This could aid in decisions on surgical candidacy and patient counseling.

Knee laxity after staircase exercise predicts radiographic disease progression in medial compartment knee osteoarthritis.

OBJECTIVE: To evaluate whether increased laxity of the knee during daily physical activities such as stair climbing is associated with progression of knee joint osteoarthritis (OA). METHODS: During the years 2001-2003, 136 patients with bilateral primary medial compartment knee joint OA were enrolled in this prospective study. Baseline data collected were body mass index (BMI), muscle power, radiographic joint space width, mechanical axis on standing radiography, and anteroposterior (AP) knee laxity before and after physical exercise. After 8 years of followup, 84 patients were reexamined to assess radiographic changes. Radiographic disease progression was defined as progression of >1 grade on the Kellgren/Lawrence scale. RESULTS: AP knee laxity increased significantly after stair climbing. Patients with OA progression and those without progression did not differ significantly in age, sex, baseline quadriceps muscle strength, mechanical axis, joint space width, and AP knee laxity before exercise. The 2 groups of patients did, however, differ significantly in baseline BMI and change in AP knee laxity due to exercise. The risk of progression of knee OA increased 4.15-fold with each millimeter of increase in the change in AP knee laxity due to exercise and 1.24-fold with each point increase in the BMI. CONCLUSION: Our results indicate that patients with OA progression have significantly greater changes in knee joint laxity during physical activities and a higher BMI than patients without OA progression. These findings suggest that larger changes in knee laxity during repetitive physical activities and a higher BMI play significant roles in the progression of knee OA.

Fracture of the acetabulum: a retrospective review of ninety-one patients treated at a single institution.

Acetabular fracture result in fairly good outcome after the anatomic reduction in the displaced fracture fragments and damaged joint structure, but some patients will inevitably suffer from hip joint problems during their courses after the insult. We retrospectively reviewed 91 patients with acetabular fractures to investigate the causes of clinical failure and relationship among the fracture types, selected treatment options and their courses. Ninety-one patients (73 men and 18 women) with an average age of 49 years (range 18-80) at the time of injury were followed up for an average of 8.6 years (range 2-18). Judet-Letournel classification of fracture type and Matta's rating regimen of functional and radiographic patient' assessment were conducted. Conservative treatment was provided in 20 patients, in which 19 attained excellent/good, and one fair clinical results. All achieved excellent/good radiographic outcome. Surgically treated patients (n = 71) with critical dislodgement of the fracture fragment showed that 64 (90%) attained excellent/good and 7 (10%) fair/poor clinical outcomes. Sixty-three (89%) attained excellent/good and 8 (11%) fair/poor postoperative radiographic outcome. Five patients with poor radiographic outcome after surgery subsequently required total hip arthroplasty, due to the development of hip joint osteoarthritis in 3 and femoral head avascular necrosis in 2. We conclude that displacement of the joint surface should be reduced to less than 3 mm in accordance with the selection of the most appropriate surgical approach for open reduction/fixation in each fracture type; however, comminuted fracture and avascular necrosis of the femoral head may be the cause of poor clinical results.

Adipose-Derived Mesenchymal Stromal Cell Transplantation for Severe Spinal Cord Injury: Functional Improvement Supported by Angiogenesis and Neuroprotection.

Mesenchymal stromal cell transplantation alone is insufficient when motor dysfunction is severe; combination therapy with rehabilitation could improve motor function. Here, we aimed to analyze the characteristics of adipose-derived MSCs (AD-MSCs) and determine their effectiveness in severe spinal cord injury (SCI) treatment. A severe SCI model was created and motor function were compared. The rats were divided into AD-MSC-transplanted treadmill exercise-combined (AD-Ex), AD-MSC-transplanted non-exercise (AD-noEx), PBS-injected exercise (PBS-Ex), and no PBS-injected exercise (PBS-noEx) groups. In cultured cell experiments, AD-MSCs were subjected to oxidative stress, and the effects on the extracellular secretion of AD-MSCs were investigated using multiplex flow cytometry. We assessed angiogenesis and macrophage accumulation in the acute phase. Spinal cavity or scar size and axonal preservation were assessed histologically in the subacute phase. Significant motor function improvement was observed in the AD-Ex group. Vascular endothelial growth factor and C-C motif chemokine 2 expression in AD-MSC culture supernatants increased under oxidative stress. Enhanced angiogenesis and decreased macrophage accumulation were observed at 2 weeks post-transplantation, whereas spinal cord cavity or scar size and axonal preservation were observed at 4 weeks. Overall, AD-MSC transplantation combined with treadmill exercise training improved motor function in severe SCI. AD-MSC transplantation promoted angiogenesis and neuroprotection.

Management of Cervical Spinal Cord Injury without Major Bone Injury in Adults.

The incidence of cervical spinal cord injury (CSCI) without major bone injury is increasing, possibly because older people typically have pre-existing cervical spinal canal stenosis. The demographics, neurological injury, treatment, and prognosis of this type of CSCI differ from those of CSCI with bone or central cord injury. Spine surgeons worldwide are debating on the optimal management of CSCI without major bone injury. Therefore, this narrative review aimed to address unresolved clinical questions related to CSCI without major bone injury and discuss treatment strategies based on current findings. The greatest divide among spine surgeons worldwide hinges on whether surgery is necessary for patients with CSCI without major bone injury. Certain studies have recommended early surgery within 24 h after injury; however, evidence regarding its superiority over conservative treatment remains limited. Delayed MRI may be beneficial; nevertheless, reliable factors and imaging findings that predict functional prognosis during the acute phase and ascertain the necessity of surgery should be identified to determine whether surgery/early surgery is better than conservative therapy/delayed surgery. Quality-of-life assessments, including neuropathic pain, spasticity, manual dexterity, and motor function, should be performed to examine the superiority of surgery/early surgery to conservative therapy/delayed surgery.

No-wash protein labeling with designed fluorogenic probes and application to real-time pulse-chase analysis.

Small molecule labeling techniques for cellular proteins under physiological conditions are very promising for revealing new biological functions. We developed a no-wash fluorogenic labeling system by exploiting fluorescence resonance energy transfer (FRET)-based fluorescein-cephalosporin-azopyridinium probes and a mutant ß-lactamase tag. Fast quencher elimination, hydrophilicity, and high resistance against autodegradation were achieved by rational refinement of the structure. By applying the probe to real-time pulse-chase analysis, the trafficking of epidermal growth factor receptors between cell surface and intracellular region was imaged. In addition, membrane-permeable derivatization of the probe enabled no-wash fluorogenic labeling of intracellular proteins.

Blockade of interleukin-6 signaling inhibits the classic pathway and promotes an alternative pathway of macrophage activation after spinal cord injury in mice.

BACKGROUND: Recent in vivo and in vitro studies in non-neuronal and neuronal tissues have shown that different pathways of macrophage activation result in cells with different properties. Interleukin (IL)-6 triggers the classically activated inflammatory macrophages (M1 phenotype), whereas the alternatively activated macrophages (M2 phenotype) are anti-inflammatory. 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. METHODS: MR16-1 antibodies versus isotype control antibodies or saline alone were administered immediately after thoracic SCI in mice. SC tissue repair was compared between the two groups by Luxol fast blue (LFB) staining for myelination and immunoreactivity for the neuronal markers growth-associated protein (GAP)-43 and neurofilament heavy 200 kDa (NF-H) and for locomotor function. The expression of T helper (Th)1 cytokines (interferon (IFN)-γ and tumor necrosis factor-α) and Th2 cytokines (IL-4, IL-13) was determined by immunoblot analysis. The presence of M1 (inducible nitric oxide synthase (iNOS)-positive, CD16/32-positive) and M2 (arginase 1-positive, CD206-positive) macrophages was determined by immunohistology. Using flow cytometry, we also quantified IFN-γ and IL-4 levels in neutrophils, microglia, and macrophages, and Mac-2 (macrophage antigen-2) and Mac-3 in M2 macrophages and microglia. RESULTS: LFB-positive spared myelin was increased in the MR16-1-treated group compared with the controls, and this increase correlated with enhanced positivity for GAP-43 or NF-H, and improved locomotor Basso Mouse Scale scores. Immunoblot analysis of the MR16-1-treated samples identified downregulation of Th1 and upregulation of Th2 cytokines. Whereas iNOS-positive, CD16/32-positive M1 macrophages were the predominant phenotype in the injured SC of non-treated control mice, MR16-1 treatment promoted arginase 1-positive, CD206-positive M2 macrophages, with preferential localization of these cells at the injury site. MR16-1 treatment suppressed the number of IFN-γ-positive neutrophils, and increased the number of microglia present and their positivity for IL-4. Among the arginase 1-positive M2 macrophages, MR16-1 treatment increased positivity for Mac-2 and Mac-3, suggestive of increased phagocytic behavior. CONCLUSION: 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.

Clinical significance of MRI/(18)F-FDG PET fusion imaging of the spinal cord in patients with cervical compressive myelopathy.

PURPOSE: (18)F-FDG PET is used to investigate the metabolic activity of neural tissue. MRI is used to visualize morphological changes, but the relationship between intramedullary signal changes and clinical outcome remains controversial. The present study was designed to evaluate the use of 3-D MRI/(18)F-FDG PET fusion imaging for defining intramedullary signal changes on MRI scans and local glucose metabolic rate measured on (18)F-FDG PET scans in relation to clinical outcome and prognosis. METHODS: We studied 24 patients undergoing decompressive surgery for cervical compressive myelopathy. All patients underwent 3-D MRI and (18)F-FDG PET before surgery. Quantitative analysis of intramedullary signal changes on MRI scans included calculation of the signal intensity ratio (SIR) as the ratio between the increased lesional signal intensity and the signal intensity at the level of the C7/T1 disc. Using an Advantage workstation, the same slices of cervical 3-D MRI and (18)F-FDG PET images were fused. On the fused images, the maximal count of the lesion was adopted as the standardized uptake value (SUV(max)). In a similar manner to SIR, the SUV ratio (SUVR) was also calculated. Neurological assessment was conducted using the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy. RESULTS: The SIR on T1-weighted (T1-W) images, but not SIR on T2-W images, was significantly correlated with preoperative JOA score and postoperative neurological improvement. Lesion SUV(max) was significantly correlated with SIR on T1-W images, but not with SIR on T2-W images, and also with postoperative neurological outcome. The SUVR correlated better than SIR on T1-W images and lesion SUV(max) with neurological improvement. Longer symptom duration was correlated negatively with SIR on T1-W images, positively with SIR on T2-W images, and negatively with SUV(max). CONCLUSION: Our results suggest that low-intensity signal on T1-W images, but not on T2-W images, is correlated with a poor postoperative neurological outcome. SUV(max) of lesions showing increased signal intensity and SUVR measured on fusion MRI/PET scans are more sensitive parameters for predicting clinical outcome than signal intensity on the MRI scan.

Apoptosis of neurons and oligodendrocytes in the spinal cord of spinal hyperostotic mouse (twy/twy): possible pathomechanism of human cervical compressive myelopathy.

INTRODUCTION: Cervical compressive myelopathy is the most serious complication of cervical spondylosis or ossification of the posterior longitudinal ligament (OPLL) and the most frequent cause of spinal cord dysfunction. There is little information on the exact pathophysiological mechanism responsible for the progressive loss of neural tissue in the spinal cord of such patients. In this study, we used the spinal hyperostotic mouse (twy/twy) as a suitable model of human spondylosis, and OPLL to investigate the cellular and molecular changes in the spinal cord. Mutant twy/twy mouse developed ossification of the ligamentum flavum at C2-C3 and exhibited progressive paralysis. MATERIALS AND METHODS: The mutant twy/twy mice, aged 16 and 24 weeks, were used in the present study. The cervical spinal cord was analyzed histologically and immunohistochemically. RESULTS: We observed that a significant correlation between the proportion of apoptotic oligodendrocytes in the compressed area of the spinal cord and the magnitude of cord compression. Immunohistochemical analysis indicated overexpression of TNFR1, CD95, and p75NTR in the twy/twy mice, which was localized by the immunofluorescence in the neurons and oligodendrocytes. CONCLUSION: The expression of such factors seems to play at least some role in the apoptotic process, which probably contributes to axonal degeneration and demyelination in the twy/twy mice spinal cords with severe compression.

Initiation and progression of ossification of the posterior longitudinal ligament of the cervical spine in the hereditary spinal hyperostotic mouse (twy/twy).

INTRODUCTION: Ossification of the posterior longitudinal ligament (OPLL) is a significantly critical pathology that can eventually cause serious myelopathy. Ossification commences in the vertebral posterior longitudinal ligaments, and intensifies and spreads with the progression of the disease, resulting in osseous projections and compression of the spinal cord. However, the paucity of histological studies the underlying mechanisms of calcification and ossification processes remain obscure. The pathological process could be simulated in the ossifying process of the ligament in mutant spinal hyperostotic mouse (twy/twy). The aim of this study is to observe that enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of the posterior longitudinal ligament of twy/twy mice. MATERIALS AND METHODS: The mutant twy/twy mice (6 to 22-week-old) were used in the present study. The vertebral column was analyzed histologically and immunohistochemically. RESULTS: We observed that the enlargement of the nucleus pulposus followed by herniation, disruption and regenerative proliferation of annulus fibrosus cartilaginous tissues participated in the initiation of ossification of posterior longitudinal ligament of twy/twy mice. In this regards, the cells of the protruded hyperplastic annulus fibrosus invaded the longitudinal ligaments and induced neovascularization and metaplasia of primitive mesenchymal cells to osteoblasts in the spinal ligaments of twy/twy mice. CONCLUSION: Since genetic mechanisms could play a role in human OPLL, the age-related enlargement of the nucleus pulposus in the twy/twy mouse may primarily occur as a result of overproduction of mucopolysaccharide matrix material induced by certain genetic abnormalities.

Another operator-theoretical proof for the second-order phase transition in the BCS-Bogoliubov model of superconductivity.

In the preceding papers, imposing certain complicated and strong conditions, the present author showed that the solution to the BCS-Bogoliubov gap equation in superconductivity is twice differentiable only on the neighborhoods of absolute zero temperature and the transition temperature so as to show that the phase transition is of the second order from the viewpoint of operator theory. Instead, we impose a certain simple and weak condition in this paper, and show that there is a unique nonnegative solution and that the solution is indeed twice differentiable on a closed interval from a certain positive temperature to the transition temperature as well as pointing out several properties of the solution. We then give another operator-theoretical proof for the second-order phase transition in the BCS-Bogoliubov model. Since the thermodynamic potential has the squared solution in its form, we deal with the squared BCS-Bogoliubov gap equation. Here, the potential in the BCS-Bogoliubov gap equation is a function and need not be a constant.

Prognostic Factors and Optimal Surgical Management for Lumbar Spinal Canal Stenosis in Patients with Diffuse Idiopathic Skeletal Hyperostosis.

Lumbar spinal canal stenosis (LSS) and diffuse idiopathic skeletal hyperostosis (DISH) tend to develop in the elderly, resulting in an increased need for lumbar surgery. However, DISH may be a risk factor for poor clinical outcomes following lumbar decompression surgery, especially in patients with DISH extending to the lumbar segment (L-DISH). This study aimed to identify the prognostic factors of LSS with L-DISH and propose an optimal surgical management approach to improve clinical outcomes. Of 934 patients who underwent lumbar decompression surgery, 145 patients (15.5%) had L-DISH. In multivariate linear regression analysis of the JOA score improvement rate, the presence of vacuum phenomenon at affected segments (estimate: −15.14) and distance between the caudal end of L-DISH and decompressed/fused segments (estimate: 7.05) were independent prognostic factors. In logistic regression analysis of the surgical procedure with JOA improvement rate > 25% in L-DISH patients with both negative prognostic factors, the odds ratios of split laminotomy and short-segment fusion were 0.64 and 0.21, respectively, with conventional laminotomy as the reference. Therefore, to achieve better clinical outcomes in cases with decompression at the caudal end of L-DISH, decompression surgery without fusion sparing the osteoligamentous structures at midline should be considered as the standard surgery.

Symptom-based pharmacotherapy for neuropathic pain related to spinal disorders: results from a patient-based assessment.

Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype (spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia) and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management.